ICOTINIB NEW PATENT WO-2013064128

ICOTINIB

4-((3-ethynylphenyl)amino)-6,7-benzo-12-crown-4-quinazoline

N-(3-Ethynylphenyl)-7,8,10,11,13,14-hexahydro[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine

[1,4,7,10]Tetraoxacyclododecino[2,3-g]quinazolin-4-amine, N-(3-ethynylphenyl)-7,8,10,11,13,14-hexahydro-

BPI 2009H, UNII-JTD32I0J83

610798-31-7  CAS BASE

Icotinib Hydrochloride, 1204313-51-8, CS-0918, HY-15164, Conmana Zhejiang Beta Pharma Ltd.

CLINICALS………http://clinicaltrials.gov/search/intervention=Icotinib

 READ AThttp://newdrugapprovals.org/2014/12/09/icotinib/

NEW PATENT

WO-2013064128

Zhejiang Beta Pharma Incorporation, 浙江贝达药业有限公司

http://www.google.co.in/patents/WO2013064128A1?cl=en

General synthetic route

Compound A, the present invention is provided for availability, but are not limited to, the following synthetic route to achieve:

The present invention is to provide beta available but are not limited to, the following synthetic route is now:

A BETA

The present invention is to provide a compound C, can be used, but are not limited to, the following synthetic route to achieve:

Wherein

And are independently selected from the group consisting of methyl, ethyl, propyl or isopropyl, or

, And they are connected in common to the N atom form a 3-7 membered ring.R ₃ and R4 are independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, iso-butyl or benzyl group, or,

R ₃ and R4 to form a 3-7 membered ring.

The present C can be used for the direct preparation of Icotinib:

Wherein

And are independently selected from the group consisting of methyl, ethyl, propyl or isopropyl, or

, And they are connected in common to the N atom form a 3-7 membered ring.

Icotinib

Icotinib Hydrochloride

Example Synthesis of compound 1 A

1 Synthesis of Compound 2

2

79.5g 3,4 – dihydroxybenzene nitrile, 272g of potassium carbonate, acetonitrile (6L) was added to a 10L three-necked reaction flask, and dissolved with stirring, heated to reflux and reflux was added dropwise an acetonitrile solution of the compound 1 (compound 1, 200 g; acetonitrile , 2L), and completion of the dropping, the HPLC monitoring of the completion of the reaction, the mixture was cooled to room temperature, filtered, and the solvent was removed, and the resulting solid was washed with ethyl acetate was dissolved, filtered, and the filtrate was concentrated, the resulting residue was dissolved in petroleum ether by rotary evaporation, the resulting solid was purified to give 18.9g of the compound 2.

¹ LAI MR (CDC1 _3-Sppm): 7.30 ~ 7.33 (m, 1H); 7.25 (s, 1H); 6.97-6.99 (d, 1H); 4.19 – 4.23 (m, 4H); 3.83 ~ 3.91 (m, 4H); 3.77 (s, 4H). MS: (M + H) +250 2 Synthesis of compound A

2 A

41.6g of compound 2 was dissolved in 580ml of acetic acid, dropwise addition of 83ml of fuming nitric acid at 30 ° C under completion of the dropping, the dropwise addition of 42ml of concentrated sulfuric acid at 30 ° C under the reaction at room temperature overnight, TLC monitoring completion of the reaction, the reaction solution was poured into ice water 4L , the precipitated solid was filtered, washed with cold water (500 mL X 2), vacuum 35 ° C and dried crude A compound 46g, isopropanol recrystallization was purified to give 33g of compound A.

¹ LAI MR (CDC1 _3-Sppm): 7.90 (s, 1H); 7.36 (s, 1H); 4.33 ~ 4.36 (m, 4H); 3.87 ~ 3.89 (m, 4H); 3.737 (s, 4H). Embodiment of Example 2 Synthesis of Compound B

AB

32g of compound A, 30.5g of iron powder, 5% acetic acid solution in methanol 1070ml 2L reaction flask was heated to reflux

TLC monitoring of the end of the reaction cooled and concentrated, dissolved in ethyl acetate, filtered, dried over anhydrous NaS0 ₄ 23g of compound B. The solvent was removed.

1HNMR (d _{6-DMSO-Sppm):} 7.07 (s, 1H); 6.36 (s, 1H); 5.73 (s, 2H); 3.95 ~ 4.22 (m, 4H); 3.77-3.78 (m, 2H); 3.34 3.62 (m, 6H). Embodiment of Example 3 Synthesis of Compound CI

B CI

500mL three-necked flask, the Add 5g compound B, 5g v, v-dimethyl formamide dimethyl acetal and 160ml of dioxane was heated to reflux the TLC monitoring progress of the reaction, the reaction time is about 12 hours, after the end of the reaction The reaction solution was cooled to room temperature, spin-dry to give 5.8g of compound Cl.

¹ LAI MR (CDCl _3-Sppm): 7.56 (s, 1H); 7.15 (s, 1H); 6.51 (s, 1H); 4.12-4.18 (m, 4H); 3.89-3.91 (m, 2H); 3.78 -3.80 (m, 6H); 3.07 (s, 6H); Example 4 Icotinib Synthesis

5 g of the compound Cl, 2.2 g inter-aminophenyl acetylene, 230ml of acetic acid was added to a 500 ml reaction flask was heated to 100 ° c,

TLC monitoring of the reaction. The end of the reaction, the reaction system spin dry methanol was added, and shock dispersion, filtration, wash with methanol, 5g Icotinib.

^ M (d _{6-DMSO-5ppm):} 11.98 (s, IH); 9.50 (s, IH); 8.53 (s 1H); 8.14 (s, IH); 8.04-8.05 (m, IH); 7.90-7.92 (m, IH); 7.38-7.42 (m, IH); 7.31 (s IH); 7.20-7.22 (m, IH); 4.29-4.30 (m, 4H); 4.21 (s, IH); 3.74-3.81 ( m, 4H); 3.64 (s, 4H); 1.91 (s, 3H);

Synthesis Example 5 Exe hydrochloride erlotinib

Exeter for Nick for; s

700mg Icotinib Add to a 100 ml reaction flask, add 40 ml of methanol, stirred pass into the hydrogen chloride gas or concentrated hydrochloric acid, and filtered to give crude hydrochloric acid Icotinib after, and purified by recrystallization from isopropanol to give 760mg hydrochloride Icotinib.

1HNMR (d _{6-DMSO-Sppm):} 11.37 (s, IH); 8.87 (s, IH); 8.63 (s, IH); 7.90 (s, IH); 7.78-7.80 (d, IH); 7.48-7.52 (m, IH); 7.40-7.41 (m, 2H); 4.36-4.38 (d, 4H); 4.30 (s, IH); 3.75-3.81 (d, 4H); 3.61 (s, 4H);

Example 18 Synthesis of Compound CI

3g compound B, 4.4g N, N-dimethyl formamide diisopropyl acetal was dissolved in 140ml dioxane was heated to reflux, tlc monitoring the progress of the reaction, the reaction time of approximately 11-12 hours after the completion of the reaction, was cooled to room temperature, the reaction solution was spin-dry to give 2.4g of the compound Cl.

The implementation of the synthesis of Example 19 Icotinib

3g compound Cl, 1.3 g inter-aminophenyl acetylene, 130 ml of acetic acid was added 250 ml reaction flask and heated to 70-80

V, TLC monitoring of the reaction. Spin dry the reaction system, methanol was added, and shock dispersion, filtered, and the methanol wash was 2.8g Icotinib. Implementation of Example 20 Icotinib synthesis

C1 Icotinib

8g compound Cl, 3.5g inter-aminophenyl acetylene, dissolved in 380ml of acetic acid, heated to 100-120 ° C, TLC monitoring of the reaction. Spin dry the reaction system, by adding ethanol shock dispersion, filter, the ethanol wash 7.2g Icotinib. Implementation of Example 21 Icotinib Synthesis

The C1 Exeter erlotinib reaction temperature of 120-15CTC Example 4 was 2.2 g Icotinib.

Example 22 Icotinib Synthesis

3g compound Cl, 1.8 g inter-aminophenyl acetylene and 130 ml of acetic acid was added 250 ml reaction flask and heated to 90-100C, TLC monitoring of the reaction. Spin dry the reaction system, isopropanol shock dispersion, filtration, isopropyl alcohol wash was 2.9g Icotinib.

The implementation of the synthesis of Example 23 Icotinib

3G compound CI and 1.3 g of m-aminophenyl acetylene dissolved in 130ml of formic acid was heated to 80-90 ° C, TLC monitoring of the reaction. Spin dry the reaction system, methanol was added, and shock dispersion, filtered, and the methanol wash was 2.7g Icotinib.

Example 24 Icotinib synthesis

3g of compound C1 and 1.3g aminophenyl acetylene dissolved in 130ml of trifluoroacetic acid was heated to 70-80 ° C, TLC monitoring of the reaction.Spin dry the reaction system, methanol was added, and shock dispersion, filtered, and the methanol wash was 2.7g Icotinib. Example 25 Icotinib Hydrochloride synthesis

Icotinib Hydrochloride

The 500mg Icotinib Add to a 100 ml reaction flask, add 30ml of ethanol was stirred under hydrogen chloride gas was passed into the after, filtered crude hydrochloride Icotinib recrystallized from isopropanol to give 515mg hydrochloride Icotinib. Example 26 Icotinib Hydrochloride Synthesis

500mg Icotinib Add 100 ml reaction flask, add 40 ml of tetrahydrofuran was stirred under hydrogen chloride gas was passed into the after, filtered crude hydrochloride Icotinib recrystallized from isopropanol to give 500mg hydrochloride Icotinib. EXAMPLE 27 Icotinib Hydrochloride Synthesis

Exeter erlotinib erlotinib hydrochloride Exeter

500mg Icotinib Add 100 ml reaction flask, add 50 ml of isopropanol and stirred under hydrogen chloride gas was passed into the after, filtered crude hydrochloride Icotinib recrystallized from isopropanol to give 500mg hydrochloride Icotinib. Example 28 Icotinib Hydrochloride synthesis

Icotinib

Icotinib Hydrochloride

  READ MORE AThttp://newdrugapprovals.org/2014/12/09/icotinib/

Which Popular Drugs Are Going Off-Patent in 2013-2016?

Good for consumers; bad for industry's bottom line.

By Kathlyn Stone

Pharma Expert 
read at 

http://pharma.about.com/od/BigPharma/a/Which-Popular-Drugs-Are-Going-Off-Patent-In-2013-2016.htm


 http://pharma.about.com/od/BigPharma/a/Which-Popular-Drugs-Are-Going-Off-Patent-In-2013-2016.htm


 http://pharma.about.com/od/BigPharma/a/Which-Popular-Drugs-Are-Going-Off-Patent-In-2013-2016.htm

 

Drug Patent Expirations for December 2 2014

http://www.biotechblog.com/2014/12/02/drug-patent-expirations-for-december-2-2014/

New patent on Avanafil WO-2014187273

AVANAFIL
(S)-4-((3-chloro-4-methoxybenzyl)amino)-2-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide

WO 2014187273

	Avanafil preparation method
	Suzhou Lixin Pharmaceutical Co Ltd; Suzhou Mingyue Medical Technology Co Ltd;
	Novel process for the synthesis of avanafil comprises reacting cytosine with 3-chlorine-4-Methoxybenzyl halogen, N-(2-methylpyrimidine) methanamide and S-hydroxymethyl pyrrolidine. Useful for treating erectile dysfunction.
	http://patent.ipexl.com/WO/woZZSLASHZZ2014ZZSLASHZZ187273.html
	AVANAFIL PREPARATION METHOD PCT Patent WO/2014/187273 [en] Disclosed is a method for preparing avanafil (I) by using cytosine as the starting material. The preparation steps comprise: using cytosine as the raw material, and enabling the cytosine to react with side chain 3-chlorine-4-Methoxybenzyl halogen, N-(2-methylpyrimidine) methanamide, and S-hydroxymethyl pyrrolidine, to prepare the target product avanafil (I). For the preparation method, the raw material is easily obtained, and the process is simple, economical, and environmentally friendly, so the method meets the requirement of industrial boost. [fr] Procédé de préparation d'avanafil (I) utilisant de la cytosine comme matière de départ. Les étapes de préparation de ce procédé consistent à utiliser de la cytosine en tant que matière de départ, et à laisser la cytosine réagir avec un halogène 3-chloro-4-méthoxybenzyle à chaîne latérale, du N-(2-méthylpyrimidine)méthanamide, et de la S-hydroxyméthyle pyrrolidine, pour préparer le produit cible : l'avanafil (I). Pour le procédé de préparation, la matière de départ est facilement obtenue, et le procédé est simple, économique et respectueux de l'environnement, de sorte que le procédé satisfait aux exigences de la croissance industrielle rapide. [zh] 本发明揭示了一种以胞嘧啶（Cytosine）为起始原料制备阿伐那非（Avanafil，I）的方法，其制备步骤包括以胞嘧啶为原料，经与侧链3-氯 -4-甲氧基苄卤素、N-(2-甲基嘧啶)甲酰胺和S-羟甲基吡咯烷反应，制得目标产物阿伐那非（I）。该制备方法原料易得、工艺简洁、经济环保，适合工 业化放大的要求。 Title [zh] 阿伐那非的制备方法 [fr] PROCÉDÉ DE PRÉPARATION DAVANAFIL [en] AVANAFIL PREPARATION METHOD Application Number PCT/CN2014/077632 Publication Number 2014/187273 Application Date May 16, 2014 Publication Date November 27, 2014 Inventor XU Xuenong Agent SUZHOU WISTONG INTELLECTUAL PROPERTY AGENCY Assignee XU Xuenong SUZHOU MIRACPHARMA TECHNOLOGY IPC C07D 403/14     SEE PATENT    http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014187273

Crash course on patents

Crash course on patents

see
https://sites.google.com/site/patentrelatedsite/crash-course-on-patents

What is Intellectual Property?

Intellectual property (IP) rights are legally recognized exclusive rights to creations of the mind.^[ Under intellectual property laws, owners are granted certain exclusive rights to a variety of intangible assets, such as musical, literary, and artistic works; discoveries and inventions; and words, phrases, symols, and designs. Common types of intellectual property rights include copyright,trademarks, patents, industrial design rights, trade dress, and in some jurisdictions trade secrets.

Although many of the legal principles governing intellectual property rights have evolved over centuries, it was not until the 19th century that the term intellectual property began to be used, and not until the late 20th century that it became commonplace in the majority of the world. The British Statute of Anne (1710) and the Statute of Monopolies (1624) are now seen as the origins ofcopyright and patent law respectively.

Generally speaking, “intellectual property” is probably best thought of (at least form a conceptual standpoint) as creations of the mind that are given the legal rights often associated with real or personal property. The rights that are obtained by the creator are a function of statutory law (i.e., law created by the legislature). These statutes may be federal or state laws, or in some instance both federal and state law govern various aspect of a single type of intellectual property.

The term intellectual property itself is now commonly used to refer to the bundle of rights conferred by each of the following fields of law: (1) patent law; (2) copyright law; (3) trade secret law; (4) the right of publicity; and (5) trademark and unfair competition law. Some people confuse these areas of intellectual property law, and although there may be some similarities among these kinds of intellectual property protection, they are different and serve different purposes.

 

What is a Patent?

Whenever you think patent you should think  invention. Thus, a patent is the grant of a property right to an inventor. Patents only exist once they have been granted, and in the United States patents are issued by the U.S. Patent and Trademark Office, which is a non-commercial federal entity and one of 14 bureaus in the Department of Commerce. Before going any further it is worth pointing out that ideas are not patentable, although every invention starts out with an idea. Still, in order to be in a position where you can obtain a patent your idea must have matured into an invention. 

There are three very different kinds of patent in the United States: (1) a utility patent, which covers the functional aspects of products and processes; (2) a design patent, which covers the ornamental design of useful objects; and (3) a plant patent, which covers a new variety of living plant.

Each type of patent confers “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States or “importing” the invention into the United States. It is important to note, however, that patents do not protect ideas, but rather protect only tangible or identifiable structures and methods.

Typically when someone refers generically to “a patent” they are talking about a utility patent. In order to obtain a utility patent it is necessary to file a non-provisional patent application and go through an examination process where a patent examiner will review the application to determine what, if any, claims can be allowed. Many are probably also familiar with aprovisional patent application, which can be used to establish priority and give the applicant “patent pending” status. A provisional patent application will never mature into a patent though. It is always necessary to file a non provisional patent application to obtain a patent.

Patent claims define the exclusive rights granted by the government. If it is not in a patent claim you do not have rights associated with it. If the claims are too detailed they can be easy to get around and not commercially useful. There is a lot that goes into any patent application, both from a technical and strategic standpoint.

Generally speaking the patent term for utility patents is now 20 years from the date on which the application for the patent was filed in the United States. Under some circumstances it is possible to obtain a 5 year extension to the patent grant, but this is rare, unless your invention relates to a pharmaceutical composition. It is also possible to obtain extension of patent term due to USPTO delay. Design patents, unlike utility patents, have a 14 year term from date of issuance.  Historically, design patents were quite weak, but as the result of an important decision from the United States Court of Appeals for the Federal Circuit in the Fall of 2008, design patents are now much stronger and should be considered an important part of a patent portfolio when your invention relates to a product.

What is a Copyright?

Copyright is a form of protection provided to the authors of “original works of authorship” including literary, dramatic, musical, artistic, and certain other intellectual works, both published and unpublished. Copyright law generally gives the owner of a copyright the exclusive right to reproduce the copyrighted work, to prepare derivative works, to distribute copies or phonorecords of the copyrighted work, to perform the copyrighted work publicly, or to display the copyrighted work publicly.

The copyright protects the form of expression rather than the subject matter of the writing. For example, a description of a machine could be copyrighted, but this would only prevent others from copying the description; it would not prevent others from writing a description of their own or from making and using the machine. In order to prevent the making and using of the machine one would have to seen patent protection. Copyrights are registered by the Copyright Office, which is a part of the Library of Congress.

Copyright protection does not and cannot exist for an idea, procedure, process, system, method of operation, concept, principle, or discovery, regardless of the form in which it is described or embodied. This is true because a copyright protects only the form of expression rather than the subject matter of the writing. It is simply not the function of the copyright laws to protect anything other than original expression. Ideas are not protected by copyright law because protecting an idea would take the idea out of the public domain and would prevent others from using the idea to create their own independent and original works of authorship.

 

What is a Trade Secret?

A trade secret is any valuable business information that is that is not generally known and is subject to reasonable efforts to preserve confidentiality. A trade secret will be protected from misappropriation from exploitation (through state law) by those who either obtain access through improper means or who breach a promise to keep the information confidential.

Trade secret misappropriation is really a type of unfair competition. Remedies for infringement of a trade secret include damages, profits, reasonable royalties, and an injunction. Some statutes also provide for enhanced damages and attorneys fees in certain circumstances.

Trade secrets are a very important part of any intellectual property portfolio. It is not at all an overstatement to say that virtually every business has trade secrets worth protection, regardless of whether the business is run as a sole proprietorship, a small business or Fortune 500 company. This is true because any business information that is valuable as a result of being kept secret qualifies for treatment as a trade secret.  Nevertheless, it may be better to say that every business has assets that could and should be protected as trade secrets, but the truth is that many companies, even large companies, fail to do so properly.  The failure to treat information as a trade secret means you have no asset at all, and no remedy if the information is taken or stolen by others.  Thus, appreciating what can be a trade secret and how to take steps to protect a trade secret are vital for inventors and businesses alike. 

 

What is a Trademark?

Generally speaking a trademark is a word, name, symbol or device which is used in trade with goods to indicate the source of the goods and to distinguish them from the goods of others. A service mark is the same as a trademark except that it identifies and distinguishes the source of a service rather than a product. The terms “trademark” and “mark” are commonly used to refer to both trademarks and service marks.

A trademark is a significant asset.  A trademark not only becomes your company seal, but it is how consumers will relate to your goods or services.  If you have high quality goods and services for a reasonable price then customers will associate your company with positive feelings and memories, so the next time they see your trademark they will conjure up in their minds a whole host of positives.  This conjuring up of positive feelings, emotions and memories of satisfaction can be powerful. 

Trademark rights may be used to prevent others from using a confusingly similar mark, but not to prevent others from making the same goods or from selling the same goods or services under a clearly different mark. Trademarks which are used in interstate or foreign commerce may be registered with the Patent and Trademark Office.

Filing a trademark application is an excellent step to take to protect your name, slogan or logo. It is, however, important to understand that not all trademarks are created equal. While every state allows you to obtain a trademark registration, federal trademark registration provides the greatest rights. This is because when you obtain a United States federal trademark your rights will exist throughout the country, and not in just one particular state or geographic locality.

The first step to acquiring federal trademark rights requires that you either (1) start using the slogan, name or logo in commerce (i.e., some kind of commercial use) and then subsequently file a trademark application; or (2) file an intent to use application which will lock in your filing date but which does not require immediate use. 

What is Trade Dress Protection?

Trade dress is the totality of elements in which a product or service is packaged or presented. These elements combine to create the whole visual image presented to customers and are capable of acquiring exclusive legal rights as a type of trademark or identifying symbol of origin. Because trade dress includes all factors making up the total image under which a product or service is presented to customers, it potentially covers almost all aspects of appearance. Things that have been held protectable under the category of trade dress include: (1) the shape and appearance of a product; (2) the shape and appearance of a container; (3) the cover of a book or magazine; (4) the layout and appearance of a business establishment such as a restaurant; (5) the theme and look of a line of greeting cards; and (6) the recognizable shape of an automobile.

 

What is the Right of Publicity?

The “right of publicity” is the inherent right of every human being to control the commercial use of his or her identity. Please note these carefully chosen words. It is the right of “every human being,” not the right of every person. In many contexts we could substitute the phrase “every human being” with the word “person,” but it is important to remember that the right of publicity is an individual right. When the word “person” is used in the law we most often define “person” to include corporations or other similar entities. This is not the case with the right of publicity. The right of publicity does not protect the persona of a corporation, partnership, institution or other similar entities; it protects only the human identity.

Infringement of the right of publicity can be triggered by any unauthorized use in which the plaintiff is “identifiable.” A plaintiff is identifiable by name, nickname, stage name, pen name, picture, photograph, voice (particularly a distinctive voice) or any object closely identified with a person. An unpermitted commercial use where the plaintiff is identifiable triggers a prima facie case of infringement of the right of publicity.