The 25-year process patent regime allowed a large number of generic companies in India to reap rich dividends, but there were few who believed in the need to go beyond the horizon of process development to tap into unexplored terrains.

In the year 2000, when Dr Ashok Kumar joined the board of Mumbai-based IPCA Labs, he was determined to implement a different strategy to accelerate IPCA’s R&D initiatives. Having seen IPCA grow from a 350-crore company to one clocking an annual turnover of over 2,500 crore, Dr Ashok Kumar, president- Center for Research and Development, IPCA Labs, is now leaving no stone unturned to exploit the biotech and drug discovery space.

 

Dr Kumar completed his M Sc in Chemistry from Kumaun University, now in Uttarakhand. He then decided to pursue his PhD in organic chemistry and joined Banaras Hindu University (BHU), but opted out three months later to do PhD from the Central Drug Research Institute (CDRI), Lucknow, under the guidance of the then director of the CDRI, Dr Nityanand.

Dr Kumar did his post doctoral studies from the University of Sussex, UK. “During the 1980s, jobs in scientific research were not available in India. It was always good to go for higher studies abroad,” he says about the reason for going abroad. “Dr Nityanand taught me to be explorative and think of new ways to approach a subject. I still follow that process,” he says. In 1984, Dr Kumar decided to return to India and took up a job at the Imperial Chemical Laboratories (ICI), Mumbai. In 1994, he joined Lupin Labs where he was once again involved in process development of small molecules.

In 2000, he joined IPCA Labs where he immediately focused on bringing about two changes – introducing a library and bringing in systems like a nuclear magnetic resonance (NMR), which at that time was the costliest instrument. “I understood the importance of high-end technologies since my PhD years at the CDRI (which housed a couple of NMRs) and then in the UK. You do not enjoy organic chemistry without an NMR. My main objective at IPCA was cost reduction along with process development.”

In the last few years, IPCA’s R&D team has brought out over 100 products. Under Dr Kumar, IPCA has an R&D center in Mumbai and another parallel R&D center in Ratlam, Madhya Pradesh. “In Mumbai, we have around 60 people. The Mumbai team takes care of basic chemistry and small-scale development. Scaling up is done in Ratlam,” he explains. IPCA is also coming up with a facility at Vadodara, Gujarat, that will look into large-scale manufacture of both organic and biotech drugs. The facility will have a strategic importance for the company. “We are growing at a rate of 20 per cent year-on-year and, next year, we intend to add 500 crore to our revenue. For that, we need more products to come to the market and more volume,” he adds.

Apart from organic chemistry, Dr Kumar is currently aligning his attention to two promising but high risk segments – fermentation-based products and biosimilars. “We are working on five-to-six molecules, mainly active metabolites that are intermediates or biotech drugs,” he adds. IPCA has also collaborated with two companies in India for the development of biosimilars. Currently, there are three biosimilar products in the pipeline.

The R&D team at IPCA ventured into drug discovery three years ago. It has two products in the pipeline; one anti-malarial and the other anti-thrombotic. “We will be filing the investigational new drug application for one molecule this year and for the other next year. The success rate here is 99 per cent,” adds Dr Kumar. IPCA has also joined hands with the CDRI and licensed two molecules in the anti-malarial space. One of these molecules is currently in phase-I stage.

JOURNEY

 

Experience

PRESIDENT – R&D

IPCA LABORATORIES LTD

2005 – Present (10 years)

Patent 1

chlorthalidone is 3-hydroxy-3-(3′-sulfamyI-4′- chlorophenyl)phtalimidine and is represented by the structural formula shown below.

Chlorthalidone Formula 1

(Scheme 2). The starting material, 2-(4′-chlorobenzoyl) benzoic acid, of Formula (2) and its preparation was reported earlier for example in patents US 4500636, US 30555904, US4379092, US 3764664.

Formula 9 CIS0₃H

Chlorthalidone Formula 10 Formula 1

 PATENT 2

 https://www.google.co.in/patents/US7847094Quetiapine and its process for preparation is first disclosed in the patent specification EP0240228 and various other processes for the preparation are disclosed in EP0282236, WO0155125, WO9906381, WO2004076431.

 PATENT 3

http://www.google.com/patents/US20080009635

  . The chemical name of Ondansetron is 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl)-1H-imidazole-1-yl)methyl]-4H-carbazol-4-one and is represented by the structural formula given below:

PATENT 4

 

Chemical Research & Development Centre

123-AB, Kandivli Industrial Estate, Kandivli (West)
Mumbai 400 067, Maharashtra

+91 (22) 6647 4755 / 56

+91 (22) 6647 4757

Regulation of Herbal (Traditional) Medicinal Products in the European Union

Introduction

The European Union (EU) regulatory framework for medicinal products is complex and is based on the need of a marketing authorization before placing medicines in the market. The main objective is to protect public health by assuring quality, efficacy and safety. The requirements and procedures to obtain a marketing authorization are laid down in regulations, directives and scientific guidelines which are contained in the “Rules Governing Medicinal Products in the European Union”. Several volumes are included which are supported by other publications with complementary information such as scientific or Good Manufacturing Practice (GMP) guidelines, between others [1].

Medicinal plants have been used since Ancient times in all parts of the world. Nonetheless, regulation of herbal medicines in a legal environment was introduced in the 20th century. The EU regulatory framework includes specific requirements for herbal medicinal products (HMP) which are independent from their legal status: traditional herbal medicinal product (THMP) or products based on clinical evidence – well established use (WEU).

Before a HMP is placed in the market, it must be approved by a MS or by the European Commission by one of the existing types of application: full marketing authorization application, well-established use marketing authorization application or Traditional use marketing registration (Table 1).

The applicant has to submit adequate quality, non-clinical and clinical documentation of the product, irrespectively of the procedure used. Quality requirements of the pharmaceutical product are the same, regardless of the type of application, while efficacy documentation differs between them. The full marketing application is chosen for new medicinal products (new chemical entity) and it has to be completed with the results of pharmaceutical tests (quality documentation), nonclinical (toxicological and pharmacological) studies and clinical trials. Safety data have to be of sufficient size according the existing guidelines; efficacy is demonstrated by results from the clinical trials which have to be in conformity with the guidelines of the corresponding therapeutic area. This type of application is open for HMP, but only a few examples of herbal products have obtained a marketing authorization in the EU in this way.

EU Pharmaceutical Legislation for Herbal Medicinal Products for Human Use

Quality requirements

The principles to assure quality of medicinal products are defined mainly in two Directives of volume 1: Directive 2001/83/EC (which was emended by Directive 2004/24/EC) and Directive 2003/63/EC.

The basic legislation lay down in Directive 2001/83/EC describes the general requirements and provides legal definitions of herbal substances, herbal preparations and herbal medicinal products (Table 2). These concepts are essential for setting quality standards for HMP, as they are by definition complex in nature and so quality requirements set for purified compounds are not suitable for herbal products.

According to the Directive 2001/83/EC, monographs in the European Pharmacopoeia (Eur. Ph.) are legally binding and applicable to all substances which are included in it. For substances which do not have a Eur. Ph. monograph, each Member State (MS) may apply its own national pharmacopoeia. Constituents which are not given in any pharmacopoeia shall be described in the form of a monograph under the same headings included in any monograph in the Eur. Ph., i.e., the name of the substance supplemented by any trade or scientific synonyms; the definition of the substance, set down in a form similar to that used in the European Pharmacopoeia; methods of identification and purity tests.

Moreover, all medicinal products have to be manufactured according to the principles and guidelines of GMP for medicinal products. GMP are applicable to both finished HMP and active substances and, according to Article 46 (f) of Directive 2001/83/EC as amended, marketing authorization holders are required to use as starting materials only active substances which have been manufactured in accordance with the guidelines on the GMP for starting materials as adopted by the Community and distributed in accordance with good distribution practices for active substances.

Additional requirements are found in the Directive 2003/63/EC, as Herbal medicinal products differ substantially from conventional medicinal products in so far as they are intrinsically associated with the very particular notion of herbal substances and herbal preparations. It is therefore appropriate to determine specific requirements in respect of these products with regards to the standardized marketing authorization requirements. Then, detailed information on the herbal medicinal product, herbal substances and herbal preparations has to be included, such as the name, address and responsibility of each herbal substance supplier or description of the plant production process, geographical source or drying and storage conditions. The application dossier of a HMP should include specifications and details of all the analytical methods used for testing herbal substances and herbal preparations, results of batch analyses and analytical validation, together with the justification for the specifications.

Most of the quality requirements for HMP are laid down in soft laws (considered as EU measures such as scientific guidelines) which do not have legal force but provide practical harmonization between the MS and the European Medicines Agency (EMA).

The guideline on quality of HMP/THMP covers the general quality aspects of HMP for human and veterinary use, including THMP for human use (EMA, 2014) and indicates which information has to be included in the application dossier. It provides definitions to be taken in account such as genuine (native) herbal preparations, markers, drug to extract ratio (DER) and specifications. Which is more important, it states that the herbal substance or herbal preparation is considered as the whole active substance. In consequence, the quality control of these products has to include appropriate fingerprint analysis to cover not only the content of markers or constituents with known therapeutic activity but also a wider range of chemical constituents.

Efficacy requirements

Before a HMP is placed in the market, it must be approved by a MS or by the European Commission by one of the existing types of application: full authorization application, well-established use authorization application or Traditional use registration (Table 3).

The applicant has to submit adequate quality, non-clinical and clinical documentation of the product, irrespectively of the procedure used. Quality requirements of the pharmaceutical product are the same, regardless of the type of application, while efficacy documentation differs between them. The full marketing application is chosen for new medicinal products (new chemical entity) and it has to be completed with the results of pharmaceutical tests (quality documentation), nonclinical (toxicological and pharmacological) studies and clinical trials. Safety data have to be of sufficient size according the existing guidelines; efficacy is demonstrated by results from the clinical trials which have to be in conformity with the guidelines of the corresponding therapeutic area. This type of application is open for HMP, but only a few examples of herbal products have obtained a marketing authorization in the EU in this way.

The well-established medicinal use (WEU) in the EU can be applied to medicinal products for which there exists a wide clinical experience within the EU (not only HMP). The assessment may be based in published controlled clinical trials, non-clinical studies and epidemiological studies. In this type of application, there are no limitations to the therapeutic indication, as this will be derived from the available documentation.

(Traditional) Herbal Medicinal Products

Under the Traditional use registration for herbal medicinal product (article 16e), there exist some herbal products that not fulfill the efficacy requirements for a marketing authorization but are endorsed with a long tradition of use. In this case, no clinical trials on these products have been conducted and the efficacy is based on the long-standing use and experience. This simplified registration procedure is limited to products which are intended for use without medical supervision, with a specified strength and posology, to be used by oral, external or inhalation ways, and which can demonstrate a period of use equal or superior to 30 years, including at least 15 years within the EU. In this case, therapeutic indications are limited to those which can be considered safe for use without the supervision of a physician such as minor disorders or symptoms that are benign or self- limiting. In case the applicant should consider another kind of indication, the product must be documented with results of clinical and non-clinical studies, so a full application would be necessary.

Simplified registration of THMP is described in Chapter 2a of Directive 2004/24/EC with three main objectives: a) to protect public health by allowing access to safe and high-quality HMP; b) to allow European citizens the access to medicines of their choice, even those HMP with a long tradition of use and which efficacy hasn’t been proved by clinical trials performed according the modern standards; c) to facilitate movement of medicinal products on the European market.

Directive 2004/24/EC has two different dimensions: the evaluation by National Competent Authorities (NCA) of applications submitted by companies at any MS in the EU and at the EMA, and the establishment of advisory scientific opinions on the medicinal use of herbal substances or preparations. The directive on THMP also established a new scientific committee, the Herbal Medicinal Products Committee (HMPC) at the EMA in London, in 2004, to replace the previous Working Party on Herbal Medicinal Products (CPMP) with the following aims: to elaborate Community monographs and List entries for herbal substances/preparations; to publish scientific guidelines useful for the application of European legal framework; to publish its scientific opinion on questions related to herbal medicinal products and coordinate its work with the European Quality group. The HMPC is made up by 33 members, one member (and one alternate) nominated by each MS of the EU and by Iceland and Norway (the EFAEFTA states). Among them, also five experts are included, representing specific fields of expertise as clinical and non-clinical pharmacology, toxicology or pediatrician medicine.

The guidelines and the monographs developed and approved by the HMPC are accepted by both companies and NCAs and are used for TUR and WEU marketing authorizations. This committee plays a key role in the harmonization of the regulation of HMP whereby Community herbal monographs have a fundamental role.

Usage of Community herbal monographs in the EU regulation of traditional HMP

These documents are established for HMP with regards to bibliographic applications (art. 10 a Directive 2001/83/EC) as well as THPMs. Community monographs reflect the scientific opinion of the HMPC on safety and efficacy data concerning a herbal substance. Any single plant or herbal preparation is assessed individually, according to the available information and includes qualitative and quantitative composition, pharmaceutical form(s), therapeutic indication(s), posology and method of administration, contraindications, special warnings and precautions of use, interactions, use in special population (pregnancy, lactation), effects on ability to drive and use machines, undesirable effects, overdose, pharmacological,pharmacodynamics, pharmacokinetic properties and preclinical safety data.

Community list entry

In the EU, a community list of herbal substances, preparations and combinations thereof for use in THMPs has been established. This list is based in the proposals form HMPC and is gradually developed. Substances or preparations which are included in the list have the main advantage that applicants do not need to provide evidence on the safe or traditional use for its registration at the NCA in the intended use and indication.

A Public statement for one herbal substance/preparation is published because of safety reasons or lack of data to comply with the conditions in the Directive 2004/24/EC (the assessment work didn’t allow a monograph to be published) [2].

Community monographs are published by the EMA while list entries are approved and published by the European Commission because they are endorsed with a wider legal status: list entries are legally binding and NCAs should not request additional data on safety and traditional use.

The establishment of monographs and list entries is based on the assessment of the published scientific data, together with the existing products in the market. Most of the assessment work is developed by the Monograph and List Working Party (MLWP) at the HMPC, which was established in 2006. In this working group, a member is designed as rapporteur and is responsible of drafting a monograph and/or list entry which will be later on considered and approved by the HPC and then, by the EMA. The documents are published on the EMA website: Community monographs have to be taken in account by the MS when assessing the application of any company. Monographs are note legally binding and MS are not obliged to follow the monographs.

More than 100 species are included in the priority list with the following data: a) scientific data being assessed (R- Rapporteur assigned); b) evaluation report in progress and discussion in the MLWP (D- Draft under discussion); c) scientific opinion under public consultation (PDraft Published); d) comments after public consultation period being evaluated (PF- Assessment close to finalization – pre-final); e) final opinion adopted (F- Final opinion adopted).

MLWP is also responsible of developing guidelines related to legal requirements for TU and WEU, as well as evaluating hazards and problems related to HMP. For the latter, coordination is established with the Safety Working Party (SWP) from the Committee for Medicinal Products for Human Use (CHMP).

Community herbal monographs to support HMPC authorization

A community monograph reflects the scientific opinion from the HMPC in relation to safety and efficacy of one herbal substance/ preparation for medicinal use. AS stated before, a community monograph may be used by a company for a TU or WEU application. That’s the reason why monographs are divided in to two columns: Well Established Use and Traditional Use (simplified application) (Figure 1). WEU is based in the existence of safety data of sufficient size and efficacy data derived from good-quality clinical trials. Traditional use is accepted for those applications which fulfill the criteria shown in the Directive 2004/24/EC.

Each herbal substance/preparation is assessed individually, as the available information may be different for each one. As a result, some substances/preparations may be included in the WEU side, while others will be included in the TU side. If no enough data are available for the substance/preparation, it won’t be included in the monograph.

The approved draft art he HMPC is published for public consultation for 3 month at the EMA website. Comments received are discussed and taken in account when necessary to achieve the final version of the monograph which will be finally published at the MA website.

By the end of 2014, 126 monographs have been adopted and published by the EMA: 104 of them for TU only; 9 of the monographs refer only to WEU (Aloe vera, Cimicifuga racemosa, Rhamnus frangula, Plantago ovata – seed and tegumentum-, Plantago afra, Rheum palmatum, Cassia senna – leaves and fruits-.among them 13 monograph include both TU and WEU.

The main application of a community monograph is to serve as a reference material for the marketing application, both for TU or WEU. Simplified registration is carried on at a national level, so the company gives the dossier to the NCA. With the aim of improving harmonization, the other MSs should recognize the first authorization granted in the first MS, considering that this is based in the European list.

Directive 2004/24/CE established an adaptation period for those herbal products which were on the European market at the moment the Directive was approved. This seven-year period finalized last April 30th, 2011 and implies that nowadays those herbal preparations that not fulfill the actual legislation will not be marketed any more.

In the public report form the EMA last June 2014, the status of updating the medicines registration in the EU was shown. The number Traditional use registrations (TUR) and Well-established use marketing authorizations (WEU) grouped for mono component and combination products has increased in the last years (Figure 2).

The European market for HMP is increasing during the last years and even exceeds prescription medicines. The indications approved cover a wide range of therapeutic areas, most of them characteristic of self-medication diseases: the main therapeutic areas are respiratory tract disorders (cough and cold), mental stress and mood disorders, urinary tract and gynecology disorders, sleep disorders and temporary insomnia (Figure 3). Most of the approved THMP until now were updates of existing authorizations and were based on Community monographs. The Summary of Product Characteristics (SoPC) reflects the items in the corresponding monograph [3].

A good correlation between the HMPC work and the evaluation of the dossiers from the companies was detected. The relevance of these documents (as shown by the accepted dossiers) is reflected in the HMPC working plan; as an example, last December 2012, 54 among the 56 species with more than 3 marketing authorizations were listed in the priority list.

Conclusión

European legal framework for medicinal products does also include herbal medicinal products to assure their quality, efficacy and safety. The specific characteristics of these products led to the development of a simplified procedure to assure pharmaceutical quality, while keeping safety and efficacy criteria according to marketing authorization granted.

Although the starting point was quite different for the MS, nowadays there exist Community monographs for most of the herbal substances/ preparations that are used in the European market and which form the basis for a harmonization scenario. Moreover, HMPC acts as an International Regulatory Body for herbal medicinal products in order to achieve global standards for this type of medicines, according to other International organization such as the International Conference on Harmonization (ICH). The main tasks the HMPC has to face are those related to herbal medicinal products which have been previously marketed abroad the EU and the increasing existence of combination products within the MS.

References

Kroes BH (2014) The legal framework governing the quality of (traditional) herbal medicinal products in the European Union. J of Ethnopharmacol 158: 449-453. Chinou I (2014) Monographs, list entries, public statements. J of Ethnopharmacol 158: 458-462. Peschel W (2014) The use of community herbal monographs to facilitate registrations and authorisations of herbal medicinal products in the European Union 2004-2012. J of Eth nopharmacol 158: 471-486.

Figure 1: European Community Monograph for Valeriana officinalis L., radix, for WEU and TU

Ruiz-Poveda OMP^*

Department of Pharmacology, Faculty of Pharmacy, Universidad Complutense de Madrid, 28040 Madrid, Spain

Ruiz-Poveda OMP
Department of Pharmacology, Faculty of Pharmacy
Universidad Complutense de Madrid, Madrid
Ciudad Universitaria s/n. 28040 Madrid, Spain
Tel: 913 941 767
Fax: 913 941 726
E-mail: olgapalomino@farm.ucm.es

Citation: Ruiz-Poveda OMP (2015) Regulation of Herbal (Traditional) Medicinal Products in the European Union. Pharmaceut Reg Affairs 4:142. doi: 10.4172/2167-7689.1000142

/////////Herbal medicines,  Good manufacturing practices,  Traditional uses

EMA: European Medicines Agency; DER: Drug to Extract Ratio; HMP: Herbal Medicinal Products; THMP: Traditional Herbal Medicinal Products

IPI 504, Retaspamycin, Retaspimycin

CAS 857402-63-2

Cas 857402-23-4 ( Retaspimycin); 857402-63-2 ( Retaspimycin  HCl).

MF C31H45N3O8 BASE

MW: 587.32067 BASE

Infinity Pharmaceuticals Inc,  INNOVATOR

[(3R,5S,6R,7S,8E,10S,11S,12Z,14E)-6,20,22-trihydroxy-5,11-dimethoxy-3,7,9,15-tetramethyl-16-oxo-21-(prop-2-enylamino)-17-azabicyclo[16.3.1]docosa-1(22),8,12,14,18,20-hexaen-10-yl] carbamate;hydrochloride

17-Allylamino-17-demethoxygeldanamycin Hydroquinone Hydrochloride

1. UNII-928Q33Q049
2. SEE………http://www.biotechduediligence.com/retaspamycin-hcl-ipi-504.html

Introduction

IPI-504 is a novel, water-soluble, potent inhibitor of heat-shock protein 90 (Hsp90).

Orphan drug designation was assigned to the compound by the FDA for the treatment of gastrointestinal stromal cancer (GIST).

Retaspimycin Hydrochloride is the hydrochloride salt of a small-molecule inhibitor of heat shock protein 90 (HSP90) with antiproliferative and antineoplastic activities. Retaspimycinbinds to and inhibits the cytosolic chaperone functions of HSP90, which maintains the stability and functional shape of many oncogenic signaling proteins and may be overexpressed or overactive in tumor cells. Retaspimycin-mediated inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins in susceptible tumor cell populations, which may result in the induction of apoptosis.

Phase I study of Retaspimycin: A phase 1 study of IPI-504 (retaspimycin hydrochloride) administered intravenously twice weekly for 2 weeks at 22.5, 45, 90, 150, 225, 300 or 400 mg/m(2) followed by 10 days off-treatment was conducted to determine the safety and maximum tolerated dose (MTD) of IPI-504 in patients with relapsed or relapsed/refractory multiple myeloma (MM). Anti-tumor activity and pharmacokinetics were also evaluated. Eighteen patients (mean age 60.5 years; median 9 prior therapies) were enrolled. No dose-limiting toxicities (DLTs) were reported for IPI-504 doses up to 400 mg/m(2).

The most common treatment-related adverse event was grade 1 infusion site pain (four patients). All other treatment-related events were assessed as grade 1 or 2 in severity. The area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2-4 h for IPI-504 and its metabolites. Four patients had stable disease, demonstrating modest single-agent activity in relapsed or relapsed/refractory MM.  (source: Leuk Lymphoma. 2011 Dec;52(12):2308-15.)

Figure Hsp90 protein partners and clients destabilized by Hsp90 inhibition (Jackson et al., 2004).

In a different approach, Infinity Pharmaceuticals has developed IPI504 (retaspimycin or 17-AAG hydroquinone, Figure 4) (Adams et al., 2005; Sydor et al., 2006), a new GA analogue, in which the quinone moiety was replaced by a dihydroquinone one. Indeed, the preclinical data suggested that the hepatotoxicity of 17-AAG was attributable to the ansamycin benzoquinone moiety, prone to nucleophilic attack.

Furthermore, it was recently reported that the hydroquinone form binds Hsp90 with more efficiency than the corresponding quinone form (Maroney et al., 2006). In biological conditions, the hydroquinone form can interconvert with GA, depending on redox equilibrium existing in cell. It has been recently proposed, that NQ01 (NAD(P)H: quinone oxidoreductase) can produce the active hydroquinone from the quinone form of IPI504 (Chiosis, 2006).

However, Infinity Pharmaceuticals showed that if the overexpression of NQ01 increased the level of hydroquinone and cell sensitivity to IPI504, it has no significant effect on its growth inhibitory activity. These results suggest that NQ01 is not a determinant of IPI504 activity in vivo (Douglas et al., 2009).

Figure 4: GA, 17-AAG, 17-DMAG and IPI504.

PATENT

http://www.google.com/patents/EP2321645A1?cl=en

Geldanamycin (IUPAC name ([18S-(4E,5Z,8R*.9R*.10E,12R*.13S*,14R*,l6S*)]- 9- [(aminocarbonyl)oxy]- 13- hydroxy- 8,14,19- trimetoxy- 4,10,12,16- tetramethyl- 2- azabicyclo[16.3.1.]docosa- 4,6.10,18,21- pentan- 3.20,22trion) is a benzoquinone ansamycin antibiotic which may be produced by the bacterium Streptorayces hygroscopicus. Geldanamycin binds specifically to HSP90 (Heat Shock Protein 90) and alters its function.

While Hsp90 generally stabilizes folding of proteins and, in particular in tumor cells, folding of overexpressed/mutant proteins such as v-Src. Bcr-Abl and p53. the Hsp90 inhibitor Geldanamycin induces degradation of such proteins.

The respectiv e formula of geldanamycin is given herein below:

E\en though geldanamycin is a potent antitumor agent, the use of geldanamycin also shows some negathe side-effects (e.g. hepatotoxicity) which led to the dev elopment of geldanamycin analogues/derivatives, in particular analogues/deriv atives containing a derivatisation at the 17 position. Without being bound by theory , modification at the 17 position of geldanamycin may lead to decreases hepatotoxicity.

Accordingly geldanamycin analogues/derivatives which are modified at the 17 position, such as 17-AAG (17-N-Allylamino-17-demethoxygeldanamycin), are preferred in context of the present invention. Also preferred herein are geldanamycin derivatives to be used in accordance with the present invention which are water-soluble or which can be dissoh ed in water completely (at least 90 %. more preferably 95 %. 96 %. 97 %, 98 % and most preferably 99 %). 17-AAG ([QS.5S,6RJS$EΛ0R,l \SΛ2E,14E)-2\- (allylamino)-6-hydroxy-5.11-diraethoxy-

3.7.9,15-tetramethyl-16.20.22-trioxo-17-azabicyclo[16.3.1]docosa-8,12.14,18,21-pentaen-10- yl] carbamate) is. as mentioned above a preferred derivative of geldanamycin. 17- AAG is commercially available under the trade name “Tanespimycin^“ (also known as KOS-953) for example from Kosan Biosciences Incorporated (Acquired by Bristol-Myers Squibb Company). Tanespimycin is presently studied in phase II clinical trials for multiple myeloma and breast cancer and is usually administered intravenously.

The respective formula of 17- AAG is given herein below:

Preferred geldanamycin-derh ative (HSP90 inhibitor) to be used in context of the present invention are IPI-504 (also known as retaspiimcin or Mcdi-561 : lnfinin Pharmaceuticals (Medlmmunc/ Astra Zeneca)). Clinical trials on the use of IPI-504 (which is usually administered intravenously) in the treatment of non-small cell lung cancer (NSCLC) and breast cancer are performed. Also alvespimycin hy drochloride (Kosan Biosciences Incorporated Acquired By : Bristol-Myers Squibb Company) is a highly potent, water-soluble and orally acti\e derivative of geldanamycin preferably used in context of the present invention.

IPI-504

PATENT

WO 2005063714

http://www.google.co.ug/patents/WO2005063714A1?cl=en

Example 24

Preparation of Air-stable Hydroquinone Derivatives of the Geldanamycin Family of Molecules

,

17-Allylamino-17-Demethoxygeldanamycin (10.0 g, 17.1 mmol) in ethyl acetate

(200 mL) was stirred vigorously with a freshly prepared solution of 10% aqueous sodium hydrosulfite (200 mL) for 2 h at ambient temperature. The color changed from dark purple to bright yellow, indicating a complete reaction. The layers were separated and the organic phase was dried with magnesium sulfate (15 g). The drying agent was rinsed with ethyl acetate (50 mL). The combined filtrate was acidified with 1.5 M hydrogen chloride in ethyl acetate (12 mL) to pH 2 over 20 min. The resulting slurry was stirred for 1.5 h at ambient temperature. The solids were isolated by filtration, rinsed with ethyl acetate (50 mL) and dried at 40 °C, 1 mm Hg, for 16 h to afford 9.9 g (91%) of off-white solid. Crude hydroquinone hydrochloride (2.5 g) was added to a stirred solution of 5% 0.01 N aq. hydrochloric acid in methanol (5 mL). The resulting solution was clarified by filtration then diluted with acetone (70 mL). Solids appeared after 2-3 min. The resulting slurry was stirred for 3 h at ambient temperature, then for 1 h at 0-5 °C. The solids were isolated by filtration, rinsed with acetone (15 mL) and dried

PAPER

17-Allylamino-17-demethoxygeldanamycin (17-AAG)¹ is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.

17-Allylamino-17-demethoxygeldanamycin Hydroquinone Hydrochloride Ia

17-AAG hydroquinone hydrochloride (1a) as an off-white solid (11 g, 18 mmol, 80% yield). HPLC purity:  99.6%;

IR (neat):  3175, 2972, 1728, 1651, 1581, 1546, 1456, 1392, 1316, 1224, 1099, 1036 cm^-1;

¹H NMR (CDCl₃:d₆-DMSO, 6:1, 400 MHz): 

δ 10.20 (1H, br), 9.62 (2H, br), 8.53 (1H, s), 8.47 (1H, s), 7.74 (1H, s), 6.72 (1H, d, J= 11.6 Hz), 6.28 (1H, dd, J = 11.6, 11.2 Hz), 5.73 (1H, dddd, J = 17.2, 10.0, 3.2, 2.4 Hz), 5.53 (1H, d, J = 10.4 Hz), 5.49 (1H, dd, J = 10.8, 10.0 Hz), 5.32 (2H, s), 5.04 (1H, d, J = 4.8 Hz), 5.02 (1H, d, J = 16.0 Hz), 4.81 (1H, s), 4.07 (1H, d, J = 9.6 Hz), 3.67 (2H, d, J = 6.4 Hz), 3.31 (1H, d,J = 8.8 Hz), 3.07 (3H, s), 3.07−3.04 (1H, m), 2.99 (3H, s), 2.64 (1H, m), 2.52−2.49 (1H, m), 1.76 (3H, s), 1.61−1.39 (3H, m), 0.78 (3H, d, J = 6.4 Hz), 0.64 (3H, d, J = 7.2 Hz);

¹³C NMR (CDCl₃:d₆-DMSO, 6:1, 100 MHz):  δ 167.3, 155.8, 143.3, 136.3, 135.0, 134.2, 132.9, 132.1, 128.8, 127.6, 125.9, 125.3, 123.7, 123.0, 115.1, 104.5, 80.9, 80.7, 80.1, 72.5, 56.2, 56.2, 52.4, 34.6, 33.2, 31.1, 27.2, 21.6, 12.1, 12.1, 11.7;

HRMS calculated for C₃₁H₄₅N₃O₈ (M⁺ + H):  588.3285, Found 588.3273.

POSTER

Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90

References

Synthesis and biological evaluation of IPI-504, an aqueous soluble analog of 17-AAG and potent inhibitor of Hsp90
231st Am Chem Soc (ACS) Natl Meet (March 26-30, Atlanta) 2006, Abst MEDI 210

Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90
J Med Chem 2006, 49(15): 4606

http://www.biotechduediligence.com/retaspamycin-hcl-ipi-504.html

///////////////////Hsp90, IPI-504, infinity pharma, Retaspamycin, Retaspimycin

XL 388

 

 

The mammalian target of rapamycin (mTOR) is a large protein kinase that integrates both extracellular and intracellular signals of cellular growth, proliferation, and survival. Both extracellular mitogenic growth factor signaling from cell surface receptors and intracellular signals that convey hypoxic stress, energy, and nutrient status converge at mTOR. mTOR exists in two distinct multiprotein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

mTORC1 is a key mediator of translation and cell growth, via its substrates p70S6 kinase (p70S6K) and eIF4E binding protein 1 (4E-BP1), and promotes cell survival via the serum and glucocorticoid-activated kinase (SGK), whereas mTORC2 promotes activation of prosurvival kinase AKT. mTORC1, but not mTORC2, can be inhibited by an intracellular complex between rapamycin and FK506 binding protein (FKBP). However, rapamycin–FKBP may indirectly inhibit mTORC2 in some cells by sequestering mTOR protein and thereby inhibiting assembly of mTORC2.

Given the role of mTOR signaling in cellular growth, proliferation, and survival as well as its frequent deregulation in cancers, several rapamycin analogues (rapalogues) that are selective allosteric mTORC1 inhibitors have been extensively evaluated in a number of cancer clinical trials.

Demonstrated clinical efficacy for rapalogues is currently limited to patients with advanced, metastatic renal cell carcinoma (RCC) despite extensive development efforts.

This result is likely attributed not only to a lack of inhibition of mTORC2 by rapalogues that leads to upregulation of Akt through a negative feedback loop, but also to only partial inhibition of mTORC1.Therefore, ATP-competitive mTOR inhibitors that should simultaneously inhibit both mTORC1 and mTORC2 may offer a clinical advantage over rapalogues.

As a key component of the phosphoinositide 3-kinase-related kinase (PIKK) family, which is comprised of phosphoinositide 3-kinases (PI3Ks), DNA-PK, ATM, and ATR, mTOR shares the highly conserved ATP binding pockets of the PI3K family with sequence similarity of 25% in the kinase catalytic domain.

In light of this fact, it is not surprising that many of the first reported ATP-competitive mTOR inhibitors such as BEZ235 and GDC-0980 also inhibited PI3Ks. PI3Ks are responsible for the production of 3-phosphoinositide lipid second messengers such as phosphatidylinositol 3,4,5-triphosphate (PIP3), which are involved in a number of critical cellular processes, including cell proliferation, cell survival, angiogenesis, cell adhesion, and insulin signaling.

Therefore, the development of ATP-competitive mTOR inhibitors that are selective over PI3Ks may offer an improved therapeutic potential relative to rapalogues as well as dual PI3K/mTOR inhibitors. Recently, several selective ATP-competitive mTOR inhibitors such as Torin 2 and AZD8055  have been reported with sufficient promise to warrant clinical trials.

PATENT

Example 2:

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl] [3-fluoro- 2-methyl-4-(methylsulfonyl)phenyl]methanone

tørt-Butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/] [l,4]oxazepine-4(5H)- carboxylate. To a mixture of 4-(te/t-butoxycarbonyl)-2,3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-ylboronic acid (1.52 g, 5.2 mmol), prepared as described in Reference Example 5, 2-amino-5-bromopyridine (900 mg, 5.2 mmol), and potassium carbonate (1.73 g, 12.5 mmol) in 1 ,2-dimethoxyethane/water (30 mL/10 mL) was added tetrakis(triphenylphosphine)palladium(0) (90 mg, 1.5 mol%) and the reaction mixture was purged with nitrogen and stirred at reflux for 3 h. The reaction was cooled to rt, diluted with water/ethyl acetate (50 mL/50 mL), and the separated aqueous layer was extracted with ethyl acetate. The resulting emulsion was removed by filtration. The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure, and the residue was triturated with toluene for 1 h. The resulting off-white solid was isolated by filtration to give the desired product (1.37 g, 77 %) as an off-white solid. MS (EI) for Ci₉H₂₃N₃O₃: 342 (MH⁺).

5-(2,3,4,5-Tetrahydrobenzo[/] [l,4]oxazepin-7-yl)pyridine-2-amine. To a stirred solution of tert-butyl 7-(6-aminopyridin-3-yl)-2,3-dihydrobenzo[/][l,4]oxazepine- 4(5H)-carboxylate (1.36 g, 3.98 mmol) in 1,4-dioxane (5 mL) was added 4 N hydrogen chloride in 1 ,4-dioxane (5 mL) and the reaction mixture was stirred at rt overnight. The reaction was concentrated on a rotary evaporator and the residue was triturated with ether. The solid was isolated by filtration. This solid was dissolved in water (5 mL) and made basic with 5 N sodium hydroxide to pH 11-12. The brownish sticky oil that aggregated at the bottom was isolated and the aqueous layer was extracted with 5 % methanol in ethyl acetate. The extracts were dried with sodium sulfate and concentrated on a rotary evaporator. The brownish sticky oil was dissolved with a mixture of methanol/ethyl acetate, combined with the isolated organic residue and concentrated under reduced pressure to give a yellow solid. This solid was triturated with dichloromethane (10 mL) for 1 h and a yellow solid was isolated by filtration and dried under high vacuum to give amine the desired product (920 mg, 96 %). MS (EI) for Ci₄Hi₅N₃O: 242 (MH⁺).

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-l,4-benzoxazepin-4(5H)-yl][3-fluoro-2- methyl-4-(methylsulfonyl)phenyl]methanone.

To a stirred suspension of 5-(2, 3,4,5- tetrahydrobenzo[/][l,4]oxazepin-7-yl)pyridine-2-amine (85 mg, 352 μmol) and triethylamine (54 μL, 387 μmol) in dichloromethane (10 mL) was added 3-fluoro-2-methyl-4- (methylsulfonyl)benzoyl chloride (91 mg, in 3 mL of dichloromethane), prepared as described in Reference Example 1, at 0 ⁰C for 2 h. After stirring for an additional 1 h at rt, the reaction mixture was diluted with water (5 mL) and the separated aqueous layer was extracted with dichloromethane. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to give a light-yellow solid that was purified via silica gel chromatography to give the desired product (113 mg, 70%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.24-8.03 (dd, IH), 7.79-7.71 (m, IH), 7.71-7.69 (dd, 0.5H), 7.57-7.57 (d, 0.5H), 7.44-7.40 (m, 1.5H), 7.29-7.19 (dd, IH), 7.05-7.01 (dd, IH), 6.64-6.63 (d, 0.5H), 6.54-6.45 (dd, IH), 6.06 (s, 2H), 4.93-4.31 (m, 2H), 4.31-3.54 (m, 4H), 3.37-3.36(d, 3H), 2.12-1.77 (d, 3H).

MS (EI) C₂₃H₂₂FN₃O₄S: 456 (MH⁺).

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

PATENT

PAPER

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00037

The benzoxazepine core is present in several kinase inhibitors, including the mTOR inhibitor 1. The process development for a scalable synthesis of 7-bromobenzoxazepine and the telescoped synthesis of 1 are reported. Compound 1 consists of three chemically rich, distinct fragments: the tetrahydrobenzo[f][1,4]oxazepine core, the aminopyridyl fragment, and the substituted (methylsulfonyl)benzoyl fragment. Routes were developed for the preparation of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (17) and tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2). The processes for the two compounds were scaled up, and over 15 kg of each starting material was prepared in overall yields of 42% and 58%, respectively.

A telescoped sequence beginning with compound 2 afforded 7.5 kg of the elaborated intermediate 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-2-amine dihydrochloride (6) in 63% yield. Subsequent coupling with benzoic acid 17 gave 7.6 kg of the target compound 1 in 84% yield. The preferred hydrochloride salt was eventually prepared. The overall yield for the synthesis of inhibitor 1 was 21% over eight isolated synthetic steps, and the final salt was obtained with 99.7% HPLC purity.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone (1)

Compound 1 was observed as a mixture of two rotational isomers in the ¹H and ¹³C NMR spectra.

¹H NMR (400 MHz, DMSO-d₆): δ 8.24–8.03 (dd, 1H), 7.79–7.71 (m, 1H), 7.71–7.69 (dd, 0.5H), 7.57–7.57 (d, 0.5H), 7.44–7.40 (m, 1.5H), 7.29–7.19 (dd, 1H), 7.05–7.01 (dd, 1H), 6.64–6.63 (d, 0.5H), 6.54–6.45 (dd, 1H), 6.06 (s, 2H), 4.93–4.31 (m, 2H), 4.31–3.54 (m, 4H), 3.37–3.36 (d, 3H), 2.12–1.77 (d, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 167.3, 167.2, 166.6, 166.6, 158.9, 158.9, 158.4, 158.4, 157.4, 157.2, 155.9. 155.8, 145.4, 145.1, 145.1, 144.0, 143.9, 135.0, 134.7, 132.9, 132.8, 129.4, 129.2, 128.2, 128.2, 128.1, 128.0, 127.0, 126.9, 126.8, 125.9, 125.6, 125.4, 123.6, 123.5, 123.3, 123.1, 122.8, 122.0, 122.0, 121.9, 121.9, 121.2, 120.7, 107.8, 107.8, 70.9, 70.8, 51.1, 51.1, 47.4, 46.5, 43.5, 43.5, 43.5, 43.4, 11.0, 10.9, 10.7, 10.6. IR (KBr pellet): 1623, 1487, 1457, 1423, 1385, 1314, 1269, 1226, 1193, 1144, 1133, 1054, 1031, 962, 821, 768 cm^–1. MS (EI) C₂₃H₂₂FN₃O₄S: found 456.2 ([M + H]⁺). High-resolution MS (FAB-MS using glycerol as a matrix) for C₂₃H₂₂FN₃O₄S: found 456.13943 ([M + H]⁺), calcd 456.13878.

[7-(6-Aminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl][3-fluoro-2-methyl-4-(methylsulfonyl)phenyl]methanone Hydrochloride (1·HCl)

REFERENCES

US20100305093

PROFILE

Chemical Development at Dermira, Inc.

Lives San jose caifornia

 

https://www.linkedin.com/pub/sriram-naganathan/3/50a/5b6

https://www.facebook.com/sriram.naganathan.5

snaganat@exelixis.com, sriramrevathi@yahoo.com

sriram.naganathan@dermira.com

Education

OLD PROFLE……Dr Sriram Naganathan received his Ph.D. from SUNY-Albany where he studied organosulfur chemistry. He is currently an Associate Director at CellGate, Inc. located in Sunnyvale, California. CellGate is involved in the commercialization of novel medicines by utilizing proprietary transporter technology, based on oligomers of arginine, to enhance the therapeutic potential of existing drugs. His responsibilities include process development, scale-up and GMP production of clinical candidates, as well some basic research. He previously held positions at Pfizer Central Research and Roche Bioscience.

Dermira

Thomas G. Wiggans | Founder & Chief Executive Officer……..http://dermira.com/about-us/management-team/

CEO TOM WIGGANS, LEFT AND CMO GENE GAUER, RIGHT

////////////mTOR inhibitor, Exelixis, Inc.,  PI3K,   phosphatidylinositol-3-kinase, XL 388, XL388, IND Filed

2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol

Tramadol (marketed as Ultram, and as generics) is an opioid pain medication used to treat moderate to moderately severepain.^[1] When taken as an immediate-release oral formulation, the onset of pain relief usually occurs within about an hour.^[5]It has two different mechanisms. First, it binds to the μ-opioid receptor. Second, it inhibits the reuptake of serotonin andnorepinephrine.^[6][7]

Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Common side effects include: constipation, itchiness and nausea, among others. A change in dosage may be recommended in those with kidney or liver problems. Its use is not recommended in women who are breastfeeding or those who are at risk of suicide.^[1]

Tramadol is marketed as a racemic mixture of both R– and S–stereoisomers.^[2] This is because the two isomers complement each other’s analgesic activity.^[2] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.^[2] Tramadol is metabolised to O-desmethyltramadol, which is a more potent opioid.^[8] It is of the benzenoid class.

Tramadol was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 inWest Germany, and 20 years later it was launched in countries such as the UK, U.S., and Australia.^[7]

Developed (from 1962) by the German company Grünenthal, and is marketed through much of the world under various trade names, including Acugersic (Malaysia), Mabron (some Eastern European countries as well as parts of the Middle and Far East), Ultram (USA), Zaldiar (France and much of Europe, as well as Russia) and Zydol (UK and Ireland).

CONFUSION ON CIS TRANS

There is some confusion within the literature as to what should be called cis and what should be called trans. For purposes of this disclosure, what is referred to herein as the trans form of Tramadol includes the R,R and S,S isomers as shown by the following two structures:

The cis form of Tramadol, as that phrase is used herein, includes the S,R and the R,S isomers which are shown by the following two structures:

Tramadol is marketed as a racemic mixture of both R and S stereoisomers. It is a μ-opioid receptor agonist, like morphine, but much less active. It inhibits reuptake of the neurotransmitters serotonin and norepinephrine, suggesting that it lifts mood and thereby may dull the brain’s perception of pain.

1R,2R-Tramadol	1S,2S-Tramadol

In the body, tramadol undergoes demethylation to several metabolites by a Cytochrome P450 enzyme (CYP2D6) in the liver, the most important of these products being O-desmethyltramadol. O-desmethyltramadol has a much stronger (200x) affinity for the μ-opioid receptor than tramadol, so in effect tramadol is a prodrug.

1R,2R–O-desmethyltramadol	1S,2S–O-desmethyltramadol

Not everyone’s liver works identically. Around 6% of the Caucasian population has a reduced CYP2D6 activity (hence reducing metabolism), so there is a reduced analgesic effect with Tramadol. These people require a dose increase of 30% to get the same pain relief as the norm. A case has been reported of a patient where, following an overdose, their ultrarapid tramadol metabolism led to excessive norepinephrine levels, with near-fatal consequences.

However, it has recently been discovered at relatively high concentrations in the roots of the African peach or pin cushion tree (Nauclea latifolia), which has a long tradition as a folk remedy. As usual, Nature got there first.

The African pin-cushion tree (Nauclea latifolia)

In the area of “legal highs”, a disturbing development is a drug blend known as “Krypton”. This isn’t the noble gas, but a mixture of O-desmethyltramadol withKratom (Mitragyna speciosa, a medicinal plant that originates in SE Asia, seemingly the local equivalent of khat), which contains an alkaloid mitragynine which is also a μ-receptor agonist. Several fatalities have been linked with its use, notably in Sweden.

SYNTHESIS

 
(1R,2R)-Tramadol     (1S,2S)-Tramadol
 
(1R,2S)-Tramadol     (1S,2R)-Tramadol

The chemical synthesis of tramadol is described in the literature.^[35] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at thecyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

• (1R,2R)-isomer
• (1S,2S)-isomer
• (1R,2S)-isomer
• (1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(–)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(–)-isomer] was described^[36] employing (R)-(–)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects^[37] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals^[38] and in humans.^[39]

Synthesised by chemists at the German company Grünenthal and brought to the market in 1977. It can readily be made by nucleophilic attack of a Grignard or RLi species upon a carbonyl group.

ALSO

Paper

http://www.jmcs.org.mx/PDFS/V49/N4/04-Alvarado.pdf

Tramadol hydrochloride (1). To a solution of 3-bromoanisol 13 (0.823 g, 4.4 mmol) in dry THF (10 mL), 1.75 M n-BuLi (2.5 mL, 4.4 mmol) was added dropwise at -78°C under argon atmosphere. The mixture was stirred at the same temperature during 45 minutes and a solution of 2-dimethylaminomethylcyclohexanone 6a (0.62 g, 4mmol) in dry THF was added dropwise. The resulting mixture was stirred at -78°C for 2 h. and the solvent was removed in vacuo. Water (30 mL) was added and the product was extracted with ethyl ether (3X30 mL). The extracts were dried over sodium sulfate, filtered and evaporated in vacuum. The residue was treated with 5mL of ethyl ether saturated with hydrogen chloride; the ethyl ether was evaporated in vacuo and the resulting solid was purified by crystallization from acetone. Tramadol hydrochloride 1 was obtained as white crystals (0.94 g, 78.6%),

MP 168- 175°C.

IR (KBr): 3410, 3185, 2935, 2826, 2782, 1601, 1249, 702 cm-1;

1H NMR (CDCl3, 300 MHz) δ 1.2-1.9 (10H, m), 2.15 (6H, s), 2.45 (1H, dd, J = 15.1, 4.4 Hz), 3.82 (3H, s), 6.76 (1H, dd, J = 8, 2.4 Hz), 7.04 (1H, d, 7.6 Hz), 7.14 (1H, s), 7.26 (1H, t, 3.9 Hz), 11.4 (1H, bs);

MS (EI): m/z 263 M+ (28), 58 (100).

PATENT

http://www.google.com.ar/patents/WO1999003820A1?cl=en

Tramadol is the compound cis(+/-)-2-[(dimethylamino)-methyl]-l-(3- methoxyphenyl) cyclohexanol which, in the form of the hydrochloride salt is widely used as an analgesic

Tramadol means the racemic mixture of cis-Tramadol as shown by the following chemical structures:

(1 R, 2R) (1S. 2S) cis-Tramadol

Step l Formation of Dimethylaminomethyl Cyclohexanone Hydrochloride

Dimethylaminomethyl Cyclohexanone Hydrochloride

Step 2 Formation of Tramadol Mannich Base

NaOH, Water

Toluene, TBME

Tramadol Mannich Base

Step 3 Formation of Tramadol Base Hydrate

Tramadol Base Hydrate (crude) Step 4 Purification of Tramadol Base Hydrate

Tramadol Base Hydrate (pure)

Step 5 Formation of Tramadol Hydrochloride

Tramadol Hydrochloride

Example 1

To produce the Tramadol base hydrate, a reaction vessel is charged successively with 69 Kg of Magnesium, 400 1 of dry Tetrahydrofuran (THF) and 15 1 of 3- bromoanisole.

With careful heating, the reactor temperature is brought up to ca. 30°C. The Grignard initiates at this point and exotherms to approximately 50°C. A further 5 1 of bromoanisole are added which maintains reflux. 400 1 of THF are then added before the remainder of the bromoanisole. This addition of the remainder of the bromoanisole is carried out slowly so as to sustain a gentle reflux. The reaction is refluxed after complete addition of 3-bromoanisole. The vessel is cooled and Mannich base is added. When addition is complete, the vessel is reheated to reflux for 30 minutes to ensure complete reaction. After cooling to ca. 10°C, 2,300 1 of water are added to quench the reaction. When complete, part of the solvents are distilled under vacuum. Approximately 260 1 of concentrated HC1 is added at a low temperature until a pH of 0 – 1 is reached. This aqueous phase is extracted with toluene. The toluene phases are discarded and ethyl acetate is added to the aqueous phase. 30% Ammonia solution is then charged to reach pH 9 – 10 and the phases are separated. The aqueous phases are extracted again with ethyl acetate and finally all ethyl acetate layers are combined and washed twice with water. Ethyl acetate is then distilled from the reaction solution at atmospheric pressure. Process water is added and the solution cooled to 20°C and seeded. After crystallisation, the vessel is cooled to -5 to 0°C and stirred for one hour.

The product is centrifuged at this temperature and washed with cold ethyl acetate 5 x 50 1. Approximately 310 – 360 Kg of moist cis-Tramadol base hydrate are obtained.

Purification

A reactor vessel is charged successively with cis-Tramadol base hydrate (crude) 200 Kg and ethyl acetate 300 1 and the contents of the vessel heated to 50°C until all solids are in solution. The vessel is then cooled to -5 to 0°C and the product crystallises. Stirring is continued for two hours and the product is then centrifuged and washed with cold ethyl acetate, 2 x 25 1. Approximately 165 – 175 Kg (moist) of cis(+/-) Tramadol base hydrate are obtained from this procedure.

The overall process produced high yields of cis-Tramadol with a trans isomer content of less than 0.03%. Analytical data of the base hydrate of cis-Tramadol

Melting point: 79 – 80°C (in comparison cis-Tramadol base anhydrous is an oil). Water content (KF) : 6.52% (= monohydrate) IR-spectrum of the base hydrate of cis-Tramadol (see Fig. 1).

IR-spectrum (=cis-Tramadol base anhydrous, see Fig. 2).

The invention provides a unique process in which a base hydrate of cis-Tramadol is selectively crystallised without impurities. The base hydrate is processed to readily form cis-Tramadol hydrochloride. The process is substantially simpler than known processes and does not require the use of potentially toxic solvents. Thus the process is environmentally friendly.

The base hydrate of cis-Tramadol prepared may also be used in various formulations.

The base hydrate of cis-Tramadol may be formulated in the form of a solid with a slow release profile. For example, slow release pellets may be prepared by coating a suitable core material with a coating, for example, of ethylcellulose/schellack solution (4:1) and suitable pharmaceutical excipients. The pellets have typical average diameter of 0.6 to 1.6 mm. The pellets may be readily converted into gelatine capsules or pressed into tablet form using well-known techniques.

Alternatively the base hydrate of cis-Tramadol may be formulated into effervescent tablets by forming granules of the base hydrate with acidity/taste modifiers and a suitable effervescent base such as sodium hydrogen carbonate /anhydrous sodium carbonate (12:1). The ingredients are typically blended in a mixer /granulator and heated until granulation occurs. The resulting granules may be pressed into tablet form, on cooling. Of particular interest is the use of the base hydrate of cis-Tramadol in a form for parenteral use/injectables. The base hydrate is typically dissolved in water together with suitable excipients (as necessary). The solution is filtered through a membrane to remove solid fibres or particles. The filtered solution may then be filled into ampoules, typically containing 10.0 mg of the active compound. Usually the formulation is prepared for intramuscular injection.

PATENT

http://www.google.com/patents/EP1346978A1?cl=en

• Various processes for the synthesis of tramadol hydrochloride have been described in the prior art. For example, US 3 652 589 and British patent specification no. 992 399 describe the preparation of tramadol hydrochloride. In this method, Grignard reaction of 2-dimethylaminomethyl cyclohexanone (Mannich base) with metabromo-anisole gives an oily mixture of tramadol and the corresponding cis isomer, along with Grignard impurities. This oily reaction mixture is subjected to high vacuum distillation at high temperature to give both the geometric isomers of the product base as an oil. This oil, on acidification with hydrogen chloride gas, furnishes insufficiently pure tramadol hydrochloride as a solid. This must then be purified, by using a halogenated solvent and 1,4-dioxane, to give sufficiently pure tramadol hydrochloride. The main drawback of this process is the use of large quantities of 1,4-dioxane and the need for multiple crystallizations to get sufficiently pure trans isomer hydrochloride (Scheme – 1).
• [0004]

  The use of dioxane for the separation of tramadol hydrochloride from the corresponding cis isomer has many disadvantages, such as safety hazards by potentially forming explosive peroxides, and it is also a category 1 carcinogen (Kirk and Othmer, 3^rd edition, 17, 48). Toxicological studies of dioxane show side effects such as CNS depression, and necrosis of the liver and kidneys. Furthermore, the content of dioxane in the final tramadol hydrochloride has been strictly limited; for example, the German Drug Codex (Deutscher Arzneimittel Codex, DAC (1991)) restricts the level of dioxane in tramadol hydrochloride to 0.5 parts per million (ppm).
• In another process, disclosed in US patent specification no. 5 414 129, the purification and separation of tramadol hydrochloride is undertaken from a reaction mixture containing the trans and cis isomers, and Grignard reaction side products, in which the reaction mixture is diluted in isopropyl alcohol and acidified with gaseous hydrogen chloride to yield (trans) tramadol hydrochloride (97.8%) and its cis isomer (2.2%), which is itself crystallized twice with isopropyl alcohol to give pure (trans) tramadol hydrochloride (Scheme – 2). This process relies on the use of multiple solvents to separate the isomers (ie butylacetate, 1-butanol, 1-pentanol, primary amyl alcohol mixture, 1-hexanol, cyclohexanol, 1-octanol, 2-ethylhexanol and anisole). The main drawback of this process is therefore in using high boiling solvents; furthermore, the yields of tramadol hydrochloride are still relatively low and the yield of the corresponding cis hydrochloride is relatively high in most cases.
• PCT patent specification no. WO 99/03820 describes a method of preparation of tramadol (base) monohydrate, which involves the reaction of Mannich base with metabromo-anisole (Grignard reaction) to furnish a mixture of tramadol base with its corresponding cis isomer and Grignard impurities. This, on treatment with an equimolar quantity of water and cooling to 0 to -5°C, gives a mixture of tramadol (base) monohydrate with the corresponding cis isomer (crude). It is further purified with ethyl acetate to furnish pure (trans) tramadol (base) monohydrate, which is again treated with hydrochloric acid in the presence of a suitable solvent to give its hydrochloride salt (Scheme – 2). The drawback of this method is that, to get pure (trans) tramadol hydrochloride, first is prepared pure (trans) tramadol (base) monohydrate, involving a two-step process, and this is then converted to its hydrochloride salt. The overall yield is low because of the multiple steps and tedious process involved.
• More recently, a process for the separation of tramadol hydrochloride from a mixture with its cis isomer, using an electrophilic reagent, has been described in US patent specification no. 5 874 620. The mixture of tramadol hydrochloride with the corresponding cis isomer is reacted with an electrophilic reagent, such as acetic anhydride, thionyl chloride or sodium azide, using an appropriate solvent (dimethylformamide or chlorobenzene) to furnish a mixture of tramadol hydrochloride (93.3 to 98.6%) with the corresponding cis isomer (1.4 to 6.66%), (Scheme – 3). The product thus obtained is further purified in isopropyl alcohol to give pure (trans) tramadol hydrochloride. However, the drawback of this process is that a mixture of tramadol base with its cis isomer is first converted into the hydrochloride salts, and this is further reacted with toxic, hazardous and expensive electrophilic reagents to get semi-pure (trans) tramadol hydrochloride. The content of the cis isomer is sufficiently high to require further purification, and this therefore results in a lower overall yield.
• Therefore, all the known methods require potentially toxic solvents and/or reagents, and multiple steps to produce the desired quality and quantity of tramadol hydrochloride. By contrast, the present invention requires a single step process (or only two steps when tramadol hydrochloride is made via the tramadol (base) monohydrate route) using a natural solvent (ie water) in the absence of carcinogenic solvents (such as the category 1 carcinogen, 1,4-dioxane) to produce pure tramadol hydrochloride, so it is ‘ecofriendly’ and easily commercialized to plant scale without any difficulties.

PATENT

http://www.google.co.in/patents/US6399829

EXAMPLE 8 Hydrochloride Formed without Improvement of the Trans:Cis Ratio

Whether a recrystallization step improves the trans:cis ratio of Tramadol depends upon the solvent composition from which the recrystallization is performed. When the hydrochloride form of Tramadol is produced and then crystallized in the presence of a solvent with a high toluene concentration, the ratio of trans:cis remains essentially unchanged. This is in contrast to the recrystallization from a solvent which has a high acetonitrile concentration as was the case in Examples 5-7.

A 21 mL solution of 1.8 g of HCl gas (bubbled at 5° C.) in acetonitrile (yielding a 2.0 M solution), was added to 10.2 g of Grignard product C (90/10 of trans/cis) in 30 mL of toluene and stirred mechanically for 3 hours. The mixture was filtered and washed with toluene. Drying in vacuo yielded 11.2 g (96% recovery). The resulting hydrochloride had a trans/cis ratio of 92:8, essentially the same trans:cis ratio as did the 10.2 g of Grignard product C.

Recrystallization from 90 mL of acetonitrile yielded 8.83 g, which was 96.6/3.4 of trans/cis by HPLC. Of this, 8.6 g was recrystallized from 75 mL of acetonitrile to give 7.44 g, trans/cis ratio of 99.6/0.4.

This example shows that the formation of the hydrochloride in the presence of a relatively large amount of toluene (here about 60%) and crystallization from toluene-acetonitrile does not improve the trans:cis ratio. As the percentage of toluene present in the mixture of toluene and acetonitrile in a crystallization step is decreased, the trans:cis ratio of the recovered product will increase. Steps in which the hydrochloride is recrystallized from acetonitrile do yield an improved trans:cis ratio.

PATENT

https://www.google.com/patents/EP0831082A1

The synthesis of Tramadol is described in U.S. Patent No. 3,652,589 and in British Patent No. 992,399. The synthesis of Tramadol consists of a Grignard reaction between 2-dimethylaminomethylcyclohexanone and 3-methoxyphenyl magnesium bromide (Equation 1). From the reaction scheme, it is clear that both isomers (RR,SS) (Structure 1) and (RS, SR) (Structure 2) are obtained in variable ratios, depending on the reaction conditions.

The original patents assigned to Gruenenthal GmbH describe the isolation of the (RR,SS) isomer, as follows:

The complex mixture of products containing both isomers of Tramadol obtained from the Grignard reaction is distilled under reduced pressure. The isomers are distilled together at 138-140°C (0.6 mm Hg). The distillate is dissolved in ether and is reacted with gaseous HCl. The resulting mixture of both isomers of Tramadol is precipitated as hydrochlorides and filtered. The resulting mixture contains about 20% of the (RS,SR) isomer. The isomer mixture is then refluxed twice with five volumes of moist dioxane, and filtered. The cake obtained consists of pure (RR,SS) isomer. The residual solution consists of “a mixture of about 20-30% of the cis (i.e. RS,SR), which cannot be further separated by boiling dioxane” [U.S. Patent 3,652,589, Example 2].

Dioxane, used in large quantities in this process, possesses many undesirable properties. It has recently been listed as a Category I carcinogen by OSHA [Kirk & Othmer, 3rd Ed., Vol. 9, p. 386], and it is known to cause CNS depression and liver necrosis [ibid., Vol. 13, p. 267]; in addition, it tends to form hazardous peroxides [ibid., Vol 17, p. 48]. As a result, the concentration of dioxane in the final product has been strictly limited to several ppb’s, and the DAC (1991) restricted the level of dioxane in Tramadol to 0.5 ppm.

A different separation method, described in Israeli Specification No. 103096, takes advantage of the fact that the precipitation of the (RR,SS) isomer of Tramadol from its solution in medium chained alcohols (C₄-C₈) occurs faster than the precipitation of the (RS,SR) isomer, which tends to separate later. The main disadvantage of this method is, that the time interval between the end of separation of the (RR,SS) isomer and the beginning of the (RS,SR) isomer separation is variable, and seems to depend sharply on the composition of the crude mixture. Therefore, variations in the yield and the quality of the product often occur. Furthermore, about 40% of the (RR,SS) isomer does not separate and remains in solution, along with the (RS,SR) isomer. This remaining mixture cannot be further purified by this method.

Another method, described in Israeli Specification No. 116281, relies on the fact that the (RS,SR) isomer of Tramadol undergoes dehydration much faster then the (RR,SS) isomer, when treated with 4-toluenesulfonic acid, or sulfuric acid; furthermore, when the reaction is carried out in an aqueous medium, a certain amount (up to 50%) of the (RS,SR) isomer is converted to the (RR,SS) isomer. This may, of course increase the efficiency of the process.

The unreacted (RR, SS) isomer is then separated from the dehydrated products and from other impurities by simple crystallization.

While further examining the results of the latter process, it was surprisingly found that the hydroxyl group of the (RS,SR) isomer of Tramadol reacts faster than the same group of the (RR,SS) with various reagents. A plausible explanation for this observation can be supplied by comparing the structures of both isomers, and their ability to form hydrogen bonds.

Looking closely at Fig. 1 [(RR,SS) Tramadol hydrochloride] and at Fig. 2 [(RS,SR) Tramadol hydrochloride], one can provide a plausible explanation for the difference in the OH group’s activity, as follows: The proton attached to the nitrogen atom of the protonated (RR,SS) isomer of Tramadol is capable of forming a stable hydrogen bonding with the oxygen atom of the hydroxyl group (see Fig. 1). Thus, any reaction involving protonation of the hydroxyl group (such as dehydration), or any reaction in which the hydroxyl group reacts as a nucleophile (such as a nucleophilic substitution or esterification process) is less favored to occur.

In the (RS,SR) isomer, on the other hand, there is no possible way of forming a stable intramolecular hydrogen bond, and therefore, any of the above-mentioned types of reactions can easily occur, considering the fact that this particular hydroxyl group is tertiary and benzyllic.

The general purification procedure of the present invention consists of reacting a mixture of both geometrical isomers of Tramadol hydrochloride with a potential electrophile under such conditions that the (RS,SR) isomer reacts almost exclusively, while the (RR,SS) isomer remains practically intact. The resulting mixture is evaporated and the resulting solid substance is then recrystallized from isopropanol or any other suitable solvent.

Example 1

11.1 g of a mixture consisting of 77% (RR,SS) Tramadol hydrochloride and 23% of the corresponding (RS,SR) isomer were dissolved in 30 ml DMF. 1.3 g acetic anhydride were added and the reaction mixture was stirred at room temperature for 12 hours. The solvent was partly evaporated under reduced pressure and 15 ml toluene were added. The suspension obtained was filtered and washed with 5 ml toluene. 5.8 g of crystals were obtained, in which the (RR,SS):(RS,SR) isomer ratio was 70:1. The product obtained was crystallized from 12 ml isopropanol and 4 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 2

19.5 g of a mixture consisting of 60.5% (RR,SS) Tramadol hydrochloride and 40.5% of the corresponding (RS,SR) isomer were suspended in 55 ml chlorobenzene. A solution of 4 ml thionyl chloride in 15 ml chlorobenzene was added dropwise for two hours. The suspension was partly evaporated, the residue was filtered and rinsed with toluene, and 8.1 g of crystals were obtained, in which the (RR,SS):(RS, SR) isomer ratio was 14:1. The product obtained was recrystallized from isopropanol, and 6.7 g of pure (RR,SS) Tramadol hydrochloride were obtained.

Example 3

33.4 g of a mixture consisting of 45% (RR,SS) Tramadol hydrochloride and 55% of the corresponding (RS,SR) isomer was immersed in 50 ml trifluoroacetic acid, 5.2 g of sodium azide was added, and the reaction mixture was stirred for 24 hours. The reaction mixture was then evaporated under reduced pressure, 50 ml water was added, and the solution was brought to pH 12 with solid potassium carbonate. The suspension was extracted with 50 ml toluene, the solvent was evaporated and 25 ml hydrogen chloride solution in isopropanol were added. The solution was cooled and filtered. 9.5 g of crude (RR,SS) Tramadol were obtained, and the crude product was purified by recrystallization from isopropanol.

The hitherto unknown (RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride was isolated from the reaction mixture, recrystallized from isopropanol and characterized as follows:

(RS,SR)-2-(dimethylaminomethyl)-1-azido-1-(3-methoxyphenyl)-cyclohexane hydrochloride

• ms : 288 m⁺
• IR : 2050 cm^-1 (N₃)

• ¹H-NMR (DMSO): 10.42 ppm: (acidic proton); 1H; 7.40-6.90 ppm: (aromatic protons) 4H; 3.79 ppm; (OCH₃ ), 3H; 2.78, 2.42 ppm: NCH₂ ; 2H; 2.58, 2.37 ppm: [N(CH₃ )₂], 6H; 2.30-1.40 ppm: cyclohexane ring protons, 9H.

• ¹³C-NMR (DMSO): 159.74 ppm: C₁; 144.12 ppm: C₅; 130.08 ppm: C₃; 117.36 ppm: C₄; 112.97, 111.35 ppm: C₂, C₆; 69.61 ppm: C₈; 59.29 ppm: C₁₄; 55.21 ppm: C₇; 44.6 ppm: C₁₅; 40.12 ppm: C₁₃; 35.94, 27.02, 23.56, 21.63 ppm: cyclohexane ring carbon nucleii.

AZIDE COMPD

Bibliography

Synthesis of Tramadol

http://www.nioch.nsc.ru/icnpas98/pdf/posters1/156.pdf

• http://www.opioids.com/tramadol/synthesis/index.html
• Patents to Grünenthal G.m.b.H.:- K. Flick and E. Frankus, U.S. Patent 3,652,589, March 28, 1972; Chem. Abs., 1972, 76, 153321; K. Flick and E. Frankus, U.S. Patent. 3,830,934, August 20, 1974; Chem. Abs., (1974), 82, 21817 (synth)
• C. Alvarado, Á. Guzmán, E. Díaz and R. Patiño, J. Mex. Chem. Soc., 49, (2005) 324-327 (synth)
• G. Venkanna, G. Madhusudhan, K. Mukkanti, A. Sankar, V. M. Kumar and S. A. Ali, J. Chem. Pharm. Res., 4 (2012) 4506-4513 (synth)
• A. Boumendjel, G. S.Taïwe, E. N. Bum, T. Chabrol, C. Beney, V. Sinniger, R. Haudecoeur, L. Marcourt, S. Challal, E. F. Queiroz, F. Souard, M. Le Borgne, T. Lomberget, A. Depaulis, C. Lavaud, R. Robins, J.-L. Wolfender, B. Bonaz and M. De Waard, Angew. Chem. Int. Ed., 52 (2013) 11780 –11784 (Tramadol in nature)

Action

• R. B. Raffa, E. Friderichs, W. Reimann, R. P. Shank, E. E. Codd and J. L. Vaught, J. Pharmacol. Exp. Ther., 260 (1992) 275-285 (means of action)
• P. Dayer, L. Collart and J. Desmeules, Drugs (Suppl. 1), (1994) 3-7.
• T. A. Bamigbade, C. Davidson, R. M. Langford and J. A. Stamford, Br. J. Anaesthes., 79 (1997) 352-356. (action of enantiomers)
• P. W. Keeley, G. Foster and L. Whitelaw, BMJ, 321 (2000) 1608 (auditory hallucinations with tramadol)
• U. M. Stamer, F. Musshoff, M. Kobilay, B. Madea, A. Hoeft and F. Stuber, Clin. Pharmacol. Ther., 82 (2007) 41-47 (different CYP2D6 Genotypes and metabolism)
• W. Leppert, Pharmacology, 87 (2011)274–285 (metabolism of tramadol to O-desmethyltramadol by CYP2D6)
• A. Elkalioubie, D. Allorge, L. Robriquet, J.-F. Wiart, A. Garat, F. Broly and F. Fourrier, Eur. J. Clin. Pharmacol., 67 (2011) 855–858 (ultrarapid metabolism of tramadol)
• C. F. Samer, K. I. Lorenzini, V. Rollason, Y. Daali and J. A. Desmeules, Molecular Diagnosis & Therapy, 17 (2013), 165–84 (variations in tramadol response)

Tramadol abuse

• M. K. Wedge, Can. Pharm. J., 142 (2009) 71-73. (tramadol and antidepressants)
• ACMD advice on O-desmethyltramadol
• Y. Progler, J. Res. Med. Sci., 15 (2010) 185-188 (Tramadol abuse and smuggling into Gaza)
• M. M. Fawzi, Egypt. J. Forensic Sci., 1 (2011) 99–102 (Tramadol abuse in Egypt)
• I. Giraudon, K. Lowitz, P. I. Dargan, D. M. Wood and R. C. Dart, Br. J. Clin. Pharmacol., 76, (2013) 823–824 (prescription opioid abuse in the UK)
• C. Stannard, BMJ, 347 (2013) f5108 (tramadol problem)
• N. Hawkes, BMJ, 347 (2013) f5336 (deaths from tramadol and legal highs)
• A. Winstock, J. Bell and R. Borschmann, BMJ 347 (2013) f5599 (monitoring Tramadol abuse)
• S. H. Park, R. C. Wackernah and G. L. Stimmel, J. Pharm. Pract., 27 (2014) 71-78.
• Unemployment in Gaza and Tramadol addiction.

Tramadol in “highs”

• T. Arndt, U. Claussen, B. Güssregen, S. Schröfel, B. Stürzer, A. Werle and G. Wolf, For. Sci. Int., 208 (2011) 47-52. (Kratom alkaloids and O-desmethyltramadol in urine of a “Krypton” herbal mixture consumer)
• R. Kronstrand, M. Roman, G. Thelander and A. Eriksson, J. Anal. Toxicol., 35 (2011) 242–247. (fatalities from mitragynine and O-desmethyltramadol combinations in Krypton herbal mixture)
• C. D. Rosenbaum, S. P. Carreiro and K. M. Babu, J. Med. Toxicol., 8 (2012) 15-32 (review of herbal marijuana alternatives, including Kratom)

Tramadol in cycling

• Michael Barry, “Shadows on the Road: Life at the Heart of the Peloton, from US Postal to Team Sky”, Faber 2014.
• Chris Froome, “The Climb: The Autobiography”, Viking, 2014.
• http://cyclingtips.com.au/2014/05/wada-proposes-tramadol-remains-a-monitored-rather-than-a-banned-substance-in-2015/
• Tramadol blamed for crashes
• Tramadol use for pain in cycling

Systematic (IUPAC) name
2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Clinical data
Trade names	Ryzolt, Tramal, Ultram
AHFS/Drugs.com	monograph
MedlinePlus	a695011
Licence data	US FDA:link
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: Class C US: Schedule IV ℞ (Prescription only)
Dependence liability	Present[1]
Routes of administration	Oral, IV, IM, rectal
Pharmacokinetic data
Bioavailability	70–75% (oral), 77% (rectal), 100% (IM)[2]
Protein binding	20%[3]
Metabolism	Liver-mediated demethylation andglucuronidation via CYP2D6 &CYP3A4[2][3]
Biological half-life	6.3 ± 1.4 hr[3]
Excretion	Urine (95%)[4]
Identifiers
CAS Registry Number	27203-92-5
ATC code	N02AX02
PubChem	CID: 33741
DrugBank	DB00193
ChemSpider	31105
UNII	39J1LGJ30J
KEGG	D08623
ChEBI	CHEBI:9648
ChEMBL	CHEMBL1066
Chemical data
Formula	C16H25NO2
Molecular mass	263.4 g/mol

DMF

Tramadol hydrochloride..CEP

SYNOPSIS FOR M. PHARM DISSERTATION

////////TRAMADOL,

(S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro- 2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gramnegative infections

(S)-3-aminomethylbenzoxaborole; ABX; AN-3365; GSK ‘052; GSK-052; GSK-2251052, GSK2251052, Epetraborole

[(S)-3-(aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy- 1,3-dihydro-2,1-benzoxaborole hydrochloride],

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride

1-Propanol, 3-(((3S)-3-(aminomethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborol-7-yl)oxy)-

AN3365,

MW 237.0614,

cas 1093643-37-8
UNII: 6MC93Z2DF9

Anacor Pharmaceuticals, Inc., INNOVATOR

Glaxosmithkline Llc DEVELOPER

Biomedical Advanced Research and Development Authority (BARDA)

GSK 2251052 • $38.5M over the 1st two years; up to $94M……..http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Bad_Bugs_No_Drugs/Press_Releases/FIS%20Slides.pdf

Originally came from Anacor about ten years ago, then was picked up by GlaxoSmithKline, and it’s an oxaborole heterocycle that inhibits leucyl tRNA synthetase

GlaxoSmithKline recently announced a contract with the Biomedical Advanced Research and Development
Authority (BARDA), a US government preparedness organization ,  The award guarantees GSK $38.5 million over 2 years towards development of GSK2251052, a molecule co-developed with Anacor Pharma a few years back, as a counter-bioterrorism agent. The full funding amount may later increase to $94 million, pending BARDA’s future option.

The goal here is to develop “GSK ‘052”, as it’s nicknamed among med-chemists, into a new antibiotic against especially vicious and virulent Gram negative bacteria, such as the classic foes plague (Yersinia pestis) or anthrax (Bacillus anthracis).

Look closely at GSK’052 (shown above): that’s a boron heterocycle there! Anacor, a company specializing in boron based lead compounds, first partnered with GSK in 2007 to develop novel benzoxaborole scaffolds. This isn’t the first company to try the boron approach to target proteins; Myogenics (which, after several acquisitions, became Millennium Pharma) first synthesizedbortezomib, a boronic acid peptide, in 1995.

Stephen Benkovic (a former Anacor scientific board member) and coworkers at Penn State first discovered Anacor’s early boron lead molecules in 2001, with a screening assay. The molecules bust bacteria by inhibiting  leucyl-tRNA synthetase, an enzyme that helps bacterial cells to correctly tag tRNA with the amino acid leucine. Compounds with cyclic boronic acids “stick” to one end of the tRNA, rendering the tRNA unable to cycle through the enzyme’s editing domain. As a result, mislabeled tRNAs pile up, eventually killing the bacterial cell.

Inhibition of synthetase function turns out to be a useful mechanism to conquer all sorts of diseases.  Similar benzoxaborozoles to GSK ‘052 show activity against sleeping sickness (see Trypanosoma post by fellow Haystack contributor Aaron Rowe), malaria, and various fungi.

Boron-containing molecules such as benzoxaboroles that are useful as antimicrobials have been described previously, see e.g. “Benzoxaboroles – Old compounds with new applications” Adamczyk-Wozniak, A. et al., Journal of Organometallic Chemistry Volume 694, Issue 22, 15 October 2009, Pages 3533-3541 , and U.S. Pat. Pubs. US20060234981 and US20070155699. Generally speaking, a benzoxaborole has the following structure and substituent numbering system:

Certain benzoxaboroles which are monosubstituted at the 3-, 6-, or 7-position, or disubstituted at the 3-/6- or 3-/7- positions are surprisingly effective antibacterials, and they have been found to bind to the editing domain of LeuRS in association with tRNA^Leu Such compounds have been described in US7, 816,344. Using combinations of certain substituted benzoxaboroles with norvaline and/or other amino acid analogs and their salts to: (a) reduce the rate of resistance that develops; and/or (b) decrease the frequency of resistance that develops; and/or (c) suppress the emergence of resistance, in bacteria exposed to compounds

Epetraborole R-mandelate
1234563-15-5

Epetraborole hydrochloride
1234563-16-6

Anacor Pharmaceuticals is out to change that. The Palo Alto, Calif.-based biotechnology company is developing a family of boron-containing small-molecule drugs. And with the assistance of Naeja Pharmaceutical, a Canadian contract research organization, Anacor has licensed one of those molecules to GlaxoSmithKline and taken another one into Phase III clinical trials.

Anacor was founded in 2002 to develop technology created by Lucy Shapiro, a Stanford University bacterial geneticist, and Stephen J. Benkovic, a Pennsylvania State University organic chemist. Through a long-standing scientific collaboration, the two researchers had discovered boron-containing compounds that inhibited specific bacterial targets.

Lucy Shapiro is a Professor in the Department of Developmental Biology at Stanford University School of Medicine where she holds the Virginia and D. K. Ludwig Chair in Cancer Research and is the Director of the Beckman Center for Molecular and Genetic Medicine. She is a member of the Scientific Advisory Board of Ludwig Institute for Cancer Research and is a member of the Board of Directors of Pacific Biosciences, Inc. She founded the anti-infectives discovery company, Anacor Pharmaceuticals, and is a member of the Anacor Board of Directors.  Professor Shapiro has been the recipient of multiple honors, including: election to the American Academy of Arts and Sciences, the US National Academy of Sciences, the US Institute of Medicine, the American Academy of Microbiology, and the American Philosophical Society. She was awarded the FASEB Excellence in Science Award, the 2005 Selman Waksman Award from the National Academy of Sciences, the Canadian International 2009 Gairdner Award, the 2009 John Scott Award, the 2010 Abbott Lifetime Achievement Award, the 2012 Horwitz Prize and President Obama awarded her the National Medal of Science in 2012. Her studies of the control of the bacterial cell cycle and the establishment of cell fate has yielded valuable paradigms for understanding the bacterial cell as an integrated system in which the transcriptional circuitry is interwoven with the three-dimensional deployment of key regulatory and morphological proteins, adding a spatial dimension to the systems biology of regulatory networks.

Stephen J. Benkovic

Office:
414 Wartik Laboratory
University Park, PA 16802
Email: sjb1@psu.edu
(814) 865-2882

http://chem.psu.edu/directory/sjb1

Naeja was a three-year-old contract research firm run by Ronald Micetich and his son Christopher Micetich. Based in Edmonton, Alberta, the firm is staffed by chemists and biologists from a variety of nations who have found Canada welcoming to highly educated immigrants.

GSK. Last July, the British firm paid Anacor $15 million and exercised its option to take over development of AN3365. David J. Payne, vice president of GSK’s antibacterial drug discovery unit, lauded the compound, now renamed GSK2251052, as having “the potential to be the first new-class antibacterial to treat serious hospital gram-negative infections in 30 years.” GSK chemists have since developed a stereospecific synthesis for commercial-scale production

david.j.payne@gsk.com

David J. Payne, vice president of GSK’s antibacterial drug discovery unit

David J Payne Dr Payne holds a BSc in Biochemistry from Brunel University, UK, and a PhD and DSc from The Medical School, University of Edinburgh, UK. Dr Payne has 20 years of experience in antibacterial drug discovery and is currently Vice President and Head of the Antibacterial Discovery Performance Unit (DPU) within the Infectious Diseases Centre of Excellence in Drug Discovery (ID CEDD) where he is responsible for GSK’s antibacterial research effort from discovery to clinical proof of concept (up to Phase II clinical trials). At GSK, Dr Payne has played a leading role in redesigning the strategy for antibacterial research and has helped create long-term alliances with innovative biotechnology companies which has expanded GSK’s discovery pipeline. Furthermore, he has created industry-leading partnerships with the Wellcome Trust and the Defense Threat Reduction Agency (US Department of Defense) to accelerate GSK’s antibacterial programmes. To date, Dr Payne has been involved with the progression of a broad diversity of novel mechanism antibacterial agents into development. Dr Payne has authored more than 190 papers and conference presentations.

PATENT

http://www.google.com/patents/US20090227541

General procedure for Chiral Synthesis of 3-aminomethylbenzoxaboroles

4-(3-Aminomethyl-1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyramide acetate salt (A5)

4-[2-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid ethyl ester

• A mixture of 4-(2-bromo-3-formyl-phenoxy)-butyric acid ethyl ester (5.50 g, 17.5 mmol), bis(neopentyl glucolato)diboron (6.80 g, 30.1 mmol), PdCl₂(dppf).CH₂Cl₂ (1.30 g, 1.79 mmol), and KOAc (5.30 g, 54.1 mmol) in anhydrous THF (600 mL) was heated with stirring at 80° C. (bath temp) O/N under an atmosphere of N2. The mixture was then filtered through Celite and concentrated in vacuo to approximately one quarter of the original volume. The resulting precipitate was isolated by filtration. The precipitate was washed with THF and EtOAc and the combined filtrate was concentrated in vacuo to give an oily residue which was used directly in the next reaction without further purification.
• ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.95 (s, 1H), 7.47-7.39 (m, 2H), 7.09-7.07 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 4.09-4.01 (m, 2H), 3.83 (s, 3H), 3.66 (s, 3H), 2.53 (t, J=8.0 Hz, 2H), 2.19-2.07 (m, 2H), 1.32-1.22 (m, 3H), 0.98 (s, 6H).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester

• MeNO₂ (1.3 mL, 25 mmol) was added dropwise to a stirred solution of crude 4-[2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid methyl ester (9.4 g), NaOH (1.0 g, 25 mmol) and H₂O (35 mL) in MeCN (90 mL) at rt. The mixture was stirred at rt O/N and then acidified (pH 2) using 4 M HCl. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO₄), and concentrated in vacuo. The residue was purified by flash chromatography (10% to 30% EtOAc in hexane) to give the title compound as a yellow oil: yield 2.52 g (45% over 2 steps).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.04 (s, 1H), 7.46-7.42 (m, 1H), 7.07-7.05 (m, 1H), 6.88-6.86 (m, 1H), 5.87 (d, J=8.2 Hz, 1H), 5.69 (dd, J=9.2, 2.5 Hz, 1H), 5.29 (dd, J=13.3, 2.7 Hz, 1H), 4.14-3.94 (m, 5H), 2.55-2.44 (m, 2H), 2.02-1.88 (m, 2H), 1.16 (t, J=7.2 Hz, 3H); MS (ESI) m/z=322 (M−1, negative).

4-(1-Hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid

• A mixture of 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester (2.51 g, 7.78 mmol), 10% NaOH (17 mL), and 1:1 MeOH/H₂O (70 mL) was stirred at rt for 5 h. The MeOH was removed in vacuo and the remaining aqueous layer was acidified to pH 1 using 2 M HCl. The aqueous layer was then extracted with EtOAc. The organic fractions were washed with brine, dried (MgSO₄), and concentrated in vacuo to give the title compound as a pale yellow foam: yield 1.85 g (81%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.08 (bs, 1H), 9.01 (bs, 1H), 7.46-7.41 (m, 1H), 7.06-7.04 (m, 1H) 6.89-6.87 (m, 1H), 5.70 (dd, J=7.0, 2.3 Hz, 1H), 5.30 (dd, J=13.3, 2.3 Hz, 1H), 4.55 (dd, J=13.6, 4.2 Hz, 1H), 4.03 (t, J=6.6 Hz, 2H), 2.40 (t, J=7.5 Hz, 2H), 1.95-1.89 (m, 2H); MS (ESI) m/z=296 (M+1, positive).

3-Aminomethyl-6-(2-hydroxy-propoxy)-3H-Benzo[c][1,2]oxaborol-1-ol acetate salt (A31)

4-(2-Benzyloxy propoxy-2-bromobenzaldehyde

• A mixture of 2-bromo-4-fluoro-benzaldehyde (30.0 g, 148 mmol), Na2CO3 (78.31 g, 738.8 mmol) and 2-benzyloxy propanol (24.56 g, 147.8 mmol) in anhydrous DMSO (300 mL) was heated with stirring at 130° C. (bath temp) for 72 h under N₂. The reaction mixture was cooled to rt and diluted with H₂O and extracted with EtOAc. The organic layer was washed with H₂O then brine, dried (MgSO₄), and concentrated in vacuo. The residue was purified by flash chromatography (hexane to 30% EtOAc in hexane) to give the title compound: yield 3.84 g (7%).
• ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.22 (s, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.42-7.20 (m, 5H), 7.12 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.8, 2.2 Hz, 1H), 4.52 (s, 2H), 4.16 (t, J=6.2 Hz, 2H), 3.65 (t, J=6.1 Hz, 2H), 2.10 (q, J=6.2 Hz, 2H).

4-(2-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde

• General procedure 5: 4-(2-benzyloxy propoxy-2-bromobenzaldehyde (4.84 g, 13.9 mmol), B₂pin₂ (5.27 g, 20.8 mmol), KOAc (4.08 g, 41.6 mmol), PdCl₂(dppf).CH₂Cl₂ (811 mg, 8 mol %), and 1,4-dioxane (50 mL). Purification: Biotage (gradient from 2% EtOAc/hexane to 20% EtOAc/hexane): yield 4.0 g (70%).
• ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.36 (s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.43-7.14 (m, 6H), 7.01 (dd, J=8.6, 2.7 Hz, 1H), 4.53 (s, 2H), 4.18 (t, J=6.2 Hz, 2H), 3.66 (t, J=6.1 Hz, 2H), 2.11 (q, J=6.1 Hz, 2H), 1.40 (s, 12H).

6-(2-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol

• General procedure 8: 4-(2-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.0 g, 7.6 mmol), MeNO₂ (924 mg, 15.1 mmol), NaOH (605 mg, 15.1 mmol), and H₂O (10 mL). Purification: flash chromatography (10% EtOAc/hexane to 40% EtOAc): yield 820 mg (30%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.46 (bs, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.41-7.18 (m, 6H), 7.09 (dd, J=8.6, 2.3 Hz, 1H), 5.71 (dd, J=9.2, 2.5 Hz, 1H), 5.31 (dd, J=13.3, 2.7 Hz, 1H), 4.58-4.40 (m, 3H), 4.08 (t, J=6.2 Hz, 2H), 3.60 (t, J=6.2 Hz, 2H), 2.08-1.94 (m, 2H).

3-Aminomethyl-6-(2-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol acetate salt (A31)

• General procedure 13: 6-(2-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (820 mg, 2.29 mmol), 20% Pd(OH)₂ (850 mg, 1 equiv w/w), and AcOH (40 mL). Purification: preparative HPLC: yield 120 mg (22%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.32 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.98 (bs, 1H), 4.04 (t, J=6.2 Hz, 2H), 3.56 (t, J=6.2 Hz, 2H), 3.03-2.85 (m, 1H), 2.61 (dd, J=12.9, 7.0 Hz, 1H), 1.89 (s, 3H), 1.97-1.67 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 97.44% (MaxPlot 200-400 nm), 97.77% (220 nm).
• 7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

  3-(3-Benzyloxy-propoxy)-2-hydroxy-benzaldehyde

  • NaH (2.95 g, 72.4 mmol) was added to an ice-cold solution of 2,3-dihydroxybenzaldehyde (5.0 g, 36 mmol) in anhydrous DMSO (45 mL). Benzyl-3-bromopropyl ether (6.45 mL, 36.2 mmol) was then added and the mixture was stirred at rt for 12 h. The mixture was neutralized using 1 N HCl and then extracted with EtOAc. The organic fraction was washed with H₂O and concentrated in vacuo. The residue was purified by flash chromatography (8:2 hexane/EtOAc) to give the title compound as a brown oil: yield 8.40 g (81%).
  • [0891]
    ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.93 (s, 1H), 7.36-7.23 (m, 6H), 7.20-7.16 (m, 2H), 6.98-6.91 (m, 1H), 4.53 (s, 2H), 4.19 (t, J=6.2 Hz, 2H), 3.70 (t, J=6.1 Hz, 2H), 2.19-2.16 (m, 2H).

  3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[/, 3, 2]dioxaborolan-2-yl)-benzaldehyde

  • [0893]
    General procedure 6: 3-(3-benzyloxy-propoxy)-2-hydroxy-benzaldehyde (7.6 g, 26 mmol), pyridine (3.42 mL, 42.5 mmol), Tf₂O (4.60 mL, 27.9 mmol), and CH₂Cl₂ (200 mL): yield 8.60 g (77%).
  • [0894]
    ¹H NMR (400 MHz, CDCl₃) δ (ppm): 10.23 (s, 1H), 7.54-7.47 (m, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.36-7.22 (m, 6H), 4.52 (s, 2H), 4.23 (t, J=6.3 Hz, 2H), 3.71 (t, J=6.1 Hz, 2H), 2.21-2.17 (m, 2H).
  • [0895]
    General procedure 5: trifluoro-methanesulfonic acid 2-(3-benzyloxy-propoxy)-6-formyl-phenyl ester (8.0 g, 19 mmol), B₂pin₂ (9.71 g, 38.2 mmol), KOAc (5.71 g, 57.4 mmol), PdCl₂(dppf).CH₂Cl₂ (1.39 g, 1.89 mmol), and anhydrous dioxane (160 mL). Purification: flash chromatography (9:1 hexane/EtOAc): yield 4.80 g (43%)-some pinacol contamination, used without further purification.
  • [0896]
    ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.93 (s, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.35-7.24 (m, 5H), 7.08 (d, J=7.8 Hz, 1H), 4.50 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 3.67 (t, J=6.3 Hz, 2H), 2.11 (quin, J=6.2 Hz, 2H), 1.43 (s, 12H).

  7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

  • General procedure 8: 3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (36 g, 91 mmol), MeNO₂ (16.6 g, 273 mmol), NaOH (3.64 g, 83 mmol), H₂O (180 mL), and THF (50 mL). Purification: flash chromatography (1:1 hexane/EtOAc). A47 was isolated as a light yellow oil: yield 15.9 g (50%).
  • ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.05 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.20 (m, 5H), 7.06 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.70 (dd, J=9.4, 2.3 Hz, 1H), 5.29 (dd, J=13.7, 2.7 Hz, 1H), 4.53 (dd, J=13.3, 9.4 Hz, 1H), 4.45 (s, 2H), 4.11 (t, J=6.1 Hz, 2H), 3.60 (t, J=6.3 Hz, 2H), 2.04-1.91 (m, 2H); MS (ESI): m/z=356 (M−1, negative); HPLC purity: 99.35% (MaxPlot 200-400 nm), 97.32% (220 nm).

  Alternative synthesis of 3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A46)

  • General procedure 13: A47 (0.50 g, 1.4 mmol), 20% Pd(OH)₂/C (0.5 g, 1:1 w/w), AcOH (20 mL), and H₂O (0.24 mL). The filtrate was concentrated and treated with 4 N HCl to give the title compound as a colorless solid: yield 0.22 g (47%).
  • ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.42 (t, J=7.8 Hz, 1H), 6.97-6.90 (m, 1H), 6.86 (d, J=8.2 Hz, 1H), 5.20 (dd, J=9.2, 2.5 Hz, 1H), 4.02 (t, J=6.2 Hz, 2H), 3.54 (t, J=6.2 Hz, 2H), 3.40 (dd, J=13.3, 2.7 Hz, 1H), 2.68 (dd, J=13.1, 9.2 Hz, 1H), 1.88-1.78 (m, 2H); MS (ESI): m/z=238 (M+1, positive).

3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A46)

Synthesis of 3-(3-Benzyloxy-propoxy)-2-bromo-benzaldehyde (C)

• To a 5° C. solution of compound A (15.0 g, 0.075 mol), B (12.0 ml, 0.075 mol) and triphenylphosphine (19.6 g, 0.075 mol) in 200 ml of anhydrous THF was added DIAD (14.8 ml, 0.075 mol) drop by drop over a period of 15 minutes. The resulting solution was warmed to room temperature over a period of 5 h and the solvent was evaporated in vacuo. The residue was dissolved in 150 ml of EtOAc and the organic layer washed with water, brine and dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) generating 13.0 g (50% yield) of C [3-(3-benzyloxy-propoxy)-2-bromo-benzaldehyde].
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.41 (s, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.32-7.25 (m, 6H), 7.08 (d, J=8.0 Hz, 1H), 4.54 (s, 2H), 4.16 (t, J=6.0 Hz, 2H), 3.74 (t, J=5.8 Hz, 2H), 2.19-2.14 (m, 2H).

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (D)

• Compound C (8.9 g, 0.025 mol), KOAc (7.5 g, 0.076 mol), and bis(pinacolato)diboron (12.9 g, 0.051 mol) were dissolved in 50 ml of dry DMF and degassed for 30 minutes. To this was added PdCl₂(dppf).DCM (0.56 g, 0.76 mmol) and the contents were again degassed for 10 minutes and then heated to 90° C. for 4 h. An additional quantity of PdCl₂(dppf).DCM (0.2 g, 0.27 mmol) was added and heating was continued for an additional 2 h. The reaction was cooled to RT, filtered through celite and the solvent evaporated in vacuo. The residue was dissolved in DCM, washed with brine and the organic layer dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of hexane to 5% EtOAc/hexane) provided 5.4 g (53% yield) of D [3-(3-benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde].
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 9.91 (s, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.2 Hz, 1H), 7.32-7.27 (m, 5H), 7.06 (d, J=8.4 Hz, 1H), 4.49 (s, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H), 2.11-2.08 (m, 2H), 1.44 (s, 12H). ESI+MS m/z, 397 (M+H)⁺.

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (E)

• To an ice cold solution of NaOH (0.68 g, 0.017 mol) in 10 ml of water was added a solution of compound D (6.8 g, 0.017 mol) dissolved in 5 ml of THF. After 15 minutes, nitromethane (0.93 ml, 0.017 mol) was added drop by drop and the content stirred at RT overnight. The THF was evaporated under reduced pressure and the contents acidified to pH-3 with 2N HCl. The aqueous layer was extracted with EtOAc several times, and the combined ethyl acetate layer was washed with brine, dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography (gradient of 10% EtOAc/hexane to 30% EtOAc/hexane) provided 3.7 g (55% yield) of E [7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol] 3.7 g.
• ¹H NMR (400 MHz, DMSO-d₆+D₂O (0.01 ml)) δ (ppm) 7.49 (t, J=7.8 Hz, 1H), 7.34-7.25 (m, 5H), 7.08 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.71 (d, J=6.4 Hz, 1H), 5.23 (dd, J=13.2, 2.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.47 (s, 2H), 4.12 (t, J=6.2 Hz, 2H), 3.63 (t, J=6.0 Hz, 2H), 2.04-2.00 (m, 2H). ESI-MS m/z, 356 [M−H]⁻. HPLC purity: 97.12% (MaxPlot 200-400 nm).

3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A46)
• Compound E (6.0 g, 0.016 mol) was dissolved in 50 ml of glacial acetic acid and to it was added Pd(OH)₂ on Carbon (20% metal content, 50% weight-wet) (5.2 g) and the content set for hydrogenation in a Parr shaker at 45 psi for 2 h. The reaction was checked for completion and the contents were filtered through Celite. The solvent was evaporated under reduced pressure at ambient temperature to yield a gummy material. To this three times was added 15 ml of dry toluene and evaporated yielding a fluffy solid. Purification was accomplished by preparative HPLC (C18 column, using acetonitrile and 0.1% AcOH/water solution) provided 1.5 g (45% yield) of compound A46 [3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol] with 0.33 mol % acetic acid (by HNMR).
• ¹H NMR (400 MHz, DMSO-d₆+D₂O (0.01 ml)) δ (ppm) 7.52 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 5.29 (dd, J=9.2, 2.4, 1H), 4.12 (t, J=6.2 Hz, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.48 (dd, J=13.2, 2.8 Hz, 1H), 2.80-2.74 (m, 1H), 1.92 (t, J=6.2 Hz, 2H). ESI+MS m/z, 238 [M+H]⁺. HPLC purity: 95.67% (MaxPlot 200-400 nm) and 96.22% (220 single wavelength).

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol hydrochloride (A49)

(3-Benzyloxy)-1-bromo-propane (2)
• A solution of 1 (160 g, 962.58 mmol) and triphenylphosphine (277.72 g, 1.1 eq, 1058.83 mmol) was dissolved in dichloromethane (800 mL) and cooled to 0° C. (ice/water). A solution of carbon tetrabromide (351.16 g, 1.1 eq, 1058.83 mmol) in dichloromethane (200 mL) was added dropwise and the mixture was left to stir at rt for 18 h. The dichloromethane solvent was evaporated to obtain a white solid. The solid was treated with an excess of hexanes, stirred for 1 h, filtered off and the solvent was evaporated to yield a crude product. The crude product was purified by silica gel column chromatography using 5-10% ethyl acetate and hexane to obtain 2 (199 g, 91%) as a colorless liquid.

3-(3-Benzyloxy-propoxy)-2-hydroxy-benzaldehyde (4)

• To a solution of aldehyde 3 (27.47 g, 1 eq, 198.88 mmol) in 0.5 L of anhydrous DMSO was added sodium tertiary-butoxide (42.3 g, 2.2 eq, 440.31 mmol) portionwise. The reaction mixture was stirred at rt for 30 minutes. A brown color solution was formed. The reaction mixture was cooled to 0° C. and added bromide (56 g, 1.2 eq, 244.41 mmol) dropwise. The mixture was stirred at rt O/N. 90% of aldehyde 3 was converted to product. The reaction mixture was acidified to pH-3 and then extracted into EtOAc and washed with water. The organic layer was concentrated, the product was purified on silica gel column (EtOAc:hexane 80:20), to yield as compound 4 (48 g, 84.31% yield) (viscous oil).

Trifluoro-methanesulfonic acid 2-(3-benzyloxy-propoxy)-6-formyl-phenyl ester (5)

• To an ice cold solution of 4 (48 g, 1.0 eq, 167.72 mmol) in 200 mL of dry DCM was added pyridine (22 mL, 1.62 eq, 272.11 mmol). To the reaction mixture trifluoromethanesulfonic anhydride (33 mL, 1.16 eq, 196.14 mol) was added drop by drop. The mixture was stirred for 3 h at 0° C. The mixture was quenched with 500 mL of 1N HCl. The compound was then extracted into DCM (300 mL) and passed through a small silica gel column and concentrated to give compound 5 (57 g, 82% yield) as a pale yellow thick oil.

3-(3-Benzyloxy-propoxy)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (6)

• Compound 5 (65 g, 1.0 eq, 155.5 mmol), bis(pinacolato)diboron (86.9 g, 2.2 eq, 342.11 mmol), KOAc (45.7 g, 3.0 eq, 466.5 mmol) were mixed together and 600 mL of dioxane was added. The mixture was degassed with N₂ for 30 minutes and PdCl₂(dppf).DCM (5.7 g, 0.05 eq, 7.77 mmol) was added. The resulting slurry was heated to 90° C. overnight. The solvent was evaporated, EtOAc was added and then filtered through a pad of Celite. The organic layer was then washed with water (2×150 mL) and the solvent was evaporated. Column chromatography using 15% EtOAc/hexanes gave compound 6 (37.1 g, 61% yield).

7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (A47)

• A solution of compound 6 (36 g, 1.0 eq, 90.91 mmol) in 50 mL of THF was cooled to 0° C. Nitromethane (16.6 g, 3.0 eq, 272.72 mmol) was added, followed by an aqueous solution of NaOH (3.64 g in 180 mL of H₂O). The reaction mixture was stirred at room temperature overnight. The starting material disappeared. The cyclization was afforded by adding 1N HCl until the solution was acidified and then extracted into EtOAc. The EtOAc was evaporated and the mixture was triturated with water and decanted. Column chromatography using 50% EtOAc/hexanes gave compound A47 (15.9 g, 50% yield).

(R) and (S) 7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol

• 4.82 g of (A47) was resolved via chiral HPLC using CHIRALPAK ADH column and CO₂:methanol (86:14) as eluent (25° C. UV detection was monitored at 230 nm. Two peaks, (S)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol and (R)-7-(3-Benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol were collected and evaporated to yellow oils. Analysis of the pooled fractions using a CHIRALPAK ADH 4.6 mm ID×250 mm analytical column and the same mobile phase provided the (S) enantiomer [0.7 g (29% yield)] with a retention time of 6.11 min and a 98.2% ee. The (R) enantiomer [1.0 g (41% yield)] had a retention time of 8.86 min and a 99.6% ee.

(S)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A49)

• (A47) (550 mg, 1.57 mmol) was dissolved in 15 mL of glacial acetic acid. 280 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 128 mg of the acetate salt of (A49). The acetate salt was treated with 10 mL of 2N HCl and stirred for 3 hours. The material was lyophilized overnight to obtain 93 mg of the hydrochloride salt of (A49) (Yield 22%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.82 (dd, J=13.3, 9.0 Hz, 1H), 1.95-1.83 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 98.74% (MaxPlot 200-400 nm), 98.38% (220 nm); Chiral HPLC=95.14% ee.

OTHER ISOMER

(R)-3-Aminomethyl-7-(3-hydroxy-propoxy)-3H-benzo[c][1,2]oxaborol-1-ol (A50)
• (R)-7-(3-benzyloxy-propoxy)-3-nitromethyl-3H-benzo[c][1,2]oxaborol-1-ol (0.70 g, 2.0 mmol) was dissolved in 20 mL of glacial acetic acid. 350 mg of 20 wt % palladium hydroxide on carbon (Pearlman’s catalyst) was added and the reaction mixture was flushed with hydrogen 3× and hydrogenated at 55 psi for 3.5 hours. The mixture was filtered through Celite to remove catalyst and rinsed with methanol. Acetic acid was evaporated to obtain the crude product. HPLC purification gave 65 mg of pure compound. After purification, this acetate salt was combined with material from another reaction. This product was treated with 2N HCl (10 mL) and stirred for 3 h at rt. The material was lyophilized overnight to obtain 74 mg of the hydrochloride salt of (A50) (Yield 14%).
• ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.48 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.4 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 5.27 (d, J=9.4 Hz, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 2.83 (dd, J=13.3, 8.6 Hz, 1H), 1.94-1.82 (m, 2H); MS (ESI): m/z=238 (M+1, positive); HPLC purity: 99.12% (MaxPlot 200-400 nm), 98.74% (220 nm); Chiral HPLC=98.82% ee.

REFERENCES

https://pubs.acs.org/cen/coverstory/89/8912cover3.html

https://www.yumpu.com/en/document/view/34463506/the-discovery-of-gsk2251052-a-first-in-class-boron-anacor

Anacor

Dr. R. G. Micetich’s research career began in 1963 as a Research Scientist with R & L Molecular Research Ltd. (established by Dr. R. U. Lemieux). This company later became Raylo Chemicals Ltd. Dr. Micetich served as the Research Director (Pharmaceutical Research) of Raylo. During the period from 1963 to 1980 Dr. Micetich’s group was involved in pharmaceutical research and process development work in antibiotics and in NSAI’s (non-steroidal anti-inflammatory agents). This work produced a drug “Mofezolac” – a NSAI which is now marketed in Japan by the Japanese company “Yoshitomi”. Market ~ U.S. $60 million.

In 1980, Dr. R. G. Micetich joined the Faculty of Pharmacy, University of Alberta as an Adjunct Professor working on projects for international big Pharma companies. The work with Taiho Pharmaceutical Company in Japan has produced another drug – a beta-lactamase inhibitor – “TAZOBACTAM” which is now marketed worldwide. This drug now produces annual sales of over US$ 1 billion.

In 1987, Dr. Micetich established a joint venture research company with Taiho, Japan called SynPhar. SynPhar had numerous patents worldwide in various therapeutic areas and many compounds and classes of compounds at various stages of development up to late preclinical.

In view of the significant growth opportunities for SynPhar and in response to the changing international market place for pharmaceuticals, Dr. Micetich acquired and transferred all the assets including intellectual property, equipment and fixtures from SynPhar to NAEJA Pharmaceutical Inc. in 1999. NAEJA is a private Albertan company, founded by the Micetich family which from an initial staff in August 1999 of 40, has grown to 130 and is still growing. NAEJA is a completely self-supporting private company with no venture capital, nor private, nor government funding. The majority of NAEJA employees hold Ph.D.’s. NAEJA has collaborative agreements with pharmaceutical companies around the world. Based on its own intellectual property, NAEJA also has a number of co-development agreements with biotech companies worldwide. Dr. Micetich laid the seeds of foundation for NAEJA and the company continues after his passing, building his legacy.

Dr. R. G. Micetich boasted over 100 publications in well know scientific journals and composed over 100 patents taken out in many countries…………..http://www.bioalberta.com/ron-micetich

more……….

RONALD G. MICETICH (1931-2006): A Scientific Career Ronald Micetich was born in Podanur, Coimbatore (South India). Following receipt of B.Sc. Honors (Chemistry, Loyola College, Madras) and M.A. (Chemistry, Madras University) degrees in India, Ron obtained a Ph.D. (Organic Chemistry, University of Saskatchewan, Canada) in 1962. Ron initiated his interest in microbiology while he was a postdoctoral fellow at the National Research Council of Canada. During the period 1963-1980, Ron held a number of industrial appointments where he rapidly advanced his industrial scientific career (research scientist → associate research director → acting research director → director pharmaceutical / agricultural research) at Raylo Chemicals in Edmonton, Alberta. In 1981 Ron joined the Faculty of Pharmacy & Pharmaceutical Sciences at the University of Alberta as an Adjunct Professor at which time a highly successful drug development program was established with Taiho Pharmaceuticals. This joint industrial collaboration led to the birth of SynPhar with Dr. Micetich as Chairman of the Board, President, CEO and Research Director (1987-1999). Ron, again as Chairman of the Board, CEO and Research Director, established NAEJA (North America, Europe, Japan, Asia) Pharmaceuticals in 1999 with a rollover of assets, including staff, equipment and intellectual property, from SynPhar Laboratories. What began as a full fledged pharmaceutical company with an extensive intellectual property portfolio and a proven track record evolved into an internationally respected pharmaceutical outsource service provider. NAEJA has carved a unique niche in the outsource industry offering extensive discovery experience and expertise. Today, NAEJA has over 120 staff that consists of over 90% scientists holding PhD degrees.,………….see link below

[PDF]RONALD G. MICETICH – University of Alberta – Journal …

https://ejournals.library.ualberta.ca/index.php/JPPS/article/…/4173

by T Yajima – ‎2008

Dr.Muhammed Majeed with Dr. Ronald Micetich, CEO, Naeja Pharmaceuticals, Edmonton Canada’.

////////////GSK 2251052, Epetraborole, Christopher Micetich, Ronald Micetich, Naeja Pharmaceuticals

B1(c2c(cccc2OCCCO)[C@H](O1)CN)O

Crisaborole

Treatment for Inflammatory Skin Diseases, including Atopic Dermatitis and Psoriasis

C₁₄H₁₀BNO_3, Average mass251.045 Da

Anacor’s lead product candidate is crisaborole, an investigational non-steroidal topical PDE-4 inhibitor in development for the potential treatment of mild-to-moderate atopic dermatitis and psoriasis

crisaborole is an investigational topical antiinflammatory drug in phase III clinical development by Anacor Pharmaceuticals for the treatment of mild to moderate atopic dermatitis and in phase II clinical trials in mild to moderate psoriasis

A novel boron-containing small molecule, Crisaborole inhibits the release of pro-inflammatory cytokines including TNF-alpha, IL-12, and IL-23, known mediators of the inflammation associated with psoriasis.

Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis
Bioorg Med Chem Lett 2009, 19(8): 2129

http://www.sciencedirect.com/science/article/pii/S0960894X09002996

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis

http://www.google.co.in/patents/WO2006089067A2?cl=en

http://www.google.com/patents/US20090291917

…………..///////////crisaborole, AN 2728

((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

N-​[(1S)​-​1-​[[(2S)​-​2-​[5-​[4′-​[[[6-​[(2R,​5S)​-​2,​5-​dimethyl-​4-​[(methylamino)​carbonyl]​-​1-​piperazinyl]​-​3-​pyridinyl]​carbonyl]​amino]​-​2′-​(trifluoromethoxy)​[1,​1′-​biphenyl]​-​4-​yl]​-​1H-​imidazol-​2-​yl]​-​1-​pyrrolidinyl]​carbonyl]​-​2-​methylpropyl]​-​, Carbamic acid, methyl ester

Carbamic acid, N-​[(1S)​-​1-​[[(2S)​-​2-​[5-​[4′-​[[[6-​[(2R,​5S)​-​2,​5-​dimethyl-​4-​[(methylamino)​carbonyl]​-​1-​piperazinyl]​-​3-​pyridinyl]​carbonyl]​amino]​-​2′-​(trifluoromethoxy)​[1,​1′-​biphenyl]​-​4-​yl]​-​1H-​imidazol-​2-​yl]​-​1-​pyrrolidinyl]​carbonyl]​-​2-​methylpropyl]​-​, methyl ester

CAS 1374883-22-3, 819.87, C₄₁ H₄₈ F₃ N₉ O₆

Theravance, Inc.  INNOVATOR

To treat hepatitis C virus infection

• ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (compound 1):
• Recent estimates place the number of people infected with the hepatitis C virus (HCV) worldwide at more than 170 million, including 3 million people in the United States. The infection rate is thought to be roughly 4 to 5 times that of the human immunodeficiency virus (HIV). While in some individuals, the natural immune response is able to overcome the virus, in the majority of cases, a chronic infection is established, leading to increased risk of developing cirrhosis of the liver and hepatocellular carcinomas. Infection with hepatitis C, therefore, presents a serious public health problem.
  The virus responsible for HCV infection has been identified as a positive-strand RNA virus belonging to the family Flaviviridae. The HCV genome encodes a polyprotein that during the viral lifecycle is cleaved into ten individual proteins, including both structural and non-structural proteins. The six non-structural proteins, denoted as NS2, NS3, NS4A, NS4B, NS5A, and NS5B have been shown to be required for RNA replication. In particular, the NS5A protein appears to play a significant role in viral replication, as well as in modulation of the physiology of the host cell. Effects of NS5A on interferon signaling, regulation of cell growth and apoptosis have also been identified. (Macdonald et al., Journal of General Virology (2004), 85, 2485-2502.) Compounds which inhibit the function of the NS5A protein are expected to provide a useful approach to HCV therapy.
  Commonly-assigned U.S. Provisional Application Nos. 61/410,267, filed on Nov. 4, 2010, 61/444,046, filed on Feb. 17, 2011, and 61/492,267, filed on Jun. 1, 2011, and U.S. application Ser. No. 13/288,216, filed on Nov. 3, 2012 disclose pyridyl-piperazinyl compounds

SYNTHESIS

CLICK ON IMAGES FOR CLEAR VIEW

PATENT

WO-2013/165796

https://www.google.co.in/patents/WO2013165796A1?cl=en

PATENT

http://www.google.com/patents/US20130295048

crystalline compound 1 is advantageously prepared directly from the crude product of the final step of the synthesis of compound 1, illustrated in the following scheme, without purification of the amorphous form.

As described in Example 3 below, ((S)-1-{(S)-2-[4-(4′-{[6-(2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl}-amino]-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2) is reacted with methylaminoformyl chloride to provide a crude product, which is recovered by conventional extraction and drying. The reaction is typically performed in the presence of an excess of base, in an inert diluent such as dichloromethane. Next, methanol is added to the crude product followed by the slow addition of water in a ratio of methanol:water of about 2.5:1 to about 2.7:1 to form a crystallization mixture. Seeds of crystalline compound 1 are added about halfway through the water addition. The crystallization mixture is stirred for a period of several days to form crystalline compound 1. To increase purity, the product can be recrystallized by a similar process: the crystalline compound is dissolved in methanol, water and seeds are added, such that the ratio of methanol to water in the mixture is about 2.5:1, and the mixture is stirred for a period of at least 12 hours to provide crystalline compound 1, which is recovered conventionally

Preparation 1: (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester(a) N-(4-Bromo-3-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide
• To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8 mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and the reaction mixture was washed with water, brine, and saturated sodium carbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43 mL) was added to the solid and then water (43 mL) was slowly added. The reaction mixture was stirred for 1.5 h, filtered, and washed with 1:4 ethanol:water (2×25 mL) to give the title intermediate as a white solid (3.87 g). Analytical HPLC: Retention time=21.3 min.

(b) (2S,5R)-4-[5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

• The product of the previous step (3.86 g, 10.2 mmol) (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (2.62 g, 12.2 mmol) and N,N-diisopropylethylamine (5.32 mL, 30.5) was dissolved in DMSO (12 mL). The reaction mixture heated at 120° C. for 3 h, diluted with EtOAc (100 mL), washed with water, and saturated NH₄Cl, water, and brine. The reaction mixture was evaporated to about 40% volume and 3 M HCl in cyclopentyl methyl ether (4.24 mL, 12.7 mmol) was added slowly. Seeds from a previous run at smaller scale were added and the reaction mixture was stirred for 2 days and filtered to provide the HCl salt of the title intermediate (5.15 g, 83% yield). Analytical HPLC: Retention time=21.1 min.

Preparation 2: (2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester

• To a solution of ((S)-1-{(S)-2-[4-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3.05 g, 6.8 mmol), bis(pinacolato)diboron (1.81 g, 7.1 mmol) and potassium acetate (1.00 g, 10.2 mmol) was added nitrogen sparged toluene (15 mL). The resulting mixture was sparged with nitrogen and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (Pd catalyst) (0.17 g, 0.204 mmol) was added. The reaction mixture was stirred at 90° C. overnight.
• The reaction mixture was cooled to RT and to this mixture was added nitrogen sparged water (7.6 mL), potassium carbonate (5.16 g, 37.3 mmol), and (2S,5R)-4-[5-(4-bromo-3-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (4.35 g, 7.13 mmol). The reaction mixture was stirred at 95° C. overnight.
• Another portion of the Pd catalyst used above (0.08 g, 0.10 mmol) was added to the reaction mixture. After 5 h, the reaction mixture was cooled to RT, diluted with EtOAc (150 mL), washed with water (150 mL) and brine (100 mL), dried over sodium sulfate, and evaporated to give a black residue (6.7 g), which was purified by silica gel chromatography (eluted with 50-100% EtOAc/hexane) to provide the title intermediate (5.3 g, 90% yield). Analytical HPLC: Retention time=14.7 min.

Preparation 3: ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

• Acetyl chloride (63.2 mL, 888 mmol) was added to ethanol (360 mL) and stirred at RT for 1 h. To the resulting HCl solution was added a solution of (2S,5R)-4-[5-(4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (73 g, 84 mmol) in ethanol (360 mL). The reaction mixture was stirred at RT overnight.
• The reaction mixture was concentrated to dryness (124 g crude). Water 500 mL) was added and the mixture was extracted with EtOAc (2×500 mL). The aqueous layer was adjusted to pH 4 with 1:1 NaOH:water. Ethyl acetate (400 mL) and sat. aq. Na₂CO₃ (100 mL) were added and the layers were separated. The organic layer was dried over Na₂SO₄ and evaporated to give the title intermediate (62.8 g; 88% yield). Analytical HPLC: Retention time=10.0 min.

Example 1Amorphous ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

(a) ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester tri-HCl

• Acetyl chloride (0.71 mL, 10.0 mmol) was added to ethanol (7 mL) and stirred at RT for 1 h. The resulting HCl solution was added to a solution of (2S,5R)-4-[5-(4′-{2-[(5)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.55 g, 1.8 mmol) in ethanol (7 mL). The reaction mixture was warmed to 35° C. and stirred overnight. The mixture was concentrated to dryness, and chased with DCM to provide the crude tri-HCl salt of the title intermediate (1.57 g) which was used directly in the next step. HPLC method C: Retention time=10.0 min.

(b) Amorphous ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-Dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

• To a solution of the product of the previous step (1.57 g crude, ca. 1.80 mmol) and N,N-diisopropylethylamine (3.14 mL, 18.0 mmol) in DCM (24 mL) was slowly added 1 M methylaminoformyl chloride in DMA (1.8 mL). The reaction mixture stirred at RT for 1 h, and then 1 M methylaminoformyl chloride in DMA (1.8 mL) was added. The reaction was quenched with sat. aq. NaHCO₃ and the reaction mixture was stirred for 20 min. The layers were separated and the organic layer was dried and evaporated to give a residue. To the residue was added methanol (15 mL) followed by 2 N LiOH/water (3 mL). The reaction mixture was stirred at RT for 1 h, diluted with water, extracted with DCM (80 mL), dried, and evaporated to give a crude product which was purified by silica gel chromatography (40 g silica, 2-8% MeOH/DCM) to provide the title compound (0.93 g, 63% yield). Analytical HPLC: Retention time=11.0 min.

HPLC

Analytical HPLC Method
• • • Column: Zorbax Bonus-RP 3.5 μm. 4.6×150 mm
    • Column temperature: 35° C.
    • Flow rate: 1.0 mL/min
    • Mobile Phases: A=Water/ACN (98:2)+0.1% TFA
      • B=Water/ACN (10:90)+0.1% TFA,
    • Injection volume: 100-1500 μL
    • Detector wavelength: 214 nm
    • Sample preparation: Dissolve in 1:1 ACN:water
    • Gradient: 29 min total (time (min)/% B): 0.5/10, 24/90, 25/90, 26/10, 29/10

  http://www.google.com/patents/US20130295048

About Theravance Biopharma
The mission of Theravance Biopharma (NASDAQ: TBPH) is to create value from a unique and diverse set of assets: an approved product; a development pipeline of late-stage assets; and a productive research platform designed for long-term growth.

Our pipeline of internally discovered product candidates includes potential best-in-class opportunities in underserved markets in the acute care setting, representing multiple opportunities for value creation. VIBATIV® (telavancin), our first commercial product, is a once-daily dual-mechanism antibiotic approved in the U.S., Europe and certain other countries for certain difficult-to-treat infections. Revefenacin (TD-4208) is an investigational long-acting muscarinic antagonist (LAMA) being developed as a potential once-daily, nebulized treatment for COPD. Axelopran (TD-1211) is an investigational potential once-daily, oral treatment for opioid-induced constipation (OIC). Our earlier-stage clinical assets represent novel approaches for potentially treating diseases of the lung and gastrointestinal tract and infectious disease. In addition, we have an economic interest in future payments that may be made by GlaxoSmithKline plc pursuant to its agreements with Theravance, Inc. relating to certain drug development programs, including the combination of fluticasone furoate, umeclidinium and vilanterol (the “Closed Triple”).

With our successful drug discovery and development track record, commercial infrastructure, experienced management team and efficient corporate structure, we believe that we are well positioned to create value for our shareholders and make a difference in the lives of patients.
For more information, please visit www.theravance.com.

THERAVANCE®, the Cross/Star logo, MEDICINES THAT MAKE A DIFFERENCE® and VIBATIV® are registered trademarks of the Theravance Biopharma group of companies.

Journal of Medicinal Chemistry (2014), 57(5), 1643-1672……….

(e)Thalladi, V. R.; Nzerem, J.; Huang, X.; Zhang, W. Crystalline form of a pyridyl-piperazinyl hepatitis C virus inhibitor. World Patent Application WO-2013/165796, November 7, 2013.

PATENT

WO 2012061552

http://www.google.com.ar/patents/WO2012061552A1?cl=en

Preparation 28: ((S)-l-{(S)-2-[4-(4′-{[6-((2_JR,5S)-2,5-Dimethyl-piperazin-l- yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2- yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

A mixture of [(5)-2-methyl-l-((5)-2- {4-[4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-phenyl]-lH-imidazol-2-yl}-pyrrolidine-l-carbonyl)-propyl]- carbamic acid methyl ester (86 mg, 0.17 mmol) and (25′,5R)-4-[5-(4-bromo-3- trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-l-carboxylic acid tert-butyl ester (100 mg, 0.2 mmol, Preparation 27) was dissolved in 1,4-dioxane (1.8 mL, 23 mmol) and water (0.25 mL, 14 mmol). Cesium carbonate (170 mg, 0.52 mmol) was added. The reaction mixture was sparged with nitrogen and then

tetrakis(triphenylphosphine)palladium(0) (12.1 mg, 0.011 mmol) was added. The reaction mixture was sealed under nitrogen and heated at 95 °C overnight. The reaction mixture was extracted with ethyl acetate/water, the organic layer was dried over sodium sulfate and concentrated to produce an orange oil.

The oil from the previous step was treated with 4 M HCl in 1,4-dioxane (2 mL, 7 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated and evaporated with ethyl acetate (2 x) to produce the HCl salt of the title compound as a yellow solid which was purified by preparative HPLC to provide the tri-TFA salt of the title compound (150 mg, 30 % overall yield), (m/z): [M+H] calcd for

763.35 found 763.7.

Example 29 ((S)-l-{(S)-2-[4-(4′-{[6-((2_JR,5S)-2,5-Dimethyl-4- methylcarbamoyl-piperazin-l-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy- biphenyl-4-yl)-lH-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2-methyl-propyl)- carbamic a

To a solution of ((5)- l – {(5)-2-[4-(4′- { [6-((2R,55)-2,5-dimethyl-piperazin- l-yl)- pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2-yl]- pyrrolidine- l-carbonyl} -2-methyl-propyl)-carbamic acid methyl ester tri-TFA (1 1.4 mg, 0.01 1 mmol; Preparation 28) and N,N-diisopropylethylamine (18 uL, 0.1 1 mmol) dissolved in DMA (0.4 mL, 4 mmol) was added 1.0 M methyl isocyanate in toluene (10 uL, 0.01 mmol). The reaction mixture was stirred at RT overnight, concentrated, dissolved in 1 : 1 acetic acid:water (1.5 mL) and purified by preparative HPLC to provide the di-TFA salt of the title compound (7.1 mg). (m/z): [M+H]⁺ calcd for C₄₁H₄₈F₃N₉0₆ 820.37 found 820.5.

Alternative synthesis of ((5)-1-{(5)-2-[ -(4′-{[6-((2Λ,ί» 2,5- Dimethyl-4-methylcarbamoyl-piperazin-l-yl)-pyridine-3-carbonyl]-amino}-2′- trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2-yl]-pyrrolidine-l-carbonyl}-2- methyl-propyl)-carbamic acid methyl ester

(a) N-(^‘4-Bromo-3-trifluoromethoxy-phenyl -6-fluoro-nicotinamide

To a solution of 4-bromo-3-trifluoromethoxy-phenylamine (3.15 g, 12.3 mmol) and triethylamine (3.43 mL, 24.6 mmol) in DCM (25 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (2.36 g, 14.8 mmol) in DCM (10 mL). After 2 h at RT, MTBE (90 mL) was added and the reaction mixture was washed with water, brine, and saturated sodium carbonate, dried, and evaporated to give a solid (5.4 g). Ethanol (43 mL) was added to the solid and then water (43 mL) was slowly added. The reaction mixture was stirred for 1.5 h, filtered, and washed with 1 :4 ethanohwater (2 x 25 mL) to give the title intermediate as a white solid (3.87 g). HPLC method C: Retention time = 21.3 min.

(b) (25^,,5R)-4-r5-(4-Bromo-3-trifluoromethoxy-phenylcarbamoyl) -pyridin-2-yl1-2,5- dimethyl-piperazin – 1 -carboxylic acid fe/t-butyl ester

The product of the previous step (3.86 g, 10.2 mmol) (2S,5R)-2,5-dimethyl- piperazine-1 -carboxylic acid tert-butyl ester (2.62 g, 12.2 mmol) and N,N- diisopropylethylamine (5.32 mL, 30.5) was dissolved in DMSO (12 mL). The reaction mixture heated at 120 °C for 3 h, diluted with EtOAc (100 mL), washed with water, and saturated NH₄C1, water, and brine. The reaction mixture was evaporated to about 40% volume and 3 M HCl in cyclopentyl methyl ether (4.24 mL, 12.7 mmol) was added slowly. Seeds from a previous run at smaller scale were added and the reaction mixture was stirred for 2 days and filtered to provide the HCl salt of the title intermediate (5.15 g, 83 % yield). HPLC method C: Retention time = 21.1 min (c) (2 .5R)-4 5-(4′-{2 ffl -((5^f)-2-Methoxycarbonylamino-3-methyl-butyrvn- pyiTolidin-2-yl1-lH-imidazol-4-yl}-2-tri

pyridin-2- -2,5-dimethyl-piperazine-l-carboxylic acid fert-butyl ester

To a solution of ((5′)-l-{(5^,)-2-[4-(4-bromo-phenyl)-lH-imidazol-2-yl]- pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (3.05 g, 6.8 mmol;), bis(pinacolato)diboron (1.81 g, 7.1 mmol) and potassium acetate (1,00 g, 10.2 mmol) was added nitrogen sparged toluene (15 mL). The resulting mixture was sparged with nitrogen and l,l’-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (Pd catalyst) (0.17 g, 0.204 mmol) was added. The reaction mixture was stirred at 90 °C overnight.

The reaction mixture was cooled to RT and to this mixture was added nitrogen sparged water (7.6 mL), potassium carbonate (5.16 g, 37.3 mmol). The reaction mixture was stirred at 95°C overnight.

Another portion of the Pd catalyst used above (0.08 g, 0.10 mmol) was added to the reaction mixture. After 5 h, the reaction mixture was cooled to RT, diluted with EtOAc (150 mL), washed with water (150 mL) and brine (100 mL), dried over sodium sulfate, and evaporated to give a black residue (6.7 g), which was purified by silica gel chromatography (eluted with 50-100 % EtOAc/hexane) to provide the title intermediate (5.3 g, 90 % yield). HPLC method C: Retention time = 14.7 min.

(d) (ffl ffl-2 4-(4′ r6-((2R,5^-2,5-Dimethyl-piperazin-l-vn-pyridine-3-carbonyl1- amino}-2′ rifluoromethoxy-biphenyl-4-yl -lH-imidazol-2-yl1-pyrrolidine-l- carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Acetyl chloride (2.57 mL, 36.2 mmol) was added to ethanol (18 mL) and stirred at RT for 1 h. To the resulting HQ solution was added a solution of the product of the previous step (3.90 g, 4.5 mmol) in ethanol (18 mL). The reaction mixture was warmed to 35 °C and stirred overnight. Acetyl chloride (1.28 mL, 18.1 mmol) was added to ethanol (7.8 mL) and stirred for 30 min. The resulting HC1 solution was added to the reaction mixture at 35 °C. The temperature was raised to 40 °C. The mixture was concentrated to dryness chased by dichloromethane to provide the crude tri-HCl salt of the title intermediate (5.4 g) which was used directly in the next step. HPLC method C: Retention time = 10.1 min.

(e) ((^-l- {(^-2-r4-(4′- {r6-((2R.5^-2.5-Dimethyl-4-methylcarbamoyl-piperazin-l-yl)- pyridine-3-carbonyl1-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-lH-imidazol-2-yl1- pyrrolidine-l-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

To a solution of the product of the previous step (5.4 g crude, ca. 3.96 mmol) and N,N-diisopropylethylamine (6.89 mL, 39.6 mmol) in DCM (52 mL) was slowly added 1 M methylaminoformyl chloride in DMA (4.3 mL). The reaction mixture stirred at room temperature for 1 h, and then water (50 mL) was added. The organic layer was washed with saturated NH₄C1 and then brine, dried over Na₂S0₄ and evaporated to give 5.2 g crude product, which was purified by silica gel chromatography (133 g silica, 2 to 8 % methanol/DCM for 15 min then 8 % methanol/DCM for 40 min) to provide the title compound (2.4 g, 74 % yield). HPLC method C: Retention time 1 1.2 min

I AM NOT SURE OF BELOW DATA, It is a cut paste for TD 6450 , NOT ABLE TO CONNECT CAS 1374883-22-3 WITH TD 6450

IF YOU HAVE A STRUCTURE PIC FOR THE SAME MAIL ME amcrasto@gmail.com, call +919323115463

POSTER

50th Annu Meet Eur Assoc Study Liver (EASL) (April 22-26, Vienna) 2015, Abst P0898

http://ilc-congress.eu/abstract_25_04/ILC2015-abstract-book-25-04-Saturday.pdf

P0898

TD-6450,

A NEXT GENERATION ONCE-DAILY NS5A INHIBITOR, HAS POTENT ANTIVIRAL ACTIVITY FOLLOWING A 3-DAY MONOTHERAPY STUDY IN GENOTYPE 1 HCV INFECTION

E. Lawitz1, M. Rodriguez-Torres2, R. Kohler3, A. Amrite3, C. Barnes3, M.L.C. Pecoraro3, J. Budman3, M. McKinnell3, C.B. Washington3. 1Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States; 2Fundacion de Investigacion, San Juan, Puerto Rico; 3Theravance Biopharma, South San Francisco, CA, United States

E-mail: cwashington@theravance.com

Background and Aims: TD-6450 is a next generation HCV NS5A inhibitor with superior in vitro potency against resistanceassociated variants (RAVs) encountered with first-generation NS5A inhibitors. This study evaluated the safety, pharmacokinetics (PK) and antiviral activity of TD-6450 following multiple oral doses in HCV patients

Theravance Biopharma Announces Positive Results From Phase 1 Proof-of-Concept Study of TD-6450, an NS5A Inhibitor to Treat Hepatitis C

240 mg Achieved a Median Maximal Viral Load Decline of 4.9 Log10 IU/mL Following Three Daily Doses in Genotype 1a Patients

Theravance Biopharma and Trek Therapeutics Announce Initiation of Phase 2a Trial of TD-6450, an NS5A Inhibitor to Treat Hepatitis C

Study Being Conducted by Trek Therapeutics Following Licensing of Worldwide Rights to Drug Candidate From Theravance Biopharma

//////////////

.

SERTINDOLE

Sertindole (brand names: Serdolect, and Serlect) is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

Sertindole is not approved for use in the United States.

Medical Uses

Sertindole appears effective as an antipsychotic in schizophrenia.^[4]

Safety and status

USA

Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,^[10] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.^[11] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.^[12] Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone.^[13] Nevertheless in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe.^[14] As of October 2010, the drug has not been approved by the FDA for use in the USA.^[15]

Europe

In Europe, sertindole was approved and marketed in 19 countries from 1996,^[12] but its marketing authorization was suspended by the European Medicines Agency in 1998^[16] and the drug was withdrawn from the market. In 2002, based on new data, the EMA’s CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.^[17][18]

Synthesis

PAPER

I. V. Sunil Kumar¹, G. S. R. Anjaneyulu¹ and V. Hima Bindu²

¹Research and Development Centre, Aptuit Laurus Private Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500078, India
²Institute of Science and Technology, JNTU, Hyderabad-500072, India

Corresponding author email

Associate Editor: N. Sewald

Beilstein J. Org. Chem. 2011, 7, 29–33.

SEE AT http://beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-7-5

Sertindole is designated chemically as 1-[2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-2-imidazolidinone. Its literature synthesis (Scheme 1) [1-5] involves the copper catalyzed N-arylation of 5-chloroindole (11) with 4-fluorobromobenzene (12). The product, 5-chloro-1-(4-fluorophenyl)indole (13), on treatment with 4-piperidinone hydrochloride monohydrate (14) under acidic conditions affords 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride (15). Reduction of 15 in the presence of platinum oxide yields 5-chloro-1-(4-fluorophenyl)-3-(4-piperdinyl)-1H-indole (9) which on condensation with 1-(2-chloroethyl)imidazolidinone (16) in the presence of a base gives sertindole (1).

During the laboratory optimization of sertindole (1), many process related impurities were identified. The guidelines recommended by ICH state that the acceptable levels for a known and unknown compound (impurity) in the drug should be less than 0.15 and 0.10%, respectively [6]. In order to meet the stringent regulatory requirements, the impurities present in the drug substance must be identified and characterized. Literature reports [5,7-9] include impurities formed due to either over reduction (e.g., 2, 3 and 6) [5,7], incomplete reduction (e.g., 4 and 5) [5,8] or due to incomplete alkylation (e.g., 9 and 10) [5,7]. However, no synthetic details have been reported. In this context, the present study describes identification, synthesis and characterization of impurities formed during sertindole synthesis.

References

• Karamatskos, E; Lambert, M; Mulert, C; Naber, D (November 2012). “Drug safety and efficacy evaluation of sertindole for schizophrenia”. Expert Opinion on Drug Safety 11 (6): 1047–1062. doi:10.1517/14740338.2012.726984. PMID 22992213.
• “PRODUCT INFORMATION SERDOLECT® TABLETS” (PDF). TGA eBusiness Services. Lundbeck Australia Pty Ltd. 16 January 2013. Retrieved 27 October 2013.
• Juruena, MF; de Sena, EP; de Oliveira, IR (May 2011). “Sertindole in the Management of Schizophrenia” (PDF). Journal of Central Nervous System Disease 3: 75–85. doi:10.4137/JCNSD.S5729. PMC 3663609. PMID 23861640.
• Lewis, R; Bagnall, AM; Leitner, M (Jul 20, 2005). “Sertindole for schizophrenia.”. Cochrane database of systematic reviews (Online) (3): CD001715. doi:10.1002/14651858.CD001715.pub2. PMID 16034864.
• Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
• Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.”. Lancet 382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019.
• Roth, BL; Driscol, J (12 January 2011). “PDSP K_i Database”. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 27 October 2013.
• Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
• http://www.trc-canada.com/detail.php?CatNum=D230095&CAS=173294-84-3&Chemical_Name=Dehydrosertindole&Mol_Formula=C24H24ClFN4O&Synonym=1-%5B2-%5B4-%5B5-Chloro-1-(4-fluorophenyl)-1H-indol-3-yl%5D-1-piperidinyl%5Dethyl%5D-1,3-dihydro-2H-Imidazol-2-one;%20Lu%2028-092
• Zeneca’s Seroquel Nears Market Approval – The Pharma Letter, 16 July 1997
• Abbott Labs Withdraws Sertindole NDA Sertindole – The Pharma Letter, 12 Jan 1998
• “WHO Pharmaceuticals Newsletter 1998, No. 03&04: Regulatory actions: Sertindole – approval application withdrawn”.
• FDA Advisory Committee provides opinion on Serdolect for the treatment of schizophrenia – Lundbeck press release, 8 Apr 2009
• Food and Drug Administration; Minutes of the Psychphamacological Drugs Advisory Committee, 7 Apr 2009
• [1]
• EU CHMP recommends lifting ban on atypical antipsychotic Serdolect (sertindole) – National electronic Library for Medicines, NHS
• COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS OPINION FOLLOWING AN ARTICLE 36 REFERRAL: SERTINDOLE – European Medicines Agency, 13 Sep 2002
• Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) – MHRA, 2002

Perregaard, J.; Arnt, J.; Boegesoe, K. P.; Hyttel, J.; Sanchez, C. (1992). “Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles”. Journal of Medicinal Chemistry 35 (6): 1092. doi:10.1021/jm00084a014.

Sertindole

Systematic (IUPAC) name
1-[2-[4-[5-chloro-1-(4-fluorophenyl)-indol-3-yl]-1-piperidyl]ethyl]imidazolidin-2-one
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: C
Legal status	AU: Prescription Only (S4) approved for marketing in approx. 20 countries
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	75%[1]
Protein binding	99.5%[1]
Metabolism	Hepatic (mostly via CYP2D6 and CYP3A4)[2][3]
Biological half-life	3 days[2]
Excretion	Faecal (the majority), Renal (4% metabolites; 1% unchanged)[2]
Identifiers
CAS Registry Number	106516-24-9
ATC code	N05AE03
PubChem	CID: 60149
IUPHAR/BPS	98
DrugBank	DB06144
ChemSpider	54229
UNII	GVV4Z879SP
KEGG	D00561
ChEBI	CHEBI:9122
ChEMBL	CHEMBL12713
Chemical data
Formula	C24H26ClFN4O
Molecular mass	440.941

///////

SCYX-7158

SCYX-7158 [4-fluoro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c]oxaborol-6-yl-2-trifluoromethyl benzamide]

• C₁₇H₁₄BF₄NO₃
• Average mass 367.103 Da

Human African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT.

The presence of a boron atom in the heterocyclic core structure has been found essential for trypanocidal activity of orally active series of benzoxaborole-6-carboxamides in murine models of human African trypanosomiasis. SCYX-7158 (Fig. 13) has been identified as an effective, safe and orally active treatment for human African trypanoso-miasis to enter preclinical studies, with expected progression to phase 1 clinical trials in 2011 (21,22)………http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764666/

A drug discovery project employing integrated biological screening, medicinal chemistry and pharmacokinetic characterization identified SCYX-7158 as an optimized analog, as it is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murine HAT models and has physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD×7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents and non-human primates, has low intravenous plasma clearance and has a 24-h elimination half-life and a volume of distribution that indicate good tissue distribution. Most importantly, in rodents brain exposure of SCYX-7158 is high, with C_max >10 µg/mL and AUC_{0–24 hr} >100 µg*h/mL following a 25 mg/kg oral dose. Furthermore, SCYX-7158 readily distributes into cerebrospinal fluid to achieve therapeutically relevant concentrations in this compartment.

Medicinal Chemistry Synthesis of SCYX-7158  SCHEME1

While the original route was eff ective for producing multi-gram quantities of the API, it was not amenable to scale-up. The route started with 2, a relatively expensive aryl boronic acid. This was protected as borocan 3 and halogen-lithium exchange followed by reaction with acetone and subsequent deprotection provided the oxaborole 4. This protection/alkylation/deprotection sequence added two steps to the overall synthesis and the metalation was not reliable. However, the biggest concern in the sequence was nitration of 4 to give 5. This was accomplished by adding a concentrated solution of 4 to cold fuming nitric acid. Besides the signifi cant safety considerations, the reaction did not scale well. Reduction of the nitro group to give aniline 6 was followed by amide formation to provide 1. While this end game was effi cient, the material produced was dark in color. The colored impurities were not removed by crystallization of 1 and furthermore a mixture of two polymorphs was formed under the original conditions.

The process chemistry route to SCYX-7158 is shown in Scheme 2. When considering alternative routes to 1, the readily available and inexpensive methyl 2-bromobenzoate (8) was identifi ed as an attractive starting point. Gratifyingly, treatment of 8 with methylmagnesium bromide aff orded 2-bromocumyl alcohol (9) in high yield using simple operating conditions. Lithiumhalogen exchange followed by reaction with triisopropyl borate and acidic work-up provided benzoxaborole 4, along with cumyl alcohol (10). While this conversion was not completely atom-effi cient, it was easily scalable and several strategies are available to suppress the by-product in the future.

With benzoxaborole 4 in hand, attention turned to the introduction of a nitrogen-linked amide at the C(6) position. This was accomplished using the same nitration/reduction/acylation strategy used in Scheme 1. Yet signifi cant changes to the chemistry were required for safety and reliability reasons. The fi rst task was introduction of the nitrogen. Nitration was demonstrated using acetic anhydride/nitric acid. However, due to slow rates of nitration and potential for accumulation of a reactive intermediate, alternative conditions had to be identifi ed. These limitations were overcome by use of trifl uoroacetic anhydride/nitric acid, which provided a more reactive nitrating intermediate, thus improving the rate of nitration and aff ording a process in which nitric acid was slowly added until 4 was consumed. Full safety assessment of the nitration reaction, including extensive calorimetry studies, demonstrated the safety of this reaction. This process was used to prepare kilogram quantities of 5.

Following reduction of nitrobenzoxaborole 5 to aniline 6 under standard catalytic hydrogenation conditions, acylation with 7 provided the fi nal drug candidate in high chemical yield. Two challenges remained which needed to be addressed through further optimization of the process. The fi rst challenge was color and purity of the API, which derived from a highly colored impurity generated in the nitration reaction which carried through to fi nal product and was not removed by crystallization. The second challenge was to consistently obtain a single polymorph of the API. Both challenges were addressed by isolation of crystalline isopropyl boronate 11 which rejected colored impurities, followed by regeneration of 1 through addition of water and azeotropic removal of isopropanol. This crystallization provided the API as a single polymorph. The API was isolated in good yield, very high purity and was white in color.

REFERENCES

http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0001151

• touguia J, Costa J (1999) Therapy of human African trypanosomiasis: current situation. Mem Inst Oswaldo Cruz 94: 221–224
• Barrett MP, Boykin DW, Brun R, Tidwell RR (2007) Human African trypanosomiasis: pharmacological re-engagement with a neglected disease. Br J Pharmacol 152: 1155–1171.

1. 1986. Epidemiology and control of African trypanosomiasis. Report of a WHO expert committee. World Health Organization. Geneva, Switzerland. Technical Report Series, No. 739. 126 pp.
2. Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis. Robert T Jacobs, Jacob J Plattner, Bakela Nare, Stephen A Wring, Daitao Chen, Yvonne Freund, Eric G Gaukel, Matthew D Orr, Joe B Perales, Matthew Jenks, Robert A Noe, Jessica M Sligar, Yong-Kang Zhang, Cyrus J Bacchi, Nigel Yarlett, and Robert Don. Future Medicinal Chemistry. August 2011. Vol. 3, No. 10. Pages 1259-1278.

http://www.swisstph.ch/fileadmin/user_upload/Pdfs/Events/2010_09_Jacobs.pdf  ……….POWERPOINT

///////////SCYX-7158

CEP-18770, Delanzomib

cas 847499-27-8

Chemical Formula: C21H28BN3O5

Exact Mass: 413.21220, UNII-6IF28942WO;

[(1R)-1-[[(2S,3R)-3-Hydroxy-2-[[(6-phenylpyridin-2-yl)carbonyl]amino]-1-oxobutyl]amino]-3-methylbutyl]boronic acid

[(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid,

Cephalon, Inc.

CEP-18770 is a reversible P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Displays anti-multimyeloma (MM) effect.

HPLC………http://www.apexbt.com/downloader/document/A4009/HPLC.pdf

NMR………http://www.apexbt.com/downloader/document/A4009/NMR.pdf

CLICK ON IMAGE FOR CLEAR VIEW

Delanzomib, also known as CEP-18770,  is An orally bioavailable synthetic P2 threonine boronic acid inhibitor of the chymotrypsin-like activity of the proteasome, with potential antineoplastic activity. Proteasome inhibitor CEP 18770 represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. The intracellular protein IkappaBalpha functions as a primary inhibitor of the proinflammatory transcription factor NF-kappaB

New series of dipeptidyl boronate inhibitors of 20S proteasome were identified to be highly potent drug-like candidates with IC₅₀ values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market

ref

The potent, selective, and orally bioavailable threonine-derived 20S human proteasome inhibitor that has been advanced to preclinical development, [(1R)-1-[ [ (2S,3R)- 3-hydroxy-2-[ (6-phenylpyridine- 2-carbonyl) amino]-1 -oxobutyl] amino]- 3-methylbutyl] boronic acid (CEP-18770, has been reported

ref .

Dorsey BD, Iqbal M, Chatterjee S, Menta E, Bernardini R, Bernareggi A, et al. Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem. 2008;51:1068–1072. [PubMed]

Further, the anti-multiple myeloma protea-some inhibitor CEP-18770 enhanced the anti-myeloma activity of bortezomib and melphalan. The combination of anti-multiple myeloma proteasome inhibitor CEP-18770 intravenously and bortezomib exhibited complete regression of bortezomib-sensitive tumours. Moreover, this combination markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone

Patent

http://www.google.com/patents/WO2010056733A1?cl=en

Preferred among these compounds is [(lR)-l-[[(2S,3R)-3-hydroxy-2- [6-phenyl-pyridine-2-carbonyl)amino]-l-oxobutyl]amino]-3-methylbutylboronic acid, also known as CEP- 18770, which has the following structure:

PATENT

http://www.google.co.in/patents/WO2005021558A2

NOT SAME BUT SIMILAR

Example E.4 Boronic acid, [(lR)-l-[[(2S,3R)-3-hydroxy-2-[[4-(3-pyridyl)benzoyl]amino]-l- oxobutyI]amino]-3-methyIbutyl].

[00275] A mixture of 4-(pyridin-3-yl)benzamide, N-[(1S,2R)-1-[[[(1R)-1-

[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-l,3,2-benzodioxaborol-2- yl]-3-methylbutyl]amino]carbonyl]-2-hydroxypropyl]- of Example D.8.3 (155 mg, 0.283 mmol), 2-methylpropylboronic acid (81 mg, 0.793 mmol) and 2N aqueous hydrochloric acid (0.3 ml) in a heterogeneous mixture of methanol (3 ml) and hexane (3 ml) was stirred at room temperature for 24 hours. The hexane layer was removed and the methanolic layer was washed with fresh hexane (about 5 ml). Ethyl acetate (10 ml) was added to the methanol layer which was then concentrated. The residue was taken up with ethyl acetate and the mixture was concentrated. This step was repeated (2-3 times) until an amorphous white solid was obtained. The solid was then triturated with diethyl ether (5 ml) and the surnatant was removed by decantation. This step was repeated. The residue (126 mg) was combined with the product of a similar preparation (140 mg) and dissolved in ethyl acetate (about 40 ml) and a small amount of methanol (2-3 ml). The solution was washed with a mixture of NaCl saturated solution (7 ml) and 10% NaHCO₃ (2 ml). The layers were separated and the aqueous phase was further washed with ethyl acetate (2 x 20 ml). The combined organic phases were dried over sodium sulfate and concentrated. The residue was taken up with ethyl acetate (about 20 ml) and the minimum amount of methanol, and then concentrated to small volume (about 5 ml). The resulting white was collected by filtration and dried under vacuum at 50°C (160 mg, 65% overall yield).

1H NMR (MeOH-d4): 8.90 (IH, s); 8.49 (IH, d, J=4.0); 8.20 (IH, d, J=8.1); 8.06 (2H, d, J=8.1); 7.85 (2H, d, J=8.1); 7.58 (IH, t br., J=6.0); 4.80 (IH, d, J=3.9); 4.40-4.29 (IH, m); 2.78 (IH, t, J=7.5); 1.73-1.61 (IH, m); 1.38 (2H, t, J=6.9); 1.31 (3H, d, J=6.3); 0.94 (6H, d, J=6.31). [00276] Further compounds prepared according to the above procedure for

Example E.4 are reported in Table E-4. Table E-4

E.4.3 IS THE COMPD

1. Fuchs, Ota. Proteasome inhibition as a therapeutic strategy in patients with multiple myeloma. Multiple Myeloma (2009), 101-125. CODEN: 69MVM2 AN 2010:737549

2. Genin, E.; Reboud-Ravaux, M.; Vidal, J. Proteasome inhibitors: recent advances and new perspectives in medicinal chemistry. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2010), 10(3), 232-256. CODEN: CTMCCL ISSN:1568-0266. CAN 152:516315 AN 2010:423458

3. Sanchez, Eric; Li, Mingjie; Steinberg, Jeffrey A.; Wang, Cathy; Shen, Jing; Bonavida, Benjamin; Li, Zhi-Wei; Chen, Haiming; Berenson, James R. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. British Journal of Haematology (2010), 148(4), 569-581. CODEN: BJHEAL ISSN:0007-1048. AN 2010:353952

4. Dick, Lawrence R.; Fleming, Paul E. \Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discovery Today (2010), 15(5/6), 243-249. CODEN: DDTOFS ISSN:1359-6446. AN 2010:318415

5. Ruggeri, Bruce; Miknyoczki, Sheila; Dorsey, Bruce; Hui, Ai-Min. The development and pharmacology of proteasome inhibitors for the management and treatment of cancer. Advances in Pharmacology (San Diego, CA, United States) (2009), 57(Contemporary Aspects of Biomedical Research: Drug Discovery), 91-135. CODEN: ADPHEL ISSN:1054-3589. AN 2010:62762

6. Chen-Kiang, Selina; Di Liberto, Maurizio; Huang, Xiangao. Targeting CDK4 and CDK6 kinases or genes thereof in cancer therapy for sensitizing drug-resistant tumors. PCT Int. Appl. (2009), 149pp. CODEN: PIXXD2 WO 2009061345 A2 20090514 CAN 150:531264 AN 2009:586623

7. Rickles, Richard; Lee, Margaret S. Use of adenosine A2A receptor agonists and phosphodiesterase (PDE) inhibitors for the treatment of B-cell proliferative disorders, and combinations with other agents. PCT Int. Appl. (2009), 70 pp. CODEN: PIXXD2 WO 2009011893 A2 20090122 CAN 150:160095 AN 2009:86451

8. Rickles, Richard; Pierce, Laura; Lee, Margaret S. Combinations for the treatment of B-cell proliferative disorders. PCT Int. Appl. (2009), 79pp. CODEN: PIXXD2 WO 2009011897 A1 20090122 CAN 150:160094 AN 2009:83374

9. Hoveyda, Hamid; Fraser, Graeme L.; Benakli, Kamel; Beauchemin, Sophie; Brassard, Martin; Drutz, David; Marsault, Eric; Ouellet, Luc; Peterson, Mark L.; Wang, Zhigang. Preparation and methods of using macrocyclic modulators of the ghrelin receptor. U.S. Pat. Appl. Publ. (2008), 178pp. CODEN: USXXCO US 2008194672 A1 20080814 CAN 149:288945 AN 2008:975261

10. Piva, Roberto; Ruggeri, Bruce; Williams, Michael; Costa, Giulia; Tamagno, Ilaria; Ferrero, Dario; Giai, Valentina; Coscia, Marta; Peola, Silvia; Massaia, Massimo; Pezzoni, Gabriella; Allievi, Cecilia; Pescalli, Nicoletta; Cassin, Mara; di Giovine, Stefano; Nicoli, Paola; de Feudis, Paola; Strepponi, Ivan; Roato, Ilaria; Ferracini, Riccardo; Bussolati, Benedetta; Camussi, Giovanni; Jones-Bolin, Susan; Hunter, Kathryn; Zhao, Hugh; Neri, Antonino; Palumbo, Antonio; Berkers, Celia; Ovaa, Huib; Bernareggi, Alberto; Inghirami, Giorgio. CEP-18770: a novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood (2008), 111(5), 2765-2775. CODEN: BLOOAW ISSN:0006-4971. CAN 149:486154 AN 2008:292777

11. Dorsey, Bruce D.; Iqbal, Mohamed; Chatterjee, Sankar; Menta, Ernesto; Bernardini, Raffaella; Bernareggi, Alberto; Cassara, Paolo G.; D’Arasmo, Germano; Ferretti, Edmondo; De Munari, Sergio; Oliva, Ambrogio; Pezzoni, Gabriella; Allievi, Cecilia; Strepponi, Ivan; Ruggeri, Bruce; Ator, Mark A.; Williams, Michael; Mallamo, John P. Discovery of a Potent, Selective, and Orally Active Proteasome Inhibitor for the Treatment of Cancer. Journal of Medicinal Chemistry (2008), 51(4), 1068-1072. CODEN: JMCMAR ISSN:0022-2623. CAN 148:345774 AN 2008:146611

12. Dorsey, Bruce D.; Menta, Ernesto; Bernardini, Raffaella; Bernareggi, Alberto; Casara, Paolo G.; D’Arasmo, Germano; Ferretti, Edmondo; De Munari, Sergi; Oliva, Ambrogio; Iqbal, Mohamed; Chatterjee, Sankar; Ruggeri, Bruce; Ator, Mark A.; Williams, Michael; Mallamo, John P. CEP-18770: Discovery of a Potent, Selective and Orally Active Proteasome Inhibitor for the Treatment of Cancer. Frontiers in CNS and Oncology Medicinal Chemistry, ACS-EFMC, Siena, Italy, October 7-9 (2007), COMC-027. CODEN: 69KAR2 AN 2007:1171000

13. Marblestone Jeffrey G Ubiquitin Drug Discovery & Diagnostics 2009 – First Annual Conference. IDrugs : the investigational drugs journal (2009), 12(12), 750-3.

/////CEP-18770, delanzomib

B(C(CC(C)C)NC(=O)C(C(C)O)NC(=O)C1=CC=CC(=N1)C2=CC=CC=C2)(O)O

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders

Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure

Dr. D. Srinivasa Reddy of NCL winner Shanti Swarup Bhatnagar Award 2015

see

http://oneorganichemistoneday.blogspot.in/2015/02/dr-d-srinivasa-reddy.html

Dr. Srinivasa Reddy of CSIR-NCL bags the

prestigious Shanti Swarup Bhatnagar Prize

sept 2015…………..http://www.biospectrumindia.com/biospecindia/news/222486/

dr-srinivasa-reddy-csir-ncl-bags-prestigious-shanti-swarup-bhatnagar-prize

The award comprises a citation, a plaque, a cash prize of Rs 5 lakh

The Shanti Swarup Bhatnagar Prize for the year 2015 in chemical sciences has been awarded to Dr. D. Srinivasa Reddy of CSIR-National Chemical Laboratory (CSIR-NCL), Pune for his outstanding contributions to the area of total synthesis of natural products and medicinal chemistry.

This is a most prestigious award given to the scientists under 45 years of age and who have demonstrated exceptional potential in Science and Technology. The award derives its value from its rich legacy of those who won this award before and added enormous value to Indian Science.

Dr. Reddy will be bestowed with the award at a formal function, which shall be presided over by the honourable Prime Minister. The award, named after the founder director general of Council of Scientific & Industrial Research (CSIR), Dr. Shanti Swarup Bhatnagar, comprises a citation, a plaque, a cash prize of Rs 5 lakh.

Dr. Reddy’s research group current interests are in the field of total synthesis and drug discovery by applying medicinal chemistry. He has also been involved in the synthesis of the agrochemicals like small molecules for crop protection. The total synthesis of more than twenty natural products has been achieved in his lab including a sex pheromone that attracts the mealy bugs and has potential use in the crop protection. On the medicinal chemistry front significant progress has been made by his group using a new concept called “Silicon-switch approach” towards central nervous system drugs. Identification of New Chemical Entities for the potential treatment of diabetes and infectious diseases is being done in collaboration with industry partners.

His efforts are evidenced by 65 publications and 30 patents. He has recently received the NASI-Reliance industries platinum jubilee award-2015 for application oriented innovations and the CRSI bronze medal. In addition, he is also the recipient of Central Drug Research Institute award for excellence in the drug research in chemical sciences and scientist of the year award by the NCL Research Foundation in the year 2013. Dr. Reddy had worked with pharmaceutical companies for seven years before joining CSIR-NCL in 2010.

AN INTRODUCTION

MYSELF WITH HIM

DEC2014 NCL PUNE INDIA

DR ANTHONY WITH DR REDDY

////////

IVACAFTOR

http://onlinelibrary.wiley.com/doi/10.1002/ejoc.201501048/abstract

SUPPORTING INFO……….http://onlinelibrary.wiley.com/store/10.1002/ejoc.201501048/asset/supinfo/ejoc_201501048_sm_miscellaneous_information.pdf?v=1&s=2b5b6ac6456ec88f478c07a692e49254e7239f80

REFERENCES

N. Vasudevan, Gorakhnath R. Jachak And D. Srinivasa Reddy, Breaking and Making of Rings: A Method for the Preparation of 4-Quinolone-3-carb­oxylic Acid Amides and the Expensive Drug Ivacaftor, Eur. J. Org. Chem., , 0000 (2015), DOI:10.1002/ejoc.201501048.

http://academic.ncl.res.in/publications/index/select-faculty/2015/ocd

READ ABOUT DR SRINIVASA REDDY at…………

ONE ORGANIC CHEMIST ONE DAY BLOG……..LINK

DEC2014 NCL PUNE INDIA

DR ANTHONY MELVIN WITH DR SRINIVASA REDDY

GKM 001……Several probables

Watch out on this post as I get to correct structure………..

Advinus Therapeutics Private L,

A glucokinase activator for treatment of type II diabetes

Advinus chief executive officer/MD Dr. Rashmi Barbhaiya.

PATENT

https://www.google.co.in/patents/WO2009047798A2?cl=en

Example Cl : (-)-{5-ChIoro-2-[2-(4-cyclopropanesulfonylphenyI)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}-acetic acid, ethyl ester

Step I: Preparation of (-)-(4-Cyclopropanesulfonylphenyl)-(2,4- difluorophenoxy)acetic acid (Cl-I):

To a solution of (4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (obtained in example Al -step III) in ethyl acetate was added (S)-(-)-l-phenylethylamine drop wise at -15 °C. After completion of addition the reaction was stirred for 4-6 hours. Solid was filtered and washed with ethyl acetate. The solid was then taken in IN HCl and extracted with ethyl acetate, ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain (-)-(4- cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid. Enantiomeric enrichment was done by repeating the diasteriomeric crystallization. [α]²³ ₅₈₉ = – 107.1 ° (c = 2%Chloroform) Enantiomeric purity > 99. % (chiral HPLC)

Step II: (-)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetyIamino]thiazol-4-yl}-acetic acid ethyl ester : To a solution of (-)-4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (Cl-I) in DCM, was added DMF and cooled to 0 °C, followed by the addition of oxalyl chloride under stirring. Stirring was continued for 1 hour at the same temperature. The resulting mixture was further cooled to -35 °C, and to that, a solution of excess (2- amino-5-chlorothiazol-4-yl)acetic acid ethyl ester in DCM was added drop wise. After completion of reaction, the reaction mixture was poured into IN aqueous HCl under stirring, organic layer was washed with IN HCl, followed by 5% brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by preparative TLC to get the title compound. [α]²³ ₅89 = – ve (c = 2%Chloroform)

¹H NMR(400 MHz, CDCl₃): δ 1.06-1.08 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.33-1.38 (m, 2H), 2.42-2.50 (m, IH), 3.73 (d, J=2 Hz, 2H), 4.22 (q, J=7.2 Hz ,2H), 5.75 (s, IH), 6.76- 6.77 (m, IH), 6.83-6.86 (m, IH), 6.90-6.98 (m, IH), 7.73 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 9.96 (bs, IH). MS (EI) m/z: 571.1 and 573.1 (M+ 1; for ³⁵Cl and ³⁷Cl respectively).

Examples C2 and C3 were prepared in analogues manner of example (Cl) from the appropriate chiral intermediate:

Example Dl : (+)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}acetic acid, ethyl ester

Preparation of (+)-(4-Cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (Dl-I):

To a solution of (4-cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid (obtained in example Al -step III) in ethyl acetate, was added (R) (+)-l- phenylethylamine drop wise at -15 °C. After completion of addition the reaction was stirred for 4-6 hours. Solid was filtered and washed with ethyl acetate. The solid was then taken in IN HCl and extracted with ethyl acetate, ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure to obtain (+)-(4-Cyclopropanesulfonylphenyl)-(2,4-difluorophenoxy)acetic acid. Enantiomeric enrichment was done by repeating the diasteriomeric crystallization. [α]²³ ₅₈₉ = +93.07° (c = 2%Chloroform) Enantiomeric purity > 99. % (by chiral HPLC)

(+)-(4-CyclopropanesuIfonylphenyI)-(2,4-difluorophenoxy)acetic acid ethyl ester (Dl)

The example Dl was prepared using (+)-4-cyclopropanesulfonylphenyl)-(2,4- difluorophenoxy)acetic acid (Dl-I), and following the same reaction condition for amide coupling as described in example Cl, [ot]²³ ₅89 = + ve (c = 2%Chloroform)

PATENT

https://www.google.co.in/patents/WO2008104994A2?cl=en

Synthesis Type-P

Example Pl : {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)- propionylamino]-thiazol-4-yI}-acetic acid

To a solution of {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl- phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (0.03 g, 0.05 mmol) in THF: Ethanol: water ( ImI + 0.3ml + 0.3 ml) was added lithium hydroxide (0.0046 g, 0.11 mmol). The resulting mixture was stirred for 5 hours at room temperature followed by removal of solvent under reduced pressure. The residue was suspended in water (15 ml), extracted with ethyl acetate to remove impurities. The aqueous layer was acidified with IN HCl (0.5 ml) and extracted with ethyl acetate (2×10 ml), This ethyl acetate layer was washed with water (15 ml), brine (20 ml), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to give solid product {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4- methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl} -acetic acid (9 mg). ¹H NMR (400 MHz, CDCl₃): δ 1.85 (s, 3H) , 3.07 (s, 3H) , 3.72 ( s, 2H), 6.64-6.69 ( m, 2H ) , 6.89-6.91 (m, IH ), 7.84 ( d, J – 8.4 Hz, 2H), 8.00 ( d, J = 8.8 Hz, 2H). MS (EI) mlz: 530.70 (M + 1), mp: 109-111 ⁰C.

Preparation of {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)- propionylamino)-thiazol-4-yl}-acetic acid methyl ester used in Example Pl:

To a mixture of 2-(2, 4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid (0.110 g, 0.22 mmol), (2-Amino-5-chloro-thiazol-4-yl)-acetic acid methyl ester (0.071 g, 0.32 mmol), HOBt (0.052g, 0.38 mmol), and EDCI (0.074 g, 0.38 mmol) in methylene dichloride (10 ml) was added N-methylmorpholine (0.039 g, 0.38 mmol). The resulting mixture was stirred at room temperature for overnight followed by dilution with 10 ml methylene dichloride. The reaction mixture was poured onto water (20 ml), and organic layer separated, washed with water (2x 20 ml), brine (20 ml), dried over sodium sulfate and solvent evaporated to get residue which was purified by preparative TLC using 50% ethyl acetate in hexane as mobile. To give desired compound (0.30 g). ¹H NMR (400 MHz, CDCl₃): δ 1.45 (t, J = 7.2 Hz, 3H), 1.93 (s, 3H), 3.14 (s, 3H), 3.77 (d, J = 2.8 Hz, IH), 4.26 (q, J = 7.2 Hz, IH), 6.69-6.77(m, 2H), 6.96-7.02 (m, IH), 7.89 (d, J = 8.4 Hz, 2H), 8.07 (d, J= 8.4Hz, IH).; MS (EI) m/z: 559 .00 (M + 1).

CLIPPINGS

Advinus’ GK-activator Achieves Early POC for Diabetes

November 29 2011

Partnership Dialog Actively Underway

Advinus Therapeutics, a research-based pharmaceutical company founded by globally experienced industry executives and promoted by the TATA Group, announced that it has successfully completed a 14-day POC study in 60 Type II diabetic patients on its lead molecule, GKM-001, a glucokinase activator. The results of the trial show effective glucose lowering across all doses tested without any incidence of hypoglycemia or any other clinically relevant adverse events.

The clinical trials on GKM-001 validate the company’s pre-clinical hypothesis that a liver selective Glucokinase activator would not cause hypoglycemia (very low blood sugar), while showing robust efficacy.

“GKM-001 is differentiated from most other GK molecules that are in development, or have been discontinued, due to its novel liver selective mechanism of action. GKM-001 has a prolonged pharmacological effect and a half-life that should support a once a day dosing as both mono and combination therapy.” said Dr. Rashmi Barbhaiya, MD & CEO, Advinus Therapeutics. He added that Advinus is actively exploring partnership options to expedite further development and global marketing of GKM-001.

GKM-001 belongs to a novel class of molecules for treatment of type II diabetes. It is an activator of Glucokinase (GK), a glucose-sensing enzyme found mainly in the liver and pancreas. Being liver selective, GKM-001 mostly activates GK in the liver and not in pancreas, which is its key differentiation from most competitor molecules that activate GK in pancreas as well. The resulting increase in insulin secretion creates a potential for hypoglycemia-a risk GKM-001 is designed to avoid. Advinus has the composition of matter patent on GKM-001 for all major markets globally. Both the Single Ascending Dose data, in healthy and type II diabetics, and the Multiple Ascending Dose Study in Type II diabetics has shown that the molecule shows effective glucose lowering in a dose dependent manner and has excellent safety and tolerability profile over a 40-fold dose range. The pharmacokinetic properties of the molecule support once a day dosing. GKM-001 has the potential to be “First-in-Class” drug to address this large, growing and yet poorly addressed market.

Advinus also has identified a clinical candidate as a back-up to GKM-001, which is structurally different. In its portfolio, the company has a growing pipeline for COPD, sickle cell disease, inflammatory bowel disease, type 2 diabetes, acute and chronic pain and rheumatoid arthritis in various stages of late discovery and pre-clinical development.

About the Diabetes Market:

The present 300 million diabetics population is estimated to jump to 450 million by 2030 worldwide. A large proportion of these patients are poorly controlled despite multiple therapies. Total sales of diabetic prescription products were $32 billion in 2010.

Advinus Therapeutics team discovers novel molecule for treatment of diabetes

• The first glucokinase modulator discovered and developed in India 
• A new concept for the management of diabetes for patients, globally 
• 100 per cent ‘made in India’ molecule for the treatment of diabetes 
• IND approved by DGCI, Phase I clinical trial shows excellent safety and tolerance profiles with efficacy

Bangalore: Advinus Therapeutics (Advinus), the research-based pharmaceutical company founded by leading global pharmaceutical executives and promoted by the Tata group, today, announced the discovery of a novel molecule for the treatment of type II diabetes — GKM-001.The molecule is an activator of glucokinase; an enzyme that regulates glucose balance and insulin secretion in the body.

GKM-001 is a completely indigenously developed molecule and the initial clinical trials have shown excellent results for both safety and efficacy.

“Considering past failures of other companies on this target, our discovery programme primarily focused on identifying a molecule that would be efficacious without causing hypoglycaemia; a side effect associated with most compounds developed for this target.

“Recently completed Phase I data indicate that Advinus’ GKM–001 is a liver selective molecule that has overcome the biggest clinical challenge of hypoglycaemia. GKM-001 is differentiated from most other GK molecules in development due to this novel mechanism of action,” said Dr Rashmi Barbhaiya, MD and CEO, Advinus Therapeutics.

He further added, “We are very proud that GKM-001 is 100 per cent Indian. Advinus’s discovery team in Pune discovered the molecule and entire preclinical development was carried out at our centre in Bangalore. The Investigational New Drug (IND) application was filed with the DGCI for approval to initiate clinical trials in India within 34 months of initiation of the discovery programme. Subsequent to the approval of the IND, we have completed the Phase I Single Ascending Dose study in India within two months.”

GKM-001 is a novel molecule for the treatment of type II diabetes. It is the first glucokinase modulator discovered and developed in India and has potential to be both first or best in class. The success in discovering GKM-001 is attributed to the science-driven efforts in Advinus laboratories and ‘breaking the conventional mold’ for selection of a drug candidate. Advinus has ‘composition of matter’ patent on the molecule for all major markets globally. Glucokinase as a class of target is considered to be novel as currently there is no product in the market or in late clinical trials. The strategy for early clinical development revolved around assessing safety (particularly hypoglycaemia) and early assessment of therapeutic activity (glucose lowering and other biomarkers) in type II diabetics. The Phase I data, in both healthy and type II diabetics, shows excellent safety and tolerability over a 40-fold dose range and desirable pharmacokinetic properties consistent with ‘once a day’ dosing. The next wave of clinical studies planned continues on this strategy of early testing in type II diabetics.

Right behind the lead candidate GKM-001, Advinus has a rich pipeline of back up compounds on the same target. These include several structurally different compounds with diverse potency, unique pharmacology and tissue selectivity. Having discovered the molecule with early indication of wide safety margins, desired efficacy and pharmacokinetic profiles, the company now seeks to out-licence GKM-001 and its discovery portfolio.

patent

wo 2008104994

wo 2008 149382

///////GKM 001, pipeline, Diabetes, Advinus, type II diabetes, glucokinase modulator, Rashmi Barbhaiya

GENERAL STRUCTURE

ZYDPLA 1……….Probable Representative structure only, I will modify it as per available info

Cadila Healthcare Limited

ZYDPLA1 is an orally active, small molecule NCE, discovered and developed by the Zydus Research Centre, the NCE research wing of Zydus. ZYDPLA1 is a novel compound in the Gliptin class of antidiabetic agents. It works by blocking the enzyme Dipeptidyl Peptidase-4 (DPP-4), which inactivates the Incretin hormone GLP-1.

By increasing the GLP-1 levels, ZYDPLA1 glucose-dependently increases insulin secretion and lowers glucagon secretion. This results in an overall improvement in the glucose homoeostasis, including reduction in HbA1c and blood sugar levels.

Zydus announces data presentations on ZYDPLA1 “A once-weekly small molecule DPP-IV inhibitor for treating diabetes”, at the ENDO conference in Chicago, Illinois, USA. Ahmedabad, India June 9, 2014 The Zydus group will be presenting data on its molecule ZYDPLA1 a novel compound in the Gliptin class of anti-diabetic agents during the joint meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014 to be held from June 21-24, 2014 in Chicago, Illinois.

ZYDPLA1, currently in Phase I clinical evaluation in USA, is an orally active, small molecule NCE, discovered and developed by the Zydus Research Centre. ZYDPLA1 works by blocking the enzyme Dipeptidyl Peptidase-4 (DPP-4), which inactivates the Incretin hormone GLP-1. By increasing the GLP- 1 levels, ZYDPLA1 glucose-dependently increases insulin secretion. This results in an overall improvement in the glucose homoeostasis, including reduction in HbA1c and blood sugar levels.

The Chairman & Managing Director of Zydus, Mr. Pankaj R. Patel said, “Currently, all available DPP-4 inhibitors are dosed once-daily. ZYDPLA1 with a once-a-week dosing regimen would provide diabetic patients with a more convenient treatment alternative. ZYDPLA1 will offer sustained action, which will result in an improved efficacy profile.”

The abstract of Poster Number: LB-PP02-4 can also be viewed on the ENDO web program at https://endo.confex.com/endo/2014endo/webprogram/authora.html. The Poster Preview is scheduled on Sunday, June 22, 2014 at McCormick Place West.

The number of diabetics in the world is estimated to be over 360 million. In 2025 nearly half of the world’s diabetic population will be from India, China, Brazil, Russia and Turkey. The sales of the DPP IV inhibitors is expected to peak at almost $14 billion by 2022. Research in the field of anti-diabetic therapy seeks to address the problems of hypoglycemia, GI side effects, lactic acidosis, weight gain, CV risks, edema, potential immunogenicity etc., which pose a major challenge in the treatment of diabetes.

About Zydus

Headquartered in Ahmedabad, India, Zydus Cadila is an innovative, global pharmaceutical company that discovers, manufactures and markets a broad range of healthcare therapies. The group employs over 16,000 people worldwide including over 1100 scientists engaged in R & D and is dedicated to creating healthier communities globally. As a leading healthcare provider, it aims to become a global researchbased pharmaceutical company by 2020. The group has a strong research pipeline of NCEs, biologics and vaccines which are in various stages of clinical trials including late stage.

About Zydus Research Centre

The Zydus Research Centre has over 20 discovery programmes in the areas of cardio-metabolic disorders, pain, inflammation and oncology. Zydus has in-house capabilities to conduct discovery research from concept to IND-enabling pre-clinical development and human proof-of-concept clinical trials. The Zydus Research group had identified and developed Lipaglyn™ (Saroglitazar) which has now become India’s first NCE to reach the market. Lipaglyn™ is a breakthrough therapy in the treatment of diabetic dyslipidemia and Hypertriglyceridemia. The company recently announced the commencement of Phase III trials of LipaglynTM (Saroglitazar) in patients suffering from Lipodystrophy.

PATENT

http://www.google.com/patents/WO2011013141A2?cl=en

Rajendra Kharul, Mukul R. Jain, Pankaj R. Patel

Substituted benzamide derivatives as glucokinase (gk) activators

Scheme 2:

Scheme 3:

Scheme 4A:

Scheme 4B.

] Scheme 5 A:

Scheme 5B:

Scheme 6:

http://zyduscadila.com/wp-content/uploads/2015/09/ZYDPLA1-a-Novel-LongActing-DPP-4-Inhibitor.pdf

http://zyduscadila.com/wp-content/uploads/2015/05/PressNote23-10-13.pdf

http://zyduscadila.com/wp-content/uploads/2015/07/annual_report_14-15.pdf

////////

DC_AC50

3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

licensed DC_AC50 to Suring Therapeutics, in Suzhou, China

INNOVATORS  Jing Chen of Emory University School of Medicine, Hualiang Jiang of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Chuan He of the University of Chicago, and coworkers

Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

• Jing Wang,
• Cheng Luo,
• Changliang Shan,
• Qiancheng You,
• Junyan Lu,
• Shannon Elf,
• Yu Zhou,
• Yi Wen,
• Jan L. Vinkenborg,
• Jun Fan,
• Heebum Kang,
• Ruiting Lin,
• Dali Han,
• Yuxin Xie,
• Jason Karpus,
• Shijie Chen,
• Shisheng Ouyang,
• Chihao Luan,
• Naixia Zhang,
• Hong Ding,
• Maarten Merkx,
• Hong Liu,
• Jing Chen,
• Hualiang Jiang
• & Chuan He

Nature Chemistry, (2015)

doi:10.1038/nchem.2381

PATENT

http://www.google.com/patents/WO2014116859A1?cl=en

COMPD IS LC-1 COMPD 50

Scheme 1 (Compounds LCI -LCI 9):

Experimental procedure for Scheme 1 :

Step a: To 1 equivalent of sodium metal in anhydrous diethyl ether is added 1-2 equivalents of ethyl formate and 1-2 equivalents of cyclopentanone. The resulting mixture is stirred overnight. The mother liquor is filtered by suction filtration to obtain crude intermediate 2.

Step b: To a solution of intermediate 2 in an organic solvent, is added 0.1 to 1 equivalent of glacial acetic acid. The reaction is stirred at 50-100 °C, then 2′ and 0.1 to 1 equivalent of glacial acetic acid are added. The resulting reaction mixture is refluxed for 1-5 hours, filtered and recrystallized to produce product 3; the said organic solvent may optionally be tetrahydrofuran, ether, dimethylformamide, ethyleneglycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. Step c: To a solution of compound 3 in an organic solvent, is added 1 equivalent of methyl bromoacetate and an appropriate amount of base. The reaction mixture is stirted at room temperature to produce intermediate 4. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.

Step d: The base described in Step c is added to a solution of compound 4 in an organic solvent. The reaction mixture is stirred and heated to produce intermediate 5. Step e: An appropriate amount of di-tert-butyl dicarbonate and alkali are added to a solution of compound 5 in an organic solvent. The reaction is stirred to produce intermediate 6.

Step f: An appropriate amount of base is added to a solution of compound 6 in an organic solvent, which is then hydro lyzed to produce intermediate 7.

Step g: 3′ and a stoichiometric amount of condensing agent are added to a solution of compound 7 in an organic solvent. The reaction mixture is stirred until 3′ reacts completely to produce the final product. The said organic so ί vers t may optional iy be tetrahydrofuran, aether, dimethyl formamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said condensing agent may optionally be DCC, EDO, HOBt, and GDI. Step h: To a solution of compound 7 in an organic solvent is added aqueous hydrochloric acid or trifluoroacetic acid. The reaction mixture is stirred vigorously to yield the BOC- deprotected final product.

Scheme 2 (Compounds LCI -LCI 9)

LCI ~LC39

Experimental procedure for Scheme 2(Compounds LC1-LC19):

Step a: Dissolve 1 equivalent of sodium in anhydrous ether, which shall be added slowly under an ice bath and rapid stirring condition. Add 1 equivalent of ethyl formate and 1 equivalent of cyclopentanone in a constant pressure dropping funnel, add 0.5 ml ethanol as an initiator, after 1 hour of stirring in ice bath, and stir overnight at room temperature until the reaction of sodium is finished. Perform suction filtration, wash with absolute ether to produce crude product for the following steps of reaction.

Step b: Dissolve the product in above steps directly in ethanol and control its amount, add an appropriate amount of glacial acetic acid, and stir and reflux under 70°C. Add cyano- sulfamide into the reaction solution, and add an appropriate amount of glacial acetic acid, react and reflux for about 3 hours. Recrystallize with ethanol to produce crude product.

Step c: Add 1 equivalent of the appropriate aniline or phenol and 2 equivalents of potassium carbonate solid in a round-bottomed flask that is placed in ice bath, add anhydrous THF to fully dissolve the solid, add 1.5 equivalents of bromoacetyl bromide into a constant pressure dropping funnel and dilute with THF, which is slowly dropped into the former said round- bottomed flask that is moved to room temperature in 10 min late and react for 1 hour; extract and dry with anhydrous sodium sulfate, filtrate by suction, and perform rotary evaporation to remove the solvent, and the crude product is obtained, which is to be used directly in the next step of reaction.

Step d: Dissolve the product from Step 2 into DMF under normal temperature by mixing, add 3 equivalents of 10% KOH solution, which is then transferred to an oil bath of 70°C and react, and add I equivalent of the product from step 3. Stir for about 3 hours and then extract directly with ethyl acetate, and recrystallize the crude product with ethanol to produce pure end product.

Steps a and b: Intermediate 3 is prepared in accordance with the method outlined in Scheme 1. Step c: 3′ and bromoacetyl bromide are condensed in the presence of a suitable base to produce intermediate 9. The said base may optionally be potassium hydroxide, sodium hydroxide, sodiumcarbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.

Step d: An appropriate amount of base is added to a solution of compound 3 in an organic solvent, and the reaction mixture is heated to 40-100 °C. Intermediate 9 is added, and the heated solution is stirred for 1-10 hours to yield the final product. The said organic solvent may optionally be tetrahydrofuran, aether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, or dichloromethane. The said base may optionally be potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and their aqueous solution in various concentrations.

NMR and mass spectral data: LC-1 (Compound 50)- 3-amino-N-(2-bromo-4,6-difluorophenyl)-6,7-dihydro-5H- cyclopenta [b] thieno [3,2-e] pyridine-2-carboxamide

1H NMR (CDCI3, 400 MHz) δ 9.15 (s, 1H), 7.61 (s, 1H), 7.13(m, 1H), 6.60 (m, 1H), 6.27 (s, 2H), 3.20 (t, 2H), 2.98 (t, 2H), 2.39 (m, 2H); ESI-MS (EI) m/z 422 (M⁺)

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List of compounds as DPP-IV inhibitors

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2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds

One Example of 2-phenyl-5-heterocyclyl-tetrahydro-2h-pyran-3-amine compounds

CAS  1601479-87-1

(2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(5-(methylsulfonyl)-5, 6- dihydropyrrolo [ 3, 4-c]pyrrol-2(lH, 3H, 4H)-yl)tetrahydro-2H-pyran-3-amine

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[5-(methylsulfonyl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]tetrahydro-2H-pyran-3-amine

MW 399.45, C18 H23 F2 N3 O3 S

INTRODUCTION

Dipeptidyl peptidase IV , CD26; DPP-IV; DP-IV inhibitors acting as glucose lowering agents reported to be useful for the treatment of type 2 diabetes.  compound inhibited human DPP-IV enzyme activity (IC50 < 10 nM) in fluorescence based assays.

It lowered glucose levels (with -49.10% glucose change) when administered to C57BL/6J mice at 0.3 mg/kg p.o. in oral glucose tolerance test (OGTT).

Compound displayed the following pharmacokinetic parameters in Wistar rats at 2 mg/kg p.o.: Cmax = 459.04 ng/ml, t1/2 = 59.48 h and AUC = 4751.59 h·ng/ml.

Dipeptidyl peptidase 4 (DPP-IV) inhibitor that inhibited human DPP-IV enzyme activity with an IC50 of < 10 nM in a fluorescence based assay.

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PATENT

http://www.google.com/patents/WO2014061031A1?cl=en

Compound 8: (2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(5-(methylsulfonyl)-5, 6- dihydropyrrolo [ 3, 4-c]pyrrol-2(lH, 3H, 4H)-yl)tetrahydro-2H-pyran-3-amine

1H NMR: (CD₃OD, 400 MHz): 7.32-7.28 (m, IH), 7.26-7.23 (m, 2H), 4.77 (d, IH, J= 10Hz), 4.32(dd, IH, J,= 2.0Hz, J₂= 10.8Hz), 4.19 (s, 4H), 3.89-3.83 (m, 4H), 3.70- 3.65 (m, IH), 3.61 (t, IH, J= 11.6Hz), 3.53-3.46 (m, IH), 3.04 (s, 3H), 2.65-2.62 (dd, IH, Ji= 1.2Hz, J₂= 12Hz), 1.84 (q, IH, J = 12 Hz); ESI-MS: (+ve mode) 400.0 (M+H)⁺ (100 %); HPLC: 99.4 %.

Compound 4: (2R, 3S, 5R)-2-(2, 5-difluorophenyl)-5-(hexahydropyrrolo[3, 4-c Jpyrrol- 2(lH)-yl)tetrahydro-2H-pyran-3-amine

1H NMR: (CD₃OD, 400 MHz):

.23-7.20 (m, 2H), 4.64 (d, IH, J= 10.4 Hz), 4.38-4.35 (dd, IH, J,= 2.4Hz, J₂= 10.4Hz), 3.69 (t, IH, J= 11Hz), 3.57-3.53 (m, 4H), 3.34-3.30 (m, 8H), 2.68-2.65 (m, IH), 2.04 (q, IH, J = 1 1.6 Hz); ESI-MS: (+ve mode) 323.9 (M+H)⁺ (100 %), 345.9 (M+Na)⁺ (20%); HPLC: 98.6 %

PATENT

IN 2012MU03030

“NOVEL DPP-IV INHIBITORS”

3030/MUM/2012

Abstract:
The present invention relates to novel compounds of the general formula (I) their tautomeric forms, their enantiomers, their diastereoisomers, their pharmaceutically accepted salts, or pro-drugs thereof, which are useful for the treatment or prevention of diabetes mellitus (DM), obesity and other metabolic disorders. The invention also relates to process for the manufacture of said compounds, and pharmaceutical compositions containing them and their use.

Pankaj R. Patel (right), Chairman and Managing Director,

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