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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Icosapent ethyl, イコサペント酸エチル


DB08887.png

Ethyl eicosapentaenoate.png

Icosapent ethyl

330.5042 , C22H34O2

cas 86227-47-6 / 73310-10-8

ethyl (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoate

Ethyl eicosapentaenoic acid

イコサペント酸エチル

(5Z,8Z,11Z,14Z,17Z)-Eicosapetaenoic acid ethyl ester
(all-Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester
5,8,11,14,17-Eicosapentaenoic acid, ethyl ester, (5Z,8Z,11Z,14Z,17Z)- [ACD/Index Name]
5,8,11,14,17-Eicosapentaenoic acid, ethyl ester, (all-Z)-
6GC8A4PAYH
86227-47-6 [RN]
all-cis-5,8,11,14,17-Eicosapentaenoic Acid Ethyl Ester
Timnodonic acid ethyl ester
Vascepa
  • 5,8,11,14,17-Eicosapentaenoic acid, ethyl ester, (all-Z)-
  • (5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester
  • (all-Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester
  • AMR 101
  • C20:5 n-3 Ethyl ester
  • Epadel
  • Epadel S 300
  • Ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate
  • Ethyl all-Z-5,8,11,14,17-eicosapentanenoate
  • Ethyl all-cis-5,8,11,14,17-eicosapentaenoate
  • Ethyl eicosapentaenoate
  • Ethyl icosapentate
  • Icosapent ethyl
  • Incromega EPA
  • Timnodonic acid ethyl ester
  • Vascepa
  • cis-Eicosapentaenoic acid ethyl ester

(all-Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester; Ethyl all-cis-5,8,11,14,17-eicosapentaenoate;Timnodonic acid ethyl ester; cis-Eicosapentaenoic acid ethyl ester; Ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate; Epadel; Icosapent; EPA ethyl ester; E-EPA; Ethyl eicosapentaenoate; OMEGA-3 ACIDS ETHYL ESTER; EPA-E;

AMARIN PHARMACEUTICALS IRELAND LTD

AMR 101 / AMR-101 / AMR101

Icosapent ethyl or ethyl eicosapentaenoic acid is a synthetic derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA). It is used as adjunct therapy for severe hypertriglyceridemia (TG levels > 500 mg/dL). FDA approved on July 26, 2012.

In 2000, Amarin licensed exclusive U.S. rights to icosapent ethyl ester from the Scottish company Laxdale, and acquired the company in July 2004. In 2015, the product was licensed to Eddingpharm by Amarin for the development and commercialization in China, Hong Kong and Taiwan. Fast-track status has been granted in the U.S. for the treatment of HD. Orphan drug designation was assigned to the compound for this indication in both the U.S. and E.U.

fda

IND 107616 was submitted on 25 March 2010 for the indication of severe hypertriglyceridemia; Epanova had been previously investigated for the treatment of Crohn’s Disease under IND in the Division of Gastroenterology Products. An end-of-phase 2 (EOP2) meeting was held on 02 June 2010. Regarding the indication under consideration at this time, a special protocol assessment (SPA) for the single phase 3 trial OM-EPA-003 (also known as “EVOLVE”) was submitted 02 July 2010 and ultimately agreed upon, after amendments, on 22 October 2010. On 25 April 2012, the applicant proposed an alternative to conducting a thorough QTc study by assessing ECGs recorded during OM-EPA-003; this was found acceptable. A clinical pre-NDA meeting was held on 14 November 2012. The nonclinical development strategy was found reasonable. A clinical package containing OM-EPA-003 (pivotal) and OMEPA-004 (a 6-week phase 3 trial , with long-term safety supported by data from the former Crohn’s disease program (“EPIC” trials), was found adequate for submission. Agreement was reached regarding the clinical pharmacology portion of the submission. Details regarding data pooling for the Integrated Summary of Safety (ISS) were found acceptable

from the former Crohn’s disease program (“EPIC” trials), was found adequate for submission. Agreement was reached regarding the clinical pharmacology portion of the submission. Details regarding data pooling for the Integrated Summary of Safety (ISS) were found acceptable

CMC Drug Substance & Drug Product Chemistry, manufacturing, and controls data related to both the drug substance (omega-3- carboxylic acids) and drug product (Epanova Capsules 1 g) are detailed in the review by Martin Haber, PhD, and Xavier Ysern, PhD. They recommend the NDA for approval. There are no pending CMC issues. The drug substance at sites in Nova Scotia and Prince Edward Island, Canada, from crude fish oil obtained from fish It is a complex mixture of PUFAs, predominantly the omega-3 acids EPA (55%), DHA (20%), and docosapentaenoic acid %). It consistently contains omega-3 and omega-6 PUFA components: total omega-3 fatty acids are limited to not less than % and total omega-6 fatty acids are limited to not more than %. The drug substance also contains 0.3% (m/m) α-tocopherol as . During purification, . Environmental pollutants (heavy metals, pesticides, are controlled by specific tests on the drug substance . Drug substance specifications include tests for acid value, saponification value, ester value, peroxide value, p-anisidine value, total oxidation value, cholesterol, oligomers, , fatty acid composition (PUFAs, EPA, DHA, DPA, total omega-3 fatty acids, total omega-6 fatty acids, other polyunsaturated fatty acids, As described in the review by Drs. Haber and Ysern, the qualitative identify of the drug substance was developed by examining consistencies of peak patterns across 21 discrete lots: there are omega-3 and omega-6 PUFA peaks consistently present in the GC chromatograms (although not necessarily always above the limit of quantitation), which can be used to establish the fingerprint identity of omega-3-carboxylic acids . The quantitative fatty acid composition is given in the table below, excerpted from p. 25 of their review:

Ethyl eicosapentaenoic acid (E-EPAicosapent ethyl) is a derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA) that is used in combination with changes in diet to lower triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia. This was the second class of fish oil-based drug to be approved for use as a drug and was approved by the FDA in 2012. These fish oil drugs are similar to fish oil dietary supplements but the ingredients are better controlled and have been tested in clinical trials.

The company that developed this drug, Amarin Corporation, challenged the FDA’s ability to limit its ability to market the drug for off-label use and won its case on appeal in 2012, changing the way the FDA regulates pharmaceutical marketing.

Medical use

E-EPA is used in addition to changes in diet to reduce triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia.[1]

Intake of large doses (2.0 to 4.0 g/day) of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater that 500 mg/dL). It appears that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides, however, DHA alone appears to raise low-density lipoprotein (the variant which drives atherosclerosis; sometimes very inaccurately called: “bad cholesterol”) and LDL-C values (always only a calculated estimate; not measured by labs from person’s blood sample for technical and cost reasons), whilst EPA alone, does not and instead lowers the parameters aforementioned.[2]

Other fish-oil based drugs

There are other omega-3 fish oil based drugs on the market that have similar uses and mechanisms of action.[3]

Dietary supplements

There are many fish oil dietary supplements on the market.[8] There appears to be little difference in effect between dietary supplements and prescription forms of omega-3 fatty acids, but EPA and DHA ethyl esters (prescription forms) work less well when taken on an empty stomach or with a low-fat meal.[2] The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been fixed and tested in clinical trials, as prescription drugs have,[9] and the prescription forms are more concentrated, requiring fewer capsules to be taken and increasing the likelihood of compliance.[8]

Side effects

Special caution should be taken with people who have with fish and shellfish allergies.[1] In addition, as with other omega-3 fatty acids, taking E-EPA puts people who are on anticoagulants at risk for prolonged bleeding time.[1][2] The most commonly reported side effect in clinical trials has been joint pain; some people also reported pain in their mouth or throat.[1] E-EPA has not been tested in pregnant women is rated pregnancy category C; it is excreted in breast milk and the effects on infants are not known.[1]

Pharmacology

After ingestion, E-EPA is metabolized to EPA. EPA is absorbed in the small intestine and enters circulation. Peak plasma concentration occurs about 5 hours after ingestion and the half-life is about 89 hours. EPA is metabolized mostly in the liver like other dietary fatty acids.[1]

Mechanism of action

EPA, the active metabolite of E-EPA, like other omega-3 fatty acid based drugs, appears to reduce production of triglycerides in the liver, and to enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles; the way it does that is not clear, but potential mechanisms include increased breakdown of fatty acids; inhibition of diglyceride acyltransferase which is involved in biosynthesis of triglycerides in the liver; and increased activity of lipoprotein lipase in blood.[1][3]

Physical and chemical properties[edit]

E-EPA is an ethyl ester of eicosapentaenoic acid, which is an omega-3 fatty acid.[1]

History

In July 2012, the US Food and Drug Administration approved E-EPA for severe hypertriglyceridemia as an adjunct to dietary measures; Amarin Corporation had developed the drug.[10]

E-EPA was the second fish-oil drug to be approved, after omega-3 acid ethyl esters (GlaxoSmithKline‘s Lovaza which was approved in 2004[11]) and sales were not as robust as Amarin had hoped. The labels for the two drugs were similar, but doctors prescribed Lovaza for people who had triglycerides lower than 500 mg/dL based on some clinical evidence. Amarin wanted to actively market E-EPA for that population as well which would have greatly expanded its revenue, and applied to the FDA for permission to do so in 2013, which the FDA denied.[12] In response, in May 2015 Amarin sued the FDA for infringing its First Amendment rights,[13] and in August 2015 a judge ruled that the FDA could not “prohibit the truthful promotion of a drug for unapproved uses because doing so would violate the protection of free speech.”[14] The ruling left open the question of what the FDA would allow Amarin to say about E-EPA, and in March 2016 the FDA and Amarin agreed that Amarin would submit specific marketing material to the FDA for the FDA to review, and if the parties disagreed on whether the material was truthful, they would seek a judge to mediate.[15]

PAPER

https://link.springer.com/article/10.1023%2FB%3ACONC.0000039128.78645.a8

Synthesis of Fatty-Acid Ethanolamides from Linum catharticum Oils and Cololabis saira Fats
Chemistry of Natural Compounds (Translation of Khimiya Prirodnykh Soedinenii) (2004), 40, (3), 222-226

PAPER

Journal of Molecular Catalysis B: Enzymatic, 84, 173-176; 2012

https://www.sciencedirect.com/science/article/pii/S1381117712000896?via%3Dihub

STARTING MATERIAL CAS 10417-94-4

  • (all-Z)-Δ5,8,11,14,17-Eicosapentaenoic acid
  • (all-cis)-5,8,11,14,17-Eicosapentaenoic acid

PATENT

CN 104846023

https://patents.google.com/patent/CN104846023A/en

Example 1

[0041] A method for preparing a concentrated fish oil fatty acid glycerides, the process steps shown in Figure 1, comprising the steps of:

[0042] S11 using crude enzyme preparation of deep sea fish art: the ratio: (m m) of deep-sea fish through the machine crushed bone formation minced, weighed 600g yue meat, meat by:: water = 0 5.1 water was added seal, in the dark, under nitrogen flow, at 75 ° C cooking lh. Using NaOH to adjust pH to 8.0. Mass fraction of 2% trypsin (trypsin: food grade, Zhengzhou Hong Cheng Chemical Products Limited), in the dark, enzyme 17h at 20 ° C. After 20min by centrifugation 3000r / min, the upper layer was enzymolysis, namely crude fish oil;

[0043] S12 is prepared refined fish oil: Crude fish oil prepared in Step S11 is added a volume ratio of 0.5% phosphoric acid: degummed (crude phosphoric acid fish oil), a concentration of 70% phosphoric acid, followed by centrifugation speed of 3000 rpm / min, and then add a volume ratio of 1% deacidification NaOH, the NaOH concentration is 20%, after centrifugation, the rotational speed of 3000- rpm / min, to obtain refined fish oil;

. [0044] S13 of the refined fish oil fatty acid ethyl ester prepared by esterification process: step S12 is added to the fish oil refining prepared in mass ratio of 0.5% of sodium ethoxide, and a mass ratio of 0.5 in ethanol (ethanol: fish oil refining ), 40 ° C water bath for 1 hour, 1% (by mass) citric acid (citric acid: fish oil refining), standing layer, the upper layer and the liquid was washed with hot deionized water, standing layered repeated three times to give fatty acid ethyl ester.

. [0045] S14 of the fatty acid ethyl ester was extracted Separation: fatty acid ethyl ester obtained in step S13 is subjected to supercritical fluid extraction (extraction process of separation vessel as a rectification column I – separation kettle II), extraction conditions: a rectification column temperature 25-30-35-40 ° C, a pressure of 6 MPa rectification column, separation kettle I temperature 25 ° C, pressure in the separator tank I is 6 MPa, the temperature in the separation tank II 30-45 ° C, C0 2 flow rate of 151,711;

. [0046] S15 of the fatty acid ethyl ester after enzymatic extraction separation processing: The fatty acid ethyl ester obtained in step S14 using Penicillium expansum lipase enzyme, 4% of the amount of enzyme added,, reaction temperature 40 ° C , reaction pH of 10, speed 150 revolutions / min, hydrolysis time 4h, to obtain fatty acid glycerides.

[0047] Example 2

[0048] A process for preparing concentrated fish oil fatty acid glycerides, comprising the steps of:

. [0049] S21 using crude enzyme preparation of deep sea fish art: The procedure of Example 1 with reference to embodiment 11, wherein the cooking temperature is 85 ° C, hydrolysis temperature 25 ° C, centrifuge speed is 4000r / min;

. [0050] S22 refined fish oil preparation: The procedure of Example 1 with reference to embodiment 12; wherein, phosphate: the crude fish oil volume ratio is 1.5%, the phosphoric acid concentration of 75%; K0H: crude fish oil volume ratio of 3%, K0H the concentration of 30%, a centrifugal speed of 4000r / min;

. [0051] S23 of the refined fish oil fatty acid ethyl ester prepared by esterification process: The procedure of Example 1 with reference to embodiment 13; wherein, potassium ethoxide: refined fish oil mass ratio of 1 billion% ethanol: refined fish oil mass ratio of 2.0 , heat the water bath 60 ° C for 3 hours, and acetic acid is acetic acid: refined fish oil mass ratio of 3.0%;

. [0052] S24 was extracted to separate fatty acid ethyl ester: The procedure of Example 1 with reference to embodiment 14; wherein the extraction conditions: temperature rectification column 30-35-40-45 ° C, a pressure rectification column is 15 megabytes Pa, temperature of separation vessel I 35 ° C, pressure in the separator tank I is 8 MPa, the temperature in the separation tank II was 40 ° C, C0 2 flow rate of 171,711;

. [0053] S25 of the fatty acid ethyl ester after enzymatic extraction is carried out the separation treatment: The procedure of Example 1 with reference to embodiment 15; wherein 10% of the amount of enzyme added, reaction temperature 50 ° C, pH 8 hydrolysis, speed 300 rpm / min, hydrolysis time 12h, to obtain fatty acid glycerides.

[0054] Example 3

[0055] – Preparation Method Species of concentrated fish oil fatty acid glycerides, comprising the steps of:

. [0056] S31 using crude enzyme preparation of deep sea fish art: The procedure of Example 1 with reference to embodiment 11, wherein the cooking temperature is 90 ° C, hydrolysis temperature 35 ° C, centrifuge speed is 5000r / min;

. [0057] S32 prepared fine fish oil: The procedure of Example 1 with reference to embodiment 12; wherein, phosphate: the crude fish oil volume ratio of 3% phosphoric acid concentration of 85%; NaOH: crude fish oil volume ratio of 6% and the concentration of NaOH 50%, a centrifugal speed of 5000r / min;

. [0058] S33 of the refined fish oil fatty acid ethyl ester prepared by esterification process: The procedure of Example 1 with reference to embodiment 13; wherein, potassium ethoxide: refined fish oil mass ratio of 1.5%, ethanol: refined fish oil mass ratio of 4.0 heat treatment is 80 ° C water bath for 5 hours, citric acid and citric acid are added: refined fish oil mass ratio of 5.0%;

. [0059] S34 was extracted to separate fatty acid ethyl ester: The procedure of Example 1 with reference to embodiment 14; wherein the extraction conditions: temperature rectification column 30-35-40-45 ° C, pressure column 17 trillion Pa, I of separation vessel temperature 40 ° C, pressure in the separator tank I is 10 MPa, the temperature in the separation tank II is 45 ° C, C0 2 flow rate is? L / h;

. [0060] S35 of the fatty acid ethyl ester after enzymatic extraction separation processing: The procedure of Example 1 with reference to embodiment 15; wherein 20% of the amount of enzyme added, reaction temperature 60 ° C, a pH of 6.5 hydrolysis, speed 300 rpm / min, hydrolysis time 24h, to obtain fatty acid glycerides.

[0061] Comparative Example

[0062] S1 • obtaining crude fish: The procedure of Example 1 with reference to embodiment 11;

. [0063] S2 refined fish oil preparation: see Example 1, Step 12;

. [0064] S3 of refined fish oil fatty acid ethyl ester prepared by esterification process: Step 1, Example 13 process embodiment with reference, to obtain fatty acid ethyl ester.

PATENT

https://patents.google.com/patent/WO2014054435A1

WO 2014054435

 In recent years, highly unsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been clarified for their pharmacological effects and are used as raw materials for pharmaceuticals and health foods. Since these polyunsaturated fatty acids have a plurality of double bonds, it is not easy to obtain them by chemical synthesis. Therefore, most of industrially used highly unsaturated fatty acids are produced by extraction or purification from marine organism-derived materials rich in polyunsaturated fatty acids, such as fish oil, etc. However, the content of highly unsaturated fatty acid is not necessarily high, because the biological material is a mixture of various kinds of fatty acids having different numbers of carbon atoms, number and position of double bonds, constitutional ratio of stereoisomers, and the like. For this reason, conventionally, it has been required to selectively purify a target highly unsaturated fatty acid from a biological raw material.
 Patent Document 1 discloses a supercritical gas extraction method after a thin film distillation method when a raw material containing a highly unsaturated fatty acid or an alkyl ester thereof is treated by a thin film distillation method, a supercritical gas extraction method and a urea addition method A method for purifying a highly unsaturated fatty acid or an alkyl ester thereof is described.
 In Patent Document 2, a raw material containing a highly unsaturated fatty acid such as EPA is subjected to vacuum precision distillation treatment, and the resulting EPA or a fraction containing a lower alcohol ester thereof is mixed with an aqueous silver nitrate solution, whereby a high purity eicosapentaene A method of purifying an acid or a lower alcohol ester thereof is described. It is described that the condition of the vacuum precision distillation is a pressure of 5 mmHg (665 Pa) or less, preferably 1 mmHg (133 Pa) or less, 215 ° C. or less, preferably 210 ° C. or less.
 Further, Patent Document 3 discloses a process for producing eicosapentaenoic acid or an ester thereof having a concentration of 80% or more by gradually distilling a raw material containing a highly unsaturated fatty acid or an alkyl ester thereof using a distillation tower having three or more stages Is described. It is described that the condition of the distillation is 10 Torr (1330 Pa) or less, preferably 0.1 Torr (13.3 Pa) or less, 210 ° C. or less, preferably 195 ° C. or less.
 However, highly unsaturated fatty acids having higher concentrations and purities than those obtained by the above-mentioned conventional methods are required as raw materials for pharmaceuticals and health foods.
There are cis and trans isomers in highly unsaturated fatty acids. Most of the highly unsaturated fatty acids in vivo are cis, however, they may be converted from cis form to trans form by heating or the like at the stage of purification from biological origin materials (Non-Patent Document 1). Therefore, polyunsaturated fatty acids conventionally purified industrially from biologically derived raw materials contain a certain amount of trans isomer. However, trans fatty acids have been reported to increase health risks, especially LDL cholesterol levels, and increase the risk of cardiovascular disease. In the United States and Canada, foods are obliged to indicate the content of trans fatty acids.
 Therefore, there is a need for a highly unsaturated fatty acid-containing composition which not only contains the targeted highly unsaturated fatty acid at a high concentration as a raw material for pharmaceuticals and health foods but also contains a trans fatty acid content as low as possible . However, conventionally, purification of highly unsaturated fatty acids has not been conducted focusing on the stereoisomer ratio.
Patent Document 1: Japanese Patent Application Laid-Open No. 10-95744
Patent Document 2: Japanese Patent Application Laid-Open No. 7-242895
Patent Document 3: Japanese Patent No. 3005638

Non-patent literature

[0010]
Non-patent document 1: Journal of the American Oil Chemists’ Society, 1989, 66 (12): 1822-1830

Example 

[0035]
 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to only these examples.

[0036]
 In the following examples, the method of composition analysis of highly unsaturated fatty acids and the method of quantitating stereoisomers are as follows.
9 μL of the measurement sample was diluted to 1.5 mL of n-hexane, and the content ratio of each fatty acid and the content ratio of isomers were analyzed using a gas chromatography analyzer (Type 6890 GC, manufactured by Agilent Technologies) under the following conditions did. The results are expressed as mass% converted from the area of the chromatogram.
<Column condition>
Column: DB-WAX 0.25 mm × 30 m manufactured by J & W Co., column temperature: 210 ° C.
He flow rate: 1.0 ml / min, He pressure: 134 kPa
<Detection condition>
2 flow rate: 30 ml / min, Air flow rate : 400 ml / min
He flow rate: 10 ml / min, DET temperature: 260 ° C.
The isomer ratio in the target highly unsaturated fatty acid was obtained by the following formula.

[0037]
[Expression 1]

[0038]
(Example 1)
Raw material: 1000 mL of anhydrous ethanol solution in which 50 g of sodium hydroxide was dissolved was added to 1 kg of sardine oil, mixed and stirred at 70 to 80 ° C. for 1 hour, then 500 mL of water was added and mixed well, 1 It was left standing for a while. The separated aqueous phase was removed and the oil phase was washed several times with water to neutralize the washings to give 820 g of ethyl esterified sardine oil.
As shown in Table 1, the composition of the sardine oil was 44.09% (mass%, hereinafter the same) of eicosapentaenoic acid (EPA), 1.52% of eicosatetraenoic acid (ETA), 1.52% of arachidonic acid (AA) 1.77%, docosahexaenoic acid (DHA) 6.92%. Also, the trans isomer ratio in EPA was 1.23%.
Step (1) 160 ml of n-hexane was added to 300 g of the ethyl esterified sardine oil prepared above, and the mixture was stirred well and dissolved. To this was added 500 mL of an aqueous solution containing 50% by weight of silver nitrate, and the mixture was stirred under conditions of 5 to 30 ° C. After standing, the separated n-hexane phase was removed, and the aqueous phase was recovered.
Step (2): 2000 mL of fresh n-hexane was added to the aqueous phase obtained in the step (1), and the mixture was sufficiently stirred at 50 to 69 ° C. to extract the fatty acid ethyl ester into n-hexane. After standing, the separated aqueous phase was removed and the n-hexane phase was concentrated. The crude fatty acid ethyl ester crude product contained in this n-hexane phase contained 74.54% EPA, 0.32% ETA, 0.17% AA and 14.87% DHA in total fatty acids as shown in Table 1 It was. Also, the trans isomer ratio in EPA was 0.19%.
Step (3): The n-hexane phase containing the fatty acid ethyl ester obtained in the step (2) was maintained under conditions of a top vacuum degree of 1 Pa or less and a distillation temperature of 170 to 190 ° C. using a packed tower precision distillation apparatus While performing vacuum distillation to obtain a highly purified EPA ethyl ester-containing composition in a yield of about 60%. As shown in Table 1, this EPA ethyl ester-containing composition contained 98.25% of EPA, 0.43% of ETA, 0.21% of AA, and 0.05% of DHA in total fatty acids. Also, the trans isomer ratio in EPA was 0.45%.
The yield of EPA in this example in which the steps were performed in the order of (1), (2), (3) was about 53%.

[0039]
Example 2 The
steps (1), (2) and (3) were carried out in the same manner as in Example 1 except that the step (3) was carried out while maintaining the distillation temperature of 180 to 185 ° C., EPA ethyl ester-containing composition was obtained in a yield of about 58%. As shown in Table 1, this EPA ethyl ester-containing composition contained 98.29% of EPA, 0.40% of ETA, 0.32% of AA, and 0.05% of DHA in total fatty acids. Also, the trans isomer ratio in EPA was 0.28%, and the trans isomer was extremely small.
Comparative Example 1 An
EPA ethyl ester-containing composition was obtained in the same manner as in Example 1, except that the top vacuum degree was set to 13.3 Pa (0.1 Torr) in the step (3). As shown in Table 1, the composition contained EPA content ratio as high as 97.44% in the total fatty acid, but the trans isomer ratio in EPA was high (1.37%).

[0040]
Comparative Example 2 The
EPA ethyl ester-containing composition was obtained by performing vacuum distillation (step (3)) of ethyl esterified sardine oil and then steps (1) and (2). The conditions of each step were the same as in Example 1. As shown in Table 1, this composition contained 95.05% EPA, 0.72% ETA, 0.50% AA, 0.21% DHA in total fatty acids, the trans isomer ratio in EPA was 1.55% Met. The yield of EPA in this comparative example in which the steps were carried out in the order of (3), (1) and (2) was about 31%, and the EPA yield greatly decreased as compared with Example 1.
By changing the condition of the vacuum distillation in this Comparative Example (0.5 Pa, 185 to 195 ° C.), it was possible to raise the content of EPA in the total fatty acids in the composition to 98.12%, however, The rate further declined and the trans isomer ratio in EPA was 2.01%, further increased.

[0041]
[table 1]

[0042]
Examples 3 to 4 and Comparative Example 3 In the
step (3), the distillation temperature was 180 ° C. (Example 3), 190 ° C. (Example 4), 200 ° C. (Comparative Example 3), and the vacuum distillation time was A highly purified EPA ethyl ester-containing composition was obtained in the same manner as in Example 1 except that various changes were made and the trans isomer ratio of EPA in the composition was determined. The results are shown in Fig. 1. 1, in Examples 3 to 4 having a distillation temperature of 190 ° C. or less, the trans isomer ratio was less than 1% by mass, but in Comparative Example 3 having a distillation temperature of 200 ° C., the trans isomer The ratio exceeds 1% by mass.

References

  1. Jump up to:a b c d e f g h Icosapent ethyl Label Last revised June 2015. Check for updates at FDA label index page here
  2. Jump up to:a b c Jacobson TA, et al, NLA Expert Panel. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol. 2015 Nov-Dec;9(6 Suppl):S1-S122.e1. PMID 26699442 Free full text
  3. Jump up to:a b Weintraub, HS (2014). “Overview of prescription omega-3 fatty acid products for hypertriglyceridemia”Postgrad Med126: 7–18. doi:10.3810/pgm.2014.11.2828PMID 25387209. Retrieved 20 April 2015.
  4. Jump up^ University of Utah Pharmacy Services (15 August 2007) “Omega-3-acid Ethyl Esters Brand Name Changed from Omacor to Lovaza”
  5. Jump up^ Omtryg Label Revised April 2014
  6. Jump up^ FDA Omega-3 acid ethyl esters products Page accessed 31 March 2016
  7. Jump up^ “Epanova (omega-3-carboxylic acids)”CenterWatch. Retrieved 15 December 2014.
  8. Jump up to:a b Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P T. 2015 Dec;40(12):826-57. PMID 26681905 Free PMC Article PMC 4671468
  9. Jump up^ Sweeney MET. Hypertriglyceridemia Pharmacologic Therapy for Medscape Drugs & Diseases, Ed. Khardori R. Updated: 14 April 2015, page accessed 1 April 2016
  10. Jump up^ CenterWatch Vascepa (icosapent ethyl) Page accessed 31 March 2016
  11. Jump up^ VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. October 2005 National PBM Drug Monograph Omega-3-acid ethyl esters (Lovaza, formerly Omacor)
  12. Jump up^ Matthew Herper for Forbes. 17 October 2013 Why The FDA Is Right To Block Amarin’s Push To Market Fish Oil To Millions
  13. Jump up^ Thomas, Katie (7 May 2015). “Drugmaker Sues F.D.A. Over Right to Discuss Off-Label Uses”New York Times. Retrieved 17 May 2017.
  14. Jump up^ Andrew Pollack for the New York Times. 7 August 2015 Court Forbids F.D.A. From Blocking Truthful Promotion of Drug
  15. Jump up^ Katie Thomas for the New York Times. 8 March 2016 F.D.A. Deal Allows Amarin to Promote Drug for Off-Label Use
CN1288732A *2000-07-122001-03-28刘玉Soft concentrated fish oil capsule and its supercritical CO2 extraction and rectification process
CN101255380A *2007-03-032008-09-03苑洪德Triglyceride type fish oil and method for making same
CN101818176A *2010-04-092010-09-01浙江兴业集团有限公司;华南理工大学Method for transforming fatty acid ethyl ester into glyceride
CN102964249A *2012-11-162013-03-13成都圆大生物科技有限公司Process capable of simultaneously producing and separating high-purity EPA (eicosapentaenoic acid) ethyl ester and high-purity DHA (docosahexaenoic acid) ethyl ester
CN102994236A *2012-12-112013-03-27成都圆大生物科技有限公司Method for preparing fatty acid ethyl ester with Omega-3 content of more than 90 percent
Ethyl eicosapentaenoic acid
Ethyl eicosapentaenoate.png
Names
IUPAC name

Ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate
Other names

Eicosapentaenoic acid ethyl ester; Ethyl eicosapentaenoate; Eicosapent; Icosapent ethyl; EPA ethyl ester; E-EPA
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
Properties
C22H34O2
Molar mass 330.51 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////Icosapent ethyl, fda 2012, Timnodonic acid ethyl ester, Vascepa, AMR 101, AMR-101, E-EPA, Ethyl eicosapentaenoic acid , Fast-track status, Orphan drug designation 

CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC

Letermovir, AIC 246


Letermovir skeletal.svg

Letermovir, MK 8828, AIC 246

2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid

 CAS 917389-32-3

Letermovir; UNII-1H09Y5WO1F; AIC-246; 2-((4S)-8-Fluoro-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-4H-quinazolin-4-yl)acetic acid; 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid; Letermovir [INN]

Molecular Formula: C29H28F4N4O4
Molecular Weight: 572.550633 g/mol

Letermovir (INN) is an antiviral drug that is being developed for the treatment of cytomegalovirus (CVM) infections. It has been tested in CMV infected patients with allogeneic stem cell transplants and may also be useful for other patients with a compromised immune system such as those with organ transplants or HIV infections.[1]

The drug has been granted fast track status by the US Food and Drug Administration (FDA) and orphan drug status by the European Medicines Agency.[1]

The drug candidate is under development by Merck & Co., Inc as investigative compound MK-8828.[2]

AIC246, also known as letermovir, is a novel anti-CMV compound with IC50 value of 5.1 ± 1.2 nM. It targets the pUL56 (amino acid 230-370) subunit of the viral terminase complex [1].
The subunit pUL56 is a component of the terminase complex which is responsible for packaging unit length DNA into assembling virions.
AIC246 has a novel mode of action targets the enzyme UL56 terminase and keep active to other drug-resistant virus. The anti-HCMV activity of AIC246 was evaluated in vitro by using different HCMV laboratory strains, GCV-resistant viruses. The result showed that the inhibitory potentcy of AIC246 surpasses the current gold standard GCV by more than 400-fold with respect to EC50s (mean, ∼4.5 nM versus ∼2 μM) and by more than 2,000-fold with respect to EC90 values (mean, ∼6.1 nM versus ∼14.5 μM).  In the CPE-RA strains, the EC50 values of AIC 246 ranged from 1.8 nM to 6.1 nM [2].
In mouse model with HCMV subcutaneous xenograft, oral administration of AIC246 caused significant a dose-dependent reduction of the HCMV titer. 30 mg/kg/d AIC246 for 9 days induced PFU reduction with maximum efficiency, compared with the gold standard GCV at the ED50 and ED90 level [2].
References:
[1].Verghese PS, Schleiss MR. Letermovir Treatment of Human Cytomegalovirus Infection Anti-infective Agent. Drugs Future. 2013, 38(5):291-298.
[2]. Lischka P1, Hewlett G, Wunberg T, et al.In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246.Antimicrob Agents Chemother. 2010, 54(3):1290-1297.

NMR

STR1

STR1

Human cytomegalovirus (HCMV) remains the leading viral cause of birth defects and life-threatening disease in transplant recipients. All approved antiviral drugs target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Attempts to discover improved anti-HCMV drugs led to the identification of the small-molecular-weight compound AIC246 (Letermovir). AIC246 exhibits outstanding anti-HCMV activity in vitro and in vivo and currently is undergoing a clinical phase IIb trial. The initial mode-of-action studies suggested that the drug acts late in the HCMV replication cycle via a mechanism distinct from that of polymerase inhibitors. Here, we extend our mode-of-action analyses and report that AIC246 blocks viral replication without inhibiting the synthesis of progeny HCMV DNA or viral proteins. The genotyping of mutant viruses that escaped AIC246 inhibition uncovered distinct point mutations in the UL56 subunit of the viral terminase complex. Marker transfer analyses confirmed that these mutations were sufficient to mediate AIC246 resistance. The mapping of drug resistance to open reading frame UL56 suggests that viral DNA processing and/or packaging is targeted by AIC246. In line with this, we demonstrate that AIC246 affects the formation of proper unit-length genomes from viral DNA concatemers and interferes with virion maturation. However, since AIC246-resistant viruses do not exhibit cross-resistance to previously published terminase inhibitors, our data suggest that AIC246 interferes with HCMV DNA cleavage/packaging via a molecular mechanism that is distinct from that of other compound classes known to target the viral terminase.

PATENT

WO 2006133822


Scheme 2:

Chromatography
on a chiral phase

Scheme 4:

Scheme 5:

Synthesis of {8-fluoro-2- [4- (3-methoxyphenyl) piperazin-l -yl] -3- [2-methoxy-5- (trifluoromethyl) phenyl] -3,4-dihydroquinazolin-4-yl }acetic acid

xample 1

N- (2-bromo-6-fluoφhenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea

2-methoxy-5-trifluoromethylphenyl isocyanate (274.3 g) are dissolved in acetonitrile (1 L), then 2-bromo-6-fluoroaniline (200 g) was added with acetonitrile (50 mL) flushed. The resulting clear solution is at 38 h reflux (ca. 85 0 stirred C), then under vacuum at 40 0 concentrated C a dogged mush. This is filtered off, with acetonitrile (260 mL, to 0-5 0 C cooled) washed and incubated overnight at 45 0 dried C in the VDO using entraining nitrogen. Thus, a total of 424.3 g of N- (2-bromo-6-fluorophenyl) -N ‘- get [2-methoxy-5- (trifluoromethyl) phenylJ-urea as a solid, corresponding to 99.2% of theory.

1 H NMR (300 MHz, d 6 -DMSO): δ = 8.93 (s, IH), 8.84 (s, IH), 8.52 (d, V = 2.3, 2H), 7, 55 (d, 2 = Vr = 7.7, IH), 7.38 to 7.26 (m, 3H), 7.22 (d, 2 J = 8.5, IH), 4.00 (s, 3H) ppm;

– – MS (API-ES-pos.): M / z = 409 [(M + H) + , 100%];

HPLC (Method 1): R τ = 22.4 and 30.6 min.

example 2

N- (2-bromo-6-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea (Alterhativsynthese)

2-methoxy-5-trifluoromethylphenyl isocyanate (1.19 kg) are at about 35 0 dissolved melted and C in acetonitrile (4.2 L), then 2-bromo-6-fluoroaniline (870 g) was added and with acetonitrile ( 380 mL) rinsed. The resulting clear solution is at 74-88 45 h 0 stirred C, then under vacuum (200 mbar) at 50 0 C to a dogged mush concentrated (amount of distillate 4.4 L). This is at room temperature with diisopropylether (1.5 L), washed aspirated, with diisopropylether (1.15 L) washed and at 45 0 C in the VDO using entraining nitrogen to constant weight (24 h) dried. Thus, a total of 1, 63 kg Η- (2-bromo-6-fluoro-phenyl) -W- – obtained [2-methoxy-5 (trifluoromethyl) phenyl] urea as a solid, corresponding to 87.5% of theory.

HPLC (Method 1): R τ = 22.6 and 30.8 min.

example 3

{8-Fluor-3-[2-methoxy-5-(trifluormethyl)phenyl]-2-oxo-l,2,3,4-tetrahydrochinazolin-4-yl}essigsäuremethylester

N- (2-bromo-6-fluorophenyl) -N- [2-methoxy-5- (trifluoromethyl) phenyl] urea (300 g) under a nitrogen atmosphere in isobutyronitrile (1.2 L) was suspended, then triethylamine

(21O mL), bis (acetonitrile) dichloropalladium (7.5 g), tris- (o-tolyl) phosphine (18.0 g) and

Methyl acrylate (210 mL) were added in this order. The resulting suspension is for 16 hours at reflux (ca. 102 0 stirred C) and then cooled to room temperature. Water (1.2 L) is added and the mixture 1 at room temperature stirred, then aspirated and washed with water / methanol h: washed and acetonitrile (10O mL) (1 1 30O mL). The residue is treated overnight at 45 0 dried C in the VDO using entraining nitrogen. Thus, a total of 208 g as a solid, corresponding to 68.5% of theory.

1 H NMR (300 MHz, d 6 -DMSO): δ = 9.73 (s, IH), 7.72 (d, 2 J = 7.3, IH), 7.71 (s, IH), 7 , 33 (d, 2 J = 9.3, IH), 7.15 (dd, 2 J = 9.6, 2 J = 8.6, IH), 7.01 (d, 2 J = 7.3 , IH), 6.99 to 6.94 (m, IH), 5.16 (t, 2 , J = 5.9, IH), 3.84 (s, 3H), 3.41 (s, 3H) , 2.81 (dd, 2 J = 15.4, 2 J = 5.8, IH), 2.62 (dd, 2 J = 15.4, 2 J = 6.3, IH) ppm;

MS (API-ES-pos.): M / z = 413 [(M + H) + , 100%], 825 [(2M + H) + , 14%];

HPLC (Method 1): R τ = 19.3 min; Pd (ICP): 16,000 ppm.

example 4

{8-Fluor-3-[2-methoxy-5-(trifluormethyl)phenyl]-2-oxo-l,2,3,4-tetrahydrochinazolin-4-yl}essigsäuremethylester (Alternative synthesis)

N- (2-bromo-6-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea (2.5 kg) is suspended under a nitrogen atmosphere in isobutyronitrile (9 L), then triethylamine (1.31 kg), bis (acetonitrile) dichloropalladium (64.9 g), tris (o-tolyl) phosphine (149 g) and methyl acrylate (1.59 kg) were added in this order. The resulting suspension is 22 hours at 90-100 0 stirred C, then cooled to room temperature. Water (9 L) is added and stirred, then aspirated and washed with water / methanol (1: 1, 2.5 L) at room temperature, the mixture for 1 hour and acetonitrile (850 mL). The residue is treated overnight at 45 0 dried C in the VDO using entraining nitrogen to constant weight (21 h). Thus, a total of 1.90 kg as a solid, corresponding to 74.9% of theory.

HPLC (Method 1): R τ = 19.4 min.

example 5

{2-Chlor-8-fluor-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäure-methylester / chlorination

A solution of 2.84 kg {8-fluoro-3- [2-methoxy-5- (trifluoromethyl) phenyl] -2-oxo-l, 2,3,4-tetrahydroquinazolin-4-yl} acetic acid methyl ester in 14.8 l of chlorobenzene is heated to reflux and the solvent is distilled off until water no longer separates. It is to 12O 0 cooled C. Within 10 min phosphorus oxychloride are metered in 3.17 kg, and then is added within a further 10 min 2.10 kg DBU. It is heated to reflux for 9 hours.

For working up the mixture is cooled to 40 0 C., stirred overnight and dosed the reactor contents to 11.4 L of water, previously estimated at 40 0 was tempered C. For dosing an internal temperature of 40-45 to 0 C, are satisfied. The mixture is allowed to cool to room temperature, 11.4 L of dichloromethane, filtered through a Seitz filter plate and the phases are separated. The organic phase is washed with 11.4 L of water, 11.4 L of an aqueous saturated sodium bicarbonate solution and again with 11.4 L of water. The organic phase is concentrated on a rotary evaporator in vacuo and the remaining residue (2.90 kg) is used without further treatment in the next step.

1 H NMR (300 MHz, d 6 -DMSO): δ = 7.93 to 7.82 (m, 2H), 7.38 (d, 2 J = 8.9, IH), 7.17 (m, 2H), 6.97 to 6.91 (m, IH), 5.45 and 5.29 (m and t, 2 , J = 5.4, IH), 3.91 and 3.84 (2s, 3H) , 3.48 (s, 3H), 3.0 to 2.6 (m, 2H) ppm;

MS (CI, NH 3 ): m / z = 431 [(M + H) + , 100%];

HPLC (Method 1): R τ = 23.5 min; typical Pd value (ICP): 170 ppm.

example 6

{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester / Amination – –

(52.5 g) is dissolved in 1,4-dioxane (10O mL), then (25.8 g) and DBU (20.4 g) was added at room temperature 3-methoxyphenylpiperazine, whereupon the temperature rises. The mixture is stirred at reflux for 22 h, then cooled to room temperature, with ethyl acetate (500 mL) and water (200 mL) and the phases separated. The organic phase (200 mL) washed with 0.2N hydrochloric acid (three times 100 mL) and water, dried over sodium sulfate and evaporated. Thus, a total of 62.5 g obtained as a solidified foam, which is reacted as the crude product without further purification.

HPLC (Method 1): R τ = 16.6 min.

example 7

{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester / Pot chlorination + amination

(50.0 g) is introduced in chlorobenzene (300 mL), then chlorobenzene is partially distilled (5O mL). The mixture is heated to 120 0 cooled C., DBU (36.9 g) is added, then at 120-128 is 0 C phosphorous oxychloride (33.4 mL) over 10 min. metered. The mixture (approximately 130 at reflux for 9 hours 0 C) stirred. Subsequently, at 40 0cooled C, slowly at 40-45 0 C with water (200 mL), cooled to room temperature and diluted with dichloromethane (200 mL), stirred and then the phases separated. The organic phase is washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL) and again water (200 mL), dried over sodium sulfate, concentrated by rotary evaporation and then under high vacuum at 50 0 dried C. The residue (48.1 g) is dissolved in chlorobenzene (20 mL), then with 1,4-dioxane (80 mL) at room temperature and 3-methoxyphenylpiperazine (23.6 g) and DBU (18.7 g) was added, whereupon the temperature rises. The mixture is stirred at reflux for 22 h, then cooled to room temperature, with ethyl acetate (500 mL) and water (200 mL) and the phases separated. The organic phase (200 mL) washed with 0.2N hydrochloric acid (three times 100 mL) and water, dried over sodium sulfate and evaporated. Thus, a total of 55.6 g obtained as a solidified foam, which is reacted as the crude product without further purification.

HPLC (Method 1): R τ = 16.2 min.

example 8

(^)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / saponification racemate

(64 g) is dissolved in 1,4-dioxane (45O mL) and IN sodium hydroxide solution (325 mL) and stirred for 2 h at room temperature, then dried in vacuo at 30 0 , a part of the solvent C is distilled off (400 mL). Toluene is added (300 mL) and the phases separated. The aqueous phase is washed with toluene (15O mL twice), then the combined organic phases again with IN sodium hydroxide solution (50 mL) are extracted. The pH of the combined aqueous phases with 2N hydrochloric acid (about 150 mL) to 7.5, then MIBK (15O mL) is added. The phases are separated, the aqueous phase extracted again with MIBK (15O mL), then dried the combined MIBK phases over sodium sulfate and at 45 0 concentrated C. Thus, a total of 64 g as an amorphous solid in quantitative yield.

HPLC (Method 1): R τ = 14.9 min.

Scheme 6:

Separation of enantiomers of {8-fluoro-2- [4- (3-methoxyphenyl) piperazin-l -yl] -3- [2-methoxy-5- (tri-fluoromethyl) phenyl] -3,4-dihydroquinazolin-4-yl } acetate

x (2S, 3S) -2,3-bis [(4-methylbenzoyl) – oxyjbemsteinsäure
x EtOAc

example 9

(2S, 3 £) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (1: 1 salt) / crystallization

(62.5 g, crude product) is dissolved and filtered in ethyl acetate (495 mL). To the filtrate is (35 25 ‘,) added 2,3-bis [(4-methylbenzoyl) oxy] succinic acid (42.0 g), the mixture for 30 minutes. stirred at room temperature, then with (35 25 “) -2,3-bis [(4-methylbenzoyl) oxy] -succinic acid – (l: l salt) (165 mg) was inoculated and stirred for 3 days at room temperature, then to 0-3 0 cooled C and stirred for a further 3 h, the suspension is suction filtered and washed with cold ethyl acetate (0-10. 0 C, 35 mL ) washed. the crystals are at 40 h 18 0 C in the VDO using entraining nitrogen dried. Thus 37.1 g of the salt are obtained as a solid, corresponding to 30.4% of theory over three stages (chlorination, amination and crystallization) on the racemate, or 60.8% based on the resulting S enantiomer.

– – 1 H NMR (300 MHz, d 6 -DMSO): δ = 7.90 (d, 2 J = 7.8, 4H), 7.56 (d, 2 J = 8.3, IH), 7 , 40 (d, 2 J = 7.8, 4H), 7.28 to 7.05 (m, 4H), 6.91 to 6.86 (m, 2H), 6.45 (d, 2 J = 8.3, IH), 6.39 to 6.36 (m, 2H), 5.82 (s, 2H), 4.94 (m, IH), 4.03 (q, 2 J = 7.1 , 2H), 3.83 (brs, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.47 to 3.36 (m, 8H and water, 2H), 2, 98 to 2.81 (m, 5H), 2.58 to 2.52 (m, IH), 2.41 (s, 6H), 1.99 (s, 3H), 1.18 (t, 2 J = 7.2, 3H) ppm;

HPLC (Method 1): R τ = 16.6 and 18.5 min.

example 10

(25,3iS) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (1: 1 salt) / recrystallization

(2S, 3S) -2,3-bis [(4-methy lbenzoyl) oxy] succinic acid – { (l: l salt) (36.8 g) is suspended in ethyl acetate (37o mL) and (77 by heating to reflux 0 C) dissolved. The mixture is slowly cooled to room temperature. Here there is a spontaneous crystallization. The suspension is stirred at RT for 16 h, then 0-5 0 cooled C and stirred for another 3 h. The suspension is suction filtered and washed with cold ethyl acetate (0-10 0 C, twice 15 ml). The crystals are at 45 h 18 0 C in the VDO using entraining nitrogen dried. Thus 33.6 g of the salt are obtained as a solid, corresponding to 91.3% of theory.

HPLC (Method 1): R τ = 16.9 and 18.8 min .;

HPLC (Method 3): 99.9% ee

example 11

(5)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl}essigsäure

(2IS I , 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (l: l salt) (10.1 g, containing 14 ppm of Pd) are suspended in ethyl acetate (100 mL) and shaken with saturated aqueous sodium bicarbonate solution (10O mL) shaken until both phases are clear. The phases are separated, the organic phase is evaporated. The residue is dissolved in 1,4-dioxane (100 mL) and IN sodium hydroxide solution (31.2 mL) and stirred for 3 h at room temperature. Subsequently, the pH is adjusted with IN hydrochloric acid (about 17 mL) is set to 7.5, MIBK (8O mL) was added, then the pH is adjusted with IN hydrochloric acid (about 2 mL) adjusted to 7.0. The phases are separated, the organic phase dried over sodium sulfate and concentrated. The residue is dissolved in ethanol and concentrated (40 mL), then again in ethanol (40 mL) and concentrated under high vacuum at 50 0 C dried. The solidified foam is at 45 h 18 0 C in the VDO using entraining nitrogen dried. Thus, a total of 5.05 g as an amorphous solid, corresponding to 85.0% of theory.

1 H NMR (300 MHz, d 6 -DMSO): δ = 7.53 (d, 2 J = 8.4, IH), 7.41 (brs, IH), 7.22 (d, 2 J = 8 , 5, IH), 7.09 to 7.01 (m, 2H), 6.86 (m, 2H), 6.45 (dd, V = 8.2, 3 J = 1.8, IH) 6.39 to 6.34 (m, 2H), 4.87 (t, 2 J = 7.3, IH), 3.79 (brs, 3H), 3.68 (s, 3H), 3.50 -3.38 (m, 4H), 2.96 to 2.75 (m, 5H), 2.45 to 2.40 (m, IH) ppm;

MS (API-ES-neg.): M / z = 571 [(MH), 100%];

HPLC (Method 1): R τ = 15.1 min;

HPLC (Method 2): 99.8% ee; Pd (ICP): <1 ppm.

example 12

(2 / ?, 3Λ) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (1: 1 salt) / crystallization R-isomer from the mother liquor

The mother liquor from a crystallization of (2IS ‘, 3S) -2,3-bis [(4-methylbenzoyl) oxy] -succinic acid – {8-fluoro-2- [4- (3-methoxyphenyl) piperazin-l -yl] -3- [2-methoxy-5- (trifluoromethyl) phenyl] -3,4-dihydroquinazolin-4-yl} acetic acid methyl ester (l: l-salt) in 279 g scale is washed with saturated aqueous sodium bicarbonate solution (1.5 L ) shaken, the phases are separated and the organic phase is shaken with semi-saturated aqueous sodium bicarbonate solution (1.5 L). The phases are separated, the organic phase dried over sodium sulfate and evaporated. The residue (188.4 g) is dissolved in ethyl acetate (1.57 L), then (2R, 3R) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (121.7 g) was added and the mixture 10 min. stirred at room temperature. Is then treated with (2R, 3R) -2,3-bis [(4-methyl-benzoyl) oxy] succinic acid – (l: l salt) (0.38 g) was inoculated and stirred for 18 h at room temperature, then to 0-3 0 cooled C and stirred for another 3 h. The suspension is suction filtered and washed with cold ethyl acetate (0-10 0 C, 50O ml). The crystals are at 40 h 18 0 C in the VDO using entraining nitrogen dried. So a total of 160 g of the salt are obtained as a solid.

HPLC (Method 1): R τ = 16.6 and 18.5 min .;

HPLC (Method 3): -99.0% ee

example 13

(i?)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / production R-isomer

(2Λ, 3 /?) – 2,3-bis [(4-methylbenzoyl) oxy] succinic acid – {8-fluoro-2- [4- (3-methoxy-phenyl) pipera-tine 1-yl] -3- [ 2-methoxy-5- (trifluormethy l) pheny l] -3, 4-dihydroquinazolin-4-y 1} -acetic acid methyl ester (1: 1 salt) (170 g) are suspended in ethyl acetate (85O mL) and as long as with saturated aqueous sodium bicarbonate (850 mL) shaken until both phases are clear (about 5 min.). The phases are separated, the solvent of the organic phase under normal pressure with 1, 4-dioxane to a final temperature of 99 0 exchanged C (portions distilled total 2.55 L solvent, and 2.55 L of 1,4-dioxane used). The mixture is cooled to room temperature and 18 at room temperature IN sodium hydroxide solution (525 mL) stirred. Subsequently, the pH value with concentrated hydrochloric acid (about 35 mL) is set to 7.5, MIBK (85O mL) was added, then the pH with concentrated hydrochloric acid (ca. 1O mL) adjusted to 7.0. The phases are separated, the organic phase dried over sodium sulfate and concentrated. The residue is dissolved in ethanol and concentrated (350 mL), then again in ethanol (350 mL) at 50 and 0 concentrated C. Thus, a total of 91.6 g as an amorphous solid, corresponding to 91.6% of theory.

HPLC (method 1): R 7 = 14.8 min.

– – Example 14

{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / racemization R-enantiomer

acetic acid (50 g) is dissolved in acetonitrile (500 mL) and treated with sodium methoxide (30% in methanol, 32.4 mL) and then stirred at reflux for 60 h. After cooling to room temperature the mixture is concentrated in vacuo to half, then with hydrochloric acid (20% strength, ca. 20 ml) adjusted to pH 7.5, MIBK (200 mL) was added and hydrochloric acid (20%) on pH 7 adjusted. The phases are separated, the organic phase dried over sodium sulfate and evaporated to the hard foam. The residue is dissolved in ethanol and concentrated (15O mL), then again in ethanol (15O mL) and concentrated. Thus, 54.2 g as an amorphous solid in quantitative yield.

HPLC (Method 1): R τ = 14.9 min .;

HPLC (method 4): 80.8 wt.%.

example 15

{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester / Esterification racemate

acetic acid (54 g) (540 g) was dissolved in methanol, then concentrated sulfuric acid (7.85 mL) is added. The mixture is stirred at reflux for 26 h, then cooled and concentrated in vacuo to about one third of the original volume. Water (15O mL) and dichloromethane (15O mL) are added, then the phases are separated. The organic phase is washed with saturated sodium bicarbonate solution (two times 140 mL), dried over sodium sulfate and concentrated to a foamy residue. This is twice in succession in ethanol (150 mL) and concentrated, dried in vacuo using entraining nitrogen then 18 h. Thus, a total of 41.6 g as an amorphous solid, corresponding to 75.2% of theory.

HPLC (Method 1): R τ = 16.8 min .;

HPLC (method 4): 85.3 wt.%;

HPLC (Method 3): -8.5% ee

example 16

(25 1 , 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – { (1: 1 salt) / crystallization of esterified racemate

(41.0 g) is suspended in ethyl acetate (287 mL), then (2S, 3IS) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid (27.5 g) was added. The mixture is 30 minutes. stirred at room temperature, then with (2 <S ‘, 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) (0.08 g) was inoculated. The suspension is stirred at RT for 16 h, then 0-5 0 cooled C and stirred for another 3 h, then filtered off with suction and washed with cold ethyl acetate (0-10 0 C, four times 16 ml). The crystals are at 45 h 18 0 C in the VDO using entraining nitrogen dried. So a total of 25.4 g of the salt are obtained as a solid, corresponding to 37.4% of theory.

HPLC (Method 1): R τ = 16.9 and 18.8 min .;

HPLC (method 4): 99.5 wt.%;

HPLC (Method 3): 99.3% ee

example 17

(iS)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / saponification crystals

(25,3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (l rl salt) (25.1 g) is suspended in ethyl acetate (25O mL) and shaken with saturated aqueous sodium bicarbonate solution (250 mL) shaken until both phases are clear. The phases are separated, the organic phase is evaporated. Dissolve the residue in 1, 4-dioxane (25O mL) and IN sodium hydroxide solution (77.4 mL) and stirred for 18 h at room temperature. Subsequently, the pH is adjusted with IN hydrochloric acid (about 50 mL) is set to 7.5, was added MIBK (240 mL), then the pH is adjusted with IN hydrochloric acid (about 15 mL) adjusted to 7.0. The phases are separated, the organic phase dried over sodium sulfate and concentrated. The residue is dissolved in ethanol and concentrated (90 mL), then again in ethanol (90 mL) and concentrated. The solidified foam is at 45 h 180 C in the VDO using entraining nitrogen dried. Thus, a total of 12 g as an amorphous solid, corresponding to 81.2% of the theory.

HPLC (Method 1): R τ = 15.1 min;

HPLC (Method 2): 97.5% ee; Pd (ICP): <20 ppm.

Alternative method for the racemization:

example 18

(i)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetic acid / saponification enriched R isomer from the mother liquor after crystallization

The mother liquor from a crystallization of (2 J S ‘, 35) -2,3-bis [(4-methylbenzoyl) oxy] -succinic acid – (l: l-salt) in 207 g scale is shaken with saturated aqueous sodium bicarbonate (500 mL), the phases are separated and the organic phase is shaken with semi-saturated aqueous sodium bicarbonate solution (500 mL). The phases are separated, the organic phase dried over sodium sulfate and evaporated. The residue is dissolved in ethanol (500 mL) and rotary evaporated to a hard foam. This is in 1,4-dioxane (1.6 L) and IN sodium hydroxide solution (1.04 L) and stirred at room temperature for 18 h, then toluene is added (1.5 L) and the phases separated. The aqueous phase is adjusted with hydrochloric acid (20% strength, ca. 155 ml) of pH 14 to pH 8, then is added MIBK (1.25 L) and hydrochloric acid (20% strength, ca. 25 mL) to pH 7 readjusted. The phases are separated, the organic phase dried over sodium sulfate and evaporated to the hard foam. This is at 45 h 18 0 C in the VDO using entraining nitrogen dried. Thus, a total of 150 g obtained as (R / S) mixture as an amorphous solid.

HPLC (Method 2): 14.6% ee

– – Example 19

(i)-{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-(2-methoxy-5-trifluormethylphenyl)-3,4-dihydrochinazolin-4-yl} acetate / racemization

(150 g, R / S mixture with -14.6% ee) is dissolved in acetonitrile (1.5 L) and treated with sodium methoxide (30% in methanol, 97.2 mL) was added, then stirred at reflux for 77 h , After cooling to room temperature the mixture is concentrated in vacuo to half, then with hydrochloric acid (20% strength, ca. 80 mL) made of pH 13 to pH 7.5, was added MIBK (0.6 L) and treated with hydrochloric acid ( 20% strength, ca. 3 mL) adjusted to pH. 7 The phases are separated, the organic phase dried over sodium sulfate and evaporated to the hard foam. The residue is dissolved in ethanol and concentrated (500 mL), then again in ethanol (500 mL) and concentrated, then 18 h at 450 dried C in the VDO using entraining nitrogen. Thus, a total of 148 g as an amorphous solid, corresponding to 98.7% of theory.

HPLC (Method 2): 1.5% ee

example 20

{8-Fluor-2-[4-(3-methoxyphenyl)piperazin-l-yl]-3-[2-methoxy-5-(trifluormethyl)phenyl]-3,4-dihydrochinazolin-4-yl}essigsäuremethylester (Esterification)

(±) – {8-fluoro-2- [4- (3-methoxyphenyl l) piperazin-1 -yl] -3- (2-methoxy-5-trifluormethy lphenyl) -3, 4-dihydroquinazolin-4-yl} acetic acid (148 g) (1480 g) was dissolved in methanol, then concentrated sulfuric acid (21.5 mL) is added. The mixture is stirred at reflux for 6 h, then cooled and concentrated in vacuo to about one third of the original volume. Water (400 mL) and dichloromethane (400 mL) are added, then the phases are separated. The organic phase (diluted twice 375 mL, 300 mL water) with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to a foamy residue. This is twice in succession in ethanol (each 400 mL) and concentrated, dried in vacuo using entraining nitrogen then 18 h. Thus, a total of 124 g as an amorphous solid, corresponding to 81.9% of theory.

HPLC (Method 1): R τ = 16.9 min .;

example 21

(25.35) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) / crystallization of esterified racemate

(2S, 3S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) (123 g, 14.4% ee) is suspended in ethyl acetate (861 mL) and filtered, then (2IS ‘, 3IS) -2,3-bis [(4-methylbenzoyl) oxy ] succinic acid (82.5 g). The mixture 30 min. stirred at room temperature, then with (2 £, 3 <S) -2,3-bis [(4-methylbenzoyl) oxy] succinic acid – (1: 1 salt) (0.24 g) was inoculated. The suspension is stirred for 4 days at RT, then concentrated to approximately 600 mL and again with (25 ‘, 3 1 -2,3-bis [(4-methylbenzoyl) oxy] succinic acid S) – (l: l salt) (0.24 g) was inoculated. The suspension is stirred for 1 week at RT, to 0-5 0 cooled C and further stirred for 3 hours, then filtered off with suction and washed with cold ethyl acetate (0-10 0 C, 4 x 40 ml). The crystals are at 45 h 18 0 C in the VDO using entraining nitrogen dried. So a total of 1 1.8 g of salt are obtained as a solid, corresponding to 5.8% of theory.

Scheme 7:

example 22

N- (2-Fluoφhenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea

2-methoxy-5-trifluoromethylphenyl isocyanate (1057.8 g) is dissolved in acetonitrile (4240 mL), then 2-fluoro aniline (540.8 g) was added with acetonitrile (50 mL) flushed.The resulting clear solution is stirred for 4 h at reflux (about 82 ° C), then seeded at about 78 ° C and about 15 min. touched. The suspension is on 0 0 cooled C, aspirated and the product with acetonitrile (950 mL, to 0-5 0 cooled C) washed. The product is dried overnight at 45 ° C in a vacuum drying oven using entraining nitrogen. Thus, a total of 1380.8 g of N- (2-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] -harnstqff obtained as a solid, corresponding to 86.4% of theory.

1 H NMR (500 MHz, d 6 -DMSO): δ = 9.36 (s, IH), 9.04 (s, IH), 8.55 (d, 1.7 Hz, IH), 8.17 ( t, 8.2 Hz, IH), 7.33 (d, 8.5 Hz, IH), 7.20 to 7.26 (m, 2H), 7.14 (t, 7.6 Hz, IH), 7, 02 (m, IH), 3.97 (s, 3H) ppm;

MS (API-ES-pos.): M / z = 329 [(M + H) + , 100%];

HPLC: R τ = 48.7 min.

Instrument: HP 1100 Multiple Wavelength detection; Column: Phenomenex-Prodigy ODS (3) 100A, 150 mm x 3 mm, 3 microns; Eluent A: (1.36 g KH 2 PO 4 +0.7 mL H 3PO 4 ) / L water, eluent B:

acetonitrile; Gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; Flow: 0.5 mL / min; Temp .: 55 0 C; UV detection: 210 nm.

example 23

Methyl (2E) -3- {3-fluoro-2 – [({[2-methoxy-5 – (trifluormethy l) pheny 1] amino} carbonylation l) amino] pheny 1} acrylate

N- (2-fluorophenyl) -N ‘- [2-methoxy-5- (trifluoromethyl) phenyl] urea (0.225 kg) is dissolved in acetic acid (6.75 L) and (30.3 g) was added with palladium acetate. Then 65% oleum is (247.5 g) is added and then methyl acrylate (90 g). The solution is stirred overnight at room temperature. Then, at about 30 0 C and about 30 mbar acetic acid (3740 g) were distilled off. The suspension is treated with water (2.25 L) and stirred for about 1 hour. The product is drained, washed twice with water (0.5 L) and incubated overnight at 50 0 dried C in a vacuum drying oven using entraining nitrogen. Thus, a total of 210.3 g of methyl (2E) -3- {3-fluoro-be 2 – [({[2-methoxy-5- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenyl} acrylate obtained as a solid, corresponding to 72.2% of theory.

1 H NMR (300 MHz, d 6 -DMSO): δ = 9.16 (s, IH), 8.84 (s, IH), 8.45 (d, 1.7 Hz, IH), 7.73 ( m, 2H), 7.33 (m, 3H), 7.22 (d, 8.6 Hz, IH), 6.70 (d, 16Hz, IH), 3.99 (s, 3H), 3.71 (s, 3H) ppm;

MS (API-ES-pos.): M / z = 429.9 [(M + NH,) + ]; 412.9 [(M + H) + ]

HPLC: R τ = 46.4 min.

Instrument: HP 1100 Multiple Wavelength detection; Column: Phenomenex-Prodigy ODS (3) 100A, 150 mm x 3 mm, 3 microns; Eluent A: (1.36 g KH 2 PO 4 +0.7 mL H 3PO 4 ) / L water, eluent B: acetonitrile; Gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; Flow: 0.5 mL / min; Temp .: 55 0 C; UV detection: 210 nm.

example 24

{8-FluorO-[2-methoxy-5-(trifluormethyl)phenyl]-2-oxo-l,2,3,4-tetrahydrochinazolin-4-yl}essigsäuremethylester

Methyl (2E) -3- {3-fluoro-2 – [({[2-methoxy-5- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenyl} acrylate (50 g) is dissolved in acetone (1.2 L) was suspended and 3.7 g) was added l, 8-diazabicyclo [5.4.0] undec-7-ene (. The suspension is heated to reflux (ca..56 ° C) and stirred for 4 h. The resulting clear solution is hot through diatomaceous earth (5 g) was filtered. The diatomaceous earth is rinsed with warm acetone (100 ml). Subsequently, acetone (550 g) was distilled off. The resulting suspension is in 3 h at O 0 cooled and stirred C. The product is drained, washed twice with cold acetone (50 ml) and incubated overnight at 45 0 dried C in a vacuum drying oven using entraining nitrogen. Thus, a total of 44.5 g of {8-fluoro-3- [2-methoxy-5- (trifluoromethyl) phenyl] -2-oxo-1, 2, 3, 4-tetrahydrochinazo-lin-4-yl} acetic acid methyl ester as a solid, corresponding to 89% of theory.

1 H NMR (300 MHz, d 6 -DMSO): δ = 9.73 (s, IH), 7.72 (d, 2 J = 7.3, IH), 7.71 (s, IH), 7 , 33 (d, 2 J = 9.3, IH), 7.15 (dd, 2 J = 9.6, 2 J = 8.6, IH), 7.01 (d, 2 J = 7.3 , IH), 6.99 to 6.94 (m, IH), 5.16 (t, 2 J =

5.9, IH), 3.84 (s, 3H), 3.41 (s, 3H), 2.81 (dd, 1 J = 15.4, V = 5.8, IH), 2.62 (dd, 2 Vr = = 15.4, V = 6.3, IH) ppm;

MS (API-ES-pos.): M / z = 413 [(M + H) + , 100%], 825 [(2M + H) + , 14%];

HPLC: R τ = 37.1 min.

Instrument: HP 1100 Multiple Wavelength detection; Column: Phenomenex-Prodigy ODS (3) 100A, 150 mm x 3 mm, 3 microns; Eluent A: (1.36 g KH 2 PO 4 +0.7 mL H 3PO 4 ) / L water, eluent B: acetonitrile; Gradient: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; Flow: 0.5 mL / min; Temp .: 55 0 C; UV detection: 210 nm.

PATENT

WO 2015088931

Human cytomegalovirus (HCMV) is ubiquitously distributed in the human population. In immunocompetent adults infections are mainly asymptomatic, but in

immunocompromised patients, such as transplant recipients or AIDS patients, life threatening infections occur at a high rate. HCMV is also the leading cause of birth defects among congenitally transmitted viral infections.

Various substituted heterocyclic compounds are inhibitors of the HCMV terminase enzyme. Included in these heterocycles are quinazolines related to Compound A, as defined and described below. These compounds and pharmaceutically acceptable salts thereof are useful in the treatment or prophylaxis of infection by HCMV and in the treatment, prophylaxis, or delay in the onset or progression of HCMV infection. Representative quinazoline compounds that are useful for treating HCMV infection are described, for example, in US Patent Patent No. 7, 196,086. Among the compounds disclosed in US7, 196,086, is (S)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-l-yl)-3,4-dihydroquinazolin-4-yl)acetic acid, hereinafter referred to as Compound A. Compound A is a known inhibitor of HCMV terminase. The structure of Compound A is as follows:

Compound A

US Patent Nos. 7,196,086 and 8,084,604 disclose methodology that can be employed to prepare Compound A and related quinazoline-based HCMV terminase inhibitors. These methods are practical routes for the preparation of Compound A and related heterocyclic compounds.

EXAMPLE 6

Preparation of Compound A

To a slurry of compound 7 (20g, 18.9 mmol) in MTBE (40.0 mL) at room temperature was added a solution of sodium phosphate dibasic dihydrate (8.42 g, 47.3 mmol) in water (80 mL) and the resulting slurry was allowed to stir at room temperature for 40 minutes. The reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed with a solution of sodium phosphate dibasic dihydrate (3.37 g, 18.91 mmol) in water (40.0 mL). A solution of KOH (4.99 g, 76 mmol) in water (80 mL) and methanol (10.00 mL) was then added to the organic phase and the resulting mixture was heated to 50 °C and allowed to stir at this temperature for 6 hours. MTBE (20 mL) and water (40 mL) were then added to the

reaction mixture and the resulting solution was transferred to a separatory funnel and the aqueous layer was collected and washed with MTBE (20 mL). Additional MTBE (40 mL) was added to the aqueous layer and the resulting solution was adjusted to pH 4-5 via slow addition of concentrated HCl. The resulting acidified solution was transferred to a separatory funnel and the organic phase was collected, concentrated in vacuo and solvent switched with acetone, maintaining a 30 mL volume. The resulting acetone solution was added dropwise to water and the precipitate formed was filtered to provide compound A as a white solid (10 g, 92%). XH NMR (500 MHz, d6-DMSO): δΗ 12.6 (1H, s), 7.52 (1H, dd, J= 8.6, 1.3 Hz), 7.41 (1H, brs), 7.22 (1H, d, J= 7.2 Hz), 7.08-7.02 (2H, m), 6.87-6.84 (2H, m), 6.44 (1H, dd, J= 8.3, 1.8 Hz), 6.39 (1H, t, J= 2.1 Hz), 6.35 (1H, dd, J= 8.1, 2.0 Hz), 4.89 (1H, t, J= 7.3 Hz), 3.79 (3H, br s), 3.68 (3H, s), 3.47 (2H, br s), 3.39 (2H, br s), 2.96-2.93 (2H, m), 2.82-2.77 (3H, m), 2.44 (1H, dd, J = 14.8, 7.4 Hz).

XAMPLE 1

Preparation of Intermediate Compound 2


N,N-dicyclohexylmethylamine

IPAC, 80°C

To a degassed solution of 2-bromo-6-fluoroaniline (1, 99.5 g, 0.524 mol), methyl acrylate (95.0 mL, 1.05 mol), Chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (0.537 g, 1.05 mmol) in isopropyl acetate (796 mL), was added degassed N,N-dicyclohexylmethylamine (135 mL, 0.628 mol). The resulting reaction was heated to 80 °C and allowed to stir at this temperature for 5 hours. The resulting slurry was cooled to 20 °C and filtered. The filtrate was washed with 1 M citric acid to provide a solution that contained compound 2 (99.3 g, 97% assay yield) in isopropyl acrylate, which was used without further purification. ‘H NMR (500 MHz, d-CHCl3): δΗ 7.79 ppm (1H, d, J= 15.9 Hz), 7.17 ppm (1H, d, J= 8.2 Hz), 7.00 ppm (1H, ddd, J= 10.7, 8.2, 1.2 Hz), 6.69 ppm (1H, td, J = 8.2, 5.1 Hz), 6.38 ppm (1H, d, J= 15.9 Hz), 4.06 ppm (2H, br s), 3.81 ppm (3H, s).

EXAMPLE 2

Preparation of Intermediate Compound 3

To a solution of compound 2 (48.8 g, 0.250 mol) in 683 mL of isopropyl acetate was added 244 mL of water, followed by di-sodium hydrogen phosphate (53.2 g, 0.375 mol). To the resulting solution was added phenyl chloroformate (39.2 mL, 0.313 mol) dropwise over 30 minutes. The resulting reaction was heated to 30 °C and allowed to stir at this temperature for 5 hours for 4 hours and then was heated to 60 °C and allowed to stir at this temperature for 5 hours for an additional 2 hours to remove excess phenyl chloroformate. An additional 293 mL of isopropyl acetate was then added and the reaction mixture was allowed to stir at room temperature until the solids completely dissolved into solution. The resulting reaction mixture was transferred to a separatory funnel and the organic phase was washed with 98 mL of water and collected to provide a solution of compound 3 in isopropyl acetate, which was used without further purification. XH NMR (500 MHz, d-acetonitrile): δΗ 7.91 ppm (1H, d, J= 15.9 Hz), 7.85 ppm (1H, br s), 7.63 ppm (1H, d, J= 7.9 Hz), 7.45-7.39 ppm (3H, m), 7.33-7.27 ppm (2H, m), 7.21 ppm (2H, br), 6.60 ppm (1H, d, J= 16.0 Hz).

EXAMPLE 3

Preparation of Intermediate Compound 4

A solution of compound 3 (79.0 g, 0.250 mol), 2-methoxy-5-(trifluoromethyl)aniline (52.7 g, 0.276 mol), and 4-dimethylaminopyridine (0.92 g, 0.0075 mol) in isopropyl acetate (780 mL) was heated to reflux and allowed to stir at this temperature for 5 hours. The resulting slurry was cooled to 20 °C, then allowed to stir at this temperature for for two hours at this temperature, then filtered. The collected filter cake was dried in vacuo to provide compound 5 (95.0 g, 0.230 mol) as a white solid, which was used without further purification. ¾ NMR (500 MHz, d-TFA): δΗ 7.98 ppm (1H, d, J= 16.1 Hz), 7.87 ppm (1H, s), 7.47 ppm (1H, d, J = 7.9 Hz), 7.41 ppm (1H, d, J= 8.5 Hz), 7.35 ppm (1H, q, J= 8.5 Hz), 7.19 ppm (1H, t, J= 8.6 Hz), 6.98 ppm (1H, d, J= 8.6 Hz), 6.56 ppm (1H, d, J= 16.0 Hz), 3.85 ppm (6H, br s).

EXAMPLE 4

Preparation of Intermediate Compound 6

To a stirred suspension of compound 4 (14.0 g, 34.0 mmol) in toluene (140 mL) at room temperature was added 2-picoline (10.1 mL, 102 mmol) followed by PCI5 (8.19 g, 37.3 mmol). The resulting reaction was heated to 40 °C and allowed to stir at this temperature for 4 hours, then was cooled to 0 °C and cautiously (internal temperature kept <15 °C) quenched with KOH (2 M, 102 mL). The resulting solution was allowed to warm to room temperature, allowed to stir for 30 minutes, then was filtered and the filtrate transferred to a separatory funnel. The organic phase was washed sequentially with H3PO4 (1M, 50 mL) and H20 (50 mL) to provide a solution of compound 5 in toluene, which was used without further purification. XH NMR (500 MHz, d6-DMSO): δΗ 7.96 (1H, d, J= 16.2 Hz), 7.74 (1H, d, J= 7.9 Hz), 7.61 (1H, dd, J= 6.7, 1.6 Hz), 7.50 (1H, d, J= 1.9 Hz), 7.43 (1H, t, J= 9.2 Hz), 7.30 (1H, d, J= 8.4 Hz), 7.28 (1H, m), 6.79 (1H, d, J= 16.2 Hz), 3.91 (3H, s), 3.74 (3H, s).

To the solution of compound 5 at room temperature was added an aqueous solution of piperazine hydrochloride (0.40 M, 93.3 mL, 37.3 mmol) followed by Na2HP04 (14.5 g, 102 mmol). The resulting reaction was allowed to stir for 1 hour at room temperature, then transferred to a separatory funnel. The organic phase was washed sequentially with aH2P04 (50 mL) and H20 (50 mL). Salicylic acid (5.16 g, 37.3 mmol) was then added to the organic phase, and the resulting solution was cooled to 0 °C and allowed to stir at this temperature for 1 hour to provide a slurry which was filtered and washed with cold toluene (50 mL). The filter cake was dried under air to provide compound 6 (23.0 g, 31.7 mmol, 93 %) as a white crystalline solid: XH NMR (500 MHz, d6-DMSO): δΗ 12.9 (1H, br s), 7.75 (1H, dd, J= 7.8, 1.8 Hz), 7.72 (1H, d, J= 16.1 Hz), 7.40 (1H, td, J= 7.2, 1.7 Hz), 7.27 (1H, d, J= 7.8 Hz), 7.17 (1H, m), 7.16 (1H, t, J= 8.2 Hz), 7.02 (1H, br s), 6.95 (1H, t, J= 8.6 Hz), 6.88-6.81 (3H, m), 6.78 (1H, br s), 6.60 (1H, dd, J= 8.2, 2.0 Hz), 6.54 (1H, m), 6.48 (1H, d, J= 16.1 Hz), 6.43 (1H, dd, J= 8.0, 2.1 Hz), 3.73 (3H, s), 3.71 (3H, s), 3.69 (4H, br s), 3.68 (3H, s).

Free Base: XH NMR (500 MHz, CD3CN): δΗ 7.91 (1H, d, J= 16.1 Hz), 7.29 (1H, d, J= 8.0 Hz), 7.24 (1H, d, J= 1.4 Hz), 7.20 (1H, t, J= 8.1 Hz), 7.15 (1H, dd, J= 8.6, 1.4 Hz), 6.94 (1H, m), 6.92 (1H, t, J= 8.1 Hz), 6.80 (1H, td, J= 8.1, 5.4 Hz), 6.60 (1H, dd, J= 8.3, 2.2 Hz), 6.54 (1H, t, J= 2.2 Hz), 6.50 (1H, d, J= 16.1 Hz), 6.47 (2H, m), 3.80 (3H, s), 3.79 (3H, s), 3.72 (3H, s), 3.63 (4H, t, J= 5.1 Hz), 3.25 (4H, t, J= 5.0 Hz).

2: 1 NDSA Salt: ‘H NMR (500 MHz, d6-DMSO): δΗ 10.2 (2H, br s), 8.86 (1H, d, J= 8.6 Hz), 7.92 (1H, d, J= 7.0 Hz), 7.47-7.37 (4H, m), 7.27-7.14 (4H, m), 6.96 (1H, d, J= 8.6 Hz), 6.65 (1H, d, J= 8.3 Hz), 6.59 (1H, s), 6.54 (1H, d, J= 15.9 Hz), 6.47 (1H, d, J= 8.3 Hz), 3.91 (4H, m), 3.77 (3H, s), 3.76 (3H, s), 3.74 (3H, s), 3.43 (4H, m). 1,5 -naphthalene disulfonic acid

EXAMPLE 5

Preparation of Intermediate Compound 7

To a suspension of compound 6 (12.5 g, 16.6 mmol) in 125 mL of toluene was added 50 mL of 0.43M aqueous K3P04. The resulting reaction was allowed to stir for 1 hour at room temperature and the reaction mixture was transferred to a separatory funnel. The organic phase was collected, washed once with 30 mL 0.43M aqueous K3P04then cooled to 0 °C and aqueous K3P04 (60 mL, 0.43 M, 25.7 mmol) was added. To the resulting solution was added a room temperature solution of ((lS,2S,4S,5R)-l-(3,5-bis(trifluoromethyl)benzyl)-2-((R)-

hydroxy( 1 -(3 -(trifluoromethyl)benzyl)quinolin- 1 -ium-4-yl)methyl)-5-vinylquinuclidin- 1 -ium bromide) (0.704 g, 0.838 mmol) in 1.45 mL of DMF. The resulting reaction was allowed to stir at 0 °C until the reaction was complete (monitored by HPLC), then the reaction mixture was transferred to a separatory funnel and the organic phase was collected and washed sequentially with 1M glycolic acid (25 mL) and water (25 mL). The organic phase was filtered through solka flok and concentrated in vacuo to a total volume of 60 mL. Ethyl acetate (20 mL) was added to the resulting solution, followed by (S,S)-Di-P-Toluoyl-D-tartaric acid (5.61 g, 14.1 mmol). Penultimate seed (0.2 g) was added the resulting solution was allowed to stir at room

temperature for 12 hours. The solution was then filtered and the collected solid was washed twice with ethyl acetate, then dried in vacuo to provide compound 7 as its DTTA salt ethyl acetate solvate (13.8 g, 78%) . ‘H NMR (500 MHz, d6-DMSO): δΗ 13.95 (2H, br s), 7.90 (4H, d, J= 8.1 Hz), 7.55 (1H, dd, J= 8.6, 1.3 Hz), 7.38 (4H, d, J= 8.1 Hz), 7.26 (1H, d, J= 7.8 Hz), 7.09-7.05 (3H, m), 6.91-6.86 (2H, m), 6.44 (1H, dd, J= 8.2, 1.7 Hz), 6.39 (1H, t, J= 2.0 Hz), 6.36 (1H, dd, J= 8.2, 2.0 Hz), 5.82 (2H, s), 4.94 (1H, t, J= 7.1 Hz), 4.02 (2H, q, J= 7.1 Hz), 3.83 (3H, br s), 3.68 (3H, s), 3.64 (3H, s), 3.47 (2H, br s), 3.37 (2H, br s), 2.95 (2H, br s), 2.87- 2.80 (3H, m), 2.56 (1H, dd, J= 14.3, 7.0 Hz), 2.39 (6H, s), 1.98 (3H, s), 1.17 (3H, t, J= 7.1 Hz).

PAPER

Asymmetric Synthesis of Letermovir Using a Novel Phase-Transfer-Catalyzed Aza-Michael Reaction

Department of Process Chemistry, Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00076
Publication Date (Web): May 13, 2016
Copyright © 2016 American Chemical Society

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Abstract Image

The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in >60% yield over a total of seven steps from commercially available materials. Key to the effectiveness of this process is a novel cinchonidine-based PTC-catalyzed aza-Michael reaction to configure the single stereocenter.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00076

(S)-2-(8-Fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic Acid (Letermovir, 1)

 letermovir (1, 20.2 g, 35.3 mmol, 100 wt %, 94%) as an amorphous white powder. 1H NMR (DMSO-d6, 600 MHz) δH 7.52 (dd, J = 8.7, 1.7 Hz, 1H), 7.40 (brs, 1H), 7.21 (m, 1H), 7.07 (t, J = 8.2 Hz, 1H), 7.04 (m, 1H), 6.87 (m, 2H), 6.44 (dd, J = 8.2, 1.9 Hz, 1H), 6.40 (t, J = 2.3 Hz, 1H), 6.36 (dd, J = 8.0, 2.0 Hz, 1H), 4.89 (t, J = 7.2 Hz, 1H), 3.80 (brs, 3H), 3.68 (s, 3H), 3.39–3.48 (m, 4H), 2.82–2.95 (m, 4H), 2.80 (dd, J = 14.8, 7.4 Hz, 1H), 2.46 (dd, J = 14.9, 7.4 Hz, 1H); 13C NMR (DMSO-d6, 150 MHz) δC 171.8, 160.2, 156.5, 154.6 (d, JCF = 246.3 Hz), 153.2, 152.2, 134.2, 132.3 (d, JCF = 11.2 Hz), 129.6, 124.1 (q, JCF = 271.3 Hz), 123.8 (q, JCF = 3.7 Hz), 122.4, 122.1 (q, JCF = 7.1 Hz), 121.4 (q, JCF = 29.2 Hz), 120.8, 114.5 (d, JCF = 19.5 Hz), 113.3, 108.3, 104.6, 101.9, 59.0, 56.3, 54.8, 47.9, 45.6, 40.0; HR-MS calcd for C29H29F4N4O4+ [M + H]+ 573.2119, found 573.2117 (Δ = 0.2 mmu).

References

Masangkay, Estel Grace (July 29, 2014). “Merck Kicks Off Phase 3 Study Of CMV Drug Letermovir”. Retrieved 8 Oct 2014.

Patent ID Date Patent Title
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Patent ID Date Patent Title
US2015133461 2015-05-14 PHARMACEUTICAL COMPOSITION CONTAINING AN ANTIVIRALLY ACTIVE DIHYDROQUINAZOLINE DERIVATIVE
US2015050241 2015-02-19 METHOD OF TREATING VIRAL INFECTIONS
US2015045371 2015-02-12 Salts of a dihydroquinazoline derivative
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US8816075 2014-08-26 Process for the preparation of dihydroquinazolines
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Letermovir
Letermovir skeletal.svg
Systematic (IUPAC) name
{(4S)-8-Fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4-quinazolinyl}acetic acid
Clinical data
Routes of
administration
Oral
Legal status
Legal status
  • Investigational
Identifiers
ATC code None
PubChem CID 45138674
ChemSpider 26352849
UNII 1H09Y5WO1F Yes
ChEMBL CHEMBL1241951
Synonyms AIC246
Chemical data
Formula C29H28F4N4O4
Molar mass 572.55 g/mol

/////Letermovir, MK 8828, AIC 246, fast track status, US Food and Drug Administrationorphan drug status ,  European Medicines Agency

COC1=C(C=C(C=C1)C(F)(F)F)N2[C@H](C3=C(C(=CC=C3)F)N=C2N4CCN(CC4)C5=CC(=CC=C5)OC)CC(=O)O

GALETERONE


 

 

File:Galeterone.svg

Galeterone

SYNTHESIS SEE BELOW

A SARM potentially for the treatment of prostate cancer.

Research Code, TOK-001; VN; 124; 124-1; 1241

TOK-001; Galeterone; 851983-85-2; VN/124; UNII-WA33E149SW; VN/124-1;

CAS No. 851983-85-2(Galeterone)

(3S,8R,9S,10R,13S,14S)-17-(benzimidazol-1-yl)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1H-cyclopenta[a]phenanthren-3-ol

Fast track 2012 f

Molecular Formula: C26H32N2O
Molecular Weight: 388.54508 g/mol

 

Galeterone (TOK-001 or VN/124-1) is a novel steroidal antiandrogen under development by Tokai Pharmaceuticals for the treatment of prostate cancer. It possesses a unique dual mechanism of action, acting as both an androgen receptor antagonist and an inhibitor of CYP17A1, an enzyme required for the biosynthesis of the androgens.[1] It shows selectivity for 17,20-lyase over 17-hydroxylase.[2]

As of 2016, galeterone is being compared to enzalutamide in a phase III clinical trial (ARMOR3-SV) for AR-V7-expressing metastatic castration-resistant prostate cancer.[3][4]

Specific Androgen Receptor Modulator CYP17 Inhibitor TOK-001 is an orally bioavailable small-molecule androgen receptor modulator and CYP17 lyase inhibitor with potential antiandrogen activity. Galeterone exhibits three distinct mechanisms of action: 1) as an androgen receptor antagonist, 2) as a CYP17 lyase inhibitor and 3) by decreasing overall androgen receptor levels in prostate cancer tumors, all of which may result in a decrease in androgen-dependent growth signaling. Localized to the endoplasmic reticulum (ER), the cytochrome P450 enzyme CYP17 (P450C17 or CYP17A1) exhibits both 17alpha-hydroxylase and 17,20-lyase activities, and plays a key role in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.

About Galeterone

Tokai’s lead product candidate is galeterone, a highly-selective, oral small molecule with the potential to transform the treatment of prostate cancer. We are focusing our late-stage development of galeterone on the treatment of men with metastatic, castration-resistant prostate cancer, or CRPC, whose prostate tumor cells express the AR-V7 splice variant.


We are conducting ARMOR3-SV, a Phase 3 clinical trial of galeterone evaluating whether administration of galeterone results in a statistically significant increase in radiographic progression-free survival as compared to Xtandi® (enzalutamide), an oral therapy currently approved for the treatment of CRPC, in AR-V7 positive metastatic CRPC patients. ARMOR3-SV is the first pivotal trial in prostate cancer to employ a precision medicine approach for patient selection. For more information regarding ARMOR3-SV, click here.

Galeterone has been studied in over 250 subjects in Phase 1 and Phase 2 clinical trials, including in CRPC patients with and without the AR-V7 splice variant. In these trials, galeterone demonstrated good tolerability and showed clinically meaningful reductions in levels of prostate specific antigen, or PSA, a biochemincal marker used to evaluate prostate cancer patients for signs of response to therapy.

We are currently focusing our late-stage development of galeterone on AR-V7 positive metastatic CRPC patients because it represents an unmet need in prostate cancer and our precision medicine approach provides an efficient development path. Based on the data we and our collaborators have produced to date, we also believe there is rationale for the broader clinical exploration of galeterone in the future.


Galeterone acts by disrupting the androgen receptor signaling pathway. This pathway is activated by the binding of male hormones (also known as androgens), such as testosterone and dihydrotestosterone (DHT) to androgen receptors in prostate cancer cells.

Galeterone disrupts the activation of the androgen receptor pathway in three ways:

  • Androgen receptor degradation, which reduces the amount of androgen receptor protein in tumor cells. There are no currently marketed drugs whose mechanism of action entails degradation of the androgen receptor. Therefore, galeterone represents a potential first-in-class therapeutic opportunity.
  • CYP17 enzyme inhibition, which blocks the synthesis of testosterone. This mechanism has been validated clinically by Zytiga (abiraterone). Zytiga must be co-administered with the steroid prednisone in order to minimize the risk of a potentially fatal side effect called mineralocorticoid excess. Unlike Zytiga, galeterone has not been shown in clinical trials to cause mineralocorticoid excess and, as a result, does not require co-administration of steroids. As a result, we believe that galeterone may be easier to administer, provide convenience for patients and enhance patient compliance.
  • Androgen receptor inhibition, which blocks the binding of testosterone or DHT with the androgen receptor. This mechanism has been validated clinically by Xtandi® (enzalutamide), which is also currently approved for the treatment of CRPC. Xtandi™ has shown a risk of grand mal seizures in clinical trials. We have not had any reports of seizures in clinical trials of galeterone and, therefore, galeterone may have certain safety advantages over Xtandi.

 


Tokai retains global rights to galeterone. We intend to commercialize galeterone in the United States on our own, and to seek a partner to further develop and commercialize galeterone outside of the United States.

Galeterone has been granted Fast Track designation by U.S. Food and Drug Administration for the treatment of CRPC. Fast Track designation is designed to facilitate the development and expedite review of drugs intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

Androgen receptor degradation, which reduces the amount of androgen receptor protein in the tumor cells.

Androgen receptor antagonism, which blocks the binding of testosterone or DHT with the androgen receptor.

Inhibition of the enzyme CYP17, which blocks the synthesis of testosterone.

Figure 3: The structures of abiraterone, orteronel and galeterone.

From CYP17 inhibitors—abiraterone, C17,20-lyase inhibitors and multi-targeting agents

Nature Reviews Urology 11,32–42 (2014)
doi:10.1038/nrurol.2013.274

 SYNTHESIS

str1
CN 104098638

DETAILED DESCRIPTION

1J loss reaction.

  (1) raw material specifications to match.

acetate pregnancy dehydropregnenolone: ​​toluene + ethanol: Batch steep: hydrochloric acid amine light = 1: 3: 0 4: 0.213, which pregnenolone acetate pregnancy 160kg, toluene + ethanol 320kg + 160kg, approved Steep 64kg, hydrochloric acid amine light 34kg.

  (2) process operation.

  In the first input 1000L tank oximation with hydroxylamine hydrochloride in pyridine, and then pumped into a mixed solvent of toluene and ethanol, the reaction solution was stirred and heated to complete dissolution, pregnancy-dehydropregnenolone acetate was added and heated under reflux for 3 hours, cooling and crystallization, The Department conducted into the centrifuge centrifugal drying, apply a recovery from the mother liquor, rinse with warm water mixture to no foam, centrifugal drying, drying to a moisture at 0.2% or less, that acetic acid in pregnancy dehydropregnenolone oxime (oxime compounds) 163kg, content of 99%, a melting point of 202-204 ° C, a yield of about 102% (for pregnenolone acetate pregnancy weight ratio).

2, heavy drain hydrolysis reaction.

  (1) raw material specifications to match.

  acetate pregnancy dehydropregnenolone waning: Benzene: Batch steep: phosphorus oxychloride and toluene: HCl + water = 1: 6 5: 0 4: 1: 3.5, which acetate pregnancy alcohol one hand 163kg, benzene 1060kg, batch steep 64kg, phosphorus oxychloride and toluene 80kg + 80kg, hydrochloric acid + water 245kg + 325kg.

(2) process operation.

The first drying 2000L rearrangement reaction tank, then pumped to the reaction tank benzene, alcohol into acetate pregnancy oxime, pulls out into benzene, stirring heated to reflux until the reaction mixture is completely dissolved, cooling to 1 (TC When, pyridine, of the reaction liquid at temperatures down to 6 ° C, start dropping a mixed solution of previously prepared phosphorus oxychloride and toluene (1: 1 mass ratio), slowly dropping, dropping control, first After slow fast reaction when dropping liquid temperature control in 4-8 ° C, the addition was complete, the reaction solution at 9-12 ° C for 3 hours the first time under.

After incubation, a solution has been a mixed solution of hydrochloric acid and water, good preparation, while dropping the reaction liquid temperature is controlled at 15-25 ° C, the addition was complete, the reaction solution at 15-25 ° C under a second Insulation 1. 5-2 hours. After incubation, stand 40 minutes, then points to lower acidic water layer, the remaining upper layer was added 0.3 times the amount of 30-35 ° C in the brine and let stand 20 minutes, a second watershed, sub lower aqueous layer was then allowed to stand for 30 minutes, a third water diversion, to give the final weight of the upper layer reaction solution was drained.

  3, the red Dingding steam distillate process.

The rearrangement reaction liquid was pumped to punch distillate tank, conduct atmospheric distillate punch, has been rushed to the reaction mixture was distilled benzene mixed solvent only, at the start of the steam valve not to open too much, so as not to rush material, distillation after cooling discharge, centrifugal drying, washing with tap water to neutral, and then into the oven dried to a moisture in the square. 5% acetic acid in dehydroepiandrosterone (rearrangement thereof) The crude product is about 142kg, content of about 97.5%, a melting point of 160 ° C _165 ° C or so, yield about 88% (for acetate pregnancy dehydropregnenolone weight ratio).

  4, refining processes.

  The drying in acetic acid Dehydroepiandrosterone crude into refined tin, adding 8 times the weight of the crude methanol and 0.10 times the weight of activated carbon, heat, stirring to dissolve, reflux billion. 5 hours, filtered , concentrated, cooled to about 5 ° C, the discharge

str1
JMC 2005, 48, 2972-84
The most potent CYP17 inhibitors were 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (5, code named VN/124-1), 3β-hydroxy-17-(51-pyrimidyl)androsta-5,16-diene (15)
PAPER
JMC 1998 41, 902-12
The most potent compounds are 3β-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (17), 3β-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (19), and 17-(1H-imidazol-1-yl)androsta-4,16-dien-3-one (28), with Ki values of 1.2, 1.4, and 1.9 nM, respectively,
Discovery and Development of Galeterone (TOK-001 or VN/124-1)
for the Treatment of All Stages of Prostate Cancer…….http://pubs.acs.org/doi/pdf/10.1021/jm501239f
str1
str1
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References

 

Silberstein, John L.; Taylor, Maritza N.; Antonarakis, Emmanuel S. (2016-04-01). “Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer”. Current Urology Reports 17 (4): 29. doi:10.1007/s11934-016-0584-4. ISSN 1534-6285. PMID 26902623.

 

Galeterone
Galeterone.svg
Systematic (IUPAC) name
17-(1H-benzimidazol-1-yl)androsta-5,16-dien-3β-ol
Clinical data
Routes of
administration
Oral
Identifiers
CAS Number 851983-85-2
PubChem CID 11188409
ChemSpider 9363493
KEGG D10125 Yes
Chemical data
Formula C26H32N2O
Molar mass 388.25

///////

C[C@]12CC[C@@H](CC1=CC[C@@H]3[C@@H]2CC[C@]4([C@H]3CC=C4N5C=NC6=CC=CC=C65)C)O

CC12CCC(CC1=CCC3C2CCC4(C3CC=C4N5C=NC6=CC=CC=C65)C)O

Nabriva’s lefamulin, BC 3781 receives FDA fast-track status to treat CABP and ABSSSI


2D chemical structure of 1061872-97-6

Nabriva’s lefamulin receives FDA fast-track status to treat CABP and ABSSS
Austria-based Nabriva Therapeutics has received qualified infectious disease product (QIDP) and fast-track status designation from the US Food and Drug Administration for its lefamulin (BC 3781).

read

http://www.pharmaceutical-technology.com/news/newsnabrivas-lefamulin-receives-fda-fast-track-status-to-treat-cabp-and-absssi-4399182?WT.mc_id=DN_News

 

Antibiotics 02 00500 i025

BC-3781

Topical pleuromutilin antibiotic agent

Gram-positive, including MRSA, PHASE 2 COMPLETED,Infection, acute bacterial skin and skin structure (ABSSSI)

Nabriva (Austria), Nabriva Therapeutics AG

BC-3781

cas 1061872-97-6

UNII-61H04Z5F9K

(3aS,4R,5S,6S,8R,9R,9aR,10R)-5-Hydroxy-4,6,9,10-tetramethyl-1-oxo-6-vinyldecahydro-3a,9-propanocyclopenta[8]annulen-8-yl [[(1R,2R,4R)-4-amino-2-hydroxycyclohexyl]sulfanyl]acetate;

14-O-[2-[(1R,2R,4R)-4-Amino-2-hydroxycyclohexylsulfanyl]acetyl]mutilin

 

BC-3781 is a pleuromutilin antibiotic in early clinical development at Nabriva for the treatment of community acquired pneumonia and for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Pleuromutilin antibiotics interfere with bacterial protein synthesis via a specific interaction with the 23S rRNA of the 50S bacterial ribosome subunit. They have a distinct antibacterial profile and show no cross-resistance with any other class of antibiotics. In 2012, a codevelopment agreement was signed between Forest and Nabriva, but, in 2014, this agreement terminated and Nabriva retained all rights.

Chemical structure for UNII-61H04Z5F9K
The pleuromutilin BC-3781 belongs to the first generation of pleuromutilins to combine excellent oral
bioavailability with substantial activity against Gram-positive pathogens and atypicals as well as some
Gram-negative pathogens. In particular, BC-3781 is highly active against multi-drug resistant (MDR)
pathogens including methicillin resistant Staphylococcus aureus (MRSA), MDR Streptococcus pneumonia
(i.e. macrolide and quinolone resistance), and vancomycin resistant Enterococcus faecium. It is
characterized by excellent in vivo activities (e.g. pneumonia model), outstanding PK/PD parameters,
allowing once a day dosing, and a novel mode of action. BC-3781 is being developed for both oral and IV
administration and is intended for the treatment of serious multi-drug resistant skin & skin structure
infections (CSSI) and moderate to severe pneumonia (CAP, HAP etc).

Pleuromutilins have been known since 1951, but only entered the market in 2007 with the approval of retapamulin for topical use. Until today, there are no pleuromutilins for systemic use approved in human clinical practice.

Nabriva is currently working on the development of new compounds is this class. The lead compound, BC-3781, if approved, will be the first pleuromutilin for systemic use in humans.

The compound shows potent in vitro activity against a large collection of staphylococcistreptococci, andE. faecium. When compared to linezolid and vancomycin, the compound shows greater overall potency againstS. aureus [121]. BC-3781 shows improved activity against most bacteria commonly associated with community-acquired respiratory tract infections, the compound is especially potent against S. pneumoniaincluding penicillin resistant strains. It also shows improved activity against H. influenzaM. catarrhalisM. pneumoniae and C. pneumoniae.

BC-3781 is undergoing Phase I clinical trials for CAP and in March of 2011 has completed a Phase II clinical study comparing it to vancomycin for treatment of aBSSSI [119,120,121,122,123]. Nabriva Therapeutics AG announced that the cooperation with Forest Laboratories to develop the compound had elapsed, and that Nabriva retained all rights in BC-3781. The company informed that the product was Phase III ready and that it was seeking partners to continue further development [203].

Nabriva is also developing BC-7013 for topical use against Gram-positive infections and working on the discovery of new pleuromutilins [119,124].

Dr William Prince, CMO Nabriva Therapeutics commented:
“This is the first patient study with a systemic pleuromutilin. It will be an important proof of concept
for an exciting new class of antibiotics. The phase II study builds on our extensive preclinical and
phase I data which have demonstrated that BC-3781 can achieve therapeutically relevant blood and
tissue levels in man with excellent tolerability when administered by either oral or intravenous
routes.”

Dr. David Chiswell, CEO Nabriva Therapeutics commented:
“With a worldwide problem due to antibiotic resistant bacteria, there is a very significant need for
new classes of antibiotics with unique modes of action such as the pleuromutilins. The commercial
prospects for BC-3781 as the leading compound of an exciting new class are excellent, especially as it
has an ideal anti-bacterial spectrum for both skin and respiratory infections and is being developed
with both oral and intravenous formulations”

BC-3781 is highly active against key pathogens, including MRSA, associated with skin infections and
community and hospital acquired pneumonia and is more potent than Linezolid and vancomycin. The
compound’s novel mode of action ensures that it overcomes resistance mechanisms affecting all
approved classes of antibiotics. BC-378

 

About Nabriva Therapeutics
Nabriva Therapeutics is a biotechnology company focused on developing a new class of antibiotics for
the treatment of serious infections caused by resistant pathogens. Nabriva’s lead systemic product,
BC-3781, is being developed for the treatment of serious skin infections and bacterial pneumonia
caused by S. aureus, , S. pneumoniae, H. influenza, Mycoplasma, Legionella and other bacteria,
including drug resistant strains such as MRSA and vancomycin resistant E. faecium. In addition,
Nabriva Therapeutics’ topical pleuromutilin product candidate, BC-7013, is in clinical phase I. Nabriva
Therapeutics has a proven track record in world-class medicinal chemistry, clinical expertise, a
seasoned management team and solid IP. Nabriva Therapeutics is located in Vienna, Austria.

For more information on Nabriva please visit http://www.nabriva.comNabriva Therapeutics AG

…………………………………………

EP 2390245

 http://www.google.com/patents/EP2390245A1?cl=en

 

……………………………………………..

http://www.google.im/patents/US20090118366?cl=es

The trivial name mutilin refers to the IUPAC systematic name (1S, 2R, 3S, 4S, 6R, 7R, 8R, 14R)-3,6-dihydroxy-2,4,7,14-tetramethyl-4-vinyl-tricyclo[5.4.3.01,8]tetradecan-9-one. In the examples, pleuromutilin derivatives are numbered in analogy to the mutilin numbering system described by H. Berner (Berner, H.; Schulz, G.; Schneider H. Tetrahedron 1980, 36, 1807-1811.):

 

…………………………………………………….

http://www.google.com/patents/WO2008113089A1?cl=en

Pleuromutilin, a compound of formula A

is a naturally occurring antibiotic, e.g. produced by the basidomycetes Pleurotus mutilus and P. passeckerianus, see e.g. The Merck Index, 13th edition, item 7617. A number of further pleuromutilins having the principle ring structure of pleuromutilin and being substituted at the hydroxy group have been developed, e.g. as antimicrobials.

From WO 02/04414 Al pleuromutilin derivatives, e.g. 14-O-[(Aminocyclohexan-2-yl (and – 3-yl)-sulfanyl)-acetyl]-mutilins; from WO 07/014409 Al e.g. 14-O-[((Mono- or dialkylamino)-cycloalkylsulfanyl)-acetyl]-mutilins and from WO 07/000004 Al e.g. [((Acyl- hydroxy-amino)-cycloalkylsulfanyl)-acetyl]-mutilins, are known.

 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin hydrochloride

Example 1 – 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin hydrochloride + (IS, 2S, 4S) diastereomer hydrochloride

Step Al. 14-O-{[(1R, 2R, 4R)-4-tert-Butoxycarbonylamino-2-hydroxy- cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4S) diastereomer and 14-O-{[(lR, 2R, 5S)-5-i’eri’-Butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin + (IS, 2S, 5R) diastereomer and

14-0-{[(lR, 2R, 4S)-4-tert-Butoxycarbonylamino-2-hydroxy-cyclohexylsuIfanyl]-acetyl}- mutilin + (IS, 2S, 4R) diastereomer

To a solution of 3,4-epoxycyclohexyl-carbamic acid tert-butyl ester (Gomez-Sanchez, E.; Marco-Contelles J. Tetrahedron 2005, 61, 1207-1219.) (4.27g, 20mmol) and pleuromutilin thiol (Nagarajan, R. Eli Lilly and Company 1978, US4, 130,709) (7.10 g, 18 mmol) in 200 ml of tetrahydrofuran was added aluminum oxide (40 g, Brockmann activity I, neutral) and the resulting mixture was stirred for 40 hours at room temperature. The suspension was filtered and concentrated under reduced pressure. The residue was subjected to chromatography (silica, cyclohcxane / ethyl acetate = 1/1) to yield 14-O-{[(1R, 2R, 4R)-4-ler(- butoxycarbonylamino-2-hydroxy-cyclohcxylsulfanyl]-acctyl}-mutilin + (IS, 2S, 4S) diastereomer (a) (Rf = 0.38, 1.34g, 12%) as well as a mixture of 14-O-{[(1R, 2R, 5S)-5-tert- butoxycarbonylumino-2-hy(lroxy-cyclohcxylsulfnnyl]-ncctyl}-niυtilin + (I S, 2S, 5R) diastereomer and 14-O-{[(1R, 2R, 4S)-4-tert-butoxycarbonylamino-2-hydroxy- cyclυhexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4R) diastereomer (b) (Rf = 0.26, 2.81 g, 25%) as colorless amorphous foams. (a): 1H NMR (400MHz, DMSOd6, δ, ppm, inter alia): 6.74 (d, IH, NH, J = 7Hz), 6.13 (dd, IH, 19-H, J – I lHz and 18Hz), 5.54 (d, IH, 14-H, J = 8Hz), 5.05 (m, 2H, 20-H), 4.90 (d, IH, 2′-OH, J = 5Hz), 4.48 (d, IH, 11-OH, J = 6Hz), 3.55 – 3.20 (m, 6H, 1 ‘-H, 2-H, 4′-H, 11-H, 22-H), 2.40 (bs, IH, 4-H), 1.36 (s, 3H, 15-CH3), 1.35 (s, 9H, tert-butyl), 1.06 (s, 3H, 18-CH3), 0.81 (d, 3H, 17-CH3, J = 7Hz), 0.62 (d, 3H, 16-CH3, J = 7Hz). MS-ESI (m/z): 630 (MNa+), 1237 (2MNa+).

(b): 1H NMR (400MHz, DMSO-de, δ, ppm, inter alia): 6.70 (d, IH, NH, J = 7Hz), 6.12 (dd, IH, 19-H, J = HHz and 18Hz), 5.34 (d, IH, 14-H, J = 8Hz), 5.05 (m, 2H, 20-H), 4.82, 4.78 (d, IH, 2′-OH, J = 4Hz), 4.48 (d, IH, 11-OH, J = 6Hz), 3.55 – 3.20 (m, 5H, 2′-H, 475′-H, 11- H, 22-H), 2.97 (m, IH, 1 ‘-H), 2.40 (bs, IH, 4-H), 1.35 (s, 12H, 15-CH3, tert-butyl), 1.05 (s, 3H, 18-CH3), 0.82 (d, 3H, 17-CH3, J = 7Hz), 0.62 (d, 3H, 16-CH3, J = 7Hz). MS-ESI (m/z): 630 (MNa+), 1237 (2MNa+).

or Step A2. 14-O-{[(1R, 2R, 4R)-4-tert-Butoxycarbonylamino-2-liydroxy- cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4S) diastereomer and

14-O-{[(1R, 2R, 5S)-5-tert-Butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin + (IS, 2S, 5R) diastereomer and

14-O-{[(1R, 2R, 4S)-4-rerf-Butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin + (IS, 2S, 4R) diastereomer

To a solution of 3,4-epoxycyclohexyl-carbamic acid tert-butyl ester (10 g, 47 mmol) and pleuromutilin thiol (16.6 g, 42 mmol) in 200 ml of methanol and 20 ml of dioxane was added 2N NaOH (21 ml, 42 mmol) and the resulting mixture was stirred for 16 hours at room temperature. After completion of the reaction the pH was set to 7 with diluted HCl and the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and brine and extracted three times with ethyl acetate. The organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and after chromatography (silica, cyclohexane / ethyl acetate = 1/1) 14-O-{[(1R, 2R, 4R) A-tert- butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl] -acetyl }-mutilin + (IS, 2S, 4S) diastereomer (Rf = 0.40, 3.1g, 12% yield) as well as a mixture of 14-O-{[(1R, 2R, 5S)-5-tert- butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 5R) diastereomer and 14-O-{[(1R, 2R, 4S)-4-tert-butoxycarbonylamino-2-hydroxy- cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4R) diastereomer (Rf = 0.25, 6.35 g, 25%) were obtained as colorless amorphous foams. or Step A3. 14-O-{[(1R, 2R, 4R)-4-tert-Butoxycarbonylamino-2-hydroxy- cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4S) diastereomer and 14-O-{ [(1R, 2R, 5S)-5-tert-Butoxycarbonylamino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin + (IS, 2S, 5R) diastereomer

To a solution of Pleuromutilin thiol (9.25 g, 23.5 mmol) in 100 ml of acetonitrile (dried over 4A molecular sieve) was added l,5-diazabicyclo[4.3.0]non-5-ene (DBN, 2.9 μl, 23.5 mmol) and after 1 hour of stirring at room temperature under argon atmosphere the mixture was ^ charged with syn-3,4-epoxycyclohexyl-carbamic acid tert-butyl ester (4.17 g, 19.5 mmol) and stirred for further 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was charged with water and brine and extracted three times with dichloromethane. The organic layers were dried over sodium sulphate and filtered. The filtrate was concentrated under reduced pressure and subjected to chromatography (silica, cyclohexane / ethyl acetate = 1/1) to yield 14-O-{[(1R, 2R, 4R)-4-teAY-butoxycarbonylamino- 2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4S) diastereomer (Rf = 0.38, 5.07g, 43%) as well as 14-O-{[(1R, 2R, 5S)-5-tert-butoxycarbonylamino-2-hydroxy- cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 5R) diastereomer (Rf = 0.25, 2.95 g, 16.5%) as colorless amorphous foams.

Step B. 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4S) diastereomer

To a solution of 14-O-{[(1R, 2R, 4R)-4-teΛ-t-butoxycarbonylamino-2-hydroxy- cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4S) diastereomer (1.34 g, 2.20 mmol) in 75 ml of dichloromethane was added trifiuoroacetic acid (4 ml) at 4°C and stirred for 5 hours at room temperature. The reaction mixture was diluted with dichloromethane and cautiously poured into a saturated NaHCO3 solution. The phases were separated and the aqueous layer was washed two times with dichloromethane. The combined organic layers are dried over sodium sulfate and filtered. After chromatography (silica, ethyl acetate/methanol/35% ammonia solution = 50/50/1) 14-O-{[(1R, 2R, 4R)-4-amino-2-hydroxy-cyclohexylsulfanyl]- acetyl}-mutilin + (IS, 2S, 4S) diastereomer (745 mg, 67% yield) was obtained as colorless amorphous foam.

1H NMR (400MHz, DMSO-de, δ, ppm, inter alia): 6.14 (dd, IH, 19-H, J = 1 IHz and 18Hz), 5.54 (d, IH, 14-H, J = 8Hz), 5.05 (m, 2H, 20-H), 4.50 (d, IH, 11-OH, J = 6Hz), 3.50 – 3.20 (m, 5H, 2′-H, 4′-H, H-H, 22-H), 2.55 (m, IH, l ‘-H), 2.40 (bs, IH, 4-H), 1.35 (s, 3H, 15- CH3), 1.06 (s, 3H, 18-CH3), 0.82 (d, 3H, 17-CH3, J = 7Hz), 0.62 (d, 3H, 16-CH3, J = 7Hz). MS-ESI (m/z): 508 (MH+), 530 (MNa+), 1015 (2MH+), 1037 (2MNa+).

Step C. 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyI]-acetyl}- mutilin hydrochloride + (IS, 2S, 4S) diastereomer hydrochloride

A solution of 14-O-{[(1R, 2R, 4R)-4-amino-2-hydroxy-cyclphexylsulfanyl] -acetyl }-mutilin + (IS, 2S, 4S) diastereomer (325 mg, 0.64 mmol) in 20 ml of dioxane was treated with IN HCl (0.64ml, 0.64 mmol). After stirring at room temperature for 30 minutes the solution was lyophilized to obtain 14-O-{[(1R, 2R, 4R)-4-amino-2-hydroxy-cyclohexylsulfanyl] -acetyl }- mutilin hydrochloride + (IS, 2S, 4S) diastereomer hydrochloride (quantitative yield) as colorless amorphous solid.

1H NMR (500MHz, DMSO-Cl6, δ, ppm, inter alia): 7.6 (bs, 3H, NH3 +), 6.14 (dd, IH, 19-H, J = 1 IHz and 18Hz), 5.55 (d, IH, 14-H, J = 8Hz), 5.05 (m, 2H, 20-H), 4.52 (d, IH, H-OH, J = 6Hz), 3.50 – 3.20 (m, 4H, 2′-H, H-H, 22-H), 3.03 (m, IH, 4′-H), 2.53 (m, IH, 1 ‘-H), 2.40 (bs, IH, 4-H), 1.37 (s, 3H, 15-CH3), 1.06 (s, 3H, 18-CH3), 0.82 (d, 3H, 17-CH3, J = 7Hz), 0.62 (d, 3H, 16-CH3, J = 7Hz). MS-ESI (m/z): 508 (MH+), 530 (MNa+), 1015 (2MH+), 1037 (2MNa+), 542 (MCl).

Example IA – 14-O-{[(1S, 2S, 4S)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin and 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsuIfanyl]-acetyl}-mutilin

The mixture of 14-O-{[(1R, 2R, 4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin + (IS, 2S, 4S) diastereomer (12 g, 23.6 mmol) from Example 1 Step B was separated on a cbiral column (250 x 20 mm CHIRALCEL OD-H, n-heptane / ethanol / diethylamine = 80/20/0.1) to yield 14-O-{[(1S*, 2S*, 4S*)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin (a) (early eluting compound, 4.76 g, 37% yield, uncorrected) and 14-O-{[(1R*, 2R*, 4R*)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin (b) (late eluting compound, 3.63 g, 30% yield, uncorrected) as colorless amorphous foams.

(a): 1H NMR (400MHz, DMSO-(I6, δ, ppm, inter alia): 6.13 (dd, IH, 19-H, J = 1 IHz and 18Hz), 5.54 (d, IH, 14-H, J = 8Hz), 5.05 (m, 2H, 20-H), 4.50 (d, IH, H-OH, J = 6Hz), 3.50 – 3.20 (m, 5H, 2′-H, 4′-H, H-H, 22-H), 2.55 (m, IH, l ‘-H), 2.40 (bs, IH, 4-H), 1.35 (s, 3H, 15- CH3), 1.05 (s, 3H, 18-CH3), 0.82 (d, 3H, 17-CH3, J = 7Hz), 0.62 (d, 3H, 16-CH3, J = 7Hz). MS-ESI (m/z): 508 (MH+), 530 (MNa+), 1015 (2MH+), 1037 (2MNa+), 506 (M-H) , 542 (MCl).

(b): 1H NMR (400MHz, DMSO-d6> δ, ppm, inter alia): 6.13 (dd, IH, 19-H, J = 1 IHz and 18Hz), 5.54 (d, IH, 14-H, J = 8Hz), 5.05 (m, 2H, 20-H), 4.50 (d, IH, H-OH, J = 6Hz), 3.50 – 3.20 (m, 5H, 2′-H, 4′-H, 11-H, 22-H), 2.55 (m, IH, 1 ‘-H), 2.40 (bs, IH, 4-H), 1.35 (s, 3H, 15- CH3), 1.05 (s, 3H, 18-CH3), 0.82 (d, 3H, 17-CH3, J = 7Hz), 0.62 (d, 3H, 16-CH3, J = 7Hz). MS-ESI (m/z): 508 (MH+), 530 (MNa+), 1015 (2MH+), 1037 (2MNa+), 506 (M-H) , 542 (MCl).

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WO 2011146954

http://www.google.com/patents/WO2011146954A1?cl=en

The present invention relates to crystalline 14-0-{[(4-amino-2-hydroxy-cyclohexyl)- sulfanyl] -acetyl }-mutilin, new processes for its preparation and crystalline salts thereof.

Pleuromutilin, a compound of formula

Pleuromutilin

is a naturally occurring antibiotic, e.g. produced by the basidiomycetes Pleurotus mutilus and P. passeckerianus, see e.g. The Merck Index, 12th edition, item 7694.

A number of further pleuromutilins having the principle ring structure of pleuromutilin and being substituted at the primary hydroxy group have been developed, e.g. as antimicrobials. Due to their pronounced antimicrobial activity, a group of pleuromutilin derivatives, amino- hydroxy-substituted cyclohexylsulfanylacetylmutilins, as disclosed in WO 2008/113089, have been found to be of particular interest. As described in WO2008/11089 14-0-{[(4- Amino-2-hydroxy-cyclohexyl)-sulfanyl] -acetyl }-mutilins are particularly useful compounds because they demonstrate activity against Gram-positive and Gram-negative pathogens e.g. associated with respiratory tract and skin and skin structure infections. For the production of substantially pure isomers/diastereomers of this group of compounds, there is a need for a production process which is convenient for use on an industrial scale and which also avoids the use of costly starting materials, environmentally hazardous reagents and solvents or time consuming and laborious purification steps. The production process described in WO 2008/113089 involves chromatographic purification of the compounds prepared according to individual synthesis steps and the final diastereomers are separated by chiral HPLC chromatography which cannot be used on industrial scale. Surprisingly, crystalline intermediates have been found which on the one hand have unexpected chemical purification potential which is important for the production processes for pure amino-hydroxy-substituted cyclohexylsulfanylacetylmutilins avoiding

chromatographic purification and separation steps.

It has to be pointed out that 14-0-{[(4-amino-2-hydroxy-cyclohexyl)-sulfanyl]-acetyl}- mutilins are potential new drug substances for the human market with regulatory

requirements defined in the corresponding ICH guidelines (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use). The ICH guideline on impurities in new drug substances (Q3 A(R2)) includes the following thresholds:

As can be seen from the ICH thresholds above it is desirable to have all individual unknown impurities below 0.10% area and the structure elucidated impurities below 0.15%, respectively. Processes provided according to the present invention enable to produce APIs (Active Pharmaceutical Ingredients) within the desired specifications and fulfilling ICH requirements.

On the other hand, even more surprisingly, the crystalline intermediates yields to significant chiral enrichment which has a huge benefit in the production of the pure stereoisomers starting from cheaper racemic materials or less chirally pure starting materials. The described processes do not involve any chromatographic purification neither normal nor chiral phase in contrast to the synthetic procedures described in WO2008/113089 wherein is disclosed e.g. in Example 1, Step B that 14-0-{[(4-amino-2-hydroxy-cyclohexyl)-sulfanyl]- acetyl}-mutilins was isolated in the form of diastereomeric mixtures as colorless amorphous foams after normal phase chromatography. The chiral pure diastereomers are described to have been received in WO2008/113089, e.g. in Example 1 A after subjecting the mixture to chiral chromatography whereafter the separated pure diastereomers were isolated in the form of colorless amorphous foams.

Chiral chromatography, however is not a technology which can be applied on industrial large scale, and moreover no crystalline salts of 14-0-{[(4-amino-2-hydroxy-cyclohexyl)- sulfanyl]-acetyl}-mutilins were obtained according to WO2008/113089. In contrast to that, according to the present invention crystalline pharmaceutical acceptable salts of 14-0-{[(4-amino-2-hydroxy-cyclohexyl)-sulfanyl]-acetyl}-mutilins having surprising and superior properties over the amorphic prior art salts disclosed in

WO2008/113089 have been found; e.g. surprisingly the chemical stability of the crystalline salts of the present invention is improved over the amorphic salt forms; and also and in addition the crystalline salts of the present invention show a surprising low hygroscopicity.

Processes for the preparation of such crystalline salts wherein the salts may be obtained in a single stereoisomeric form from 14-0-{[(4-amino-2-hydroxy-cyclohexyl)-sulfanyl]-acetyl}- mutilins and processes for the preparation of stereoisomerically pure 14-0-{[(4-amino-2- hydroxy-cyclohexyl)-sulfanyl]-acetyl}-mutilins in crystalline form as a basis for the crystalline salts have also been found.

In one aspect the present invention provides a process for the preparation of a compound of formula I

in the form of a single stereoisomer in crystalline form, comprising

deprotecting the amine group

either in a compound of formula Ila

in a mixture of a compound of formula Ila with a compound of formula lib

wherein R is an amine protecting group, and isolating a compound of formula I obtained in the form of a single diastereomer in crystalline form either directly from the reaction mixture or via recrystallization in organic solvent.

In another aspect the present invention provides a compound of formula I as defined above in the form of a single stereoisomer in crystalline form.

Compounds of formula Ila are new and also form part of the present invention.

In another aspect the present invention provides a compound of formula Ha.

In a compound of formula I, or Ha, respectively, the carbon atoms of the cyclohexyl ring to which the hydroxy group, the amine group and the sulfanyl-acetyl-mutilin group are attached are all in the R configuration and thus a compound of formula I, or Ila represents an optionally amine protected 14-0-{[(l ?,2i?,4 ?)-4-amino-2-hydroxy-cyclohexylsulfanyl]- acetyl}-mutilin. In contrast to that, in a compound of formula lb

or lib the carbon atoms of the cyclohexyl ring to which the hydroxy group, the amine group and the sulfanyl-acetyl-mutilin group are attached are all in the S configuration and thus a compound of formula lib represents an optionally amino protected 14-0-{[(lS,2S,4S)-4-Amino-2-hydroxy- cyclohexylsulfanyl] -acetyl } -mutilin. An amine protecting group includes protecting groups known to a skilled person and which are removable under acidic, basic, hydrogenating, oxidative or reductive methods, e.g. by hydrogenolysis, treatment with an acid, a base, a hydride, a sulfide. Appropriate amine protecting groups e.g. are described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, 4th edition, 2007, particularly p. 696-868.

Example 1

tert-Butyl [(lR3Ri4R)-3-hydroxy-4-mercapto-cyclohexyl]-carbamate

3.94 Kg of {(li?,2J?,4i?)-4-[(tert-Butoxycarbonyl)-amino]-2-hydroxy-cyclohexyl}-benzene- carbothioate and 37 L of CH2C12 were charged to a vessel and the mixture obtained was stirred at 15-25°C. 0.39 Kg of 1,4-dithio-DL-threitol (10% wt) was added to the mixture and rinsed through with 2 L of CH2C12. To the mixture obtained 0.84 Kg of hydrazine monohydrate was added. The mixture obtained was stirred at 18 to 22°C for 3 h and the reaction was followed by HPLC. Upon completion of the reaction, 39 L of 1 M phosphoric acid solution was added and the mixture obtained was stirred for a further 15-30 min. Two phases formed were separated and the organic phase obtained was washed with 39 L of of 1 M phosphoric acid solution followed by 39 L 1% aqueous NaCl solution. The organic layer obtained was concentrated in vacuo at <40°C, to the concentration residue 20 L of CH2C12 was added and the mixture obtained again was concentrated. To the concentration residue obtained a further 8 L of CH2C12 was added and the mixture obtained was concentrated to dryness.

2.89 Kg of tert-Butyl [(l ?,3/?,4i?)-3-hydroxy-4-mercapto-cyclohexyl]-carbamate in the form of a white solid was obtained.

1H NMR (200 MHz, DMSO-de, ppm) δ 6.79 (d, J=7.8Hz, 1H), 4.99 (d, J=5.8Hz, 1H), 3.34 – 3.24 (m, 1H), 3.14 – 3.04 (m, 1H), 2.37 (d, J=3.8 Hz, 1H), 2.00 -1.89 (m, 1H), 1.87 – 1.82 (m, 1H), 1.73 – 1.67 (m, 1H), 1.47 – 1.04 (m, 12H)

Example 2

22-0-TosylpIeuromutilin

22-O-Tosylpleuromutilin is a known compound from literature. However a preparation procedure is outlined below.

A solution of 13.0 kg of pleuromutilin and 6.57 kg of 4-toluenesulfonyl chloride in 42.1 L of CH2CI2 at 10 to 15 °C was treated with 9.1 L of 5.7 M aqueous NaOH over 20 min, maintaining a temperature < 25 °C. The resulting off-white suspension was heated to reflux for 20 h and the reaction was followed until completion determined by HPLC. Upon reaction completion the mixture obtained was cooled to 20 to 30 °C, diluted with 52 L of CH2C12, stirred at 15 to 25 °C for 10 min, and the layers obtained were separated. The organic phase obtained was washed several times with 52 L of water until a pH of the aqueous layer was adjusted to < 9. The organic layer obtained was concentrated to 4 volumes and

azeotropically dried twice with 52 L of CH2C12. To the solution obtained 52 L of heptane were added dropwise and the solution obtained was concentrated at < 40 °C to

approximately 4 volumes. To the concentrate obtained 52 L of heptane was added and the resulting suspension was stirred at 20 to 25 °C for 2 to 2.5 h, filtered, the filter cake obtained was washed with 39 L of heptane and pulled dry on the filter.

The solid was dried under vacuum at < 40 °C for at least 12 h.

16.9 kg of 22-O-tosylpleuromutilin in the form of a white solid was obtained.

1H NMR (200 MHz, DMSO-d6, ppm, inter alia) δ 7.81 (d, 2H), 7.47 (d, 2H), 6.14 – 6.0 (m, 1H), 5.54 (d, J=7.8Hz, 1H), 5.08 – 4.99 (m, 2H), 4.70 (AB, J=16.2Hz, 2H), 3.41 (d, J=5.2Hz, 1H), 2.41(s, 4H), 1.04(s, 3H), 0.81 (d, 3H), 0.51 (d, 3H)

Example 3

14-0-{[(l/?,2R,4R)-4-ter/-Butoxycarbonylamino-2-hydroxy-cyclohexyI-sulfanyl]-acetyl}- mutilin

4.75 Kg of Pleuromutilin tosylate (Tos-PLEU) and 44.4 L of MTBE were charged into a vessel and to the mixture obtained 0.31 Kg of benzyl-tri-«-butylammonium chloride was added and rinsed through with 2.4 L of MTBE. To the mixture obtained 20 L of IM aqueous NaOH solution and 2.84 Kg of tert-Butyl [(lif,3i?,4^)-3-hydroxy-4-mercapto-cyclohexyl]- carbamate were added and the mixture obtained was stirred at 17 to 23 °C for 3 h. Upon completion of the reaction (determined by HPLC) two layers formed were separated and the lower aqueous layer was removed. The organic phase obtained was washed with 19 L of IM aqueous NaOH solution, twice with 20 L of 0.1 M phosphoric acid, 20 L of 10% aqueous NaHC03 solution and twice with 20 L of water. The organic liquors obtained were concentrated, the concentrate obtained was taken up in 7.46 Kg of 2-propanol, the mixture obtained was concentrated again and dried in vacuo at <40°C. 6.66 Kg of 14-O- { [( 1 -¾,2i?,4i?)-4-/ert-Butoxycarbonylamino-2-hydroxy-cyclohexyl-sulfanyl]-acetyl } -mutilin in the form of a white foam was obtained.

Ή NMR (200 MHz, DMSO-d6, ppm, inter alia) δ 6.78 (d, J=7.8Hz, 1H), 6.22 – 6.08 (m,lH), 5.55 (d, J=7.8Hz, 1H), 5.13 – 5.02 (m, 2H), 4.95 (d, J=5Hz, 1H), 4.52 (d, J=6Hz, 1H), 3.36 (AB, J=15Hz, 2H), 2.40 (s, broad, 1H), 2.15 – 2.0 (m, 3H), 1.9 – 1.8 (m, 1H), 1.35 (s, 9H), 0.81 (d, J=7Hz, 3H), 0.62 (d, J=6.6Hz, 3H)

MS (ESI, g/mol): m/z 653 [M+2Na] +

Example 4

14-0-{[(lR,2R,4R)-4-Amino-2-hydroxy-cyclohexyIsulfanyI]-acetyl}-mutilin, crystalline Form 2

Step A: 14-O-{[(li?.2i?,4i?)-4-Amino-2Thvdroxy-cyclohexylsulfanvn-acetvU-mutilin in crystalline Form 1

6.6 Kg of 14-O-{[(li?,2if,4/?)-4-tert-Butoxycarbonylamino-2-hydroxy-cyclohexyl-sulfanyl]- acetyl}-mutilin and 13.2 L of isopropanol were charged into a vessel and stirred at 20 to 25°C. 11.20 kg of 85% phosphoric acid was added and the mixture obtained was heated to approximately 50°C for at least 16 h. The mixture obtained was analyzed for reaction completion by HPLC. Upon completion of the reaction the mixture was cooled to 20 to 25°C and 52 L of CH2C12 was added. The mixture obtained was cooled to 0 to 5°C and 51 L of 30% aqueous K2CO3 solution was added over 1 h at <25°C. The mixture obtained was warmed to rt, stirred for 30 min and the pH of the aqueous layer was determined. To the mixture obtained a further 15 L of 30% aqueous K2C03 solution was added at <25°C, the mixture obtained was stirred at 15°C to 25 °C for 30 min and the two phases obtained were separated. The aqueous phase obtained was extracted with 51 L of CH2CI2 and the combined organic phases were washed with 51 L of purified water. The mixture obtained was concentrated to a volume of 25 L, 33.6 Kg of CH2C12 was added and the mixture obtained was concentrated to 25 L. To the concentrate obtained 33.6 Kg of CH2C12 was added and the mixture obtained was concentrated to 10 L. The concentration residue obtained was cooled to 18 to 22°C and 50 L of di-wopropyl ether was added over a period of 1 h. The slurry obtained was stirred at 15 to 25°C for a minimum of 2 h, filtered and the solid obtained was washed with 10 L of di-wopropyl ether and was dried.

3.79 Kg of 14-0-{[(li?,2i?,4if)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin in crystalline Form 1 was obtained.

Step B: 14-O-{r(l-R.2i?,4j?)-4-amino-2-hvdroxy-cvclohexylsulfanyl1-acetv -mutilin. in crystalline Form 2

For further purification 14-O-{[(l ?,2 ?,4i?)-4-Amino-2-hydroxy-cyclohexylsulfanyl]- acetyl}-mutilin from Step A and 18.75 L of n-butanol were heated to 88 to 92°C until complete dissolution and stirred for 30 to 60 min. The mixture obtained was allowed to cool to 40 to 45°C over at least 2 h and further stirred at this temperature for 2 h. The mixture obtained was filtered and the precipitate obtained was washed with 3.75 L of «-butanol followed by 3.75 L of MTBE. That purification procedure was repeated and the resultant product was dried in vacuo at <40°C.

3.27 Kg of crystalline 14-0-{[(li?,2if,4i?)-4-amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}- mutilin in crystalline Form 2 was obtained in the form of a white solid.

lH NMR (400 MHz, CDC13, ppm, inter alia) δ 6.51 – 6.44 (m, 1H), 5.78 (d, J=8Hz, 1H), 5.38 – 5.20 (m, 2H), 3.48 – 3.40 (m, 1H), 3.36 (d, J=7Hz, 1H), 3.25 (AB, J=15Hz, 2H), 2.92 – 2.82 (m, 1H), 2.6 – 2.5 (m, 1H), 1.45 (s, 3H), 1.20 (s, 3H), 0.88 (d, J=7Hz, 3 H), 0.73 (d, J=8Hz, 3H)

MS (ESI, g/mol): m/z 508 [M+H] +

Example 5

14-0-{[(lR^/f,4R)-4-Amino-2-hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin, crystalline

To a solution of 900 g of 14-0-{[(li?,2i?,4i?)-4-tert-butoxycarbonylamino-2-hydroxy- cyclohexyl-sulfanyl]-acetyl}-mutilin in 9 L of CH2C12 at 15 to 25°C was added 1.8 L of TFA at 15 to 25°C and the resulting solution was stirred for 2 h. Following reaction completion the reaction mixture was concentrated under vacuum and the concentration residue obtained was azeo-dried with a total of 9 L of CH2C12. The concentrate obtained was dissolved in 4.5 L of CH2C12, the solution obtained cooled to 0 to 5°C and the pH was adjusted to pH 11 with aqueous 3.6 L 2CO3 (2.5M) solution. The biphasic mixture obtained was warmed to 15 to 20°C and stirred for 5 to 10 minutes. The layers obtained were separated, the aqueous phase obtained was extracted with 1.8 L of CH2C12, the organic phases obtained were combined, washed with 2.3 L of H20, dried over Na2S04 and concentrated to dryness under vacuum at <40°C. Crude 14-0- { [( 1 R,2R,4R)-4- Amino-2-hydroxy-cyclohexyl-sulfanyl]-acetyl } -mutilin was obtained. Yield: 744 g

For further purification the following procedure was applied:

To 744 g of crude 14-O-{[(li?,2i?,4i-)-amino-2-hydroxy-cyclohexyl-sulfanyl]-acetyl}- mutilin was added 2.23 L of THF and the resulting suspension was stirred at 15 to 25°C for 60 min. To the mixture obtained 7.44 L of MTBE was added over 15 to 30 min, the suspension obtained was aged for 60 min and filtered under nitrogen. The collected solids were washed with a total of 3 L of MTBE and pulled dry on the filter under nitrogen for 1.5 h.

626 g of 14-0-{[(li?,2i?,4i?)-4-Amino-2-hydroxy-cyclohexyl-sulfanyl]-acetyl}-mutilin in crystalline Form 1 was obtained.

The Ή NMR pattern confirms the structure of 14-O-{[(li?,2i?,4i?)-4-amino-2-hydroxy- cyclohexylsulfanyl] -acetyl} -mutilin. The NMR pattern for 14-O-{[(l ?,2i?,4/?)-4-amino-2- hydroxy-cyclohexylsulfanyl]-acetyl}-mutilin is described in example 4.

…………………………………………………………

REF

http://www.phase4-partners.com/wp-content/uploads/2013/09/100412.pdf

http://www.glsv-vc.com/downloads/2010-06-02_First%20Patient_PressRelease.pdf

119

Nabriva. Pleuromutilins. Available online: http://www.nabriva.com/programs/pleuromutilins/ (accessed on 7 December 2012).
120

Forest Laboratories. Our pipeline: Solid, and set for further growth. Available online: http://www.frx.com/research/pipeline.aspx (accessed on 13 April 2013).
121

Sader, H.S.; Biedenbach, D.J.; Paukner, S.; Ivezic-Schoenfeld, Z.; Jones, R.N. Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother. 2012,56, 1619–1623, doi:10.1128/AAC.05789-11.

122
Sader, H.S.; Paukner, S.; Ivezic-Schoenfeld, Z.; Biedenbach, D.J.; Schmitz, F.J.; Jones, R.N. Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs). J. Antimicrob. Chemother. 201267, 1170–1175, doi:10.1093/jac/dks001.

123
Nabriva Therapeutics AG. Study comparing the safety and efficacy of two doses of BC-3781 vs. vancomycin in patients with acute bacterial skin and skin structure infection (ABSSSI). Available online: http://www.clinicaltrials.gov/ct2/show/NCT01119105 (accessed on 13 April 2013).

124
Novak, R. Are pleuromutilin antibiotics finally fit for human use? Ann. NY Acad. Sci. 20111241, 71–81, doi:10.1111/j.1749-6632.2011.06219.x.

 

Valnemulin.svgvalnemulin

 

retapamulin

 

 

WO2002004414A1 * Jul 9, 2001 Jan 17, 2002 Gerd Ascher Pleuromutilin derivatives having antibacterial activity
WO2007000004A1 * Jun 26, 2006 Jan 4, 2007 Nabriva Therapeutics Forschung Pleuromutilin derivatives containing a hydroxyamino- or acyloxyaminocycloalkyl group
WO2007014409A1 * Jul 26, 2006 Feb 8, 2007 Nabriva Therapeutics Forschung Pleuromutilin derivatives useful as antibacterials

 

 

WO2008011089A2 Jul 19, 2007 Jan 24, 2008 Mark B Gagner Wagering game with special-event eligibility feature based on passive game play
WO2008113089A1 Mar 19, 2008 Sep 25, 2008 Nabriva Therapeutics Ag Pleuromutilin derivatives for the treatment of diseases mediated by microbes
US20060276503 * Aug 30, 2004 Dec 7, 2006 Glaxo Group Limited Novel process salts compositions and use

 

 

TIDEGLUSIB ..An NSAID and neuroprotective agent.



Tideglusib

M.Wt: 334.39
Formula: C19H14N2O2S
CAS No.: 865854-05-3
4-Benzyl-2-(naphthalen-1-yl)-1,2,4-thiadiazolidine-3,5-dione

Glycogen Synthase Kinase 3 beta (GSK-3beta; tau Protein Kinase I) Inhibitors

Treatment of Neurologic Drugs (Miscellaneous)
Alzheimer’s Dementia, Treatment ofCerebrovascular Diseases, NP031112; NP-031112, Nypta  Zentylor

  • NP 031112
  • NP-12
  • NP031112
  • Tideglusib
  • UNII-Q747Y6TT42

Noscira (Originator)
Tideglusib (NP-12NP031112) is a potent, selective and irreversible[1] small molecule non-ATP-competitive GSK3 inhibitor that has been investigated as a potential treatment for Alzheimer’s disease and paralysis supranuclear palsy in Phase IIa[2] and IIb clinical trials.[3][4][5][6] The first clinical trial conducted with tideglusib to be published (in English, at least) was phase II and demonstrated that overall tideglusib was well tolerated, except for some moderate, asymptomatic, fully reversible increases in liver enzymes (≥2.5xULN; where ULN=Upper Limit of Normal).[4]

tideglusib

NP-031112 is an inhibitor of glycogen synthase kinase-3 beta (GSK-3beta) in early clinical development for the oral treatment of Alzheimer’s disease. The compound had been in phase II clinical trials for the treatment of progressive supranuclear palsy and for the treatment of Alzheimer’s disease; however the development was discontinued in 2011 and 2012 respectively, due to lack of efficacy.

The neuroprotective effects demonstrated in animal studies have also suggested its potential use in stroke and other brain disorders. It is being developed by Noscira (formerly known as NeuroPharma). In 2009, orphan drug designation was received in the E.U. and the U.S. for the treatment of progressive supranuclear palsy. In 2010, fast track designation was assigned in the U.S. by Noscira for this indication.

Fast Track status is granted to facilitate development and expedite the review of a drug for a serious or potentially fatal illness and to meet an unmet medical need

The Phase II trial for Progressive Supranuclear Palsy (PSP) commenced in December 2009 and is currently in progress

Belen Sopesen, CEO of Noscira: ‘Fast Track status is very positive for the company and is an incentive to continue advancing in the clinical development of Tideglusib (ZentylorTM) in Progressive Supranuclear Palsy’

Overexpression of GSK-3 leads to hyperphosphorylation of the tau protein, an anomaly which occurs in a number of neurodegenerative diseases known collectively as tauopathies, which include Alzheimer’s disease (AD), Progressive Supranuclear Palsy (PSP) and Pick disease. NP-12 is a GSK-3 inhibitor with oral bioavailability and great therapeutic potential as a disease-modifying treatment for Alzheimer’s.

NP-12 is currently undergoing  clinical trials for Alzheimer’s disease in the EU. NP-12, the only GSK-3 inhibitor under clinical development for AD, has proven to be capable of acting on all of the histopathological lesions associated with the disease in experimental models: it reduces phosphorylation of the tau protein and hippocampal and entorhinal cortex neuron loss, improves spatial memory deficits and significantly reduces the accumulation of amyloid plaques in the brain. NP-12 also provides neuroprotection in vivo and has a potent anti-inflammatory effect in a range of animal models.

About Progressive Supranuclear Palsy

PSP is a neurodegenerative disease characterized by oculomotor disturbances, specifically difficulties in moving the eye vertically, falling down and Parkinsonian symptoms.

The disease affects an estimated 5-6.4 out of every 100,000 people.

There is currently no treatment capable of delaying or altering the progression of the illness.

TIDEGLUSIB

  1.  Domínguez, JM; Fuertes, A; Orozco, L; del Monte-Millán, M; Delgado, E; Medina, M (January 2012). “Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3 by Tideglusib”The Journal of Biological Chemistry 287 (2): 893–904.doi:10.1074/jbc.M111.306472PMC 3256883PMID 22102280.
  2.  Teodoro Del Ser (2010). “Phase IIa clinical trial on Alzheimer’s disease with NP12, a GSK3 inhibitor”. Alzheimer’s & Dementia 6 (4): S147. doi:10.1016/j.jalz.2010.05.455.
  3.  Eldar-Finkelman, H; Martinez, A (2011). “GSK-3 Inhibitors: Preclinical and Clinical Focus on CNS”Frontiers in Molecular Neuroscience 4: 32.doi:10.3389/fnmol.2011.00032PMC 3204427PMID 22065134.
  4.  Del Ser, T; Steinwachs, KC; Gertz, HJ; Andrés, MV; Gómez-Carrillo, B; Medina, M; Vericat, JA; Redondo, P et al. (2013). “Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: A pilot study”. Journal of Alzheimer’s disease 33 (1): 205–15.doi:10.3233/JAD-2012-120805PMID 22936007.
  5.  “FDA Grants Fast Track Status to Tideglusib (ZentylorTM) for Progressive Supranuclear Palsy”. PR Newswire Europe Including UK Disclose. 10 September 2010. Retrieved 11 August 2013.
  6.  Dominguez, JM; Fuertes, A; Orozco, L; Del Monte-Millan, M; Delgado, E; Medina, M (2011). “Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3 by Tideglusib”Journal of Biological Chemistry 287 (2): 893–904.doi:10.1074/jbc.M111.306472PMC 3256883PMID 22102280.
  7. WO 2005097117
  8. WO 2006045581
  9. WO 2006084934
  10. WO 2008057933
  11. WO 2011151359
  12. Evidence for irreversible inhibition of glycogen synthase kinase-3β by tideglusib.

    Domínguez JM, Fuertes A, Orozco L, del Monte-Millán M, Delgado E, Medina M.

    J Biol Chem. 2012 Jan 6;287(2):893-904. doi: 10.1074/jbc.M111.306472. Epub 2011 Nov 18

    13. MARTINEZ A ET AL.: “First Non-ATP Competitive Glycogen Synthase Kinase 3.beta. (GSK-3.beta.) Inhibitors: Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer’s Disease” JOURNAL OF MEDICINAL CHEMISTRY, vol. 45, no. 6, 2002, pages 1292-1299

4-18-2012
GSK-3 Inhibitors
5-13-2009
GSK-3 inhibitors
6-27-2008
Use Of Heterocyclic Compounds As Neurogenic Agents

CLINICAL TRIALS

http://clinicaltrials.gov/search/intervention=NP+031112

http://clinicaltrials.gov/show/NCT01350362

………….

http://www.google.com/patents/WO2005097117

For example, the following procedure can be used to produce 4-N-benzyl substituted thiadiazolidinones :

Figure imgf000014_0002

The general experimental procedure of Scheme 1 is described for example in Slomczynska,

U.; Barany, G., “Efficient Synthesis of l,2,4-Dithiazolidine-3,5-diones (Dithiasuccinoyl- amines) and observations on formation of l,2,4-Thiadiazolidine-3,5-dione by related

Chemistry”, J. Heterocyclic Chem., 1984, 21, 241-246.

For example, sulfuryl chloride is added dropwise with stirring, under nitrogen atmosphere, preferably at low temperature, preferably at about 5 °C, to a solution of benzyl isothiocyanate and the isocyanate indicated in each case, in a suitable solvent such as hexane, ether or THF. When the addition is finished, the mixture is left to react, for example by stirring for 20 hours at room temperature. After this time, the resulting product is isolated by conventional methods such as suction filtration or solvent evaporation and then, the purification is performed (e.g. by recristallization or silica gel column chromatography using the appropriate eluent). Other alternative procedures will be apparent to the person skilled in the art, such as the use of any other chlorinating agent instead of sulfuryl chloride, variations in the order of addition of the reactants and reaction conditions (solvents, temperature, etc).

Example 2

4-Benzyl-2-naphthalen-l-yl-[l,2,4]thiadiazolidine-3,5-dione (2)

Reagents: Benzyl-isothiocianate (13 mmol, 1.72 mL), 1-naphthyl-isocyanate (13 mmol, 1.9 mL) and SO2CI2 (13 mmol, 1.04 mL) in hexane (50 mL). Isolation: filtration of reaction mixture. Purification: recrystallization from EtOH. Yield: 3.8 g (87%), white needles. mp= 150 °C

1H-RMN (CDC13): 4.9 (s, 2H, CH2PI1); 7.3-7.9 (m, 12Η, arom.) 13C-RMN (CDCI3): 46.5 (CH2Ph); 128.3; 128.6; 129.0; 135.0 (C arom, Ph); 122.0; 125.3; 126.8; 127.2; 127.5; 128.5; 130.8; 134.4 (C arom, naphthyl); 152.2 (3-00); 165.9 (5- C=O).

Anal (C19H14N2O2S), C, H, N, S

Sulfuryl chloride is added dropwise with stirring, under nitrogen atmosphere, at 5 °C to a solution of benzyl isothiocyanate and the isocyanate indicated in each case, in hexane, ether or THF. When the addition is finished, the mixture is stirred for 20 hours at room temperature. After this time, the resulting product is isolated by suction filtration or by solvent evaporation and then, the purification is performed by recristallization or silica gel column chromatography using the appropriate eluent. More details can be found in Slomczynska, U.; Barany, G., “Efficient Synthesis of l,2,4-Dithiazolidine-3,5-diones (Dithiasuccinoyl-amines) and observations on formation of l,2,4-Thiadiazolidine-3,5-dione by related Chemistry”, J Heterocyclic Client., 1984, 21, 241-246.

…………

WO2006045581A1 * Oct 21, 2005 May 4, 2006 Neuropharma Sa The use of 1, 2, 4-thiadiazolidine-3, 5-diones as ppar activators
WO2011151359A1 Jun 1, 2011 Dec 8, 2011 Noscira, S.A. Combined treatment with a cholinesterase inhibitor and a thiadiazolidinedione derivative
WO2013124413A1 Feb 22, 2013 Aug 29, 2013 Noscira, S.A. Thiadiazolidinediones as gsk-3 inhibitors
EP2177510A1 Oct 17, 2008 Apr 21, 2010 Universität des Saarlandes Allosteric protein kinase modulators
EP2527323A1 May 24, 2011 Nov 28, 2012 Noscira, S.A. Urea carbonyl disulfide derivatives and their therapeutic uses

………..

 

ANTHONY MELVIN CRASTO

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

did you feel happy, a head to toe paralysed man’s soul in action for you round the clock

need help, email or call me

MOBILE-+91 9323115463
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I was  paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family

 

 

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VBL Therapeutics announced FDA has granted Fast Track designation to its lead oncology drug VB-111


GT-111
VB-111
GT-111 is a gene therapy product candidate in early clinical development for the treatment of advanced differentiated thyroid cancer, for the treatment of relapsed glioblastoma multiform and for the treatment of ovarian cancer.
patents, VBL Therapeutics
WO 2011083466, WO-2011083464, WO-2012052878

VBL Therapeutics announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to its lead oncology drug VB-111, for prolongation of survival in patients with recurrent glioblastoma multiforme (rGBM).

Read more…http://www.dddmag.com/news/2013/11/vbls-cancer-drug-gets-fast-tracked?et_cid=3625663&et_rid=523035093&type=cta

VB-111 – highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth

VB-111 is the first highly targeted anti-angiogenic agent for the specific inhibition of tumor vascular growth to use VTS™™, our proprietary platform technology, for cancer therapy. VB-111 is an IV-administered anti angiogenic agent that works in a manner akin to a “biological knife” to destroy tumor vasculature, thus cutting off blood vessels feeding the tumor.

Preclinical Insights

VB-111 has shown significant promise as a targeted cancer treatment with the potential to work synergistically in combination with conventional chemotherapy treatments to provide an effective treatment regimen for cancer patients. Pharmacological and toxicology studies of VB-111 have showed tissue specificity for the tumor tissue, no significant damage to normal non-cancerous tissues or to the normal vasculatures in the body and more than 90 percent tumor burden reduction in a metastatic lung cancer model with only one injection. Similar efficacy was shown in other tumor models.

Completed Clinical Trials

Phase 1 Clinical Trial – in a Phase 1 “all comers” dose escalation study in 33 patients with advanced metastatic cancer, therapeutic doses of VB-111 demonstrated antitumor activity and was found to be safe and well tolerated with no effect on liver function or major changes in complete blood count. Findings have been presented at the American Association of Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO) annual meetings.

FDA Grants QIDP and Fast Track Designations for Cubist’s Late-Stage Antibiotic Candidates


  • QIDP granted for ceftolozane/tazobactam in HABP/VABP and cUTI
  • Fast track status provided for ceftolozane/tazobactam (CXA-201) in cIAI

February 28, 2013

LEXINGTON, Mass.,  Cubist Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) has designated the company’s late-stage antibiotic candidate, ceftolozane/tazobactam, as a Qualified Infectious Disease Product (QIDP) for the indications of Hospital-Acquired Bacterial Pneumonia (HABP)/Ventilator-Associated Bacterial Pneumonia (VABP) and Complicated Urinary Tract Infections (cUTI).

Additionally, the company received from the FDA notification that Cubist’s antibiotic candidates, ceftolozane/tazobactam and surotomycin, have been granted Fast Track status in their previously granted QIDP indications, Complicated Intra-Abdominal Infections (cIAI) and Clostridium difficile-Associated Diarrhea (CDAD) respectively.

“We are excited to receive the QIDP and Fast Track designations for ceftolozane/tazobactam and surotomycin, which further reinforce the importance the FDA places on helping to advance critically needed antibiotics,” said Steven Gilman, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer of Cubist Pharmaceuticals. “In a very short period of time, the GAIN Act has shown its value in helping to incentivize antibiotic development.”

The QIDP designation for ceftolozane/tazobactam will enable Cubist to benefit from certain incentives for the development of new antibiotics, including priority review, eligibility for Fast Track status, and if ceftolozane/tazobactam is ultimately approved by the FDA, a five year extension of Hatch-Waxman exclusivity. These incentives are provided under the Generating Antibiotic Incentives Now Act (GAIN Act), which received strong bipartisan support in Congress and was signed into law by President Obama in July 2012 as part of the FDA Safety and Innovation Act (FDASIA), the fifth authorization of the Prescription Drug User Fee Act.

Ceftolozane/tazobactam is currently being studied in pivotal Phase 3 trials as a potential first-line intravenous therapy for the treatment of cIAI and cUTI caused by Gram-negative pathogens, including those caused by multi-drug resistant Pseudomonas aeruginosa. Cubist expects to initiate a Phase 3 VABP program for ceftolozane/tazobactam by mid-year. Surotomycin, a rapidly bactericidal lipopeptide, is currently in Phase 3 being studied as a potential treatment for patients with a severe and sometimes life-threatening diarrhea caused by CDAD.

About The GAIN Act

The GAIN Act, Title VIII (Sections 801 through 806) of the FDASIA, provides pharmaceutical and biotechnology companies with incentives to develop new antibacterial and antifungal drugs for the treatment of life-threatening infectious diseases caused by drug resistant pathogens. Qualifying pathogens are defined by the GAIN Act to include multi-drug resistant Gram-negative bacteria, including Pseudomonas, Acinetobacter, Klebsiella, and Escherichia coli species; resistant Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; multi-drug resistant tuberculosis; and Clostridium difficile.

About Gram-negative bacteria

The diseases caused by Gram-negative bacteria include intra-abdominal infections, urinary tract infections, pneumonia, peritonitis, septicemia, neonatal meningitis, and burn and wound infections. In the US in 2003, Gram-negative bacteria were associated with many of the most frequent types of hospital-acquired infections including 71% of urinary tract infections, 65% of pneumonia episodes, 34% of surgical site infections, and 24% of bloodstream infections. Important Gram-negative bacteria include Pseudomonas, Escherichia coli, Klebsiella, and Acinetobacter.

About CDAD

CDAD is a disease caused by an overgrowth of, and toxin production by C. difficile, a Gram-positive bacterium naturally found in the lower gastrointestinal tract. This overgrowth is caused by the use of antibiotics for the treatment of common community and hospital acquired infections. Many antibiotics cure the underlying infection but, as a consequence, disrupt the natural balance of intestinal bacteria which allows C. difficile to overgrow. The overgrown C. difficile bacteria produce enterotoxin and cytotoxin, two proteins that can lead to potentially life-threatening severe diarrhea and sepsis (blood infection). CDAD rates and severity are increasing, due in part to the spread of a new strain with increased virulence and greater resistance to fluoroquinolones, a standard of care treatment. According to an article in the October 2008 issue of the New England Journal of Medicine, during the mid- and late-1990s, the reported incidence of C. difficile infections in acute care hospitals in the United States remained stable at 30 to 40 cases per 100,000. However in 2001, this number rose to almost 50, with subsequent increases to the point that the number of cases that were reported in 2005 (84 per 100,000) was nearly three times the 1996 rate (31 per 100,000).

About Cubist

Cubist Pharmaceuticals, Inc. is a biopharmaceutical company focused on the research, development, and commercialization of pharmaceutical products that address significant unmet medical needs in the acute care environment. Cubist is headquartered in Lexington, Mass. Additional information can be found at Cubist’s web site at www.cubist.com.

ceftolozane

credit —kegg

http://www.ama-assn.org/resources/doc/usan/ceftolozane.pdf

89293-68-3 cas no

………………………………………………………………………………………………………………………

tazobactum

cas no89786-04-9

Tazobactam is a compound that inhibits the action of bacterial beta-lactamases. It is combined with the extended spectrum beta-lactam antibiotic piperacillin in the drug Tazocin (also Zosyn, Piprataz)one of the preferred antibiotic treatment for CAP caused by P. aeruginosa. It broadens the spectrum of piperacillin by making it effective against organisms that express beta-lactamase and would normally degrade piperacillin.

Tazobactam sodium is a derivative of the penicillin nucleus and is a penicillanic acid sulfone.

 

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