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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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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 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, 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...... , 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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FDA permits marketing of device to treat diabetic foot ulcers


Today, the U.S. Food and Drug Administration permitted the marketing of the Dermapace System, the first shock wave device intended to treat diabetic foot ulcers. Continue reading.

December 28, 2017


FDA permits marketing of device to treat diabetic foot ulcers


Today, the U.S. Food and Drug Administration permitted the marketing of the Dermapace System, the first shock wave device intended to treat diabetic foot ulcers.

“Diabetes is the leading cause of lower limb amputations,” said Binita Ashar, M.D., director of the division of surgical devices in FDA’s Center for Devices and Radiological Health. “The FDA is dedicated to making technologies available that can help improve the quality of life for those with chronic diseases. Additional options for successfully treating and healing ulcer wounds may help prevent lower limb amputations.”

An estimated 30.3 million people in the United States have been diagnosed with diabetes, according to the Centers…

View original post 404 more words


Pexidartinib, New Patent, WO 2017215521, Crystal Pharmatech Co Ltd


Pexidartinib, New Patent, WO, 2017215521, Crystal Pharmatech Co Ltd




CHEN, Minhua; (CN).
ZHANG, Yanfeng; (CN).
ZOU, Po; (CN).
ZHANG, Xiaoyu; (CN)

Novel crystalline forms of PLX3397 hydrochloride (designated as Forms CS2 and CS3), processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating giant cell tumor of the tendon sheath.

The present invention relates to a PLX3397 hydrochloride crystal form, a preparation method therefor and use thereof. The PLX3397 hydrochloride crystal form has higher solubility, larger particle size, and good stability, especially better mechanical stability, is favorable for separation of products in subsequent production, provides a better choice for preparing PLX3397-containing pharmaceutical preparations, and is very important to medicinal development.

front page image

Pexidartinib (PLX3397) is a new drug used to treat tenosynovial giant cell tumor (TGCT). Tenoid sheath giant cell tumor is a rare type of tendon sheath cancer. At present, the disease is usually treated surgically by surgical resection, and the surgical treatment of the disease may lead to the deterioration of dysfunction and serious complications. And since TGCTs have multiple types, which typically occur at bone tissue and joints, the advent of new interventional therapies is urgently needed in the clinic. The PLX3397 is currently in Phase III clinical trials and has received the FDA’s breakthrough drug therapy certification. The structural formula of PLX3397 is shown in formula (I).
Example 1 Preparation of monohydrochloride form CS2

Weigh 101.6 mg of PLX3397 solids in a 5 mL glass vial and add 2 mL of n-heptane at 5 ° C. Under magnetic stirring, 440 μL of 0.6 mol / L diluted hydrochloric acid was added and the reaction was carried out for 40 min. The mixture was filtered and dried to obtain an off-white solid.

Upon testing, the solid obtained in this example is the monohydrochloride form CS2. The XRPD pattern is shown in Figure 1, and the XRPD data is shown in Table 1. The resulting solid was monohydrochloride salt of PLX3397 as determined by ion chromatography. 1 H NMR is shown in FIG. 4.

When differential scanning calorimetry was used, the endothermic peak began to form when heated to about 72 ° C. When heated to around 227 ° C, the endothermic peak started to appear. The DSC is shown in FIG. 2.

When subjected to thermogravimetric analysis, crystalline form CS2 has a mass loss gradient of about 8.3% when heated to 137 ° C, the TGA of which is shown in FIG. 3. Form CS2 is hydrate.

[Figure 0009]   

Fig. 1 H NMR chart of crystalline form CS3 in Example 3. Fig

//////////////Pexidartinib, New Patent, WO 2017215521, Crystal Pharmatech Co Ltd

Biocon Launches KRABEVA® in India, A Biosimilar Bevacizumab for Treating Several Types of Cancer

Image result for KRABEVA®

Biocon Launches KRABEVA® in India,  A Biosimilar Bevacizumab for Treating Several Types of Cancer

On November 23, 2017, Biocon India’s premier Biopharmaceuticals Company announced that it has launched KRABEVA®, a biosimilar Bevacizumab for the treatment of patients with metastatic colorectal cancer and other types of lung, kidney, cervical, ovarian and brain cancers, in India 1.
KRABEVA®, a monoclonal antibody (mAb) developed by Biocon, will help expand access to a world-class, high quality biosimilar Bevacizumab for cancer patients in India. It is the world´s first and only Bevacizumab with a unique ´QualCheck ´ mechanism, which ensures that patients get a quality-ascertained product right up to infusion.
Bevacizumab is indicated as a first-line treatment of patients with metastatic colorectal cancer (mCRC), and is accepted as a standard treatment option in combination with chemotherapy for patients with non-small-cell lung cancer (NSLC), metastatic renal cell carcinoma or recurrent ovarian cancer.
KRABEVA® is the second key oncologic biosimilar product, from Biocon´s global biosimilars portfolio to be launched in India. It is being offered to patients at an MRP of Rs 24,000 for 100 mg / 4 ml vials and Rs 39,990 for 400 mg / 16 ml vials, making it a high quality affordable alternative to the innovator brand. In comparison, the Innovator brand for Bevacizumab marketed as Avastin® by Roche India Private Limited costs over Rs 10, 7065 for 400mg / 16ml vial.
Bevacizumab is a monoclonal antibody (mAb) targeting Vascular Endothelial Growth Factor- A (VEGF-A), a cell protein that induces growth of blood vessels that feed tumors. By blocking this protein, Bevacizumab cuts the  supply of food and oxygen to the tumor, thus starving it.

Bevacizumab is prescribed in the treatment of several cancers including metastatic colorectal cancer, ovarian cancer, advanced non-small-cell lung cancer, recurrent glioblastoma, cervical cancer and renal cancer. Bevacizumab was first approved by the United States Food and
Drug Administration (USFDA), in February 2004 2.

It also features in the World Health Organization’s (WHO) list of essential medicines 3. The WHO list of essential medicines contains the medications considered to be most effective and safe to meet the most important needs in a health system. The list is frequently used by countries to help develop their own local lists of essential medicine.

Approval and launch of a Bevacizumab biosimilar in India would provide an affordable therapy option for patients of various types of cancer.

//////////Biocon, KRABEVA®, India,  Biosimilar,  Bevacizumab, Cancer

Empesertib , BAY 1161909


2D chemical structure of 1443763-60-7

Empesertib , BAY 1161909, Mps1-IN-5,  (-)-BAY-1161909

CAS 1443763-60-7
Chemical Formula: C29H26FN5O4S
Molecular Weight: 559.6164

[a]D20 : -78.9° (in DMSO). WO 2014198647




Benzeneacetamide, 4-fluoro-N-(4-(2-((2-methoxy-4-(methylsulfonyl)phenyl)amino)(1,2,4)triazolo(1,5-a)pyridin-6-yl)phenyl)-alpha-methyl-, (alphaR)-



Image result


WO 2014198647

Analytical UPLC-MS was performed as follows:

Method A: System: UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass spectrometer; Column: Acquity BEH C18 1 .7μηη 2.1 x50mm; Temperature: 60° C; Solvent A: Water + 0.1 % formic acid; Solvent B: acetonitrile; Gradient: 99 % A – 1 % A (1 .6 min) -> 1 % A (0.4 min) ; Flow: 0.8 mL/min; Injection Volume: 1 .0 μΐ (0.1 mg-1 mg/ml_ sample concentration); Detection: PDA scan range 210-400 nm – Fixed and ESI (+), scan range 170-800 m/z

LC-MS methods:

Method 1 :

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1 .8 μ 50 x 1 mm; Eluent A: 1 I Wasser + 0.25 ml 99%ige Formic acid, Eluent B: 1 I Acetonitril + 0.25 ml 99%ige Formic acid; Gradient: 0.0 min 90% A → 1 .2 min 5% A→ 2.0 min 5% A Ofen: 50° C; Flow: 0.40 ml/min; UV-Detection: 208 – 400 nm.

1H-NMR (300 MHz, DMSO-d6), δ [ppm] = 1 .39 (3H), 3.16 (3H), 3.83 (1 H), 3.95 (3H), 7.08-7.20 (2H), 7.34-7.45 (3H), 7.51 (1 H), 7.63-7.77 (5H), 7.92 (1 H), 8.48 (1 H), 8.64 (1 H), 9.1 1 (1 H), 10.19 (1 H).

[a]D20 : -78.9° (in DMSO).

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OD-RH 150×4.6; Flow: 1 .00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1 % : > 99%.

Empesertib, also known as BAY1161909, is an orally bioavailable, selective inhibitor of the serine/threonine monopolar spindle 1 (Mps1) kinase, with potential antineoplastic activity. Upon administration, the Mps1 kinase inhibitor BAY1161909 binds to and inhibits the activity of Mps1. This causes inactivation of the spindle assembly checkpoint (SAC), accelerated mitosis, chromosomal misalignment, chromosomal missegregation, mitotic checkpoint complex destabilization, and increased aneuploidy. This leads to the induction of cell death in cancer cells overexpressing Mps1.

BAY-1161909 is an oral dual specificity protein kinase TTK inhibitor in early clinical trials at Bayer for the treatment of advanced malignancies in combination with paclitaxel.

Bayer and INSERM are developing BAY-1161909 , presumed to be the lead from monopolar spindle-1 inhibitors, including Mps-BAY-2b and Mps-BAY-2c, for the oral treatment of cancer; in July 2016, BAY-1161909 was reported to be in phase I clinical trial.

Mps-1 (Monopolar Spindle 1 ) kinase (also known as Tyrosine Threonine Kinase, TTK). Mps-1 is a dual specificity Ser/Thr kinase which plays a key role in the activation of the mitotic checkpoint (also known as spindle checkpoint, spindle assembly checkpoint) thereby ensuring proper chromosome segregation during mitosis [Abrieu A et al., Cell, 2001 , 106, 83-93]. Every dividing cell has to ensure equal separation of the replicated chromosomes into the two daughter cells. Upon entry into mitosis, chromosomes are attached at their kinetochores to the microtubules of the spindle apparatus. The mitotic checkpoint is a surveillance mechanism that is active as long as unattached kinetochores are present and prevents mitotic cells from entering anaphase and thereby completing cell division with unattached chromosomes [Suijkerbuijk SJ and Kops GJ, Biochemica et Biophysica Acta, 2008, 1786, 24- 31 ; Musacchio A and Salmon ED, Nat Rev Mol Cell Biol., 2007, 8, 379-93]. Once all kinetochores are attached in a correct amphitelic, i.e. bipolar, fashion with the mitotic spindle, the checkpoint is satisfied and the cell enters anaphase and proceeds through mitosis. The mitotic checkpoint consists of a complex network of a number of essential proteins, including members of the MAD (mitotic arrest deficient, MAD 1 -3) and Bub (Budding uninhibited by benzimidazole, Bub 1 -3) families, the motor protein CENP-E, Mps-1 kinase as well as other components, many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al., Clinical Cancer Research, 2006, 12, 405-10]. The essential role of Mps-1 kinase activity in mitotic checkpoint signalling has been shown by shRNA-silencing, chemical genetics as well as chemical inhibitors of Mps-1 kinase [Jelluma N et al., PLos ONE, 2008, 3, e2415; Jones MH et al., Current Biology, 2005, 15, 160-65; Dorer RK et al., Current Biology, 2005, 15, 1070-76; Schmidt M et al., EMBO Reports, 2005, 6, 866-72].

There is ample evidence linking reduced but incomplete mitotic checkpoint function with aneuploidy and tumorigenesis [Weaver BA and Cleveland DW, Cancer Research, 2007, 67, 10103-5; King RW, Biochimica et Biophysica Acta, 2008, 1786, 4-14]. In contrast, complete inhibition of the mitotic checkpoint has been recognised to result in severe chromosome missegregation and induction of apoptosis in tumour cells [Kops GJ et al., Nature Reviews Cancer, 2005, 5, 773-85; Schmidt M and Medema RH, Cell Cycle, 2006, 5, 159-63; Schmidt M and Bastians H, Drug Resistance Updates, 2007, 10, 162-81]. Therefore, mitotic checkpoint abrogation through pharmacological inhibition of Mps-1 kinase or other components of the mitotic checkpoint represents a new approach for the treatment of proliferative disorders including solid tumours such as carcinomas and sarcomas and leukaemias and lymphoid malignancies or other disorders associated with uncontrolled cellular proliferation.

Different compounds have been disclosed in prior art which show an inhibitory effect on Mps-1 kinase:

WO 2009/024824 A1 discloses 2-Anilinopurin-8-ones as inhibitors of Mps-1 for the treatment of proliferate disorders. WO 2010/124826 A1 discloses substituted imidazoquinoxaline compounds as inhibitors of Mps-1 kinase. WO 2011 /026579 A1 discloses substituted aminoquinoxalines as Mps-1 inhibitors.

Substituted triazolopyndine compounds have been disclosed for the treatment or prophylaxis of different diseases:

WO 2008/025821 A1 (Cellzome (UK) Ltd) relates to triazole derivatives as kinase inhibitors, especially inhibitors of ITK or PI3K, for the treatment or prophylaxis of immunological, inflammatory or allergic disorders. Said triazole derivatives are exemplified as possessing an amide, urea or aliphatic amine substituent in position 2.

WO 2009/047514 A1 (Cancer Research Technology Limited) relates to [1 ,2,4]- triazolo-[1 ,5-a]-pyridine and [1 ,2,4]-triazolo-[1 ,5-c]-pyrimidine compounds which inhibit AXL receptor tyrosine kinase function, and to the treatment of diseases and conditions that are mediated by AXL receptor tyrosine kinase, that are ameliorated by the inhibition of AXL receptor tyrosine kinase function etc., including proliferative conditions such as cancer, etc.. Said compounds are exemplified as possessing a substituent in the 5-position and a substituent in the 2-position.

WO 2009/010530 A1 discloses bicyclic heterorayl compounds and their use as phosphatidyli nositol (PI) 3-kinase. Among other compounds also substituted triazolopyridines are mentioned.

WO 2009/027283 A1 discloses triazolopyridine compounds and their use as ASK (apoptosis signal-regulating kinase) inhibitors for the treatment of autoimmune diseases and neurodegenerative diseases. WO 2010/092041 A1 (Fovea Pharmaceuticals SA) relates to [1 ,2,4]-triazolo- [1 ,5-a] -pyridines, which are said to be useful as selective kinase inhibitors, to methods for producing such compounds and methods for treating or ameliorating kinase-mediated disorder. Said triazole derivatives are exemplified as possessing a 2-chloro-5-hydroxyphenyl substituent in the 6- position of the [1 ,2,4]-triazolo-[1 ,5-a]-pyridine.

WO 2011 /064328 A1 , WO 2011 /063907 A1 , and WO 2011 /063908 A1 (Bayer Pharma AG) relate to [1 ,2,4]-triazolo-[1 ,5-a]-pyridines and their use for inhibition of Mps-1 kinase.

WO 2011 /064328 A1 discloses com ounds of fomula S2:

Figure imgf000005_0001


in which

R1 is an aryl- or heteroaryl- group; wherein the aryl- or heteroaryl- group can be substituted inter alia with -N(H)C(=0)R6 or -C(=0)N(H)R6 ; in which R6represents a hydrogen or a Ci-C6-alkyl- group; the Ci-C6-alkyl- group optionally being substituted with halo-, hydroxyl-, d-C3-alkyl, R70-. WO 2011 /064328 A1 does not disclose compounds of the present invention as defined below.

WO 2011 /063907 A1 discloses compounds of fomula S1 :

Figure imgf000005_0002


in which

R1 is an aryl group which is substituted at least one time; whereas the at least one substituent inter alia can be -N(H)C(=0)R6 or -C(=0)N(H)R6 ; in which R6represents a group selected from C3-C6-cycloalkyl, 3- to 10-membered heterocyclyl-, aryl-, heteroaryl-, -(CH2)q-(C3-C6-cycloalkyl), -(CH2)q-(3- to 10- membered heterocyclyl), -(CH2)q-aryl, or -(CH2)q-heteroaryl, wherein R6 is optionally substituted, and q is 0, 1 , 2 or 3;

R2 represents a substituted or unsubstituted aryl- or heteroaryl- group;

R3 and R4 inter alia can be hydrogen; and

R5 represents a substituted or unsubstituted Ci-C6-alkyl group.

WO 2011 /063908 A1 discloses com ounds of fomula S3:

Figure imgf000006_0001


in which

R1 is an aryl group which is substituted at least one time; whereas the at least one substituent inter alia can be -N(H)C(=0)R6 or -C(=0)N(H)R6 ; in which R6inter alia represents a group selected from C3-C6-cycloalkyl, 3- to 10- membered heterocyclyl-, aryl-, heteroaryl-, -(CH2)q-(C3-C6-cycloalkyl), -(CH2)q– (3- to 10-membered heterocyclyl), -(CH2)q-aryl, and -(CH2)q-heteroaryl, wherein R6 is optionally substituted, and q is 0, 1 , 2 or 3;

R2 represents a substituted or unsubstituted aryl- or heteroaryl- group;

R3 and R4 inter alia can be hydrogen; and

R5 is hydrogen.

There are patent applications which are related to [1 ,2,4]-triazolo-[1 ,5-a]- pyridines and their use for inhibition of Mps-1 kinase, but which have not been published at the time of filing of this patent application: Subject matter of the EP patent applications No. 11167872.8, and No. 11167139.2 as well as of the patent application PCT/EP2011 /059806 are com ounds of fomula S4:

Figure imgf000007_0001


in which

R1 represents inter alia a phenyl- group which is substituted at least one time; whereas the at least one substituent inter alia can be -N(H)C(=0)R6; in which R6inter alia can be -(CH2)q-aryl, wherein R6 is optionally substituted, and q is 0, 1 , 2 or 3;

R2 represents a substituted or unsubstituted aryl- or heteroaryl- group;

R3 and R4 inter alia can be hydrogen; and

R5 is hydrogen. However, the state of the art described above does not specifically disclose the substituted triazolopyridine compounds of general formula (I) of the present invention, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as “compounds of the present invention”, or their pharmacological activity.

The above mentioned patent applications which are related to [1 ,2,4]-triazolo- [1 ,5-a] -pyridines mainly focus on the effectiveness of the compounds in inhibiting Mps-1 kinase, expressed by the half maximal inhibitory concentration (IC50) of the compounds. For example, in WO 2011 /063908 A1 the effectiveness in inhibiting Mps-1 kinase was measured in an Mps-1 kinase assay with a concentration of 10 μΜ adenosine triphosphate (ATP).

The cellular concentration of ATP in mammals is in the millimolar range. Therefore it is important that a drug substance is also effective in inhibiting Mps-1 kinase in a kinase assay with a concentration of ATP in the millimolar range, e.g. 2 mM ATP, in order to potentially achieve an antiproliferative effect in a cellular assay. In addition, as one of ordinary skill in the art knows, there a many more factors determining the druglikeness of a compound. The objective of a preclinical development is to assess e.g. safety, toxicity, pharmacokinetics and metabolism parameters prior to human clinical trials. One important factor for assessing the druglikeness of a compound is the metabolic stability. The metabolic stability of a compound can be determined e.g. by incubating the compound with a suspension of liver microsomes from e.g. a rat, a dog and/or a human (for details see experimental section). Another important factor for assessing the druglikeness of a compound for the treatment of cancer is the inhibition of cell proliferation which can be determined e.g. in a HeLa cell proliferation assay (for details see experimental section). Surprisingly it was found, that the compounds of the present invention are characterized by :

– an IC50 lower than or equal to 1 nM (more potent than 1 nM) in an Mps-1 kinase assay with a concentration of 10 μΜ ATP, and

– an IC50 lower than 10 nM (more potent than 10 nM) in an Mps-1 kinase assay with a concentration of 2 mM ATP, and – a maximum oral bioavailability (Fmax) in rat that is higher than 50 % determined by means of rat liver microsomes as described below, and

– a maximum oral bioavailability (Fmax) in dog that is higher than 45 % determined by means of dog liver microsomes as described below, and

– a maximum oral bioavailability (Fmax) in human that is higher than 45 %, determined by means of human liver microsomes as described below, and

– an IC50 lower than 600 nM in a HeLa cell proliferation assay as described below. Hence, the compounds of the present invention have surprising and advantageous properties. These unexpected findings give rise to the present selection invention. The compounds of the present invention are purposively selected from the above mentioned prior art due to their superior properties. In particular, said compounds of the present invention may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Mps-1 kinase, such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.



Inventors Volker SchulzeDirk KosemundAntje Margret WengnerGerhard SiemeisterDetlef STÖCKIGTMichael Bruening
Applicant Bayer Intellectual Property GmbhBayer Pharma Aktiengesellschaft

Synthesis of Examples

Compounds of the present invention


(2 ?)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]- amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propanamide

Figure imgf000139_0001

To a stirred suspension of Int08.011 (6.0 g) in DMF (48 mL) and dichloromethane (96 mL) was added sodium bicarbonate (3.69 g), (2/?)-2-(4- fluorophenyl)propanoic acid (2.71 g) and HATU (8.36 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethyl acetate to give 7,44 g of the title compound. 1H-NMR (400MHz, DMSO-d6): δ [ppm]= 1.40 (d, 3H), 3.16 (s, 3H), 3.84 (q, 1H), 3.96 (s, 3H), 7.09 – 7.18 (m, 2H), 7.36 – 7.44 (m, 3H), 7.51 (dd, 1H), 7.63 – 7.76 (m, 5H), 7.92 (dd, 1H), 8.48 (d, 1H), 8.60 (s, 1H), 9.10 (d, 1 H), 10.16 (s, 1H).

[a]D20 : -77.0° (in DMSO).

Column: Chiralcel OD-RH 150×4.6; Flow: 1.00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1% : > 99%. Racemate01.01.r

Figure imgf000140_0001

Starting with Int01.05 and Int03.02, Racemate01.01.r was prepared analogously to the procedure for the preparation of Int08.020.




Analytical UPLC-MS was performed as follows:

Method A: System: UPLC Acquity (Waters) with PDA Detector und Waters ZQ mass spectrometer; Column: Acquity BEH C18 1 .7μηη 2.1 x50mm; Temperature: 60° C; Solvent A: Water + 0.1 % formic acid; Solvent B: acetonitrile; Gradient: 99 % A – 1 % A (1 .6 min) -> 1 % A (0.4 min) ; Flow: 0.8 mL/min; Injection Volume: 1 .0 μΐ (0.1 mg-1 mg/ml_ sample concentration); Detection: PDA scan range 210-400 nm – Fixed and ESI (+), scan range 170-800 m/z

LC-MS methods:

Method 1 :

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1 .8 μ 50 x 1 mm; Eluent A: 1 I Wasser + 0.25 ml 99%ige Formic acid, Eluent B: 1 I Acetonitril + 0.25 ml 99%ige Formic acid; Gradient: 0.0 min 90% A → 1 .2 min 5% A→ 2.0 min 5% A Ofen: 50° C; Flow: 0.40 ml/min; UV-Detection: 208 – 400 nm.

Preparation of compound A1

Route I

(2/?)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]propanamide

To a stirred suspension of Int08.011 (6.0 g) in DMF (48 mL) and dichloromethane (96 mL) was added sodium bicarbonate (3.69 g), (2/?)-2-(4-fluorophenyl)propanoic acid (2.71 g) and HATU (8.36 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated with ethyl acetate to give 7.44 g of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.40 (d, 3H), 3.16 (s, 3H), 3.84 (q, 1 H), 3.96 (s, 3H), 7.09 – 7.18 (m, 2H), 7.36 – 7.44 (m, 3H), 7.51 (dd, 1 H), 7.63 – 7.76 (m, 5H), 7.92 (dd, 1 H), 8.48 (d, 1 H), 8.60 (s, 1 H), 9.10 (d, 1 H), 10.16 (s, 1 H).

[a]D20 : -77.0° (in DMSO).

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OD-RH 150×4.6; Flow: 1.00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1% : > 99%.

Intermediate Int08.01 1

6-(4-aminophenyl)-N-[2-methoxy-4-(methylsulfonyl)phenyl][ 1 ,2,4]-triazolo[1 ,5-a]pyridin-2-amine

To a stirred suspension of Int08.010 (12.3 g) in dichloromethane (40 mL) was added TFA (46 mL). The mixture was stirred at room temperature for 16 h. Further TFA was added (1 mL) and the mixture was stirred at room temperature for 5 h. A saturated solution of potassium carbonate was added until pH 9 was reached. The mixture was extracted with dichloromethane and methanol (10:1 mixture). The solution was dried (sodium sulfate) and the solvent was removed in vacuum. The residue was triturated with ethanol to give 9.2 g of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm]= 3.16 (s, 3H), 3.95 (s, 3H), 5.30 (s, 2H), 6.63 (d, 2H), 7.38 – 7.46 (m, 3H), 7.51 (dd, 1 H), 7.61 (d, 1 H), 7.84 (dd, 1 H), 8.48 (d, 1 H), 8.55 (s, 1 H), 8.93 (d, 1 H).

Intermediate Int08.010

ieri-butyl [4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[ 1 ,2,4]-triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamate

To a stirred suspension of Int01.03 (4.0 g) in toluene (250 mL) and NMP (25 mL) was added Int03.02 (8.31 g), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1 ,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butylether adduct (1.08 g), X-Phos (0.64 g) and powdered potassium phosphate (16.6 g). The flask was degassed twice and backfilled with argon. The mixture was heated to reflux for 16 h.

The reaction mixture was filtered through a microfilter and the solvent was removed in vacuum. The residue was triturated with dichloromethane to give 12.3 g of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.46 (s, 9H), 3.16 (s, 3H), 3.96 (s, 3H), 7.43 (d, 1 H), 7.48 – 7.59 (m, 3H), 7.63 – 7.72 (m, 3H), 7.92 (dd, 1 H), 8.48 (d, 1 H), 8.58 (s, 1 H), 9.06 – 9.12 (m, 1 H), 9.46 (s, 1 H).

Intermediate Int01.03.

ieri-butyl [4-(2-amino[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]carbamate

To a stirred solution of Int01.02 (5.82 g) in 1 -propanol (400 mL) was added 2M potassium carbonate solution (41 mL), {4-[(tert-butoxycarbonyl) amino] phenyl} boronic acid (8.6 g), triphenylphosphine (150 mg) and PdCl2(PPh3)2 (1.9 g). The mixture was heated to reflux for 4 h, the solvent was removed in vacuum, water (150 mL) was added and the mixture was extracted with ethyl

acetate (500 mL). The organic phase was dried (sodium sulfate), filtered through Celite and the solvent was removed in vacuum. The residue was triturated with DCM to give the title compound as a white solid. Yield: 7.2 g. 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.37 – 1.55 (m, 9H), 5.99 (s, 2H), 7.36 (dd, 1 H), 7.48 – 7.55 (m, 2H), 7.55 – 7.62 (m, 2H), 7.69 (dd, 1 H), 8.78 (dd, 1 H), 9.44 (s, 1 H).

Intermediate Int01.02

6-Bromo[1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine

Hydroxylammonium chloride (39.8 g) was suspended in methanol (200 mL) and ethanol (190 mL) and Hiinig Base (59 mL) was added at r.t. The mixture was heated to 60°C, Int01.01 (30 g) was added portionwise, and the mixture was stirred at 60 °C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum.

Yield: 19.3 g of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 6.10 (s, 2H), 7.28 (dd, 1 H), 7.51 (dd, 1 H), 8.88 (dd, 1 H).

Intermediate Int01.01

Eth l [(5-bromopyridin-2-yl)carbamothioyl]carbamate

Ethoxycarbonylisothiocyanate (16.7 g) was added to a stirred solution of 2-amino-5-brompyridine (20 g) in dioxane (200 mL). The mixture was stirred for 2h at r.t. A white solid precipitated. Hexane (20 mL) was added and the white solid was collected by filtration.

Yield: 30.4 g of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 1 .22 (t, 3H), 4.19 (q, 2H), 8.08 (dd, 1 H), 8.49 (d, 1 H), 8.57 (br. d, 1 H), 1 1 .37 – 12.35 (m, 2H).

Intermediate Int03.02

1 -bromo-2-methoxy-4-(methylsulfonyl)benzene

To a stirred solution of Int03.01 (265 mg) in chloroform (10 mL) was added 3-chlorobenzenecarboperoxoic acid (mCPBA) (890 mg). The mixture was stirred at room temperature for 1 h. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 252 mg of the title compound.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 3.22 (s, 3H), 3.93 (s, 3H), 7.39 (dd, 1 H), 7.50 (d, 1 H), 7.84 (d, 1 H).

Intermediate Int03.01

1 -bromo-2-methoxy-4-(methylsulfanyl)benzene

To a stirred solution of 1 -bromo-4-fluoro-2-methoxybenzene (4.0 g) in DMF (40 mL) was added sodium methanethiolate (2.76 g). The mixture was stirred at room temperature for 30 minutes and at 85 °C for 2 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 280 mg of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 2.46 (s, 3H), 3.82 (s, 3H), 6.74 (dd, 1 H), 6.91 (d, 1 H), 7.44 (d, 1 H).

Intermediate Int03.00

1 -bromo-2-methoxy-4-(methylsulfanyl)benzene (alternative procedure)

To a stirred solution of 1 -bromo-4-fluoro-2-methoxybenzene (10.0 g) in DMF (100 mL) was added sodium methanethiolate (4.44 g). The mixture was stirred at 65°C for 2 h. The mixture was cooled to 0°C and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h and further sodium methanethiolate (4.44 g) was added. The mixture was stirred at 65 °C for 1 h. The mixture was cooled to 0°C and methyl iodide (4.55 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 6.2 g of the title compound as a 2:1 mixture with the starting material. The mixture was used for the next step without purification.

Route II


amino}[1 ,2,4]triazolo[1 ,5-a]pyridin-6-yl)phenyl]propanamide

To a stirred suspension of Int21.06 (550 mg) in toluene (18 mL) was added potassium fluoride (260 mg) and powdered potassium phosphate (842 mg) and the flask was degassed twice and backfilled with argon. The mixture was stirred for 15 minutes at r.t.. Int21.03 (350 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (81 mg) and palladium acetate (22 mg) were added and the flask was degassed twice and backfilled with argon. The mixture was heated to 85 °C for 3 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silica-gel chromatography gave a solid that was triturated with a mixture of dichloromethane and hexane to give 452 mg of the title compound.

1H-NMR (300 MHz, DMSO-d6), δ [ppm] = 1 .39 (3H), 3.16 (3H), 3.83 (1 H), 3.95 (3H), 7.08-7.20 (2H), 7.34-7.45 (3H), 7.51 (1 H), 7.63-7.77 (5H), 7.92 (1 H), 8.48 (1 H), 8.64 (1 H), 9.1 1 (1 H), 10.19 (1 H).

[a]D20 : -78.9° (in DMSO).

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OD-RH 150×4.6; Flow: 1 .00 mL/min; Solvent: A: Water with 0.1 % formic acid, B: Acetonitrile; Solvent mixture: 40% A + 60% B. Run Time: 30 min. Retention Time: 12.83 min; UV 254 nm; Enantiomeric Ratio: <1 % : > 99%.

Intermediate Int21.06

(2R)-2-(4-fluorophenyl)-N-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]propanamide

To a stirred solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (1.0 g) in DMF (45 mL) and dichloromethane (90 mL) was added sodium bicarbonate (766 mg), Int09.03 (844 mg) and HATU (2.6 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica-gel chromatography gave 1.53 g of the title compound.

1H-NMR (400 MHz, DMSO-d6), δ [ppm] = 1.23 (12H), 1.37 (3H), 3.74-3.87 (1 H), 7.06-7.16 (2H), 7.31 -7.42 (2H), 7.51 -7.61 (4H), 10.12 (1 H).

Intermediate Example Int21.05

(4-{[(2R)-2-(4-fluorophenyl)propanoyl]amino}phenyl)boronic acid

To a stirred solution of (4-aminophenyl)boronic acid hydrochloride (2.00 g) in DMF (42 mL) was added sodium bicarbonate (2.9 g), (2R)-2-(4-

fluorophenyl)propanoic acid (2.04 g) and HATU (6.58 g). The mixture was stirred at room temperature for 72 h. Water (140 mL) was added, and the mixture was stirred for 2 h. The white precipitate was collected by filtration and was washed with water and was dried in vacuum to give 2.86 g of the title compound.

1H-NMR (300 MHz, DMSO-d6), δ [ppm] = 1.39 (3H), 3.84 (1 H), 7.08-7.21 (2H), 7.35-7.44 (2H), 7.52 (2H), 7.69 (2H), 7.88 (2H), 10.07 (1 H).

Intermediate Int09.03

2/?)-2-(4-fluorophenyl)propanoic acid

To a stirred solution of Int09.02 (23.6 g) in refluxing ethyl acetate (250ml_) was added a solution of (1S)-1 -phenylethanamine (17.35 g) in ethyl acetate. The mixture was allowed to cool down to room temperature within 1 h. A white solid was collected by filtration, was washed with ethyl acetate and dried in vacuum to give 27.5 g of a solid. The solid was recrystallized from 400 mL refluxing ethyl acetate. The mixture was allowed to cool down to room temperature. A white solid was collected by filtration, was washed with ethyl acetate and dried in vacuum to give 18.3 g of a solid. The solid was twice recrystallized from refluxing ethyl acetate (350 mL; 300 mL). A white solid was collected by filtration, was washed with ethyl acetate and dried in vacuum to give 10.51 g of a solid. The solid was dissolved in water, hydrochloric acid (c=2.0 M) was added until pH 5 was reached and the reaction mixture was extracted with dichloromethane. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum to give 5.6 g of the title product. The crude product was used without further purification.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 1.31 (d, 3H), 3.66 (q, 1 H), 7.05 – 7.16 (m, 2H), 7.24 – 7.33 (m, 2H), 12.28 (br. s., 1 H).

[a]D20 : -79.3° (in DMSO)

Determination of enantiomeric purity by analytical chiral HPLC:

Column: Chiralcel OJ-H 150×4.6; Flow: 1.00 mL/min; Solvent: A: Hexane, B: 2-propanol with 0.1 % formic acid; Solvent mixture: 80% A + 20% B. Run Time: 30 min. Retention Time: 3.41 min; UV 254 nm; Enantiomeric Ratio: 99.8% : 0.2%.

Intermediate Int09.02

Rac-2- 4-fluorophenyl)propanoic acid

To a stirred solution of Int09.01 (18.9 g) in ethanol (200 mL) was added a solution of potassium hydroxide (35 g), dissolved in water (200 mL). The mixture was stirred at 0 °C for 4 h. Hydrochloric acid (c=4.0 M) was added until pH 5 was reached and the reaction mixture was extracted with ethyl acetate. The organic phase was separated and the solvent was removed in vacuum to give 15.64 g of the title product. The crude product was used without further purification.

1H-NMR (300MHz, DMSO-d6): δ [ppm] = 1.31 (d, 3H), 3.66 (q, 1 H), 7.05 – 7.15 (m, 2H), 7.24 – 7.33 (m, 2H), 12.30 (s, 1 H).

Intermediate Int09.01

Rac-meth l 2-(4-fluorophenyl)propanoate

To a stirred solution of diisopropylamine (13.0 g) in tetrahydrofurane (160 mL) was added a solution of n-butyllithium in hexane (51.4 mL; c= 2.5 M) at -78 °C. The solution was stirred at 0 °C for 15 minutes. The solution was cooled to -78 °C and a solution of methyl (4-fluorophenyl)acetate (18.0 g), dissolved in tetrahydrofurane (40 mL) was added. The solution was stirred at -78 °C for 30 minutes. Methyl iodide (10.0 mL) was added at -78 °C, and the solution was allowed to warm up to 0 °C within 1 h. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 18.9 g of the title compound.

1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.34 (d, 3H), 3.55 (s, 3H), 3.79 (q, 1 H), 7.08 – 7.15 (m, 2H), 7.25 – 7.32 (m, 2H).

Intermediate Int21.03

6-chloro-N-[2-methoxy-4-(methylsulfonyl)phenyl][1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine

To a stirred suspension of Int21.02 (0.7 g) in toluene (28 mL) was added Int03.02 (1.27 g), chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1 ,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butylether adduct (343 mg), X-Phos (202 mg) and powdered potassium phosphate (3.09 g). The flask was degassed twice and backfilled with argon. The mixture was heated to reflux for 3 h. Further chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1 ,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(ll) methyl-tert-butylether adduct (30 mg) and X-Phos (19 mg) were added and the mixture was heated to reflux

for 15 h. The solvent was removed in vacuum. Silicagel chromatography gave a solid that was triturated ethyl acetate to give 1.0 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.16 (3H), 3.95 (3H), 7.42 (1 H), 7.50 (1 H), 7.62-7.69 (2H), 8.41 (1 H), 8.70 (1 H), 9.17 (1 H).

Intermediate Int21.02

6-chloro[1 ,2,4]triazolo[1 ,5-a]pyridin-2-amine

Hydroxylammonium chloride (4.4 g) was suspended in methanol (35 mL) and ethanol (35 mL) and Hiinig Base (10.2 mL) was added at r.t. The mixture was heated to 60° C, Int21.01 (4.4 g) was added portionwise, and the mixture was stirred at 60 °C for 2h. The solvent was removed in vacuum and water (150 mL) was added. A solid was collected by filtration and was washed with water and dried in vacuum.

Yield: 2.0 g of the title compound.

1H-NMR (300 MHz, DMSO-d6): δ [ppm] = 6.09 (2H), 7.28-7.37 (1 H), 7.39-7.49

(1 H), 8.84 (1 H).

Intermediate Int21.01

Eth l [(5-chloropyridin-2-yl)carbamothioyl]carbamate

Ethoxycarbonylisothiocyanate (3.37 g) was added to a stirred solution of 2-amino-5-cloropyridine (3.0 g) in dioxane (100 mL). The mixture was stirred at r.t. for 14 h. The solvent was removed in vacuum. The solid was dissolved in dichloromethane and methanol (100 : 1 ), filtered and the solvent was removed in vacuum to give a solid that was recystallized from ethyl acetate to give 4.4 g of the title compound.

1H-NMR (400 MHz, CHLOROFORM-d): δ [ppm] = 1.35 (3H), 4.31 (2H), 7.71 (1 H), 8.03 (1 H), 8.34 (1 H), 8.83 (1 H), 12.09 (1 H).



Novel crystalline polymorphic forms of (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2- methoxy-4-(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propan-amide 4-toluenesulfonate (empesertib), and crystalline (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propanamide 4- toluenesulfonate monohydrate, composition comprising them and their preparation methods are claimed. Also claims their use for treating various cancers. It is disclosed that empesertib is a potent Mps-1 kinase inhibitor.


The present invention covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy^-imethylsulfonyljphenyllaminojll^^ltriazololl^-olpyridin-e-yljphenyllpropan-amide 4-toluenesulfonate, and crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate monohydrate, as compounds per se, a method of preparing said crystalline, anhydrous compound, pharmaceutical compsitions and pharmaceutical combinations comprising said crystalline, anhydrous compound, and uses of said crystalline, anhydrous compound in the treatment or prophylaxis of cancer, in particular pancreatic cancer, glioblastoma, ovarian cancer, non-small cell lung carcinoma, breast cancer, and/or gastric cancer.


(2R)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide is known to be a very potent inhibitor of Mps-1 kinase.

WO 2013/087579 Al discloses the compound, data showing its pharmaceutical activity, and a method for the preparation of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide.

WO 2014/009219 Al discloses an improved method for the preparation of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propan-amide.

WO 2014/195408 Al discloses pharmaceutical compositions comprising (2 ?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propan-amide mainly in amorphous form.

Surprisingly and unexpectedly, it was observed that a crystalline form of the anhydrous 4-toluenesulfonate salt of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)-phenyl]amino}[l,2,4]triazolo[l,5-o]pyridin-6-yl)phenyl]propanamide shows superior properties in terms of its pharmacological usability compared to the free base (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide or other salts thereof.

In accordance with a first aspect, the present invention thus covers crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide 4-toluenesulfonate, of formula (I) :


hereinafter also referred to as the “anhydrous tosylate salt” or “anhydrous 4-toluenesulfonate salt”,

Example 1 : Preparation of crystalline, anhydrous (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenvnamino}fl,2,41triazolofl,5-a1pyridin-6-vDphenyllpropanamide 4-toluene-sulfonate : method 1 (without seeding)

Without seeding:

10 g (17.9 mmol) of (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (100 ml) and heated to 65°C 4.08 g (21.4 mmol) 4-toluenesulfonic acid monohydrate in 2-butanone (20 ml) were added at 65°C. The suspension dissolved and the product precipitated from solution. The mixture was stirred for 21h at 65°C. The mixture was cooled to 20°C over 2h. After 2h stirring at 20°C the precipitate was isolated by suction filtration and washed two times with 100 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 7h. 12.4 g (95 % of theory) were isolated.

Example 3 : Preparation of crystalline (2/?)-2-(4-fluorophenyl)-/V-[4-(2-{[2-methoxy-4- (methylsulfonyl)phenyllannino}[l,2,41triazolo[l,5-alpyriclin-6-yl)phenyllpropanamide 4; toluene-sulfonate monohydrate: method 1 : without seeding

10 g (17.9 mmol) of (2/?)-2-(4-fluorophenyl)-W-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]-amino}[l,2,4]triazolo[l,5-a]pyridin-6-yl)phenyl]propanamide were suspended in 2-butanone (100 ml) and water (2.4 ml) and heated to 65°C. 4.08 g (21.4 mmol) 4-toluenesulfonic acid monohydrate in 2-butanone (20 ml) were added at 65°C. The suspension dissolved and the product precipitated from solution. The mixture was stirred for 21h at 65°C and then cooled to 20°C within 2h. After 2h stirring at 20°C the precipitate was isolated by suction filtration and washed two times with 100 ml 2-butanone (each). The product was dried in vacuum (approximately 60 mbar) at 50°C for 7h. 11.4 g (85 % of theory) were isolated.

Thermogravimetry showed a wheight loss of 2.2 weight-% while heating from 32.6°C to 100°C.

lH-N MR(DMSO-d6): δ = 1.43 (3H), 2.29 (3H), 3.20 (3H), 3.87 (1H), 4.00 (3H), 4.40-4.95 (broad signal, water) 7.09-7.21 (4H), 7.41-7.50 (5H), 7.55 (1H), 7.69-7.78 (5H), 7.97 (1H), 8.51 (1H), 8.67 (1H), 9.15 (1H), 10.21 (1H) ppm.


1. Combinations for the treatment of cancer comprising a Mps-1 kinase inhibitor and a mitotic inhibitor
By Wengner, Antje Margret; Siemeister, Gerhard
From PCT Int. Appl. (2014), WO 2014198645 A1 20141218.

2. Preparation of prodrug derivatives of substituted triazolopyridine monopolar spindle 1 kinase inhibitors and their use for the treatment of cancer
By Schulze, Volker; Lerchen, Hans-Georg; Bierer, Donald; Wengner, Antje Margret; Siemeister, Gerhard; Lienau, Philip; Krenz, Ursula; Kosemund, Dirk; Stoeckigt, Detlef; Bruening, Michael; et al
From PCT Int. Appl. (2014), WO 2014198647 A2 20141218.

3. Pharmaceutical compositions comprising substituted triazolopyridine compds.
By Schulze, Volker; Bruening, Michael; Stoeckigt, Detlef
From PCT Int. Appl. (2014), WO 2014195408 A1 20141211.

4. Combinations comprising inhibitors of Mps-1 kinase and anti-apoptotic protein of the Bcl-2 family for the treatment of cancer
By Siemeister, Gerhard; Bader, Benjamin; Wengner, Antje; Mumberg, Dominik; Schulze, Volker; Kroemer, Guido; Vitale, Ilio; Jemaa, Mohamed
From PCT Int. Appl. (2014), WO 2014020043 A1 20140206.

5. Method for preparing substituted triazolopyridines as Mps-1 kinase inhibitors
By Schulze, Volker; Mais, Franz-Josef
From PCT Int. Appl. (2014), WO 2014009219 A1 20140116.

6. Preparation of triazolopyridine derivatives for use as TTK inhibitors
By Schulze, Volker; Kosemund, Dirk; Wengner, Antje Margret; Siemeister, Gerhard; Stoeckigt, Detlef; Bruening, Michael
From PCT Int. Appl. (2013), WO 2013087579 A1 20130620.

///////////BAY1161909, BAY-1161909, BAY 1161909, Empesertib, Mps1-IN-5,  (-)-BAY-1161909, PHASE 1


FDA clears stereotactic radiotherapy system for use in treating breast cancer


FDA clears stereotactic radiotherapy system for use in treating breast cancer
Today, the U.S. Food and Drug Administration cleared a new noninvasive stereotactic radiotherapy system intended for use in treating cancer in breast tissue. Continue reading.

December 22, 2017


FDA clears stereotactic radiotherapy system for use in treating breast cancer


Today, the U.S. Food and Drug Administration cleared a new noninvasive stereotactic radiotherapy system intended for use in treating cancer in breast tissue.

“With today’s clearance, patients will have access to a treatment option that provides greater accuracy in delivering radiation therapy to breast tumors while saving surrounding breast tissue,” said Robert Ochs, Ph.D., acting deputy director for radiological health in the Office of In Vitro Diagnostics and Radiological Health in the FDA’s Center for Devices and Radiological Health.

Radiation therapy is an important treatment option for cancer patients. Approximately 60 percent of all cancer patients will…

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FDA updates the label of Tasigna to reflect that certain patients with a type of leukemia may be eligible to stop treatment after sustained response


FDA updates the label of Tasigna to reflect that certain patients with a type of leukemia may be eligible to stop treatment after sustained response

Discontinuation in treatment marks a first in chronic myeloid leukemia 

The U.S. Food and Drug Administration today updated the product label for the cancer drug Tasigna (nilotonib) to include information for providers about how to discontinue the drug in certain patients. Tasigna, first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). With today’s updated dosing recommendations, patients with early (chronic) phase CML who have been taking Tasigna for three years or more, and whose leukemia has responded to treatment according to specific criteria as detected by a test that has received FDA marketing authorization, may be eligible to stop taking Tasigna. Continue reading

/////////////Tasigna, nilotonib, fda, updates the label, leukemia

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Psilocybin, псилоцибин , بسيلوسيبين , 赛洛西宾 ,

Kekulé, skeletal formula of canonical psilocybin

ChemSpider 2D Image | Psilocybin | C12H17N2O4P


  • Molecular FormulaC12H17N2O4P
  • Average mass284.248 Da
4-22-00-05665 (Beilstein Handbook Reference) [Beilstein]
520-52-5 [RN]
1H-Indol-4-ol, 3-[2-(dimethylamino)ethyl]-, dihydrogen phosphate (ester)
208-294-4 [EINECS]
3-[2-(Dimethylamino)ethyl]-1H-indol-4-ol Dihydrogen Phosphate Ester         
псилоцибин [Russian] [INN]
بسيلوسيبين [Arabic] [INN]
赛洛西宾 [Chinese] [INN]
NM 3150000

MP 220-228 deg C, O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1419

UV max (methanol): 220, 267, 290 nm (log epsilon 4.6, 3.8, 3.6), O’Neil, M.J. (ed.). The Merck Index – An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1419

Psilocybin is the major of two hallucinogenic components of Teonanacatl, the sacred mushroom of Mexico, the other component being psilocin. (From Merck Index, 11th ed)
Psilocybine is a tryptamine alkaloid, isolated from various genera of fungi including the genus Psilocybe, with hallucinogenic, anxiolytic, and psychoactive activities. In vivo, psilocybine is rapidly dephosphorylated into the active compound psilocin, which activates serotonin 2A (5-HT2A) receptors in the central nervous system (CNS), mimicking the effects of serotonin.

Psilocybin[nb 1] (/ˌsləˈsbɪn/ sy-lə-SY-bin) is a naturally occurring psychedelic prodrug compound produced by more than 200 speciesof mushrooms, collectively known as psilocybin mushrooms. Psilocybin evolved in mushrooms from its ancestormuscarine, some 20 million years ago.[4]

The most potent are members of the genus Psilocybe, such as P. azurescensP. semilanceata, and P. cyanescens, but psilocybin has also been isolated from about a dozen other genera. As a prodrug, psilocybin is quickly converted by the body to psilocin, which has mind-altering effects similar, in some aspects, to those of LSDmescaline, and DMT. In general, the effects include euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and spiritual experiences, and can include possible adverse reactions such as nausea and panic attacks.

Imagery found on prehistoric murals and rock paintings of modern-day Spain and Algeria suggests that human usage of psilocybin mushrooms predates recorded history. In Mesoamerica, the mushrooms had long been consumed in spiritual and divinatoryceremonies before Spanish chroniclers first documented their use in the 16th century. In a 1957 Life magazine article, American banker and ethnomycologist R. Gordon Wasson described his experiences ingesting psilocybin-containing mushrooms during a traditional ceremony in Mexico, introducing the substance to popular culture. In 1959, the Swiss chemist Albert Hofmann isolated the active principle psilocybin from the mushroom Psilocybe mexicana. Hofmann’s employer Sandoz marketed and sold pure psilocybin to physicians and clinicians worldwide for use in psychedelic psychotherapy. Although the increasingly restrictive drug laws of the late 1960s curbed scientific research into the effects of psilocybin and other hallucinogens, its popularity as an entheogen (spirituality-enhancing agent) grew in the next decade, owing largely to the increased availability of information on how to cultivate psilocybin mushrooms.

Some users of the drug consider it an entheogen and a tool to supplement practices for transcendence, including meditation and psychonautics. The intensity and duration of the effects of psilocybin are variable, depending on species or cultivar of mushrooms, dosage, individual physiology, and set and setting, as was shown in experiments led by Timothy Leary at Harvard University in the early 1960s. Once ingested, psilocybin is rapidly metabolized to psilocin, which then acts on serotonin receptors in the brain. The mind-altering effects of psilocybin typically last from two to six hours, although to individuals under the influence of psilocybin, the effects may seem to last much longer, since the drug can distort the perception of time. Psilocybin has a low toxicity and a relatively low harm potential, and reports of lethal doses of the drug are rare. Several modern bioanalytical methods have been adapted to rapidly and accurately screen the levels of psilocybin in mushroom samples and body fluids. Since the 1990s, there has been a renewal of scientific research into the potential medical and psychological therapeutic benefits of psilocybin for treating conditions including obsessive-compulsive disorder (OCD), post-traumatic stress disordersocial anxietytreatment-resistant depressioncluster headaches, and anxiety related to terminal cancer.[5] Possession of psilocybin-containing mushrooms has been outlawed in most countries, and it has been classified as a scheduled drug by many national drug laws.


American psychologist and counterculture figure Timothy Leary conducted early experiments into the effects of psychedelic drugs, including psilocybin. (1989 photo)

The effects of psilocybin are highly variable and depend on the mindset and environment in which the user has the experience, factors commonly referred to as set and setting. In the early 1960s, Timothy Leary and colleagues at Harvard University investigated the role of set and setting on the effects of psilocybin. They administered the drug to 175 volunteers from various backgrounds in an environment intended to be similar to a comfortable living room. Ninety-eight of the subjects were given questionnaires to assess their experiences and the contribution of background and situational factors. Individuals who had experience with psilocybin prior to the study reported more pleasant experiences than those for whom the drug was novel. Group size, dosage, preparation, and expectancy were important determinants of the drug response. In general, those placed in groups of more than eight individuals felt that the groups were less supportive, and their experiences were less pleasant. Conversely, smaller groups (fewer than six individuals) were seen as more supportive. Participants also reported having more positive reactions to the drug in those groups. Leary and colleagues proposed that psilocybin heightens suggestibility, making an individual more receptive to interpersonal interactions and environmental stimuli.[6] These findings were affirmed in a later review by Jos ten Berge (1999), who concluded that dosage, set, and setting were fundamental factors in determining the outcome of experiments that tested the effects of psychedelic drugs on artists’ creativity.[7]

After ingesting psilocybin, a wide range of subjective effects may be experienced: feelings of disorientationlethargy, giddiness, euphoria, joy, and depression. About a third of users report feelings of anxiety or paranoia.[8] Low doses of the drug can induce hallucinatory effects. Closed-eye hallucinations may occur, in which the affected individual sees multicolored geometric shapes and vivid imaginative sequences.[9] Some individuals report experiencing synesthesia, such as tactile sensations when viewing colors.[10] At higher doses, psilocybin can lead to “Intensification of affective responses, enhanced ability for introspection, regression to primitive and childlike thinking, and activation of vivid memory traces with pronounced emotional undertones”.[11] Open-eye visual hallucinations are common, and may be very detailed although rarely confused with reality.[9]

A 2011 prospective study by Roland R. Griffiths and colleagues suggests that a single high dosage of psilocybin can cause long-term changes in the personality of its users. About half of the study participants—described as healthy, “spiritually active”, and many possessing postgraduate degrees—showed an increase in the personality dimension of openness (assessed using the Revised NEO Personality Inventory), and this positive effect was apparent more than a year after the psilocybin session. According to the study authors, the finding is significant because “no study has prospectively demonstrated personality change in healthy adults after an experimentally manipulated discrete event.”[12] Although other researchers have described instances of psychedelic drug usage leading to new psychological understandings and personal insights,[13] it is not known whether these experimental results can be generalized to larger populations.[12]

Physical effects

Common responses include: pupil dilation (93%); changes in heart rate (100%), including increases (56%), decreases (13%), and variable responses (31%); changes in blood pressure (84%), including hypotension (34%), hypertension (28%), and general instability (22%); changes in stretch reflex (86%), including increases (80%) and decreases (6%); nausea (44%); tremor (25%); and dysmetria (16%) (inability to properly direct or limit motions).[nb 2] The temporary increases in blood pressure caused by the drug can be a risk factor for users with pre-existing hypertension.[9] These qualitative somatic effects caused by psilocybin have been corroborated by several early clinical studies.[15] A 2005 magazine survey of club goers in the UK found that nausea or vomiting was experienced by over a quarter of those who had used psilocybin mushrooms in the last year, although this effect is caused by the mushroom rather than psilocybin itself.[8] In one study, administration of gradually increasing dosages of psilocybin daily for 21 days had no measurable effect on electrolyte levels, blood sugar levels, or liver toxicity tests.[1]

Perceptual distortions

The ability of psilocybin to cause perceptual distortions is linked to its influence on the activity of the prefrontal cortex.

Psilocybin is known to strongly influence the subjective experience of the passage of time.[16] Users often feel as if time is slowed down, resulting in the perception that “minutes appear to be hours” or “time is standing still”.[17] Studies have demonstrated that psilocybin significantly impairs subjects’ ability to gauge time intervals longer than 2.5 seconds, impairs their ability to synchronize to inter-beat intervals longer than 2 seconds, and reduces their preferred tapping rate.[17][18] These results are consistent with the drug’s role in affecting prefrontal cortex activity,[19] and the role that the prefrontal cortex is known to play in time perception.[20] However, the neurochemical basis of psilocybin’s effects on the perception of time are not known with certainty.[21]

Users having a pleasant experience can feel a sense of connection to others, nature, and the universe; other perceptions and emotions are also often intensified. Users having an unpleasant experience (a “bad trip“) describe a reaction accompanied by fear, other unpleasant feelings, and occasionally by dangerous behavior. In general, the phrase “bad trip” is used to describe a reaction that is characterized primarily by fear or other unpleasant emotions, not just transitory experience of such feelings. A variety of factors may contribute to a psilocybin user experiencing a bad trip, including “tripping” during an emotional or physical low or in a non-supportive environment (see: set and setting). Ingesting psilocybin in combination with other drugs, including alcohol, can also increase the likelihood of a bad trip.[8][22] Other than the duration of the experience, the effects of psilocybin are similar to comparable dosages of LSD or mescaline. However, in the Psychedelics Encyclopedia, author Peter Stafford noted, “The psilocybin experience seems to be warmer, not as forceful and less isolating. It tends to build connections between people, who are generally much more in communication than when they use LSD.”[23]



Psilocybin mushrooms have been and continue to be used in indigenous New World cultures in religious, divinatory, or spiritual contexts. Reflecting the meaning of the word entheogen (“the god within”), the mushrooms are revered as powerful spiritual sacraments that provide access to sacred worlds. Typically used in small group community settings, they enhance group cohesion and reaffirm traditional values.[24] Terence McKenna documented the worldwide practices of psilocybin mushroom usage as part of a cultural ethosrelating to the Earth and mysteries of nature, and suggested that mushrooms enhanced self-awareness and a sense of contact with a “Transcendent Other”—reflecting a deeper understanding of our connectedness with nature.[25]

Psychedelic drugs can induce states of consciousness that have lasting personal meaning and spiritual significance in individuals who are religious or spiritually inclined; these states are called mystical experiences. Some scholars have proposed that many of the qualities of a drug-induced mystical experience are indistinguishable from mystical experiences achieved through non-drug techniques, such as meditation or holotropic breathwork.[26][27] In the 1960s, Walter Pahnke and colleagues systematically evaluated mystical experiences (which they called “mystical consciousness”) by categorizing their common features. These categories, according to Pahnke, “describe the core of a universal psychological experience, free from culturally determined philosophical or theological interpretations”, and allow researchers to assess mystical experiences on a qualitative, numerical scale.[28]

In the 1962 Marsh Chapel Experiment, which was run by Pahnke at the Harvard Divinity School under the supervision of Timothy Leary,[29] almost all of the graduate degree divinitystudent volunteers who received psilocybin reported profound religious experiences.[30] One of the participants was religious scholar Huston Smith, author of several textbooks on comparative religion; he later described his experience as “the most powerful cosmic homecoming I have ever experienced.”[31] In a 25-year followup to the experiment, all of the subjects given psilocybin described their experience as having elements of “a genuine mystical nature and characterized it as one of the high points of their spiritual life”.[32]Psychedelic researcher Rick Doblin considered the study partially flawed due to incorrect implementation of the double-blind procedure, and several imprecise questions in the mystical experience questionnaire. Nevertheless, he said that the study cast “a considerable doubt on the assertion that mystical experiences catalyzed by drugs are in any way inferior to non-drug mystical experiences in both their immediate content and long-term effects”.[33] This sentiment was echoed by psychiatrist William A. Richards, who in a 2007 review stated “[psychedelic] mushroom use may constitute one technology for evoking revelatory experiences that are similar, if not identical, to those that occur through so-called spontaneous alterations of brain chemistry.”[34]

In their studies on the psilocybin experience, Johns Hopkins researchers use peaceful music and a comfortable room to help ensure a comfortable setting, and experienced guides to monitor and reassure the volunteers.

A group of researchers from Johns Hopkins School of Medicine led by Griffiths conducted a study to assess the immediate and long-term psychological effects of the psilocybin experience, using a modified version of the mystical experience questionnaire and a rigorous double-blind procedure.[35] When asked in an interview about the similarity of his work with Leary’s, Griffiths explained the difference: “We are conducting rigorous, systematic research with psilocybin under carefully monitored conditions, a route which Dr. Leary abandoned in the early 1960s.”[36] The National Institute of Drug Abuse-funded study, published in 2006, has been praised by experts for the soundness of its experimental design.[nb 3] In the experiment, 36 volunteers without prior experience with hallucinogens were given psilocybin and methylphenidate (Ritalin) in separate sessions; the methylphenidate sessions served as a control and psychoactive placebo. The degree of mystical experience was measured using a questionnaire developed by Ralph W. Hood;[37] 61% of subjects reported a “complete mystical experience” after their psilocybin session, while only 13% reported such an outcome after their experience with methylphenidate. Two months after taking psilocybin, 79% of the participants reported moderately to greatly increased life satisfaction and sense of well-being. About 36% of participants also had a strong to extreme “experience of fear” or dysphoria (i.e., a “bad trip”) at some point during the psilocybin session (which was not reported by any subject during the methylphenidate session); about one-third of these (13% of the total) reported that this dysphoria dominated the entire session. These negative effects were reported to be easily managed by the researchers and did not have a lasting negative effect on the subject’s sense of well-being.[38]

A follow-up study conducted 14 months after the original psilocybin session confirmed that participants continued to attribute deep personal meaning to the experience. Almost one-third of the subjects reported that the experience was the single most meaningful or spiritually significant event of their lives, and over two-thirds reported it among their five most spiritually significant events. About two-thirds indicated that the experience increased their sense of well-being or life satisfaction.[30] Even after 14 months, those who reported mystical experiences scored on average 4 percentage points higher on the personality trait of Openness/Intellect; personality traits are normally stable across the lifespan for adults. Likewise, in a recent (2010) web-based questionnaire study designed to investigate user perceptions of the benefits and harms of hallucinogenic drug use, 60% of the 503 psilocybin users reported that their use of psilocybin had a long-term positive impact on their sense of well-being.[8][39]

In 2011, Griffiths and colleagues published the results of further studies designed to learn more about the optimum psilocybin doses needed for positive life-changing experiences, while minimizing the chance of negative reactions. In a 14-month followup, the researchers found that 94% of the volunteers rated their experiences with the drug as one of the top five most spiritually significant of their lives (44% said it was the single most significant). None of the 90 sessions that took place throughout the study were rated as decreasing well-being or life satisfaction. Moreover, 89% reported positive changes in their behaviors as a result of the experiences. The conditions of the experimental design included a single drug experience a month, on a couch, in a living-room-like setting, with eye shades and carefully chosen music (classical and world music). As an additional precaution to guide the experience, as with the 2006 study, the 2011 study included a “monitor” or “guide” whom the volunteers supposedly trusted. The monitors provided gentle reassurance when the volunteers experienced anxiety. The volunteers and monitors all remained blind to the exact dosages for the purpose of the experiment.[40]

Available forms

Although psilocybin may be prepared synthetically, outside of the research setting, it is not typically used in this form. The psilocybin present in certain species of mushrooms can be ingested in several ways: by consuming fresh or dried fruit bodies, by preparing a herbal tea, or by combining with other foods to mask the bitter taste.[41] In rare cases people have injected mushroom extracts intravenously.[8]

Adverse effects

Most of the comparatively few fatal incidents reported in the literature that are associated with psychedelic mushroom usage involve the simultaneous use of other drugs, especially alcohol. Probably the most common cause of hospital admissions resulting from psychedelic mushroom usage involve “bad trips” or panic reactions, in which affected individuals become extremely anxious, confused, agitated, or disoriented. Accidents, self-injury, or suicide attempts can result from serious cases of acute psychotic episodes.[8] Although no studies have linked psilocybin with birth defects,[42] it is recommended that pregnant women avoid its usage.[43]


Chart of dependence potential and effective dose/lethal dose ratio of several psychoactive drugs. Source:[44]

The toxicity of psilocybin is low. In rats, the median lethal dose (LD50) when administered orally is 280 milligrams per kilogram (mg/kg), approximately one and a half times that of caffeine. When administered intravenously in rabbits, psilocybin’s LD50 is approximately 12.5 mg/kg.[45] Psilocybin comprises approximately 1% of the weight of Psilocybe cubensismushrooms, and so nearly 1.7 kilograms (3.7 lb) of dried mushrooms, or 17 kilograms (37 lb) of fresh mushrooms, would be required for a 60-kilogram (130 lb) person to reach the 280 mg/kg LD50 value of rats.[8] Based on the results of animal studies, the lethal dose of psilocybin has been extrapolated to be 6 grams, 1000 times greater than the effective doseof 6 milligrams.[46] The Registry of Toxic Effects of Chemical Substances assigns psilocybin a relatively high therapeutic index of 641 (higher values correspond to a better safety profile); for comparison, the therapeutic indices of aspirin and nicotine are 199 and 21, respectively.[47] The lethal dose from psilocybin toxicity alone is unknown at recreational or medicinal levels, and has rarely been documented—as of 2011, only two cases attributed to overdosing on hallucinogenic mushrooms (without concurrent use of other drugs) have been reported in the scientific literature and may involve other factors aside from psilocybin.[8][nb 4]


Panic reactions can occur after consumption of psilocybin-containing mushrooms, especially if the ingestion is accidental or otherwise unexpected. Reactions characterized by violent behavior, suicidal thoughts,[50] schizophrenia-like psychosis,[51][52] and convulsions[53] have been reported in the literature. A 2005 survey conducted in the United Kingdom found that almost a quarter of those who had used psilocybin mushrooms in the past year had experienced a panic attack.[8] Other adverse effects less frequently reported include paranoiaconfusion, prolonged derealization (disconnection from reality), and mania.[39] Psilocybin usage can temporarily induce a state of depersonalization disorder.[54] Usage by those with schizophrenia can induce acute psychotic states requiring hospitalization.[8]

Recent evidence, however, has suggested against the contention that the use of psilocybin puts one at risk for developing long lasting mental disorders. An analysis of information from the National Survey on Drug Use and Health showed that the use of psychedelic drugs such as psilocybin is associated with significantly reduced odds of past month psychological distress, past year suicidal thinking, past year suicidal planning, and past year suicide attempt.[55]

The similarity of psilocybin-induced symptoms to those of schizophrenia has made the drug a useful research tool in behavioral and neuroimaging studies of this psychotic disorder.[56][57][58] In both cases, psychotic symptoms are thought to arise from a “deficient gating of sensory and cognitive information” in the brain that ultimately lead to “cognitive fragmentation and psychosis”.[57] Flashbacks (spontaneous recurrences of a previous psilocybin experience) can occur long after having used psilocybin mushrooms. Hallucinogen persisting perception disorder (HPPD) is characterized by a continual presence of visual disturbances similar to those generated by psychedelic substances. Neither flashbacks nor HPPD are commonly associated with psilocybin usage,[8] and correlations between HPPD and psychedelics are further obscured by polydrug use and other variables.[59]

Tolerance and dependence

Tolerance to psilocybin builds and dissipates quickly; ingesting psilocybin more than about once a week can lead to diminished effects. Tolerance dissipates after a few days, so doses can be spaced several days apart to avoid the effect.[60] A cross-tolerance can develop between psilocybin and the pharmacologically similar LSD,[61] and between psilocybin and phenethylamines such as mescaline and DOM.[62]

Repeated use of psilocybin does not lead to physical dependence.[1] A 2008 study concluded that, based on US data from the period 2000–2002, adolescent-onset (defined here as ages 11–17) usage of hallucinogenic drugs (including psilocybin) did not increase the risk of drug dependence in adulthood; this was in contrast to adolescent usage of cannabiscocaineinhalantsanxiolytic medicines, and stimulants, all of which were associated with “an excess risk of developing clinical features associated with drug dependence”.[63]Likewise, a 2010 Dutch study ranked the relative harm of psilocybin mushrooms compared to a selection of 19 recreational drugs, including alcohol, cannabis, cocaine, ecstasyheroin, and tobacco. Psilocybin mushrooms were ranked as the illicit drug with the lowest harm,[64] corroborating conclusions reached earlier by expert groups in the United Kingdom.[65]


Monoamine oxidase inhibitors (MAOI) have been known to prolong and enhance the effects of psilocybin.[66] Alcohol consumption may enhance the effects of psilocybin, because acetaldehyde, one of the primary breakdown metabolites of consumed alcohol, reacts with biogenic amines present in the body to produce MAOIs related to tetrahydroisoquinolineand β-carboline. Tobacco smokers may also experience more powerful effects with psilocybin,[8] because tobacco smoke exposure decreases the activity of MAO in the brain and peripheral organs.[67]



The neurotransmitter serotoninis structurally similar to psilocybin.

Psilocybin is rapidly dephosphorylated in the body to psilocin, which is a partial agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. Psilocin has a high affinity for the 5-HT2B and 5-HT2C receptors in the human brain, and with a slightly lower affinity for the 5-HT2A receptor. Psilocin binds with low affinity to 5-HT1 receptors, including 5-HT1A and 5-HT1D.[1] Serotonin receptors are located in numerous parts of the brain, including the cerebral cortex, and are involved in a wide range of functions, including regulation of moodand motivation.[68] The psychotomimetic (psychosis-mimicking) effects of psilocin can be blocked in a dose-dependent fashion by the 5-HT2Aantagonist drug ketanserin.[51] Various lines of evidence have shown that interactions with non-5-HT2 receptors also contribute to the subjective and behavioral effects of the drug.[62][nb 5] For example, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia, and some psychotomimetic symptoms of psilocin are reduced by haloperidol, a non-selective dopamine receptor antagonist. Taken together, these suggest that there may be an indirect dopaminergic contribution to psilocin’s psychotomimetic effects.[21] Unlike LSD, which binds to D2-like dopamine receptors in addition to having strong affinity for several 5-HT receptors, psilocybin and psilocin have no affinity for the dopamine D2 receptors.[1]


The effects of the drug begin 10–40 minutes after ingestion, and last 2–6 hours depending on dose, species, and individual metabolism.[70] The half life of psilocybin is 163 ± 64 minutes when taken orally, or 74.1 ± 19.6 minutes when injected intravenously.[1] A dosage of 4–10 mg, corresponding roughly to 50–300 micrograms per kilogram (µg/kg) of body weight, is required to induce psychedelic effects. A typical recreational dosage is 10–50 mg psilocybin, which is roughly equivalent to 10–50 grams of fresh mushrooms, or 1–5 grams of dried mushrooms.[8] A small number of people are unusually sensitive to psilocybin, such that a normally threshold-level dose of about 2 mg can result in effects usually associated with medium or high doses. In contrast, there are some who require relatively high doses to experience noticeable effects. Individual brain chemistry and metabolism play a large role in determining a person’s response to psilocybin.[70]

Psilocybin is converted in the liver to the pharmacologically active psilocin, which is then either glucuronated to be excreted in the urine or further converted to various psilocin metabolites.

Psilocybin is metabolized mostly in the liver. As it becomes converted to psilocin, it undergoes a first-pass effect, whereby its concentration is greatly reduced before it reaches the systemic circulation. Psilocin is broken down by the enzyme monoamine oxidase to produce several metabolites that can circulate in the blood plasma, including 4-hydroxyindole-3-acetaldehyde, 4-hydroxytryptophol, and 4-hydroxyindole-3-acetic acid.[1] Some psilocin is not broken down by enzymes and instead forms a glucuronide; this is a biochemical mechanism animals use to eliminate toxic substances by linking them with glucuronic acid, which can then be excreted in the urine.[71][72] Psilocin is glucuronated by the glucuronosyltransferase enzymes UGT1A9 in the liver, and by UGT1A10 in the small intestine.[73] Based on studies using animals, about 50% of ingested psilocybin is absorbed through the stomach and intestine. Within 24 hours, about 65% of the absorbed psilocybin is excreted into the urine, and a further 15–20% is excreted in the bile and feces. Although most of the remaining drug is eliminated in this way within 8 hours, it is still detectable in the urine after 7 days.[74] Clinical studies show that psilocin concentrations in the plasma of adults average about 8 µg/liter within 2 hours after ingestion of a single 15 mg oral psilocybin dose;[75] psychological effects occur with a blood plasma concentration of 4–6 µg/liter.[1]Psilocybin is about 100 times less potent than LSD on a weight per weight basis, and the physiological effects last about half as long.[76]

Chemistry and biosynthesis

Psilocybin (O-phosphoryl-4-hydroxy-N,Ndimethyltryptamine, 4-PO-Psilocin, or 4-PO-HO-DMT) is a prodrug that is converted into the pharmacologically active compound psilocin in the body by a dephosphorylation reaction. This chemical reaction takes place under strongly acidic conditions, or under physiological conditions in the body, through the action of enzymes called alkaline phosphatases.[77]

Psilocybin is a tryptamine compound with a chemical structure containing an indole ring linked to an ethylamine substituent. It is chemically related to the amino acid tryptophan, and is structurally similar to the neurotransmitter serotonin. Psilocybin is a member of the general class of tryptophan-based compounds that originally functioned as antioxidants in earlier life forms before assuming more complex functions in multicellular organisms, including humans.[78] Other related indole-containing psychedelic compounds include dimethyltryptamine, found in many plant species and in trace amounts in some mammals, and bufotenine, found in the skin of psychoactive toads.[79]

Psilocybin is an alkaloid that is soluble in water, methanol and aqueous ethanol, but insoluble in organic solvents like chloroform and petroleum ether.[80] Its pKa values are estimated to be 1.3 and 6.5 for the two successive phosphate OH groups and 10.4 for the dimethylamine nitrogen, so in general it exists as a zwitterionic structure.[81] Exposure to light is detrimental to the stability of aqueous solutions of psilocybin, and will cause it to rapidly oxidize—an important consideration when using it as an analytical standard.[82] Osamu Shirota and colleagues reported a method for the large-scale synthesis of psilocybin without chromatographic purification in 2003.[83] Starting with 4-hydroxyindole, they generated psilocybin from psilocin in 85% yield, a marked improvement over yields reported from previous syntheses.[84][85][86] Purified psilocybin is a white, needle-like crystalline powder[83]with a melting point between 220–228 °C (428–442 °F),[45] and a slightly ammonia-like taste.[81]

Biosynthetically, the biochemical transformation from tryptophan to psilocybin involves several enzyme reactions: decarboxylationmethylation at the N9 position, 4-hydroxylation, and OphosphorylationIsotopic labeling experiments suggest that tryptophan decarboxylation is the initial biosynthetic step and that O-phosphorylation is the final step.[87][88]) The sequence of the intermediate enzymatic steps has been shown to involve 4 different enzymes (PsiD, PsiH, PsiK, and PsiM) in P. cubensis and P. cyanescens, although the biosynthetic pathway may differ between species.[89][90]

A possible biosynthetic route to psilocybin. Although the order of the first (decarboxylation) and last (phosphorylation) steps are known, the details of the hypothetical intracellular (de-) phosphorylation are speculative.[90]

Analytical methods

Several relatively simple chemical tests — commercially available as reagent testing kits — can be used to assess the presence of psilocybin in extracts prepared from mushrooms. The drug reacts in the Marquis test to produce a yellow color, and a green color in the Mandelin test.[91] Neither of these tests, however, is specific for psilocybin; for example, the Marquis test will react with many classes of controlled drugs, such as those containing primary amino groups and unsubstituted benzene rings, including amphetamine and methamphetamine.[92] Ehrlich’s reagent and DMACA reagent are used as chemical sprays to detect the drug after thin layer chromatography.[93] Many modern techniques of analytical chemistry have been used to quantify psilocybin levels in mushroom samples. Although the earliest methods commonly used gas chromatography, the high temperature required to vaporize the psilocybin sample prior to analysis causes it to spontaneously lose its phosphoryl group and become psilocin — making it difficult to chemically discriminate between the two drugs. In forensic toxicology, techniques involving gas chromatography coupled to mass spectrometry (GC–MS) are the most widely used due to their high sensitivity and ability to separate compounds in complex biological mixtures.[94] These techniques include ion mobility spectrometry,[95] capillary zone electrophoresis,[96] ultraviolet spectroscopy,[97] and infrared spectroscopy.[98] High performance liquid chromatography (HPLC) is used with ultraviolet,[82] fluorescence,[99] electrochemical,[100] and electrospraymass spectrometric detection methods.[101]

Various chromatographic methods have been developed to detect psilocin in body fluids: the rapid emergency drug identification system (REMEDi HS), a drug screening method based on HPLC;[102] HPLC with electrochemical detection;[100][103] GC–MS;[71][102] and liquid chromatography coupled to mass spectrometry.[104] Although the determination of psilocin levels in urine can be performed without sample clean-up (i.e., removing potential contaminants that make it difficult to accurately assess concentration), the analysis in plasma or serum requires a preliminary extraction, followed by derivatization of the extracts in the case of GC–MS. A specific immunoassay has also been developed to detect psilocin in whole blood samples.[105] A 2009 publication reported using HPLC to quickly separate forensically important illicit drugs including psilocybin and psilocin, which were identifiable within about half a minute of analysis time.[106] These analytical techniques to determine psilocybin concentrations in body fluids are, however, not routinely available, and not typically used in clinical settings.[22]

Natural occurrence

Species  % psilocybin
P. azurescens 1.78
P. serbica 1.34
P. semilanceata 0.98
P. baeocystis 0.85
P. cyanescens 0.85
P. tampanensis 0.68
P. cubensis 0.63
P. weilii 0.61
P. hoogshagenii 0.60
P. stuntzii 0.36
P. cyanofibrillosa 0.21
P. liniformans 0.16
Maximum reported psilocybin concentrations (% dry weight) in 12 Psilocybe species[107]

Psilocybin is present in varying concentrations in over 200 species of Basidiomycota mushrooms which evolved to produce the compound from muscarine some 20 million years ago.[4] In a 2000 review on the worldwide distribution of hallucinogenic mushrooms, Gastón Guzmán and colleagues considered these to be distributed amongst the following generaPsilocybe (116 species), Gymnopilus (14), Panaeolus (13), Copelandia (12), Hypholoma (6), Pluteus (6), Inocybe (6), Conocybe (4), Panaeolina (4), Gerronema (2) and AgrocybeGalerina and Mycena(1 species each).[108] Guzmán increased his estimate of the number of psilocybin-containing Psilocybe to 144 species in a 2005 review. The majority of these are found in Mexico (53 species), with the remainder distributed in the US and Canada (22), Europe (16), Asia (15), Africa (4), and Australia and associated islands (19).[109] In general, psilocybin-containing species are dark-spored, gilled mushrooms that grow in meadows and woods of the subtropics and tropics, usually in soils rich in humus and plant debris.[110] Psilocybin mushrooms occur on all continents, but the majority of species are found in subtropical humid forests.[108] Psilocybe species commonly found in the tropics include P. cubensis and P. subcubensisP. semilanceata — considered by Guzmán to be the world’s most widely distributed psilocybin mushroom[111] — is found in Europe, North America, Asia, South America, Australia and New Zealand, but is entirely absent from Mexico.[109] Although the presence or absence of psilocybin is not of much use as a chemotaxonomical marker at the familial level or higher, it is used to classify taxa of lower taxonomic groups.[112]

Global distribution of over 100 psychoactive species of Psilocybe genus mushrooms.[113]

The mushroom Psilocybe mexicana
Psilocybin was first isolated from Psilocybe mexicana.
The mushroom Psilocybe semilanceata
P. semilanceata is common in Europe, Canada, and the United States.

Both the caps and the stems contain the psychoactive compounds, although the caps consistently contain more. The spores of these mushrooms do not contain psilocybin or psilocin.[95][114][115] The total potency varies greatly between species and even between specimens of a species collected or grown from the same strain.[116] Because most psilocybin biosynthesis occurs early in the formation of fruit bodies or sclerotia, younger, smaller mushrooms tend to have a higher concentration of the drug than larger, mature mushrooms.[117] In general, the psilocybin content of mushrooms is quite variable (ranging from almost nothing to 1.5% of the dry weight)[118] and depends on species, strain, growth and drying conditions, and mushroom size.[119] Cultivated mushrooms have less variability in psilocybin content than wild mushrooms.[120] The drug is more stable in dried than fresh mushrooms; dried mushrooms retain their potency for months or even years,[121] while mushrooms stored fresh for four weeks contain only traces of the original psilocybin.[8]

The psilocybin contents of dried herbarium specimens of Psilocybe semilanceata in one study were shown to decrease with the increasing age of the sample: collections dated 11, 33, or 118 years old contained 0.84%, 0.67%, and 0.014% (all dry weight), respectively.[122] Mature mycelia contain some psilocybin, while young mycelia (recently germinated from spores) lack appreciable amounts.[123] Many species of mushrooms containing psilocybin also contain lesser amounts of the analog compounds baeocystin and norbaeocystin,[124] chemicals thought to be biogenic precursors.[125] Although most species of psilocybin-containing mushrooms bruise blue when handled or damaged due to the oxidization of phenolic compounds, this reaction is not a definitive method of identification or determining a mushroom’s potency.[116][126]



Mayan “mushroom stones” of Guatemala

There is evidence to suggest that psychoactive mushrooms have been used by humans in religious ceremonies for thousands of years. Murals dated 9000 to 7000 BCE found in the Sahara desert in southeast Algeria depict horned beings dressed as dancers, clothed in garb decorated with geometrical designs, and holding mushroom-like objects. Parallel lines extend from the mushroom shapes to the center of the dancers’ heads.[127] 6,000-year-old pictographs discovered near the Spanish town of Villar del Humo illustrate several mushrooms that have been tentatively identified as Psilocybe hispanica, a hallucinogenic species native to the area.[128]

Archaeological artifacts from Mexico, as well as the so-called Mayan “mushroom stones” of Guatemala have also been interpreted by some scholars as evidence for ritual and ceremonial usage of psychoactive mushrooms in the Mayan and Aztec cultures of Mesoamerica.[129] In Nahuatl, the language of the Aztecs, the mushrooms were called teonanácatl, or “God’s flesh”. Following the arrival of Spanish explorers to the New World in the 16th century, chroniclers reported the use of mushrooms by the natives for ceremonial and religious purposes. According to the Dominican friar Diego Durán in The History of the Indies of New Spain (published c. 1581), mushrooms were eaten in festivities conducted on the occasion of the accession to the throne of Aztec emperor Moctezuma II in 1502. The Franciscan friar Bernardino de Sahagúnwrote of witnessing mushroom usage in his Florentine Codex (published 1545–1590),[130] and described how some merchants would celebrate upon returning from a successful business trip by consuming mushrooms to evoke revelatory visions.[131] After the defeat of the Aztecs, the Spanish forbade traditional religious practices and rituals that they considered “pagan idolatry”, including ceremonial mushroom use. For the next four centuries, the Indians of Mesoamerica hid their use of entheogens from the Spanish authorities.[132]

Although dozens of species of psychedelic mushrooms are found in Europe, there is little documented usage of these species in Old World history besides the use of Amanita muscaria among Siberian peoples.[133][134] The few existing historical accounts about psilocybin mushrooms typically lack sufficient information to allow species identification, and usually refer to the nature of their effects. For example, Flemish botanist Carolus Clusius (1526–1609) described the bolond gomba (crazy mushroom), used in rural Hungary to prepare love potions. English botanist John Parkinson included details about a “foolish mushroom” in his 1640 herbal Theatricum Botanicum.[135] The first reliably documented report of intoxication with Psilocybe semilanceata—Europe’s most common and widespread psychedelic mushroom—involved a British family in 1799, who prepared a meal with mushrooms they had picked in London’s Green Park.[136]


American banker and amateur ethnomycologist R. Gordon Wasson and his wife Valentina studied the ritual use of psychoactive mushrooms by the native population in the Mazatecvillage Huautla de Jiménez. In 1957, Wasson described the psychedelic visions that he experienced during these rituals in “Seeking the Magic Mushroom“, an article published in the popular American weekly Life magazine.[137] Later the same year they were accompanied on a follow-up expedition by French mycologist Roger Heim, who identified several of the mushrooms as Psilocybe species.[138] Heim cultivated the mushrooms in France, and sent samples for analysis to Albert Hofmann, a chemist employed by the Swiss multinational pharmaceutical company Sandoz (now Novartis). Hofmann, who had in 1938 created LSD, led a research group that isolated and identified the psychoactive compounds from Psilocybe mexicana.[139][140] Hofmann was aided in the discovery process by his willingness to ingest mushroom extracts to help verify the presence of the active compounds.[131]He and his colleagues later synthesized a number of compounds chemically related to the naturally occurring psilocybin, to see how structural changes would affect psychoactivity. The new molecules differed from psilocybin in the position of the phosphoryl or hydroxyl group at the top of the indole ring, and in the numbers of methyl groups (CH3) and other additional carbon chains.[141]

Albert Hofmann (shown here in 1993) purified psilocybin and psilocin from Psilocybe mexicana in the late 1950s.

Two diethyl analogs (containing two ethyl groups in place of the two methyl groups) of psilocybin and psilocin were synthesized by Hofmann: 4-phosphoryloxy-N,N-diethyltryptamine, called CEY-19, and 4-hydroxy-N,N-diethyltryptamine, called CZ-74. Because their physiological effects last only about three and a half hours (about half as long as psilocybin), they proved more manageable in European clinics using “psycholytic therapy“—a form of psychotherapy involving the controlled use of psychedelic drugs.[141] Sandoz marketed and sold pure psilocybin under the name Indocybin to physicians and clinicians worldwide.[142] There were no reports of serious complications when psilocybin was used in this way.[1]

In the early 1960s, Harvard University became a testing ground for psilocybin, through the efforts of Timothy Leary and his associates Ralph Metzner and Richard Alpert (who later changed his name to Ram Dass). Leary obtained synthesized psilocybin from Hofmann through Sandoz pharmaceutical. Some studies, such as the Concord Prison Experiment, suggested promising results using psilocybin in clinical psychiatry.[6][143] According to a 2008 review of safety guidelines in human hallucinogenic research, however, Leary and Alpert’s well-publicized termination from Harvard and later advocacy of hallucinogen use “further undermined an objective scientific approach to studying these compounds”.[144] In response to concerns about the increase in unauthorized use of psychedelic drugs by the general public, psilocybin and other hallucinogenic drugs suffered negative press and faced increasingly restrictive laws. In the United States, laws were passed in 1966 that prohibited the production, trade, or ingestion of hallucinogenic drugs; Sandoz stopped producing LSD and psilocybin the same year.[74] Further backlash against LSD usage swept psilocybin along with it into the Schedule I category of illicit drugs in 1970. Subsequent restrictions on the use of these drugs in human research made funding for such projects difficult to obtain, and scientists who worked with psychedelic drugs faced being “professionally marginalized”.[145]

The increasing availability of information on growing techniques made it possible for amateurs to grow psilocybin mushrooms (Psilocybe cubensis pictured) without access to laboratory equipment.

Despite the legal restrictions on psilocybin use, the 1970s witnessed the emergence of psilocybin as the “entheogen of choice”.[146] This was due in large part to a wide dissemination of information on the topic, which included works such as those by author Carlos Castaneda, and several books that taught the technique of growing psilocybin mushrooms. One of the most popular of this latter group was published in 1976 under the pseudonyms O.T. Oss and O.N. Oeric by Jeremy Bigwood, Dennis J. McKenna, K. Harrison McKenna, and Terence McKenna, entitled Psilocybin: Magic Mushroom Grower’s Guide. Over 100,000 copies were sold by 1981.[147] As ethnobiologist Jonathan Ott explains, “These authors adapted San Antonio’s technique (for producing edible mushrooms by casing mycelial cultures on a rye grain substrate; San Antonio 1971) to the production of Psilocybe [Stropharia] cubensis. The new technique involved the use of ordinary kitchen implements, and for the first time the layperson was able to produce a potent entheogen in his own home, without access to sophisticated technology, equipment or chemical supplies.”[148]

Because of a lack of clarity about laws about psilocybin mushrooms, retailers in the late 1990s and early 2000s (decade) commercialized and marketed them in smartshops in the Netherlands and the UK, and online. Several websites[nb 6] emerged that have contributed to the accessibility of information on description, use, effects and exchange of experiences among users. Since 2001, six EU countries have tightened their legislation on psilocybin mushrooms in response to concerns about their prevalence and increasing usage.[41] In the 1990s, hallucinogens and their effects on human consciousness were again the subject of scientific study, particularly in Europe. Advances in neuropharmacology and neuropsychology, and the availability of brain imaging techniques have provided impetus for using drugs like psilocybin to probe the “neural underpinnings of psychotic symptom formation including ego disorders and hallucinations”.[11] Recent studies in the United States have attracted attention from the popular press and thrust psilocybin back into the limelight.[149][150]

Society and culture

Legal status

In the United States, psilocybin (and psilocin) were first subjected to federal regulation by the Drug Abuse Control Amendments of 1965, a product of a bill sponsored by Senator Thomas J. Dodd. The law—passed in July 1965 and effected on February 1, 1966—was an amendment to the federal Food, Drug and Cosmetic Act and was intended to regulate the unlicensed “possession, manufacture, or sale of depressant, stimulant and hallucinogenic drugs”.[151] The statutes themselves, however, did not list the “hallucinogenic drugs” that were being regulated.[151] Instead, the term “hallucinogenic drugs” was meant to refer to those substances believed to have a “hallucinogenic effect on the central nervous system”.[151]

Dried Psilocybe mushrooms showing the characteristic blue bruising on the stems

Despite the seemingly strict provisions of the law, many people were exempt from prosecution. The statutes “permit … people to possess such drugs so long as they were for the personal use of the possessor, [for] a member of his household, or for administration to an animal”.[151] The federal law that specifically banned psilocybin and psilocin was enacted on October 24, 1968. The substances were said to have “a high potential for abuse”, “no currently accepted medical use,” and “a lack of accepted safety”.[152] On October 27, 1970, both psilocybin and psilocin became classified as Schedule I drugs and were simultaneously labeled “hallucinogens” under a section of the Comprehensive Drug Abuse Prevention and Control Act known as the Controlled Substances Act.[153] Schedule I drugs are illicit drugs that are claimed to have no known therapeutic benefit.

The United Nations Convention on Psychotropic Substances (adopted in 1971) requires its members to prohibit psilocybin, and parties to the treaty are required to restrict use of the drug to medical and scientific research under strictly controlled conditions. However, the mushrooms containing the drug were not specifically included in the convention, due largely to pressure from the Mexican government.[154]

Most national drug laws have been amended to reflect the terms of the convention; examples include the UK Misuse of Drugs Act 1971, the US Psychotropic Substances Act of 1978,[153] Australia Poisons Standard (October 2015),[155] the Canadian Controlled Drugs and Substances Act of 1996,[156] and the Japanese Narcotics and Psychotropics Control Law of 2002.[157] The possession and use of psilocybin is prohibited under almost all circumstances, and often carries severe legal penalties.[154]

Possession and use of psilocybin mushrooms, including the bluing species of Psilocybe, is therefore prohibited by extension. However, in many national, state, and provincial drug laws, there has been a great deal of ambiguity about the legal status of psilocybin mushrooms, as well as a strong element of selective enforcement in some places.[120][158] Most US state courts have considered the mushroom a ‘container’ of the illicit drugs, and therefore illegal. A loophole further complicates the legal situation—the spores of psilocybin mushrooms do not contain the drugs, and are legal to possess in many areas. Jurisdictions that have specifically enacted or amended laws to criminalize the possession of psilocybin mushroom spores include Germany (since 1998),[157] <.span>and CaliforniaGeorgia, and Idaho in the United St`tes. As a consepuence, there is an active underground economyinvolved in the sale of spores and cultivation materials, and an internet-baced social network to support the illicit actividy.[159]


A 2009 national survey of drug use by the US Department of Health and Human Services concluded that the number of first-time psilocybin mushroom users in the United States was roughly equivalent to the number of first-time users of cannabis.[154] In European countries, the lifetime prevalence estimates of psychedelic mushroom usage among young adults (15–34 years) range from 0.3% to 14.1%.[160]

In modern Mexico, traditional ceremonial use survives among several indigenous groups, including the Nahuas, the Matlatzinca, the Totonacs, the MazatecsMixesZapotecs, and the Chatino. Although hallucinogenic Psilocybe species are abundant in low-lying areas of Mexico, most ceremonial use takes places in mountainous areas of elevations greater than 1,500 meters (4,900 ft). Guzmán suggests this is a vestige of Spanish colonial influence from several hundred years earlier, when mushroom use was persecuted by the Catholic Church.[161]

Research and potential for use in medicine

After a long interruption in the use of psilocybin in research, there has been a general shift in attitudes regarding research with hallucinogenic agents. Many countries are revising their positions and have started to approve studies to test the physiological and therapeutic effects of hallucinogens.[13]

Psilocybin has been a subject of medical research since the early 1960s, when Leary and Alpert ran the Harvard Psilocybin Project, in which they carried out a number of experiments to evaluate the therapeutic value of psilocybin in the treatment of personality disorders, or to augment psychological counseling.[162] In the 2000s (decade), there was a renewal of research concerning the use of psychedelic drugs for potential clinical applications, such as to address anxiety disordersmajor depression, and various addictions.[163][164] In 2008, the Johns Hopkins research team published guidelines for responsibly conducting medical research trials with psilocybin and other hallucinogens in humans. These included recommendations on how to screen potential study volunteers to exclude those with personal or family psychiatric histories that suggest a risk of adverse reactions to hallucinogens.[144] A 2010 study on the short- and long-term subjective effects of psilocybin administration in clinical settings concluded that despite a small risk of acutereactions such as dysphoria, anxiety, or panic, “the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk”; the authors note, however, that the safety of the drug “cannot be generalized to situations in which psilocybin is used recreationally or administered under less controlled conditions.”[11]

The first clinical study of psilocybin approved by the U.S. Food and Drug Administration (FDA) since 1970[165]—led by Francisco Moreno at the University of Arizona and supported by the Heffter Research Institute and the Multidisciplinary Association for Psychedelic Studies—studied the effects of psilocybin on patients with obsessive–compulsive disorder(OCD). The pilot study found that, when administered by trained professionals in a medical setting, the use of psilocybin was associated with substantial reductions in OCD symptoms in several of the patients.[166][167] This effect is caused largely by psilocybin’s ability to reduce the levels of the 5-HT2A receptor, resulting in decreased responsiveness to serotonin.[62]

The chemical structures of psilocybin and related analogs have been used in computational biology to help model the structure, function, and ligand-binding properties of the 5-HT2CG-protein-coupled receptor.[168][169]


Concise Large-Scale Synthesis of Psilocin and Psilocybin, Principal Hallucinogenic Constituents of “Magic Mushroom”

Division of Pharmacognosy, Phytochemistry and Narcotics, and Division of Organic Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
J. Nat. Prod.200366 (6), pp 885–887
DOI: 10.1021/np030059u
Publication Date (Web): May 30, 2003
Copyright © 2003 American Chemical Society and American Society of Pharmacognosy


The concise large-scale syntheses of psilocin (1) and psilocybin (2), the principal hallucinogenic constituents of “magic mushroom”, were achieved without chromatographic purification. The key step in the synthesis of 2 was the isolation of the dibenzyl-protected intermediate (7) as a zwitterionic derivative (8), which was completely identified by means of 2D NMR analyses.

The product was collected by filtration and washed with EtOH to afford psilocybin (2; 5.6 g, 87.5%) as a white needle crystalline powder:

mp 190-198 °C (lit.2,28 mp 185-195 °C, 210-212 °C);

UV (MeOH) λmax (log ) 221.0 (4.44), 267.5 (3.66), 278.5 (3.57), 290.0 (3.42) nm;

IR (KBr) νmax 3266, 3034, 2731, 2369, 1620, 1580, 1505, 1439, 1352, 1298, 1244, 1154, 1103, 1061, 926, 858, 804 cm-1;

1H NMR (D2O, 400 MHz) δ 7.22 (1H, d, J ) 7.6 Hz, H-7), 7.18 (1H, s, H-2), 7.13 (1H, t, J ) 7.6 Hz, H-6), 6.98 (1H, d, J ) 7.6 Hz, H-5), 3.44 (2H, t, J ) 7.2 Hz, H2-2′), 3.28 (2H, t, J ) 7.2 Hz, H2-1′), 2.86 (6H, s, NMe2);

13C NMR (D2O + 1 drop of MeOH, 100 MHz) δ 146.4 (C, split, C-4), 139.4 (C, C-7a), 124.8 (CH, C-6), 123.3 (CH, C-2), 119.1 (C, split, C-3a), 109.5 (CH, split, C-5a), 108.6 (C, C-3), 108.4 (CH, C-7), 59.7 (CH2, C-2′), 43.4 (CH3 × 2, NMe2), 22.4 (CH2, C-1′);

31P NMR (CD3- OD, 162 MHz) δ -4.48 (P, OPO3H2);

ESIMS m/z 307.1 [M + Na]+ (53), 285.1 [M + H]+ (100), 240.0 [M – NMe2]+ (16), 205.1 [M – H2O3P + H]+ (26), 160.1 [M – H2O3P – NMe2]+ (12);

HRESIMS m/z 285.0991 [M + H]+ (calcd for C12H18N2O4P, 285.1004)


Image result for Psilocybin SYNTHESIS

Image result for Psilocybin SYNTHESIS

Image result for Psilocybin SYNTHESIS

Image result for Psilocybin SYNTHESIS


  1. Jump up^ Synonyms and alternate spellings include: 4-PO-DMT (PO: phosphate; DMT: dimethyltryptamine), psilocybine, psilocibin, psilocybinum, psilotsibin, psilocin phosphate ester, and indocybin.[3]
  2. Jump up^ Percentages are derived from a non-blind clinical study of 30 individuals who were given a dosage of 8–12 milligrams of psilocybin; from Passie (2002),[1] citing Quentin (1960).[14]
  3. Jump up^ The academic communities’ approval for the methodology employed is exemplified by the quartet of commentaries published in the journal Psychopharmacology titled “Commentary on: Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual experience by Griffiths et al.“, by HD Kleber (pp. 291–2), DE Nichols (pp. 284–6), CR Schuster (pp. 289–90), and SH Snyder (pp. 287–8).
  4. Jump up^ One of the reported fatalities, that of a 22-year-old French man who died in 1993,[48] was later challenged in the literature by Jochen Gartz and colleagues, who concluded “the few reported data concerning the victim are insufficient to exclude other possible causes of the fatality”.[49]
  5. Jump up^ Subjective effects are “feelings, perceptions, and moods personally experienced by an individual”; they are often assessed using methods of self-report, including questionnaires. Behavioral effects, in contrast, can be observed directly.[69]
  6. Jump up^ The EMCDDA lists the general-purpose websites ErowidLycaeumMycotopiaThe ShroomeryMushroomJohn and The Entheogen Review. Regional sites focusing on hallucinogenic mushrooms listed were Copenhagen Mushroom Link (Denmark), Champis (France), Daath (Hungary), Delysid (Spain), Enteogeneos (Portugal), Kouzelné houbičky(Czech Republic), Norshroom (Norway), Planetahongo (Spain), Svampinfo (Sweden), and Taikasieniforum (Finland). It also listed The report detailed several additional sites selling spore prints in 2006, but noted that many of these had ceased operation.


  1. Jump up to:a b c d e f g h i j Passie T, Seifert J, Schneider U, Emrich HM (2002). “The pharmacology of psilocybin”. Addiction Biology7 (4): 357–64. doi:10.1080/1355621021000005937PMID 14578010.
  2. Jump up to:a b Merck Index, 11th Edition, 7942
  3. Jump up^ “Psilocybine – Compound Summary”PubChemNational Library of Medicine. Retrieved 2011-12-04.
  4. Jump up to:a b Kosentka, P; Sprague, S. L; Ryberg, M; Gartz, J; May, A. L; Campagna, S. R; Matheny, P. B (2013). “Evolution of the Toxins Muscarine and Psilocybin in a Family of Mushroom-Forming Fungi”PLoS ONE8 (5): e64646. Bibcode:2013PLoSO…864646Kdoi:10.1371/journal.pone.0064646PMC 3662758Freely accessiblePMID 23717644.
  5. Jump up^ Michael Pollan. “The Trip Treatment: Research into psychedelics, shut down for decades, is now yielding exciting results”.
  6. Jump up to:a b Leary T, Litwin GH, Metzner R (1963). “Reactions to psilocybin administered in a supportive environment”. Journal of Nervous and Mental Disease137 (6): 561–73. doi:10.1097/00005053-196312000-00007PMID 14087676.
  7. Jump up^ Berge JT. (1999). “Breakdown or breakthrough? A history of European research into drugs and creativity”. Journal of Creative Behavior33 (4): 257–76. doi:10.1002/j.2162-6057.1999.tb01406.xISSN 0022-0175.
  8. Jump up to:a b c d e f g h i j k l m n van Amsterdam J, Opperhuizen A, van den Brink W (2011). “Harm potential of magic mushroom use: a review” (PDF). Regulatory Toxicology and Pharmacology59 (3): 423–9. doi:10.1016/j.yrtph.2011.01.006PMID 21256914. Archived from the original (PDF) on 2012-11-05.
  9. Jump up to:a b c Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX (2004). “Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study”. Psychopharmacology172 (2): 145–56. doi:10.1007/s00213-003-1640-6PMID 14615876.
  10. Jump up^ Ballesteros et al. (2006), p. 175.
  11. Jump up to:a b c Studerus E, Kometer M, Hasler F, Vollenweider FX (2011). “Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies”. Journal of Psychopharmacology25 (11): 1434–52. doi:10.1177/0269881110382466PMID 20855349.
  12. Jump up to:a b MacLean KA, Johnson MW, Griffiths RR (2011). “Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness”Journal of Psychopharmacology25 (11): 1453–61. doi:10.1177/0269881111420188PMC 3537171Freely accessiblePMID 21956378.
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  14. Jump up^ Quentin A-M. (1960). La Psilocybine en Psychiatrie Clinique et Experimentale [Psilocybin in Clinical and Experimental Psychiatry] (PhD thesis) (in French). Paris, France: Paris University Medical Dissertation.
  15. Jump up^ See for example:
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    • Hollister LE, Prusmack JJ, Paulsen A, Rosenquist N (1960). “Comparison of three psychotropic drugs (psilocybin, JB-329, and IT-290) in volunteer subjects”. Journal of Nervous and Mental Disease131 (5): 428–34. doi:10.1097/00005053-196011000-00007PMID 13715375.
    • Malitz S, Esecover H, Wilkens B, Hoch PH (1960). “Some observations on psilocybin, a new hallucinogen, in volunteer subjects”. Comprehensive Psychiatry1: 8–17. doi:10.1016/S0010-440X(60)80045-4PMID 14420328.
    • Rinkel M, Atwell CR, Dimascio A, Brown J (1960). “Experimental psychiatry. V. Psilocybine, a new psychotogenic drug”. New England Journal of Medicine262 (6): 295–7. doi:10.1056/NEJM196002112620606PMID 14437505.
    • Parashos AJ. (1976). “The psilocybin-induced “state of drunkenness” in normal volunteers and schizophrenics”. Behavioral Neuropsychiatry8 (1–12): 83–6. PMID 1052267.
  16. Jump up^ Heimann H. (1994). “Experience of time and space in model psychoses”. In Pletscher A, Ladewig D. 50 Years of LSD. Current Status and Perspectives of Hallucinogens. New York, New York: The Parthenon Publishing Group. pp. 59–66. ISBN 1-85070-569-0.
  17. Jump up to:a b Wittmann M, Carter O, Hasler F, Cahn BR, Grimberg U, Spring P, Hell D, Flohr H, Vollenweider FX (2007). “Effects of psilocybin on time perception and temporal control of behaviour in humans”. Journal of Psychopharmacology (Oxford)21 (1): 50–64. doi:10.1177/0269881106065859PMID 16714323.
  18. Jump up^ Wackermann J, Wittmann M, Hasler F, Vollenweider FX (2008). “Effects of varied doses of psilocybin on time interval reproduction in human subjects”. Neuroscience Letters435 (1): 51–5. doi:10.1016/j.neulet.2008.02.006PMID 18325673.
  19. Jump up^ Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F, Vollenweider FX (2005). “Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors”. Journal of Cognitive Neuroscience17 (10): 1497–508. doi:10.1162/089892905774597191PMID 16269092.
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  21. Jump up to:a b Coull JT, Cheng RK, Meck WH (2011). “Neuroanatomical and neurochemical substrates of timing”Neuropsychopharmacology Reviews36 (1): 3–25. doi:10.1038/npp.2010.113PMC 3055517Freely accessiblePMID 20668434.
  22. Jump up to:a b Attema-de Jonge ME, Portier CB, Franssen EJ (2007). “Automutilatie na gebruik van hallucinogene paddenstoelen” [Automutilation after consumption of hallucinogenic mushrooms]. Nederlands Tijdschrift voor Geneeskunde (in Dutch). 151 (52): 2869–72. PMID 18257429.
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  31. Jump up^ Smith H. (2000). Cleansing the Doors of Perception: The Religious Significance of Entheogenic Plants and Chemicals. New York, New York: Jeremy P. Tarcher/Putnam. p. 101. ISBN 978-1-58542-034-6.
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Cited literature[edit]

Kekulé, skeletal formula of canonical psilocybin
Spacefill model of canonical psilocybin
IUPAC name

[3-(2-Dimethylaminoethyl)-1H-indol-4-yl] dihydrogen phosphate
3D model (JSmol)
ECHA InfoCard 100.007.542
EC Number 208-294-4
MeSH Psilocybine
PubChem CID
RTECS number NM3150000
oral: 163±64 min
intravenous: 74.1±19.6 min[1]
Legal status
Molar mass 284.25 g·mol−1
Melting point 220–228 °C (428–442 °F)[2]
Solubility soluble in methanol
slightly soluble in ethanol
negligible in chloroformbenzene
Lethal dose or concentration (LDLC):
LD50 (median dose)
285 mg/kg (mouse, i.v.)
280 mg/kg (rat, i.v.)
12.5 mg/kg (rabbit, i.v.)[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////////psilocybin, псилоцибин بسيلوسيبين , 赛洛西宾 ,


FDA approves drug Giapreza (angiotensin II) to treat dangerously low blood pressure

FDA approves drug to treat dangerously low blood pressure

The U.S. Food and Drug Administration today approved Giapreza (angiotensin II) injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock. Continue reading.


December 21, 2017


The U.S. Food and Drug Administration today approved Giapreza (angiotensin II) injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock.

“Shock, the inability to maintain blood flow to vital tissues, can result in organ failure and death,” said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research. “There is a need for treatment options for critically ill hypotensive patients who do not adequately respond to available therapies.”

Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Hypotension is abnormally low blood pressure. Shock is a critical condition in which blood pressure drops so low that the brain, kidneys and other vital organs can’t receive enough blood flow to function properly.

In a clinical trial of 321 patients with shock and a critically low blood pressure, significantly more patients responded to treatment with Giapreza compared to those treated with placebo. Giapreza effectively increased blood pressure when added to conventional treatments used to raise blood pressure.

Giapreza can cause dangerous blood clots with serious consequences (clots in arteries and veins, including deep venous thrombosis); prophylactic treatment for blood clots should be used.

This application received a Priority Review, under which the FDA’s goal is to take action on an application within six months when the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

The FDA granted the approval of Giapreza to La Jolla Pharmaceutical Company.

///////////Giapreza ,  La Jolla Pharmaceutical Company, fda 2017,  low blood pressure, angiotensin II

Applications and perspectives of nanomaterials in novel vaccine development

Applications and perspectives of nanomaterials in novel vaccine development

Med. Chem. Commun., 2018, Advance Article
DOI: 10.1039/C7MD00158D, Review Article
Yingbin Shen, Tianyao Hao, Shiyi Ou, Churan Hu, Long Chen
Vaccines show great potential for both prophylactic and therapeutic use in infections, cancer, and other diseases

Applications and perspectives of nanomaterials in novel vaccine development

* Corresponding authors


Vaccines show great potential for both prophylactic and therapeutic use in infections, cancer, and other diseases. With the rapid development of bio-technologies and materials sciences, nanomaterials are playing essential roles in novel vaccine formulations and can boost antigen effectiveness by operating as delivery systems to enhance antigen processing and/or as immune-potentiating adjuvants to induce or potentiate immune responses. The effect of nanoparticles in vaccinology showed enhanced antigen stability and immunogenicity as well as targeted delivery and slow release. However, obstacles remain due to the lack of fundamental knowledge on the detailed molecular working mechanism and in vivo bio-effects of nanoparticles. This review provides a broad overview of the current improvements in nanoparticles in vaccinology. Modern nanoparticle vaccines are classified by the nanoparticles’ action based on either delivery system or immune potentiator approaches. The mechanisms of interaction of nanoparticles with the antigens and the immune system are discussed. Nanoparticle vaccines approved for use are also listed. A fundamental understanding of the in vivo bio-distribution and the fate of nanoparticles will accelerate the rational design of new nanoparticles comprising vaccines in the future.

Image result for Department of Food Science and Engineering, School of Science and Engineering, Jinan University

Department of Food Science and Engineering, School of Science and Engineering, Jinan University

//////////////nanomaterials, vaccine

Synthesis of highly functional carbamates through ring-opening of cyclic carbonates with unprotected α-amino acids in water

Green Chem., 2018, Advance Article
DOI: 10.1039/C7GC02862H, Paper
Peter Olsen, Michael Oschmann, Eric V. Johnston, Bjorn Akermark
Ring opening of cyclic carbonates with unprotected amino acids in water – a route to highly functional carbamates.

Synthesis of highly functional carbamates through ring-opening of cyclic carbonates with unprotected α-amino acids in water

 Author affiliations


The present work shows that it is possible to ring-open cyclic carbonates with unprotected amino acids in water. Fine tuning of the reaction parameters made it possible to suppress the degree of hydrolysis in relation to aminolysis. This enabled the synthesis of functionally dense carbamates containing alkenes, carboxylic acids, alcohols and thiols after short reaction times at room temperature. When Glycine was used as the nucleophile in the ring-opening with four different five membered cyclic carbonates, containing a plethora of functional groups, the corresponding carbamates could be obtained in excellent yields (>90%) without the need for any further purification. Furthermore, the orthogonality of the transformation was explored through ring-opening of divinylenecarbonate with unprotected amino acids equipped with nucleophilic side chains, such as serine and cysteine. In these cases the reaction selectively produced the desired carbamate, in 70 and 50% yield respectively. The synthetic design provides an inexpensive and scalable protocol towards highly functionalized building blocks that are envisioned to find applications in both the small and macromolecular arena.


Image result for Peter Olsén stockholm

Stockholm University

  • Stockholm, Sweden
  • PostDoc Position

Research experience

  • Jun 2010–Feb 2016
    PhD Student
    KTH Royal Institute of Technology · Department of Fibre and Polymer Technology
    Sweden · Stockholm
Stockholms universitet hem
Image result for Björn Åkermark stockholm


  • Jan 1962–Jun 1967
    KTH Royal Institute of Technology
    Organic Chemistry and Catalysis · PhD
    Sweden · Stockholm

Awards & achievements

  • Jun 2009

    Award: Bror Holmberg Medal, Swedish Chemical Society

  • Feb 2009

    Award: Ulla and Stig Holmquists Prize, Uppsala University

  • Oct 1997

    Award: Dr hc, University D´Aix-Marseille

  • Oct 1991

    Award: KTH Prize for Excellence in Teaching

  • Oct 1978

    Award: Arrhenius Medal, Swedish Chemical Society

  • Aug 1977

    Scholarship: Zorn Fellowship, Swden America Foundation

  • Nov 1976

    Award: Letterstedt Award, Roy Swed. Acad. of Science


Dr. Eric Johnston, Ph.D.

Sigrid Therapeutics

Chief Technology Officer

Dr. Eric V. Johnston obtained his Master of Science degree in 2008 at the Department of Organic Chemistry, Stockholm University, Sweden. In the same year, he started his graduate studies under the supervision of Prof. Jan-Erling Bäckvall. During his PhD, he worked on the development of new homogeneous and heterogeneous transition-metal catalysts.

After receiving his PhD in 2012, he joined Prof. Samuel J. Danishefskys research group at Memorial Sloan-Kettering Cancer Center, New York, USA as a postdoctoral fellow supported by The Swedish Research Council. Here he was engaged in the total chemical synthesis of glycolsylated proteins that play important roles in modern cancer treatment.

In 2014 he returned to the Department of Organic Chemistry at Stockholm University to establish his own group. The goal of his research is to contribute new advances to the strategy and methodology for the preparation of synthetic macromolecules such as proteins, glycopeptides, sequence and length-controlled polymers. He is also a Co-Supervisor for Prof. Björn Åkermarks research group, which aims at studying and developing new homogeneous, as well as heterogeneous, water oxidation catalysts.

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