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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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GSK 6853


STR1

STR1

GSK 6853

CAS  1910124-24-1

C22 H27 N5 O3, 409.48
Benzamide, N-[2,3-dihydro-1,3-dimethyl-6-[(2R)-2-methyl-1-piperazinyl]-2-oxo-1H-benzimidazol-5-yl]-2-methoxy-
(R)-N-(1 ,3- dimethyl-6-(2-methylpiperazin-1 -yl)-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5-yl)-2- methoxybenzamide

A white solid.

LCMS (high pH): Rt = 0.90 min, [M+H+]+ 410.5.

δΗ NMR (600 MHz, DMSO-d6) ppm 10.74 (s, 1 H), 8.39 (s, 1 H), 8.05 (dd, J = 7.7, 1.8 Hz, 1 H), 7.57 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.23 (s, 1 H), 7.17-7.1 1 (m, 1 H), 4.10 (s, 3H), 3.33 (s, 3H), 3.32 (s, 3H), 3.30 (br s, 1 H), 3.07-3.02 (m, 1 H), 3.02-2.99 (m, 1 H), 2.92-2.87 (m, 1 H), 2.80 (td, J = 1 1.3, 2.7 Hz, 1 H), 2.73 (td, J = 1 1 .0, 2.7 Hz, 1 H), 2.68-2.63 (m, 1 H), 2.55 (dd, J = 12.0, 9.8 Hz, 1 H), 0.71 (d, J = 6.1 Hz, 3H).

δ0 NMR (151 MHz, DMSO-d6) ppm 162.1 , 156.8, 154.1 , 134.4, 133.2, 131.5, 130.1 , 126.6, 125.7, 121.9, 121.0, 1 12.5, 103.0, 99.4, 56.8, 55.4, 55.3, 53.3, 46.3, 26.8, 26.6, 16.7.

[aD]25 °c = -50.1 (c = 0.3, MeOH).

Scheme 1

STR1

The genomes of eukaryotic organisms are highly organised within the nucleus of the cell. The long strands of duplex DNA are wrapped around an octomer of histone proteins (most usually comprising two copies of histones H2A, H2B, H3 and H4) to form a

nucleosome. This basic unit is then further compressed by the aggregation and folding of nucleosomes to form a highly condensed chromatin structure. A range of different states of condensation are possible, and the tightness of this structure varies during the cell cycle, being most compact during the process of cell division. Chromatin structure plays a critical role in regulating gene transcription, which cannot occur efficiently from highly condensed chromatin. The chromatin structure is controlled by a series of post-translational

modifications to histone proteins, notably histones H3 and H4, and most commonly within the histone tails which extend beyond the core nucleosome structure. These modifications include acetylation, methylation, phosphorylation, ubiquitinylation, SUMOylation and numerous others. These epigenetic marks are written and erased by specific enzymes, which place the tags on specific residues within the histone tail, thereby forming an epigenetic code, which is then interpreted by the cell to allow gene specific regulation of chromatin structure and thereby transcription.

Histone acetylation is usually associated with the activation of gene transcription, as the modification loosens the interaction of the DNA and the histone octomer by changing the electrostatics. In addition to this physical change, specific proteins bind to acetylated lysine residues within histones to read the epigenetic code. Bromodomains are small (=1 10 amino acid) distinct domains within proteins that bind to acetylated lysine residues commonly but not exclusively in the context of histones. There is a family of around 50 proteins known to contain bromodomains, and they have a range of functions within the cell.

BRPF1 (also known as peregrin or Protein Br140) is a bromodomain-containing protein that has been shown to bind to acetylated lysine residues in histone tails, including H2AK5ac, H4K12ac and H3K14ac (Poplawski et al, J. Mol. Biol., 2014 426: 1661-1676). BRPF1 also contains several other domains typically found in chromatin-associated factors, including a double plant homeodomain (PHD) and zinc finger (ZnF) assembly (PZP), and a chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain. BRPF1 forms a tetrameric complex with monocytic leukemia zinc-finger protein (MOZ, also known as KAT6A or MYST3) inhibitor of growth 5 (ING5) and homolog of Esa1 -associated factor (hEAF6). In humans, the t(8;16)(p1 1 ;p13) translocation of MOZ (monocytic leukemia zinc-finger protein, also known as KAT6A or MYST3) is associated with a subtype of acute myeloid leukemia and

contributes to the progression of this disease (Borrow et al, Nat. Genet., 1996 14: 33-41 ). The BRPF1 bromodomain contributes to recruiting the MOZ complex to distinct sites of active chromatin and hence is considered to play a role in the function of MOZ in regulating transcription, hematopoiesis, leukemogenesis, and other developmental processes (Ullah et al, Mol. Cell. Biol., 2008 28: 6828-6843; Perez-Campo et al, Blood, 2009 1 13: 4866-4874). Demont et al, ACS Med. Chem. Lett., (2014) (dx.doi.org/10.1021/ml5002932), discloses certain 1 ,3-dimethyl benzimidazolones as potent, selective inhibitors of the BRPF1 bromodomain.

BRPF1 bromodomain inhibitors, and thus are believed to have potential utility in the treatment of diseases or conditions for which a bromodomain inhibitor is indicated. Bromodomain inhibitors are believed to be useful in the treatment of a variety of diseases or conditions related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the prevention and treatment of viral infections. Bromodomain inhibitors may be useful in the treatment of a wide variety of chronic autoimmune and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis (including atopic dermatitis), alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer’s disease, depression, Sjogren’s syndrome, sialoadenitis, central retinal vein occlusion, branched retinal vein occlusion, Irvine-Gass syndrome (post-cataract and post-surgical), retinitis pigmentosa, pars planitis, birdshot retinochoroidopathy, epiretinal membrane, cystic macular edema, parafoveal telengiectasis, tractional maculopathies, vitreomacular traction syndromes, retinal detachment,

neuroretinitis, idiopathic macular edema, retinitis, dry eye (kerartoconjunctivitis Sicca), vernal keratoconjunctivitis, atopic keratoconjunctivitis, uveitis (such as anterior uveitis, pan uveitis, posterior uveits, uveitis-associated macula edema), scleritis, diabetic retinopathy, diabetic macula edema, age-related macula dystrophy, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison’s disease, hypophysitis, thyroiditis, type I diabetes, type 2 diabetes and acute rejection of transplanted organs. Bromodomain inhibitors may be useful in the treatment of a wide variety of acute inflammatory conditions such as acute gout, nephritis including lupus nephritis, vasculitis with organ involvement such as

glomerulonephritis, vasculitis including giant cell arteritis, Wegener’s granulomatosis, Polyarteritis nodosa, Behcet’s disease, Kawasaki disease, Takayasu’s Arteritis, pyoderma gangrenosum, vasculitis with organ involvement and acute rejection of transplanted organs. Bromodomain inhibitors may be useful in the treatment of diseases or conditions which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute

lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus. Bromodomain inhibitors may be useful in the treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebro-vascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism. Bromodomain inhibitors may be useful in the treatment of disorders of lipid metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer’s disease. Bromodomain inhibitors may be useful in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, postoperative stricture, keloid scar formation, scleroderma (including morphea) and cardiac fibrosis. Bromodomain inhibitors may be useful in the treatment of a variety of diseases associated with bone remodelling such as osteoporosis, osteopetrosis, pycnodysostosis, Paget’s disease of bone, familial expanile osteolysis, expansile skeletal hyperphosphatasia, hyperososis corticalis deformans Juvenilis, juvenile Paget’s disease and Camurati

Engelmann disease. Bromodomain inhibitors may be useful in the treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. Bromodomain inhibitors may be useful in the treatment of cancer, including hematological (such as leukaemia, lymphoma and multiple myeloma), epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumours. Bromodomain inhibitors may be useful in the treatment of one or more cancers selected from brain cancer (gliomas), glioblastomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer, Wilm’s tumor, Ewing’s sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma cancer, osteosarcoma, giant cell tumor of bone, thyroid cancer,

lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, acute myeloid leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukaemia, erythroleukemia, malignant lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, lymphoblastic T-cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. In one embodiment the cancer is a leukaemia, for example a leukaemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia,

acute myeloid leukemia and mixed lineage leukaemia (MLL). In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt’s lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is breast cancer. In another embodiment the cancer is colarectal cancer. In one embodiment the disease or condition for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia. In this embodiment the

bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac or gastro-intestinal injury and mortality. In another embodiment the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome). In a particular embodiment the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock and endotoxaemia. In another embodiment, the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another embodiment the bromodomain is indicated for the treatment of burns. In one embodiment the disease or condition for which a bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, human immunodeficiency virus (HIV), cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus. In one particular embodiment a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia. In one embodiment the bromodomain inhibitor is indicated for the treatment of latent HIV infection.

PATENT

WO 2016062737

http://www.google.com/patents/WO2016062737A1?cl=en

Scheme 1

Example 1

Step 1

5-fluoro-1 H-benzordlimidazol-2(3H)-one

A stirred solution of 4-fluorobenzene-1 ,2-diamine (15.1 g, 120 mmol) in THF (120 mL) under nitrogen was cooled using an ice-bath and then was treated with di(1 -/-imidazol-1 -yl)methanone (23.4 g, 144 mmol) portion-wise over 15 min. The resulting mixture was slowly warmed to room temperature then was concentrated in vacuo after 2.5 h. The residue was suspended in a mixture of water and DCM (250 mL each) and filtered off. This residue was then washed with water (50 mL) and DCM (50 mL), before being dried at 40 °C under vacuum for 16 h to give the title compound (16.0 g, 105 mmol, 88%) as a brown solid.

LCMS (high pH): Rt 0.57 min; [M-H+] = 151.1

δΗ NMR (400 MHz, DMSO-d6) ppm 10.73 (br s, 1 H), 10.61 (br s, 1 H), 6.91-6.84 (m, 1 H), 6.78-6.70 (m, 2H).

Step 2

5-fluoro-1 ,3-dimethyl-1 /-/-benzo[dlimidazol-2(3/-/)-one

A solution of 5-fluoro-1 H-benzo[d]imidazol-2(3H)-one (16.0 g, 105 mmol) in DMF (400 mL) under nitrogen was cooled with an ice-bath, using a mechanical stirrer for agitation. It was then treated over 10 min with sodium hydride (60% w/w in mineral oil, 13.1 g, 327 mmol) and the resulting mixture was stirred at this temperature for 30 min before being treated with iodomethane (26.3 mL, 422 mmol) over 30 min. The resulting mixture was then allowed to warm to room temperature and after 1 h was carefully treated with water (500 mL). The aqueous phase was extracted with EtOAc (3 x 800 mL) and the combined organics were washed with brine (1 L), dried over MgS04 and concentrated in vacuo. Purification of the brown residue by flash chromatography on silica gel (SP4, 1.5 kg column, gradient: 0 to 25% (3: 1 EtOAc/EtOH) in cyclohexane) gave the title compound (15.4 g, 86 mmol, 81 %) as a pink solid.

LCMS (high pH): Rt 0.76 min; [M+H+]+ = 181.1

δΗ NMR (400 MHz, CDCI3) ppm 6.86-6.76 (m, 2H), 6.71 (dd, J = 8.3, 2.3 Hz, 1 H), 3.39 (s, 3H), 3.38 (s, 3H).

Step 3

5-fluoro-1 ,3-dimethyl-6-nitro-1 /-/-benzordlimidazol-2(3/-/)-one

A stirred solution of 5-fluoro-1 ,3-dimethyl-1 H-benzo[d]imidazol-2(3/-/)-one (4.55 g, 25.3 mmol) in acetic anhydride (75 mL) under nitrogen was cooled to -30 °C and then was slowly treated with fuming nitric acid (1 .13 mL, 25.3 mmol) making sure that the temperature was kept below -25°C. The solution turned brown once the first drop of acid was added and a thick brown precipitate formed after the addition was complete. The mixture was allowed to slowly warm up to 0 °C then was carefully treated after 1 h with ice-water (100 mL). EtOAc (15 mL) was then added and the resulting mixture was stirred for 20 min. The precipitate formed was filtered off, washed with water (10 mL) and EtOAc (10 mL), and then was dried under vacuum at 40 °C for 16 h to give the title compound (4.82 g, 21 .4mmol, 85%) as a yellow solid.

LCMS (high pH): Rt 0.76 min; [M+H+]+ not detected

δΗ NMR (600 MHz, DMSO-d6) ppm 7.95 (d, J = 6.4 Hz, 1 H, (H-7)), 7.48 (d, J = 1 1.7 Hz, 1 H, (H-4)), 3.38 (s, 3H, (H-10)), 3.37 (s, 3H, (H-12)).

δ0 NMR (151 MHz, DMSO-d6) ppm 154.3 (s, 1 C, (C-2)), 152.3 (d, J = 254.9 Hz, 1 C, (C-5)), 135.5 (d, J = 13.0 Hz, 1 C, (C-9)), 130.1 (d, J = 8.0 Hz, 1 C, (C-6)), 125.7 (s, 1 C, (C-8)), 104.4 (s, 1 C, (C-7)), 97.5 (d, J = 28.5 Hz, 1 C, (C-4)), 27.7 (s, 1 C, (C-12)), 27.4 (s, 1 C, (C-10)).

Step 4

(R)-tert-but \ 4-( 1 ,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1 H-benzordlimidazol-5-yl)-3-methylpiperazine-1-carboxylate

A stirred suspension of 5-fluoro-1 ,3-dimethyl-6-nitro-1 H-benzo[d]imidazol-2(3/-/)-one (0.924 g, 4.10 mmol), (R)-ie f-butyl 3-methylpiperazine-1 -carboxylate (1.23 g, 6.16 mmol), and DI PEA (1 .43 mL, 8.21 mmol) in DMSO (4 mL) was heated to 120 °C in a Biotage Initiator microwave reactor for 13 h, then to 130 °C for a further 10 h. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The aqueous was extracted with EtOAc and the combined organics were dried (Na2S04), filtered, and concentrated in vacuo to give a residue which was purified by silica chromatography (0-100% ethyl acetate in cyclohexane) to give the title compound as an orange/yellow solid (1.542 g, 3.80 mmol, 93%).

LCMS (formate): Rt 1.17 min, [M+H+]+ 406.5.

δΗ NMR (400 MHz, CDCI3) ppm 7.36 (s, 1 H), 6.83 (s, 1 H), 4.04-3.87 (m,1 H), 3.87-3.80 (m, 1 H), 3.43 (s, 6H), 3.35-3.25 (m, 1 H), 3.23-3.08 (m, 2H), 3.00-2.72 (m, 2H), 1.48 (s, 9H), 0.81 (d, J = 6.1 Hz, 3H)

Step 5

(RHerf-butyl 4-(6-amino-1 ,3-dimethyl-2-oxo-2,3-dihydro-1 /-/-benzordlimidazol-5-yl)-3-methylpiperazine-1-carboxylate

To (R)-iert-butyl 4-(1 ,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1 H-benzo[d]imidazol-5-yl)-3-methylpiperazine-1-carboxylate (1 .542 g) in /so-propanol (40 mL) was added 5% palladium on carbon (50% paste) (1.50 g) and the mixture was hydrogenated at room temperature and pressure. After 4 h the mixture was filtered, the residue washed with ethanol and DCM, and the filtrate concentrated in vacuo to give a residue which was purified by silica chromatography (50-100% ethyl acetate in cyclohexane) to afford the title compound (1.220 g, 3.25 mmol, 85%) as a cream solid.

LCMS (high pH): Rt 1 .01 min, [M+H+]+ 376.4.

δΗ NMR (400 MHz, CDCI3) ppm 6.69 (s, 1 H), 6.44 (s, 1 H), 4.33-3.87 (m, 4H), 3.36 (s, 3H), 3.35 (s, 3H), 3.20-2.53 (m, 5H), 1.52 (s, 9H), 0.86 (d, J = 6.1 Hz, 3H).

Step 6

(flVferf-butyl 4-(6-(2-methoxybenzamidoV 1 ,3-dimethyl-2-oxo-2,3-dihvdro-1 H-benzordlimidazol-5-yl)-3-methylpiperazine-1 -carboxylate

A stirred solution of (R)-iert-butyl 4-(6-amino-1 ,3-dimethyl-2-oxo-2,3-dihydro-1 /-/-benzo[d]imidazol-5-yl)-3-methylpiperazine-1 -carboxylate (0.254 g, 0.675 mmol) and pyridine (0.164 ml_, 2.025 mmol) in DCM (2 mL) at room temperature was treated 2-methoxybenzoyl chloride (0.182 mL, 1.35 mmol). After 1 h at room temperature the reaction mixture was concentrated in vacuo to give a residue which was taken up in DMSO:MeOH (1 :1 ) and purified by HPLC (Method C, high pH) to give the title compound (0.302 g, 0.592 mmol, 88%) as a white solid.

LCMS (high pH): Rt 1 .27 min, [M+H+]+ 510.5.

δΗ NMR (400 MHz, CDCI3) ppm 10.67 (s, 1 H), 8.53 (s, 1 H), 8.24 (dd, J = 7.8, 1.7 Hz, 1 H), 7.54-7.48 (m, 1 H), 7.18-7.12 (m, 1 H), 7.07 (d, J = 8.1 Hz, 1 H), 6.82 (s, 1 H), 4.27-3.94 (m, 2H), 4.08 (s, 3H), 3.45 (s, 3H), 3.40 (s, 3H), 3.18-2.99 (m, 2H), 2.92-2.70 (m, 3H), 1.50 (s, 9H), 0.87 (d, J = 6.1 Hz, 3H).

Step 7

(R)-N-( 1 ,3-dimethyl-6-(2-methylpiperazin-1 -yl)-2-oxo-2,3-dihydro-1 H-benzordlimidazol-5-yl)-2-methoxybenzamide

A stirred solution of (R)-ie f-butyl 4-(6-(2-methoxybenzamido)-1 ,3-dimethyl-2-oxo-2,3-dihydro-1 /-/-benzo[d]imidazol-5-yl)-3-methylpiperazine-1-carboxylate (302 mg, 0.592 mmol) in DCM (4 mL) at room temperature was treated with trifluoroacetic acid (3 ml_). After 15 minutes the mixture was concentrated in vacuo to give a residue which was loaded on a solid-phase cation exchange (SCX) cartridge (5 g), washed with MeOH, and then eluted with methanolic ammonia (2 M). The appropriate fractions were combined and concentrated in vacuo to give a white solid (240 mg). Half of this material was taken up in DMSO:MeOH (1 :1 ) and purified by HPLC (Method B, high pH) to give the title compound (101 mg, 0.245 mmol, 41 %) as a white solid.

LCMS (high pH): Rt = 0.90 min, [M+H+]+ 410.5.

δΗ NMR (600 MHz, DMSO-d6) ppm 10.74 (s, 1 H), 8.39 (s, 1 H), 8.05 (dd, J = 7.7, 1.8 Hz, 1 H), 7.57 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.23 (s, 1 H), 7.17-7.1 1 (m, 1 H), 4.10 (s, 3H), 3.33 (s, 3H), 3.32 (s, 3H), 3.30 (br s, 1 H), 3.07-3.02 (m, 1 H), 3.02-2.99 (m, 1 H), 2.92-2.87 (m, 1 H), 2.80 (td, J = 1 1.3, 2.7 Hz, 1 H), 2.73 (td, J = 1 1 .0, 2.7 Hz, 1 H), 2.68-2.63 (m, 1 H), 2.55 (dd, J = 12.0, 9.8 Hz, 1 H), 0.71 (d, J = 6.1 Hz, 3H).

δ0 NMR (151 MHz, DMSO-d6) ppm 162.1 , 156.8, 154.1 , 134.4, 133.2, 131.5, 130.1 , 126.6, 125.7, 121.9, 121.0, 1 12.5, 103.0, 99.4, 56.8, 55.4, 55.3, 53.3, 46.3, 26.8, 26.6, 16.7.

[aD]25 °c = -50.1 (c = 0.3, MeOH).

CLIPS

STR1

STR1

STR1

STR1

PAPER

Abstract Image

The BRPF (Bromodomain and PHD Finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. A selective benzimidazolone BRPF1 inhibitor showing micromolar activity in a cellular target engagement assay was recently described. Herein, we report the optimization of this series leading to the identification of a superior BRPF1 inhibitor suitable for in vivo studies.

GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain

Epinova Discovery Performance Unit, Quantitative Pharmacology, Experimental Medicine Unit, §Flexible Discovery Unit, and Platform Technology and Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
Cellzome GmbH, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany
# WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, U.K.
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00092
SEE

//////////////BRPF1,  BRPF2,   bromodomain, chemical probe,  inhibitor, GSK 6853, PRECLINICAL

  • Supporting Info  SEE NMR COMPD 34,  SMILES       COc1ccccc1C(=O)Nc2cc4c(cc2N3CCNC[C@H]3C)N(C)C(=O)N4C
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CCT 245737


CCT 245737

CAS:1489389-18-5
M.Wt: 379.34
Formula: C16H16F3N7O

2-Pyrazinecarbonitrile, 5-[[4-[[(2R)-2-morpholinylmethyl]amino]-5-(trifluoromethyl)-2-pyridinyl]amino]-

(R)-5-(4-(Morpholin-2-ylmethylamino)-5-(trifluoromethyl)pyridin-2-ylamino)pyrazine-2-carbonitrile

(+)-5-[[4-[[(2R)-Morpholin-2-ylmethyl]amino]-5-(trifluoromethyl)pyridin-2-yl]amino]pyrazine-2-carbonitrile

Cancer Research Technology Limited   INNOVATOR

SAREUM

IND Filed, Sareum FOR CANCER

Synthesis, Exclusive by worlddrugtracker

STR1

5-[[4-[[morpholin-2-yl]methylamino]-5- (trifluoromethyl)-2-pyridyl]amino]pyrazine-2-carbonitrile compounds (referred to herein as “TFM compounds”) which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1 , that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or a thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; (e) ionising radiation; (f) an inhibitor of a mitosis regulator or a mitotic checkpoint regulator; (g) an inhibitor of a DNA damage signal transducer; or (h) an inhibitor of a DNA damage repair enzyme.

Checkpoint Kinase 1 (CHK1)

Progression through the cell division cycle is a tightly regulated process and is monitored at several positions known as cell cycle checkpoints (see, e.g., Weinert and Hartwell,

1989; Bartek and Lukas, 2003). These checkpoints are found in all four stages of the cell cycle; G1 , S (DNA replication), G2 and M (Mitosis) and they ensure that key events which control the fidelity of DNA replication and cell division are completed correctly. Cell cycle checkpoints are activated by a number of stimuli, including DNA damage and DNA errors caused by defective replication. When this occurs, the cell cycle will arrest, allowing time for either DNA repair to occur or, if the damage is too severe, for activation of cellular processes leading to controlled cell death.

All cancers, by definition, have some form of aberrant cell division cycle. Frequently, the cancer cells possess one or more defective cell cycle checkpoints, or harbour defects in a particular DNA repair pathway. These cells are therefore often more dependent on the remaining cell cycle checkpoints and repair pathways, compared to non-cancerous cells (where all checkpoints and DNA repair pathways are intact). The response of cancer cells to DNA damage is frequently a critical determinant of whether they continue to proliferate or activate cell death processes and die. For example, tumour cells that contain a mutant form(s) of the tumour suppressor p53 are defective in the G1 DNA damage checkpoint. Thus inhibitors of the G2 or S-phase checkpoints are expected to further impair the ability of the tumour cell to repair damaged DNA. Many known cancer treatments cause DNA damage by either physically modifying the cell’s DNA or disrupting vital cellular processes that can affect the fidelity of DNA replication and cell division, such as DNA metabolism, DNA synthesis, DNA transcription and microtubule spindle formation. Such treatments include for example, radiotherapy, which causes DNA strand breaks, and a variety of chemotherapeutic agents including topoisomerase inhibitors, antimetabolites, DNA-alkylating agents, and platinum- containing cytotoxic drugs. A significant limitation to these genotoxic treatments is drug resistance. One of the most important mechanisms leading to this resistance is attributed to activation of cell cycle checkpoints, giving the tumour cell time to repair damaged DNA. By abrogating a particular cell cycle checkpoint, or inhibiting a particular form of DNA repair, it may therefore be possible to circumvent tumour cell resistance to the genotoxic agents and augment tumour cell death induced by DNA damage, thus increasing the therapeutic index of these cancer treatments.

CHK1 is a serine/threonine kinase involved in regulating cell cycle checkpoint signals that are activated in response to DNA damage and errors in DNA caused by defective replication (see, e.g., Bartek and Lukas, 2003). CHK1 transduces these signals through phosphorylation of substrates involved in a number of cellular activities including cell cycle arrest and DNA repair. Two key substrates of CHK1 are the Cdc25A and Cdc25C phosphatases that dephosphorylate CDK1 leading to its activation, which is a

requirement for exit from G2 into mitosis (M phase) (see, e.g., Sanchez et al., 1997). Phosphorylation of Cdc25C and the related Cdc25A by CHK1 blocks their ability to activate CDK1 , thus preventing the cell from exiting G2 into M phase. The role of CHK1 in the DNA damage-induced G2 cell cycle checkpoint has been demonstrated in a number of studies where CHK1 function has been knocked out (see, e.g., Liu et ai, 2000; Zhao et al., 2002; Zachos et al., 2003).

The reliance of the DNA damage-induced G2 checkpoint upon CHK1 provides one example of a therapeutic strategy for cancer treatment, involving targeted inhibition of CHK1. Upon DNA damage, the p53 tumour suppressor protein is stabilised and activated to give a p53-dependent G1 arrest, leading to apoptosis or DNA repair (Balaint and Vousden, 2001). Over half of all cancers are functionally defective for p53, which can make them resistant to genotoxic cancer treatments such as ionising radiation (IR) and certain forms of chemotherapy (see, e.g., Greenblatt et al., 1994; Carson and Lois, 1995). These p53 deficient cells fail to arrest at the G1 checkpoint or undergo apoptosis or DNA repair, and consequently may be more reliant on the G2 checkpoint for viability and replication fidelity. Therefore abrogation of the G2 checkpoint through inhibition of the CHK1 kinase function may selectively sensitise p53 deficient cancer cells to genotoxic cancer therapies, and this has been demonstrated (see, e.g., Wang et al., 1996; Dixon and Norbury, 2002). In addition, CHK1 has also been shown to be involved in S phase cell cycle checkpoints and DNA repair by homologous recombination. Thus, inhibition of CHK1 kinase in those cancers that are reliant on these processes after DNA damage, may provide additional therapeutic strategies for the treatment of cancers using CHK1 inhibitors (see, e.g., Sorensen et al., 2005). Furthermore, certain cancers may exhibit replicative stress due to high levels of endogenous DNA damage (see, e.g., Cavalier et al., 2009; Brooks et al., 2012) or through elevated replication driven by oncogenes, for example amplified or overexpressed MYC genes (see, e.g., Di Micco et al. 2006; Cole et al., 2011 ; Murga et al. 2011). Such cancers may exhibit elevated signalling through CHK1 kinase (see, e.g., Hoglund et al., 2011). Inhibition of CHK1 kinase in those cancers that are reliant on these processes, may provide additional therapeutic strategies for the treatment of cancers using CHK1 inhibitors (see, e.g., Cole et al., 2011 ; Davies et al., 2011 ; Ferrao et al., 2011).

Several kinase enzymes are important in the control of the cell growth and replication cycle. These enzymes may drive progression through the cell cycle, or alternatively can act as regulators at specific checkpoints that ensure the integrity of DNA replication through sensing DNA-damage and initiating repair, while halting the cell cycle. Many tumours are deficient in early phase DNA-damage checkpoints, due to mutation or deletion in the p53 pathway, and thus become dependent on the later S and G2/M checkpoints for DNA repair. This provides an opportunity to selectively target tumour cells to enhance the efficacy of ionising radiation or widely used DNA-damaging cancer chemotherapies. Inhibitors of the checkpoint kinase CHK1 are of particular interest for combination with genotoxic agents. In collaboration with Professor Michelle Garrett (University of Kent, previously at The Institute of Cancer Research) and Sareum (Cambridge) we used structure-based design to optimise the biological activities and pharmaceutical properties of hits identified through fragment-based screening against the cell cycle kinase CHK1, leading to the oral clinical candidate CCT245737. The candidate potentiates the efficacy of standard chemotherapy in models of non-small cell lung, pancreatic and colon cancer. In collaboration with colleagues at The Institute of Cancer Research (Professor Louis Chesler, Dr Simon Robinson and Professor Sue Eccles) and Newcastle University (Professor Neil Perkins), we have shown that our selective CHK1 inhibitor has efficacy as a single agent in models of tumours with high replication stress, including neuroblastoma and lymphoma.

The checkpoint kinase CHK2 has a distinct but less well characterised biological role to that of CHK1. Selective inhibitors are valuable as pharmacological tools to explore the biological consequences of CHK2 inhibition in cancer cells. In collaboration with Professor Michelle Garrett (University of Kent, previously at The Institute of Cancer Research), we have used structure-based and ligand-based approaches to discover selective inhibitors of CHK2. We showed that selective CHK2 inhibition has a very different outcome to selective CHK1 inhibition. Notably, while CHK2 inhibition did not potentiate the effect of DNA-damaging chemotherapy, it did sensitize cancer cells to the effects of PARP inhibitors that compromise DNA repair.

Synthesis 

(R)-5-(4-(Morpholin-2-ylmethylamino)-5-(trifluoromethyl)pyridin-2-ylamino)pyrazine-2-carbonitrile 

 as a pale-yellow amorphous solid.
1H NMR ((CD3)2SO, 500 MHz) δ 10.7 (br s, 1H), 9.10 (d, J = 1.4 Hz, 1H), 8.77 (d, J = 1.4 Hz, 1H), 8.20 (s, 1H), 7.19 (s, 1H), 6.32 (br t, J = 5.5 Hz, 1H), 3.75 (br d, J = 11.0 Hz, 1H), 3.64–3.59 (m, 1H), 3.43 (ddd, J = 10.7, 10.7, and 3.4 Hz, 1H), 3.22 (m, 2H), 2.82 (dd, J = 12.1 and 2.1 Hz, 1H), 2.67–2.59 (m, 2H), 2.42 (dd, J = 12.1 and 10.0 Hz, 1H).
13C NMR ((CD3)2SO, 125 MHz) δ 155.7, 151.9, 151.6, 147.2, 145.9 (q, JCF = 6.3 Hz), 136.8, 124.8 (q, JCF= 270.9 Hz), 118.9, 117.1, 104.4 (q, JCF = 30.0 Hz), 93.2, 73.6, 67.2, 48.9, 45.4, 44.9.
LCMS (3.5 min) tR = 1.17 min; m/z (ESI+) 380 (M + H+).
HRMS m/z calcd for C16H17F3N7O (M + H) 380.1441, found 380.1438.

PATENT

WO 2013171470

http://www.google.com/patents/WO2013171470A1?cl=enSynthesis 1 D

5-[[4-[[(2R)-Morpholin-2-yl]methylamino]-5-(trifluoromethyl)-2-pyridyl]amino]py

carbonitrile (Compound 1)

Figure imgf000044_0002

A solution of (S)-tert-butyl 2-((2-(5-cyanopyrazin-2-ylamino)-5-(trifluoromethyl)pyridin-4- ylamino)methyl)morpholine-4-carboxylate (1.09 g, 2.273 mmol) in dichloromethane (8 mL) was added dropwise over 10 minutes to a solution of trifluoroacetic acid (52.7 mL, 709 mmol) and tnisopropylsilane (2.61 mL, 12.73 mmol) in dry dichloromethane (227 mL) at room temperature. After stirring for 30 minutes, the mixture was concentrated in vacuo. The concentrate was resuspended in dichloromethane (200 mL) and

concentrated in vacuo, then resuspended in toluene (100 mL) and concentrated.

The above procedure was performed in triplicate (starting each time with 1.09 g (S)-tert- butyl 2-((2-(5-cyanopyrazin-2-ylamino)-5-(trifluoromethyl)pyridin-4- ylamino)methyl)morpholine-4-carboxylate) and the three portions of crude product so generated were combined for purification by ion exchange chromatography on 2 x 20 g Biotage NH2 Isolute columns, eluting with methanol. The eluant was concentrated and 10% methanol in diethyl ether (25 mL) was added. The resulting solid was filtered, washed with diethyl ether (30 mL), and dried in vacuo to give the title compound as a light straw coloured powder (2.30 g, 89%). H NMR (500 MHz, CD3OD) δ 2.62 (1 H, J = 12, 10 Hz), 2.78-2.84 (2H, m), 2.95 (1 H, dd, J = 12, 2 Hz), 3.27-3.38 (2H, m), 3.63 (1 H, ddd, J = 14, 9.5, 3 Hz), 3.73-3.78 (1 H, m), 3.91 (1 H, ddd, J = 11 , 4, 2 Hz), 7.26 (1 H, s), 8.18 (1 H, s), 8.63 (1 H, s), 9.01 (1 H, s).

LC-MS (Agilent 4 min) Rt 1.22 min; m/z (ESI) 380 [M+H+]. Optical rotation [a]D 24 = +7.0 (c 1.0, DMF).

Synthesis 2B

(R)-tert- Butyl 2-((2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)methyl)morpholine-

Figure imgf000046_0001

To a solution of 2-chloro-5-(trifluoromethyl)pyridin-4-amine (1 g, 5.09 mmol) in

dimethylformamide (32.6 mL) was added sodium hydride (60% by wt in oil; 0.407 g, 10.18 mmol) portionwise at room temperature followed by stirring for 10 minutes at 80°C. (S)- tert-Butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (2.268 g, 6.1 1 mmol) was then added portionwise and the reaction mixture was stirred at 80°C for 2.5 hours. After cooling, the mixture was partitioned between saturated aqueous sodium

hydrogencarbonate solution (30 mL), water (100 mL) and ethyl acetate (30 mL). The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (2 x 70 mL), dried over magnesium sulfate, filtered, concentrated and dried thoroughly in vacuo. The crude material was purified by column chromatography on a 90 g Thomson SingleStep column, eluting with an isocratic mix of 2.5% diethyl ether / 2.5% ethyl acetate in dichloromethane, to give the title compound as a clear gum that later crystallised to give a white powder (1.47 g, 73%). H NMR (500 MHz, CDCI3) δ 1.48 (9H, s), 2.71-2.83 (1 H, m), 2.92-3.05 (1 H, m), 3.18- 3.23 (1 H, m), 3.33-3.37 (1 H, m), 3.56-3.61 (1 H, m), 3.66-3.71 (1 H, m), 3.80-4.07 (3H, m), 5.32 (1 H, broad s), 6.61 (1 H, s), 8.24 (1 H, s). LC-MS (Agilent 4 min) Rt 3.04 min; m/z (ESI) 396 [MH+]. Svnthesis 2C

(R)-tert-Butyl 2-((2-(5-cyanopyrazin-2-ylamino)-5-(trifluoromethyl)pyridin-4-

Figure imgf000047_0001

(R)-tert-Butyl 2-((2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)methyl)morpholine-4- carboxylate (1.44 g, 3.64 mmol), 2-amino-5-cyanopyrazine (0.612 g, 5.09 mmol, 1.4 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.267 g, 0.291 mmol, 0.08 eq.), rac-2,2′- bis(diphenylphosphino)-1 ,1 ‘-binaphthyl (0.362 g, 0.582 mmol, 0.16 eq.) and caesium carbonate (2.37 g, 7.28 mmol) were suspended in anhydrous dioxane (33 ml_) under argon. Argon was bubbled through the mixture for 30 minutes, after which the mixture was heated to 100°C for 22 hours. The reaction mixture was cooled and diluted with dichloromethane, then absorbed on to silica gel. The pre-absorbed silica gel was added to a 100 g KP-Sil SNAP column which was eluted with 20-50% ethyl acetate in hexanes to give the partially purified product as an orange gum. The crude product was dissolved in dichloromethane and purified by column chromatography on a 90 g SingleStep Thomson column, eluting with 20% ethyl acetate in dichloromethane, to give the title compound (1.19 g, 68%). H NMR (500 MHz, CDCI3) δ 1.50 (9H, s), 2.71-2.88 (1 H, m), 2.93-3.08 (1 H, m), 3.27- 3.32 (1 H, m), 3.40-3.44 (1 H, m), 3.55-3.64 (1 H, m), 3.71-3.77 (1 H, m), 3.82-4.11 (3H, m), 5.33 (1 H, broad s), 7.19 (1 H, s), 8.23 (1 H, s), 8.58 (1 H, s), 8.84 (1 H, s). LC-MS (Agilent 4 min) Rt 2.93 min;m/z (ESI) 480 [MH+].

Paper

Abstract Image

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic–pharmacodynamic (PK–PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.

Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737)

Cancer Research UK Cancer Therapeutics Unit and Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SM2 5NG, U.K.
§ Sareum Ltd., Cambridge CB22 3FX, U.K.
J. Med. Chem., Article ASAP
DOI: 10.1021/acs.jmedchem.5b01938
Publication Date (Web): May 11, 2016
Copyright © 2016 American Chemical Society
*Phone: +44 2087224000. Fax: +44 2087224126. E-mail: ian.collins@icr.ac.uk.

///////////CCT 245737, IND, PRECLINICAL, Cancer Research Technology Limited, SAREUM

N#CC(C=N1)=NC=C1NC2=NC=C(C(F)(F)F)C(NC[C@@H]3OCCNC3)=C2

[F-18](2S,4S)-4-(3-Fluoropropyl)glutamine


STR1

[F-18](2S,4S)-4-(3-Fluoropropyl)glutamine

CAS 1196963-79-7

MF C8 H15 F N2 O3
Heptanoic acid, 2-amino-4-(aminocarbonyl)-7-(fluoro-18F)-, (2S,4S)-
[18F](2S,4S)-4-FPGln

[18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4

The early diagnosis of malignant tumors plays a very important role in the survival prognosis of cancer patients. In this non-invasive diagnosis, diagnostic imaging procedures are an important tool. In the last few years has mainly PET technology (P ositronen- E mission- Tomographie) proved to be particularly useful. The sensitivity and specificity of PET technology depends significantly on the used signal-emitting substance (tracer) and their distribution in the body from. In the search for suitable tracers one tries to take advantage of certain properties of tumors differ, the tumor tissue from healthy, surrounding tissue. The preferred commercially used isotope which finds application for PET, 18 F 18 F represents by its short half-life of less than 2 hours special requirements for the preparation of suitable tracer. Complex, long synthetic routes and purifications are with this isotope is not possible, because otherwise a significant portion of the radioactivity of the isotope has already decayed before the tracer can be used for diagnosis. It is therefore often not possible to established synthetic routes for non-radioactive fluorination to be applied to the synthesis of18 F-tracer. Furthermore, the high specific activity of 18 F (80 GBq / nmol) at very low substance amounts of [18 F] fluoride for the tracer synthesis, which in turn an extreme excess of precursor-related and the success of a non-radioactive fluorination based Radio synthetic strategy designed unpredictable

FDG ([18 F] F 2 luoro d esoxy lukose g) -PET is a widely accepted and popular tool in the diagnosis and other clinical tracking of tumor diseases. Malignant tumors compete with the host organism to glucose supply to the nutrient supply (Warburg O. About the metabolism of carcinoma cell Biochem;.. Kellof G. Progress and Promise of FDG PET Imaging for Cancer Patient Management and Oncologic Drug Development Clin Cancer Res 2005;.. 11 (8): 2785-2807) where tumor cells compared to surrounding cells of normal tissue usually an increased glucose metabolism. This is used when using fluorodeoxyglucose (FDG), a glucose derivative, which is amplified transported into the cells, but there included metabolically after phosphorylation as FDG-6-phosphate (“Warburg effect”). 18 F-labeled FDG is Therefore, an effective tracer for the detection of tumors in patients using PET technology. Imaging were looking for new PET tracers in recent years increasingly amino acids for 18 F PET used (eg (review): Eur J Nucl Med Mol Imaging 2002 May; 29 (5):.. 681-90). In this case, some of the 18 F-labeled amino acids for the measurement of the speed rate of protein synthesis, the most useful derivatives but for the direct measurement of the cellular uptake in the tumor. Known 18 F-labeled amino acids are, for example, from tyrosine, phenylalanine, proline, aspartic and unnatural amino acids derived (eg J. Nucl Med 1991; 32:.. 1338-1346, J Nucl Med 1996; 37: 320-325, J Nucl Med 2001; 42: 752-754 J Nucl Med and 1999, 40: 331-338).. Glutamic acid and glutamine than 18 F-labeled derivatives not known, whereas non-radioactive fluorinated glutamine and glutamic acid derivatives are well known; Thus, for Example those which at γ-position (for Ex (review):Amino Acids (2003) April; 24 (3):… 245-61).. or at β-position (e.g. ExTetrahedron. Lett. .; 30; 14; 1989, 1799-1802, J. Org Chem .; 54; 2; 1989, 498-500, Tetrahedron: Asymmetry, 12, 9; 2001; 1303-1312) havefluorine..

Of glutamic acid having the chemical functionalities protecting groups in β and γ position or a leaving group, has already been reported in the past. So was informed of glutamate as mesylate or bromide in γ-position whose acid and amine functions were provided with ester or Z-protecting groups (J. Chem Soc Perkin Trans. 1;.. 1986, 1323-1328) or, for example, of γ-chloro-glutamic acid without protecting groups(Synthesis, (1973); 44-46). About similar derivatives, but where the leaving group is positioned in β-position has also been reported on several occasions. Z Ex. Chem. Pharm. Bull .; 17; 5; (1969); 879-885,J.Gen.Chem.USSR (Engl.Transl.); 38; (1968); 1645-1648, Tetrahedron Lett .; 27; 19; (1986); 2143-2144, Chem. Pharm. Bull .; EN; 17; 5; 1969;873-878, patent FR 1461184 , Patent JP 13142 .)

The current PET tracers, which are used for tumor diagnosis have some undisputed disadvantages: in FDG accumulates preferably in those cells with increased glucose metabolism on, but there are also other pathological and physiological conditions of increased glucose metabolism in the cells involved and tissues, eg, Ex. of infection or wound healing (summarized in J. Nucl. Med. Technol. (2005), 33, 145-155). It is still often difficult to decide whether a detected by FDG-PET lesion actually neoplastic origin or due to other physiological or pathological state of the tissue. Overall, the diagnostic activity by FDG-PET in oncology has a sensitivity of 84% and a specificity of 88% to(Gambhir et al., ” A tabulated summary of the FDG PET literature “J. Nucl. Med. 2001, 42, 1- 93S). Tumors in the brain can be represented very difficult in healthy brain tissue, for example, by the high accumulation of FDG.

The previously known 18 F-labeled amino acid derivatives are in some cases well suited to detect tumors in the brain ((review): Eur J Nucl Med Mol Imaging 2002 May; 29 (5):. 681-90), but they can in other tumors do not compete with the imaging properties of the “gold standard” [18 F] 2-FDG. The metabolic accumulation and retention of previously F-18 labeled amino acids in tumorous tissue is usually lower than for FDG. Moreover, the accessibility of isomerically pure F-18-labeled non-aromatic amino acids is chemically very demanding.

Similar to glucose increased metabolism in proliferating tumor cells has been described (Medina, J Nutr 1131: 2539S-2542S, 2001; Souba, Ann Surg 218:. 715-728, 1993) for glutamic acid and glutamine. The increased rate of protein and nucleic acid synthesis and energy production per se be accepted as reasons for increased Glutaminkonsum of tumor cells. The synthesis of the corresponding C-11 and C-14 labeled with the natural substrate thus identical compounds, has already been described in the literature (eg. Ex.Antoni, enzymes Catalyzed Synthesis of L- [4-C-11] Aspartate and L – [5-C-11] Glutamate J. Labelled Compd Radiopharm 44; (4) 2001: 287-294) and Buchanan, The biosynthesis of showdomycin: studies with stable isotopes and the determination of principal precursor J….. Chem. Soc. Chem. Commun .; EN; 22; 1984, 1515-1517). First indications with the C-11 labeled compound indicate no significant tumor accumulation.

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [(18)F](2S,4R)- and [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with (18)F and (19)F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[(3)H]glutamine ([(3)H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [(18)F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[(3)H]glutamine and the new probe showed that the uptake of [(3)H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [(18)F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.

STR1

[18F](2S,4S)-4-(3-Fluoropropyl)glutamine as a Tumor Imaging Agent

http://pubs.acs.org/doi/full/10.1021/mp500236y

Departments of Radiology and Pharmacology, University of Pennsylvania, 3700 Market Street, Philadelphia, Pennsylvania 19104, United States
Mol. Pharmaceutics, 2014, 11 (11), pp 3852–3866
DOI: 10.1021/mp500236y
Publication Date (Web): August 05, 2014
Copyright © 2014 American Chemical Society
*Email: kunghf@sunmac.spect.upenn.edu. Phone: 215-662-3096. Fax: 215-349-5035.

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

This article is part of the Positron Emission Tomography: State of the Art special issue.

Abstract

Abstract Image

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [18F](2S,4R)- and [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with 18F and 19F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[3H]glutamine ([3H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [18F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[3H]glutamine and the new probe showed that the uptake of [3H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.

PATENT

US 20100290991

http://www.google.com/patents/US20100290991

Figure US20100290991A1-20101118-C00029

PATENT

WO 2009141091

https://patentscope.wipo.int/search/ko/detail.jsf?docId=WO2009141091&recNum=70&maxRec=287&office=&prevFilter=%26fq%3DOF%3ACU&sortOption=Relevance&queryString=&tab=PCTDescription

PATENT

http://www.google.co.ug/patents/EP2123621A1?cl=en

REFERENCES

https://www.researchgate.net/publication/264538736_F-182S4S-4-3-Fluoropropylglutamine_as_a_Tumor_Imaging_Agent

Molecular Pharmaceutics (2014), 11(11), 3852-3866

EP1923382A1 * 18 Nov 2006 21 May 2008 Bayer Schering Pharma Aktiengesellschaft [18F] labelled L-glutamic acid, [18F] labelled glutamine, their derivatives, their use and processes for their preparation
FR1461184A Title not available
JPS58113142A Title not available
WO2008052788A1 * 30 Oct 2007 8 May 2008 Bayer Schering Pharma Aktiengesellschaft [f-18]-labeled l-glutamic acid, [f-18]-labeled l-glutamine, derivatives thereof and use thereof and processes for their preparation

////////

Rovatirelin Hydrate


2D chemical structure of 204386-76-5

img

Rovatirelin Hydrate, S-0373, 

Rovatirelin, RN: 204386-76-5
UNII: 9DL0X410PY

(4S,5S)-5-methyl-N-((2S)-1-((2R)-2-methylpyrrolidin-1-yl)-1-oxo-3-((1,3-thiazol-4-yl)methyl)propan-2-yl)-2-oxo-1,3-oxazolidine-4-carboxamide

(4S,5S)-5-methyl-N-((S)-1-((R)-2-methylpyrrolidin-1-yl)-1-oxo-4-(thiazol-4-yl)butan-2-yl)-2-oxooxazolidine-4-carboxamide4-Oxazolidinecarboxamide, 5-methyl-N-[2-(2-methyl-1-pyrrolidinyl)-2-oxo-1-(4-thiazolylmethyl)ethyl]-2-oxo-, [4S-[4α[R*(S*)],5α]]-

Phase III

A thyrotropin-releasing hormone potentially for the treatment of spinocerebellar ataxia.

CAS No.204386-76-5(Rovatirelin)

879122-87-9(Rovatirelin Hydrate)

C17H24N4O4S
Exact Mass: 380.1518

Rovatirelin is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). Rovatirelin increased locomotor activity. Rovatirelin may have an orally effective therapeutic potential in patients with SCD.

Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.

PATENT

WO 9808867

PATENT

WO 9945000 

PATENT

WO 2002017954

Example

Preparation of the compound represented by Example 1 set (IX)

The second step

Two

(First step)

Method described in the literature (Synth. Commun., 20, 3507 (1990)) synthesized N- in (tert- butoxide deer Lupo sulfonyl) one 3- (4 one-thiazolyl) one L Aranin (1, 21.79 g, 80 mmol) in Torifuruoro and the mixture was stirred acetic acid (80 ml) were added under ice-cooling for 2 hours and a half. Then stirred for 30 minutes at room temperature was added to the reaction mixture p- toluenesulfonic acid hydrate (15.22 g, 80 mmol). The reaction mixture was concentrated to dryness under reduced pressure. To remove excess Torifuruoro acetic acid by the obtained residue concentrated to dryness under reduced pressure by addition of water and methanol.Obtained obtained residue was collected by filtration crystals ether was added to precipitate the compound (2) 29.8 g (quantitative).

NMR (CD 3 OD): 9.01 (1H, d-, J = 1.8 Hz), 7.70 (2H ; yd), 7.46 (lH, d-, J = 1.8 Hz), 7.23 (2H, yd), 4.38 (1H, dd , J = 4.8 from and 3.8 from Hz), 3.45 (2H ; yd), 2.37 (3H, s).

(Second step)

I 匕合 product (2) 38.85 g E evening Nord (200 ml) of (112.8 mmol) – in THF (600 ml) solution, diphenyl di § zone methane while 攪袢 at room temperature (39 g, 201 mmol) in small portions over 30 minutes were added. The reaction mixture was stirred for 1 hour at room temperature, Ziv E sulfonyl di § zone methane (10 g, 51.5 mmol) was added and stirred for one hour. To the reaction mixture

After decomposing the excess reagent by the addition of acetic acid (0.1 ml), it was concentrated to dryness under reduced pressure and distilled off the solvent. The resulting residue (92 g) with ether (1 L) was crystallized to give compound (3) 49.05 g (96.1%).

mp: 139-140 ° C

[A] D = -34.7 ° (C = 1.006, CHC1 3) 23 ° C)

^ Cm IRCKB ” 1 : 1753, 1602, 1512, 1496, 1260, 1224, 1171, 1124, 1036, 1012. NMR (CD 3 0D): 8.92 (1H, D, J = 2 Hz), 7.70 (2H ; M ), 7.2-7.4 (13H, m) , 6.91 (1H, s), 4.62 (1H, t, J = 5.8 Hz), 3.47 (2H, d, J = 5.8 Hz), 2.36 (3H, s).

Elemental analysis (C 2E H 2S N 2 0 5 S 2 )

Calculated: C, 61.16; H, 5.13; N, 5.49; S, 12.56.

Measured value: C, 61.14; H, 5.32; N, 5.41; S, 12.46.

(Third step)

Cis-one L one 5-methyl-2-one O Kiso O Kisa ethylbenzthiazoline one 4-carboxylic acid 13.95 g (96.14 mmol), compound (3) 49.09 g (96.14 mmol ), N-hydroxybenzotriazole To Riazoru 2.6 g (19.23 mmol) and under ice-cooling in THF (1L) solution of Toryechiruamin 14.1 ml (lOlmmol), was added to the DCC (20.83g, 101 mmol). The cooling bath was removed after stirring for 10 minutes at the same temperature, and stirred for an additional 2 0 hours at room temperature. After removing the precipitated precipitate and the filtrate concentrated to dryness under reduced pressure an oily residue (82.7 g was obtained). The residue was filtered off and dissolved by heating to insoluble matter in acetic acid Echiru (700 ml). The filtrate was successively washed with sodium carbonate aqueous solution and water.After the addition of methanol (20 ml) the organic layer was dried with sulfuric acid mug Neshiumu, was concentrated to a small volume under reduced pressure.Precipitated collected by filtration and acetic acid E Ji Le crystals – ether (2: 3) washing to compound with a mixture (4) 35.69 g (79.8% ) was obtained. After addition was concentrated to dryness under reduced pressure of the mother liquor, and crystallized from acetic acid E Chiru ether mixture compound (4) 2.62 g (5.9% ) was obtained.

mp: 176-177 ° C

[A] D = -39.2 ° (C = 1.007, CHC1 3 , 24 ° C)

^ Cm IRiKB 1 : 1739, 1681, 1508, 1453, 1386, 1237, 1193, 1089.

NMR (CDC1 3 ): 8.71 (1H, d-, J = 1.8 Hz), 8.18 (lH, d-‘J = 3.9 from Hz), 7.2-7.4 (10H ; yd), 6.82 (1H, s), 6.66 (1H, d-, J = 1.8 Hz), 5.79 (1H, s), 5.12 (1H, yd), 4.94 (lH, yd), 4.35 (1H ; dd, J = 1.8 and 4.5 from Hz), 3.40 (1H ; dd, J 5.7 and 15 = Hz), 3.29 (1H ; dd, J = 4.5 of and 15 Hz), 1.27 (3H, d-, J = 6.3 Hz).

Elemental analysis (C 24 H 23 N 3 0 5 S)

Calculated: C, 61.92; H, 4.98; N, 9.03; S, 6.89.

Measured value: C ! 61.95; H, 5.01; N, 8.94; S ) 6.62.

(Fourth step)

Compound (4) 41.24 under ice-cooling to g (88.59 mmol), and the mixture was stirred Anisoru (240ml) and To Rifuruoro acetic acid (120 ml) and the mixture for 15 minutes. And the mixture was stirred for 2 hours 3 0 minutes further room temperature after removal of the cooling bath. The reaction mixture was added to the E one ether (500 ml) to the oily residue obtained by concentrated to dryness under reduced pressure was collected by filtration and pulverized. The resulting powder is water (50 ml) – was removed by filtration methanol (300 ml) warming dissolved insoluble matter in a mixture. The filtrate was concentrated to small volume under reduced pressure, and allowed to stand at room temperature for 3 days adding a seed crystal and methanol. The precipitated crystals were obtained Shi preparative filtration compound (5) 14.89 g (56.1%). The mother liquor was concentrated to dryness under reduced pressure, to give again further compound was crystallized from methanol one ether mixture of the (5) 10.3 g (38%). mp: 214-215 ° C

[]. -4.2 ° = (C = 0.5, H 2 0, 22 ° C)

^ Cm IRCKB 1 : 1753, 1707, 1655, 1548, 1529, 1409, 1343, 1264, 1236, 1102, 1092. NMR (DMS0-D6): 9.02 (1H, D, J = 1.8 Hz), 8.46 (1H, d- ; J = 3.9 from Hz), 7.74 (1H, s),

7.38 (1H, d, J = 1.8 Hz), 4.77 (1H, dq, J = 6.6 and 8.7 Hz), 4.66 (1H, m), 4.21 (1H, d,

J = 8.7 Hz), 3.24 (IH, dd, J = 5.1 and 15 Hz), 3.13 (1H, dd, J = 8.4 and 15 Hz),

1.13 (3H, d, J = 6.6 Hz).

Elemental analysis (C U H 13 N 3 0 5 S)

Calculated: C ; 44.14; H, 4.38; N, 14.04; S ) 10.71.

Measured value: C, 43.94; H, 4.478; N, 14.09; S, 10.58.

(Fifth step)

Compound (5) 12.1 g, (40.48 mmol) and N- hydroxysuccinimide (4.66 g, 40,48 mM) under ice-cooling to THF (242 ml) suspension of,: DCC (8.35 g, 40.48 mmol) was added to 3 and the mixture was stirred for 10 minutes. The cooling bath was removed, and the mixture was further stirred at room temperature for 2 hours. The resulting compound N- hydroxysuccinimide ester solution of (5) was synthesized in a way described in the literature (Tetrahedron, 27, 2599 (1971 )) (R) – (+) – 2- Mechirupiro lysine hydrochloride (5.42 g) and Toryechiruamin (8.46 ml, was added at room temperature to THF (121 ml) suspension of 60.72 mmol). The reaction mixture was stirred for an additional 1 5 hrs. The filtrate after removal of the insoluble matter that has issued analysis was concentrated to dryness under reduced pressure. Residue (24.6 Ga) the insoluble material was removed by filtration was dissolved in water (150 ml). The filtrate was purified by gel filtration column chromatography one (MCI Gel CHP-20P, 600 ml). 4 0% aqueous methanol solution compound of the collected crude eluted cut off fractionated (IX) was obtained 8.87 g. Then after purification by silica gel column chromatography (black port Holm one methanol mixture), to give the compound was freeze-dried (IX) 5.37 g (35.7% ).

mp: 192-194 ° C

[A] D = -1.9 ° (C = 1.005, H 2 0, 25 ° C)

KB Cm- IR 1 : 1755, 1675, 1625, 1541, 1516, 1448, 1232, 1097.

NMR (CD 3 0D): 8.97 (1H, t, J = 2.1 Hz), 7.34 (1H, t, J = 2.1 Hz), 5.19 and 5.04 (total the IH, the each t, J = 7.5 Hz), 4.92 (1H , Dq, J = 6.6 And 8.7 Hz), 4.36 And 4.35 (1H, D, J = 8.7 Hz), 4.07 And 3.92 (Total IH, Eac M), 3.78 (1H ; M), 3.42 (1¾ M), 3.22 (2H, m), 1.5-2.0 ( 4H, m), 1.28 and 1.22 (total 3H, each d, J = 6.6 Hz), 1.21 and 1.02 (total 3H, each d, J = 6.6 Hz).

Elemental analysis (C 16 H 22 N 4 0 4 S H 2 0)

Calculated: C, 49.99; H, 6.29; N, 14.57; S, 8.34.

Measured value: C, 49.99; H, 6.29; N, 14.79; S, 8.36.

PATENT

WO 2006028277

Example

Example 1

B

Figure imgf000007_0001

Step 1 l-N-[N<tert-butoxycarbonyl)-3-(^^^

N.N-dicyclohexylcarbodiimide (10.83 g, 52.5 mmol), N-hydroxybenzotriazole (2.03 g, 15 mmol) and triethylamine (7.7 ml, 55.2 mmol) were added to a solution (130 ml) of N-(tert-butoxycarbonyl)-3-(thiazol-4-yl)-L-alanine (1) (13.62 g, 50 mmol) obtained by the method described in literatures (J. Am. Chem. Soc. 73, 2935 (1951) and Chem. Pharm. Bull. 38, 103 (1950)) and 2(R)-2-methylpyrrolidine p-toluenesulfonic acid (2) (12.79 g, 50 mmol) obtained by the method described in a literature (HeIv. Chim. Acta, 34, 2202 (1951)) in tetrahydrofuran. The mixture was stirred for 20 hours at room temperature. After the precipitates are filtered off, the obtained filtrate was concentrated under reduced pressure. Thus-obtained residue was dissolved in ethyl acetate (200 ml) and the solution were washed with an aqueous solution of sodium hydrogencarbonate and water, successively. The organic layers were dried over magnesium sulfate and concentrated under reduced pressure to give a title compound (3) (16.45 g, 100%) as oil.

NMR (CDCl3): OH 8.76 and 8.75 (1 H, each d, J=2.1Hz, Thia-H-2), 7.08 (1 H, d, J=2.fflz, thia-H-5), 5.45 (1 H, m, NH), 3.45-3.64 (1 H, m, AIa-CoH), 4.14 and 3.81 (1 H, each m, Pyr-CαH), 3.51 (1 H, m, PVr-NCH2), 3.1-3.4 (3 H, m, Pyr-CH2and AIa-CH2), 1.39 (9 H, s, BOC), 1.3-2.0 (4 H, m, PyT-CH2), 1.06 (3 H, d, J=6Hz, Pyr-Me)

Step 2 l-N-[3-(thiazol-4-yl)-L-alanyl]-(2R)-2-methylpyrroHdine di-p-toluenesulfcnate (4)

Compound (3) (33.77 g, 99.48 mmol) and p-toluenesulfonic acid hydrate (37.85 g, 199 mmol) were dissolved in ethyl acetate (101 ml) and the solution was cooled with ice. To the mixture, 4 mol/L solution of hydrogen chloride-ethyl acetate (125 ml) was added, and the mixture was stirred for 2 hours 45 minutes. After the mixture was concentrated under reduced pressure, methanol was added to the residue. The mixture was concentrated. Methanol-toluene (1: 1) was added to the residue and concentrated under reduced pressure to give crystalline residue. The residue was washed with acetone and filtered to give compound (4) as crystals (36 g, 62%). After the mother liquor was concentrated under reduced pressure, methanol and toluene were added to the residue and concentrated. Obtained crystalline residue was washed with acetone to give compound (4) (10.67 g, 18.4%). mp 188-189 0C [α]D 24 +2.2 (c, 1.0, MeOH) IR(KBr)Cm“1: 3431, 3125, 3080, 2963, 1667, 1598, 1537, 1497, 1451, 1364, 1229, 1198, 1170, 1123, 1035, 1011.

NMR (CD3OD): δH 9.04 and 9.03 (1 H, each d, J=2.1Hz, Thia-H-2), 7.70 (2 H, m, aromaticH), 7.46 (1H, d, J=2.1Hz, thia-H-5), 7.23 (2H, m, aromaticH), 4.49and4.46 (1 H, each d, J=6.9Hz, Ala-CαH), 4.14 and 3.75 (1 H, each m, Pyr-CαH), 3.51 (1 H, m, pyr-NCH2), 3.2-3.4 (3 H, m, PyT-CH2 and AIa-CH2), 2.36 (3 H, s, aromatic Me), 1.3-2.0 (4 H, m, pyr-CH2), 1.19 and 1.07 (3 H, each d, J=6.3Hz, Pyr-Me) Anal Calcd For C11H17N3OS 2C7H8O3S Calculated: C, 51.44%; H1 5.70%; N, 7.20%; S, 16.48%. Found: C, 51.36%; H, 5.69%; N, 7.23%; S, 16.31%.

Step 3 l-[N-[(4S,5S)-(5-methyl-2-oxooxazolidin-4-yl)carbonyl]-3-(thiazol-4-yl)-L-alanyl-(2R)-2- methylpyrrolidine trihydrate (I- 1) Step 3 (1) Method A

(4S, 5S)-5-methyl-2-oxooxazolidin-4-yl carboxylic acid (5) (1.368 g, 9.43 mmol) obtained by the method described in literatures (J. Chem. Soc. 1950, 62; Tetrahedron 48; 2507 (1992) and Angew. Chem. 101, 1392 (1989)), Compound (4) (5 g, 8.56 mmol) and N-hydiOxysuccinimide (217 mg, 1.89 mmol) were dissolved in N, N-dimethylformamide (10 ml), and tetrahydrofuran (65 ml) was added. After the mixture was cooled with ice in a cool bath, triethylamine (2.63 ml, 18.86 mmol) and N, N-dicyclohexylcarbodiimide (2.04 g, 9.89 mmol) were added with stirred and the mixture was stirred for additional 30 minutes. The cooling bath was removed and the mixture was stirred for 15 hours at room temperature. The precipitated were filtered off and the filtrate was concentrated under reduced pressure. Water (100 ml) was added to thus-obtained residue (9.95 g) and the mixture was stirred for 1.5 hours at room temperature. After insoluble substance was filtered off, the filtrate was concentrated until it was reduced to about half volume under reduced pressure. The small amount of insoluble substance was filtered off and the filtrate was concentrated until it was reduced to about 2O g under reduced pressure. After the mixture was allowed to stand in a refrigerator for 3 days, the precipitated crystals (2.98 g) were collected by filtration and washed with cold water. The filtrate was extracted twice with chloroform, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (5 ml) was added to oil residue (1.05 g) and the mixture was stirred to give crystals (136 mg). The obtained crystals were combined and dissolved in purified water (45 ml) with heating. After the solution was allowed to cool to room temperature, the precipitated insoluble substance was filtered off The filtrate was concentrated under reduced pressure and allowed to stand at room temperature overnight. The mixture was cooled with ice, and the crystals were collected by filtration to give Compound (1-1, 2.89 g, 80.3%). mp 194-196 0C

[α]D 22 -2.0 ± 0.4 ° (c, 1.008, H2O), [α]365 +33.1 ± 0.7 ° (c, 1.008, H2O)

IR(Nujor)cm”1: 3517, 3342, 3276, 3130, 3092, 3060, 1754, 1682, 1610, 1551, 1465, 1442,

1379, 1235, 1089. NMR(CD3OD): δH 8.97 and 8.96 (total 1 H, d, J=2.1Hz, Thia-H-2), 7.34 and 7.33 (total 1

H, d, J=2.1Hz, Thia-H-5), 5.18 and 5.04 (total 1 H, each t, J=7.5Hz, Ala-CαH), 4.92 (1

H, dq, J=6.6 and 8.7Hz, Oxa-H-5), 4.36 and 4.35 (total 1 H, d, J=8.7Hz, Oxa-H-4), 4.07 and 3.92 (total 1 H, each m, Pyr-Cα-H), 3.78 (1 H, m, Pyr-NCH2), 3.42 (1 H, m, Pyr- 5 NCH2), 3.22 (2 H, m, AIa-CH2), 1.5-2.0 (4 H, m, Pyr-CH2), 1.28 and 1.22 (total 3 H, each d, J=6.6Hz, Oxa-5-Me), 1.21 and 1.02 (total 3 H, each d, J=6.6Hz, Pyr-2-Me)

Anal. Calcd For C16H22N4O4S 3H2O

Calculated: C, 45.00%; H, 6.71%; N, 13.33%; S, 7.63%.

Found: C, 45.49%; H, 6.60%; N, 13.58%, S, 7.88%. 10

Step 3 (2)

Method B

After Compound (1-2) (410 g, 1.119 mmol) was dissolved in purified water (6.3 L) with heating, the solution was concentrated until the total weight of the mixture was 15 reduced to 1370 g under reduced pressure. The concentrated solution was allowed to stand at room temperature overnight. The solution was cooled with ice for 1 hour and filtered to give the precipitated crystals. The obtained crystals were washed with cold water to give

Compound (T- 1) (448 g, 95.2%) as colorless crystals. Mother liquor was mixed with purified water (300 mL) with heating and the solution was concentrated to 55 g under reduced pressure. 20 After the concentrated solution was allowed to stand at room temperature overnight, the solution was filtered to give the precipitated crystals (T-1, 16.3 g, 3.5%, total amount 464.3 g, 98.7%). mp 194-196 0C

[α]D 22 -0.9 ± 0.4 ° (c, 1.007, H2O), [α]365 + 35.4 ± 0.8 ° (c, 1.007, H2O)

IR(NuJOr)Cm“1: 3511, 3348, 3276, 3130, 3093, 3060, 1755, 1739, 1682, 1611, 1551, 1465, 25. 1442, 1379, 1235, 1089.

AnalCalcdFor: C16H22N4O4S 3H2O

Calculated: C, 45.00%;H, 6.71%;N, 13.33%; S, 7.63%.

Found: C, 45.56%; H, 6.66%; N, 13.43%, S, 7.69%.

30 Step 4 l-[N-[(4S)5S)-(5-methyl-2-oxooxazolidin-4-yl)carbonyl]-3-(thiazol-4-yl)-L-alanyl-(2R)-2- methylpyrrolidine (1-2)

Method A

After l-[N-[(4S,5S)-(5-methyl-2-oxooxazolidin-4-yl)carbonyl]-3-(thiazol-4-yl)-L- 35 alanyl-(2R)-2-methylpyrrolidine monohydrate (4.77 g) obtained by the method described in Patent Literature 8 was crushed in a mortar, it was dried under reduced pressure (66.5 Pa) at 100 0C for 15 hours to give 4.54 g of Compound (1-2). mp 194.5-196.5 0C [α]D 25 -2.1 +. 0.4 ° (c, 1.004, H2O), [α]365 +36.8 ± 0.8 ° (c, 1.004, H2O) Water measurement (Karl Fischer method): 0.27%

IR(NuJOr)Cm”1: 3276, 3180, 3104, 1766, 1654, 1626, 1548, 1517, 1457, 1380, 1235, 1102, 979. NMR(CD3OD):δH 8.97 and 8.96 (total 1 H, d, J 2.1 Hz, Thia-H-2), 7.34 and 7.33 (total 1 H, d, J 2.1 Hz, Thia-H-5), 5.19 and 5.04 (total 1 H, each t, J 7.5 Hz, Ala- CaH), 4.92 (1 H, dq, J 6.6 and 8.7 Hz, Oxa-H-5), 4.36 and 4.35 (total 1 H, d, J 8.7 Hz, Oxa-H-4), 4.07 and 3.92 (total 1 H, each m, Pyr-Cα-H), 3.78 (1 H, m, Pyr-NCH2), 3.42 (1 H, m, Pyr-NCH2), 3.22 (2 H, m, AIa-CH2), 1.5-2.0 (4 H, m, Pyr-CH2), 1.28 and 1.22 (total 3 H, each d, J 6.6 Hz, Oxa-5-Me), 1.21 and 1.02 (total 3 H, each d, J 6.6 Hz, Pyr-2-Me). Anal Calcd For: C16H22N4O4S

Calculated: C, 52.44%; H, 6.05%; N, 15.29%; S, 8.75%. Found: C, 52.24%; H, 5.98%; N, 15.27%, S, 8.57%.

Method B

After Compound (1-1) (17.89 g, 47.3 mmol) was crushed in a mortar, it was dried under reduced pressure (66.5 Pa) at 100 °C for 14 hours to give Compound (1-2, 17.31 g). mp 193-194 0C [α]D 25 -1.9 ± 0.4 ° (c, 1.002, H2O), [α]365 +37.2 ± 0.8 ° (c, 1.002, H2O)

Water measurement (Karl Fischer method): 0.22%

IR(NuJOr)Cm“1: 3273, 3180, 3111, 1765, 1685, 1653, 1626, 1549, 1516, 1456, 1346, 1331,

1277, 1240, 1097, 980.

Anal Calcd For C16H22N4O4S Calculated: C, 52.44%; H, 6.05%; N, 15.29%; S, 8.75%.

Found: C, 52.19%; H, 5.98%; N, 15.42%, S, 8.74%.

REFERENCES

1: Ijiro T, Nakamura K, Ogata M, Inada H, Kiguchi S, Maruyama K, Nabekura J,
Kobayashi M, Ishibashi H. Effect of rovatirelin, a novel thyrotropin-releasing
hormone analog, on the central noradrenergic system. Eur J Pharmacol. 2015 Aug
15;761:413-22. doi: 10.1016/j.ejphar.2015.05.047. Epub 2015 Jul 2. PubMed PMID:
26142830.

////////Rovatirelin Hydrate, S-0373, Rovatirelin, 204386-76-5, clinical, phase 3

C[C@@H]1CCCN1C(=O)[C@H](Cc2cscn2)NC(=O)[C@@H]3[C@@H](OC(=O)N3)C

Difelikefalin


img

Difelikefalin, CR-845; MR-13A-9; MR-13A9

4-amino-1- (D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl) piperidine-4-carboxylic acid

Phase III

C36H53N7O6, 679.40573

Originator Ferring Pharmaceuticals
Developer Cara Therapeutics
Class Analgesic drugs (peptides)
Mechanism Of Action Opioid kappa receptor agonists
Who Atc Codes D04A-X (Other antipruritics), N02A (Opioids)
Ephmra Codes D4A (Anti-Pruritics, Including Topical Antihistamines, Anaesthetics, etc), N2A (Narcotics)
Indication Pain, Osteoarthritis, Pruritus

A kappa opioid receptor agonist potentially for treatment of post-operative pain and uremic pruritus.

Difelikefalin, also known CR845, is a novel and potent kappa opioid receptor agonist. CR845 exhibit low P450 CYP inhibition and low penetration into the brain. CR845 may be useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions .

No. CAS 1024828-77-0

2D chemical structure of 1024828-77-0

Difelikefalin ( INN ) (Developmental Code Names CR845 , FE-202845 ), Also Known As D -Phe- D -Phe- D -Leu- D -Lys- [Ganma- (4-N-Piperidinyl) Amino Carboxylic Acid] (As The Acetate Salt ), Is An Analgesic Opioid Peptide [2] Acting As A Peripherally-Specific , Highly Selective Agonist Of The kappa-Opioid Receptor (KOR). [1] [3] [4] [5] It Is Under Development By Cara Therapeutics As An Intravenous Agent For The Treatment Of Postoperative Pain . [1] [3] [5] An Oral Formulation Has Also Been Developed. [5] Due To Its Peripheral Selectivity, Difelikefalin Lacks The Central Side Effects Like Sedation , Dysphoria , And Hallucinations Of Previous KOR-Acting Analgesics Such As Pentazocine And Phenazocine . [1] [3] In Addition To Use As An Analgesic, Difelikefalin Is Also Being Investigated For The Treatment Of Pruritus (Itching). [1] [3] [4 ] Difelikefalin Has Completed Phase II Clinical Trials For Postoperative Pain And Has Demonstrated Significant And “Robust” Clinical Efficacy, Along With Being Safe And Well-Tolerated. [3] [5] It Is Also In Phase II Clinical Trials For Uremic Pruritus In Hemodialysis Patients. [4]

Difelikefalin Acts As An Analgesic By Activating KORs On Peripheral Nerve Terminals And KORs Expressed By Certain Immune System Cells . [1] Activation Of KORs On Peripheral Nerve Terminals Results In The Inhibition Of Ion Channels Responsible For Afferent Nerve Activity , Causing Reduced Transmission Of Pain Signals , While Activation Of KORs Expressed By Immune System Cells Results In Reduced Release Of Proinflammatory , Nerve-Sensitizing Mediators (Eg, Prostaglandins ). [1]

PATENT

WO 2015198505

κ opioid receptor agonists are known to be useful as therapeutic agents for various pain. Among, kappa opioid receptor agonist with high selectivity for peripheral kappa opioid receptors, are expected as a medicament which does not cause the central side effects. Such as peripherally selective κ opioid receptor agonist, a synthetic pentapeptide has been reported (Patent Documents 1 and 2).
 The following formula among the synthetic pentapeptide (A)
[Formula 1] Being Represented By Compounds Are Useful As Pain Therapeutics. The Preparation Of This Compound, Solid Phase Peptide Synthesis Methods In Patent Documents 1 And 2 Have Been Described.

Document 1 Patent: Kohyo 2010-510966 JP
Patent Document 2: Japanese Unexamined Patent Publication No. 2013-241447
 Compound (1) or a salt thereof and compound (A), for example as shown in the following reaction formula, 4-aminopiperidine-4-carboxylic acid, D- lysine (D-Lys), D- leucine (D-Leu) , it can be prepared by D- phenylalanine (D-Phe) and D- phenylalanine (D-Phe) sequentially solution phase peptide synthesis methods condensation.
[Of 4]

The present invention will next to examples will be described in further detail.
Example
1 (1) Synthesis of Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3)
to the four-necked flask of 2L, α-Boc-Pic- OMe · HCl [α-Boc-4 – aminopiperidine-4-carboxylic acid methyl hydrochloride] were charged (2) 43.7g (148mmol), was suspended in EtOAc 656mL (15v / w). To the suspension of 1-hydroxybenzotriazole (HOBt) 27.2g (178mmol), while cooling with Cbz-D-Lys (Boc) -OH 59.2g (156mmol) was added an ice-bath 1-ethyl -3 – (3-dimethylcarbamoyl amino propyl) was added to the carbodiimide · HCl (EDC · HCl) 34.1g (178mmol). After 20 minutes, stirring was heated 12 hours at room temperature. After completion of the reaction, it was added and the organic layer was 1 N HCl 218 mL of (5.0v / w). NaHCO to the resulting organic layer 3 Aq. 218ML (5.0V / W), Et 3 N 33.0 g of (326Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 218ML 1N (5.0V / W), NaHCO 3 Aq. 218mL (5.0v / w), NaClaq . Was washed successively with 218ML (5.0V / W), Na 2 SO 4 dried addition of 8.74g (0.2w / w). Subjected to vacuum filtration, was concentrated under reduced pressure resulting filtrate by an evaporator, and pump up in the vacuum pump, the Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3) 88.9g as a white solid obtained (96.5% yield, HPLC purity 96.5%).

[0033]
(2) D-Lys (Boc) Synthesis Of -Arufa-Boc-Pic-OMe (4)
In An Eggplant-Shaped Flask Of 2L, Cbz-D-Lys (Boc) -Arufa-Boc-Pic-OMe (3) 88.3g (142mmol) were charged, it was added and dissolved 441mL (5.0v / w) the EtOAc. The 5% Pd / C to the reaction solution 17.7g (0.2w / w) was added, After three nitrogen substitution reduced pressure Atmosphere, Was Performed Three Times A Hydrogen Substituent. The Reaction Solution Was 18 Hours With Vigorous Stirring At Room Temperature To Remove The Pd / C And After The Completion Of The Reaction Vacuum Filtration. NaHCO The Resulting Filtrate 3 Aq. 441ML And (5.0V / W) Were Added For Liquid Separation, And The Organic Layer Was Extracted By The Addition Of EtOAc 200ML (2.3V / W) In The Aqueous Layer. NaHCO The Combined Organic Layer 3 Aq. 441ML And (5.0V / W) Were Added for liquid separation, and the organic layer was extracted addition of EtOAc 200mL (2.3v / w) in the aqueous layer. NaClaq the combined organic layers. 441mL and (5.0v / w) is added to liquid separation, was extracted by the addition EtOAc 200ML Of (2.3V / W) In The Aqueous Layer. The Combined Organic Layer On The Na 2 SO 4 Dried Addition Of 17.7 g of (0.2W / W), Then The Filtrate Was Concentrated Under Reduced Pressure Obtained Subjected To Vacuum Filtration By an evaporator, and pump up in the vacuum pump, D-Lys (Boc) -α-Boc-Pic- OMe (4) to give 62.7g (90.5% yield, HPLC purity 93.6%).
(3) Cbz-D-Leu -D-Lys (Boc) -α-Boc-Pic-OMe synthesis of (5)
in the four-necked flask of 2L, D-Lys (Boc) -α-Boc-Pic-OMe (4) was charged 57.7 g (120 mmol), was suspended in EtOAc 576mL (10v / w). HOBt 19.3g (126mmol) to this suspension, was added EDC · HCl 24.2g (126mmol) while cooling in an ice bath added Cbz-D-Leu-OH 33.4g (126mmol). After 20 minutes, after stirring the temperature was raised 5 hours at room temperature, further the EDC · HCl and stirred 1.15 g (6.00 mmol) was added 16 h. After completion of the reaction, it was added liquid separation 1N HCl 576mL (10v / w) . NaHCO to the resulting organic layer 3 Aq. 576ML (10V / W), Et 3 N 24.3 g of (240Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 576ML 1N (10V / W), NaHCO 3 Aq. 576mL (10v / w), NaClaq . Was washed successively with 576ML (10V / W), Na 2 SO 4 dried addition of 11.5g (0.2w / w). After the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and pump up in the vacuum pump, the Cbz-D-Leu-D- Lys (Boc) -α-Boc-Pic-OMe (5) 85.8g It was obtained as a white solid (98.7% yield, HPLC purity 96.9%).
(4) D-Leu-D -Lys (Boc) -α-Boc-Pic-OMe synthesis of (6)
in an eggplant-shaped flask of 1L, Cbz-D-Leu- D-Lys (Boc) -α-Boc-Pic -OMe the (5) 91.9g (125mmol) were charged, was added and dissolved 459mL (5.0v / w) the EtOAc. The 5% Pd / C to the reaction solution 18.4g (0.2w / w) was added, After three nitrogen substitution reduced pressure atmosphere, was performed three times a hydrogen substituent. The reaction solution was subjected to 8 hours with vigorous stirring at room temperature to remove the Pd / C and after the completion of the reaction vacuum filtration. NaHCO the resulting filtrate 3 Aq. 200mL (2.2v / w) were added to separate liquid, NaHCO to the organic layer 3 Aq. 200mL (2.2v / w), NaClaq . It was sequentially added washed 200mL (2.2v / w). To the resulting organic layer Na 2 SO 4 dried added 18.4g (0.2w / w), to the filtrate concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and a pump-up with a vacuum pump. The resulting amorphous solid was dissolved adding EtOAc 200mL (2.2v / w), was crystallized by the addition of heptane 50mL (1.8v / w). Was filtered off precipitated crystals by vacuum filtration, the crystals were washed with a mixed solvent of EtOAc 120mL (1.3v / w), heptane 50mL (0.3v / w). The resulting crystal 46.1g to added to and dissolved EtOAc 480mL (5.2v / w), was crystallized added to the cyclohexane 660mL (7.2v / w). Was filtered off under reduced pressure filtered to precipitate crystals, cyclohexane 120mL (1.3v / w), and washed with a mixed solvent of EtOAc 20mL (0.2v / w), and 30 ° C. vacuum dried, D-Leu- as a white solid D-Lys (Boc) -α- Boc-Pic-OMe (6) to give 36.6 g (48.7% yield, HPLC purity 99.9%).
(5) Synthesis of Cbz-D-Phe-D- Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7)
to the four-necked flask of 1L, D-Leu-D- Lys (Boc) -α-Boc-Pic-OMe with (6) 35.8g (59.6mmol) was charged, it was suspended in EtOAc 358mL (10v / w). To this suspension HOBt 9.59g (62.6mmol), Cbz- D-Phe-OH 18.7g was cooled in an ice bath is added (62.6mmol) while EDC · HCl 12.0g (62.6mmol) It was added. After 20 minutes, a further EDC · HCl After stirring the temperature was raised 16 hours was added 3.09 g (16.1 mmol) to room temperature. After completion of the reaction, it was added and the organic layer was 1N HCl 358mL of (10v / w). NaHCO to the resulting organic layer 3 Aq. 358ML (10V / W), Et 3 N 12.1 g of (119Mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer HCl 358ML 1N (10V / W), NaHCO 3 Aq. 358mL (10v / w), NaClaq . Was washed successively with 358ML (10V / W), Na 2 SO 4 dried addition of 7.16g (0.2w / w). After the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, and pump up in the vacuum pump, Cbz-D-Phe-D -Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7) was obtained 52.5g as a white solid (yield quant, HPLC purity 97.6%).
(6) D-Phe-D -Leu-D-Lys (Boc) synthesis of -α-Boc-Pic-OMe ( 8)
in an eggplant-shaped flask of 2L, Cbz-D-Phe- D-Leu-D-Lys ( Boc) -α-Boc-Pic- OMe (7) the 46.9g (53.3mmol) were charged, the 840ML EtOAc (18V / W), H 2 added to and dissolved O 93.8mL (2.0v / w) It was. The 5% Pd / C to the reaction mixture 9.38g (0.2w / w) was added, After three nitrogen substitution reduced pressure atmosphere, was performed three times a hydrogen substituent. The reaction solution was subjected to 10 hours with vigorous stirring at room temperature to remove the Pd / C and after the completion of the reaction vacuum filtration. NaHCO the resulting filtrate 3 Aq. 235mL (5.0v / w) were added to separate liquid, NaHCO to the organic layer 3 Aq. 235mL (5.0v / w), NaClaq . It was added sequentially cleaning 235mL (5.0v / w). To the resulting organic layer Na 2 SO 4 dried addition of 9.38g (0.2w / w), then the filtrate was concentrated under reduced pressure obtained subjected to vacuum filtration by an evaporator, pump up with a vacuum pump to D-Phe -D-Leu-D-Lys ( Boc) -α-Boc-Pic-OMe (7) was obtained 39.7g (yield quant, HPLC purity 97.3%).
351mL was suspended in (10v / w). To this suspension HOBt 7.92g (51.7mmol), Boc-D-Phe-OH HCl HCl
(8) D-Phe-D -Phe-D-Leu-D-Lys-Pic-OMe Synthesis Of Hydrochloric Acid Salt (1)
In An Eggplant-Shaped Flask Of 20ML Boc-D-Phe-D -Phe-D- Leu-D- lys (Boc) -α -Boc- Pic-OMe (9) and 2.00gg, IPA 3.3mL (1.65v / w), was suspended by addition of PhMe 10mL (5v / w). It was stirred at room temperature for 19 hours by addition of 6N HCl / IPA 6.7mL (3.35v / w). The precipitated solid was filtered off by vacuum filtration and dried under reduced pressure to a white solid of D-Phe-D-Phe- D- Leu-D-Lys-Pic- OMe 1.59ghydrochloride (1) (yield: 99 .0%, HPLC purity 98.2%) was obtained.
(9) D-Phe-D -Phe-D-Leu-D-Lys-Pic-OMe Purification Of The Hydrochloric Acid Salt (1)
In An Eggplant-Shaped Flask Of 20ML-D-Phe-D- Phe D-Leu -D-Lys- pic-OMe hydrochloride crude crystals (1) were charged 200mg, EtOH: MeCN = 1: after stirring for 1 hour then heated in a mixed solvent 4.0 mL (20v / w) was added 40 ° C. of 5 , further at room temperature for 2 was time stirring slurry. Was filtered off by vacuum filtration, the resulting solid was dried under reduced pressure a white solid ((1) Purification crystals) was obtained 161 mg (80% yield, HPLC purity 99.2% ).
(10) D-Phe-D -Phe-D-Leu-D-Lys-Pic Synthesis (Using Purified
(1)) Of (A) To A Round-Bottomed Flask Of 10ML D-Phe-D-Phe-D- -D-Lys Leu-Pic-OMe Hydrochloride Salt (1) Was Charged With Purified Crystal 38.5Mg (0.0488Mmol), H 2 Was Added And Dissolved O 0.2ML (5.2V / W). 1.5H Was Stirred Dropwise 1N NaOH 197MyuL (0.197mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 48.8μL (0.0488mmol), to obtain a D-Phe-D-Phe- D-Leu-D-Lys- Pic (A) (yield: quant , HPLC purity 99.7%).

D-Phe-D-Phe- D-Leu-D-Lys-Pic-OMe (1) physical properties 1 H NMR (400 MHz, 1M DCl) [delta] ppm by: 0.85-1.02 (yd,. 6 H), 1.34-1.63 ( m, 5 H), 1.65-2.12 ( m, 5 H), 2.23-2.45 (m, 2 H), 2.96-3.12 (m, 4 H), 3.19 (ddt, J = 5.0 & 5.0 & 10.0 Hz), 3.33-3.62 (m, 1 H), 3.68-3.82 (m, 1 H), 3.82-3.95 (m, 4 H), 3.95-4.18 (m, 1 H), 4.25-4.37 (m, 2 H), 4.61-4.77 (M, 2 H), 7.21-7.44 (M, 10 H) 13 C NMR (400MHz, 1M DCl) Deruta Ppm: 21.8, 22.5, 24.8, 27.0, 30.5, 30.8, 31.0, 31.2, 31.7, 37.2 , 37.8, 38.4, 39.0, 39.8, 40.4, 40.6, 41.8, 42.3, 49.8, 50.2, 52.2, 52.6, 54.6, 55.2, 57.7, 57.9, 127.6, 128.4, 129.2, 129.6, 129.7, 129.8 dp 209.5 ℃

Example 2
(Trifluoroacetic Acid (TFA)
Use) (1) D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe TFA Synthesis Of Salt (1)
TFA 18ML Eggplant Flask Of 50ML (18V / W) , 1- Dodecanethiol 1.6ML (1.6V / W), Triisopropylsilane 0.2ML (0.2V / W), H 2 Sequentially Added Stirring The O 0.2ML (0.2V / W) Did. The Solution To The Boc-D-Phe- D- Phe-D-Leu-D -Lys (Boc) -α-Boc-Pic-OMe the (9) 1.00g (1.01mmol) was added in small portions with a spatula. After completion of the reaction, concentrated under reduced pressure by an evaporator, it was added dropwise the resulting residue in IPE 20mL (20v / w). The precipitated solid was filtered off, the resulting solid was obtained and dried under reduced pressure to D-Phe-D-Phe- D-Leu -D-Lys-Pic-OMe · TFA salt as a white solid (1) (Osamu rate 93.0%, HPLC purity 95.2%).
(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic synthesis of (A)
to a round-bottomed flask of 10mL D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe TFA were charged salt (1) 83mg (0.0843mmol), was added and dissolved H2O 431μL (5.2v / w). Was 12h stirring dropwise 1N NaOH 345μL (0.345mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 84.3μL (0.0843mmol), to obtain a D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) ( yield: quant, HPLC purity 95.4%).
Example
3 (HCl / EtOAc
Use) (1) In An Eggplant-Shaped Flask Of 30ML Boc-D-Phe-D -Phe-D-Leu-D-Lys (Boc) -Arufa-Boc-Pic-OMe (9) 1. It was charged with 00g (1.01mmol ), was added and dissolved EtOAc7.0mL (7.0v / w). 4N HCl / EtOAc 5.0mL (5.0v / w) was added after 24h stirring at room temperature, the precipitated solid was filtered off by vacuum filtration, washed with EtOAc 2mL (2.0v / w). The resulting solid D-Phe-D-Phe- D-Leu-D-Lys-Pic-OMe hydrochloride (1) was obtained 781mg of a white solid was dried under reduced pressure (the 96.7% yield, HPLC purity 95.4%).
(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic (A) Synthesis of
eggplant flask of 10mL D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe hydrochloride were charged salt (1) 90 mg (0.112 mmol), H 2 was added and dissolved O 0.47mL (5.2v / w). Was 12h stirring dropwise 1N NaOH 459μL (0.459mmol) at room temperature. After completion of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 0.112μL (0.112mmol), was obtained D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) ( yield: quant, HPLC purity 93.1%).
4 Example
Compound (1) Of The Compound By Hydrolysis Synthesis Of (The A) (Compound (1) Without
Purification) Eggplant Flask 10ML D-Phe-D-Phe -D-Leu-D-Lys-Pic-OMe (1) Charged Hydrochloride Were (Without Pre-Step Purification) 114.5Mg (0.142Mmol), H 2 Was Added And Dissolved O 595MyuL (5.2V / W). Was 14H Stirring Dropwise 1N NaOH 586MyuL (0.586Mmol) At Room Temperature. After Completion Of the reaction, concentrated under reduced pressure by an evaporator added 1N HCl 0.15μL (0.150mmol), was obtained D-Phe-D-Phe- D-Leu-D-Lys-Pic (A) (yield: quant, HPLC purity 95.2 %).
Example 1 Comparative
Path Not Via The Compound (1) (Using Whole Guard Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -Alpha-Boc-Pic-OMe
(A)) (1) D–Boc Phe- D-Phe-D-Leu-D-Lys (Boc) -Arufa-Boc-Pic-OH Synthesis Of
Eggplant Flask Of 30ML Boc-D-Phe-D -Phe-D-Leu-D- Lys (Boc) -α- Boc-Pic -OMe (9) were charged 1.00g (1.00mmol), was added and dissolved MeOH 5.0mL (5.0v / w). After stirring for four days by the addition of 1N NaOH 1.1 mL (1.10mmol) at room temperature, further MeOH 5.0mL (5.0v / w), 1N NaOH 2.0mL the (2.0mmol) at 35 ℃ in addition 3h and the mixture was stirred. After completion of the reaction, 1 N HCl 6.1 mL was added, After distilling off the solvent was concentrated under reduced pressure was separated and the organic layer was added EtOAc 5.0mL (5.0mL) .NaClaq. 5.0mL (5.0v / w) Wash the organic layer was added, the organic layer as a white solid was concentrated under reduced pressure to Boc-D-Phe-D- Phe-D-Leu-D-Lys (Boc) – α-Boc-Pic-OH 975.1mg (99.3% yield, HPLC purity 80.8% )
(2) D-Phe-D -Phe-D-Leu-D-Lys-Pic synthesis of (A)
to a round-bottomed flask of 20mL Boc-D-Phe-D -Phe-D-Leu-D-Lys (Boc) It was charged -α-Boc-Pic-OH ( 10) 959mg (0.978mmol), was added and dissolved EtOAc 4.9mL (5.0v / w). And 4h stirring at room temperature was added dropwise 4N HCl / EtOAc 4.9mL (5.0mL) at room temperature. After completion of the reaction, it was filtered under reduced pressure, a white solid as to give D-Phe-D-Phe- D-Leu-D-Lys-Pic the (A) (96.4% yield, HPLC purity 79.2%) .
 If not via the compound of the present invention (1), the purity of the compound obtained (A) was less than 80%.
PATENT

References

  1.  S. Sinatra Raymond; Jonathan S. Jahr;. J. Michael Watkins-Pitchford (14 October 2010) The Essence Of Analgesia And Analgesics …. Cambridge University Press Pp 490-491 ISBN  978-1-139-49198-3 .
  2.  A Janecka, Perlikowska R, Gach K, Wyrebska A, Fichna J (2010) “Development Of Opioid Peptide Analogs For Pain Relief”.. Curr Pharm Des… 16 (9):. 1126-35 Doi : 10.2174 / 138161210790963869 . PMID  20030621 .
  3. Apfelbaum Jeffrey (8 September 2014). Ambulatory Anesthesia, An Issue Of Anesthesiology Clinics, . Elsevier Health Sciences. Pp. 190-. ISBN  978-0-323-29934-3 .
  4.  Cowan Alan;. Gil Yosipovitch (10 April 2015) Pharmacology Of Itch …. Springer Pp 307- ISBN  978-3-662-44605-8 .
  5.  Allerton Charlotte (2013). Pain Therapeutics: Current And Future Treatment Paradigms …. Royal Society Of Chemistry Pp 56- ISBN  978-1-84973-645-9 .

REFERENCES

1: Cowan A, Kehner GB, Inan S. Targeting Itch With Ligands Selective For kappa Opioid
. Receptors Handb Exp Pharmacol 2015; 226:.. 291-314 Doi:
.. 10.1007 / 978-3-662-44605-8_16 Review PubMed PMID: 25861786.

Difelikefalin
Difelikefalin.svg
Systematic (IUPAC) Name
Amino–4 1- ( D -Phenylalanyl- D -Phenylalanyl- D -Leucyl- D -Lysyl) Piperidine-4-Carboxylic Acid
Clinical data
Of Routes
Administration
Intravenous
Pharmacokinetic Data
Bioavailability Pasento 100 ( IV ) [1]
Metabolism Metabolized Not [1]
Biological half-life Hours 2 [1]
Excretion As Unchanged Excreted
Drug Via Bile And Urine [1]
Identifiers
CAS Number 1024828-77-0
ATC code None
ChemSpider 44208824
Chemical data
Formula C 36 H 53 N 7 O 6
Molar mass 679.85 g / mol

///// Difelikefalin,  CR845 , FE-202845,  Phase III, PEPTIDES

CC (C) C [C @ H] (C (= O) N [C @ H] (CCCCN) C (= O) N1CCC (CC1) (C (= O) O) N) NC (= O) [ C @@ H] (Cc2ccccc2) NC (= O) [C @@ H] (Cc3ccccc3) N

[18F]AMG 580


STR1

[18F]AMG 580

CAS 1879904-74-1
MF C26 H24 F N5 O3

NOTE………CAS OF AMG 580 IS 1227067-71-1, WITHOUT 18F

AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one],

STR1

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington’s disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography–tandem mass spectrometry technology. [3H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

PAPER

Abstract Image

We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors in the clinic. To find a tracer with higher binding potential (BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washout rate in vivo. Five candidates (26) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines (2, 3) and one keto-benzimidazole (5) exhibited PDE10A target specificity and brain uptake comparable to or better than 1 in the in vivo LC–MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [18F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.

Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies

Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, §Department of Neuroscience, and ΔDepartment of Early Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States
Department of Neuroscience and ±Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States
Department of Molecular Structure and Characterization, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00185
*Phone: 805-313-5300. E-mail: ehu@amgen.com.
STR1

PATENT FOR AMG 580

WO 2010057121

https://www.google.com/patents/WO2010057121A1?cl=en

PAPER

Nuclear Medicine and Biology (2015), 42(8), 654-663.

http://www.sciencedirect.com/science/article/pii/S0969805115000724

Phosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important second messengers for neurotransmission. Inhibition of PDE10A has been identified as a potential target for treatment of various neuropsychiatric disorders. To assist drug development, we have identified a selective PDE10A positron emission tomography (PET) tracer, AMG 580. We describe here the radiosynthesis of [18 F]AMG 580 and in vitro and in vivo characterization results.

AMG 580 has an in vitro KD of 71.9 pM. Autoradiography showed specific uptake in striatum. Mean activity of 121 ± 18 MBq was used in PET studies. In Rhesus, the baseline BPND for putamen and caudate was 3.38 and 2.34, respectively, via 2TC, and 3.16, 2.34 via Logan, and 2.92, and 2.01 via SRTM. A dose dependent decrease of BPNDwas observed by the pre-treatment with a PDE10A inhibitor. In baboons, 0.24 mg/kg dose of AMG 580 resulted in about 70% decrease of BPND. The in vivo KD of [18 F]AMG 580 was estimated to be around 0.44 nM in baboons.

Conclusion

[18 F]AMG 580 is a selective and potent PDE10A PET tracer with excellent specific striatal binding in non-human primates. It warrants further evaluation in humans.

REFERNCES

http://jpet.aspetjournals.org/content/352/2/327.full

///Phosphodiesterasetracer,  receptor occupancy,  positron emission tomographyradiotracer,  brain penetrationAMG 580, Phosphodiesterase 10A, PDE10A, PET Tracer, [18F]AMG 580

FDA approves new diagnostic imaging agent FLUCICLOVINE F-18 to detect recurrent prostate cancer


FLUCICLOVINE F-18

Cyclobutanecarboxylic acid, 1-amino-3-(fluoro-18F)-, trans- [

  • Molecular FormulaC5H818FNO2
  • Average mass132.124 Da
Axumin (fluciclovine F 18)
fluciclovinum (18F)
GE-148
NMK36
trans-1-Amino-3-(18F)fluorcyclobutancarbonsäure [German] [ACD/IUPAC Name]
trans-1-Amino-3-(18F)fluorocyclobutanecarboxylic acid [ACD/IUPAC Name]
UNII-38R1Q0L1ZE
anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid
cas 222727-39-1
05/27/2016 11:27 AM EDT
The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

May 27, 2016

Release

The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

Prostate cancer is the second leading cause of death from cancer in U.S. men. In patients with suspected cancer recurrence after primary treatment, accurate staging is an important objective in improving management and outcomes.

“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, M.D., Ph.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Axumin is shown to provide another accurate imaging approach for these patients.”

Two studies evaluated the safety and efficacy of Axumin for imaging prostate cancer in patients with recurrent disease. The first compared 105 Axumin scans in men with suspected recurrence of prostate cancer to the histopathology (the study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. Radiologists onsite read the scans initially; subsequently, three independent radiologists read the same scans in a blinded study.

The second study evaluated the agreement between 96 Axumin and C11 choline (an approved PET scan imaging test) scans in patients with median PSA values of 1.44 ng/mL. Radiologists on-site read the scans, and the same three independent radiologists who read the scans in the first study read the Axumin scans in this second blinded study. The results of the independent scan readings were generally consistent with one another, and confirmed the results of the onsite scan readings. Both studies supported the safety and efficacy of Axumin for imaging prostate cancer in men with elevated PSA levels following prior treatment.

Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure to patients and healthcare providers during administration. Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.

The most commonly reported adverse reactions in patients are injection site pain, redness, and a metallic taste in the mouth.

Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom

Patent

http://www.google.com/patents/WO2014023775A1?cl=en

The non-natural amino acid [ F]-l-amino-3-fluorocyclobutane-l-carboxylic acid

([18F]-FACBC, also known as [18F]-Fluciclovine) is taken up specifically by amino acid transporters and has shown promise for tumour imaging with positron emission tomography (PET).

A known synthesis of [18F]-FACBC begins with the provision of the protected precursor compound 1 -(N-(t-butoxycarbonyl)amino)-3 –

[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester. This precursor compound is first labelled with [18F]-fluoride:

II before removal of the two protecting groups:

IT III

EP2017258 (Al) teaches removal of the ethyl protecting group by trapping the [18F]- labelled precursor compound (II) onto a solid phase extraction (SPE) cartridge and incubating with 0.8 mL of a 4 mol/L solution of sodium hydroxide (NaOH). After 3 minutes incubation the NaOH solution was collected in a vial and a further 0.8 mL 4 mol/L NaOH added to the SPE cartridge to repeat the procedure. Thereafter the SPE cartridge was washed with 3 mL water and the wash solution combined with the collected NaOH solution. Then 2.2 mL of 6 mol/L HCl was then added with heating to 60°C for 5 minutes to remove the Boc protecting group. The resulting solution was purified by passing through (i) an ion retardation column to remove Na+ from excess NaOH and Cl~ from extra HCl needed to neutralise excess of NaOH to get a highly acidic solution before the acidic hydrolysis step, (ii) an alumina column, and (iii) a reverse-phase column. There is scope for the deprotection step(s) and/or the

purification step in the production of [18F]-FACBC to be simplified.

Example 1: Synthesis of f FIFACBC

No-carrier- added [18F]fluoride was produced via the 180(p,n)18F nuclear reaction on a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo). Irradiations were performed using a dual-beam, 30μΑ current on two equal Ag targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6 ml of > 96% [180]water (Marshall Isotopes). Subsequent to irradiation and delivery to a hotcell, each target was washed with 1.6 ml of [160]water (Merck, water for GR analysis), giving approximately 2-5 Gbq in 3.2 ml of [160]water. All radiochemistry was performed on a commercially available GE FASTlab™ with single-use cassettes. Each cassette is built around a one-piece-moulded manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connection with five prefilled vials, one water bag (100 ml) as well as various SPE cartridges and filters. Fluid paths are controlled with nitrogen purging, vacuum and the three syringes. The fully automated system is designed for single-step fluorinations with cyclotron-produced [18F]fluoride. The FASTlab was programmed by the software package in a step-by-step time-dependent sequence of events such as moving the syringes, nitrogen purging, vacuum, and temperature regulation. Synthesis of

[18F]FACBC followed the three general steps: (a) [18F]fluorination, (b) hydrolysis of protection groups and (c) SPE purification.

Vial A contained K222 (58.8 mg, 156 μπιοΐ), K2C03 (8.1 mg, 60.8 μπιοΐ) in 79.5% (v/v)

MeCN(aq) (1105 μΐ). Vial B contained 4M HC1 (2.0 ml). Vial C contained MeCN

(4.1ml). Vial D contained the precursor (48.4 mg, 123.5 μιηοΐ) in its dry form (stored at -20 °C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml). The 30 ml product collection glass vial was filled with 200 mM trisodium citrate (10 ml). Aqueous

[18F]fluoride (1-1.5 ml, 100-200 Mbq) was passed through the QMA and into the 180-

H20 recovery vial. The QMA was then flushed with MeCN and sent to waste. The trapped [18F]fluoride was eluted into the reactor using eluent from vial A (730 μΐ) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 μΐ, vial C). Approximately 1.7 ml of MeCN was mixed with precursor in vial D from which 1.0 ml of the dissolved precursor (corresponds to 28.5 mg, 72.7 mmol precursor) was added to the reactor and heated for 3 min at 85°C. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was washed with water, and then incubated with 2M NaOH (2.0 ml) for 5 min after which the 2M NaOH was sent to waste. The labelled intermediate (without the ester group) was then eluted off the tC18 cartridge into the reactor using water. The BOC group was hydrolysed by adding 4M HC1 (1.4 ml) and heating the reactor for 5 min at 60 °C. The reactor content with the crude [18F]FACBC was sent through the HLB and Alumina cartridges and into the 30 ml product vial. The HLB and Alumina cartridges were washed with water (9.1 ml total) and collected in the product vial. Finally, 2M NaOH (0.9 ml) and water (2.1 ml) was added to the product vial, giving a purified formulation of [18F]FACBC with a total volume of 26 ml. Radiochemical purity was measured by radio-TLC using a mixture of MeCN:MeOH:H20:CH3COOH (20:5:5: 1) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [18F]FACBC fraction divided by the total used [18F]fluoride activity (decay corrected). Total synthesis time was 43 min.

The RCY of [18F]FACBC was 62.5% ± 1.93 (SD), n=4.

/////FDA,  diagnostic imaging agent,  recurrent prostate cancer, fda 2016, Axumin, marketed, Blue Earth Diagnostics, Ltd., Oxford, United Kingdom, fluciclovine F 18

C1[C@@](C[C@H]1[18F])(N)C(=O)O

SETIPIPRANT


Setipiprant structure.png

Setipiprant, KYTH-105

CAS  866460-33-5

2-(2-(1-naphthoyl)-8-fluoro-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)acetic acid

2-[8-fluoro-2-(naphthalene-1-carbonyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5-yl]acetic acid

5H-Pyrido(4,3-b)indole-5-acetic acid, 8-fluoro-1,2,3,4-tetrahydro-2-(1-naphthalenylcarbonyl)-

MF C24H19FN2O3

MW 402.4176632

IND FILED BY ALLERGAN FOR Alopecia

ACT-129968, a CRTH2 receptor antagonist, had been in phase II clinical trials at Actelion

Setipiprant; UNII-BHF20LA2GM; ACT-129968; 866460-33-5;

Setipiprant is a prostaglandin D2 (PGD2) antagonist. Essentially, it inhibits PGD2 receptor activity

KYTH-105 had previously been studied as a potential allergic inflammation treatment and had undergone eight clinical trials, resulting in a safety database of more than 1,000 patients. Treatment in all studies was well tolerated across all treatment groups.

Intellectual Property
KYTHERA acquired exclusive worldwide rights to KYTH-105, as well as certain patent rights covering the use of PGD2 receptor antagonists for the treatment of hair loss (often presenting as male pattern baldness, or androgenic alopecia).

Next Steps
KYTHERA plans to file an Investigational New Drug (IND) application and initiate a proof-of-concept study to establish the efficacy of KYTH-105 in male subjects with androgenic alopecia (AGA).

In 2015, Allergan acquired Kythera.

2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid

mp 224.0 °C.

LC(1)/ESI-MS tR = 0.83 min; m/z [M + H+] = 403.09.

1H NMR (DMSO-d6), 65:35 mixture of two rotamers, δ: 8.02 (m, 2 H), 7.76 (d, J = 7.8 Hz, 0.65 H), 7.72 (m, 0.35 H), 7.49–7.64 (m, 3.35 H), 7.35–7.49 (m, 2.35 H), 6.98 (ddd, JH–F = 9.3 Hz, J1 = 9.3 Hz, J2 = 2.4 Hz, 0.65 H), 6.88 (m, 0.65 H), 4.85–5.14 (m, 3.3 H), 4.42 (m, 0.35 H), 4.32 (m, 0.7 H), 4.06 (m, 0.35 H), 3.50 (t, J = 5.5 Hz, 1.3 H), 2.95 (m, 0.70 H), 2.68 (m, 0.65 H), 2.58 (m, 0.65 H).

13C NMR (DMSO-d6) δ: 170.7, 169.2, 157.7 (d, JC–F = 232 Hz), 157.4 (d, JC–F = 233 Hz), 137.1, 136.2, 135.1, 134.9, 134.0, 133.8, 133.5, 129.6, 129.5, 129.4, 129.3, 128.9, 128.8, 127.5, 127.4, 127.0, 126.9, 126.0, 125.9, 125.7 (d, JC–F = 10 Hz), 125.2, 125.1, 125.0, 124.1, 123.9, 110.9 (d, JC–F = 10 Hz), 110.8 (m), 109.3 (d, JC–F = 26 Hz), 109.1 (d, JC–F = 26 Hz), 106.7 (m), 103.3 (d, JC–F = 23 Hz), 103.0 (d, JC–F = 23 Hz), 44.73, 44.70, 44.5, 44.4, 39.5, 39.3, 23.1, 22.3.

HRMS (ESI): m/zcalcd for C24H20N2O3F [M + H+] 403.1458, found 403.1458.

SYNTHERSIS

STR1

Setipiprant (INN) (developmental code names ACT-129,968, KYTH-105) is a drug originally developed by Actelion which acts as a selective, orally available antagonist of the prostaglandin D2 receptor 2 (DP2).[1] It was initially researched as a treatment for allergies and inflammatory disorders, particularly asthma, but despite being well tolerated in clinical trials and showing reasonable efficacy against allergen-induced airway responses in asthmatic patients,[2][3] it failed to show sufficient advantages over existing drugs and was discontinued from further development in this application.[4]

However, following the discovery in 2012 that the prostaglandin D2 receptor (DP/PGD2) is expressed at high levels in the scalp of men affected by male pattern baldness,[5] the rights to setipiprant were acquired by Kythera with a view to potentially developing this drug as a novel treatment for baldness, with a previously unexploited mechanism of action.[6] While it is too early to tell whether setipiprant will be an effective treatment for this condition, the favorable pharmacokinetics and relative lack of side effects seen in earlier clinical trials mean that fresh clinical trials for this new application can be conducted fairly quickly.[7]

Prostaglandin D2 is a known agonist of the thromboxane A2 (TxA2) receptor, the PGD2 (DP) receptor and the recently identified G-protein-coupled “chemoattractant receptor- homologous molecule expressed on Th2 cells” (CRTH2).

The response to allergen exposure in a previously sensitized host results in a cascade effect involving numerous cell types and release of a number of cytokines, chemokines, and multiple mediators. Among these critical initiators are the cytokines interleukin (IL)-4, IL-13, and IL-5, which play critical roles in Th2 cell differentiation, immunoglobulin (Ig)E synthesis, mast cell growth and differentiation, upregulation of CD23 expression, and the differentiation, recruitment, and activation of eosinophils. The stimulated release of the array of mediators, causes end-organ damage, including constriction and hyperresponsi- veness, vascular permeability, edema, mucous secretion, and further inflammation.

Because of the number of responses targeted, corticosteroids have proven to be the most effective therapy. Rather than antagonizing these specific responses in a directed way, another approach is to alter the immune response, that is, to change the nature of the immunological response to allergen. CRTH2 is preferentially expressed on Th2 cells and is a chemoattractant receptor for PGD2 that mediates PGD2-dependent migration of blood Th2 cells. Chemoattractants are responsible for the recruitment of both Th2 cells and other effector cells of allergic inflammation, which can provide the conceptual basis for the development of new therapeutic strategies in allergic conditions.

So far, few compounds having CRTH2 antagonistic activity have been reported in the patent literature. Bayer AG claims the use of Ramatroban ((3R)-3-(4-fluorobenzene- sulfonamido)-l,2,3,4-tetrahydrocarbazole-9-propionic acid) for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjuvatitis

(GB 2388540). Further, (2-tert.-butoxycarbonyl-l, 2, 3, 4-tetrahydro-pyrido[4,3-b]indol-5- yl)-acetic acid and (2-ethoxycarbonyl-l, 2, 3, 4-tetrahydro-pyrido[4,3-b]indol~5-yl)-acetic acid are disclosed by Kyle F. et al in two patent applications (US 5817756 and WO 9507294, respectively).

Furthermore, oral bioavailability of the Ramatroban and its ability to inhibit prostaglandin D2-induced eosinophil migration in vitro has been reported (Journal of Pharmacology and Experimental Therapeutics, 305(1), p.347-352 (2003)).

Description of the invention:

It has now been found that compounds of the general Formulae (I) and (II) of the present invention are CRTH2 receptor antagonists. These compounds are useful for the treatment of both chronic and acute allergic/immune disorders such as allergic asthma, rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis, basophil- related diseases, such as basophilic leukemia and basophilic leukocytosis.

The compounds of general Formulae (I) and (II), especially those mentioned as being preferred, display high selectivity towards the CRTH2 receptor. No antagonistic effects (IC50 >10 μM) are observed on e.g. prostaglandin D2 receptor DPI; PGI2 receptor (IP), PGE2 receptors (EPl, EP2, EP3, EP4), PGF2 receptor (FP), thromboxane receptor A2 (TxA2), leukotriene receptors (CysLTl, CysLT2, LTB4), complement receptor (C5a), angiotensin receptors (ATI, AT2) or serotonin receptor 5HT2c.

The solubility of compounds of general Formulae (I) and (II) in buffer at pH 7 is generally >800 μg/ml.

In vitro assays with rat and dog liver microsomes, or with rat and human hepatocytes revealed high metabolic stability for compounds of general Foπnulae (I) and (II), especially for those compounds mentioned as being preferred.

The compounds of general Formulae (I) and (II), especially those mentioned as being preferred, do not interfere with cytochrome P-450 enzymes, e.g. they are neither degraded by, nor do they inhibit such enzymes.

Excellent pharmacokinetic profiles have been observed for compounds of general Formulae (I) and (II), especially for those compounds mentioned as being preferred, after oral administration (10 mg/kg) to rats and dogs (bioavailability 20-80%, Tmax 30 min, Cmax 2000- 6000 ng/ml, low clearance, T] 24-8 h). The compounds of general Formulae (I) and (II), especially those mentioned as being preferred, are efficacious in vitro, inhibiting PGD2-induced migration of eosinophils or other CRTH2 expressing cells in a cell migration assay. A number of techniques have been developed to assay such chemotactic migration (see, e.g., Leonard et al., 1995, “Measurement of α- and β-Chemokines”, in Current Protocols in Immunology, 6.12.1- 6.12.28, Ed. Coligan et al, John Wiley & Sons, Inc. 1995). The compounds of the present invention are tested using a protocol according to H. Sugimoto et al. (J Pharmacol Exp Ther. 2003, 305(1), 347-52), or as described hereinafter: Purified eosinophils are labeled with a fluorescent dye, i.e. Calcein-AM and loaded in BD Falcon FluoroBlock upper inserts. Test compounds are diluted and incubated with eosinophils in the BD Falcon

FluoroBlock upper inserts for 30 min at 37 °C in a humidified CO2 incubator. A constant amount of PGD2 is added to BD Falcon FluoroBlock lower chamber, at a concentration known to have a chemotactic effect on CRTH2 cells. As a control, at least one aliquot in the upper well does not contain test compound. The inserts are combined with the chambers and are incubated for 30 min at 37 °C in a humidified CO2 incubator. After an incubation period, the number of migrating cells on the lower chamber is counted using a fluorescent reader, i.e. an Applied Biosystems Cyto Fluor 4000 plate reader. The contribution of a test compound to the chemotactic activity of PGD2 is measured by comparing the chemotactic activity of the aliquots containing only dilution buffer with the activity of aliquots containing a test compound. If addition of the test compound to the solution results in a decrease in the number of cells detected in the lower chamber relative to the number of cells detected using a solution containing only PGD2, then there is identified an antagonist of PGD2 induction of chemotactic activity of eosinophils.

PAPER

Journal of Medicinal Chemistry (2013), 56(12), 4899-4911

http://pubs.acs.org/doi/abs/10.1021/jm400122f

Identification of 2-(2-(1-Naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic Acid (Setipiprant/ACT-129968), a Potent, Selective, and Orally Bioavailable Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) Antagonist

Drug Discovery Unit, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
J. Med. Chem., 2013, 56 (12), pp 4899–4911
DOI: 10.1021/jm400122f
Abstract Image

Herein we describe the discovery of the novel CRTh2 antagonist 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 28 (setipiprant/ACT-129968), a clinical development candidate for the treatment of asthma and seasonal allergic rhinitis. A lead optimization program was started based on the discovery of the recently disclosed CRTh2 antagonist 2-(2-benzoyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid 5. An already favorable and druglike profile could be assessed for lead compound 5. Therefore, the lead optimization program mainly focused on the improvement in potency and oral bioavailability. Data of newly synthesized analogs were collected from in vitro pharmacological, physicochemical, in vitro ADME, and in vivo pharmacokinetic studies in the rat and the dog. The data were then analyzed using a traffic light selection tool as a visualization device in order to evaluate and prioritize candidates displaying a balanced overall profile. This data-driven process and the excellent results of the PK study in the rat (F = 44%) and the dog (F = 55%) facilitated the identification of 28 as a potent (IC50 = 6 nM), selective, and orally available CRTh2 antagonist.

PAtent

WO 2005095397

http://www.google.co.in/patents/WO2005095397A1?cl=en

Formula 6.

Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003

Scheme 1

Step a)

Figure imgf000032_0001

Step b)

Figure imgf000032_0002

Scheme 2

Formula (I).

Figure imgf000033_0001

References

  1.  Fretz H, Valdenaire A, Pothier J, Hilpert K, Gnerre C, Peter O, Leroy X, Riederer MA. Identification of 2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (setipiprant/ACT-129968), a potent, selective, and orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonist. J Med Chem. 2013 Jun 27;56(12):4899-911. doi: 10.1021/jm400122f PMID 23721423
  2.  Sidharta PN, Diamant Z, Dingemanse J. Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects. Fundam Clin Pharmacol. 2014 Dec;28(6):690-9. doi: 10.1111/fcp.12079 PMID 24734908
  3.  Diamant Z, Sidharta PN, Singh D, O’Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse J. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy. 2014 Aug;44(8):1044-52. doi: 10.1111/cea.12357 PMID 24964348
  4.  Norman P. Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs. Expert Opin Investig Drugs. 2014 Jan;23(1):55-66. doi: 10.1517/13543784.2013.839658 PMID 24073896
  5. Garza LA, et al. Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia. Science Translational Medicine, 21 March 2012; 4(126):126ra34. doi: 10.1126/scitranslmed.3003122
  6.  George Cotsarelis, Garret Fitzgerald, Luis Garza. Compositions and methods for regulating hair growth. US Patent application 2015/0072963
  7.  Pipeline KYTH-105 (setipiprant)
  8. http://files.shareholder.com/downloads/AMDA-MFNLA/4023632629x0x817836/4E5AC47A-B9EE-4296-9D97-631C0F6B7C97/KYTH-105_setipiprant_.pdf

Patent ID Date Patent Title
US2015072963 2015-03-12 COMPOSITIONS AND METHODS FOR REGULATING HAIR GROWTH
US2014328861 2014-11-06 Combination of CRTH2 Antagonist and a Proton Pump Inhibitor for the Treatment of Eosinophilic Esophagitis
US2010234396 2010-09-16 Tetrhydropyridoindole Derivatives
US7714132 2010-05-11 Tetrahydropyridoindole derivatives

STR1

S etipiprant
Setipiprant structure.png
Systematic (IUPAC) name
2-[8-fluoro-2-(naphthalene-1-carbonyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5-yl]acetic acid
Clinical data
Administration Oral
Identifiers
CASRN 866460-33-5
ATC code none
PubChem CID 49843471
Chemical data
Formula C24H19FN2O3
Molar mass 402.417 g/mol

///////Setipiprant, KYTH-105, 866460-33-5, ALLERGAN,  Alopecia, KYTHERA

c15ccccc5cccc1C(=O)N(CC3)Cc2c3n(CC(O)=O)c(cc4)c2cc4F

Flow synthesis of Fluoxetine


[1860-5397-11-134-i8]

Scheme 1: Flow synthesis of fluoxetine (46).

PIC CREDIT, The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry,  Marcus Baumann and Ian R. Baxendale, Beilstein J. Org. Chem. 2015, 11, 1194–1219.,doi:10.3762/bjoc.11.134

One of the early published examples of industry-based research on multi-step flow synthesis of a pharmaceutical was reported in 2011 by scientists from Eli Lilly/UK and detailed the synthesis of fluoxetine 46, the API of Prozac[1]. In this account each step was performed and optimised individually in flow, with analysis and purification being accomplished off-line. The synthesis commences with the reduction of the advanced intermediate ketone 47 using a solution of pre-chilled borane–THF complex (48) to yield alcohol 49 (Scheme 1).

Conversion of the pendant chloride into iodide 51 was attempted via Finckelstein conditions, however, even when utilising phase-transfer conditions in order to maintain a homogeneous flow regime the outcome was not satisfactory giving only low conversions. Alternatively direct amination of chloride 49 utilising high temperature flow conditions (140 °C) allowed the direct preparation of amine 50 in excellent yield.

Flow processing using a short residence time (10 min) at the elevated temperature allowed for a good throughput; in addition, the handling of the volatile methylamine within the confines of the flow reactor simplifies the practical aspects of the transformation, however, extra precautions were required in order to address and remove any leftover methylamine that would pose a significant hazard during scaling up.

The final arylation of 50 was intended to be performed as a SNAr reaction, however, insufficient deprotonation of the alcohol 50 under flow conditions (NaHMDS or BEMP instead of using a suspension of NaH as used in batch) required a modification to the planned approach. To this end a Mitsunobu protocol based on the orchestrated mixing of four reagent streams (50, 54 and reagents 52 and 53) was developed and successfully applied to deliver fluoxetine (46) in high yield.

Overall, this study is a good example detailing the intricacies faced when translating an initial batch synthesis into a sequence of flow steps for which several adaptations regarding choice of reagents and reaction conditions are mandatory in order to succeed.

Marcus

Dr Marcus Baumann
Postdoc

Marcus Baumann studied chemistry at the Philipps-University Marburg/Germany, from where he graduated in 2007. His studies involved a 6 month period as an Erasmus student at the Innovative Technology Centre at the University of Cambridge, UK (with Prof. Steven V. Ley and Dr Ian R. Baxendale), where he developed a new flow-based oxazole synthesis. He soon returned to Cambridge to pursue his doctoral studies with Prof. Steven V. Ley where he developed flow processes for Curtius rearrangements, different fluorination reactions as well as important heterocycle syntheses. Upon completion of his PhD in 2010 Marcus was awarded a Feodor Lynen Postdoctoral Fellowship (Alexander von Humboldt Foundation, Germany) allowing him to join the group of Prof. Larry E. Overman at UC Irvine, USA (2011-2013). During his time in California his research focused on the synthesis of naturally occurring terpenes as well as analogues of ETP-alkaloids. The latter project generated potent and selective histone methyltransferase inhibitors and opened routes towards new probes for epigenetic diseases which are currently under further investigation. In early 2013 Marcus returned to the UK and took up a postdoctoral position with Prof. Ian R. Baxendale at the University of Durham, where his interests concentrate on the development of flow and batch based strategies towards valuable compounds en route for regenerative medicines.

Prof. Ian R. Baxendale

Personal web page

Professor in the Department of Chemistry
Telephone: +44 (0) 191 33 42185

(email at i.r.baxendale@durham.ac.uk)

Research Interests

My general areas of interest are: Organic synthesis (natural products, heterocyclic and medicinal chemistry), Organometallic chemistry, Catalyst design and application, Meso flow chemistry, Microfluidics, Microwave assisted synthesis, Solid supported reagents and scavengers, and facilitated reaction optimisation using Robotics and Automation.

My primary research direction is the synthesis of biologically potent molecules which encompasses the design, development and integration of new processing techniques for their preparation and solving challenges associated with the syntheses of new pharmaceutical and agrochemical compounds. In our work we utilise the latest synthesis tools and enabling technologies such as microwave reactors, solid supported reagents and scavengers, enzymes, membrane reactors and flow chemistry platforms to facilitate the bond making sequence and expedite the purification procedure. A central aspect of our investigations is our pioneering work on flow chemical synthesis and microreactor technology as a means of improving the speed, efficiency, and safety of various chemical transformations. As a part of these studies we are attempting to devise new chemical reactions that are not inherently feasible or would be problematic under standard laboratory conditions. It is our further challenge to enhance the automation associated with these reactor devices to impart a certain level of intelligence to their function so that repetitive wasteful actions currently performed by chemists can be delegated to a machine; for example, reagent screening or reaction optimisation. We use these technologies as tools to enhance our synthetic capabilities but strongly believe in not becoming slaves to any methodology or equipment.

For those interested in our research and wishing to find out more we invite you to visit our website at: http://www.dur.ac.uk/i.r.baxendale/

 

  1. Ahmed-Omer, B.; Sanderson, A. J. Org. Biomol. Chem. 2011, 9, 3854–3862. doi:10.1039/C0OB00906G
    Paper

    Preparation of fluoxetine by multiple flow processing steps

    *Corresponding authors
    aEli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, UK
    Org. Biomol. Chem., 2011,9, 3854-3862

    DOI: 10.1039/C0OB00906G

    http://pubs.rsc.org/en/Content/ArticleLanding/2011/OB/c0ob00906g#!divAbstract

Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.

Graphical abstract: Preparation of fluoxetine by multiple flow processing steps

1 The general method set-up of flow process used for the synthesis of (±)- fluoxetine.

Scheme 1 Synthesis of (±)-fluoxetine in flow: (i) BH3·THF, r.t., 5 min (77%); (ii) NaI, toluene: water, 100 °C, 20 min (43%); (iii); MeNH2 (aq), …

//////////Flow synthesis, fluoxetine

WHO issues revised Guideline on HVAC Systems


DRUG REGULATORY AFFAIRS INTERNATIONAL

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems for the manufacture of non-sterile forms. As most guidelines on this topic address the requirements for sterile dosage forms, the previous version was gladly accepted by industry. Learn more about the revised guideline on HVAC systems.

http://www.gmp-compliance.org/enews_05358_WHO-issues-revised-Guideline-on-HVAC-Systems_15160,15221,15661,15612,Z-PEM_n.html

The World Health Organization (WHO) recently issued a guideline for commenting which describes the requirements for HVAC systems used for the manufacture of non-sterile dosage forms. As most guidelines on this topic address the requirements for sterile forms, the previous version (TRS 961, Annex 1) from 2011 was gladly accepted by industry. Mentioned are non-sterile dosage forms as tablets, capsules, liquids or ointments, but also for the final steps in the manufacture of APIs. The WHO guideline means to provide guidance specifically for the areas design, installation, qualification and maintenance of ventilation systems. For the manufacture of…

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