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ABBV 2222

April 10, 2017 10:25 am / Leave a comment

ABBV 2222

Benzoic acid, 4-[(2R,4R)-4-[[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl]amino]-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]-

4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}- amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid

CAS 1918143-53-9

MF C₂₈ H₂₁ F₄ N O₇

MW 559.46

1H NMR (400 MHz, CDCl.sub.3) .delta. 8.17-8.03 (m, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.16-6.99 (m, 4H), 6.73-6.67 (m, 2H), 6.38 (d, J=73.6 Hz, 1H), 5.48 (td, J=10.4, 6.1 Hz, 1H), 5.36 (d, J=8.8 Hz, 1H), 5.31-5.21 (m, 1H), 2.52 (ddd, J=13.3, 6.0, 2.2 Hz, 1H), 1.86-1.71 (m, 2H), 1.68-1.60 (m, 1H), 1.10 (q, J=3.7, 2.4 Hz, 2H);

MS (ESI-) m/z=558 (M-H).sup.-.

Philip R. Kym, Xueqing Wang, Xenia B. Searle, Bo Liu, Ming C. Yeung, Robert J. Altenbach, Eric Voight, Andrew Bogdan, John R. Koenig, Weniger «
	Abbvie Inc.

Image result

DESCRIPTION

Cystic fibrosis (CF), one of the most common autosomal recessive genetic diseases in the Caucasian population, is caused by loss of function mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which is located on chromosome 7 (http://www.cff.org/AboutCF/; Rowe S. M et al. (2005); N Eng J Med. (352), 1992-2001). Approximately 1:3500 and 1:3000 infants born in the United States and in Europe, respectively, are affected by CF, resulting in ˜75,000 cases worldwide, ˜30,000 of which are in the United State. Approximately 1,000 new cases of CF are diagnosed each year, with more than 75% of patients being diagnosed by 2 years of age. Nearly half the CF population is currently 18 years of age and older. The CFTR protein (Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362; Riordan, J. R. et al. (1989) Science 245:1066-1073) is a cAMP/ATP-mediated ion channel expressed in a variety of cell types, including secretory and absorptive epithelial cells. CFTR regulates chloride and bicarbonate anion flux across the cell membrane, maintaining electro neutrality and osmolarity across the epithelial membrane (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). CFTR is also responsible for regulating the activity of other ion channels and proteins (Guggino, W. B. et al. (2006), Nat Revs Molecular Cell Biology 7, 426-436).

Aberrations in CFTR function result in imbalance of the airway surface liquid, leading to mucus dehydration, inflammation, recurrent bacterial infection and irreversible lung damage, which lead to premature death in affected patients. Besides respiratory disease, CF patients suffer from gastrointestinal problems and pancreatic insufficiency. The majority of males (95%) with cystic fibrosis are infertile as a result of azoospermia caused by altered vas deferens; which may be absent, atrophic, or fibrotic. Fertility is also decreased among females with cystic fibrosis due to abnormal cervical mucus.

The F508del mutation, the most common of the approximately 1900 identified polymorphisms in CFTR, results in defective processing of CFTR in the endoplasmic reticulum (ER) (http://www.cftr2.org/index.php). Approximately 90% of the CF patients carry at least one copy of the F508del mutation (deletion of a phenylalanine on position 508), and 50%-60% of the patients are homozygous for this mutation. The defective processing of CFTR results in early CFTR degradation, which leads to reduced trafficking or absence of the protein on the membrane. As there have been over 100 CF disease-causing mutations identified, they have been classified according to their phenotypic consequences and belong to synthesis, maturation, regulation, conductance, reduced number due to quantity and reduced number due to stability classifications.

Current CF drug discovery efforts focus upon developing two classes of compounds to modulate CFTR. One class, called Correctors, helps to overcome the folding defects of the mutated CFTR protein to promote its maturation resulting in higher cell surface expression. The other classes of compounds, called Potentiators, help overcome the defective regulation and/or conductance of the protein by increasing the probability of channel opening on the membrane surface.

In addition, as the modulation of CFTR protein mutations to promote proper protein folding is beneficial for CF, there are other diseases mediated by CFTR. For example, Sjögren’s Syndrome (SS), an autoimmune disorder that results in symptoms of xerostomia (dry mouth) and keratoconjunctivitis sicca (KCS, dry eyes) may result from dysregulation of moisture producing glands throughout the body. Chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD), which is a progressive and irreversible airflow limitation in the airways is result of several physiologic abnormalities, including mucus hyper secretion and impaired mucociliary secretion. Increasing the anion secretion by CFTR potentiators have been suggested to overcome these phenotypic complexities with Sjögren’s Syndrome by increasing the corneal hydration and by overcoming the impaired mucociliary secretion in COAD (Bhowmik A, et al. (2009) Vol. 103(4), 496-502; Sloane P, et al. PLOS One (2012) Vol 7(6), 239809 (1-13)).

STEP 1

(R)-methyl 4-(7-hydroxy-4-oxochroman-2-yl)benzoate

RXN……….By reacting 7-hydroxy-4H-chromen-4-one AND (4-(methoxycarbonyl)phenyl)boronic acid

STEP 2

(R)-methyl 4-(7-hydroxy-4-(methoxyimino)chroman-2-yl)benzoate

Reacting ABOVE compd and O-methylhydroxylamine,

STEP 3

Methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate

reacting ABOVE compd with 5% platinum (0.05 equivalent) on carbon in acetic acid. The reaction was stirred at room temperature under hydrogen

THEN STEP 4

Methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate isolated AS trifluroroacetic acid salt

STEP 5
methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-hydroxychroman-2-yl)benzoate

by reacting 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, the ABOVE compound AND N-ethyl-N-isopropylpropan-2-amine

STEP 6

Methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-(difluoromethoxy)chroman-2-yl)benzoate

by reacting ABOVE compound and diethyl(bromodifluoromethyl)phosphonate

AND FINAL STEP7 is ESTER HYDROLYSIS USING lithium hydroxide to get ABBV 2222

PATENT

US 20160120841

Example 122

4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}- amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid

[1880] To Example 123E (130 mg, 0.227 mmol) in methanol (2 mL) and water (0.5 mL) was added lithium hydroxide (32.6 mg, 1.360 mmol). The mixture was stirred at 35.degree. C. for 4 hours, LC/MS showed the conversion was complete. Solvent was removed under reduced pressure and water (2 mL) was added. The pH of the mixture was adjusted to pH 1-2 with the addition of 2 M HCl. The precipitated white solid was collected by filtration, and dried to provide the title compound (110 mg, 0.197 mmol, 87% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.17-8.03 (m, 2H), 7.49 (d, J=8.2 Hz, 2H), 7.16-6.99 (m, 4H), 6.73-6.67 (m, 2H), 6.38 (d, J=73.6 Hz, 1H), 5.48 (td, J=10.4, 6.1 Hz, 1H), 5.36 (d, J=8.8 Hz, 1H), 5.31-5.21 (m, 1H), 2.52 (ddd, J=13.3, 6.0, 2.2 Hz, 1H), 1.86-1.71 (m, 2H), 1.68-1.60 (m, 1H), 1.10 (q, J=3.7, 2.4 Hz, 2H); MS (ESI-) m/z=558 (M-H).sup.-.

Example 123

methyl 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]ca- rbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoate

Example 123A

(R)-methyl 4-(7-hydroxy-4-oxochroman-2-yl)benzoate

[1881] A mixture of bis(2,2,2-trifluoroacetoxy)palladium (271 mg, 0.816 mmol), (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (200 mg, 0.979 mmol), ammonium hexafluorophosphate(V) (798 mg, 4.90 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2203 mg, 12.24 mmol) and dichloroethane (8 mL) in a 20 mL vial was stirred for 5 minutes at room temperature, followed by the addition of 7-hydroxy-4H-chromen-4-one (CAS 59887-89-7, MFCD00209371, 1323 mg, 8.16 mmol) and water (256 mg, 14.19 mmol). The vial was capped and the mixture was stirred at 60.degree. C. overnight. The reaction gradually turned black, with Pd plated out on the sides of the vial. The mixture was filtered through a plug of celite and eluted with ethyl acetate to give a red solution which was washed with brine. The solvent was removed in vacuo and the crude material was chromatographed using a 100 g silica gel cartridge and eluted with a gradient of 5-40% ethyl acetate in heptane to provide the title compound (1.62 g, 66.6% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15-8.04 (m, 2H), 7.87 (d, J=8.7 Hz, 1H), 7.60-7.49 (m, 2H), 6.62-6.45 (m, 2H), 5.87 (s, 1H), 5.53 (dd, J=12.8, 3.2 Hz, 1H), 3.94 (s, 3H), 3.07-2.80 (m, 2H); MS (ESI+) m/z=299 (M+H).sup.+.

Example 123B

(R)-methyl 4-(7-hydroxy-4-(methoxyimino)chroman-2-yl)benzoate

[1882] The mixture of Example 123A (960 mg, 3.22 mmol), sodium acetate (528 mg, 6.44 mmol) and O-methylhydroxylamine, hydrochloric acid (538 mg, 6.44 mmol) in methanol (10 mL) was stirred at 60.degree. C. overnight. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic layers was dried over MgSO.sub.4, filtered, and concentrated. The residue was washed with ether to provide the title compound (810 mg, 2.475 mmol, 77% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15-8.03 (m, 2H), 7.81 (d, J=8.7 Hz, 1H), 7.58-7.43 (m, 2H), 6.50 (dd, J=8.6, 2.5 Hz, 1H), 6.45 (d, J=2.5 Hz, 1H), 5.21 (d, J=3.0 Hz, 1H), 5.12 (dd, J=12.2, 3.2 Hz, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.45 (dd, J=17.2, 3.2 Hz, 1H), 2.63 (dd, J=17.2, 12.2 Hz, 1H); MS (ESI+) m/z 328 (M+H).sup.+.

Example 123C

Methyl 4-((2R,4R)-4-amino-7-hydroxychroman-2-yl)benzoate

[1883] A mixture of Example 123B (570 mg, 1.741 mmol) was treated with 5% platinum (0.05 equivalent) on carbon in acetic acid (5 mL). The reaction was stirred at room temperature under hydrogen (1 atmosphere) for 24 hours, LC/MS showed conversion over 95%. The mixture was filtered through a celite pad and solvent removed under reduced pressure. The residue was purified by preparative LC method TFA2 to provide the trifluroroacetic acid salt of the title compound (300 mg, 44% yield). LC/MS m/z 283 (M-NH.sub.2).sup.+.

Example 123D

methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-hydroxychroman-2-yl)benzoate

[1884] A mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (162 mg, 0.668 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 380 mg, 1.0 mmol) in DMF (2 mL) was stirred for 5 minutes at room temperature, followed by the addition of Example 123C (200 mg, 0.334 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.466 ml, 2.67 mmol). The mixture was stirred at room temperature for 2 hours, LC/MS showed reaction complete. The mixture was loaded on to a 25 g silica gel cartridge eluting with 5-50% ethyl acetate in heptane provide the title compound (204 mg, 58.3% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.11-7.90 (m, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.16-7.02 (m, 2H), 6.94 (dd, J=37.7, 8.3 Hz, 2H), 6.49-6.32 (m, 2H), 5.67 (s, 1H), 5.36 (dt, J=15.3, 8.7 Hz, 2H), 5.18 (d, J=10.7 Hz, 1H), 3.93 (s, 3H), 2.56-2.36 (m, 1H), 1.80-1.70 (m, 2H), 1.26 (d, J=2.2 Hz, 1H), 1.10-1.04 (m, 2H); MS (ESI-) m/z=521.9 (M-H).sup.-.

Example 123E

Methyl 4-((2R,4R)-4-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanec- arboxamido)-7-(difluoromethoxy)chroman-2-yl)benzoate

[1885] To Example 123D (190 mg, 0.363 mmol) and diethyl(bromodifluoromethyl)phosphonate (0.129 ml, 0.726 mmol) in a mixture of acetonitrile (2 mL) and water (1 mL) was added 50% aqueous potassium hydroxide (244 mg, 2.178 mmol) drop wise via syringe while stirring vigorously. After the addition was completed, LC/MS showed conversion was complete with a small by-product peak. Additional water was added to the mixture and the mixture was extracted with ethyl acetate (3.times.20 mL). The combined organic extracts were washed with 1 M HCl (5 mL) and water, dried over MgSO.sub.4, filtered, and concentrated. The residue was purified by preparative LC method TFA2 to provide the title compound (150 mg, 72% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.09-8.00 (m, 2H), 7.49-7.41 (m, 2H), 7.15-6.99 (m, 4H), 6.75-6.66 (m, 2H), 5.50-5.40 (m, 1H), 5.33 (d, J=8.9 Hz, 1H), 5.25 (dd, J=11.3, 2.0 Hz, 1H), 3.93 (s, 3H), 2.50 (ddd, J=13.4, 6.1, 2.1 Hz, 1H), 1.84-1.71 (m, 2H), 1.65 (d, J=2.8 Hz, 1H), 1.11-1.06 (m, 2H); MS (ESI-) m/z=572 (M-H).sup.-.

REFERENCE

Next up is Xueqing Wang of @abbvie speaking about a collaboration with @GalapagosNV on a different cystic fibrosis treatment #ACSSanFran

///////////ABBV 2222

O=C(O)c1ccc(cc1)[C@@H]3Oc2cc(OC(F)F)ccc2C(C3)NC(=O)C4(CC4)c5ccc6OC(F)(F)Oc6c5

BMS 986158

April 10, 2017 10:23 am / 1 Comment on BMS 986158

BMS 986158

MF C₃₀H₃₃N₅O₂, MW495.627 g/mol

CAS 1800340-40-2

5H-Pyrido[3,2-b]indole-7-methanol, 3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-α,α-dimethyl-5-[(S)-phenyl(tetrahydro-2H-pyran-4-yl)methyl]-

MOA：Bromodomain and extraterminal domain protein inhibitor

Indication：Solid tumoursStatus：

Phase II ：Bristol-Myers Squibb (Originator)

Phase I/IISolid tumours

Originator Bristol-Myers Squibb
Class Antineoplastics; Small molecules
Mechanism of Action Bromodomain and extraterminal domain protein inhibitors

01 Jun 2015 Phase-I/II clinical trials for Solid tumours (Late-stage disease, Metastatic disease) in Canada (NCT02419417)
02 Apr 2015 Bristol-Myers Squibb plans a phase I/IIa trial for Solid tumours (Late-stage disease) in USA, Australia and Canada (NCT02419417)

The genomes of eukaryotic organisms are highly organized within the nucleus of the cell. The long strands of duplex DNA are wrapped around an octomer of histone proteins 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. There has been appreciation recently that chromatin templates form a fundamentally important set of gene control mechanisms referred to as epigenetic regulation. By conferring a wide range of specific chemical modifications to histones and DNA (such as acetylation, methylation, phosphorylation, ubiquitinylation and SUMOylation) epigenetic regulators modulate the structure, function and accessibility of our genome, thereby exerting a huge impact in gene expression.

Histone acetylation is most 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 (-110 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. The BET family of bromodomain containing proteins

comprises 4 proteins (BRD2, BRD3, BRD4 and BRD-T) which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction.

BRD2 and BRD3 are reported to associate with histones along actively

transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008 30(1):51-60), while BRD4 appears to be involved in the recruitment of the pTEF-I3 complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Cell, 2009 138(1): 1294145). All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division – suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al., Cell, 2004 117(3):349-60).

Recent articles relating to this target include Prinjha et al., Trends in

Pharmacological Sciences, March 2012, Vol. 33, No. 3, pp. 146-153; Conway, ACS Med. Chem. Lett., 2012, 3, 691-694 and Hewings et al, J. Med. Chem., 2012, 55, 9393-9413.

Small molecule BET inhibitors that are reported to be in development include GSK-525762A, OTX-015, TEN-010 as well as others from the University of Oxford and Constellation Pharmaceuticals Inc.

Hundreds of epigenetic effectors have been identified, many of which are chromatin-binding proteins or chromatin-modifying enzymes. These proteins have been associated with a variety of disorders such as neurodegenerative disorders, metabolic diseases, inflammation and cancer. Thus, these compounds which inhibit the binding of a bromodomain with its cognate acetylated proteins, promise new approaches in the treatment of a range of autoimmune and inflammatory diseases or conditions and in the treatment of various types of cancer.


Inventors	Derek J. Norris, George V. Delucca, Ashvinikumar V. Gavai, Claude A. Quesnelle, Patrice Gill, Daniel O’MALLEY, Wayne Vaccaro, Francis Y. Lee, Mikkel V. DEBENEDETTO, Andrew P. Degnan, Haiquan Fang, Matthew D. Hill, Hong Huang, William D. Schmitz, JR John E. STARRETT, Wen-Ching Han, John S. Tokarski, Sunil Kumar MANDAL
Applicant	Bristol-Myers Squibb Company

PATENT

WO 2015100282

Examples 54 & 55

2-[3-(Dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2- b] indol-7-yl] pr opan-2-ol

Enantiomer A, Example 54 Enantiomer B, Example 55

Step 1 : 2-C hloro-5-(l ,4-dimethyl- 1H- 1 ,2,3-triazol-5-yl)pyridin-3-amine

To a 100 mL round bottom flask containing 5-bromo-2-chloropyridin-3-amine (2.90 g, 14.0 mmol), l,4-dimethyl-5-(tributylstannyl)-lH-l,2,3-triazole (2.70 g, 6.99 mmol) [Seefeld, M.A. et al. PCT Int. AppL, 2008, WO2008098104] and Pd(PPh₃)₄ (0.61 g, 0.52 mmol) in DMF (20 mL) was added cuprous iodide (0.20 g, 1.05 mmol) and Et₃N (1.9 mL, 14.0 mmol). The reaction mixture was purged with N₂ for 3 min and then heated at 100 °C for 1 h. After cooling to room temperature, the mixture was diluted withl0% LiCl solution and extracted with EtOAc (2x). The combined organics were washed with sat. NaCl, dried over MgS0₄, filtered and concentrated. CH₂C1₂ was added, and the resulting precipitate was collected by filtration. The mother liquor was concentrated and purified using ISCO silica gel chromatography (40 g column, gradient from 0% to 100% EtOAc/CH₂Cl₂). The resulting solid was combined with the precipitate and triturated with cold EtOAc to give the title compound (740 mg, 47%) as a light tan solid. LCMS (M+H) = 224.1; HPLC RT = 1.03 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH: water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 2: Methyl 3-((2-chloro-5-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate

Following a procedure analogous to that described in Step 2 of Example 1, 2-chloro-5-(l ,4-dimethyl-lH-l,2,3-triazol-5-yl)pyridin-3-amine (740 mg, 3.31 mmol) was converted to the title compound (644 mg, 54%). 1H NMR (400 MHz, CDC1₃) δ 7.94 (t, J=1.9 Hz, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.83 (dt, J=7.8, 1.3 Hz, 1H), 7.49 (t, J=7.9 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.36 (ddd, J=8.0, 2.3, 0.9 Hz, 1H), 6.38 (s, 1H), 3.99 (s, 3H), 3.93 (s, 3H), 2.34 (s, 3H); LCMS (M+H) = 358.2; HPLC RT = 2.34 min (Column:

Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 3: Methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-6]indole-7-carboxylate

Following a procedure analogous to that described in Step 3 of Example 1 , methyl 3-((2-chloro-5-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)pyridin-3-yl)amino)benzoate (2.82 g, 7.88 mmol) was converted to the title compound (1.58 g, 62%). 1H NMR (500 MHz, DMSO-de) δ 11.93 (s, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.36 (dd, J=8.2, 0.6 Hz, 1H), 8.29 -8.22 (m, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.91 (dd, J=8.2, 1.4 Hz, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 2.31 (s, 3H); LCMS (M+H) = 322.3; HPLC RT = 1.98 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Alternate synthesis of Methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-b] indole-7-carboxylate

A mixture of methyl 3-bromo-5H-pyrido[3,2-b]indole-7-carboxylate (Step 2 of Example 40, 3.000 g, 9.83 mmol), l,4-dimethyl-5-(tributylstannyl)-lH-l,2,3-triazole (4.18 g, 10.82 mmol), copper (I) iodide (0.281 g, 1.475 mmol), Pd(Ph₃P)₄ (0.738 g, 0.639 mmol) and triethylamine (2.74 mL, 19.66 mmol) in DMF (25 mL) was purged under a nitrogen stream and then heated in a heating block at 95 °C for 2 hours. After cooling to room temperature the reaction mixture was diluted with water and extracted into ethyl acetate. Washed with water, NH₄OH, brine and concentrated. The residue was triturated with 100 mL CHC1₃, filtered off the solid and rinsed with CHC1₃ to give. 1.6 g of product. The filtrate was loaded unto the ISCO column (330 g column, A: DCM; B:

10%MeOH/DCM, 0 to 100% gradient) and chromatographed to give an additional 0.7 g. of methyl 3 -( 1 ,4-dimethyl- 1 H- 1 ,2,3 -triazol-5 -yl)-5H-pyrido [3 ,2-b]indole-7-carboxylate (2.30 g total, 7.16 mmol, 72.8 % yield).

Step 4: Methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

Following a procedure analogous to that described in Step 4 of Example 1 , methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-¾]indole-7-carboxylate (80 mg, 0.25 mmol) was converted to the title compound (65 mg, 53%) after purification by prep HPLC (Column: Phen Luna C 18, 30 x 100 mm, 5 μιη particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1% TFA; Mobile Phase B : 95 : 5 acetonitrile: water with 0.1% TFA; Gradient: 10-100% B over 14 min, then a 2-min hold at 100% B; Flow: 40 mL/min). 1H NMR (400 MHz, CDC1₃) δ 8.51 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 8.10 (dd, J=8.1, 1.1 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.40 – 7.30 (m, 3H), 5.62 (d, J=10.6 Hz, 1H), 4.11 – 4.03 (m, 4H), 3.92 – 3.83 (m, 4H), 3.56 (td, J=l 1.9, 1.8 Hz, 1H), 3.35 (td, J=l 1.9, 1.9 Hz, 1H), 3.18 – 3.05 (m, 1H), 2.30 (s, 3H), 2.04 (d, J=13.0 Hz, 1H), 1.71 – 1.58 (m, 1H), 1.50 – 1.37 (m, 1H), 1.09 (d, J=12.8 Hz, 1H); LCMS (M+H) = 496.3; HPLC RT = 2.93 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min).

Step 5 : 2- [3-(Dimethyl- lH-1 ,2,3-triazol-5-yl)-5- [oxan-4-yl(phenyl)methyl] -5H-pyrido [3,2-6] indol-7-yl] pr opan-2-ol,

Following a procedure analogous to that described in Step 5 of Example 1 , methyl 3-(l ,4-dimethyl- IH- 1 ,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (65 mg, 0.13 mmol) was converted to racemic 2-[3-(dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2-¾]indol-7-yl]propan-2-ol, which was separated by chiral prep SFC (Column: Chiralpak IB 25 x 2 cm, 5 μιη; Mobile Phase: 70/30 C0₂/MeOH; Flow: 50 mL/min);to give Enantiomer A (24 mg, 36%) and Enantiomer B (26 mg, 38%). Enantiomer A: 1H NMR (500 MHz, CDC1₃) 5 8.44 (d, J=1.8 Hz, IH), 8.36 (d, J=8.2 Hz, IH), 7.98 (s, IH), 7.56 (d, J=1.7 Hz, IH), 7.47 – 7.41 (m, 3H), 7.37 – 7.32 (m, 2H), 7.31 – 7.28 (m, IH), 5.59 (d, J=10.5 Hz, IH), 4.06 (dd, J=11.8, 2.8 Hz, IH), 3.90 – 3.84 (m, 4H), 3.55 (td, J=11.9, 2.0 Hz, IH), 3.35 (td, J=11.9, 2.0 Hz, IH), 3.15 – 3.04 (m, IH), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, IH), 1.92 (s, IH), 1.75 (s, 6H), 1.69 – 1.58 (m, IH), 1.47 – 1.38 (m, IH), 1.12 (d, J=13.4 Hz, IH); LCMS (M+H) = 496.4; HPLC RT = 2.46 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0- 100% B over 4 min; Flow: 4 mL/min). SFC RT = 5.50 min (Column: Chiralpak IB 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C0₂/MeOH; Flow: 2 mL/min); SFC RT = 1.06 min (Column:

Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 50/50 C0₂/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min); [a]_D²° = -117.23 (c = 0.08, CHC1₃). Enantiomer B: 1H NMR (500 MHz, CDC1₃) δ 8.44 (d, J=l .8 Hz, IH), 8.36 (d, J=8.2 Hz, IH), 7.98 (s, IH), 7.56 (d, J=1.7 Hz, IH), 7.47 – 7.41 (m, 3H), 7.37 – 7.32 (m, 2H), 7.31 – 7.28 (m, IH), 5.59 (d, J=10.5 Hz, IH), 4.06 (dd, J=11.8, 2.8 Hz, IH), 3.90 – 3.84 (m, 4H), 3.55 (td, J=11.9, 2.0 Hz, IH), 3.35 (td, J=l 1.9, 2.0 Hz, IH), 3.15 – 3.04 (m, IH), 2.30 (s, 3H), 2.04 (d, J=13.6 Hz, IH), 1.92 (s, IH), 1.75 (s, 6H), 1.69 – 1.58 (m, IH), 1.47 – 1.38 (m, IH), 1.12 (d, J=13.4 Hz, IH); LCMS (M+H) = 496.4; HPLC RT = 2.46 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH:water with 0.1% TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min). SFC RT = 8.30 min (Column: Chiralpak IB 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C0₂/MeOH; Flow: 2 mL/min); SFC RT = 2.83 min (Column: Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 50/50 C0₂/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min); [a]_D²° = +88.78 (c = 0.10, CHC1₃).

Alternate Synthesis of Examples 54

2-[3-(Dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido[3,2- b] indol-7-yl] propan-2-ol.

Enantiomer A, Example 54

Step 1: (S)-methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate

The enantiomers of phenyl(tetrahydro-2H-pyran-4-yl)methanol ( 2.0 g, 10.4 mmol) [Orjales, A. et al. J. Med. Chem. 2003, 46, 5512-5532], were separated on preperative SFC. (Column: Chiralpak AD 5 x 25 cm, 5 μιη; Mobile Phase: 74/26

C0₂/MeOH; Flow: 270 mL/min; Temperature 30°C). The separated peaks were concentrated and dried under vacuum to give white solids. Enantiomer A: (S)-phenyl(tetrahydro-2H-pyran-4-yl)methanol: (0.91 g, 45.5%) SFC RT = 2.32 min

(Column: Chiralpac AD 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C0₂/MeOH; Flow: 3 mL/min); Temperature 40°C. Enantiomer B: (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol. (0.92 g, 46%) SFC RT = 3.09 min (Column: Chiralpac AD 250 x 4.6 mm, 5 μιη; Mobile Phase: 70/30 C0₂/MeOH; Flow: 3 mL/min); Temperature 40°C.

Following a procedure analogous to that described in Step 4 of Example 1 except using toluene (120mL) as the solvent, methyl 3-(l ,4-dimethyl-lH-l,2,3-triazol-5-yl)-5H-pyrido[3,2-b]indole-7-carboxylate (4 g, 12.45 mmol) and (R)-phenyl(tetrahydro-2H-pyran-4-yl)methanol (Enantiomer B above, 5.86 g, 30.5 mmol) was converted to the title compound (5.0 g, 81%). HPLC RT = 2.91 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOFLwater with 0.1% TFA; Mobile Phase B: 90: 10 MeOFLwater with 0.1% TFA; Temperature: 40 °C; Gradient: 0- 100% B over 4 min; Flow: 4 mL/min).

Step 2. (S)-2-[3-(Dimethyl-lH-l,2,3-triazol-5-yl)-5-[oxan-4-yl(phenyl)methyl]-5H-pyrido [3,2-b] indol-7-yl] propan-2-ol

A 500 mL round bottom flask containing (S)-methyl 3-(l,4-dimethyl-lH-l,2,3-triazol-5-yl)-5-(phenyl(tetrahydro-2H-pyran-4-yl)methyl)-5H-pyrido[3,2-b]indole-7-carboxylate (5.0 g, 10.09 mmol) in THF (150 mL) was cooled in an ice/MeOH bath. MeMgBr, (3M in Et₂0, 17.0 mL, 51.0 mmol) was added slowly over 4 min. The resulting solution was stirred for 2 h and then quenched carefully with sat. NH₄C1. The reaction mixture was diluted with 10% LiCl solution extracted with EtOAc. The organic layer was dried over MgS0₄, filtered and concentrated. The crude material was purified using ISCO silica gel chromatography (120 g column, gradient from 0%> to 6%>

MeOH/CH₂Cl₂). The product was collected and concentrated then dissolved in hot MeOH(35mL). To the mixture was added 15mL water and the mixture was cooled to room temperature. The resulting white precipitate was collected by filtration with 2: 1 MeOH/water rinse then dried under vacuum to give the title compound (3.2 g, 62%>). 1H

NMR (500 MHz, CDC1₃) δ 8.40 (d, J=1.8 Hz, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.93 (s, 1H), 7.53 (d, J=l .8 Hz, 1H), 7.46 (d, J=7.3 Hz, 2H), 7.42 (dd, J=8.2, 1.4 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.30 – 7.28 (m, 1H), 5.56 (d, J=10.5 Hz, 1H), 4.06 (d, J=8.9 Hz, 1H), 3.89 – 3.83 (m, 1H), 3.55 (td, J=11.9, 2.1 Hz, 1H), 3.35 (td, J=11.9, 2.1 Hz, 1H), 3.10 (q, J=10.8 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H), 2.03 (d, J=14.2 Hz, 1H), 1.89 (s, 1H), 1.74 (s, 6H), 1.68 -1.59 (m, 1H), 1.46 – 1.36 (m, 1H), 1.12 (d, J=12.2 Hz, 1H); LCMS (M+H) = 496.3; HPLC RT = 2.44 min (Column: Chromolith ODS S5 4.6 x 50 mm; Mobile Phase A: 10:90 MeOH: water with 0.1% TFA; Mobile Phase B: 90: 10 MeOH: water with 0.1%

TFA; Temperature: 40 °C; Gradient: 0-100% B over 4 min; Flow: 4 mL/min); SFC RT = 2.01 min (Column: Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 60/40 C0₂/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min). SFC RT = 1.06 min (Column: Chiralcel OD-H 250 x 4.6 mm, 5 μιη; Mobile Phase: 50/50 C0₂/(1 : 1 MeOH/CH3CN); Flow: 2 mL/min).

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Patent ID	Patent Title	Submitted Date	Granted Date
US9458156	Tricyclic compounds as anticancer agents	2014-12-23	2016-10-04

3rd speaker at #MEDI 1st time disclosures is Ashvin Gavai of @bmsnews talking about an oral BET inhibitor to treat cancer #ACSSanFran

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CC(C)(O)c2cc3n(c1cc(cnc1c3cc2)c4c(C)nnn4C)[C@@H](C5CCOCC5)c6ccccc6

GLGP 1837

April 7, 2017 9:59 am / Leave a comment

GLGP 1837

CAS 1654725-02-6

MF C₁₆ H₂₀ N₄ O₃ S, MW 348.42

For cystic fibrosis treatment

N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide

1H-Pyrazole-3-carboxamide, N-[3-(aminocarbonyl)-4,7-dihydro-5,5,7,7-tetramethyl-5H-thieno[2,3-c]pyran-2-yl]-

Inventors	Der Plas Steven Emiel Van, Sébastien Laurent Xavier MARTINA, Sébastien Jean-Jacques Cédric DROPSIT-MONTOVERT, Martin James Inglis Andrews, Hans KELGTERMANS
Applicant	Galapagos Nv

SYNTHESIS

GLGP 1837

ABC transporters are a family of homologous membrane transporter proteins regulating the transport of a wide variety of pharmacological agents (for example drugs, xenobiotics, anions, etc…) that bind and use cellular adenosine triphosphate (ATP) for their specific activities. Some of these transporters were found to defend malignant cancer cells against chemotherapeutic agents, acting as multidrug resistance proteins (like the MDRl-P glycoprotein, or the multidrug resistance protein, MRP 1). So far, 48 ABC transporters, grouped into 7 families based on their sequence identity and function, have been identified.

ABC transporters provide protection against harmful environmental compounds by regulating a variety of important physiological roles within the body, and therefore represent important potential drug targets for the treatment of diseases associated with transporter defects, outwards cell drug transport, and other diseases in which modulation of ABC transporter activity may be beneficial.

The cAMP/ATP -mediated anion channel, CFTR, is one member of the ABC transporter family commonly associated with diseases, which is expressed in a variety of cells types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. The activity of CFTR in epithelial cells is essential for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. (Quinton, 1990)

The gene encoding CFTR has been identified and sequenced (Kerem et al., 1989). CFTR comprises about 1480 amino acids that encode a protein made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The pair of

transmembrane domains is linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

Cystic fibrosis is caused by a defect in this gene which induces mutations in CFTR. Cystic fibrosis is the most common fatal genetic disease in humans, and affects -0.04% of white individuals(Bobadilla et al., 2002), for example, in the United States, about one in every 2,500 infants is affected, and up to 10 million people carry a single copy of the defective gene without apparent ill effects; moreover subjects bearing a single copy of the gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea. This effect might explain the relatively high frequency of the CF gene within the population.

In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.

In cystic fibrosis patients, mutations in endogenous respiratory epithelial CFTR fails to confer chloride and bicarbonate permeability to epithelial cells in lung and other tissues, thus leading to reduced apical anion secretion and disruptions of the ion and fluid transport. This decrease in anion transport causes an enhanced mucus and pathogenic agent accumulation in the lung triggering microbial infections that ultimately cause death in CF patients.

Beyond respiratory disease, CF patients also suffer from gastrointestinal problems and pancreatic insufficiency that result in death if left untreated. Furthermore, female subjects with cystic fibrosis suffer from decreased fertility, whilst males with are infertile.

A variety of disease causing mutations has been identified through sequence analysis of the CFTR gene of CF chromosomes (Kerem et al., 1989). AF508-CFTR, the most common CF mutation (present in at least 1 allele in~90 % of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. This deletion prevents the nascent protein from folding correctly, which protein in turn cannot exit the endoplasmic reticulum (ER) and traffic to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating. Indeed, even if AF508-CFTR is allowed to reach the cell plasma membrane by low-temperature (27°C) rescue where it can function as a cAMP-activated chloride channel, its activity is decreased significantly compared with WT-CFTR (Pasyk and Foskett, 1995).

Other mutations with lower incidence have also been identified that alter the channel regulation or the channel conductance. In case of the channel regulation mutants, the mutated protein is properly trafficked and localized to the plasma membrane but either cannot be activated or cannot function as a chloride channel (e.g. missense mutations located within the nucleotide binding domains), examples of these mutations are G551D, G178R, G1349D. Mutations affecting chloride conductance have a CFTR protein that is correctly trafficked to the cell membrane but that generates reduced chloride- flow (e.g. missense mutations located within the membrane-spanning domain), examples of these mutations are Rl 17H, R334W.

In addition to cystic fibrosis, CFTR activity modulation may be beneficial for other diseases not directly caused by mutations in CFTR, such as, for example, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren’s Syndrome.

[0014] COPD is characterized by a progressive and non-reversible airflow limitation, which is due to mucus hypersecretion, bronchiolitis, and emphysema. A potential treatment of mucus hypersecretion and impaired mucociliary clearance that is common in COPD could consist in using activators of mutant or wild-type CFTR. In particular, the anion secretion increase across CFTR may facilitate fluid transport into the airway surface liquid to hydrate the mucus and optimize periciliary fluid viscosity. The resulting enhanced mucociliary clearance would help in reducing the symptoms associated with COPD.

[0015] Dry eye disease is characterized by a decrease in tear production and abnormal tear film lipid, protein and mucin profiles. Many factors may cause dry eye disease, some of which include age, arthritis, Lasik eye surgery, chemical/thermal burns, medications, allergies, and diseases, such as cystic fibrosis and Sjogrens’s syndrome. Increasing anion secretion via CFTR could enhance fluid transport from the corneal endothelial cells and secretory glands surrounding the eye, and eventually improve corneal hydration, thus helping to alleviate dry eye disease associated symptoms. Sjogrens’s syndrome is an autoimmune disease where the immune system harms moisture-producing glands throughout the body, including the eye, mouth, skin, respiratory tissue, liver, vagina, and gut. The ensuing symptoms, include, dry eye, mouth, and vagina, as well as lung disease. Sjogrens’s syndrome is also associated with rheumatoid arthritis, systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis. The cause of the disease is believed to lie in defective protein trafficking, for which treatment options are limited. As a consequence, modulation of CFTR activity may help hydrating the various organs and help to elevate the associated symptoms.

In addition to CF, the defective protein trafficking induced by the AF508-CFTR has been shown to be the underlying basis for a wide range of other diseases, in particular diseases where the defective functioning of the endoplasmic reticulum (ER) may either prevent the CFTR protein to exit the cell, and/or the misfolded protein is degraded (Morello et al., 2000; Shastry, 2003; Zhang et al., 2012).

[0017] A number of genetic diseases are associated with a defective ER processing equivalent to the defect observed with CFTR in CF such as glycanosis CDG type 1, hereditary emphysema (α-1-antitrypsin (PiZ variant)), congenital hyperthyroidism, osteogenesis imperfecta (Type I, II, or IV procollagen), hereditary hypofibrinogenemia (fibrinogen), ACT deficiency (α-1-antichymotrypsin), diabetes insipidus (DI), neurophyseal DI (vasopvessin hormoneN2 -receptor), neprogenic DI (aquaporin II), Charcot-Marie Tooth syndrome (peripheral myelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer’s disease (APP and presenilins), Parkinson’s disease, amyotrophic lateral sclerosis, progressive supranuclear plasy, Pick’s disease, several polyglutamine neurological disorders such as Huntington’s disease, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy,

dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform encephalopathies, such as hereditary Creutzfeldt-Jakob disease (prion protein processing defect), Fabry disease (lysosomal a-galactosidase A), Straussler-Scheinker syndrome, chronic obstructive pulmonary disease (COPD), dry eye disease, and Sjogren’s Syndrome.

In addition to up-regulation of the activity of CFTR, anion secretion reduction by CFTR modulators may be beneficial for the treatment of secretory diarrheas, in which epithelial water transport is dramatically increased as a result of secretagogue activated chloride transport. The mechanism involves elevation of cAMP and stimulation of CFTR.

[0019] Regardless of the cause, excessive chloride transport is seen in all diarrheas, and results in dehydration, acidosis, impaired growth and death. Acute and chronic diarrheas remain a major medical problem worldwide, and are a significant factor in malnutrition, leading to death in children of less than five years old (5,000,000 deaths/year). Furthermore, in patients with chronic inflammatory bowel disease (IBD) and/or acquired immunodeficiency syndrome (AIDS), diarrhea is a dangerous condition

GLGP 1837

PATENT

WO 2015018823

Scheme 1: synthesis of the core and subsequent amide coupling

1 M HCI

amide coupling

HO Λ R-i

Example 2. Synthesis of intermediates

Intermediate 2: 2,2, 6,6-tetramethyltetrahydro-4H-pyran-4-one

Phorone or 2,6-dimethyl-2,5-heptadien-4-one (1 eq) is mixed with an aqueous 1 M HCI solution and the obtained emulsion is stirred at 40°C for 6 days. The water phase is extracted with DCM, and the organic phase is concentrated and purified by distillation to afford the desired product.

Alternative synthesis of Intermediate 2

[00208] A 20 L reactor is charged with aqueous 6M HCI and is warmed up to 30 °C. Molten Phorone is added while stirring vigorously at 40°C for up to 3 h until completion. The resulting solution is then cooled to 30°C and extracted with 4 x 1 L DCM. The combined organic phases are washed with saturated NaHC0₃ solution (400 niL) and are dried over Na₂S0₄. The resulting crude misture is then concentrated under vacuo, and finally purified by distillation.

Intermediate 3: 2-Amino-5,5, 7, 7-tetramethyl-4, 7-dihydro-5H-thieno[2, 3-c]pyran-3-carboxylic acid amide

Route 1 :

To a flask containing 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (Int 2, 1 eq), cyanoacetamide (1 eq), sulfur (0.9 eq) and diethylamine (1.1 eq) are added. EtOH is then added and the resulting mixture is stirred at 40°C overnight. The reaction is diluted with water and partially concentrated by evaporation causing the precipitation of a solid that is separated by filtration. The cake is then washed with water and hexane to afford the desired product.

Alternative synthesis 1 of intermediate 3

Starting from 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (Int 2, 1 eq), cyanoacetamide (1.1 eq) and morpholine (1.5 eq) are heated in EtOH at 80°C under inert atmosphere. After 6 h of heating, the mixture is cooled down, and sulfur (1.1 eq) is added. Next, the mixture is heated at 80°C overnight, then concentrated in vacuo and extracted with saturated NH₄C1 and NaHCOs. The organic phase is subsequently dried over MgSO i, filtered and concentrated in vacuo. The residue obtained can finally be purified by column chromatography.

Alternative synthesis 2 of intermediate 3

A 20L glass reactor with a mechanical stirrer (400 rpm) and a reflux condenser is charged with 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (Int 2) (1.466 kg, 9.01 mol, l eq) and 2-cyanoacetamide (1.363 kg, 1.8 eq.) followed by absolute EtOH (4.5 L) and morpholine (0.706 kg, 0.9 eq.). The resulting suspension is heated for 23 h at 75°C (internal temperature). After 23 h, sulfur (0.26 kg, 0.9 eq.) is added in one portion at 75°C and the resulting suspension is stirred further for 90 min after which the resulting solution is cooled to 20°C. Then, the entire solution is concentrated in vacuo (50 mbar / 45°C) to yield a solid residue. Water (13.5 L) is added in one portion at 75°C and the mixture is cooled to 22°C. Stirring (700 rpm at 22°C) is continued for 2.5h. The solids are separated by filtration, dried under vacuum suction, and subsequently in the vacuum oven at 40°C over 3d to obtain yield the desired product.

Intermediate 11: Dipyrazolo l,5-a;l ‘,5’-dJpyrazine-4,9-dione

[00213] 10 g (89 mmol) of pyrrazole carboxylic acid is suspended in toluene 100 mL at room temperature. Then, 2 equivalents of thionyl chloride are added, followed by a catalytic amount of DMF (0.5 ml). The mixture was stirred for lh at 75°C. After lh at 70 °C, the reaction was cooled to room temperature, the solid material was collected by filtration, washed with toluene and resuspended in DCM. Triethylamine (2 equivalents) was added and the suspension was stirred for 2h at room temperature. The product was collected by filtration, washed with DCM and dried at 40°C under vacuum to afford the desired product.

Example 4. Illustrative examples for the Preparation of the Compounds of Invention

Compound 2: N-(3-carbamoyl-5, 5, 7, 7 -tetramet yl-5 , 7-dihydro-4H-thieno[2, 3-c]pyran-2-yl)-lH-pyr zole-5-carboxamide

[00274] Intermediate 3 (15 g, 59 mmol) and 2H-pyrazole-3-carboxylic acid (9.9 g, 88 mmol) are suspended in DCM (250 mL). Mukaiyama reagent (2-chloro-l-methylpyridinium iodide) (18.1 g, 71 mmol), TEA (24.7 mL, 177 mmol) and DMAP (3.6 g, 29 mmol) are added. The reaction mixture is stirred at 40°C overnight and then cooled. The mixture is evaporated and the obtained crude is suspended in a 1 M HC1 solution. After stirring for 10 min, the suspension is filtered and obtained precipitate is isolated. This precipitate is re-suspended in a 0.1 M citric acid solution. Again, filtration gives a precipitate. A third trituration is done using ether as a solvent to give a precipitate after filtration. Finally, the precipitate (13.6 g) is suspended in EtOH (816 mL) and heated at reflux. To this suspension, 65 mL of DMF is added and a clear solution is obtained. The solution is concentrated to 275 mL and cooled at 0°C. A suspension is obtained, the solid is separated by filtration, and the cake is dried affording the desired product.

Alternative route

[00275] To a stirred (400 rpm) solution of 600 g (2.36 mol) of Intermediate 3 in DMAc (6 L), is added at ambient temperature 1.3 equivalents of Intermediate 11. To this resulting suspension, at room temperature, DIPEA (618 mL, 1.5 eq.) is added in small portions over a period of 5 min. The resulting suspension is heated to 80 °C and stirred for 18h at this temperature. The resulting mixture is cooled to 15°C and an aqueous saturated NH₄C1 solution (7.5 L) is added over 30 minutes thus maintening the internal temperature between 15-24 °C. The resulting solid product is collected by filtration, and triturated with water (7.5 L) under mechanical stirring (600 rpm) for 30 min. The resulting suspension is filtered and the resulting solid is triturated in MTBE (8 L) under mechanical stirring for 45 minutes. The resulting solid is separated by filtration, and dried in a vacuum stove.

[00276] Finally, the solid is purified by hot trituration in ethanol. Therefore, the crude solid is suspended in absolute EtOH (16 L) for 1.5 h at 78 °C. The suspension is cooled to 20 °C and subsequently stirred for another hour. The solid product was collected by filtration, washed with 500 mL and again with 200 ml absolute EtOH, then dried to yield the desired product.

1H NMR PREDICT

13 C NMR PREDICT

REFERENCES

Patent ID	Patent Title	Submitted Date	Granted Date
US2015045327	NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF CYSTIC FIBROSIS	2014-08-05	2015-02-12
US2016022633	NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF CYSTIC FIBROSIS	2015-07-24	2016-01-28
US2016122331	SUBSTITUTED TETRAHYDROPYRANS AND METHOD OF USE	2015-10-29	2016-05-05
US2016120841	SUBSTITUTED CHROMANES AND METHOD OF USE	2015-10-28	2016-05-05

First speaker at 1st disclosures is Steven Van der Plas of @GalapagosNV talking about a cystic fibrosis treatment #ACSSanFran

http://acsmeetings.cenmag.org/first-time-disclosures-of-clinical-candidates-at-acssanfran/?utm_source=Facebook&utm_medium=Social&utm_campaign=MeetingSF17

//////////////GLGP 1837

NC(=O)c2c3CC(C)(C)OC(C)(C)c3sc2NC(=O)c1ccnn1

EVP 4593

April 6, 2017 1:38 pm / Leave a comment

QNZ

Image result for EVP 4593

EVP4593; EVP 4593; EVP-4593

M.Wt	356.42	545380-34-5; QNZ (EVP4593); QNZ; 6-Amino-4-(4-phenoxyphenylethylamino)quinazoline; N4-(4-phenoxyphenethyl)quinazoline-4,6-diamine;
Formula	C₂₂H₂₀N₄O
CAS No	545380-34-5

QNZ(EVP4593) is a derivative of 6-aminoquinazoline class that has been previously isolated as an inhibitor of PMA/PHA-induced NF-κB pathway activation in Jurkat cells (IC50= 9 nM).

QNZ(EVP4593) is a derivative of 6-aminoquinazoline class that has been previously isolated as an inhibitor of PMA/PHA-induced NF-κB pathway activation in Jurkat cells (IC50= 9 nM).
IC50 Value: 9 nM [1]
Target: NF-kB signaling
in vitro: The efficacy of EVP4593 was dose-dependent in the range between 100 uM and 400 uM in the fly food. The EVP4593 had no significant effect on climbing performance of HD flies at 50 ?M. The EVP4593 had no toxic effects on Drosophila in the range of concentrations tested in our assays (50 – 400 ?M) [1]. Addition of 300 nM of EVP4593 resulted in strong attenuation of SOC Ca2+ influx in YAC128 MSN neurons. On average the amplitude of SOC Ca2+ entry in YAC128 MSN was reduced from 0.30 ± 0.02 (n = 29) in the presence of DMSO control to 0.11 ± 0.02 (n = 54) in the presence of 300 nM of EVP4593 (p < 0.001).
in vivo:

Paper

Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I

Robin Krishnathas,^a Erik Bonke,^b Stefan Dröse,^b Volker Zickermann^c^d and Hamid R. Nasiri*^a

Author affiliations

*Corresponding authors

^aJohann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Straße 7, D-60438 Frankfurt am Main, Germany
E-mail: Nasiri@nmr.uni-frankfurt.de

^bDepartment of Anaesthesiology, Intensive-Care Medicine and Pain Therapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany

^cStructural Bioenergetics Group, Institute of Biochemistry II, Medical School, Goethe-University, 60438 Frankfurt am Main, Germany

^dCluster of Excellence Frankfurt “Macromolecular Complexes,”, Goethe-University, 60438 Frankfurt am Main, Germany

Abstract

By probing the quinone substrate binding site of mitochondrial complex I with a focused set of quinazoline-based compounds, we identified substitution patterns as being critical for the observed inhibition. The structure activity relationship study also resulted in the discovery of the quinazoline 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (EVP4593) as a highly potent inhibitor of the multisubunit membrane protein. EVP4593 specifically and effectively reduces the mitochondrial complex I-dependent respiration with no effect on the respiratory chain complexes II–IV. Similar to established Q-site inhibitors, EVP4593 elicits the release of reactive oxygen species at the flavin site of mitochondrial complex I. Recently, EVP4593 was nominated as a lead compound for the treatment of Huntingtons disease. Our results challenge the postulated primary mode-of-action of EVP4593 as an inhibitor of NF-κB pathway activation and/or store-operated calcium influx.

PAPER

Bioorganic & Medicinal Chemistry (2003), 11(3), 383-391.

Abstract

We disclose here a new structural class of low-molecular-weight inhibitors of NF-κB activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure–activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-κB transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-κB transcriptional activation and TNF-α production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.

Compound 11q exhibited a highly inhibitory activity toward NF-κB activation and also showed an anti-inflammatory effect.


11q (72 mg, 77% yield):

mp 168–170 C;

1 H NMR (DMSO-d6) d 8.33 (br s, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.40–7.34 (m, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.20–7.07 (m, 3H), 6.98–6.92 (m, 4H), 5.59 (br s, 2H), 3.79–3.72 (m, 2H), 2.95 (t, J=7.3 Hz, 2H);

MS (TOF) m/z 357 (M + H)+; anal. calcd for C22H20N4O 1.0H2O: C, 70.57; H, 5.65; N, 14.96. Found: C, 70.48; H, 5.60; N, 14.87.

REF
Bioorganic & Medicinal Chemistry (2003), 11(18), 3869-3878.
JP 2004059454
CN 1709259
Bioorganic & Medicinal Chemistry Letters (2009), 19(19), 5665-5669
Journal of Medicinal Chemistry (2014), 57(6), 2247-2257

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//////////

C1=CC=C(C=C1)OC2=CC=C(C=C2)CCNC3=NC=NC4=C3C=C(C=C4)N

Process Development and Good Manufacturing Practice Production of a Tyrosinase Inhibitor via Titanium-Mediated Coupling between Unprotected Resorcinols and Ketones

April 4, 2017 10:25 am / Leave a comment

(S)-4-(2,4-Dihydroxyphenyl)-N-(1-phenylethyl)piperidine-1-carboxamide (1)

In a………………….. to yield crude 1 (3.51 kg, 77%, 97.7 A% purity). Recrystallization: In a 100 L double jacketed reactor were charged crude 1 (3.51 kg, 10.31 mol, 1.0 equiv), iPrOH (27.0 L, 7.5 vol), AcOH (74.1 g), and water (27.0 L, 7.5 vol). The suspension was warmed to reflux and turned to a solution after 30 min of reflux. Heating was stopped, and the reaction medium was allowed to cool to 23 °C over 20 h. The suspension was filtered through a 25 μm filter medium; the cake was washed with a mixture of water (3.6 L) and AcOH (7.3 g) and the solid collected and dried under vacuum at 45 °C for 48 h to yield 1 (2.86 kg, 81%, 98.5 A% purity).

¹H NMR (400 MHz, DMSO-d₆): δ 9.11 (s, 1H), 8.96 (s, 1H), 7.30–7.31 (m, 4), 7.19–7.20 (m, 1H), 6.79 (d, J = 8.3 Hz, 2H), 6.7 (d, J = 7.9 Hz, 2H), 6.28 (d, J = 2.4 Hz, 1H), 6.16 (dd, J = 8.3, 2.4 Hz, 1H), 4.85–4.87 (m, 1 H), 4.13 (d, J = 12.9 Hz, 2H), 2.85 (t, J = 11.9 Hz, 1H), 2.70 (t, J = 12.7 Hz, 2H), 1.64 (d, J = 12.1 Hz, 2H), 1.40–1.41 (m, 5H).

¹³C NMR (101 MHz, DMSO-d₆) δ 156.6, 156.0, 155.2, 146.3, 127.9, 126.7, 126.1, 125.9, 122.5, 106.0, 102.4, 49.3, 44.4, 34.7, 31.8, 31.7, 22.9;

mp: 200–201 °C;

HRMS (m/z, ES⁺) for C₂₀H₂₅N₂O₃ (M + H)⁺ calcd. 341.1865, measd. 341.1859.

Process Development and Good Manufacturing Practice Production of a Tyrosinase Inhibitor via Titanium-Mediated Coupling between Unprotected Resorcinols and Ketones

Thibaud Gerfaud ^*

, Cédric Martin, Karinne Bouquet, Sandrine Talano, Corinne Millois-Barbuis, Branislav Musicki, Jean-Guy Boiteau ^*

, and Isabelle Cardinaud

Nestlé Skin Health R&D, 2400 Route des colles BP 87, 06902 Sophia-Antipolis Cedex, France

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00036

*E-mail: Thibaud.Gerfaud@galderma.com., *E-mail: Jean-Guy.Boiteau@galderma.com.

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

Thibaud Gerfaud

Team Leader Process Chemistry

Boiteau Jean-Guy

Head of Process Research & Development

Nestlé Skin Health

Abstract

A concise and economically attractive process for the synthesis of a novel tyrosinase inhibitor has been developed and implemented on a multikilogram scale under GMP. A major achievement to the success of the process is the development of a direct coupling between free resorcinol and ketone. First developed under basic conditions, this coupling has been turned to a novel titanium(IV) mediated process allowing good selectivity, easy isolation, and high atom efficiency. Other key steps feature an alkene reduction by palladium catalyzed transfer hydrogenation and a urea formation using N,N′-disuccinimidyl carbonate as the carbonyl source. This route allowed us to produce kilogram batches of the candidate to support preclinical and clinical studies.

Boiteau, J.-G.; Bouquet, K.; Talano, S.; Millois-Barbuis, C. Patent WO 2010/063774 A1, 2010.

More………………

Cas 1228342-28-6

MF C₂₀ H₂₄ N₂ O_3,

_{MW 340.42}

1-Piperidinecarboxamide, 4-(2,4-dihydroxyphenyl)-N-[(1S)-1-phenylethyl]-

4-(2,4-Dihydroxyphenyl)-N-[(1S)-1-phenylethyl]-1-piperidinecarboxamide
4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid N-((S)-1-phenylethyl)amide

Inventors	Jean-Guy Boiteau , Karine Bouquet , Sandrine Talano , Barbuis Corinne Millois
Applicant	Galderma Research & Development

Hyperpigmentation disorders such as melasma are characterized by an increase in melanin synthesis which accumulates in the epidermis and is responsible for a darkening of the skin. Melanogenesis occurs in the basal layer of the epidermis into specific organelles of the melanocytes called melanosomes.

A detailed analysis of the biosynthetic pathway reveals that tyrosinase is a key enzyme in melanogenesis and is responsible for the oxidation of tyrosine into DOPA (3,4-dihydroxyphenylalanine) and DOPA quinone.

It is a melanogenesis inhibitor working through the inhibition of tyrosinase (IC₅₀ = 0.1 μM on normal human epidermal melanocytes) currently under development at Nestlé Skin Health R&D for the topical treatment of hyperpigmentation disorders. REF 1-5

WO 2010063774

Novel 4- (azacycloalkyl)benzene-l ,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and in cosmetics

The invention relates to novel 4- (azacycloalkyl) benzene-1, 3-diol compounds as industrial and useful products. It also relates to the process for the preparation thereof and to the use thereof, as tyrosinase inhibitors, in pharmaceutical or cosmetic compositions for use in the treatment or prevention of pigmentary disorders.

Skin pigmentation, in particular human skin pigmentation, is the result of melanin synthesis by dendritic cells, melanocytes. Melanocytes contain organelles called melanosomes which transfer melanin into the upper layers of keratinocytes which are then transported to the surface of the skin through differentiation of the epidermis (Gilchrest BA, Park HY, Eller MS, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing VJ, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909) .

Among the enzymes of melanogenesis, tyrosinase is a key enzyme which catalyses the first two steps of melanin synthesis. Homozygous mutations of tyrosinase cause oculocutaneous albinism type I characterized by a complete lack of melanin synthesis (Toyofuku K, Wada I, Spritz RA, Hearing VJ, The molecular basis of oculocutaneous albinism type 1 (OCAl) : sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem J 2001; 355: 259-269) .

In order to treat pigmentation disorders resulting from an increase in melanin production, for which there is no treatment that meets all the expectations of patients and dermatologists, it is important to develop new therapeutic approaches.

Most of the skin-lightening compounds that are already known are phenols or hydroquinone derivatives.

These compounds inhibit tyrosinase, but the majority of them are cytotoxic to melanocytes owing to the formation of quinones. There is a risk of this toxic effect causing a permanent depigmentation of the skin. The obtaining of compounds that can inhibit melanogenesis while at the same time being very weakly cytotoxic or devoid of toxicity to melanocytes is most particularly sought.

Among the compounds already described in the literature, patent application WO 99/15148 discloses the use of 4-cycloalkyl resorcinols as depigmenting agents .

Patent FR2704428 discloses the use of 4-halo-resorcinols as depigmenting agents.

Patent applications WO 2006/097224 and WO 2006/097223 disclose the use of 4-cycloalkylmethyl resorcinols as depigmenting agents.

Patent application WO 2005/085169 discloses the use of alkyl 3- (2, 4-dihydroxyphenyl) propionate as a depigmenting agent.

Patent application WO 2004/017936 discloses the use of 3- (2, 4-dihydroxyphenyl) acrylamide as a depigmenting agent.

Patent application WO 2004/052330 discloses the use of 4- [ 1, 3] dithian-2-ylresorcinols as depigmenting agents .

More particularly, patent EP0341664 discloses the use of 4-alkyl resorcinols as depigmenting agents, among which 4-n-butyl resorcinol, also known as rucinol, is part of the composition of a depigmenting cream sold under the name Iklen^®.

The applicant has now discovered, unexpectedly and surprisingly, that novel compounds of 4- (azacycloalkyl) benzene-1, 3-diol structure have a very good tyrosinase enzyme-inhibiting activity and a very low cytotoxicity. Furthermore, these compounds have a tyrosinase enzyme-inhibiting activity that is greater than that of rucinol while at the same time being less cytotoxic with respect to melanocytes than rucinol.

These compounds find uses in human medicine, in particular in dermatology, and in the cosmetics field.

FR 2939135

References

Briganti, S.; Camera, E.; Picardo, M. Pigm. Cell Res. 2003, 16, 101, DOI: 10.1034/j.1600-0749.2003.00029.x
2.

Brenner, M.; Hearing, V. J. Photochem. Photobiol. 2008, 84, 539, DOI: 10.1111/j.1751-1097.2007.00226.x
3.

(a) Schallreuter, K. U.; Kothari, S.; Chavan, B.; Spencer, J. D. Exp. Dermatol. 2008, 17, 395, DOI: 10.1111/j.1600-0625.2007.00675.x

(b) Cooksey, C. J.; Garratt, P. J.;Land, E. J.; Pavel, S.; Ramsden, C. A.; Riley, P. A.; Smit, N. P.J. Biol. Chem. 1997, 272, 26226, DOI: 10.1074/jbc.272.42.26226

(c) Stratford, M. R. L.; Ramsden, C. A.; Riley, P. A.Bioorg. Med. Chem. 2013, 21, 1166, DOI: 10.1016/j.bmc.2012.12.031
4.

Chang, T. S. Int. J. Mol. Sci. 2009, 10, 2440, DOI: 10.3390/ijms10062440
5.

Hypopigmentation effect have already been demonstrated for resorcinols; see:

(a) Kim, D. S.; Kim, S. Y.;Park, S. H.; Choi, Y. G.; Kwon, S. B.; Kim, M. K.; Na, J. I.; Youn, S. W.; Park, K. C. Biol. Pharm. Bull. 2005,28, 2216, DOI: 10.1248/bpb.28.2216

(b) Khemis, A.; Kaiafa, A.;Queille-Roussel, C.; Duteil, L.; Ortonne, J. P. Br. J. Dermatol.2007, 156, 997, DOI: 10.1111/j.1365-2133.2007.07814.x

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

O=C(N[C@@H](C)c1ccccc1)N2CCC(CC2)c3ccc(O)cc3O

Enantioselective synthesis of a cyclobutane analogue of Milnacipran

April 4, 2017 10:23 am / Leave a comment

(1R,2S)-2-(Aminomethyl)-N,N-diethyl-1 phenylcyclobutanecarboxamide (19)

1 H NMR (CDCl3) δ 7.36–7.33 (m, 4H), 7.25–7.21 (m, 1H), 3.51–3.43 (qd, J = 13.8 Hz, 6.8 Hz, 1H), 3.15–2.87 (m, 7H), 2.81–2.72 (m, 2H), 2.23–2.14 (m, 1H), 2.04–1.97 (m, 1H), 1.62 (tdd, J = 10.5 Hz, 5.7 Hz, 2.6 Hz, 1H), 1.07 (t, J = 7.1 Hz, 3H), 0.35 (t, J = 7.1 Hz, 3H) ppm;

13C NMR (CDCl3) δ 172.7, 143.3, 128.8, 126.4, 125.3, 54.6, 44.4, 42.4, 41.0, 39.5, 31.1, 19.0, 12.2, 12.0 ppm;

IR (neat) 3364, 1622, 1437, 905, 728 cm−1 ;

[α] 20 D +1.5 (c 0.5, CHCl3) (lit.5 [α]D +0.84);

ESI-MS (ES+ ) 261 [M + H]+ ; HRMS m/z calcd for C16H25N2O: 261.1958, found: 261.1961;

chiral HPLC (CHIRALCEL OJ-RH 150 × 4.6 mm, H2O/MeOH 35 : 65, flow rate 1 mL min−1 , detection at 254 nm), tmajor = 8.5 min, tminor = 6.7 min, er 95 : 5. Of note, compound 19 was acetylated with acetic anhydride/NEt3 prior to HPLC analysis.

5 S. Cuisiat, A. Newman-Tancredi, O. Vitton and B. Vacher, WO patent, 112597, 2010

Enantioselective synthesis of a cyclobutane analogue of Milnacipran

Org. Chem. Front., 2017, Advance Article
DOI: 10.1039/C7QO00140A, Research Article

Dinh-Vu Nguyen, Edmond Gravel, David-Alexandre Buisson, Marc Nicolas, Eric Doris
An optically active cyclobutane analogue of Milnacipran was synthesized from phenylacetonitrile, and its cis-stereochemistry was controlled by an epimerization step.

Enantioselective synthesis of a cyclobutane analogue of Milnacipran

Dinh-Vu Nguyen,^a Edmond Gravel,^a David-Alexandre Buisson,^a Marc Nicolas^b and Eric Doris*^a

^aService de Chimie Bioorganique et de Marquage (SCBM), CEA, Université Paris-Saclay, 91191 Gif-sur-Yvette, France

E-mail: eric.doris@cea.fr

^bInstitut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 avenue Hubert Curien, 31035 Toulouse, France

Abstract

The asymmetric synthesis of a cyclobutane analogue of the antidepressant drug Milnacipran is reported. The optically active derivative incorporates a central cyclobutane ring in lieu of the cyclopropane unit classically found in Milnacipran. The two stereogenic centres borne by the cyclobutane were sequentially installed starting from phenylacetonitrile.

//////////Enantioselective, cyclobutane analogue Milnacipran

The greening of peptide synthesis

April 4, 2017 10:19 am / Leave a comment

The greening of peptide synthesis

Stefan B. Lawrenson,^a Roy Arav^a and Michael North*^a

*Corresponding authors

^aGreen Chemistry Centre of Excellence, Department of Chemistry, University of York, York, UK
E-mail: Michael.north@york.ac.uk

Abstract

The synthesis of peptides by amide bond formation between suitably protected amino acids is a fundamental part of the drug discovery process. However, the required coupling and deprotection reactions are routinely carried out in dichloromethane and DMF, both of which have serious toxicity concerns and generate waste solvent which constitutes the vast majority of the waste generated during peptide synthesis. In this work, propylene carbonate has been shown to be a green polar aprotic solvent which can be used to replace dichloromethane and DMF in both solution- and solid-phase peptide synthesis. Solution-phase chemistry was carried out with Boc/benzyl protecting groups to the tetrapeptide stage, no epimerisation occurred during these syntheses and chemical yields for both coupling and deprotection reactions in propylene carbonate were at least comparable to those obtained in conventional solvents. Solid-phase peptide synthesis was carried out using Fmoc protected amino acids on a ChemMatrix resin and was used to prepare the biologically relevant nonapeptide bradykinin with comparable purity to a sample prepared in DMF.

Boc-Ala-Phe-OBn 5a ref S1

Boc-Ala-OH (324 mg, 1.71 mmol) and HCl.H-Phe-OBn (500 mg, 1.71 mmol) were coupled according to the general coupling procedure. The residue was purified using flash column chromatography (35:65, EtOAc:PE) to give Boc-Ala-Phe-OBn 5a as a white crystalline solid (682 mg, 93%). RF = 0.34 (40:60, EtOAc:PE);

mp 95.6-96.3 °C;

[α]D 23 -27.7 (c 1.0 in MeOH);

IR (Neat) νmax 3347 (m), 3063 (w), 3029 (w), 2928 (m), 2852 (w), 1735 (w), 1684

1666

and 1521 (s) cm-1;

1H NMR (400 MHz, CDCl3): δ = 7.36-7.31 (m, 3H, ArH), 7.29-7.24 (m, 2H, ArH), 7.26-7.21 (m, 3H, ArH), 7.04-6.97 (m, 2H, ArH), 6.72 (d J 7.7 Hz, 1H, Phe-NH), 5.16-5.10 (m, 1H, Ala-NH), 5.13 (d J 12.1 Hz, 1H, OCH2Ph), 5.07 (d J 12.1 Hz, 1H, OCH2Ph), 4.88 (dt, J 7.7, 5.9 1H, PheNCH), 4.11 (br, 1H, Ala-NCH), 3.13 (dd J 13.9, 6.1 Hz, 1H, CH2Ph), 3.08 (dd J 13.9, 6.1 Hz, 1H, CH2Ph), 1.41 (s, 9H, C(CH3)3), 1.29 (d J 6.6 Hz, 3H, CH3);

13C NMR (100 MHz, CDCl3): δ = 172.3 (C=O), 171.2 (C=O), 155.6 (NC=O), 135.7 (ArC), 135.1 (ArC), 129.5 (ArCH), 128.7 (ArCH), 128.6 (ArCH), 127.2 (ArCH), 80.2 (CMe3), 67.4 (OCH2Ph), 53.3 (Phe-NCH), 50.3 (Ala-NCH), 38.0 (CH2Ph), 28.4 (C(CH3)3), 18.5 (CH3);

MS (ESI) m/z 449 [(M+Na)+ , 100]; HRMS (ESI) m/z calculated for C24H30N2O5Na 449.2048 (M+Na)+ , found 449.2047 (0.6 ppm error).

S1 J. Nam, D. Shin, Y. Rew and D. L. Boger, J. Am. Chem. Soc., 2007, 129, 8747–8755; Q. Wang, Y. Wang and M. Kurosu, Org. Lett., 2012, 14, 3372–3375.

General procedure for peptide coupling reactions in PC To a suspension of an N-Boc-amino acid (1.0 eq.) and an amino acid or peptide benzyl ester (1.0 eq.) in PC (5 mL mmol-1), at 0 °C, was added a solution of HOBt (1.1 eq.) and i Pr2EtN (3.0 eq.) in a minimal quantity of PC. EDC (1.1 eq.) was added dropwise and the reaction mixture was allowed to stir at room temperature for 16h. The reaction mixture was then diluted using EtOAc (50 mL) and washed with 1M HClaq (3 × 25 mL), saturated Na2CO3 (3 × 25 mL) and H2O (3 × 25 mL). The organic layer was dried (MgSO4 ), filtered and concentrated in vacuo. Any residual PC was removed via short path distillation. Purification details for each peptide and characterising data are given in the supplementary information. General procedure for Boc deprotections in PC An N-Boc-peptide benzyl ester (1.0 eq.) was dissolved in a minimum amount of PC and trifluoroacetic acid (60 eq.) was added. The reaction mixture was allowed to stir for 3h. at room temperature before being concentrated in vacuo. Any residual PC was removed via short path distillation. Characterising data for each deprotected peptide are given in the supplementary information.

Procedure for Boc deprotection of dipeptide 5a using HCl in PC Boc-Ala-Phe-OBn 5a (50 mg, 0.117 mmol) was dissolved in PC (2.34 mL). MeOH (0.40 mL, 9.8 mmol) was added and the solution cooled to 0 o C. Acetyl chloride (0.67 mL, 9.36 mmol) was added dropwise and the solution allowed to stir at room temperature for 2h. Then, PC was removed by short path distillation. The residue was suspended in Et2O and stirred for 5 minutes before being filtered to give HCl.Ala-Ph-OBn as a white solid (32.4 mg, 76%).

Propylene carbonate 1 has been shown to be a green replacement for reprotoxic amide based solvents which are widely used in peptide synthesis. Both solution- and solidphase peptide synthesis can be carried out in propylene carbonate using acid and base labile amine protecting groups respectively. No significant racemisation of the activated amino acids occurs in propylene carbonate and the viability of solid-phase peptide synthesis in propylene carbonate was demonstrated by the synthesis of the nonapeptide bradykinin.

///////////

Debio-1452

April 3, 2017 10:32 am / Leave a comment

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Debio-1452, AFN 1252

AFN-1252; UNII-T3O718IKKM; API-1252; CAS 620175-39-5; CHEMBL1652621; (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

MFC₂₂ H₂₁ N₃ O₃
2-Propenamide, N-methyl-N-[(3-methyl-2-benzofuranyl)methyl]-3-(5,6,7,8-tetrahydro-7-oxo-1,8-naphthyridin-3-yl)-, (2E)-
MW375.42
Phase 2, clinical trials for the oral treatment of staphylococcal infections, including hospital and community-acquired MRSA and acute bacterial skin and skin structure infections
Qualified Infectious Disease Product designation

GlaxoSmithKline plc INNOVATOR

Debiopharm SA,

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Image result for Affinium

Melioidosis, Enoyl ACP reductase Fabl inhibitor

Debio-1452, a novel class fatty acid biosynthesis (FAS) II pathway inhibitor, was studied in phase II clinical trials for the oral treatment of staphylococcal infections, including hospital and community-acquired MRSA and acute bacterial skin and skin structure infections. Debiopharm is developing oral and IV formulations of a prodrug of Debio-1452, Debio-1450.

Infections caused by or related to bacteria are a major cause of human illness worldwide. Unfortunately, the frequency of resistance to standard antibacterials has risen dramatically over the last decade, especially in relation to Staphylococcus aureus. For example, such resistant S. aureus includes MRSA, resistant to methicillin, vancomycin, linezolid and many other classes of antibiotics, or the newly discovered New Delhi metallo-beta-lactamase- 1 (NDM-1) type resistance that has shown to afford bacterial resistant to most known antibacterials, including penicillins, cephalosporins, carbapenems, quinolones and fluoroquinolones, macrolides, etc. Hence, there exists an urgent, unmet, medical need for new agents acting against bacterial targets..

In recent years, inhibitors of Fabl, a bacterial target involved in bacterial fatty acid synthesis, have been developed and many have been promising in regard to their potency and tolerability in humans, including a very promising Fabl inhibitor, (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-l,8-naphthyridin-3-yl)acrylamide. This compound, however, has been found to be difficult or impracticable to formulate into acceptable oral and parenteral (e.g., intravenous or subcutaneous) formulations, and has marked insolubility, poor solution stability, and oral bioavailability. Much effort, over a decade or more, has been expended to design and synthesize an alternative compound that retains the significant inhibition of Fabl upon administration, but has improved physical and chemical characteristics that finally allow for practical oral and parenteral formulations. Up to now, no such compound has been identified that has adequate stability in the solid state, in aqueous solutions, together with excellent oral bioavailability that is necessary for oral and/or a parenteral administration, and is capable of being formulated into an oral and/or intravenous or intramuscular drug product using practical and commonly utilized methods of sterile formulation manufacture.

Debio-1452 is expected to have high potency against all drug-resistant phenotypes of staphylococci, including hospital and community-acquired MRSA.

Affinium obtained Debio-1452, also known as API-1252, through a licensing deal with GlaxoSmithKline. In 2014, Debiopharm acquired the product from Affinium.

In 2013, Qualified Infectious Disease Product designation was assigned to the compound for the treatment of acute bacterial skin and skin structure infections (ABSSSI).

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SYNTHESIS

Heck coupling of 6-bromo-3,4-dihydro-1,8-naphthyridin-2-one with t-butyl acrylate in the presence of Pd(OAc)2, DIEA and P(o-tol)3 in propionitrile/DMF or acetonitrile/DMF affords naphthyridinyl-acrylate,

Whose t-butyl ester group is then cleaved using TFA in CH2Cl2 to furnish, after treatment with HCl in dioxane, 3-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)acrylic acid hydrochloride

SEE BELOW………

Finally, coupling of acid with N-methyl-N-(3-methylbenzofuran-2-ylmethyl)amine using EDC, HOBt and DIEA in DMF provides the target AFN-1252

Preparation of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)amine :

Chlorination of 3-methylbenzofuran-2-carboxylic acid with (COCl)2 and catalytic DMF, followed by condensation with CH3NH2 in CH2Cl2 yields the corresponding benzofuran-2-carboxamide,

Which is then reduced with LiAlH4 in THF to furnish N-methyl-N-(3-methylbenzofuran-2-ylmethyl)amine.

CONTD……..

Reduction of 2-aminonicotinic acid with LiAlH4 in THF gives (2-amino-3-pyridinyl)methanol ,

which upon bromination with Br2 in AcOH yields (2-amino-5-bromo-3-pyridinyl)methanol hydrobromide.

Substitution of alcohol with aqueous HBr at reflux provides the corresponding bromide,

which undergoes cyclocondensation with dimethyl malonate in the presence of NaH in DMF/THF to furnish methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate.

Hydrolysis of ester with NaOH in refluxing MeOH, followed by decarboxylation in refluxing HCl leads to 6-bromo-3,4-dihydro-1,8-naphthyridin-2-one

PATENT

US-20170088822

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Aurigene Discovery Technologies Ltd

Novel co-crystalline polymorphic form of a binary enoyl-acyl carrier protein reductase (FabI) and FabI inhibitor ie AFN-1252. The FabI was isolated from Burkholderia pseudomallei (Bpm). The co-crystal is useful for identifying an inhibitor of FabI, which is useful for treating BpmFabI associated disease ie melioidosis. Appears to be the first patenting to be seen from Aurigene Discovery Technologies or its parent Dr Reddy’s that focuses on BpmFabI crystal; however, see WO2015071780, claiming alkylidine substituted heterocyclyl derivatives as FabI inhibitors, useful for treating bacterial infections. Aurigene was investigating FabI inhibitors, for treating infectious diseases, including bacterial infections such as MRSA infection, but its development had been presumed to have been discontinued since December 2015; however, publication of this application would suggest otherwise.

WO2015071780

PATENTS

US 20060142265

http://www.google.co.in/patents/US20060142265

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013190384&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Patent ID	Patent Title	Submitted Date	Granted Date
US8901105	Prodrug derivatives of (E)-N-methyl-N-((3-M ethylbenzofuran-2-yl)methyl)-3-(7-oxo-5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-3-yl)acrylamide	2013-08-26	2014-12-02
US2015065415	PRODRUG DERIVATIVES OF (E)-N-METHYL-N-((3-METHYLBENZOFURAN-2-YL)METHYL)-3-(7-OXO-5, 6, 7, 8-TETRAHYDRO-1, 8-NAPHTHYRIDIN-3-YL)ACRYLAMIDE	2014-11-06	2015-03-05

Patent ID	Patent Title	Submitted Date	Granted Date
US7049310	Fab I inhibitors	2004-07-29	2006-05-23
US7250424	Fab I inhibitors	2006-06-01	2007-07-31
US7879872	Compositions comprising multiple bioactive agents, and methods of using the same	2006-06-29	2011-02-01
US2009042927	Salts, Prodrugs and Polymorphs of Fab I Inhibitors	2009-02-12
US7741339	Fab I Inhibitors	2009-09-03	2010-06-22
US8153652	Fab I Inhibitors	2011-04-28	2012-04-10
US2012010127	Compositions Comprising Multiple Bioactive Agents, and Methods of Using the Same	2012-01-12
US2013281442	Compounds for Treatment of Bovine Mastitis	2011-06-13	2013-10-24
US2013150400	SALTS, PRODRUGS AND POLYMORPHS OF FAB I INHIBITORS	2012-08-09	2013-06-13
US2014309191	SALTS, PRODRUGS AND POLYMORPHS OF FAB I INHIBITORS	2013-11-08	2014-10-16

////////////Debio-1452, AFN 1252,AFN-1252, UNII-T3O718IKKM, API-1252, 620175-39-5, PRECLINICAL, Phase 2, Qualified Infectious Disease Product designation

CC1=C(OC2=CC=CC=C12)CN(C)C(=O)C=CC3=CC4=C(NC(=O)CC4)N=C3

FDA approves new drug to treat multiple sclerosis Ocrevus (ocrelizumab)

March 30, 2017 12:55 am / 1 Comment on FDA approves new drug to treat multiple sclerosis Ocrevus (ocrelizumab)

FDA approves new drug to treat multiple sclerosis

03/29/2017

On March 28, the U.S. Food and Drug Administration approved Ocrevus (ocrelizumab) to treat adult patients with relapsing forms of multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS). This is the first drug approved by the FDA for PPMS. Ocrevus is an intravenous infusion given by a health care professional.

“Multiple sclerosis can have a profound impact on a person’s life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy not only provides another treatment option for those with relapsing MS, but for the first time provides an approved therapy for those with primary progressive MS.”

MS is a chronic, inflammatory, autoimmune disease of the central nervous system that disrupts communication between the brain and other parts of the body. It is among the most common causes of neurological disability in young adults and occurs more frequently in women than men. For most people with MS, episodes of worsening function (relapses) are initially followed by recovery periods (remissions). Over time, recovery may be incomplete, leading to progressive decline in function and increased disability. Most people experience their first symptoms of MS between the ages of 20 and 40.

PPMS is characterized by steadily worsening function from the onset of symptoms, often without early relapses or remissions. The U.S. Centers for Disease Control and Prevention estimates that approximately 15 percent of patients with MS have PPMS.

The efficacy of Ocrevus for the treatment of relapsing forms of MS was shown in two clinical trials in 1,656 participants treated for 96 weeks. Both studies compared Ocrevus to another MS drug, Rebif (interferon beta-1a). In both studies, the patients receiving Ocrevus had reduced relapse rates and reduced worsening of disability compared to Rebif.

In a study of PPMS in 732 participants treated for at least 120 weeks, those receiving Ocrevus showed a longer time to the worsening of disability compared to placebo.

Ocrevus should not be used in patients with hepatitis B infection or a history of life-threatening infusion-related reactions to Ocrevus. Ocrevus must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Ocrevus can cause infusion-related reactions, which can be serious. These reactions include, but are not limited to, itchy skin, rash, hives, skin redness, flushing, low blood pressure, fever, tiredness, dizziness, headache, throat irritation, shortness of breath, swelling of the throat, nausea, and fast heartbeat. Additionally, Ocrevus may increase the risk for malignancies, particularly breast cancer. Delay Ocrevus treatment for patients with active infections. Vaccination with live or live attenuated vaccines is not recommended in patients receiving Ocrevus.

In addition to the infusion-related reactions, the most common side effect of Ocrevus seen in the clinical trials for relapsing forms of MS was upper respiratory tract infection. The most common side effects in the study of PPMS were upper respiratory tract infection, skin infection, and lower respiratory tract infection.

The FDA granted this application breakthrough therapy designation, fast track designation, and priority review.

The FDA granted approval of Ocrevus to Genentech, Inc.

//////multiple sclerosis, Ocrevus, ocrelizumab, fda 2017, genentech,

FDA approves new eczema drug Dupixent (dupilumab)

March 29, 2017 12:53 am / 1 Comment on FDA approves new eczema drug Dupixent (dupilumab)

FDA aes new eczema drug Dupixentpprov

03/28/2017 11:14

The U.S. Food and Drug Administration today approved Dupixent (dupilumab) injection to treat adults with moderate-to-severe eczema (atopic dermatitis). Dupixent is intended for patients whose eczema is not controlled adequately by topical therapies, or those for whom topical therapies are not advisable. Dupixent can be used with or without topical corticosteroids.

“FDA’s approval of Dupixent demonstrates our commitment to approving new and innovative therapies for patients with skin disease,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. “Eczema can cause significant skin irritation and discomfort for patients, so it is important to have a variety of treatment options available to patients, including those patients whose disease is not controlled by topical therapies.”

Atopic dermatitis, a chronic inflammatory skin disease, is often referred to as “eczema,” which is a general term for several types of inflammation of the skin. Atopic dermatitis is the most common of the many types of eczema; onset typically begins in childhood and can last through adulthood. The cause of atopic dermatitis is a combination of genetic, immune and environmental factors. In atopic dermatitis, the skin develops red, scaly and crusted bumps, which are extremely itchy. Scratching leads to swelling, cracking, “weeping” clear fluid, and finally, coarsening and thickening of the skin.

Dupixent is administered as an injection under the skin. Dupixent’s active ingredient is an antibody (dupilumab) that binds to a protein [interleukin-4 (IL-4) receptor alpha subunit (IL-4Ra)], that causes inflammation. By binding to this protein, Dupixent is able to inhibit the inflammatory response that plays a role in the development of atopic dermatitis.

The safety and efficacy of Dupixent were established in three placebo-controlled clinical trials with a total of 2,119 adult participants with moderate-to-severe atopic dermatitis not adequately controlled by topical medication(s). Overall, participants who received Dupixent achieved greater response, defined as clear or almost clear skin, and experienced a reduction in itch after 16 weeks of treatment.

Dupixent can cause side effects such as serious allergic reactions and eye problems, such as pink eye (conjunctivitis) and inflammation of the cornea (keratitis). If patients experience new or worsening eye symptoms such as redness, itching, pain or visual changes, they should consult a health care provider. The most common side effects include injection site reactions; cold sores in the mouth or on the lips; and eye and eyelid inflammation, including redness, swelling and itching.

The safety and efficacy of Dupixent have not been established in the treatment of asthma. Patients who also have asthma should not adjust or stop their asthma treatment without talking to their physicians.

The FDA granted the application for Dupixent Priority Review and Breakthrough Therapy designation.

The FDA granted the approval of Dupixent to Regeneron Pharmaceuticals, Inc.

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GLGP 1837

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Process Development and Good Manufacturing Practice Production of a Tyrosinase Inhibitor via Titanium-Mediated Coupling between Unprotected Resorcinols and Ketones

Thibaud Gerfaud

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Boiteau Jean-Guy

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Nestlé Skin Health

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Enantioselective synthesis of a cyclobutane analogue of Milnacipran

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