GSK-2881078

phase 1, Uncategorized Comments Off

Jun 142016

GSK-2881078

(R)-1-[1-(Methylsulfonyl)propan-2-yl]-4-(trifluoromethyl)-1H-indole-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

A selective androgen receptor modulator potentially for the treatment of cachexia.

Inventors	Philip Stewart Turnbull, Rodolfo Cadilla
Applicant	Glaxosmithkline Intellectual Property (No.2) Limited

CAS Number	1539314-06-1
Chemical Name	GSK-2881078
Synonyms	GSK-2881078
Molecular Formula	C14H13NF3N2O2S
Formula Weight	330.33

Originator GlaxoSmithKline
Mechanism of Action Selective androgen receptor modulators

Phase I Cachexia

Most Recent Events

03 Sep 2015 GlaxoSmithKline initiates enrolment in a phase I trial for Cachexia (In volunteers) in USA (NCT02567773)
01 Mar 2015 GlaxoSmithKline completes a phase I trial in Cachexia (In volunteers) in USA (NCT02045940)
31 Jan 2014 Phase-I clinical trials in Cachexia (In volunteers) in USA (PO)

GSK2881078 is a selective androgen receptor modulator (SARM) that is being evaluated for effects on muscle growth and strength in subjects with muscle wasting to improve their physical function. Part A of this study will evaluate the safety, efficacy and pharmacokinetics of GSK2881078 in healthy, older men and post-menopausal women who will take daily dosing for 28 days and be followed for a total of 70 days. Part B of this study will characterize the effect of Cytochrome P450 3A4 (CYP3A4) inhibition on the GSK2881078 pharmacokinetics. Part B will only be conducted if safe and efficacious dose is identified in Part A. Part A will include healthy older males and post-menopausal females; and randomize approximately 60 subjects (about 15 per cohort [4 cohorts]) to complete approximately 48 (about 12 per cohort). Part B will enroll one cohort of approximately 15 healthy male subjects to complete approximately 12. The study duration will be approximately 115 days for Part A and 122 days for Part B.

Steroidal nuclear receptor (NR) ligands are known to play important roles in the health of both men and women. Testosterone (T) and dihydrotestosterone (DHT) are endogenous steroidal ligands for the androgen receptor (AR) that appear to play a role in every tissue type found in the mammalian body. During the development of the fetus, androgens play a role in sexual differentiation and development of male sexual organs. Further sexual development is mediated by androgens during puberty. Androgens play diverse roles in the adult, including stimulation and maintenance of male sexual accessory organs and maintenance of the musculoskeletal system. Cognitive function, sexuality, aggression, and mood are some of the behavioral aspects mediated by androgens. Androgens have a physiologic effect on the skin, bone, and skeletal muscle, as well as blood, lipids, and blood cells (Chang, C. and Whipple, G. Androgens and Androgen Receptors. Kluwer Academic Publishers: Boston, MA, 2002)

Many clinical studies with testosterone have demonstrated significant gains in muscle mass and function along with decreases in visceral fat. See, for example,

Bhasin (2003) S. J. Gerontol. A Biol. Sci. Med. Sci. 58:1002-8, and Ferrando, A. A. et al. (2002) Am. J. Phys. Endo. Met. 282: E601-E607. Androgen replacement therapy (ART) in men improves body composition parameters such as muscle mass, strength, and bone mineral density (see, for example, Asthana, S. et al. (2004) J. Ger, Series A: Biol. Sci. Med. Sci. 59: 461 -465). There is also evidence of improvement in less tangible parameters such as libido and mood. Andrologists and other specialists are increasingly using androgens for the treatment of the symptoms of androgen deficiency. ART, using T and its congeners, is available in transdermal, injectable, and oral dosage forms. All current treatment options have contraindications (e.g., prostate cancer) and side-effects, such as increased hematocrit, liver toxicity, and sleep apnoea. Side-effects from androgen therapy in women include: acne, hirsutism, and lowering of high-density lipoprotein (HDL) cholesterol levels, a notable side-effect also seen in men.

Agents that could selectively afford the benefits of androgens and greatly reduce the side-effect profile would be of great therapeutic value. Interestingly, certain NR ligands are known to exert their action in a tissue selective manner (see, for example, Smith et al. (2004) Endoc. Rev. 2545-71 ). This selectivity stems from the particular ability of these ligands to function as agonists in some tissues, while having no effect or even an antagonist effect in other tissues. The term “selective receptor modulator” (SRM) has been given to these molecules. A synthetic compound that binds to an intracellular receptor and mimics the effects of the native hormone is referred to as an agonist. A compound that inhibits the effect of the native hormone is called an antagonist. The term “modulators” refers to compounds that have a spectrum of activities ranging from full agonism to partial agonism to full antagonism.

SARMs (selective androgen receptor modulators) represent an emerging class of small molecule pharmacotherapeutics that have the potential to afford the important benefits of androgen therapy without the undesired side-effects. Many SARMs with demonstrated tissue-selective effects are currently in the early stages of development See, for example, Mohler, M. L. et al. (2009) J. Med. Chem. 52(12): 3597-617. One notable SARM molecule, Ostarine™, has recently completed phase I and II clinical studies. See, for example, Zilbermint, M. F. and Dobs, A. S. (2009) Future Oncology 5(8):121 1-20. Ostarine™ appears to increase total lean body mass and enhance functional performance. Because of their highly-selective anabolic properties and demonstrated androgenic-sparing activities, SARMs should be useful for the prevention and/or treatment of many diseases in both men and women, including, but not limited to sarcopenia, cachexias (including those associated with cancer, heart failure, chronic obstructive pulmonary disease (COPD), and end stage renal disease (ESRD), urinary incontinence, osteoporosis, frailty, dry eye and other conditions associated with aging or androgen deficiency. See, for example, Ho et al. (2004) Curr Opin Obstet Gynecol. 16:405-9; Albaaj et al. (2006) Postgrad Med J 82:693-6; Caminti et al. (2009) J Am Coll Cardiol. 54(10):919-27; lellamo et al. (2010) J Am Coll Cardiol. 56(16): 1310-6; Svartberg (2010) Curr Opin Endocrinol Diabetes Obes. 17(3):257-61 , and Mammadov et al. (201 1 ) Int Urol Nephrol 43:1003-8. SARMS also show promise for use in promoting muscle regeneration and repair (see, for example, Serra et al. (Epub 2012 Apr 12)

doi:10.1093/Gerona/gls083),in the areas of hormonal male contraception and benign prostatic hyperplasia (BPH), and in wound healing (see, for example, Demling (2009) ePIasty 9:e9).

Preclinical studies and emerging clinical data demonstrate the therapeutic potential of SARMs to address the unmet medical needs of many patients. The demonstrated advantages of this class of compounds in comparison with steroidal androgens (e.g. , tissue-selective activity, oral administration, AR selectivity, and lack of androgenic effect) position SARMs for a bright future of therapeutic applications.

Although amorphous forms of SARMs may be developed for some uses, compounds having high crystallinity are generally preferred for pharmaceutical use due to their improved solubility and stability. Accordingly, there remains a need in the art for crystalline form of SARMs for therapeutic use.

Patent

WO 2015110958

EXAMPLES

Example 1 – Synthesis of (R)-1 -(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)- -indole-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)^-(trifluoromethyl)-1 H-indole-5-carbonitrile

Method 1 :

A. (R)-1 -(Methylthio)propan-2 -amine

Step 1

To a solution of commercially available (R)-2-aminopropan-1 -ol (5 g, 66.6 mmol) in MeCN (20 mL), in an ice bath, is added very slowly, dropwise, chlorosulfonic acid (4.46 mL, 66.6 mmol) (very exothermic). The reaction mixture is kept in the cold bath for ~10 min, and then at rt for ~ 30 min. After stirring for another ~ 10 minutes, the solids are collected by filtration, washed sequentially with MeCN (40 mL) and hexanes (100 mL), and dried by air suction for ~ 40 min. to produce the intermediate ((R)-2-aminopropyl hydrogen sulfate.

Step 2:

To a solution of sodium thiomethoxide (5.60 g, 80 mmol) in water (20 mL) is added solid NaOH (2.66 g, 66.6 mmol) in portions over ~ 10 min. Then the intermediate from step 1 is added as a solid over ~ 5 min. The mixture is then heated at 90 °C for ~10 h. The reaction mixture is biphasic. Upon cooling, MTBE (20 mL) is added, and the organic phase (brownish color) is separated. The aqueous phase is extracted with MTBE (2 x 20 mL). The original organic phase is washed with 1 N NaOH (15 mL). The basic aqueous phase is re-extracted with MTBE (2 x 20 mL). All the ether phases are combined, dried over Na₂S0₄, filtered, and concentrated (carefully, since the product is volatile) to afford the crude product as a light yellow oil.

Method 2

(R)-1-(methylthio)propan-2 -amine hydrochloride

A. (R)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

Step 1

Commercially available (R)-2-aminopropan-1 -ol (135 g, 1797 mmol) is dissolved in MeOH 1350 mL). The solution is cooled to 5°C with an icebath, then Boc₂0 (392 g, 1797 mmol) is added as a solution in MeOH (1000 mL). The reaction temperature is kept below 10°C. After the addition, the cooling bath is removed, and the mixture is stirred for 3 h. The MeOH is removed under vacuum (rotavap bath: 50°C). This material is used as is for the next step.

Step 2

The residue is dissolved in CH₂CI₂ (1200 mL) and NEt₃ (378 mL, 2717 mmol) is added, then the mixture is cooled on an ice bath. Next, MsCI (166.5 mL, 2152 mmol) is added over ~2 h, while keeping the reaction temperature below 15°C. The mixture is stirred in an icebath for 1 h then the bath was removed. The mixture is stirred for 3 d, then washed with a 10% NaOH solution (500 mL 3 x), then with water. The organic phase is dried with MgS0₄, filtered, then stripped off (rota, 50°C waterbath. The impure residue is dissolved in a mix of 500mL EtOAc (500 mL) and MTBE (500 mL) and then extracted with water to remove all water-soluble salts. The organic phase is dried with MgS0₄, filtered, then stripped off to afford a white solid residue.

B. (R)-tert-Butyl (1 -(methylthio)propan-2-yl)carbamate

NaSMe (30 g, 428 mmol) is stirred with DMF (200 mL) to afford a suspension. Next, (R)-2-((tertbutoxycarbonyl)amino)propyl methanesulfonate (97 g, 383 mmol) is added portionwise while the temperature is kept below 45°C (exothermic). After the addition, the mixture is stirred for 2 h, then toluene (100 mL) is added. The mixture is washed with water (500 mL, 4 x), then dried with MgS0₄, and filtered. The filtrate is stripped off (rotavap) to a pale yellow oil.

C. (R)-1 -(Methylthio)propan-2 -amine hydrochloride

Acetyl chloride (150 mL,) is added to a stirred solution of MeOH (600 mL) cooled with an icebath. The mixture is stirred for 30 min in an icebath, then added to (R)-tert-butyl (1 -(methylthio)propan-2-yl)carbamate (78 g, 380 mmol). The mixture is stirred at rt for 2 h, (C0₂, (CH₃)₂C=CI-l2 evolution) and then stripped off to a white solid.

D. 4-Fluoro-3-iodo-2-(trifluoromethyl)benzonitrile

To a freshly prepared solution of LDA (1 19 mmol) in anhyd THF (250 mL) at -45°C is added a solution of commercially available 4-fluoro-2-(trifluoromethyl)benzonitrile (21 .5 g, 1 14 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained < -40°C (became dark brown during addition). The mixture is stirred 30 min at -45°C, cooled to -70°C and iodine (31 .7 g, 125 mmol) is added in one portion (-70°C→ -52°C). The mixture is stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na₂S₂0₃ (ca. 250 mL) and 1 N HCI (ca. 125 mL). The mixture is extracted with EtOAc (x3). Combined organics are washed (water, brine), dried over Na₂S0₄ and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc / hexanes, gradient elution) followed by

recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (15.79 g, 50.1 mmol, 44.1 % yield) as a pale yellow solid.

E. 4-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile

A 20 mL vial is charged with 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile,(0.315 g, 1 .00 mmol), Pd(PPh₃)₂CI₂ (0.014 g, 0.020 mmol) and Cul (0.0076 g, 0.040 mmol), and sealed with a rubber septum. Anhyd PhMe (5 mL) and DIPA (0.210 mL, 1 .500 mmol) are added via syringe and the mixture is degassed 10 min by sparging with N₂while immersed in an ultrasonic bath. Ethynyltrimethylsilane (0.155 mL, 1 .100 mmol) is added dropwise via syringe and the septum is replaced by a PTFE-faced crimp top. The mixture is stirred in a heating block at 60°C. Upon cooling the mixture is diluted with EtOAc and filtered through Celite. The filtrate is washed (satd NH₄CI, water, brine), dried over Na₂S0₄ and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc / hexanes, gradient elution) affording 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile .

F. (R)-1 -(1 -(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

A mixture of 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (1 .16 g, 4.07 mmol), (R)-1 -(methylthio)propan-2-amine (0.599 g, 5.69 mmol) and DIEA (1 .42 mL, 8.13 mmol) in DMSO (7 mL) is heated (sealed tube) at 100°C for 50 min. Upon cooling, the reaction mixture is diluted with EtOAc (50 mL) and washed with water (30 mL). The organic phase is washed with water and brine, dried over Na₂S0₄, filtered and concentrated to give the intermediate aniline. This intermediate is dissolved in NMP (7 mL), treated with KOtBu (1 M in THF) (5.69 mL, 5.60 mmol) and heated at 50°C. The reaction is monitored by LCMS, and deemed complete after 40 min. Upon cooling, the reaction mixture is diluted with EtOAc (40 mL) and washed with water (30 mL). The organic phase is washed with more water and brine, dried over Na₂S0₄, filtered and concentrated. The residue is chromatographed over silica gel using a 5-40% EtOAc-hexane gradient to give the thioether intermediate:

G. (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

To an ice-cold solution of (R)-1 -(1 -(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (0.560 g, 1.88 mmol) in MeOH (10 mL) is added a solution of Oxone (4.04 g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture is diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue is chromatographed over silica gel using 100% CH₂CI₂ to give (R)-1-(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-l H-indole-5-carbonitrile as a white foam that is crystallized from

CH₂CI₂/hexanes to afford a white solid.

Example 2- Preparation of crystalline form 1 of (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .74kg, 1wt) was dissolved in ethyl acetate (12.0 Kg, 6.9 wt) at 20-30°C. The solution was transferred into a clean reaction vessel via an in-line cartridge filter. The solution was concentrated to ~3.0-5.0 volumes under reduced pressure, keeping the temperature below 50°C. The solution was cooled to 20-30°C, and n-heptane (23.0 Kg, 13.2 wt) was added slowly over ~1 hour. The solution was stirred 1 -2 hrs at 20-30°C, heated to 50-55°C for 2-3 hours, cooled back to 20-30°C and stirred for 1 -2 hours. The slurry was sampled and analyzed by XRPD. The solid was collected by filtration, washed with n-heptane (1 .4 Kg, 0.8 wt), and dried in vacuo at 40-50 °C to provide crystalline

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .54 Kg, Form 1 ; 88.5 % yield, 99.5% purity) as a slightly colored solid.

Example 3- Preparation of crystalline form 2 of (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

Crude (R)-1 -(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .54 g [theoretical], 1 wt) was dissolved in dichloromethane (5mL, 3.25 vol) and loaded onto a 12-g ISCO column (Si0₂). The column was eluted with DCM (-500 mL, 325 vol) and the product-containing fractions were combined and concentrated in vacuo. The resulting residue was triturated in n-heptane. The solid was collected by filtration, air-dried, and placed under high vacuum for 3 h to provide GSK2881078A (1 .009 g, Form 2; 65.1 % yield, 100% AUC HPLC-UV) as a white solid.

PATENT

https://www.google.com/patents/WO2014013309A1?cl=en22

Example 26

1-(1-(Methylsulfonyl)propan-2-yl)-4-(trifiuoromethyl)-1H-indole-5-carbonitrile Synthesized in a manner similar to Example 9 using 1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (Example 25): MS (ESI): m/z 331 (MH+).

Example 27

(R)-1 -(1 -(Methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

A. (R)-1-(Methylthio)propan-2-amine

Step l

To a solution of commercially available (R)-2-aminopropan-1-ol (5 g, 66.6 mmol) in MeCN (20 mL), in an ice bath, was added very slowly, dropwise, chlorosulfonic acid (4.46 mL, 66.6 mmol) (very exothermic). A gummy beige precipitate formed. The reaction mixture was kept in the cold bath for -10 min, and then at rt for ~ 30 min. The reaction mixture was scratched with a spatula to try to solidify the gummy precipitate. After a few minutes, a beige solid formed. After stirring for another ~ 10 minutes, the solids were collected by filtration, washed sequentially with MeCN (40 mL) and hexanes (100 mL), and dried by air suction for ~ 40 min. The intermediate ((R)-2-aminopropyl hydrogen sulfate, weighed 0.46 g (~ 96% yield).

Step 2:

To a solution of sodium thiomethoxide (5.60 g, 80 mmol) in water (20 mL) was added solid NaOH (2.66 g, 66.6 mmol) in portions over – 10 min. Then the intermediate from step 1 was added as a solid over ~ 5 min. The mixture was then heated at 90 °C for -10 h. The reaction mixture was biphasic. Upon cooling, MTBE (20 mL) was added, and the organic phase (brownish color) was separated. The aqueous phase was extracted with MTBE (2 x 20 mL). The original organic phase is washed with 1 NaOH (15 mL) (this removes most of the color). The basic aqueous phase was re-extracted with MTBE (2 x 20 mL). All the ether phases are combined, dried over Na₂S0₄, filtered, and

concentrated (carefully, since the product is volatile) to afford the crude product as a light yellow oil: ¹H NMR (400 MHz, DMSO-cf₆) δ 2.91-2.87 (m, 1 H), 2.43-2.31 (m, 2 H), 2.04 (s, 3 H), 1.50 (bs, 2 H), 1.01 (d, J = 6.3 Hz, 3 H).

Alternative synthesis of example 27A:

(R)-1 -(Methylthio)propan-2 -amine hydrochloride

A. (R)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

Step 1

Commercially available (R)-2-aminopropan-1-ol (135 g, 1797 mmol) was dissolved in MeOH 1350 mL). The solution was cooled to 5°C with an icebath, then Boc₂0 (392 g, 1797 mmol) was added as a solution in MeOH (1000 mL). The reaction temperature was kept below 10°C. After the addition, the cooling bath was removed, and the mixture was stirred for 3 h. The MeOH was removed under vacuum (rotavap bath: 50°C). The resulting residue was a colorless oil that solidified overnight to a white solid. This material was used as is for the next step.

Step 2

The residue was dissolved in CH₂CI₂ (1200 mL) and NEt₃ (378 mL, 2717 mmol) was added, then the mixture was cooled on an ice bath. Next, MsCI (166.5 mL, 2152 mmol) was added over ~2 h, while keeping the reaction temperature below 15°C. The mixture was stirred in an icebath for 1 h then the bath was removed. The mixture was stirred for 3 d, then washed with a 10% NaOH solution (500 mL 3 x), then with water. The organic phase was dried with MgS0 , filtered, then stripped off (rota, 50°C waterbath. The impure residue was dissolved in a mix of 500mL EtOAc (500 mL) and MTBE (500 mL) and then, extracted with water to remove all water-soluble salts.The organic phase was dried with MgS0₄, filtered, then stripped off to afford a white solid residue: ¹H NMR (400 MHz, DMSO-d_s) δ 6.94-6.92 (m, 1 H), 4.02 (d, J = 5.8 Hz, 2 H), 3.78-3.71 (m, 1 H), 3.16 (s, 3 H), 1.38 (s, 9 H), 1.06 (d, J = 6.8 Hz, 3 H).

B. (R)-tert-Butyl (1-(methylthio)propan-2-yl)carbamate

NaSMe (30 g, 428 mmol) was stirred with DMF (200 mL) to afford a suspension. Next, (R)-2-((tertbutoxycarbonyl)amino)propyl methanesulfonate (97 g, 383 mmol) was added

portionwise while the temperature was kept below 45°C (exothermic).. After the addition, the mixture was stirred for 2 h, then toluene (100 ml_) was added. The mixture was washed with water (500 ml_, 4 x), then dried with MgS0₄, and filtered. The filtrate was stripped off (rotavap) to a pale yellow oil: ¹H NMR (400 MHz, DMSO-d₆) δ 6.77-6.75 (m, 1 H), 3.60-3.54 (m, 1 H), 2.54-2.50 (m, 1 H), 2.43-2.38 (m, 1 H), 2.05 (s, 3 H), 1.38 (s, 9 H), 1.08 (d, J = 7.8 Hz, 3 H).

C. (R)-1-(Methylthio)propan-2-amine hydrochloride

Acetyl chloride (150 mL,) was added to a stirred solution of MeOH (600 mL) cooled with an icebath. The mixture was stirred for 30 min in an icebath, then added to (R)-tert-butyl (1-(methylthio)propan-2-yl)carbamate (78 g, 380 mmol). The mixture was stirred at rt for 2 h, (C0₂, (CH₃)₂C=CH₂ evolution) and then stripped off to a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (bs, 3 H), 3.36-3.29 (m, 1 H), 2.80-2.75 (m, 1 H), 2.64-2.59 (m, 1 H (d, J = 6.6 Hz, 3 H).

D. (R)-1 -(1 -(Methylthio)propan-2-yl)-4-(trif luoromethy l)-1 H-indole-5-carbonitrile

A mixture of 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (Example 21 D,1.16 g, 4.07 mmol), (R)-1-(methylthio)propan-2-amine (0.599 g, 5.69 mmol) and DIEA (1.42 mL, 8.13 mmol) in DMSO (7 mL) was heated (sealed tube) at 100°C for 50 min. Upon cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL). The organic phase was washed with water and brine, dried over Na₂S0₄, filtered and concentrated to give the intermediate aniline. This intermediate was dissolved in NMP (7 mL), treated with KOtBu (1 M in THF) (5.69 mL, 5.60 mmol) and heated at 50°C. The reaction was monitored by LCMS, and deemed complete after 40 min. Upon cooling, the reaction mixture was diluted with EtOAc (40 mL) and washed with water (30 mL). The organic phase was washed with more water and brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed over silica

gel using a 5-40% EtOAc-hexane gradient to give the thioether intermediate: MS (ESI):

E. (R)-1-(1-(Methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

To an ice-cold solution of (R)-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (0.560 g, 1.88 mmol) in MeOH (10 mL) was added a solution of Oxone (4.04 g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed over silica gel using 100% CH₂CI₂ to give (R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-l H-indole-5-carbonitrile as a white foam that was crystallized from CH₂CI₂/hexanes to afford a white solid (0.508 g, 79% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J = 8.6 Hz, 1 H), 8.12 (d, J = 3.5 Hz, 1 H), 7.81 (d, J – 8.5 Hz, 1 H), 6.87-6.84 (m, 1 H), 5.43-5.35 (m, 1 H), 4.01 (dd, J = 14.8, 8.6 Hz, 1 H), 3.83 (dd, J = 14.8, 4.9 Hz, 1 H), 2.77 (s, 3 H), 1.59 (d, J = 6.8 Hz, 3 H); MS (ESI): m/z 331 (M+H).

Philip Turnbull

Director of Chemistry

https://www.linkedin.com/in/philip-turnbull-21266a8

Experience

Director of Chemistry

Receptos, a wholly-owned subsidiary of Celgene

June 2015 – Present (1 year 1 month)Greater San Diego Area

Director

GSK

April 2010 – June 2015 (5 years 3 months)RTP

Section Head

GSK

April 2007 – April 2010 (3 years 1 month)RTP

Group Manager

GlaxoSmithKline

April 2003 – April 2007 (4 years 1 month)RTP

Investigator

GSK

June 1998 – April 2003 (4 years 11 months)RTP

Research Associate

Biophysica Foundation

February 1988 – September 1991 (3 years 8 months)La Jolla, Ca

Education

The Scripps Research Institute

post doc, Organic chemistry

1996 – 1998

University of California, Irvine

Doctor of Philosophy (Ph.D.), Organic synthesis

1991 – 1996

////////GSK-2881078, 1539314-06-1, Phase 1, clinical trials, Cachexia , GlaxoSmithKline

GSK-2879552

phase 1, Uncategorized Comments Off

Jun 142016

GSK-2879552

CAS 1401966-69-5 (ABS), 1401966-63-9(REL)

C₂₃ H₂₈ N₂ O_2, 364.48

Benzoic acid, 4-[[4-[[[(1R,2S)-2-phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]-

4-((4-((((lR,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid

4-[[4-[[[(1R,2S)-2-Phenylcyclopropyl]amino]methyl]-1-piperidinyl]methyl]benzoic acid
4-[[4-[[((1R,2S)-2-Phenylcyclopropyl)amino]methyl]piperidin-1-yl]methyl]benzoic acid

4-((4-((((1R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid

Glaxosmithkline Llc INNOVATOR

Neil W. Johnson, Jiri Kasparec, William Henry Miller, Meagan B. Rouse, Dominic Suarez, Xinrong Tian,

A LSD1 inhibitor potentially for the treatment of small cell lung cancer and acute myeloid leukemia.

GSK2879552 is an orally available, irreversible, inhibitor of lysine specific demethylase 1 (LSD1), with potential antineoplastic activity. Upon administration, GSK2879552 binds to and inhibits LSD1, a demethylase that suppresses the expression of target genes by converting the dimethylated form of lysine at position 4 of histone H3 (H3K4) to mono- and unmethylated H3K4. LSD1 inhibition enhances H3K4 methylation and increases the expression of tumor-suppressor genes. This may lead to an inhibition of cell growth in LSD1-overexpressing tumor cells. LSD1, overexpressed in certain tumor cells, plays a key role in tumor cell growth and survival. Check for active clinical trials or closed clinical trials using this agent.

GSK-2879552 chemical structure

Formula: C₂₃H₂₉ClN₂O₂
M.Wt: 400.94

GSK2879552, LSD1 Inhibitor

CAS 1902123-72-1

Molecular Weight:	437.41
Formula:	C₂₃H₂₈N₂O₂.2HCl

Chromatin modification plays an essential role in transcriptional regulation (T. Kouzarides, 2007, Cell 128: 693-705). These modifications, which include DNA methylation, histone acetylation and hsitone methylation, are disregulated in tumors. This epigenetic disregulation plays an important role in the silencing of tumor suppressors and overexpression of oncogenes in cancer (M. Esteller, 2008, N Engl J Med 358: 1148-59. P. Chi et al, 2010, Nat Rev Cane 10:457-469.). The enzymes that regulate histone methylation are the histone methyl transferases and the histone demethylases.

Lysine-specific demethylase 1 (LSDl; also known as BHC110) is a histone lysine demethylase reported to demethylate H3K4mel/2 (Y. Shi et al, 2004, Cell 119: 941-953) and H3K9mel/2 (R. Schule et al.,2005, Nature 437: 436-439). LSDl is overexpressed in multiple human cancers, including prostate where it is associated with more frequent relapse (P. Kahl et al, 2006, Cane. Res. 66: 11341-11347), breast (J. Kirfel et al, 2010, Carcinogenesis 31: 512-520) neuroblastoma (J. Kirfel et al, 2009, Cane. Res. 69: 2065-2071. G. Sun et al, 2010, Mol. Cell. Biol. 28: 1997-2000). LSDl is essential for transcriptional regulation mediated by a number of nuclear hormone receptors, including androgen receptor in prostate cancer (R. Schuele et al, 2005, Nature 437: 436-439. R. Schuele et al, 2007, Nat. Cell Biol. 9: 347-353. R. Schuele et al, 2010, Nature 464: 792-796), estrogen receptor in breast carcinomas (M.G. Rosenfeld et al, 2007, Cell 128: 505-518), and TLX receptor in neuorblastoma (S. Kato et al, 2008, Mol. Cell. Biol. 28: 3995-4003). These studies have shown that knockdown of LSDl expression results in decreased cancer cell proliferation. Additionally, LSDl is overexpressed in multiple cancer types that are nuclear hormone receptor-independent. Those tumors include ER-negative breast (J. Kirfel et al, 2010, Carcinogenesis 31: 512-520), small-cell lung, bladder, head & neck, colon, serous ovary, and kidney Wilm’s tumor. Therefore, potent selective small molecule inhibitors of LSDl may be useful for treatment of cancers that are nuclear hormone receptor-dependent and/or nuclear hormone receptor-independent.

The compositions and methods provided herein can potentially be useful for the treatment of cancer including tumors such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can potentially be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm’s tumor

(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, meduUoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes

(carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplasia syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi’s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” as provided herein, includes a cell afflicted by any one of or related to the above identified conditions.

SYNTHESIS

GSK-2879552

PATENT

WO 2012135113

https://www.google.co.in/patents/WO2012135113A2?cl=en

Example 2

1 , 1 -Dimethylethyl 4-( { \( 1 R,2S)-2-phenylcyclopropyl] amino I methyl)- 1 -piperidinecarboxylate

Following a procedure analogous to the procedure described in Example 1 using [(1R,2S)-2-phenylcyclopropyl]amine ((-) isomer) (94 mg, 0.703 mmol) afforded 1,1 -dimethylethyl 4-({[(lR,2S)-2-phenylcyclopropyl]amino}methyl)-l-piperidinecarboxylate (92 mg, 0.264 mmol, 56.4 % yield) as white solid. 1H NMR (400 MHz, METHANOL-d₄) δ 7.29 – 7.37 (m, 2H), 7.23 – 7.28 (m, 1H), 7.17 – 7.22 (m, 2H), 4.14 (d, J= 12.63 Hz, 2H), 3.14 (d, J = 7.07 Hz, 2H), 3.01 (dt, J= 4.14, 7.64 Hz, 1H), 2.81 (br. s., 2H), 2.53 (ddd, J= 3.54, 6.63, 10.29 Hz, 1H), 1.97 (ddd, 1H), 1.80 (d, J= 12.13 Hz, 2H), 1.55 (ddd, J= 4.29, 6.63, 10.55 Hz, 1H), 1.47 (s, 9H), 1.36 – 1.45 (m, 1H), 1.23 (qd, J= 4.29, 12.38 Hz, 2H); LC-MS Rt = 0.78 min; MS (ESI): 331.3 [M+H]⁺.

Example 6

[(lR,2S)-2-Phenylcyclopropyll(4-piperidinylmethyl)amine

Following a procedure analogous to the procedure described in Example 4 using 1,1-dimethylethyl 4-({[(lR,2S)-2-phenylcyclopropyl]amino}methyl)-l-piperidinecarboxylate (Example 2, 60 mg, 0.182 mmol) afforded [(lR,2S)-2-phenylcyclopropyl](4-piperidinylmethyl)amine (41 mg, 0.146 mmol, 80 % yield)as white solid. 1H NMR (400 MHz, METHANOLS) δ 7.29 – 7.38 (m, 2H), 7.23 – 7.29 (m, 1H), 7.18 – 7.23 (m, 2H), 3.47 (d, J= 13.39 Hz, 2H), 3.21 (d, 2H), 2.89 – 3.13 (m, 3H), 2.60 (ddd, J= 3.79, 6.57, 10.36 Hz, 1H), 2.13 – 2.28 (m, J= 3.85, 3.85, 7.61, 11.21 Hz, 1H), 1.99 – 2.13 (m, 2H), 1.49 – 1.71 (m, 3H), 1.35 – 1.48 (m, 1H); LC-MS Rt = 0.44 min; MS (ESI): 231.2

Example 26

4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin- 1 -yl)methyl)benzoic acid

To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol, Example l ib) and 4-(bromomethyl)benzoic acid (198 mg, 0.919 mmol) in acetonitrile (6 mL) was added potasium carbonate (254 mg, 1.838 mmol). The reaction mixture was stirred for 3 hours at the 90 °C. The reaction mixture was then filtered and evaporated. The crude oil was mixed with 10 mL of 10 % acetic acid and 10 mL of ethyl acetate. Layers were separated, and the organic layer was discharged. Aqueous layer was neutralized with 1 M Na₂C0₃, and the product was extracted into 10 mL of ethyl acetate. The organic layer was washed with brine, dried over MgS0₄, filtered and evaporated. The oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 min, and then it was concentrated. The solution was then partioned between 2 ml of water and 5 mL of ethyl acetate. The organic layer was separated and evaporated. The oil was purified on preparatory HPLC (2 to 10 % AcCN: H₂0 with 0.1 % formic acid modifier). The fractions were collected. To each

fraction was added 1 ml of 1 M HCl, and the fractions were evaporated to dryness. 4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid (50 mg, 0.118 mmol, 19.33 % yield) was isolated as a white solid. 1H NMR (400 MHz,

METHANOLS) δ 8.16 (d, J= 8.34 Hz, 2H), 7.70 (d, J= 8.34 Hz, 2H), 7.30 – 7.37 (m, 2H), 7.23 – 7.29 (m, 1H), 7.20 (d, J= 7.33 Hz, 2H), 4.44 (br. s., 2H), 3.57 (d, J= 11.62 Hz, 2H), 3.07 – 3.27 (m, 4H), 3.04 (dt, J= 3.95, 7.52 Hz, 1H), 2.59 (ddd, J= 3.54, 6.57, 10.11 Hz, lH), 2.12 (d, J= 13.89 Hz, 3H), 1.54 – 1.81 (m, 3H), 1.42 (q, 1H); LC-MS Rt = 0.47 min; MS (ESI): 365.3 [M+H]⁺.

[M+H]⁺.

Example 29

4-((4-((((lR,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid

Step 1.

tert-Butyl 4-((4-(hydroxymethyl)piperidin-l-yl)methyl)benzoate

tert-Butyl 4-(bromomethyl)benzoate (1 g, 3.13 mmol) and piperidin-4-ylmethanol (0.361 g, 3.13 mmol) were dissolved in acetonitrile (25 mL). K₂CO₃ (1.300 g, 9.40 mmol) was added and the reaction mixture was heated to reflux for 20 min. The reaction mixture was cooled down to room temperature, filtered and evaporated. The resulting solid was partitioned between ethyl acetate (50mL) and 1 M HC1 (50 mL). The layers were separated and the aqueous layer was washed with ethyl acetate and the organic layers were discarded. The aqueous layer was basified with 8 M NaOH to pH -10 and extracted 2 times with 50 mL of ethyl acetate. The organic layers were combined, washed with brine and dried over MgSC^, filtered and evaporated. tert-Butyl 4-((4- (hydroxymethyl)piperidin-l-yl)methyl)benzoate (0.95 g, 2.99 mmol, 95 % yield) was isolated as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (d, J= 8.34 Hz, 2H), 7.39 (d, J = 8.08 Hz, 2H), 3.56 (s, 2H), 3.51 (d, J = 6.57 Hz, 2H), 2.90 (d, J= 11.37 Hz, 2H), 1.94 – 2.04 (m, 2H), 1.73 (d, J= 14.15 Hz, 2H), 1.61 (s, 9H), 1.40 – 1.56 (m, 2H), 1.30 – 1.37 (m, 2H); LC-MS Rt = 0.67 min; MS (ESI): 306.2 [M+H]⁺.

Step 2.

tert-Butyl 4-((4-formylpiperidin- 1 -yl)methyl)benzoate

To a solution of oxalyl chloride (0.408 mL, 4.67 mmol) in dichloromethane (5 mL) at -60 °C was added a solution of DMSO (0.508 mL, 7.15 mmol) in 15 mL of dichloromethane over 30 minutes. The reaction was stirred for 30 minutes at -60 °C A solution of tert-butyl 4-((4-(hydroxymethyl)piperidin-l-yl)methyl)benzoate (950 mg, 3.11 mmol) in 5 mL of dichloromethane was added over 10 minutes at -60 °C. The reaction mixture was stirred for 3 hours at – 60 °C, then triethylamine (2.168 mL, 15.55 mmol) was added and after 10 minutes 10 mL of water was added. The reaction mixture was allowed to warm up to the room temperature. The layers were separated. The pH of the water layer was adjusted to ~7 with 1 M HC1 and then extracted with 20 mL of dichloromethane. The combined organic layers were washed with water and brine, then dried over MgSO, filtered and evaporated. The resulting oil was purified on a silica column eluting with EtOAc to yield tert-butyl 4-((4-formylpiperidin-l-yl)methyl)benzoate (550 mg, 1.722 mmol, 55.4 % yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 9.67 (d, J= 1.26 Hz, 1H), 7.96 (d, J= 8.34 Hz, 2H), 7.38 (d, J= 8.34 Hz, 2H), 3.56 (s, 2H), 2.75 – 2.92 (m, 2H), 2.21 – 2.35 (m, 1H), 2.14 (t, J= 10.48 Hz, 2H), 1.91 (dd, J= 2.78, 13.14 Hz, 2H), 1.65 – 1.81 (m, 2H), 1.58 – 1.64 (m, 9H); LC-MS Rt = 0.69 min; MS (ESI): 304.2

[M+H]⁺, 322.2 [M+H₂0]⁺, 336.6 [M+Na]⁺

Step 3.

tert-Butyl 4-((4-(((( 1 R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin- 1 -yl)methyl)benzoate

To a solution of tert-butyl 4-((4-formylpiperidin-l-yl)methyl)benzoate (6.7 g, 22.08 mmol) in methanol (50 mL) was added (lR,2S)-2-phenylcyclopropanamine (3.53 g, 26.5 mmol). The reaction mixture was refluxed for 5 minutes then cooled down to the room temperature. Sodium cyanotrihydroborate (2.082 g, 33.1 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organics were washed with 10 % acetic acid (50 mL). The layers were separated and 50 mL of brine was added slowly as a solid crashed out. The solid was filtered and suspended in isopropanol. The suspension was sonicated and filtered. tert-Butyl 4-((4-(((( 1 R,2S)-2-phenylcyclopropyl)amino)methyl)piperidin- 1 -yl)methyl)benzoate (5.8 g, 13.65 mmol, 61.8 % yield) was isolated as a white solid. 1H NMR (400 MHz,

METHANOLS) δ 8.07 (d, J= 8.34 Hz, 2H), 7.70 (d, J= 8.08 Hz, 2H), 7.28 – 7.37 (m, 2H), 7.10 – 7.28 (m, 3H), 4.43 (br. s., 2H), 3.54 (d, J= 10.86 Hz, 2H), 3.08 – 3.26 (m, 4H), 3.03 (dt, J= 3.76, 7.39 Hz, 1H), 2.54 – 2.71 (m, 1H), 2.03 – 2.29 (m, 3H), 1.67 – 1.84 (m, 2H), 1.58 – 1.67 (m, 10H), 1.40 (q, J = 6.82 Hz, lH); LC-MS Rt = 0.76 min; MS (ESI): 421.4 [M+H]⁺.

Step 4.

4-((4-((((lR,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid

A suspension of tert-butyl 4-((4-((((lR,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoate (5.8 g, 13.79 mmol) in HCL – 1 M (80 ml, 80 mmol) was heated to 89 °C (internal temperature) for 2 hr. The solution was cooled down to the room temperature and held in an ice -bath for 1 hour and then filtered. 4-((4-((((lR,2S)-2-phenylcyclopropyl)amino)methyl)piperidin-l-yl)methyl)benzoic acid (3.8 g, 8.25 mmol, 59.8 % yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d₄) 5 8.15 (d, J= 8.34 Hz, 2H), 7.72 (d, J= 8.59 Hz, 2H), 7.29 – 7.37 (m, 2H), 7.14 – 7.28 (m, 3H), 4.45 (br. s., 2H), 3.55 (d, J= 10.36 Hz, 2H), 3.07 – 3.29 (m, 4H), 3.04 (dt, J= 3.98, 7.71 Hz, 1H), 2.61 (ddd, J= 3.66, 6.57, 10.23 Hz, 1H), 1.98 – 2.31 (m, 3H), 1.72 (br. s., 2H), 1.62 (ddd, J= 4.42, 6.51, 10.55 Hz, 1H), 1.41 (q, J= 6.82 Hz, lH); LC-MS Rt = 0.49 min; MS (ESI): 365.3 [M+H]⁺.

Neil Johnson

US Lead of Chemistry Talent Development, External Engagement and Recruitment at GSK

https://www.linkedin.com/in/neil-johnson-6628894

Experience

US Lead of Chemistry Talent Development, External Engagement and Recruitment

GSK

March 2016 – Present (4 months)Greater Philadelphia Area

Manager

GSK

July 1999 – Present (17 years)

Investgator

GlaxoSmithKline

1999 – Present (17 years)

Senior Scientist

Cephalon

September 1994 – June 1999 (4 years 10 months)

Education

The Johns Hopkins University

Doctor of Philosophy (PhD), Organic Chemistry

1988 – 1994

Fort Lewis College

BS, Chemistry

1984 – 1988

///////////GSK-2879552, 1401966-63-9, , A LSD1 inhibitor, small cell lung cancer, acute myeloid leukemia, 1401966-69-5, 1902123-72-1

O=C(O)C1=CC=C(CN2CCC(CN[C@H]3[C@H](C4=CC=CC=C4)C3)CC2)C=C1

O=C(O)c1ccc(cc1)CN2CCC(CC2)CN[C@@H]4C[C@H]4c3ccccc3

GSK-2816126

phase 1, Uncategorized Comments Off

Jun 142016

GSK-2816126

N-[(1,2-Dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-3-methyl-1-[(1S)-1-methylpropyl]-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide, GSK 126, GSK 2816126, GSK 2816126A

N-[(4,6-Dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-((1S)-1-methylpropyl)-6-[6-(1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide

Formula	C₃₁H₃₈N₆O₂
Formula Wt.	526.67

An histone-lysine n-methyltransferase EZH2 inhibitor potentially for the treatment of B-cell lymphoma.

Research Code GSK-2816126; GSK-126; 2816126

CAS No. 1346574-57-9

Originator GlaxoSmithKline
Class Antineoplastics
Mechanism of Action EZH2 enzyme inhibitors; Histone modulators

Phase I Diffuse large B cell lymphoma; Follicular lymphoma
Preclinical Acute myeloid leukaemia

Most Recent Events

31 Mar 2014 Phase-I clinical trials in Follicular lymphoma (Second-line therapy or greater) in USA and United Kingdom (IV)
31 Mar 2014 Phase-I clinical trials in Diffuse large B cell lymphoma (Second-line therapy or greater) in USA and United Kingdom (IV)
16 Jan 2014 Preclinical trials in Diffuse large B cell lymphoma & Follicular lymphoma in United Kingdom (IV)

GSK-126 is an inhibitor of mutant EZH2, a histone methyltransferase (HMT) that exhibits point mutations at key residues Tyr641 and Ala677; this compound does not appreciably affect WT EZH2. EZH2 is responsible for modulating expression of a variety of genes. GSK-126 competes with cofactor S-adenylmethionine (SAM) for binding to EZH2. GSK-126 displays anticancer chemotherapeutic activity by inhibiting proliferation in in vitro and in vivo models of diffuse large B-cell lymphoma.

SYNTHESIS

PATENT

CN 105541801

https://www.google.com/patents/CN105541801A?cl=zh

Example 79: Add (S) in a three-necked flask 100 Qiu – bromo – Shu – (isobutyl) – N – ((4,6-dimethyl-2-oxo -l, 2- dihydropyridin-3-yl) methyl) -3-methyl-1 hydrogen – indole carboxamide (365mg, 0.82mmol), 2- (piperazin-1-yl) pyridine-5-boronic acid pinacol ester (309mg, 1.07mmol, 1 · 3eq), potassium phosphate (522mg, 2.46mmol, 3eq), water, and I, 4- diepoxy-hexadecane as the solvent. Then, under nitrogen was added [I, Γ- bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (53.9mg, 0.066mmo 1), and at 90 ° C reaction, to give the desired product after purification 400mg (92% yield). Goo NMR (500MHz, DMSO- (I6) JO.70-0 · 78 (ιή, 3H), 1.37-1.44 (m, 4H), 1.75-1.87 (m, 2H), 2.11 (s, 3H), 2.16 ( s, 3H), 2.22-2.27 (m, 3H), 2.77-2.85 (m, 4H), 3.41-3.49 (m, 4H), 4.35 (d, J = 5.31Hz, 2H), 4.56-4.68 (m, lH), 5.87 (s, 1H), 6.88 (d, J = 8.84Hz, 1H), 7.17 (d J = 1.52Hz, 1H), 7.26 (s, lH), 7.73 (d J = 1.26Hz, 1H) , 7.91 (dd, J = 8.84Hz, lH), 8.16 (t, J = 5.05Hz, lH), 8.50 (d, J = 2.53Hz, lH); 13C NMR (125MHz, DMSO- (I6) Sll .6 , 12.6,19.1, 19.9,21.7,30.4,35.9,46.3,46.9,52.4,107.6,108.2,108.5,110.6,116.9,122.6,123.8, 130.6,131.5,136.7,138.6,143.5,146.4,150.2,159.2,164.0 , 169.6.

PATENT

WO 2013067296

Examples 267 and 268

(S)-6-bromo-1 -(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3- methyl-1 H-indole-4-carboxamide (Ex 267) and (R)-6-Bromo-1 -(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (Ex 268)

6-Bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methy methyl-1 H-indole-4-carboxamide (racemic mixture, 1.9 g) was resolved by chiral HPLC (column : Chiralpak AD-H, 5 microns, 50 mm x 250 mm, UV detection :240 nM, flow rate: 100 mL/min, T = 20 deg C, eluent: 60:40:0.1 n-heptane:ethanol:isopropylamine

(isocratic)). For each run, 100 mg of the racemic compound was dissolved in 30 volumes (3.0 ml.) of warm ethanol with a few drops of isopropylamine added. A total of 19 runs were performed. Baseline resolution was observed for each run. The isomer that eluted at 8.3-10.1 min was collected (following concentration) as a white solid, which was dried at 50 °C (< 5 mm Hg) to afford 901 mg, and was determined to be the S isomer^* (Ex. 267; chiral HPLC: >99.5% ee (no R isomer detected). The isomer that eluted at 10.8-13.0 min was collected as a white solid, which was dried at 50 °C (< 5 mm Hg) to afford 865 mg, and was determined to be the R isomer^* (Ex. 268; chiral HPLC: 99.2% ee; 0.4% S isomer detected). ¹H NMR and LCMS were consistent with the parent racemate.

* The absolute configuration was determined by an independent synthesis of each enantiomer from the corresponding commercially available homochiral alcohols via Mitsunobu reaction. The sterochemical assignments were also consistent by vibrational circular dichroism (VCD) analysis.

Example 269

1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-6-(6- (piperazin-1 -yl)pyridin-3-yl)-1 -indole-4-carboxamide

Added sequentially to a reaction vial were 6-bromo-1 -(sec-butyl)-N-((4,6-dimethyl- 2-OXO-1 , 2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (0.15 g, 0.338 mmol), 1-(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.127 g, 0.439 mmol), and potassium phosphate (tribasic) (0.287 g, 1.350 mmol), followed by 1 ,4- Dioxane (3 mL) and water (0.75 mL). The suspension was stirred under N₂ degassing for 10 min., and then added PdCI₂(dppf)-CH₂CI₂adduct (0.028 g, 0.034 mmol). The reaction vial was sealed, placed into a heat block at 95 °C, and stirred for 1.5 h. The contents were removed from heating and allowed to cool to room temperature. The aq layer was removed from bottom of the reaction vial via pipette. The reaction mixture was diluted into EtOAc (20 mL) followed by addition of 0.2 g each of Thiol-3 silicycle resin and silica gel. The volatiles were removed in vacuo and the residue dried on hi-vac for 1 h. The contents were purified by silica gel chromatography (dry loaded, eluent : A:

Dichloromethane, B: 10% (2M Ammonia in Methanol) in Chloroform, Gradient B: 8- 95%). The obtained solid was concentrated from TBME and dried in vacuum oven at 45 °C for 18 h. The product was collected as 129 mg (70%). ¹H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (t, J=7.33 Hz, 3H), 1.40 (d, J=6.57 Hz, 3H), 1.80 (dq, J=10.07, 7.08 Hz, 2H), 2.1 1 (s, 3H), 2.14 – 2.19 (m, 3H), 2.24 (s, 3H), 2.76 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 – 4.67 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.26 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.53 Hz, 1 H), 1 1.48 (br. s.,1 H) ; LCMS MH+ =527.3.

Example 270

A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -[(1 S)-1 -methylpropyl]-6- [6-(1-piperazinyl)-3-pyridinyl]-1 H-indole-4-carboxamide

To a 30 mL microwave vial were added (S)-6-bromo-1 -(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (100 mg, 0.225 mmol), 1 -(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCI₂(dppf)-CH₂CI₂ adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1 % NH₄OH to 60%

ACN/H₂0, 0.1 % NH₄OH ) to give 91 mg of product as off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.70 – 0.78 (m, 3H), 1.37 – 1.44 (m, 3H), 1 .75 – 1.87 (m, 2H), 2.1 1 (s, 3H), 2.16 (s, 3H), 2.22 – 2.27 (m, 3H), 2.77 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.31 Hz, 2H), 4.56 – 4.68 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.52 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.53 Hz, 1 H); LCMS: 527.8 (MH+).

Example 271

A/-[(4,6-dimethyl-2-oxo-1 ,2-dihydro-3-pyridinyl)methyl]-3-methyl-1 -[(1 /?)-1-methylpropyl]- 6-[6-(1 -piperazinyl)-3-pyridinyl]-1 -indole-4-carboxamide

To a 30 mL microwave vial were added (R)-6-bromo-1-(sec-butyl)-N-((4,6- dimethyl-2-oxo-1 ,2-dihydropyridin-3-yl)methyl)-3-methyl-1 H-indole-4-carboxamide (100 mg, 0.225 mmol), 1 -(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCI₂(dppf)-CH₂Cl2 adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1 % NH₄OH to 60%

ACN/H₂0, 0.1 % NH₄OH ) to give 90 mg of product as off-white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.1 1 (s, 3H), 2.15 – 2.20 (m, 3H), 2.24 (s, 3H), 2.77 – 2.83 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 – 4.68 (m, 1 H), 5.87 (s, 1 H), 6.88 (d, J=8.84 Hz, 1 H), 7.17 (d, J=1.52 Hz, 1 H), 7.26 (s, 1 H), 7.73 (d, J=1.26 Hz, 1 H), 7.91 (dd, J=8.84, 2.53 Hz, 1 H), 8.16 (t, J=5.05 Hz, 1 H), 8.50 (d, J=2.27 Hz, 1 H); LCMS: 527.7 (MH+)

PATENT

WO 2011140324

Example 270

N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l-[(15)-l-methylpropyl]-6-[6-(l-piperazinyl)-3-pyridinyl]-lH-indole-4-carboxamide

To a 30 niL microwave vial were added (S)-6-bromo-l-(sec-butyl)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3 -methyl- lH-indole-4-carboxamide (100 mg, 0.225 mmol), l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCi₂(dppf)-CH₂Ci₂ adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1% NH₄OH to 60% ACN/H₂0, 0.1% NH₄OH ) to give 91 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 – 0.78 (m, 3H), 1.37 – 1.44 (m, 3H), 1.75 – 1.87 (m, 2H), 2.11 (s, 3H), 2.16 (s, 3H), 2.22 – 2.27 (m, 3H), 2.77 – 2.85 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.31 Hz, 2H), 4.56 – 4.68 (m, IH), 5.87 (s, IH), 6.88 (d, J=8.84 Hz, IH), 7.17 (d, J=1.52 Hz, IH), 7.26 (s, IH), 7.73 (d, J=1.26 Hz, IH), 7.91 (dd, J=8.84, 2.53 Hz, IH), 8.16 (t, J=5.05 Hz, IH), 8.50 (d, J=2.53 Hz, IH); LCMS: 527.8 (MH+).

Example 271

N-[(4,6-dimethyl-2-oxo-l,2-dihydro-3-pyridinyl)methyl]-3-methyl-l-[(li?)-l-methylpropyl]-6-[6-(l-piperazinyl)-3-pyridinyl]-l -indole-4-carboxamide

To a 30 mL microwave vial were added (R)-6-bromo-l-(sec-butyl)-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-3 -methyl- lH-indole-4-carboxamide (100 mg, 0.225 mmol), l-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (85 mg, 0.293 mmol), 1 ,2-Dimethoxyethane (DME) (3 mL), water (1.000 mL) and sodium carbonate (0.338 mL, 0.675 mmol), and the mixture was degassed for 5 min by bubbling nitrogen. PdCl₂(dppf)-CH₂Cl₂ adduct (14.70 mg, 0.018 mmol) was added and the tube was sealed. The mixture was irradiated (microwave) at 140 °C for 10 min. The mixture was concentrated and the residue was taken up into MeOH and filtered. The filtrate was purified using reverse-phase HPLC (eluent: 25%ACN/H₂0, 0.1% NH₄OH to 60% ACN/H₂0, 0.1% NH₄OH ) to give 90 mg of product as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (m, 3H), 1.41 (d, J=6.57 Hz, 3H), 1.81 (td, J=7.14, 2.91 Hz, 2H), 2.11 (s, 3H), 2.15 – 2.20 (m, 3H), 2.24 (s, 3H), 2.77 – 2.83 (m, 4H), 3.41 – 3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54 -4.68 (m, 1H), 5.87 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 7.17 (d, J=1.52 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 8.16 (t, J=5.05 Hz, 1H), 8.50 (d, J=2.27 Hz, 1H); LCMS: 527.7 (MH+).

REF

Tian X, Zhang S, Liu HM, et al. Histone lysine-specific methyltransferases and demethylases in carcinogenesis: new targets for cancer therapy and prevention. Curr Cancer Drug Targets. 2013 Jun 10;13(5):558-79. PMID: 23713993.

McCabe MT, Ott HM, Ganji G, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012 Dec 6;492(7427):108-12. PMID: 23051747.

WO2005034845A2 *	Jul 13, 2004	Apr 21, 2005	Supergen, Inc.	Compositions and methods for treatment of cancer
WO2007053114A1 *	Oct 30, 2006	May 10, 2007	S*Bio Pte Ltd	Method of predicting a response to hdac inhibitors
WO2010090723A2 *	Feb 2, 2010	Aug 12, 2010	University Of Georgia Research Foundation, Inc.	Methods of inhibiting fibrogenesis and treating fibrotic disease
US20110035336	May 1, 2008	Feb 10, 2011	Yigang Cai	Rating change for a prepaid session based on movement of a mobile device
US20110035340	Aug 7, 2009	Feb 10, 2011	Fibre-Craft Materials Corp.	Decorating system and method of marketing and enhancing a surface area using a decorating system
US20110035344	Aug 6, 2009	Feb 10, 2011	International Business Machines Corporation	Computing mixed-integer program solutions using multiple starting vectors
US20110064664 *	Oct 8, 2008	Mar 17, 2011	The Board Of Regents Of The University Of Texas System	Methods and compositions involving chitosan nanoparticles

WO2015077194A1 *	Nov 18, 2014	May 28, 2015	Bristol-Myers Squibb Company	Inhibitors of lysine methyl transferase
WO2015132765A1 *	Mar 6, 2015	Sep 11, 2015	Glaxosmithkline Intellectual Property (No.2) Limited	Enhancer of zeste homolog 2 inhibitors
WO2015141616A1 *	Mar 16, 2015	Sep 24, 2015	第一三共株式会社	1,3-benzodioxole derivative
WO2016066697A1 *	Oct 28, 2015	May 6, 2016	Glaxosmithkline Intellectual Property (No.2) Limited	Enhancer of zeste homolog 2 inhibitors
US9051269	Nov 19, 2012	Jun 9, 2015	Constellation Pharmaceuticals, Inc.	Modulators of methyl modifying enzymes, compositions and uses thereof
US9085583	Feb 11, 2013	Jul 21, 2015	Constellation—Pharmaceuticals, Inc.	Modulators of methyl modifying enzymes, compositions and uses thereof
US20150344459 *	Dec 20, 2013	Dec 3, 2015	Epizyme, Inc.	1,4-pyridone bicyclic heteroaryl compounds

/////////GSK-2816126, GSK-126, 2816126, 1346574-57-9, GSK 126, GSK 126, GSK 2816126, GSK 2816126A

CC=5C=C(C)NC(=O)C=5CNC(=O)c1cc(cc2c1c(C)cn2[C@@H](C)CC)c3cnc(cc3)N4CCNCC4

GSK-2838232

phase 1, Uncategorized Comments Off

Jun 132016

GSK-2838232

4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-((3-chlorobenzyl)(2-(dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid.

28-Norlup-18-en-21-one, 3-(3-carboxy-3-methyl-1-oxobutoxy)-17-[(1R)-2-[[(4-chlorophenyl)methyl][2-(dimethylamino)ethyl]amino]-1-hydroxyethyl]-, (3β)-

Glaxosmithkline Llc INNOVATOR

Mark Andrew HATCHER, Brian Alvin Johns,Michael Tolar Martin, Elie Amine TABET, Jun Tang

A reverse transcriptase inhibitor potentially for the treatment of HIV infection.

GSK-2838232; GSK-8232; 2838232

CAS No. 1443460-91-0

C48H73ClN2O6,809.56

SYNTHESIS

PART 1

PART2

PART3

PART 4

AND UNWANTEDISOMER SHOWN BELOW

PART5

GSK2838232 is a novel human immune virus (HIV) maturation inhibitor being developed for the treatment of chronic HIV infection. GSK2838232 is a betulin derivative

Human immunodeficiency virus type 1 (HIV-1 ) leads to the contraction of acquired immune deficiency disease (AIDS). The number of cases of HIV continues to rise, and currently over twenty-five million individuals worldwide suffer from the virus. Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which have been shown to greatly increase patient survival and quality of life.

However, additional therapies are still required because of undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; and drug resistance due to mutation of the enzyme target.

Currently, almost all HIV positive patients are treated with therapeutic regimens of antiretroviral drug combinations termed, highly active antiretroviral therapy (“HAART”). However, HAART therapies are often complex because a combination of different drugs must be administered often daily to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur. The emergence of multidrug-resistant HIV-1 isolates has serious clinical consequences and must be suppressed with a new drug regimen, known as salvage therapy.

Current guidelines recommend that salvage therapy includes at least two, and preferably three, fully active drugs. Typically, first-line therapies combine three to four drugs targeting the viral enzymes reverse transcriptase and protease. One option for salvage therapy is to administer different combinations of drugs from the same mechanistic class that remain active against the resistant isolates.

However, the options for this approach are often limited, as resistant mutations frequently confer broad cross-resistance to different drugs in the same class.

Alternative therapeutic strategies have recently become available with the development of fusion, entry, and integrase inhibitors. However, resistance to all three new drug classes has already been reported both in the lab and in patients. Sustained successful treatment of HIV-1 -infected patients with antiretroviral drugs will therefore require the continued development of new and improved drugs with new targets and mechanisms of action.

Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. To date, a number of approved drugs have been shown to greatly increase patient survival. However, therapeutic regimens known as highly active antiretroviral therapy (HAART) are often complex because a combination of different drugs must be administered to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur.

The HIV Gag polyprotein precursor (Pr55Gag), which is composed of four protein domains – matrix (MA), capsid (CA), nucleocapsid (NC) and p6 – and two spacer peptides, SP1 and SP2, represents a new therapeutic target. Although the cleavage of the Gag polyprotein plays a central role in the progression of infectious virus particle production, to date, no antiretroviral drug has been approved for this mechanism.

In most cell types, assembly occurs at the plasma membrane, and the

MA domain of Gag mediates membrane binding. Assembly is completed by budding of the immature particle from the cell. Concomitant with particle release, the virally encoded PR cleaves Gag into the four mature protein domains, MA, CA, NC and p6, and the two spacer peptides, SP1 and SP2. Gag-Pol is also cleaved by PR, liberating the viral enzymes PR, RT and IN. Gag proteolytic processing induces a

morphological rearrangement within the particle, known as maturation. Maturation converts the immature, donut-shaped particle to the mature virion, which contains a condensed conical core composed of a CA shell surrounding the viral RNA genome in a complex with NC and the viral enzymes RT and IN. Maturation prepares the virus for infection of a new cell and is absolutely essential for particle infectivity.

Bevirimat (PA-457) is a maturation inhibitor that inhibits the final step in the processing of Gag, the conversion of capsid-SP1 (p25) to capsid, which is required for the formation of infectious viral particles. Bevirimat has activity against ART-resistant and wild-type HIV, and has shown synergy with antiretrovirals from all classes. Bevirimat reduced HIV viral load by a mean of 1.3 logi₀/mL in patients who achieved trough levels of >= 20 μg/mL and who did not have any of the key baseline Gag polymorphisms at Q369, V370 or T371. However, Bevirimat users with Gag polymorphisms at Q369, V370 or T371 demonstrated significantly lower load reductions than patients without Gag polymorphisms at these sites.

Other examples of maturation inhibitors can be found in PCT Patent

Application No. WO201 1/100308, “Derivatives of Betulin”; PCT Patent Application No. PCT/US2012/024288, “Novel Anti-HIV Compounds and Methods of Use Thereof ; Chinese PCT Application No. PCT/CN201 1/001302, “Carbonyl Derivatives of Betulin”; Chinese PCT Application No. PCT/CN201 1/001303, “Methylene Derivatives of Betulin”; Chinese PCT Application Nos. PCT/CN201 1/002105 and PCT/CN201 1/002159, “Propenoate Derivatives of Betulin”. Maturation inhibitors in the prior art leave open gaps in the areas of polymorphism coverage whereby potency against a broad range of clinically relevant gag sequences is extremely important, along with overall potency including the clinically relevant protein adjusted antiviral activity that will be required for robust efficacy in long term durability trials. To date, no maturation inhibitor has achieved an optimal balance of these properties.

PATENT

WO 2013090664

https://www.google.com/patents/WO2013090664A1?cl=en

Example 17: Compound 50

4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((S)-1-Acetoxy-2-((4- chlorobenzyl)amino)ethyl)-1-isopropyl-5a, 5b, 8, 8, 11 a-pentamethyl-2-oxo- 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

[00241] The title compound was made in a similar manner to Example 16 and isolated as a TFA salt. ¹H NMR (400MHz ,CHLOROFORM-d) δ = 7.49 – 7.30 (m, 4 H), 5.85 – 5.71 (m, 1 H), 4.59 – 4.40 (m, 1 H), 4.31 – 4.03 (m, 2 H), 3.41 – 2.79 (m, 4 H), 2.79 – 2.50 (m, 2 H), 2.37 (d, J = 18.1 Hz, 2 H), 2.02 – 0.63 (m, 49 H); LC/MS: m/z calculated 779.5, found 780.3 (M+1 )⁺.

Example 18: Compound 51

4-(((3aR, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aS)-3a-((R)-2-((4-Chlorobenzyl)(2- (dimethylamino)ethyl)amino)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8, 11a-pe

2-0X0-3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,9, 10, 11, 11a, 11b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid

[00242] To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (6.75 g, 54.6 mmol) in methanol (20 ml_) was added 4-

(((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)amino)-1 – hydroxyethyl)-1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethyl-2-oxo- 3,3a,4,5,5a,5b,6,7,7a,8,9,10,1 1 ,1 1 a,1 1 b,12,13,13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid , Trifluoroacetic acid salt (46) (9.5 g, 10.92 mmol). The pH was adjusted to 7-8 with Et₃N. The reaction mixture was stirred at rt for 2 h. Sodium cyanoborohydride (0.686 g, 10.92 mmol) was then added and the mixture was stirred at rt overnight. After the reaction was complete, water (15 ml_) and EtOAc (15 ml_) were added, and then the organic phase was removed and concentrated under reduced presure. The product was extracted with EtOAc (80 ml_x3), the combined organic phase was washed with brine, dried, and concentrated. The product was purified by flash chromatography (DCM:EtOAc=2: 1 to 1 : 1 , then DCM:MeOH=100: 1 to 20: 1 ) to give 4- (((3aR,5aR,5bR,7aR,9S, 1 1 aR, 1 1 bR, 13aS)-3a-((R)-2-((4-chlorobenzyl)(2- (dimethylamino)ethyl)amino)-1 -hydroxyethyl)-1 -isopropyl-5a,5b,8,8, 1 1 a-pentamethyl- 2-0X0-3, 3a,4, 5, 5a, 5b, 6, 7, 7a, 8, 9, 10, 1 1 , 1 1 a, 1 1 b, 12, 13, 13a-octadecahydro-2H- cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (51 ) (6 g, 7.41 mmol, 67.9 % yield) as white solid. Multiple batches of this material (were combined 95 g), dissolved in 600 mL of dichloromethane and washed with NaHC0₃ (400 ml_*3) and the organic phase was dried over Na₂S0₄, filtered and concentrated. The solids were washed with a mixture of EtOAc: petroleum ether (600 mL), and filtered followed by lyophilization to provide the final title compound 62 g as a white solid. ¹H NMR (400MHz ,METHANOL-d₄) δ = 7.47 – 7.29 (m, 4 H), 4.48 (dd, J = 5.8, 10.3 Hz, 1 H), 4.15 – 4.04 (m, 1 H), 3.80 (d, J = 13.8 Hz, 1 H), 3.57 (d, J = 14.1 Hz, 1 H), 3.21 – 2.82 (m, 5 H), 2.72 – 2.41 (m, 9 H), 2.37 – 2.05 (m, 4 H), 2.05 – 0.74 (m, 45 H);

LC/MS: m/z calculated 808.5, found 809.5 (M+1 )⁺.

REFERENCES

Hatcher, Mark Andrew; Johns, Brian Alvin; Martin, Michael Tolar; Tabet, Elie Amine; Tang, Jun. Preparation of betulin derivatives for the treatment of HIV, PCT Int. Appl. (2013), WO 2013090664 A1 20130620.

////////GSK-2838232, 1443460-91-0, GSK 2838232, GSK-8232, 2838232, treatment of HIV, phase1

O=C(C1)C(C(C)C)=C2[C@@]1([C@@H](O)CN(CCN(C)C)CC3=CC=CC(Cl)=C3)CC[C@]4(C)[C@]2([H])CC[C@@]5([H])[C@@]4(C)CC[C@]6([H])[C@]5(C)CC[C@H](OC(CC(C)(C)C(O)=O)=O)C6(C)C

Karl Landsteiner’s 148th birthday

TD 1607

phase 1, Uncategorized Comments Off

Jun 132016

TD-1607

A glycopeptide-cephalosporin heterodimer potentially for the treatment of gram-positive bacterial infection.

CAS No. 827040-07-3

C₉₅ H₁₀₉ Cl₃ N₁₈ O₃₁ S_2,

Molecular Weight, 2169.47

Vancomycin, 29-[[[2-[[6-[[[1-[[(6R,7R)-7-[[(2Z)-2-(2-amino-5-chloro-4-thiazolyl)-2-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]pyridinium-4-yl]methyl]amino]-1,6-dioxohexyl]amino]ethyl]amino]methyl]-, inner salt

Vancomycin, 29-[[[2-[[6-[[[1-[[(6R,7R)-7-[[(2Z)-(2-amino-5-chloro-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]pyridinium-4-yl]methyl]amino]-1,6-dioxohexyl]amino]ethyl]amino]methyl]-, inner salt

Originator Theravance
Developer Theravance Biopharma
Class Antibacterials; Cephalosporins; Glycopeptides
Mechanism of Action Cell wall inhibitors
- Phase I Gram-positive infections
Most Recent Events
- 21 Apr 2016 Phase I development is ongoing in USA
- 01 Jul 2014 Theravance completes a phase I trial in Healthy volunteers in in USA (NCT01949103)
- 02 Jun 2014 Theravance Biopharma is formed as a spin-off of Theravance
- Company Theravance Biopharma Inc.
  
  Description Glycopeptide cephalosporin heterodimer antibiotic
  
  Molecular Target
  
  Mechanism of Action
  
  Therapeutic Modality Small molecule: Combination
  
  Latest Stage of Development Phase I
  
  Standard Indication Gram-negative bacterial infection
  
  Indication Details Treat Gram-positive bacterial infections

PATENT

WO 2005005436

https://www.google.com/patents/WO2005005436A2?cl=en29

The present invention provides novel cross-linked glycopeptide – cephalosporin compounds that are useful as antibiotics. The compounds of this invention have a unique chemical structure in which a glycopeptide group is covalently linked to a pyridinium moiety of a cephalosporin group. Among other properties, compounds of this invention have been found to possess surprising and unexpected potency against Gram-positive bacteria including methicillin-resistant Staphylococci aureus (MRSA). Accordingly, in one aspect, the invention provides a compound of formula I:

////////Theravance Biopharma, TD 1607, phase 1, glycopeptide-cephalosporin heterodimer , gram-positive bacterial infection

PIERRE FABRE CDMO Supercritical Fluids – A supercritical CO2 GMP Unit for Pharmaceutical Applications.

companies, PROCESS Comments Off

Jun 132016

Pierre Fabre's Supercritical CO2 GMP unit.

read all by clicking

http://www.pharmaceutical-technology.com/contractors/contract/supercritical-fluids/?WT.mc_id=WN_Comp

The article gives contact details of below person

…….//////PIERRE FABRE CDMO, Supercritical Fluids, supercritical CO2 GMP Unit, Pharmaceutical Applications.

Temanogrel

Phase 3 drug, Uncategorized Comments Off

Jun 122016

ChemSpider 2D Image | temanogrel | C24H28N4O4

Temanogrel

APD 791

3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholinoethoxy)phenyl]benzamide

Benzamide,3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-

UNII:F42Z27575A

TEMANOGREL; APD791; CHEMBL1084617; UNII-F42Z27575A; 887936-68-7; 3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide;
Molecular Formula:	C₂₄H₂₈N₄O₄
Molecular Weight:	436.50352 g/mol

Originator Arena Pharmaceuticals
Developer Arena Pharmaceuticals; Ildong Pharmaceutical
Class Antithrombotics; Small molecules
Mechanism of Action Serotonin 2A receptor inverse agonists

Phase I Arterial thrombosis

Most Recent Events

30 Mar 2016 Arena Pharmaceuticals has patents pending for Temanogrel in 12 regions, including Brazil (Arena Pharmaceuticals 10-K; march 2016)
30 Mar 2016 Arena Pharmaceuticals has patent protection for Temanogrel in 87 regions, including USA, Japan, China, Germany, France, Italy, the United Kingdom, Spain, Canada, Russia, India, Australia and South Korea
01 Mar 2015 Ildong Pharmaceutical initiates enrolment in a phase I trial for Arterial thrombosis in South Korea (NCT02419820)

A 5-HT2A inverse agonist potentially for the reduction of the risk of arterial thrombosis.

APD-791

CAS No. 887936-68-7

ChemSpider 2D Image | Temanogrel hydrochloride | C24H29ClN4O4

Temanogrel hydrochloride

Molecular FormulaC₂₄H₂₉ClN₄O₄
Average mass472.965

957466-27-2 CAS

Benzamide, 3-methoxy-N-[3-(1-methyl-1H-pyrazol-5-yl)-4-[2-(4-morpholinyl)ethoxy]phenyl]-, hydrochloride (1:1) [ACD/Index Name]

Temanogrel hydrochloride [USAN]

UNII:5QEY8NZP3T

Temanogrel, also known as APD791, is a highly selective 5-hydroxytryptamine2A receptor inverse agonist under development for the treatment of arterial thrombosis. APD791 displayed high-affinity binding to membranes (K(i) = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC(50) = 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT(2A) receptor. APD791 was greater than 2000-fold selective for the 5-HT(2A) receptor versus 5-HT(2C) and 5-HT(2B) receptors. APD791 inhibited 5-HT-mediated amplification of ADP-stimulated human and dog platelet aggregation (IC(50) = 8.7 and 23.1 nM, respectively)

Arterial thrombosis is the formation of a blood clot or thrombus inside an artery or arteriole that restricts or blocks the flow of blood and, depending upon location, can result in acute coronary syndrome or stroke. The formation of a thrombus is usually initiated by blood vessel injury, which triggers platelet aggregation and adhesion of platelets to the vessel wall. Treatments aimed at inhibiting platelet aggregation have demonstrated clear clinical benefits in the setting of acute coronary syndrome and stroke. Current antiplatelet therapies include aspirin, which irreversibly inhibits cyclooxygenase (COXa

Abbreviations: COX, cyclooxygenase; ADP, adenosine diphosphate; SAR, structure−activity relationship; hERG, human ether-a-go-go-related gene; CNS, central nervous system; 5-HT, serotonin; AUC, area under the plasma concentration time curve, iv, intravenous; IP, inositol phosphate.

) and results in reduced thromboxane production, clopidogrel and prasugrel, which inhibit platelet adenosine diphosphate (ADP) P₂Y₁₂ receptors, and platelet glycoprotein IIb/IIIa receptor antagonists. Another class of antiplatelet drugs, protease-activated thrombin receptor (PAR-1) antagonists, are also being evaluated in the clinic for the treatment of acute coronary syndrome. The most advanced candidate in this class, N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-1-methyl-3-oxoperhydro-naphtho[2,3-c]furan-6-yl]-carbamic acid ethyl ester (SCH-530348), is currently in phase 3 trials for the prevention of arterial thrombosis.

The 5-HT_2A receptor is one of 15 different serotonin receptor subtypes.

In the cardiovascular system, modulation of 5-HT_2A receptors on vascular smooth muscle cells and platelets is thought to play an important role in the regulation of cardiovascular function. Platelets are activated by a variety of agonists such as ADP, thrombin, thromboxane, serotonin, epinephrine, and collagen. Upon platelet activation at the site of blood vessel injury, a number of factors including serotonin (5-HT) are released. Although by itself serotonin is a weak activator of platelet aggregation, in vitro it can amplify aggregation induced by other agonists as mentioned above. Therefore, serotonin released from activated platelets may induce further platelet aggregation and enhance thrombosis.

The 5-HT_2A receptor antagonist ketanserin was shown in clinical studies to reduce early restenosis(7) and decrease myocardial ischemia during coronary balloon angioplasty.(8)However, in another study, ketanserin did not significantly improve clinical outcomes, and the rate of adverse events was higher than that observed in the control group.(9) Some of the adverse events reported in the latter study could be specific to ketanserin and resulted from its lack of 5-HT_2A receptor selectivity. Other 5-HT_2A antagonists with improved selectivity profiles have shown promise in clinical studies. For example, sarpogrelate was shown to inhibit restenosis following coronary stenting.

Figure 1. Serotonin and known 5-HT_2A receptor antagonists.

Because the 5-HT_2A receptor is expressed both in peripheral tissues and in the central nervous system (CNS), compounds with limited CNS partitioning would be preferred to maximize cardiovascular and blood platelet pharmacological activity while minimizing CNS effects. In addition, because 5-HT_2A receptor inverse agonists are thought to reduce thrombus formation via inhibition of serotonin-mediated amplification of platelet aggregation without inhibiting agonist driven aggregation per se, it is possible that this class of inhibitors will have an improved bleeding risk side effect profile compared to what has been observed with other classes of antithrombotic drugs.

SYNTHESIS

PAPER

Journal of Medicinal Chemistry (2010), 53(11), 4412-4421.

http://pubs.acs.org/doi/abs/10.1021/jm100044a

Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT_2A receptor. 5-HT_2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT_2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC₅₀ = 8.7 nM and had negligible binding affinity for the closely related 5-HT_2B and 5-HT_2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial

Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, California 92121

J. Med. Chem., 2010, 53 (11), pp 4412–4421

DOI: 10.1021/jm100044a

Publication Date (Web): May 10, 2010

*To whom correspondence should be addressed. Phone: +1 858-453-7200. Fax: +1 858-453-7210. E-mail:yxiong@arenapharm.com.

3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-benzamide (10k)

10k was prepared in a manner similar to that described for 10c, using 9d (120 mg, 0.40 mmol) and 3-methoxybenzoyl chloride (81 mg, 0.48 mmol) to give the TFA salt of 10k as a white solid (88 mg, 51%); mp (HCl salt, recrystallized from iPrOH) 214−216 °C. ¹H NMR (acetone-d₆, 400 MHz) δ: 2.99−3.21 (m, 2H), 3.22−3.45 (m, 2H), 3.66 (t, J = 4.8 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79−3.89 (m, 4H), 4.58 (t, J = 4.8 Hz, 2H), 6.29 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 2.5, 8.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.52 (t, J = 1.7 Hz, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.80−7.83 (m, 1H), 7.91−7.96 (m, 1H), 9.54 (s, 1H). LCMSm/z = 437.5 [M + H]⁺.

Additional Information

Oral administration of APD791 to dogs resulted in acute (1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT(2A) receptor antagonist with potent activity on platelets and vascular smooth muscle.(http://www.ncbi.nlm.nih.gov/pubmed/19628629).

PATENT

WO 2006055734

https://google.com/patents/WO2006055734A2?cl=en

Example 1.88: Preparation of 3-methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin~

4-yl-ethoxy)-phenyl]-benzamide (Compound 733).

A mixture of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (120 mg, 0.40 mmole), 3-methoxy-benzoyl chloride (81 mg, 0.48 mmole), and triethylamine (0.1 mL, 0.79 mmole) in 5 mL THF was stirred at room temperature for 10 minutes. The mixture was purified by HPLC to give the title compound as a white solid (TFA salt, 88 mg, 51 %). ¹H NMR ( Acetone-^, 400 MHz) 2.99-3.21 (m, 2H), 3.22-3.45 (m, 2H), 3.66 (t, J= 4.80 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H), 3.79-3.89 (m, 4H), 4.58 (t, J= 4.80 Hz, 2H), 6.29 (d, J= 2.02 Hz IH), 7.13 (dd, J= 8.34, 2.53 Hz, IH), 7.22 (d, J= 8.84 Hz, IH), 7.42 (t, J= 7.83 Hz, IH), 7.47 (d, J= 1.77 Hz, IH), 7.52 (t, J= 1.77 Hz, IH), 7.56 (d, J= 7.07 Hz, IH), 7.80-7.83 (m, IH), 7.91-7.96 (m, IH), 9.54 (s, NH). Exact mass calculated for C₂₄H₂₈N₄O₄ 436.2, found 437.5 (MH⁺).

References

1: Xiong Y, Teegarden BR, Choi JS, Strah-Pleynet S, Decaire M, Jayakumar H, Dosa
PI, Casper MD, Pham L, Feichtinger K, Ullman B, Adams J, Yuskin D, Frazer J,
Morgan M, Sadeque A, Chen W, Webb RR, Connolly DT, Semple G, Al-Shamma H.
Discovery and structure-activity relationship of
3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide
(APD791): a highly selective 5-hydroxytryptamine2A receptor inverse agonist for
the treatment of arterial thrombosis. J Med Chem. 2010 Jun 10;53(11):4412-21.
doi: 10.1021/jm100044a. PubMed PMID: 20455563.

2: Przyklenk K, Frelinger AL 3rd, Linden MD, Whittaker P, Li Y, Barnard MR, Adams
J, Morgan M, Al-Shamma H, Michelson AD. Targeted inhibition of the serotonin
5HT2A receptor improves coronary patency in an in vivo model of recurrent
thrombosis. J Thromb Haemost. 2010 Feb;8(2):331-40. doi:
10.1111/j.1538-7836.2009.03693.x. Epub 2009 Nov 17. PubMed PMID: 19922435; PubMed
Central PMCID: PMC2916638.

3: Adams JW, Ramirez J, Shi Y, Thomsen W, Frazer J, Morgan M, Edwards JE, Chen W,
Teegarden BR, Xiong Y, Al-Shamma H, Behan DP, Connolly DT. APD791,
3-methoxy-n-(3-(1-methyl-1h-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide,
a novel 5-hydroxytryptamine 2A receptor antagonist: pharmacological profile,
pharmacokinetics, platelet activity and vascular biology. J Pharmacol Exp Ther.
2009 Oct;331(1):96-103. doi: 10.1124/jpet.109.153189. Epub 2009 Jul 23. PubMed
PMID: 19628629.

Patent ID	Date	Patent Title
US2015361031	2015-12-17	STAT3 INHIBITOR
US8785441	2014-07-22	3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
US2013296321	2013-11-07	CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF PHENYL-PYRAZOLES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
US2012252813	2012-10-04	CRYSTALLINE FORMS OF CERTAIN 3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148417	2012-04-03	PRIMARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US8148418	2012-04-03	ETHERS, SECONDARY AMINES AND DERIVATIVES THEREOF AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US2011105456	2011-05-05	3-PHENYL-PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
US7884101	2011-02-08	3-Phenyl-pyrazole derivatives as modulators of the 5-HT2a serotonin receptor useful for the treatment of disorders related thereto
US2010234380	2010-09-16	CRYSTALLINE FORMS AND PROCESSES FOR THE PREPARATION OF PHENYL-PYRAZOLES USEFUL AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR
US2007244086	2007-10-18	3-Phenyl-Pyrazole Derivatives as Modulators of the 5-Ht2A Serotonin Receptor Useful for the Treatment of Disorders Related Thereto

///////////APD-791 , 887936-68-7, Temanogrel , PHASE 1, ARENA,

CN1C(=CC=N1)C2=C(C=CC(=C2)NC(=O)C3=CC(=CC=C3)OC)OCCN4CCOCC4

C(=O)(c1cc(ccc1)OC)Nc1ccc(c(c1)c1n(ncc1)C)OCCN1CCOCC1

DR ANTHONY’S ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS

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Jun 112016

ORGANIC SPECTROSCOPY INTERNATIONAL HITS 4 LAKH VIEWS

LINK https://orgspectroscopyint.blogspot.in/

SEE SNAPSHOT

ORGANIC SPECTROSCOPY INTERNATIONAL

Organic Chemists from Industry and academics to Interact on Spectroscopy Techniques for Organic Compounds ie NMR, MASS, IR, UV Etc. Starters, Learners, advanced, all alike, contains content which is basic or advanced, by Dr Anthony Melvin Crasto, Worlddrugtracker.

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MAKING INDIANS FEEL PROUD

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Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database

MONOCLONAL ANTIBODIES Comments Off

Jun 112016

Antibodies are used extensively for a wide range of basic research and clinical applications. While an abundant and diverse collection of antibodies to protein antigens have been developed, good monoclonal antibodies to carbohydrates are much less common. Moreover, it can be difficult to determine if a particular antibody has the appropriate specificity, which antibody is best suited for a given application, and where to obtain that antibody. Herein, we provide an overview of the current state of the field, discuss challenges for selecting and using antiglycan antibodies, and summarize deficiencies in the existing repertoire of antiglycan antibodies. This perspective was enabled by collecting information from publications, databases, and commercial entities and assembling it into a single database, referred to as the Database of Anti-Glycan Reagents (DAGR). DAGR is a publicly available, comprehensive resource for anticarbohydrate antibodies, their applications, availability, and quality

Monoclonal antibodies have transformed biomedical research and clinical care. In basic research, these proteins are used widely for a myriad of applications, such as monitoring/detecting expression of biomolecules in tissue samples, activating or antagonizing various biological pathways, and purifying antigens. To illustrate the magnitude and importance of the antibody reagent market, one commercial supplier sells over 50 000 unique monoclonal antibody clones. In a clinical setting, antibodies are used frequently as therapeutic agents and for diagnostic applications. As a result, monoclonal antibodies are a multibillion dollar industry, with antibody therapeutics estimated at greater than $40 billion annually, diagnostics at roughly $8 billion annually, and antibody reagents at $2 billion annually as of 2012

Perspectives on Anti-Glycan Antibodies Gleaned from Development of a Community Resource Database

Eric Sterner, Natalie Flanagan, and Jeffrey C. Gildersleeve^*

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States

ACS Chem. Biol., Article ASAP

DOI: 10.1021/acschembio.6b00244

Publication Date (Web): May 25, 2016

*E-mail: gildersj@mail.nih.gov.

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.

http://pubs.acs.org/doi/full/10.1021/acschembio.6b00244

Jeffrey C. Gildersleeve, Ph.D.

Senior Investigator

Chemical Biology Laboratory

Head, Chemical Glycobiology Section

Link to additional information about Dr. Gildersleeve’s research.

Areas of Expertise

1) glycan array technology, 2) cancer biomarkers, 3) cancer vaccines, 4) synthesis of carbohydrate antigens

Contact Info

Jeffrey C. Gildersleeve, Ph.D.
Center for Cancer Research
National Cancer Institute
Building 376, Room 208
Frederick, MD 21702-1201
Ph: 301-846-5699
gildersj@mail.nih.gov (link sends e-mail)

Permalink

The Gildersleeve group works at the interface of chemistry, glycobiology, and immunology. We use chemical approaches to 1) aid the design and development of cancer and HIV vaccines, 2) identify clinically useful biomarkers, and 3) better understand the roles of carbohydrates in cancer and HIV immunology. To facilitate these studies, we have developed a glycan microarray that allows high-throughput profiling of serum anti-glycan antibody populations. A number of other groups have also developed glycan arrays; our array is unique in that we use multivalent neoglycoproteins as our array components. This format allows us to readily translate array results to other applications and affords novel approaches to vary glycan presentation.

The main focus of our current and future research is to study the roles of anti-glycan antibodies in the development, progression, and treatment of cancer. These projects are shedding new light on how cancer vaccines work and are uncovering new biomarkers for the early detection, diagnosis, and prognosis of cancer. In particular, we are studying immune responses induced by PROSTVAC-VF, a cancer vaccine in Phase III clinical trials for the treatment of advanced prostate cancer. In addition, we are identifying biomarkers for the early detection and prognosis of ovarian and lung cancer. These projects are highly collaborative in nature and are focused on translating basic research from the bench to the clinic. We rely heavily on glycan array technology to study immune responses to carbohydrates, and we continually strive to improve this technology. First, carbohydrate-protein interactions often involve formation of multivalent complexes. Therefore, presentation is a key feature of recognition. We have developed several new approaches to vary carbohydrate presentation on the surface of the array, including methods to vary glycan density and neoglycoprotein density. Second, we use synthetic organic chemistry to obtain a diverse set of tumor-associated carbohydrates and glycopeptides to populate our array.

Collaborations and Carbohydrate Microarray Screening. We are frequently asked to screen lectins, antibodies, and other entities on our array. Although we are not a core facility and do not provide screening services per se, we are happy to collaborate on many projects. Please contact Jeff Gildersleeve for more details.

Scientific Focus Areas:

Chemical Biology, Immunology

CBL's Eric Sterner wins NIH FARE Award

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CBL’s Eric Sterner wins NIH FARE Award

Dr. Eric Sterner, a postdoctoral CRTA Fellow in the Gilderlseeve Lab was presented with a FARE award for his abstract entitled, “Profiling Mutational Significance in Germline-to-Affinity Mature 3F8 Variants” in the NIH-wide FARE 2016 competition. This award is given to abstracts that are deemed outstanding based on scientific merit, originality, experimental design and overall quality and presentation. FARE 2016 is sponsored by the NIH Scientific Directors, the Office of Intramural Training & Education and FelCom. The FARE 2016 Award is a $1000 travel grant to attend and present this work at a scientific meeting within the United States.

Natalie Flanagan

Postbaccalaureate Fellow – Cancer Research Training Award (CRTA) at National Cancer Institute (NCI)

https://www.linkedin.com/in/natalie-flanagan-602a98109

Experience

Postbaccalaureate Fellow – Cancer Research Training Award (CRTA)

National Cancer Institute (NCI)

June 2015 – Present (1 year 1 month)Frederick, Maryland

Organic Chemistry Lab TA

University of Maryland

September 2014 – May 2015 (9 months)College Park, Maryland

– Ran on section of the Organic Chemistry I laboratory course for two semesters
– Worked with students in a laboratory setting and office hours to help them understand course materials and experimental procedures
– Worked with professors and other TAs to help develop and grade examinations

Summer Intern

Pfizer

June 2013 – August 2013 (3 months)Groton, Connecticut

– Used protein crystallization to research ligand binding in a protein kinase system
– Learned a variety of laboratory techniques, including: expression and purification of proteins, and various protein crystallization techniques
– Gained a basic knowledge for how to interpret electron density maps used in three-dimensional protein structure determination
– Presented my research project at an internal poster presentation

Education

University of Maryland College Park

Bachelor’s Degree, Cell Biology and Genetics

2011 – 2015

Activities and Societies: Organic Chemistry Tutor – Primannum Honor Society, Chemistry TA, Phi Beta Kappa, Clinical Volunteer – HSC Pediatric Center

Ledyard High School

High School, General Studies

2007 – 2011

//////////Anti-Glycan Antibodies, Gleaned, Community Resource Database

FDA approves vaccine Vaxchora to prevent cholera for travelers

FDA 2016, VACCINE Comments Off

Jun 112016

FDA approves vaccine to prevent cholera for travelers

06/10/2016 04:22 PM EDT

The U.S. Food and Drug Administration today approved Vaxchora, a vaccine for the prevention of cholera caused by serogroup O1 in adults 18 through 64 years of age traveling to cholera-affected areas. Vaxchora is the only FDA-approved vaccine for the prevention of cholera.

June 10, 2016

Release

Cholera, a disease caused by Vibrio cholerae bacteria, is acquired by ingesting contaminated water or food and causes a watery diarrhea that can range from mild to extremely severe. Often the infection is mild; however, severe cholera is characterized by profuse diarrhea and vomiting, leading to dehydration. It is potentially life threatening if treatment with antibiotics and fluid replacement is not initiated promptly. According to the World Health Organization, serogroup O1 is the predominant cause of cholera globally.

“The approval of Vaxchora represents a significant addition to the cholera-prevention measures currently recommended by the Centers for Disease Control and Prevention for travelers to cholera-affected regions,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

While cholera is rare in the U.S., travelers to parts of the world with inadequate water and sewage treatment and poor sanitation are at risk for infection. Travelers to cholera-affected areas have relied on preventive strategies recommended by the CDC to protect themselves against cholera, including safe food and water practices and frequent hand washing.

Vaxchora is a live, weakened vaccine that is taken as a single, oral liquid dose of approximately three fluid ounces at least 10 days before travel to a cholera-affected area.

Vaxchora’s efficacy was demonstrated in a randomized, placebo-controlled human challenge study of 197 U.S. volunteers from 18 through 45 years of age. Of the 197 volunteers, 68 Vaxchora recipients and 66 placebo recipients were challenged by oral ingestion of Vibrio cholerae, the bacterium that causes cholera. Vaxchora efficacy was 90 percent among those challenged 10 days after vaccination and 80 percent among those challenged three months after vaccination. The study included provisions for administration of antibiotics and fluid replacement in symptomatic participants. To prevent transmission of cholera into the community, the study included provisions for administration of antibiotics to participants not developing symptoms.

Two placebo-controlled studies to assess the immune system’s response to the vaccine were also conducted in the U.S. and Australia in adults 18 through 64 years of age. In the 18 through 45 year age group, 93 percent of Vaxchora recipients produced antibodies indicative of protection against cholera. In the 46 through 64 years age group, 90 percent produced antibodies indicative of protection against cholera. The effectiveness of Vaxchora has not been established in persons living in cholera-affected areas.

The safety of Vaxchora was evaluated in adults 18 through 64 years of age in four randomized, placebo-controlled, multicenter clinical trials; 3,235 study participants received Vaxchora and 562 received a placebo. The most common adverse reactions reported by Vaxchora recipients were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea.

The FDA granted the Vaxchora application fast track designation and priority review status. These are distinct programs intended to facilitate and expedite the development and review of medical products that address a serious or life-threatening condition. In addition, the FDA awarded the manufacturer of Vaxchora a tropical disease priority review voucher, under a provision included in the Food and Drug Administration Amendments Act of 2007. This provision aims to encourage the development of new drugs and biological products for the prevention and treatment of certain tropical diseases.

Vaxchora is manufactured by PaxVax Bermuda Ltd., located in Hamilton, Bermuda.

Company	PaxVax Inc.
Description	Live attenuated vaccine against Vibrio cholerae
Molecular Target
Mechanism of Action	Vaccine
Therapeutic Modality	Preventive vaccine: Viral vaccine

Latest Stage of Development	Registration
Standard Indication	Cholera
Indication Details	Prevent cholera infection; Treat cholera
Regulatory Designation	U.S. – Fast Track (Prevent cholera infection); U.S. – Priority Review (Prevent cholera infection)

FDA Approves Vaxchora, PaxVax’s Single-Dose Oral Cholera Vaccine

Vaxchora™ is the only approved vaccine in the U.S. for protection against cholera

June 10, 2016 04:32 PM Eastern Daylight Time

REDWOOD CITY, Calif.—-PaxVax, today announced that it has received marketing approval from the United States (U.S.) Food and Drug Administration (FDA) for Vaxchora, a single-dose oral, live attenuated cholera vaccine indicated for use in adults 18 to 64 years of age. Vaxchora is the only vaccine available in the U.S. for protection against cholera and the only single-dose vaccine for cholera currently licensed anywhere in the world.

FDA Approves Vaxchora, PaxVax’s Single-Dose Oral Cholera Vaccine

“FDA approval of a new vaccine for a disease for which there has been no vaccine available is an extremely rare event. The approval of Vaxchora is an important milestone for PaxVax and we are proud to provide the only vaccine against cholera available in the U.S.,” said Nima Farzan, Chief Executive Officer and President of PaxVax. “We worked closely with the FDA on the development of Vaxchora and credit the agency’s priority review program for accelerating the availability of this novel vaccine. In line with our social mission, we have also begun development programs focused on bringing this vaccine to additional populations such as children and people living in countries affected by cholera.”

“As more U.S. residents travel globally, there is greater risk of exposure to diseases like cholera,” added Lisa Danzig, M.D., Vice President, Clinical Development and Medical Affairs. “Cholera is an underestimated disease that is found in many popular global travel destinations and is thought to be underreported in travelers. Preventative measures such as food and water precautions can be challenging to follow effectively and until now, U.S. travelers have not had access to a vaccine to help protect against this potentially deadly pathogen.”

Cholera is an acute intestinal diarrheal infection acquired by ingesting contaminated water and food. Annually, millions of people around the world are impacted by this extremely virulent disease¹ which can cause death in less than 24 hours if left untreated². More than 80 percent of reported U.S. cases³ are associated with travel to one of the 69 cholera-endemic countries⁴ in Africa, Asia and the Caribbean. A recent report from the Centers for Disease Prevention and Control suggests that the true number of cholera cases in the U.S. is at least 30 times higher than observed by national surveillance systems⁵. The currently recommended intervention to prevent cholera infection is the avoidance of contaminated water and food, but studies have shown that 98 percent of travelers do not comply with these precautions when travelling⁶.

“This important FDA decision is the culmination of years of dedicated work by many researchers,” said Myron M. Levine, MD, DTPH, the Simon and Bessie Grollman Distinguished Professor at the University of Maryland School of Medicine (UM SOM). “For travelers to the many parts of the world where cholera transmission is occurring and poses a potential risk, this vaccine helps protect them from this disease. It is a wonderful example of how public-private partnerships can develop medicines from bench to bedside.” Dr. Levine is co-inventor of the vaccine, along with James B. Kaper, PhD, Chairman of the UM SOM Department of Microbiology and Immunology. In addition, the Center for Vaccine Development at UM SOM worked closely with PaxVax during the development of Vaxchora.

The attenuated cholera vaccine strain used in Vaxchora is CVD 103-HgR, which was in-licensed from the Center for Vaccine Development at UM SOM in 2010. Vaxchora is expected to be commercially available in Q3 2016. Vaxchora will be distributed through PaxVax’s U.S. marketing and sales organization, which currently commercializes Vivotif^®, an FDA-approved oral typhoid fever vaccine.

About Vaxchora (Cholera Vaccine, Live, Oral)

Vaxchora is an oral vaccine indicated for active immunization against disease caused by Vibrio cholerae serogroup O1. Vaxchora is approved for use in adults 18 through 64 years of age traveling to cholera-affected areas. The effectiveness of Vaxchora has not been established in persons living in cholera-affected areas or in persons who have pre-existing immunity due to previous exposure to V. cholerae or receipt of a cholera vaccine. Vaxchora has not been shown to protect against disease caused by V. cholerae serogroup O139 or other non-O1 serogroups.

The FDA approval of Vaxchora is based on positive results from a 10 and 90-day cholera challenge trial, as well as two safety and immunogenicity trials in healthy adults that demonstrated efficacy of more than 90 percent at 10 days and 79 percent at 3 months post vaccination⁷. The most common adverse reactions were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea. More than 3,000 participants were enrolled in the Phase 3 clinical trial program that evaluated Vaxchora at sites in Australia and the United States.

For the full Prescribing Information, please visit www.vaxchora.com.

Young man drinking contaminated water. Close-up of vibrio cholerae bacteria.

A bacterial disease causing severe diarrhoea and dehydration, usually spread in water

About PaxVax

PaxVax develops, manufactures and commercializes innovative specialty vaccines against infectious diseases for traditionally overlooked markets such as travel. PaxVax has licensed vaccines for typhoid fever (Vivotif) and cholera (Vaxchora), and vaccines at various stages of research and clinical development for adenovirus, anthrax, hepatitis A, HIV, and zika. As part of its social mission, PaxVax is also working to make its vaccines available to broader populations most affected by these diseases. PaxVax is headquartered in Redwood City, California and maintains research and development and Good Manufacturing Practice (GMP) facilities in San Diego, California and Bern, Switzerland and other operations in Bermuda and Europe. More information is available at www.PaxVax.com.

References:

¹ Centers for Disease Control and Prevention. Cholera: General Information. November 2014. http://www.cdc.gov/cholera/general. Accessed June 2016.

² World Health Organization website. Cholera Fact Sheet. July 2015. http://www.who.int/mediacentre/factsheets/fs107/en/. Accessed June 2016.

³ Loharikar A et al. Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel. Epidemiol Infect. 2015;143(4):695-703. doi:10.1017/S0950268814001186.

⁴ Ali M et al. Updated global burden of cholera in endemic countries. PLoS Negl Trop Dis. 2015; 9: e0003832 doi: 10.1371/journal.pntd.0003832.

⁵ Scallan E et al. Foodborne Illness Acquired in the United States –Major Pathogens. Emerg Infect Dis. 2011. http://dx.doi.org/10.3201/eid1701.P11101.

⁶ Kozicki M et al. Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea?. Int J. Epidemiol. 1985; 14(1):169-72.

⁷ Chen WH et al. Single-Dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection with Vibrio cholerae O1 El Tor. Clinical Infectious Diseases 2016. 62 (11) 1329-1335. doi: 10.1093/cid/ciw145.

Contacts

PaxVax Inc.
Colin Sanford, 415-870-9188
colin.sanford@W2comm.com

/////FDA. vaccine, Vaxchora, choleram travelers, PaxVax Bermuda Ltd.,Hamilton, Bermuda.

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Company	Theravance Biopharma Inc.
Description	Glycopeptide cephalosporin heterodimer antibiotic
Molecular Target
Mechanism of Action
Therapeutic Modality	Small molecule: Combination

Latest Stage of Development	Phase I
Standard Indication	Gram-negative bacterial infection
Indication Details	Treat Gram-positive bacterial infections

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Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis