New Drug Approvals

Home » Posts tagged 'premature ejaculation'

Tag Archives: premature ejaculation

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 4,186,834 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,792 other subscribers
Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,792 other subscribers
DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Epelsiban being developed by GlaxoSmithKline for the treatment of premature ejaculation in men.


Epelsiban.svg

Epelsiban

557296
GSK-557296
GSK-557296-B

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione

(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione

(3R, 6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1-[(1R)- 1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1 S)-1-methylpropyl]-2,5- piperazinedione

Glaxo Group Limited  INNOVATOR

Epelsiban (GSK-557,296-B)[1][2] is an oral drug which acts as a selective, sub-nanomolar (Ki=0.13 nM) oxytocin receptor antagonist with >31000-fold selectivity over the related vasopressin receptors and is being developed by GlaxoSmithKline for the treatment of premature ejaculation in men.[3][4]

EPELSIBAN BESYLATE.png

benzenesulfonic acid;(3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-morpholin-4-yl-2-oxoethyl]piperazine-2,5-dione,CAS 1159097-48-9

UNII-H629P9T4UN, GSK557296B, Epelsiban besylate (USAN), Epelsiban besylate [USAN], 1159097-48-9, H629P9T4UN

GSK-557296 is being developed in early clinical studies at GlaxoSmithKline for enhancement of embryo and or blastocyst implantation in women undergoing IVF treatment. The product has been in phase II clinical development for the treatment of premature ejaculation.

Preterm labor is a major clinical problem leading to death and disability in newborns and accounts for 10% of all births and causes 70% of all infant mortality and morbidity.

Oxytocin (OT) is a potent stimulant of uterine contractions and is responsible for the initiation of labor via the interaction with the OT receptors in the mammalian uterus. OT antagonists have been shown to inhibit uterine contractions and delay preterm delivery. So there is increasing interest in OT antagonists because of their potential application in the prevention of preterm labor. Although several tocolytics have already been approved in clinical practice, they have harmful maternal or fetal side effects.

The first clinically tested OT antagonist atosiban has a much more tolerable side effect profile and has recently been approved for use in Europe. However, atosiban is a peptide and a mixed OT/vasopressin V1a receptor antagonist that has to be given by iv infusion and is not suitable for long-term maintenance treatment, as it is not orally bioavailable.

Hence there has been considerable interest in overcoming the shortcomings of the peptide OT antagonists by identifying orally active nonpeptide OT antagonists with a higher degree of selectivity toward the vasopressin receptors (V1a, V1b, V2) with good oral bioavailability. Although several templates have been investigated as potential selective OT antagonists, few have achieved the required selectivity for the OT receptor vs the vasopressin receptors combined with the bioavailability and physical chemical properties required for an efficacious oral drug.

Therefore our objective was to design a potent, orally active OT antagonist with high levels of selectivity over the vasopressin receptor with good oral bioavailability in humans that would delay labor safely by greater than seven days and with improved infant outcome, as shown by a reduced combined morbidity score.

Patent Submitted Granted
Compounds [US7919492] 2010-12-02 2011-04-05
Piperazinediones as Oxytocin Receptor Antagonists [US7550462] 2007-11-01 2009-06-23
Compounds [US8202864] 2011-06-23 2012-06-19
Novel compounds [US2009247541] 2009-10-01

………………………………………

PATENT

https://www.google.com/patents/US7919492

 

Example 3

Method A

(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione

as a white lyophilisate (88 mg, 23%) after freeze-drying from 1,4-dioxane

HPLC Rt=2.70 minutes (gradient 2); m/z [M+H]+=519

1H NMR (CDCl3) δ 7.49 (d, 1H), 7.27-7.15 (m, 4H), 7.10 (d, 1H), 6.68 (s, 1H), 6.40 (d, 1H), 4.10 (dd, 1H), 4.01 (d, 1H), 3.74-3.52 (m, 5H), 3.28-3.07 (m, 5H), 2.97-2.84 (m, 2H), 2.79-2.71 (m, 1H), 2.62 (s, 3H), 2.59 (s, 3H), 1.65-1.53 (m, 1H), 0.98-0.80 (m, 2H), 0.70 (t, 3H), 0.45 (d, 3H).

Example 3

Method B

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione

A suspension of {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride (5.0 g, 10.3 mmol) (intermediate 5) in dry dichloromethane (50 ml) was treated with 1,1-carbonyldiimidazole (2.6 g, 16 mmol) and the reaction mixture was stirred under nitrogen for 18 hours. Morpholine (4.8 ml, 55 mmol) was added and the resultant solution was left to stand under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was separated between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. This was applied to a basic alumina cartridge (240 g) and eluted using a gradient of 0-7.5% methanol in diethyl ether (9CV), 7.5-10% methanol in diethyl ether (1CV) and 10% methanol in diethyl ether (1CV). The required fractions were combined and evaporated in vacuo to give (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione as a white solid (2.4 g, 45%).

HPLC Rt=2.72 minutes (gradient 2); m/z [M+H]+=519

 

………………………………………

WO 2011051814

 http://www.google.com/patents/WO2011051814A1?cl=en

This invention relates to novel crystalline forms of (3R, 6R)-3-(2,3-dihydro-1 H- inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1 S)-1 – methylpropyl]-2,5-piperazinedione benzenesulfonate salt, processes for their preparation, pharmaceutical compositions containing them and to their use in medicine. The benzenesulfonate salt of Compound A is represented by the following structure:

Figure imgf000004_0001

In one aspect, the present invention provides a crystalline form of {3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate, wherein said crystalline form provides an X-ray powder diffraction pattern substantially in accordance with Figure 1 .

In another aspect, the invention encompasses a crystalline form of (3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate, wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising the peaks:

Figure imgf000004_0002

In an additional aspect, the invention includes a crystalline form of {3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said compound is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 2.

In certain aspects, the invention encompasses a crystalline form of (3R, 6R)-3- (2,3-dihydro-1 H-inden-2-yl)-1 -[(1 R)-1 -(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2- oxoethyl]-6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said compound is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 2 In one aspect, the invention also provides a crystalline form of {3R, 6R)-3-(2,3- dihydro-1 H-inden-2-yl)-1-[(1 R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]- 6-[(1 S)-1 -methylpropyl]-2,5-piperazinedione benzenesulfonate hydrate, wherein said crystalline form is characterized by an X-ray powder diffraction pattern comprising the peaks:

Figure imgf000005_0001

Experimental

Process Scheme

Figure imgf000012_0001

Stage 4

Acetone / Water Recrystallisation

Compound A-form I Ste8e 5 Besylate salt

MW 676.83 Acetone / Water

Recrystallisation MW 676.83 Process description for isolation of Compound A-Form 1

Stage 0

methyl d-alloisoleucinate hydrochloride (Compound 2) was charged to ethyl acetate. A solution of potassium carbonate in water was then added. The mixture was then stirred vigorously at room temperature for 1 hour. The two layers were separated and the aqueous layer further extracted with ethyl acetate. The organic layers were combined and washed with brine. The organic layers were then concentrated in vacuo and filtered to yield methyl D-alloisoleucinate (Compound 3) as a pale yellow oil.

Stage 1

2,6-dimethyl-3-pyridinecarbaldehyde (Compound 4) in methanol at ambient temperature was treated with D-alloisoleucinate (Compound 3) in methanol followed by 2,2,2- trifluoroethanol and the reaction mixture was warmed to 40°C. When formation of the intermediate imine (methyl A/-[(2,6-dimethyl-3-pyridinyl)methylidene]-D-alloisoleucine) was complete Compound 5 was added followed by 1-isocyano-2- [(phenylmethyl)oxy]benzene (Compound 6) and the reaction mixture was stirred at 40°C until formation of Compound 7 was deemed complete.

Stage 2

Palladium on carbon catalyst was treated with a solution of Compound 7 in methanol and 2,2,2-trifluoroethanol and diluted with acetic acid. The vessel was purged with nitrogen and the reaction mixture warmed to 50°C and hydrogenated at 4.0-4.5 barg. When the reaction was deemed complete it was cooled to ambient temperature and the catalyst removed by filtration and washed through with methanol. The organic solution of 2- {(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1-piperazinyl}- 2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8) was concentrated at reduced pressure and then diluted with /so-propyl acetate and concentrated at reduced pressure.

The residue was diluted with /so-propyl acetate and washed with aqueous ammonia. The aqueous phase was separated and extracted into another portion of /so-propyl acetate. The combined organic phases were washed with water, concentrated by distillation at reduced pressure, diluted with /so-propyl acetate and concentrated by distillation at reduced pressure, to leave a concentrated solution of 2-{(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1 – piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8). The product was finally dissolved in 1 ,4-dioxane for the next stage and stored into drums.

Stage 3 Solution of 2-{(3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-6-[(1 S)-1 -methylpropyl]-2,5-dioxo-1 – piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-/\/-(2-hydroxyphenyl)acetamide (Compound 8) in 1 ,4-dioxane was treated with 1 ,1 ‘-carbonyl diimidazole at ambient temperature to form a solution containing (3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1 -[1-(2,6-dimethyl-3-pyridinyl)- 2-oxo-2-(2-oxo-1 ,3-benzoxazol-3(2H)-yl)ethyl]-6-[(1 S)-1 -methylpropyl]-2,5- piperazinedione (Compound 9).

In a separate vessel morpholine in 1 ,4-dioxane was heated to 80-85°C. The solution containing (3R,6R)-3-(2,3-dihydro-1 H-inden-2-yl)-1-[1 – (2,6-dimethyl-3-pyridinyl)-2-oxo-2-(2-oxo-1 ,3-benzoxazol-3(2H)-yl)ethyl]-6-[(1 S)-1- methylpropyl]-2,5-piperazinedione (Compound 9) was slowly added to the morpholine in 1 ,4-dioxane. The reaction mixture was stirred for one hour at 80-85°C and cooled before concentration by distillation at reduced pressure.

The concentrated solution of Compound A was diluted with /so-propyl acetate and washed with aqueous sodium hydroxide followed by water. The /so-propyl acetate solution of COMPOUND A was then concentrated by distillation at reduced pressure and cooled to ambient temperature. The concentrated solution of Compound A was then diluted with acetone and treated with benzenesulfonic acid and seed crystals were added and the reaction mixture stirred until crystallisation occurred. The slurry of Compound A besylate was heated to 50°C, a temperature cycle was performed, and finally the slurry was cooled to -10°C and isolated by filtration. The filter cake was washed with cold acetone (-10°C) to give Compound A besylate (intermediate grade) as a wet cake.

Yield: 44% from Compound 5

39% from Compound 5

Stage 4

Compound A besylate (intermediate grade wet cake, Compound A besylate ) was suspended in acetone (17.4 vol including acetone content of wet cake) and heated to 55- 60°C. Water (0.66 vol) was added until dissolution was observed. The reaction mixture was then filtered into another vessel and the lines washed through with acetone (3.2 vol). The temperature of the reaction mixture was adjusted to 45-50°C before the addition of seed crystals (0.00025wt). When crystallisation was complete the reaction mixture was cooled to 20-25°C and stirred at 20-25°C for 30mins.

The reaction mixture was heated to 45-50°C and stirred at 45-50°C for 30mins. The reaction mixture was cooled to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was heated to 45-50°C and stirred at 45-50°C for 30mins. The reaction mixture was cooled to -3-2°C over 4.5 h and stirred for at least 1 h before the product was isolated by filtration. The wet cake was washed with acetone at 0°C (3 x 3.1 vol) and blown dry before being unloaded. COMPOUND A besylate was dried at 50°C under vacuum for 3 days. Compound A besylate was then milled. Yield: 66% Stage 5

Compound A besylate (OBU-D-02) was suspended in acetone (8 vol) and water (1 .1 vol) and heated to 48-52°C until dissolution was observed. The reaction mixture was then filtered into another vessel and the lines washed through with acetone (2 vol). The reaction mixture was cooled to 20-25°C before the addition of Form 1 seed crystals (0.0025wt). When crystallisation was complete the reaction mixture was cooled to 0-5°C over 1 h and stirred at 0-5°C for 30mins. The reaction mixture was heated to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was cooled to 0-5°C over 1 h and stirred at 0-5°C for 30mins.

The reaction mixture was heated to 20-25°C and stirred at 20-25°C for 30mins. The reaction mixture was cooled to -12— 8°C over 3.5 h and stirred for 15 h before the product was isolated by filtration. The wet cake was washed with acetone at -10°C (2 x 3 vol) and blown dry before being unloaded. Compound A besylate was dried at ambient temperature under vacuum for 6 days with a wet nitrogen bleed to afford Form 1 . Compound A besylate was then milled. Yield: 67%

Recrystallisation of Compound A besylate anhydrate (Form 2)

Figure imgf000015_0001

Besylate salt ………………………………………………………………Besylate salt

C30H38 4O4■ C6H603S C30H38 4O4

MW 676.83 MW 676.83

COMPOUND A besylate is charged to the vessel and treated with methyl ethyl ketone (MEK) (8vol) and water (0.35vol) and the solution heated until dissolution is observed (ca. 55-60°C). The solution is then filtered and recharged to the vessel. Pressure is then reduced to 650mbar and the reaction mixture heated further to distil out solvent. MEK is added at the same rate as solvent is removed by distillation keeping the reaction mixture volume constant. After 4 volumes of MEK have been added the reaction mixture is treated with Form 2 seed crystals (2%wt) and the distillation continued in the same manner until another 7 volumes of MEK has been added. The vacuum is then released to an atmospheric pressure of nitrogen and the temperature of the reaction mixture adjusted to 65°C. The reaction mixture is then filtered and washed with pre heated MEK (2vol at 65°C). The purified COMPOUND A besylate anhydrate is then sucked dry and dried further in a vacuum oven at 65°C at l OOmbar with a nitrogen bleed. Yield 89%

NMR data is the same for Forms 1 and 2.

1 H NMR (500MHz, DMSO-d6) 5ppm 0.71-0.80(m, 6H) 0.87-0.98(m, 1 H) 1 .31 (br. S, 1 H) 1.69(br. S, 1 H) 2.68(s, 3H) 2.69(s, 3H) 2.72-2.79(m, 1 H) 2.80-2.87(m, 1 H) 2.88-3.01 (m, 3H) 3.18-3.25(m, 1 H) 3.27-3.33(m, 1 H) 3.38-3.46(m, 1 H) 3.47-3.52(m, 1 H)3.53-3.57(m, 1 H) 3.60-3.71 (m, 3H) 3.83(dd, J=9.46,3.15 Hz, 1 H) 3.89 (br. S, 1 H)6.10(br. S, 1 H) 7.1 1 – 7.14(m, 2H) 7.19-7.23(m, 2H) 7.30-7.35(m, 3H)7.59-7.63(m, 2H) 7.67(d, J=7.25Hz, 1 H) 8.12(br. S, 1 H) 8.50(d, J=3.78Hz, 1 H)

 

Compounds of the present invention can be tested according to the description of International Publication No. WO2006000399 (US2007254888A1 ).

 

………………………………………..

PAPER

J. Med. Chem., 2012, 55 (2), pp 783–796
DOI: 10.1021/jm201287w

http://pubs.acs.org/doi/abs/10.1021/jm201287w

Abstract Image

A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines oxytocin antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3′-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pKi > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2′,6′-dimethyl-3′-pyridyl Rsec-butyl morpholine amide Epelsiban (69), a highly potent oxytocin antagonist (pKi = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral safety profile in female rats.

(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione (69 EPELSIBAN)

A ………………………. gave colorless needles (75%)
mp 140 °C.
1H NMR (CDCl3) δ 7.49 (d, J =7.8 Hz, 1H, pyridyl-4H),
7.26–7.15 (m, 4H, indanyl-arylH),
7.10 (d, J =8.1 Hz, 1H, pyridyl-5H),
6.68 (s, 1H, NCHpyridyl),
6.49 (d, J = 2.8 Hz, 1H, lactam-NH),
4.10 (dd, J = 10.1 Hz, 4.0 Hz, 1H, NCHindanyl),
4.01 (d, J = 4.5 Hz, NCHsec-butyl),
3.75–2.71 (m, 13H, 8× morpholinyl-H, indanyl-3H, –1H, –2H),
2.62 and 2.58 (2s, 6H, pyridyl-2Me,-6Me),
1.64–1.52 (m, 1H, CHHMe),
0.98–0.79 (m, 2H, CHHMe, CHMeCH2),
0.70 (t, J = 7.1 Hz, 3H, CH2Me),
0.45 (d, J = 6.8 Hz, 3H, CHMe).
LCMS m/z 519 (MH+) single component, gradient 2 (tR 2.70 min).
HRMS calcd for C30H38N4O4(MH+) 519.29658, found 519.29667.
HPLC: 100% (tR 10.388 min).
EPELSIBAN BESYLATE SALT
To a ……………………………….give the besylate (3.214 g, 92.6%) as white crystals of 69B
mp 179–183 °C.
1H NMR (CD3OD) δ 8.30 (d, 1H, J = 8.1 Hz, pyridyl-4H),
7.84–7.80 (m, 2H, PhSO3ortho-H),
7.78 (d, J = 8.3 Hz, 1H, pyridyl-5H),
7.45–7.38 (m, 3H, PhSO3meta-H, para-H),
7.23–7.09 (m, 4H, indanyl-arylH),
6.08 (broad s, 1H, NCHpyridyl),
4.00 (d, J =4.6 Hz, 1H, NCHsec-butyl),
3.92 (d, J = 9.9 Hz, 1H, NCHindanyl),
3.78–3.39 and 3.14–2.80 (m, 13H, 8× morpholinyl-H, indanyl-3H, –1H, –2H)),
2.79 and 2.78 (2s, 6H, pyridyl-2Me, -6Me),
1.85–1.74 (m, 1H, CHHMe),
1.59–1.48 (m, 1H, CHHMe),
1.15–1.01 (m, 1H, CHMeCH2),
0.92 (d, J =6.3 Hz, 3H, CHMe),
0.85 (t, J = 7.3 Hz, 3H, CH2Me).
LCMS m/z 519 MH+ single components, tR2.72 min;
circular dichroism (CH3CN) λmax 225.4 nm, dE −15.70, E15086; λmax 276 nm, dE 3.82, E5172.
HRMS calcd for C30H38N4O4 (MH+) 519.2971, found 519.2972.
Anal. (C30H38N4O4·C6H6O3S·3.0H2O) C, H, N, S.

References

  1. Borthwick AD, Liddle J, Davies DE, Exall AM, Hamlett C, Hickey DM, Mason AM, Smith IE, Nerozzi F, Peace S, Pollard D, Sollis SL, Allen MJ, Woollard PM, Pullen MA, Westfall TD, Stanislaus DJ (January 2012). “Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency”. Journal of Medicinal Chemistry 55 (2): 783–96. doi:10.1021/jm201287w. PMID 205501.

 

 

Epelsiban
Epelsiban.svg
Systematic (IUPAC) name
(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-(morpholin-4-yl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]piperazine-2,5-dione
Clinical data
Legal status
  • Non-regulated
Identifiers
CAS number 872599-83-2
1159097-48-9 (besylate)
ATC code None
PubChem CID 11634973
ChemSpider 9809717
KEGG D10117 Yes
Chemical data
Formula C30H38N4O4 
Molecular mass 518.6 g/mol
Cited Patent Filing date Publication date Applicant Title
WO2003053443A1 Dec 20, 2002 Jul 3, 2003 Glaxo Group Ltd Substituted diketopiperazines as oxytocin antagonists
WO2006000399A1 Jun 21, 2005 Jan 5, 2006 Glaxo Group Ltd Novel compounds
EP2005006760W Title not available
US6914160 Jul 31, 2003 Jul 5, 2005 Pfizer Inc Oxytocin inhibitors
US20070254888 Jun 21, 2005 Nov 1, 2007 Glaxo Group Limited Piperazinediones as Oxytocin Receptor Antagonists
US8202864 * Feb 25, 2011 Jun 19, 2012 Glaxo Group Limited Compounds
US8716286 Oct 28, 2010 May 6, 2014 Glaxo Group Limited Crystalline forms of (3R, 6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione
US8742099 May 20, 2013 Jun 3, 2014 Glaxo Group Limited Compounds
US8815856 Mar 18, 2014 Aug 26, 2014 Glaxo Group Limited Crystalline forms of (3R, 6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione
US20120202811 * Apr 19, 2012 Aug 9, 2012 Glaxo Group Limited Novel compounds

FDA APPROVED PRODUCT FOR PREMATURE EJACULATION


 

VISIT

http://www.promescent.com/

…a significant delay in
ejaculation and an improved
sex life. It is easy, and it works.
Michael Chancellor, MD, Director of Neurourology Program

 

Ixchelsis, a start-up company that has come out of Pfizer’s former R D site at Sandwich, UK, is progressing a treatment for premature ejaculation boosted by the backing of Eli Lilly.


 

Lilly, through its venture fund set up with TVM Capital Life Science, has
invested in Ixchelsis, made up of former Pfizer scientists and headed by Gary
Muirhead. The company is based on an oxytocin receptor antagonist called IX-01
originally discovered at Sandwich which the investors say “has the potential to
be the best-in-class pharmacological approach for the treatment of
PE”.

Ixchelsis, which is based at the Sandwich site, now called Discovery
Park, will collaborate with the autonomous early phase virtual drug discovery
arm of Lilly, known as Chorus. Dr Muirhead told PharmaTimes that the
TVM model will fund through to the agreed exit point, which is completion of
proof-of-concept and this requires about $14 million.

read all at

http://www.pharmatimes.com/Article/13-08-08/Lilly_backs_Ixchelsis_a_start-up_born_at_Pfizer.aspx

………..

………….

……………….

…………….

%d bloggers like this: