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Tuesday 23 September 2014

LY 3000328

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Abstract Image
LY 3000328
Eli Lilly….INNOVATOR
(3R,4S)-4-(4-fluorobenzamido)-6-(4-(oxetan-3-yl)piperazin-1-yl methylcarbamate
Specific rotation: [α]D25 = 55.19 (c = 10,DMSO).
Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25.
On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5(LY3000328) was selected for clinical development.
Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm
http://pubs.acs.org/doi/full/10.1021/ml500283g
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/ml500283g
Publication Date (Web): August 27, 2014
Copyright © 2014 American Chemical Society
see
 http://pubs.acs.org/doi/suppl/10.1021/ml500283g/suppl_file/ml500283g_si_001.pdf
ABDOMINAL AORTIC ANEURYSM
Classification and external resources
AneurysmAorta.jpg
CT reconstruction image of an abdominal aortic aneurysm
Abdominal aortic aneurysm (also known as AAA,[1] pronounced “triple-a”) is a localized dilatation (ballooning) of the abdominal aortaexceeding the normal diameter by more than 50 percent, and is the most common form of aortic aneurysm. Approximately 90 percent of abdominal aortic aneurysms occurinfrarenally (below the kidneys), but they can also occur pararenally (at the level of the kidneys) orsuprarenally (above the kidneys). Such aneurysms can extend to include one or both of the iliac arteries in the pelvis.
Abdominal aortic aneurysms occur most commonly in individuals between 65 and 75 years old and are more common among men and smokers. They tend to cause no symptoms, although occasionally they cause pain in the abdomen and back (due to pressure on surrounding tissues) or in the legs (due to disturbed blood flow). The major complication of abdominal aortic aneurysms is rupture, which is life-threatening, as large amounts of blood spill into theabdominal cavity, and can lead to death within minutes.[2] Mortality of rupture repair in the hospital is 60% to 90%.
Treatment is usually recommended when an AAA grows to >5.5 cm in diameter. While in the past the only option for the treatment of AAA was open surgery, today most are treated with Endovascular Aneurysm Repair (EVAR).[3] EVAR has been widely adopted, as EVAR has a lower risk of death associated with surgery (0.5% for EVAR vs 3% for open surgery).[4] Open surgery is sometimes still preferred to EVAR, as EVAR requires long-term surveillance with CT Scans.[5]
There is moderate evidence to support screening in individuals with risk factors for abdominal aortic aneurysms (e.g., males ≥65).
DATA
HPLC purity = 98.6% (tR = 24.2 min) by HPLC method 3. ee = 99.9% (tR = 23.6 min) by Chiral HPLC method 4.
Specific rotation: [α]D25 = +55.19 (c = 10,DMSO).
1H NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 7.8 Hz, 1H), 8.01 – 7.90 (m, 2H), 7.34 –
7.23 (m, 2H), 7.19 (q, J = 4.5 Hz, 1H), 6.87 (dd, J = 9.0, 2.9 Hz, 1H), 6.78 – 6.69 (m, 2H), 5.03
(dd, J = 8.1, 3.7 Hz, 1H), 4.86 (td, J = 4.1, 1.8 Hz, 1H), 4.52 (t, J = 6.5 Hz, 2H), 4.41 (t, J = 6.0
Hz, 2H), 4.23 (dd, J = 11.8, 1.9 Hz, 1H), 4.13 (ddd, J = 11.8, 4.4, 1.6 Hz, 1H), 3.39 (p, J = 6.3
Hz, 1H), 2.96 (t, J = 4.9 Hz, 4H), 2.52 (d, J = 4.5 Hz, 3H), 2.34 (t, J = 4.9 Hz, 4H).
13C NMR (DMSO-d6, 100 MHz): δ 165.4, 164.5 (d, J = 248.7 Hz), 156.1, 148.2, 146.2, 131.0, 130.8 (d, J =
9.5 Hz), 120.9, 118.6, 117.6, 117.2, 115.6 (d, J = 21.3 Hz), 74.8, 68.7, 64.3, 58.9, 49.8, 49.5,
47.7, 27.4.
HRMS (ESI+): calcd. for C25H30FN4O5 (M+1): 485.2195, found 485.2188.
1H nmr LY3000328
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13 C nmr LY3000328
 
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  1. Logan, Carolynn M.; Rice, M. Katherine (1987). Logan’s Medical and Scientific Abbreviations. Philadelphia: J. B. Lippincott Company. p. 3.ISBN 0-397-54589-4.
  2.  Upchurch GR, Schaub TA (2006). “Abdominal aortic aneurysm”. Am Fam Physician 73(7): 1198–204. PMID 16623206.
  3.  Chadi SA et al (2012). “Trends in management of abdominal aortic aneurysms”. J Vasc Surg 55 (4): 924–8. doi:10.1016/j.jvs.2011.10.094.PMID 22226189.
  4.  Lederle FA, Freishlag JA et al (209). “Outcomes Following Endovascular vs Open Repair of Abdominal Aortic Aneurysm: A Randomized Trial”.JAMA 302 (14): 1535–42.doi:10.1001/jama.2009.1426PMID 19826022.
  5.  Kirkpatrick VE et al (Dec 2013). “Surveillance Computed Tomographic Arteriogram (CTA) Does Not Change Management before Three Years in Patients Who Have a Normal Post-EVAR Study”. Ann Vasc Surg 28 (4): 831–6. doi:10.1016/j.avsg.2013.09.017.PMID 24361383

Keywords:

Cathepsin, abdominal aortic aneurysm, development candidate, noncovalent, Cathepsin S Inhibitor,  LY3000328,

Sunday 21 September 2014

Byakangelicin



Byakangelicin

C18H20O7, 348.00


IR
(KBr) 1728, 1617, 1479, 1143



MASS
FABMS m/z 349 [M + H]+



1H NMR

(300 MHz, CDCL3)

δ : 1.26 (3H, s, H-4"),

1.29 (3H, s, H-5"),

3.81 (1H, m, H-2"),

4.16 (OCH3),

4.23 (1H, dd, J = 7.9, 10.1 Hz, H-1b"),

4.57 (1H, dd, J= 2.7, 10.1 Hz, H-1a"),

6.27 (1H, d, J = 9.7 Hz, H-3),

6.99 (1H, d, J = 2.4 Hz, H-3'),

7.61 (1H, d, J = 2.4 Hz, H-4'),

8.10 (1H, d, J = 9.7 Hz, H-4)







13 C NMR


(75 MHz, CDCL3) 

δ : 24.99 (C-4"), 

26.62 (C-5"), 

60.61 (OCH3), 

71.50 (C-3"), 

75.91 (C-2"), 

76.04 (C-1"),
105.34 (C-3'), 

107.32 (C-10),

112.70 (C-3), 

114.39 (C-6), 

126.67 (C-8), 

139.58 (C-4), 

143.77 (C-9),

144.80 (C-5), 

145.21 (C-2'), 

150.09 (C-7), 

160.33 (C-2)








Saturday 20 September 2014

Tricyclo[3.3.1.13,7]decan-1-amine hydrochloride

Inline image 1

Tricyclo[3.3.1.13,7]decan-1-amine hydrochloride


A solution of acetamide (0.97 g, 5.0 mmol) in dry THF (15 mL) was treated with
pyridine (0.485 mL, 6.00 mmol) and cooled to 0 °C. Dropwise addition of oxalyl
chloride (0.480 mL, 5.50 mmol) was accompanied by vigorous bubbling and conversion
of the clear, colorless solution to a bright yellow and then turbid orange solution. After
stirring at 0 °C for 30 min., dry propylene glycol (0.73 mL, 10.0 mmol) was added in one
portion and the reaction warmed to room temperature.
During this warming phase, the solution changed, first turning orange brown before lightening to yellow. The reaction was diluted with ethanol before being concentrated to an orange brown oil. The oil was
partitioned between 1 N HCl (10 mL) and MtBE (10 mL) and the organic layer washed
with 1 N HCl (2 x 5 mL). The combined aqueous layers were basified with 4 N NaOH to
pH 11, extracted with EtOAc (3 x 40 mL), dried over Na2SO4, filtered, and concentrated
in vacuo.
The oily residue was suspended in Et2O (8 mL) and treated with 1 M HCl in
Et2O (8 mL). This addition formed a lightly colored slurry which was filtered and
washed with Et2O. After drying under vacuum at 50oC for 16 h, 0.66 g of an off-white solid was recovered
decomp. >330 °C.

1H NMR (400 MHz, DMSO-d6)
δ 8.06 (br s, 3H),
2.06 (br s, 3H),
1.77 (m, 6H),
1.59 (m, 6H).

Inline image 3



13C NMR (100 MHz, DMSO-d6)
δ 50.8,
40.1,
35.1,
28.2.

Inline image 4



 Substance data agrees with previously reported information.8


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Friday 19 September 2014

PHENYLMETHANAMIE HYDROCHLORIDE


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\
1H NMR


δ 8.61 (br s, 3H), 
7.51 (m, 2H), 
7.35 (m, 3H), 
3.97 (s, 2H). NH-CH2



Inline image 4





13 C NMR


13C NMR (100 MHz, DMSO-d6) 

δ 134.1, 
128.9, 
128.4, 
128.3, 
42.0.  NH-CH2




Inline image 5

Dasotraline, 1R,4S Transnorsertraline, SEP-225289


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Dasotraline,  SEP-225289, DSP-225289  

1R,4S Transnorsertraline
Generic Name:Dasotraline
Synonym: SEP-225289
Chemical Name:(1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
4(S)-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1(R)-ylamine hydrochloride
CAS Number:675126-05-3, Cas of THE DRUG SUBSTANCE hydrochloride is 675126-08-6
Indication:Attention deficit hyperactivity disorder (ADHD)
Drug Company:Sunovion Pharmaceuticals. Inc. in phase 2 as on sept 2014, Sunovion Pharmaceuticals Inc.

SEE
PRONUNCIATION da soe tra’ leen
THERAPEUTIC CLAIM Treatment of attention deficit hyperactivity
disorder (ADHD)
CHEMICAL NAMES
1. 1-Naphthalenamine, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-, (1R,4S)-
2. (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine
MOLECULAR FORMULA C16H15Cl2N
MOLECULAR WEIGHT 292.2
SPONSOR Sunovion Pharmaceuticals. Inc.
CODE DESIGNATION SEP-225289
CAS REGISTRY NUMBER 675126-05-3
UNII 4D28EY0L5T
WHO NUMBER 9885


Koenig, Stefan G.; Vandenbossche, Charles P.; Zhao, Hang; Mousaw, Patrick; Singh, Surendra P.; Bakale, Roger P.
Organic Letters, 2009 ,  vol. 11,  2  pG . 433 - 436
Abstract Image
Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride, can be harnessed for a selective and practical deprotection sequence. Treatment of these intermediates with 2 equiv of propylene glycol and warming enables the rapid release of amine hydrochloride salts in good yields. Notably, the reaction conditions are mild enough to allow for a swift deprotection with no observed epimerization of the amino center.
Supporting Information             A Facile Deprotection of Secondary Acetamides
(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride – Compound 1, Scheme 1 / Table 3, entry 1A:
decomp. > 290 °C.
1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 3H), 7.71 (d, 1H, J = 7.7 Hz), 7.53 (d, 1H, J = 8.1 Hz), 7.34 (s, 1H), 
7.29 (m, 1H), 7.22 (m, 1H), 7.01 (d, 1H, J = 8.1 Hz), 6.81 (d, 1H, J = 7.7 Hz), 4.56 (s, 
1H), 4.26 (s, 1H), 2.26 (m, 1H), 2.15 (m, 1H), 1.83 (m, 2H).
13C NMR (100 MHz, DMSO-d6) δ 147.3, 138.8, 133.5, 130.9, 130.5, 130.4, 130.0, 128.9, 128.8, 128.3, 128.1, 
126.7, 47.8, 43.0, 27.7, 25.1.
NMR  GRAPHS GIVEN
 Inline image 1

13 C NMR

Inline image 2

Thursday 18 September 2014

CARMEGLIPTIN


CARMEGLIPTIN, 813452-18-5, 结构式
 
CARMEGLIPTIN


Org. Process Res. Dev. 2011, 15, 503–514. doi:10.1021/op2000207
http://pubs.acs.org/doi/full/10.1021/op2000207
 
Abstract Image
A short and high-yielding synthesis of carmegliptin (1) suitable for large-scale production is reported. The tricyclic core was assembled efficiently by a decarboxylative Mannich addition−Mannich cyclization sequence. Subsequent crystallization-induced dynamic resolution of enamine 7 using (S,S)-dibenzoyltartaric acid was followed by diastereoselective enamine reduction to give the fully functionalized tricyclic core with its three stereogenic centers. The C-3 nitrogen was introduced by Hofmann rearrangement of amide 28, and the resulting amine 10was coupled with (S)-fluoromethyl lactone 31. Following cyclization to lactam 13 and amine deprotection, 1 was obtained in 27−31% overall yield with six isolated intermediates.
Preparation of (2S,3S,11βS)-1-(2-Amino-9,10-dimethoxy-1,3,4,6,7,11β-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-(4S)-fluoromethyl-pyrrolidin-2-one Dihydrochloride (1)   CARMEGLIPTIN
A suspension of carbamate 13 (136 kg, 285 mol) in a mixture of H2O (112 kg) and acetone (122 kg) was treated at 50 °C within 60 min with 37% aq HCl (98.0 kg). After 90 min at 47−52 °C the solution was polish filtered through a 5 μm filter. The first reactor and the transfer lines were washed with a hot (47−52 °C) mixture of H2O (13.0 kg) and acetone (116 kg). The filtrate was cooled to 25 °C and treated at this temperature within 80 min with acetone (1600 kg) whereupon the product crystallized out. The resulting suspension was stirred for 1 h at 25 °C and subsequently centrifuged. The crystals were washed in two portions with acetone (391 kg) and dried at 50 °C and <30 mbar until constant weight to afford 122.4 kg (95%) of the title compound as colorless crystals with an assay (HPLC) of 98.8% (w/w).
 
1H NMR (400 MHz, D2O) δ 2.11−2.22 (m, 1H); 2.45 (dd, J = 17.6 Hz, 6.7 Hz; 1H); 2.76 (dd, J = 17.6 Hz, 9.55 Hz, 1H); 2.90−3.05 (m, 1H); 3.08−3.19 (m, 2H); 3.24−3.36 (m, 1H); 3.43 (dd, J = 9.8 Hz, 5.75 Hz, 1H); 3.49−3.58 (m, 1H); 3.70−3.84 (m, 4H); 3.87 (s, 3H); 3.88 (s, 3H); 4.12 (td, J = 11.6 Hz, 4.5 Hz, 1H); 4.45−4.55 (m, 1H); 4.56−4.68 (m, 3H); 6.91 (s, 1H), 6.95 (s, 1H).
 
 
IR (cm−1): 3237, 2925, 1682, 496, 478.
 
MS (ESI): m/z 378.3 ([M + H]+ (free amine)).
 
Anal. Calcd for C20H30Cl2FN3O3: C, 53.34; H, 6.71; N, 9.33; Cl, 15.74; F 4.22; O, 10.66. Found: C, 53.04; H, 6.43; N, 9.45; Cl, 15.66; F, 4.29; O, 11.09.
 
REF FOR ABOVE
 
MatteiP.; BöhringerM.; Di GiorgioP.; FischerH.; HennigM.; HuwylerJ.; KocerB.; KuhnB.; LöfflerB. M.; MacDonaldA.; NarquizianR.; RauberE.; SebokovaE.; SprecherU. Bioorg. Med. Chem. Lett. 2010201109
BöhringerM.KuhnB.LübbersT.MatteiP.NarquizianR.Wessel,H. P. (F. Hoffmann-La Roche AG). U.S. Pat. Appl. 2004/0259902, 2004.

(1S,2S,5R,6S) -2-tert-Butoxycarbonylamino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid

Synthesis of (1S,2S,5R,6S) -2-tert-Butoxycarbonylamino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid

Figure US20040138304A1-20040715-C00013



 A 1 L flask was charged with (1S,2S,5R,6S)-2-amino-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid monohydrate (24.4 g, 0.12 mol, 1 equiv), dioxane (200 mL) and di-tert-butyl dicarbonate (52.4 g, 0.24 mol, 2.0 equiv). The suspension was vigorously stirred while sodium hydroxide 1N (420 mL, 3.5 equiv) was added. The mixture was stirred for 2 days, then 2.0 more equiv of di-tert-butyl dicarbonate were added and the reaction stirred for 3 additional days at rt. After 5 total days of reaction, water (400 mL) was added to dissolve the salts. The aqueous layer was extracted with ethyl acetate (4×100 mL) to remove the excess of reagent, and then taken to ca. pH=2 using 6 N hydrochloric acid. The acidic aqueous phase was then extracted using ethyl ether (6×200 mL). The combined organic layers were washed with water (250 mL) and brine (250 mL). After drying over sodium sulfate, solvents were evaporated in vacuum to afford a foamy white solid (26.4 g).

77% Yield. 
mp 100-101° C. 

[α]D 25=−41.1° (c=1.0, MeOH). 

1H NMR (Methanol-d4) δ: 4.98 (brs, 1H), 2.44 (dd, 1H, J=6.2, 2.6 Hz), 2.19-1.92 (m, 4H), 1.62 (t, 1H, J=2.8 Hz), 1.43 (s, 9H), 1.29 (m, 1H). 


13C NMR (Methanol-d4) δ: 175.6, 175.2, 158.2, 60.1, 34.6, 31.9, 28.4, 27.2, 25.6, 20.6. MS (Neg. Electrospray): 284.2 (M+−H).