Saturday 20 September 2014

Dasotraline, 1R,4S Transnorsertraline, SEP-225289………For treatment of Attention deficit hyperactivity disorder (ADHD)

Inline image 1

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.
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
SEP-225289 is an antidepressant which had been in early clinical trials at Sepracor (now Sunovion Pharmaceuticals) for the treatment of major depressive disorder (MDD). In 2010, the company discontinued development of the compound for this indication. At present, phase II clinical trials are under way for the treatment of attention deficit/hyperactivity disorder (ADHD). In preclinical studies, the drug has been shown to be a potent and balanced reuptake inhibitor of serotonin, norepinephrine and dopamine (SNDRI). A drug candidate with a triple mechanism of action as such may provide a broader spectrum of therapy than currently marketed antidepressants.
Recently, drug candidates for blocking the monoamine reuptake transporters have sparked considerable interest in the pharmaceutical industry for treatment of central nervous system disorders. Various candidates are in clinical evaluation in addition to numerous others at the preclinical stage. Sertraline 2is a selective serotonin reuptake inhibitor (SSRI), marketed by Pfizer as Zoloft for depression. (1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride 1 is structurally similar to sertraline 2 and is currently under investigation for a number of potential central nervous system disorder indications at Sepracor.
Figure
ABOUT SERTRALINE
Sertraline2DACS2.svg
Sertraline-A-3D-balls.png
(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine
SERTRALINE
Clinicians recognize a distinction among central nervous system illnesses, and there have been many schemes for categorizing mental disorders. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed., Text Revision, (hereinafter, the “DSM-IV-TR™”), published by the American Psychiatric Association, and incorporated herein by reference, provides a standard diagnostic system upon which persons of skill rely. According to the framework of the DSM-IV-TR™, the CΝS disorders of Axis I include: disorders diagnosed in childhood (such as, for example, attention deficit disorder or “ADD” and attention deficit / hyperactivity disorder or “ADHD”) and disorders diagnosed in adulthood. CΝS disorders diagnosed in adulthood include
(1) schizophrenia and psychotic disorders; (2) cognitive disorders;(3) mood disorders; (4) anxiety related disorders; (5) eating disorders; (6) substance related disorders; (7) personality disorders; and (8) “disorders not yet included” in the scheme.
Of particular interest to the present invention are adulthood disorders of DSM-IN-TR™ categories (1) through (7) and sexual disorders, currently classified in category (8). Mood disorders of particular interest include depression, seasonal affective disorder and bipolar disorder. Anxiety related disorders of particular interest are agoraphobia, generalized anxiety disorder, phobic anxiety, obsessive compulsive disorder (OCD), panic disorder, acute stress disorder, posttraumatic stress disorder, premenstrual syndrome, social phobia, chronic fatigue disorder, perimenopause, menopause and male menopause.
In general, treatment for psychoses, such as schizophrenia, for example, is quite different than treatment for mood disorders. While psychoses are treated with D2 antagonists such as olanzapine (the “typical” and “atypical” antipsychotics), mood disorders are treated with drugs that inhibit the neuronal reuptake of monoamines, in particular, serotonin (5-HT), norepinephrine (ΝE) and dopamine (DA).
[005] Common therapeutic agents for mood disorders include, but are not limited to, selective serotonin reuptake inhibitors (SSRI’s), including fluoxetine, citalopram, nefazodone, fluvoxamine, paroxetine, and sertraline.
Sertraline, whose chemical name (lS,4S)-c/5 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-Ν-methyl-l-napthalenamine, is approved for the treatment of depression by the United States Food and Drug Administration, and is available under the trade name ZOLOFT® (Pfizer Inc., NY, NY, USA). In the human subject, sertraline has been shown to be metabolized to (lS,4S)-c« 4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-napthalenamine, also known as desmethylsertraline or norsertraline. Desmethylsertraline has been described as “not contributing significantly to the serotonergic action of sertraline” Ronfield et al, Clinical Pharmacokinetcs, 32:22-30 (1997). Reports from Hamelin et al, Clinical Pharmacology & Therapeutics, 60:512 (1996) and Serebruany et al, Pharmacological Research, 43:453-461 (2001), have stated that norsertraline is “neurologically inactive”. These statements appear to be based on results observed in serotonin-induced syndrome and ptosis in mouse models in vivo, whereas the original Pfizer research papers suggested on the basis of data in vitro that desmethylsertraline was a selective serotonin uptake inhibitor. Koe et al, JPET, 226:686-700 (1983). Sanchez et al, Cellular and Molecular Neurobiology, 19: 467 (1999), speculated that despite its lower potency, desmethylsertraline might play a role in the therapeutic effects of sertraline but, there is presently no evidence in the literature to support this theory.
] The primary clinical use of sertraline is in the treatment of depression. In addition, United States Patent 4,981,870 discloses and claims the use of sertraline and norsertraline, as well as (lR,4S)-trans 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-N-methyl-l-napthalenamine and (lS,4R)-trαra 4-(3 ,4- dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 -napthalenamine for the treatment of psychoses, psoriasis, rheumatoid arthritis and inflammation. The receptor pharmacology of the individual (1S,4R) and (1R,4S) enantiomers of trα«5 4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l -napthalenamine is described by Welch et al, J. Med. Chem., 27:1508-1515 (1984). Summary of the Invention
It has now been discovered that {\R,4S)-trans 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-napthalenamine (P) and (lS,4R)-tra«_ 4-(3 ,4- dichlorophenyl)- 1,2,3, 4-tetrahydro-l-napthalenamine (Q) are useful in the treatment of CNS-related disorders that are modulated by monoamine activity, and produce diminished side effects as compared to the current standards of treatment. Treatable CNS disorders include, but are not limited to, mood disorders {e.g., depression), anxiety disorders {e.g., OCD), behavioral disorders {e.g., ADD and ADHD), eating disorders, substance abuse disorders and sexual function disorders. The compounds are also useful for the prophylaxis of migraine.
Compounds P and Q are represented by the formulae:
Figure imgf000005_0001
In one aspect, the present invention relates to a method for treating CNS disorders, which involves the administration of a therapeutically effective amount of P or Q, or a pharmaceutically acceptable salt of either.
In another aspect, the invention relates to trans- 4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-napthalenamine of the formula (PQ):
NH2
Figure imgf000006_0001
(PQ)
Skeletal formulae of chlorprothixene and tametraline, from which sertraline was derived
Norsertraline, sertraline’s chief active metabolite
………………………………………..
PATENT
(Scheme 2).
Figure US20090149549A1-20090611-C00025
In a preferred embodiment, the compound prepared by the route of Scheme 2 is (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine. Even more preferred is the preparation of the compound substantially free of its cis isomer.
Example 1
Synthesis of N—((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1-yl)acetamide (3)1.1. Synthesis of Oxime 2
A suspension formed from a mixture of (S)-tetralone 1 (56.0 g, 0.192 mol), hydroxylamine hydrochloride (14.7 g, 0.212 mol), and sodium acetate (17.4 g, 0.212 mol) in methanol (168 mL) was heated to reflux for 1 to 5 hours under a N2atmosphere. The progress of the reaction was monitored by HPLC. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was diluted with toluene (400 mL) and 200 mL water. The organic layer was separated and washed with an additional 200 mL water. The organic layer was concentrated and dried to give crude solid oxime 2 (58.9 g, 100%), m. p. 117-120° C.
1H NMR (400 MHz, CDCl3) δ (ppm) 9.17 (br, 1H, OH), 7.98 (m, 1H), 7.36 (d, 1H, J=8.0 Hz), 7.29 (m, 2H), 7.20 (d, 1H, J=2.4 Hz), 6.91 (m, 2H), 4.11 (dd, 1H, J=7.2 Hz, 4.4 Hz), 2.82 (m, 2H), 2.21 (m, 1H), 2.08 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 154.94, 144.41, 140.40, 132.83, 130.92, 130.82, 130.68, 130.64, 129.98, 129.38, 128.12, 127.64, 124.48, 44.52, 29.51, 21.27.
1.2. Synthesis of Enamide 3
The solution of the crude oxime 2 (59 g, 0.193 mol) in toluene (500 mL) was purged with Nfor 30 min. Et3P (25 g, 0.212 mol) was charged. After stirring for 10 min, acetic anhydride (21.6 g, 20 mL, 0.212 mol) was added. The reaction mixture was refluxed for 8 to 13 h. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to room temperature. 6N NaOH (aq) (86 mL, 0.516 mol) and 1.0 M (n-Bu)4NOH in methanol (1.0 mL) were added. The hydrolysis was complete in about 2 to 4 h. The organic layer was separated and diluted with EtOAc (300 mL) and 2-BuOH (30 mL). The diluted organic solution was washed with 1% HOAc (aq) solution (300 mL) and DI water (3×300 mL) and concentrated to about 350 mL of a slurry in vacuo. The slurry was diluted with heptane (100 mL) and 2-BuOH (4 mL) and heated to reflux to form a clear solution. Heptane (50 to 200 mL) was slowly added until a cloudy solution formed. The suspension was slowly cooled to rt. The product was filtered out, washed with 30% toluene and 70% heptane (3×100 mL) solution and dried in a vacuum oven to give 56.9 g white solid (enamide 3, 89% yield), m. p. 167-168° C.
(S)-Tetralone 1 (50.0 g, 0.172 mol) was slurried in methanol (150 mL) with hydroxylamine hydrochloride (13.1 g, 0.189 mol) and sodium acetate (15.5 g, 0.189 mol). The resulting suspension was heated to reflux for 2 to 6 h under an inert atmosphere with progress monitored by HPLC. On completion, the mixture was cooled to 25° C., diluted with toluene (300 mL) and quenched with 1.7 N NaOH (100 mL). The mixture was concentrated in vacuo under reduced pressure, the aqueous layer removed and the organic layer washed further with DI water (100 mL). Further toluene (300 mL) was charged to the vessel and water removed by azeotropic distillation. Once at ambient temperature, n-Bu3P (47.1 mL, 0.183 mol) was charged to the reactor, followed by acetic anhydride (32.5 mL, 0.344 mol). The reaction was heated to reflux and monitored by HPLC. After 20-24 h, the reaction was cooled to ambient temperature and quenched with 6 N NaOH (120 mL). This mixture was allowed to react for 2 to 6 h before the aqueous layer was removed. The organic phase was washed with DI water (100 mL). Concentration of the mixture in vacuo, cooling to room temperature and diluting with isopropanol (50 mL) was done prior to addition of heptane to assist with crystallization. An initial charge of heptane (50 mL) was followed by an additional 650 mL. Aging of the slurry followed by filtration, washing (4×100 mL heptane) and drying yielded a light yellow solid (enamide 3, 44.1 g, 77%).
1H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, 1H, J=8.4 Hz), 7.26 (m, 3H), 7.17 (m, 1H), 7.05 (dd, 1H, J=8.0, 1.6 Hz), 7.00 (br, 1H), 6.87 (m, 0.82H, 82% NH rotamer), 6.80 (br, 0.18H, 18% NH rotamer), 6.31 (t, 0.82H, J=4.8 Hz, 82% H rotamer), 5.91 (br, 0.18H, 18% H rotamer), 4.12 (br, 0.18H, 18% H rotamer), 4.03 (t, 0.82H, J=8.0 Hz, 82% H rotamer), 2.72 (m, 1H), 2.61 (ddd, 1H, J=16.8, 8.0, 4.8 Hz), 2.17 (s, 2.46H, 82% CHrotamer), 1.95 (s, 0.54H, 18% CH3rotamer). 100 MHz13CNMR (CDCl3) δ 169.3, 143.8, 137.7, 132.3, 131.8, 131.4, 130.5, 130.3, 130.2, 128.8, 128.1, 127.8, 127.2, 123.8, 122.5, 121.2, 117.5, 42.6, 30.3, 24.1.
Example 2Synthesis of N-((1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (4)
The enamide 3 (24 g, 72 mmol) was slurried in degassed isopropanol (200 mL). The resulting slurry was transferred to the appropriate reactor. Prior to the addition of the catalyst solution, the content of the reactor was purged with nitrogen. A solution of (R,R)-MeBPE(COD)RhBFcatalyst (20.1 mg, 0.036 mmol, 0.05 mol %) in isopropanol (IPA) (100 mL) was added to the reactor. The content was cooled to 0° C. and purged with nitrogen three times. The reactor was then purged with hydrogen and pressurized to 90 psig. The reaction was aged with agitation at 0° C. for 7.5 h and conversion was monitored by the hydrogen uptake. The content was then warmed to RT and hydrogen was vented. After purging with nitrogen, the contents were drained. The reaction mixture was heated to 50° C. and filtered through a pad of Celite. The clear orange solution was concentrated to ˜50% volume (150 mL) and diluted with toluene (5.9 g, 5 wt %). The suspension was heated to 65° C. and water (14.7 mL) was added dropwise to form a cloudy solution. The slurry was slowly cooled to −10° C. and aged for 30 minutes. The solid was filtered and washed with cold IPA (2×45 mL). The cake was dried under vacuum at 45° C. overnight to afford 20.0 g (83% yield) of trans acetamide 4 (>99% de).
1H NMR (CDCl3) 400 MHz δ 7.34 (dd, 2H, J=7.9, 2.4 Hz), 7.23 (t, 1H, J=7.5 Hz), 7.15 (m, 2H), 6.85 (dd, 1H, J=8.2, 2.0 Hz), 6.82 (d, 1H, J=7.7 Hz), 5.72 (d, 1H, J=8.4 Hz), 5.31 (dd, 1H, J=13.2, 8.1 Hz), 4.10 (dd, 1H, J=7.0, 5.9 Hz), 2.17 (m, 2H), 2.06 (s, 3H), 1.87 (m, 1H). 1.72 (m, 1H); 13C NMR (CDCl3) 100 MHz δ 169.7, 146.9, 138.8, 137.7, 132.6, 130.8, 130.6, 130.5, 130.3, 128.4, 128.3, 127.9, 127.4, 47.9, 44.9, 30.5, 28.4, 23.8.
Example 3
Synthesis of (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine Hydrochloride (5)
A solution of trans-acetamide 4 (9.0 g, 26.9 mmol), n-propanol (45 mL) and 5M hydrochloric acid (45 mL) was refluxed for approximately 48 h (90-93° C.). During this time, the reaction temperature was maintained at ≧90° C. by periodically collecting the distillate until the reaction temperature was >92° C. Additional n-propanol was added periodically to maintain the solution at its original volume. After the hydrolysis was complete, the solution was slowly cooled to 0° C., resulting in a slurry, which was aged for one hour at 0° C. The reaction mixture was filtered, and the cake was washed with 1:1 methanol/water (20 mL), followed by t-butyl methyl ether (20 mL). The wet-cake was dried under vacuum at 45 to 50° C. to afford 7.0 g of the amine hydrochloride 5 (80% yield).
1H NMR (DMSO-d6) δ 1.81-1.93 (m, 2H), 2.12-2.21 (m, 1H), 2.28-2.36 (m, 1H), 4.28 (t, 1H, J=6.8), 4.59 (br.s, 1H), 6.84 (d, 1H, J=7.6), 7.05 (dd, 1H, J=8.4, 1.6), 7.25 (t, 1H, J=7.6), 7.32 (t, 1H, J=7.6), 7.37 (d, 1H, J=1.6), 7.56 (d, 1H, J=8.4), 7.76 (d, 1H, J=7.2), 8.80 (br.s, 3H);
13C NMR (DMSO-d6) 147.4, 138.9, 133.6, 131.0, 130.5, 130.4, 130.1, 129.0, 128.9, 128.4, 128.2, 126.8, 47.9, 43.1, 27.8, 25.2.
INTERMEDIATE
Example 5 Catalytic Asymmetric Hydrogenation of the Enamide 3 Using (R,S,R,S)-MePenn Phos(COD)RhBFas the Catalyst
As shown in Scheme 4, the enamide 3 was subjected to homogeneous catalytic asymmetric hydrogenation in the presence of a chiral catalyst, H2, and a solvent. In this example the catalyst was derived from the complex of the transition metal rhodium with the chiral phosphine ligand, (1R,2S,4R,5S)—P,P-1,2-phenylenebis {(2,5-endo-dimethyl)-7-phosphabicyclo[2.2.1]heptane}(R,S,R,S-MePennPhos). The hydrogenations were carried out at a substrate concentration of about 0.12 M to about 0.24 M of compound 3.
Figure US20090149549A1-20090611-C00043
………………………………………..
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
………………………………………..
Jerussi, T. P.; Fang, Q. K.; Currie, M. G. PCT Int. Appl. WO 2004042669 A1 200440325, 2004.
Figure
The discovery route involved preparation of (S)-tetralone (4S)-3 from racemic tetralone(4RS)-3 via chromatographic separation of sulfinyl imine (Rs,4RS)-5diastereomers, followed by hydrolysis. The sulfinyl imine isomers were generated by condensation with (R)-tert-butylsulfinamide ((R)-TBSA), (Rs)-4, in the presence of titanium ethoxide. The yield of sulfinyl imine diastereomer (Rs,4S)-5 was ∼15% after chromatographic purification. The low recovery yield was due to chromatographic loss and the instability of compound 5 on silica gel. The resulting (S)-tetralone (4S)-3 was converted to N-formyl amine (1RS,4S)-6 as a mixture of two diastereomers that were again separated by chromatography to afford the desired diastereomer(1R,4S)-6 in 17% yield over two steps. (1R,4S)-trans-norsertraline 1 was obtained after the acidic hydrolysis of (1R,4S)-6 in 71% yield. The overall yield of this route was less than 2% and involved two chromatographic purifications, making it impractical for an efficient large-scale synthesis of 1.
Jerussi, T. P.; Fang, Q. K.; Currie, M. G. PCT Int. Appl. WO 2004042669 A1 200440325, 2004.http://www.google.com/patents/WO2004024669A1?cl=en
……………………………………………
PAPER
Development of a large-scale stereoselective process for (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride
Org Process Res Dev 2007, 11(4): 726
Abstract Image
A convenient, multikilogram-scale, stereoselective process for the synthesis of (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride 1 is described. The key steps involve synthesis of sulfinyl imine(Rs,4S)-5 from (S)-tetralone (4S)-3 and (R)-tert-butylsulfinamide (Rs)-4, and its stereoselective reduction with 9-BBN to produce the (1R)-amine center of 1. The process has been scaled up to multikilogram scale and gives 1 in an overall yield of >50% with a chemical purity of 99.7 A% by HPLC and stereochemical purity of >99.9% by chiral HPLC.
(1R,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-ylamine HCl (1).
 
1H NMR (400 MHz, DMSO-d6) δ 1.81−1.93 (m, 2H), 2.12−2.21 (m, 1H), 2.28−2.36 (m, 1H), 4.28 (t, 1H, J = 6.8 Hz), 4.59 (br s, 1H), 6.84 (d, 1H, J = 7.6 Hz), 7.05 (dd, 1H, J = 8.4, 1.6 Hz), 7.25 (t, 1H, J = 7.6 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.37 (d, 1H, J = 1.6 Hz), 7.56 (d, 1H, J = 8.4 Hz), 7.76 (d, 1H, J = 7.2 Hz), 8.80 (br s, 3H).
 
13C NMR (100 MHz, DMSO-d6) δ 147.4, 138.9, 133.6, 131.0, 130.5, 130.4, 130.1, 129.0, 128.9, 128.4, 128.2, 126.8, 47.9, 43.1, 27.8, 25.2.
 
Anal. Calcd for C16H15Cl2N:  C, 58.47; H, 4.91; N, 4.26; Cl, 32.36. Found:  C, 58.44; H, 4.79; N, 4.21; Cl, 32.53.
……………………………………………………………..
WO 2004024669
Preparation of compounds of the present invention is illustrated below in Scheme 1 and its accompanying narrative.
Figure imgf000007_0001
[0015] In the compound
Figure imgf000008_0001
of Scheme 1,
R is R,° , wherein R1, R2 and R3 are each independently alkyl. In a preferred embodiment of the compounds, R is tert-butyl.
[0016] N-[4-(3 ,4-dichlorophenyl)- 1 ,2,3 ,4-tefrahydronaphthalen- 1 -yl]formamide, the intermediate in the synthesis shown in Scheme 1 , exists in four stereoisomeric forms:
Figure imgf000008_0002
C (1S,4S) D (1R.4R) [0017] When N-[4-(3 ,4-dichlorophenyl)- 1 ,2,3,4-tetrahydronaρhthalen-l - yl]formamide is synthesized from achiral starting materials via non- stereoselective syntheses, all four isomers will be produced. The mixture can be readily separated into a racemic cis diastereomer and a racemic trans diastereomer by means, such as recrystallization or chromatography on achiral media, that rely on chemical and physical differences.
[0018] The trans diastereomer, represented as E below, is a 1 :1 mixture of A and B. When E is hydrolyzed, PQ is produced; when A is hydrolyzed, P is produced; when B is hydrolyzed, Q is produced. The cis diastereomer, represented as F below, is a 1 : 1 mix of C and D.
Figure imgf000009_0001
E = A + B F = C + D
……………………………………………………………………………………………
WO 2007006003
Figure imgf000027_0001
Scheme 3
Production (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4-tetrahydro-naphthalen-l-ylamine HCl from 4-(S)-(3,4-dichloro-phenyl)-3,4-dihydro-2H-naphthalen-l-one.
Figure imgf000031_0001
(S)-(3,4-Dichloro-phenyl)-3,4- (1 R,4S)-4-(3,4-Dichloro-phenyl)-1 ,2,3,4-tetrahydro- d ιhydro-2H-naphthalen-1 -one naphthalen-1 -ylamine; [0080] Charge 4-(S)-(3,4-dichloro-phenyl)-3,4-dihydro-2H-naρhthalen-l-one (1 kg, 3.4 mol) and (R)-tert-butylsulphinamide (TBSA, 464 g, 3.8 mol) to a suitable reactor and dissolved in about 7 L THF. Add a 20%wt solution of Titanium ethoxide in ethanol (about 7.8 kg, 6.9 mol) and heat the mixture to about 70 0C for about 24h. The reaction is monitored by HPLC, and after the reaction is complete, cool the mixture to room temperature and added a 24% wt aqueous solution of NaCl to the mixture. The resultant slurry was filtered and washed multiple times with about 1 L total of ethyl acetate. The mother liquors and washes were concentrated to a minimum volume. The aqueous phase was extracted with about 5 L of ethyl acetate and evaporated to dryness.
[0081] The contents were then dissolved in about 7 L of THF and cooled to about —10 0C. About 9 kg, (~5 mol) of a 0.5 M solution of 9-borabicycIononane (9-BBN) in THF, was added slowly (about 3h) and the mixture was stirred at 00C until reaction completion. A 6N HCl/methanol (~2L) was added to the mixture and stirred until the hydrolysis reaction was complete. After neutralization with about 2 L of 6N aqueous NaOH, the mixture was distilled to remove THF and the residue (aqueous phase) was extracted twice with methyl t- butyl ether (2x6L). The organic phase was then washed with water. The organic phase was concentrated, then cooled to 00C followed by addition of 2N HCl in methyl t-butyl ether (3 L). The product slowly precipitated as the HCl salt during the addition. The slurry was filtered and washed with methyl t-butyl ether (2x2L). The product was dried under vacuum at about 45°C to afford about 850 g of Re-Crystallization of crude (lR,4S)-4-(3,4-dichloro-phenyl)- 1,2,3,4-tetrahydro-naphthalen-l-ylamine HCl.
[0082] The resulting (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4-tetrahydro- naphthalen-1-ylamine HCl (85Og) was charged to a suitable reactor and about 30 L of denatured ethanol was added. The mixture was heated to reflux, the volume was reduced to about 50% via distillation, and then cooled to 50°C. About 30 L of Hexane was added to the slurry to complete the product crystallization and then the slurry was cooled to about 00C. The product was isolated by filtration, the cake was washed with about 2 L of ethanol/hexane (1/3 v/v) and then about 2 L of ethyl acetate, followed by about 3 L of hexane. The wet cake was dried under vacuum at about 45°C to afford 630 g of product.
[0083] Another alternative process for preparation of compound P is presented below.
[0084] 4-(S)-(3,4-dichloro-phenyl)-3,4-dichloro-2H-naphthalen-l-one (4.11 kg) and (R)-tert-butylsulphinamide (TBSA, 1.9 kg) were charged to a suitable reactor and dissolved in 29 L THF. A 20%wt solution of titanium ethoxide in ethanol (31.6 kg) was added and the mixture was heated to 70 °C with stirring. The reaction is monitored by HPLC, and after the reaction was complete (20-24 h) the mixture was cooled to room temperature and added to 20 L of a 24 wt% aqueous solution of NaCl. The resultant slurry was filtered and washed 3 times with ethyl acetate (4.1 L). The mother liquors and washes were concentrated to a minimum volume. The aqueous phase was extracted with about 20 L of a 1 :1 mix of ethyl acetate and toluene. The organic phases were combined and concentrated to half volume to give a solution of 2. A purified sample of 2 was analyzed: m.p. 104 0C, 1HNMR (400 MHz, CDCl3) δ (ppm) 8.23 (dd, IH, J= 7.9, 0.9 Hz), 7.38 (ddd, IH, J= 14.7, 7.3, 1.5 Hz), 7.37 (d, IH, J= 8.4 Hz), 7.33 (d, IH, J= 7.7 Hz), 7.17 (d, IH, J= 1.8 Hz), 6.93 (d, IH, J= 7.7 Hz), 6.89 (dd, IH, J= 8.4, 2.2 Hz), 4.18 (dd, IH, J= 7.3, 4.8 Hz), 3.36 (ddd, IH, J= 17.5, 8.8, 4.4 Hz), 2.93 (ddd, IH, J= 17.6, 8.3, 4.2 Hz), 2.33 (m, IH), 2.15 (m, IH), 1.34 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 175.8, 144.2, 142.7, 132.6, 130.8, 130.7, 129.7, 128.1, 127.6, 127.4, 57.8, 44.3, 31.1, 29.4, 22.8. HRMS calc for C20H2ICl2NOS 394.0799, found 394.0767.
[0085] The solution of imine (2) was cooled to -10 0C and 36.3 kg of a 0.5 M solution of 9-borabicyclononane (9-BBN) in THF, was added slowly (over 3h) and the mixture was stirred at 0 0C until reaction completion. A 4N HCl/methanol (8 L) was added to the mixture and stirred until the hydrolysis reaction was complete. After neutralization with about 15 kg of 6N aqueous NaOH (pH 8), the mixture was distilled to remove THF and methanol. The residue (aqueous phase) was extracted twice with methyl t-butyl ether (2 x 16L). The organic phase was then washed with water. The organic phase was concentrated, then cooled to 00C followed by addition of 2N HCl in methyl t- butyl ether (5.4 kg). The product precipitated as the HCl salt. The slurry was filtered, washed with methyl t-butyl ether (2 x 8L) and dried under vacuum at 450C to afford about 3.73 kg of crude (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4- tetrahydro-naphthalen-1-ylamine HCl (compound P).
A purified sample of P was analyzed:  NOTE P IS DASOTRALINE
m.p. 152 – 154 0C,
1H NMR (400 MHz, CDCl3) δ (ppm) 7.58 (d, IH, J= 7.7 Hz), 7.29 (m, 2H), 7.18 (br. t, IH, J= 7.5 Hz), 7.09 (d, IH, J= 1.8 Hz), 6.87 (d, IH, J= 7.7 Hz), 6.80 (dd, IH, J= 8.3, 2.0 Hz), 4.65 (dd, IH, J= 4.4, 4.4 Hz), 4.15 (t, IH, J= 5.5 Hz), 3.30 (d, IH, J= 3.7 Hz), 2.35 (m, IH), 1.95 (m, IH), 1.85 (m, IH), 1.75 (m, IH), 1.23 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 147.1, 138.4, 138.0, 132.6, 130.8, 130.6, 130.5, 129.8, 128.3, 127.9, 55.8, 53.3, 44.0, 28.2, 27.7, 22.9.
HRMS calc for C20H23Cl2NOS 396.0956, found 396.0968.
[0086] The crude (lR,4S)-4-(3,4-dichloro-phenyl)-l,2,3,4-tetrahydro- naphthalen-1-ylamine HCl (3.63 kg) was charged to a suitable reactor and 128 L of denatured ethanol was added. The mixture was stirred at reflux and polish filtered. The volume was reduced to about 50% via distillation, and then cooled to 500C. 80 L of heptane was added to the slurry to complete the product crystallization and then the slurry was cooled to -5 °C. The product was filtered, the cake was washed twice with 5.7 L of ethanol/heptane (1/1 v/v) and then washed with 6 L of hexane. The wet cake was dried under vacuum at about 45°C to afford 2.57 kg of product. The product had a chemical purity of 99.65 A% and a diastereomeric purity in excess of 99%
…………………………………………………………………………
PATENT
WO 2011069032
Transnorsertraline, i. e. , (1 R,4S)-trans-4-(3 ,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro- 1 – naphthalenamine and (lS,4R)-trans-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l- naphthalenamine are described in, for example, U.S. Patent No. 7,087,785 B2 (“the ‘785 patent”; incorporated herein by reference in its entirety), have the following chemical structures, respectively:
Figure imgf000002_0001
Uses of transnorsertraline in the treatment, prevention, or management of affective disorders and other various CNS disorders are also disclosed in the ‘785 patent. Such disorders include, but are not limited to, depression, mood disorders, anxiety disorders, behavioral disorders, eating disorders, substance abuse disorders, and sexual function disorders.
ref
A Randomized, Double-Blind, Parallel-Group, Multicenter Efficacy and Safety Study of SEP-225289 Versus Placebo in Adults With Attention Deficit Hyperactivity Disorder (ADHD) (NCT01692782)
ClinicalTrials.gov Web Site 2012, September 27
Characterization of the electrophysiological properties of triple reuptake inhibitors on monoaminergic neurons
Int J Neuropsychopharmacol 2011, 14(2): 211
PET evaluation of serotonin and dopamine transporter occupancy associated with administration of SEP-225289
Biol Psychiatry 2010, 67(9, Suppl. 1): Abst 102
[65th Annu Meet Soc Biol Psychiatry (SOBP) (May 20-22, New Orleans) 2010]
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
Thalen, Lisa K.; Zhao, Dongbo; Sortais, Jean-Baptiste; Paetzold, Jens; Hoben, Christine; Baeckvall, Jan-E.
Chemistry – A European Journal, 2009 ,  vol. 15, ( 14)  pg. 3403 – 3410
US8134029Jul 30, 2010Mar 13, 2012Sunovion Pharmaceuticals Inc.Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
US8658700Dec 4, 2012Feb 25, 2014Sunovion Pharmaceuticals Inc.Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
US20010044474*Dec 20, 2000Nov 22, 2001Curatolo William J.Hydrogel-driven layered drug dosage form
US20060257475*Aug 17, 2006Nov 16, 2006Boehringer Ingelheim International GmbhStable Sertraline Hydrochloride Formulation and Method
US20080280993*Jul 15, 2008Nov 13, 2008Sepracor Inc.Treatment of CNS Disorders With trans 4-(3,4-Dichlorophenyl)-1,2,3,4-Tetrahydro-1-Napthalenamine

Sunday 14 September 2014

Highly regioselective lithiation of pyridines bearing an oxetane unit by n-butyllithium,


GA

G. Rouquet, D.C. Blakemore, S.V. Ley,Chem. Comm.2014, 50, 8908-8911
The first regioselective ortho-lithiation at the 4-position of simple pyridine derivatives containing a 3-oxetane unit has been achieved using n-butyllithium as base. Electrophilic quenching of the resulting lithio species provides a rapid access to a broad range of new functionalized pyridine oxetane building blocks.

Monday 8 September 2014

Tecadenoson…………Atrial Fibrillation

Tecadenoson

Tecadenoson
CAS : 204512-90-3
N-[(3R)-Tetrahydro-3-furanyl]adenosine
(2R,3S,4R,5R)-2-(hydroxymethyl)-5-[6-[[(3R)-oxolan-3-yl]amino]purin-9-yl]oxolane-3,4-diol
Manufacturers’ Codes: CVT-510
UNII-GZ1X96601Z; AC1L4KMO;
Molecular Formula: C14H19N5O5
Molecular Weight: 337.33
Percent Composition: C 49.85%, H 5.68%, N 20.76%, O 23.71%
Therap-Cat: Antiarrhythmic.
Tecadenoson is a novel selective A1 adenosine receptor agonist that is currently being evaluated for the conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. It is being developed by CV Therapeutics, Inc.
Tecadenoson is an adenosine A1 agonist which had been in phase II clinical evaluation by Gilead Sciences for treatment of atrial fibrillation. The company was also conducting phase III clinical trials for the treatment of paroxysmal supraventricular tachycardia (PSVT); however, no recent developments have been reported for these indications.
Due to the fact that tecadenoson selectively stimulates the A1 receptor and slows electrical impulses in the heart’s conduction system without significantly stimulating the A2 receptor, the intravenous administration of CVT-510 may hold potential for rapid intervention in the control of atrial arrhythmias without lowering blood pressure.
The reaction of 3-tetrahydrofuroic acid (I) with diphenyl phosphoryl azide (DPPA) in refluxing dioxane gave the intermediate isocyanate (II), which was treated with benzyl alcohol (III) to yield carbamate (IV). Subsequent hydrogenolysis in the presence of Pd/C afforded racemic amine (V), which was resolved by treatment with S-(+)-10-camphorsulfonyl chloride (VI) in pyridine, followed by column chromatography and recrystallization from acetone of the resulting sulfonamide (VII). Then, hydrolysis in HCl-AcOH provided the S-amine (VIII). Condensation of amine (VIII) with 6-chloropurine riboside (IX) in the presence of triethylamine in refluxing MeOH furnished the title compound.
EP 0920438; EP 0992510; JP 2000501426; US 5789416; WO 9808855
……………………………
………………………….
CVT-510 (tecadenoson) has chemical structure (8 :
Figure imgf000011_0002
…………………………………….
Compound I can be prepared through reaction of the corresponding primary amino compound, R1NH2, through heating with commercially available 6-chloroadenosine in the appropriate solvent (e.g. n-butanol, dimethylformamide, and ethanol). The primary amino compound, R1NH2, is either commercially available or can be prepared as previously described (International Patent Application WO 98/08855).
Figure US06576619-20030610-C00008
 ……………………………
EXAMPLE 1
The compounds of this invention may be prepared by conventional methods of organic chemistry. The reaction sequence outlined below, is a general method, useful for the preparation of compounds of this invention.
Figure imgf000015_0001
Figure imgf000015_0002
According to this method, oxacycloalkyl carboxylic acid is heated in a mixture of dioxane, diphenylphosphoryazide and triethylamine for 1 hour. To this mixture is added benzyl alcohol and the reaction is further heated over night to give intermediate compound 1. Compound 1 is dissolved in methanol. Next, concentrated HC1, Pd/C is added and the mixture is placed under hydrogen at 1 atm. The mixture is stirred overnight at room temperature and filtered. The residue is recrystallized to give intermediate compound 2. 6-chloropurine riboside is combined and the mixture is compound 2 dissolved in methanol and treated with triethylamine. The reaction is heated to 80° C for 30 hours. Isolation and purification leads to Compound 3.
EXAMPLE 2
Compounds of this invention prepared according to the method of Example 1 were tested in two functional models specific for adenosine A, receptor agonist function. The first was the A , receptor mediated inhibition of isoproterenol stimulated cAMP accumulation in DDT cells. The EC50 of each derivative is shown in Table I. Also shown in Table I is the ability of each derivative to stimulate cAMP production in PC 12 cells, a function of agonist stimulation of adenosine A2 receptors. The ratio of the relative potency of each compound in stimulating either an A, receptor or an A2 receptor effect is termed the selectivity of each compound for the A, receptor. As can be seen in Table I, each derivative is relatively selective as an A, receptor agonist. The use of measuring cAMP metabolism as an assay for adenosine A , receptor function has been previously described (Scammells, P., Baker, S., Belardinelli, L., and Olsson, R. , 1994, Substituted 1 ,3-dipropylxanthines as irreversible antagonists of A, adenosine receptors. J. Med. Chem 37: 2794-2712, 1994).
Table I
Compound R EC50 (nM) ECS, (nM) A,/A2 A-/A, DDT cells PC 12 cells
I 4-arninopyran 12 970 0.012 80.0
II (±)-3-aminotetrahydrofuran 13 1400 0.0093 107.6
III (R)-3-aminotetrahydrofuran 1.08 448 0.0024 414
IV ( 1 )-caprolactam 161 181 0.889 1.12
V (S)-3-aminotetrahydrofuran 3.40 7680 0.00044 2258
Compounds were also tested in a whole organ model of A, receptor activation with respect to atrial and AV nodal function. In this model, guinea pig hearts are isolated and perfused with saline containing compound while atrial rate and AV nodal conduction time are assessed by electrographic measurement of atrial cycle length and AV intervals, as detailed in Belardinelli, L, Lu, J. Dennis, D. Martens, J, and Shryock J. (1994); The cardiac effects of a novel A,-adenosine receptor agonist in guinea pig isolated heart. J. Pharm. Exp. Therap. 271:1371-1382 (1994). As shown in Figure 1, each derivative was effective in slowing the atrial rate and prolonging the AV nodal conduction time of spontaneously beating hearts in a concentration-dependent manner, demonstrating efficacy as adenosine A, receptor agonists in the intact heart.
EXAMPLE 3
Preparation ofN-benzyloxycarbonyl-4-aminopyran.
A mixture of 4-pyranylcarboxylic acid (2.28 gm, 20 mmol), diphenylphosphorylazide (4.31 ml, 20 mmol), triethylamine (2.78 ml, 20 mmol) in dioxane (40 ml) was heated in a 100° C oil bath under dry nitrogen for 1 hour. Benzyl alcohol (2.7 ml, 26 mmol) was added, and heating was continued at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice with EtOAc. The extracts were washed with water, sodium bicarbonate, brine and then dried over MgSO4, and concentrated to an oil which solidified upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 1.85 g of a white solid (40%).
Preparation of 4-aminopyran.
N-benzyloxycarbonyl-4-aminopyran (1.85 gm, 7.87 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C ( 10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of eelite and concentrated. The residue was co-evaporated twice with MeOH/EtOAc and recrystallized from MeOH/EtOAc to afford 980 mg (91 %) of white needles (mp 228-230° C).
Preparation of 6-(4-aminopyran)-purine riboside. A mixture of 6-chloropurine riboside (0.318 gm, 1. 1 mmol), 4-aminopyran-HCl
(0.220 mg,
1.6 mmol) and triethylamine (0.385 ml, 2.5 mmol) in methanol (10 ml) was heated to 80° C for 30 hours. The mixture was cooled, concentrated and the residue chromatographed (90: 10: 1, CH2 Cl2/MeOH/PrNH2). The appropriate fractions were collected and recliromatographed using a chromatotron
(2 mm plate, 90: 10: 1, CH2 Cl2/MeOH/PrNH2) to give an off white foam (0.37 gm, 95%).
EXAMPLE 4
Preparation of N-benzyloxycarbonyl-3-aminotetrahydrofuran. A mixture of 3-tetrahydrofuroic acid (3.5 gm, 30 mmol), diphenylphosphorylazide (6.82 ml, 32 mmol), triethylamine (5 ml, 36 mmol) in dioxane (35 ml) was stirred at RT for 20 min then heated in a 100° C oil bath under dry nitrogen for 2 hours. Benzyl alcohol (4.7 ml, 45 mmol) was added, and continued heating at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice using EtOAc. The extracts were washed with water, sodium bicarbonate, brine dried over MgSO4, and then concentrated to an oil which solidifies upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 3.4 g of an oil (51
%).
Preparation of 3-aminotetrahydrofuran.
N-benzyloxycarbonyl-3-aminotetrahydrofuran (3.4 gm, 15 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C (10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of celite and concentrated. The residue was co-evaporated two times with MeOH/EtOAc and recrystallized from MeOH/EtOAc to give 1.9 g of a yellow solid.
Preparation of 6-(3-aminotetrahydrofuranyl)purine riboside. A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), 3-aminotetrahydrofuran
(0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C for 40 hours. The mixture was cooled, and concentrated. The residue was filtered through a short column of silica gel eluting with 90/10/1 (CH2Cl2/MeOH/PrNH2), the fractions containing the product were combined and concentrated. The residue was chromatorgraphed on the chromatotron (2 mm plate, 92.5/7.5/1 , CH2CL2/MeOH/P.NH2). The resulting white solid was recrystallized from MeOH/EtOAc to give 0.27 gm of white crystals (mp 128-130° C).
EXAMPLE 5
Resolution of 3-arninotetrahydrofuran hydrochloride
A mixture of 3-aminotetrahydrofuran hydrochloride (0.5 gm, 4 mmol) and
(S)-(+)-10-camphorsulfonyl chloride (1.1 gm, 4.4 mmol) in pyridine (10 ml) was stirred for 4 hours at room temperature and then concentrated. The residue was dissolved in EtOAc and washed with 0.5N HC1, sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated to give 1. 17 g of a brown oil (97%) which was chromatographed on silica gel (25% to 70% EtOAc/Hex). The white solid obtained was repeatedly recrystallized from acetone and the crystals and supernatant pooled until an enhancement of greater than 90% by 1H NMR was acheived.
Preparation of 3-(S)-aminotetrahydrofuran hydrochloride.
The sulfonamide (170 mg, 0.56 mmol) was dissolved in cone. HCl/AcOH (2 mL each), stirred for 20 hours at room temperature, washed three times with CH2C12 (10 ml) and concentrated to dryness to give 75 mg (qaunt ) of a white solid

Preparation of 6-(3-(S)-aminotetrahydrofuranyl)puπne riboside.
A mixture of 6-chloropurιne riboside (30 mg, 0.10 mmol),
3-(S)-amιnotetrahydrofuran hydrochloride (19 mg, 0.15 mmol) and triethylamine (45 ml, 0.32 mmol) in methanol
(0.5 ml) was heated to 80° C for 18 hours. The mixture was cooled, concentrated and chromatographed with 95/5 (CH2Cl /MeOH) to give 8 mg (24%) of a white solid.
Chemical structure for tecadenoson
Literature References:
Selective adenosine A1-receptor agonist. Prepn: R. T. Lum et al., WO 9808855eidemUS5789416 (both 1998 to CV Therapeutics).
Clinical effect on AV nodal conduction: B. B. Lerman et al., J. Cardiovasc. Pharmacol. Ther.6, 237 (2001).
Clinical evaluation in paroxysmal supraventricular tachycardia: E. N. Prystowsky et al., J. Am. Coll. Cardiol. 42, 1098 (2003); K. A. Ellenbogen et al., Circulation 111, 3202 (2005).
Review of pharmacology and clinical experience: A. Zaza, Curr. Opin. Invest. Drugs 3, 96-100 (2002); J. W. Cheung, B. B. Lerman, Cardiovasc. Drug Rev. 21, 277-292 (2003).
US7144871*19 Feb 20035 Dec 2006Cv Therapeutics, Inc.Partial and full agonists of A1 adenosine receptors
US7696181*24 Aug 200613 Apr 2010Cv Therapeutics, Inc.Partial and full agonists of A1 adenosine receptors
Keywords: Antiarrhythmic,  Adenosine Receptor Agonist, Tecadenoson, CVT-510, CV Therapeutics

Infinity and AbbVie partner to develop and commercialise duvelisib for cancer





Duvelisib

Infinity and AbbVie partner to develop and commercialise duvelisib for cancer
INK 1197; IPI 145; 8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone



Molecular Formula
C22H17ClN6O
Molecular Weight
416.86
CAS Registry Number
1201438-56-3

 
Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, to treat patients with cancer. 

 



Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K gamma, to treat patients with cancer.
Duvelisib has shown clinical activity against different blood cancers, such as indolent non-Hodgkin's lymphoma (iNHL) and chronic lymphocytic leukemia (CLL).
AbbVie executive vice-president and chief scientific officer Michael Severino said: "We believe that duvelisib is a very promising investigational treatment based on clinical data showing activity in a broad range of blood cancers."
http://www.pharmaceutical-technology.com/news/newsinfinity-abbvie-partner-develop-commercialise-duvelisib-cancer-4363381?WT.mc_id=DN_News 

 

Duvelisib (IPI-145,  INK-1197), an inhibitor of PI3K-delta and –gamma, originated at Takeda subsidiary Intellikine. It is now being developed by Infinity Pharmaceuticals, which began a phase III trial in November, following US and EU grant of orphan drug status for both CLL and small lymphocytic leukemia


more on this drug

http://newdrugapprovals.org/2014/09/09/infinity-and-abbvie-partner-to-develop-and-commercialise-duvelisib-for-cancer-for-the-treatment-of-chronic-lymphocytic-leukemia/

KEY     Duvelisib, IPI-145,  INK-1197, AbbVie, INFINITY

Monday 1 September 2014

A Step Toward Making Painkillers Without Poppies Bioengineering: Modified yeast produce morphine and semisynthetic opioids starting from thebaine

09235-notw4-thebaine
 
Using thebaine as the starting material, the same set of enzymes can catalyze reactions in different pathways leading to either morphine or neomorphine. With the addition of bacterial enzymes, they can produce semisynthetic opioids such as oxycodone. 
 
READ AT.
The supply chain for some of the world’s most prescribed painkillers—natural opioids such as morphine and semisynthetic opioids such as oxycodone—depends on the cultivation of opium poppies, Papaver somniferum. Although poppy farming is a relatively cheap way to obtain the needed materials, it risks diversion to illicit drugs.
 

Drug Assembly On-Site... Drug Delivery: Click reaction links small molecules to form larger potential drug inside cells

09235-notw6-reactioncxd_17863669-690
When a number of derivatized small-molecule inhibitors bind to an RNA repeat sequence in cells, their alkyne and azide groups react with one another, producing potent oligomers.

If a multicomponent bioactive agent is too big to slip into cells, it would be nice to get its components into cells first and then combine them on-site. That’s what Matthew D. Disney, Suzanne G. Rzuczek, and HaJeung Park at Scripps Research Institute Florida did with a potential myotonic dystrophy type 2 (DM2) treatment (Angew. Chem. 2014, DOI: 10.1002/ange.201406465).
DM2 is a rare condition characterized by muscle pain and weakness. It’s caused by a genetic defect that generates toxic RNA with a four-nucleotide repeat pattern.
READ