insulin peglispro SYNONYMS macrogol 20000 pegylated insulin lispro: [28B-(6-N-{[ω-methoxypoly(oxyethylene)]carbonyl}-L-lysine), 29B-L-proline]human insulin CAS 1200440-65-8 antidiabetic;

………….

Taltirelin Талтирелин

N-{[(4S)-1-methyl-2,6-dioxohexahydropyrimidin-4-yl]carbonyl}-L-histidyl-L-prolinamide

(S)-1-Methyl-4,5-dihydroorotyl-L-histidyl-L-prolinamide
(S)-N-(1-Methyl-2,6-dioxohexahydropyrimidin-4-ylcarbonyl)-L-histidyl-L-prolinamide

launched 2000 by Mitsubishi Tanabe Pharma

103300-74-9
201677-75-0

Taltirelin (marketed under the tradename Ceredist) is a thyrotropin-releasing hormone (TRH) analog, which mimics the physiological actions of TRH, but with a much longer half-life and duration of effects,^[1] and little development of tolerance following prolonged dosing.^[2] It has nootropic,^[3] neuroprotective^[4] and analgesic effects.^[5]

Taltirelin is primarily being researched for the treatment of spinocerebellar ataxia; limited research has also been carried out with regard to other neurodegenerative disorders, e.g., spinal muscular atrophy.^[6][7][8]

Taltirelin is a thyrotropin-releasing hormone (TRH) analog that was first commercialized by Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) in Japan in 2000 for the oral treatment of ataxia due to spinocerebellar degeneration.

In 2008, the company filed a regulatory application seeking approval of taltirelin orally disintegrating tablets for the treatment of spinocerebellar degeneration, and in 2009 the approval was received for this formulation.

TRH is a tripeptide hormone that stimulates the release of thyroid-stimulating hormone and prolactin by the anterior pituitary. TRH is produced by the hypothalamus and travels across the median eminence to the pituitary via the hypophyseal portal system.

Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a superagonist at TRH-R

……………………………

Synthesis and central nervous system actions of thyrotropin-releasing hormone analogues containing a dihydroorotic acid moiety
J Med Chem 1990, 33(8): 2130\

http://pubs.acs.org/doi/abs/10.1021/jm00170a013

………………

http://www.google.com/patents/US4665056

EXAMPLE 2

(1) 1.56 g of 1-methyl-L-4,5-dihydroorotic acid and 1.15 g of N-hydroxysuccinimide are dissolved in 30 ml of dimethylformamide, and 2.06 g of dicyclohexylcarbodiimide are added thereto at 0° C. The mixture is stirred at room temperature for 2 hours. The solution thus obtained is hereinafter referred to as “Solution A”. On the other hand, 3.43 g of benzyl L-histidyl-L-prolinate.2HCl are dissolved in dimethylformamide, and 1.67 g of triethylamine are added thereto. The mixture is stirred at 0° C. for 20 minutes, and insoluble materials are filtered off. The filtrate is added to “Solution A”, and the mixture is stirred at 0° C. for 4 hours and then at 10° C. for one day. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure at 40° C. to remove dimethylformamide. The residue is dissolved in water, and insoluble materials are filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. The column is washed with 500 ml of water, 500 ml of 20% methanol and 300 ml of 50% methanol, successively. Then, the desired product is eluted with 70% methanol. The fractions which are positive to the Pauly’s reaction are collected from the eluate and concentrated under reduced pressure, whereby 3.65 g of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are obtained as an oil.

IRν_max ^chloroform (cm^-1) 3300, 1725, 1680.

650 mg of the product obtained above are dissolved in 1 N-HCl and then lyophilized to give 690 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate.HCl.H₂ O as powder.

[α]_D ²² : -39.8° (C=0.5, H₂ O).

IRν_max ^nujol (cm^-1): 1720, 1640-1680.

NMR (DMSO-d₆, δ): 1.7-2.4 (m, 4H), 2.90 (s, 3H), 2.4-3.9 (m, 6H), 3.9-4.2 (m, 1H), 4.3-4.5 (m, 1H), 4.6-5.0 (m, 1H), 5.09 (s, 2H), 7.2-7.5 (m, 5H), 8.96 (s, 1H).

Mass (m/e): 496 (M⁺).

(2) 700 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are dissolved in 20 ml of methanol, and 20 mg of palladium-black are added thereto. The mixture is stirred at room temperature for 3 hours in hydrogen gas. 20 ml of water are added to the reaction mixture, and the catalyst is filtered off. The filtrate is evaporated to remove solvent. The residue is crystallized with methanol, whereby 290 mg of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline.5/4 H₂ O are obtained.

M.p.: 233°-236° C. (decomp.).

[α]_D ²⁰ : -17.2° (C=0.5, H₂ O).

IRν_max ^nujol (cm^-1): 1715, 1680, 1630.

NMR (D₂ O, δ): 1.7-2.4 (m, 4H), 2.6-3.9 (m, 6H), 3.03 (s, 3H), 4.0-4.45 (m, 2H), 4.95 (t, 1H), 7.27 (s, 1H), 8.57 (s, 1H).

(3) A mixture of 4.29 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline, 1.15 g of N-hydroxysuccinimide, 2.26 g of dicyclohexylcarbodiimide and 30 ml of dimethylformamide is stirred at 0° C. for 40 minutes and at room temperature for 80 minutes. 30 ml of 15% ammonia-methanol are then added to the mixture at 0° C., and the mixture is stirred at 0° C. for 30 minutes and at room temperature for one hour. Insoluble materials are filtered off, and the filtrate is evaporated to remove dimethylformamide. The residue is dissolved in 20 ml of water, and insoluble materials are again filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. After the column is washed with 2 liters of water, the desired product is eluted with 10% methanol. The fractions which are positive to the Pauly’s reaction are collected and concentrated under reduced pressure. The residue is dissolved in 10 ml of water, and allowed to stand in a refrigerator. Crystalline precipitates are collected by filtration, washed with water, and then dried at 25° C. for one day, whereby 3.3 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinamide.7/2 H₂ O are obtained.

M.p.: 72°-75° C.

[α]_D ²⁵ : -13.6° (C=1, H₂ O).

IRν_max ^nujol (cm^-1): 3400, 3250, 1710, 1660, 1610, 1540.

References

External links

• (Japanese) Ceredist セレジスト錠 (PDF) Mitsubishi Tanabe Pharma. October 2007.

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Capromorelin

N-[(2R)-1-[(3aR)-2-methyl-3-oxo-3a-(phenylmethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl]-1-oxo-3-(phenylmethoxy)propan-2-yl]-2-amino-2-methylpropanamide

2-Amino-N-[2-[3a(R)-benzyl-2-methyl-3-oxo-3,3a,4,5,6,7-hexahydro-2H-pyrazolo[4,3-c]pyridin-5-yl]-1(R)-(benzyloxymethyl)-2-oxoethyl]isobutyramide

CP-424391-18, (3ar)-3a-benzyl-2-methyl-5-(2-methylalanyl-o-benzyl-d-seryl)-3-oxo-3,3a,4,5,6,7-hexahydro-2h-pyrazolo[4,3-c]pyridine

Gastro-esophageal reflux disease (GERD)

193273-66-4 free form
193270-49-4 (monoHCl)
193273-67-5 (monomesylate)
193273-69-7 (L-tartrate(1:1))

505.6086

C28 H35 N5 O4

CP-424391
RQ-00000005
CP-424391-18 (tartrate)

Pfizer (Originator)
RaQualia

Phase II

Capromorelin (CP-424,391) is an investigational medication developed by the Pfizer drug company.^{[2] [3]} It functions as a growth hormone secretagogue and ghrelin mimetic which causes the body to secrete human growth hormone in a way usually seen at puberty and in young adulthood. Initial studies have shown the drug to directly raise insulin growth factor 1 (IGF-1) and growth hormone levels.^[4]

The drug is being considered for its therapeutic value in aging adults because elderly people have much lower levels of growth hormone and less lean muscle mass, which can result in weakness and frailty.^[5]

In a one-year treatment trial (starting 1999) with 395 seniors between 65 and 84 years old, patients who received the drug gained an average of 3 lb (1.4 kg) in lean body mass in the first six months and also were better able to walk in a straight line in a test of balance, strength and coordination. After 12 months, patients receiving capromorelin also had an improved ability to climb stairs, however the results were not good enough to continue the trial for the 2nd planned year.^[6]

Capromorelin, however, has not been approved by major regulatory bodies such as the World Health Organization, the European Medicines Agency or the United States FDA. In the U.S. at least, approval is not expected to be forthcoming any time soon, because the FDA does not consider aging a disease, and so requires extraordinary evidence of benefit and non-toxicity to approve a drug for use as an anti-aging agent.^[7]

Ghrelin is a peptide that promotes a growth hormone secreted by the stomach and exhibits a variety of physiological effects, including the promotion of appetite, gastrointestinal tract motility and stomach acid secretion, as well as improved heart function. Capromorelin (RQ-00000005) is a ghrelin receptor agonist and, because it has been shown to increase body weight without increasing body fat and to improve motility and appetite in the elderly, it has the potential for many uses, including frailty and GERD.

…………………………………………………………………

WO 1997024369

 https://www.google.com/patents/WO1997024369A1?cl=en

…………………………..

EP 0869968; JP 1999501945; WO 9724369

The intermediate dipeptide (VI) was prepared by two similar ways. Treatment of N-Boc-O-benzyl-D-serine (I) with MeI and K2CO3 produced the methyl ester (II). Subsequent deprotection of the Boc group of (II) with trifluoroacetic acid gave aminoester (III), which was coupled with N-Boc-alpha-methylalanine (IV) using EDC and HOBt yielding (V). Hydrolysis of the resulting dipeptide ester (V) then provided intermediate (VI). In an alternative procedure, N-Boc-alpha-methyl alanine (IV) was activated as the N-hydroxysuccinimidyl ester (VII), which was condensed with O-benzyl-D-serine (VIII) to produce dipeptide (VI).

Methyl 4-oxopiperidine-3-carboxylate (IX) was protected as the tert-butyl carbamate (X) with Boc2O. This was alkylated with benzyl bromide in the presence of NaH to provide the racemic benzyl derivative (XI). Subsequent cyclization of (XI) with methylhydrazine produced the pyrazolopyridine (XII), which was deprotected with trifluoroacetic acid. The resulting amine (XIII) was then coupled with dipeptide (VI) using EDC and HOBt to afford the diastereomeric amides (XIV). After chromatographic isolation of the (R,R)-diastereoisomer, acid deprotection of the Boc group furnished the title compound.

References

1. Khojasteh-Bakht SC, O’donnell JP, Fouda HG, Potchoiba MJ. Metabolism, pharmacokinetics, tissue distribution, and excretion of [14C]CP-424391 in rats. Drug Metabolism and Disposition. 2005 Jan;33(1):190-9. PMID 15486077
2. Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Murray MC, Cook ER, DiBrino JN, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Lewis SK, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, Pettersen JC, DaSilva-Jardine PA, Wilson TC, Thompson DD. Discovery and biological characterization of capromorelin analogues with extended half-lives. Bioorganic and Medicinal Chemistry Letters. 2002 Nov 18;12(22):3279-82. PMID 12392732
3. Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Cook ER, DiBrino JN, Campeta AM, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, DaSilva-Jardine PA, Wilson TC, Thompson DD. Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin. Bioorganic and Medicinal Chemistry. 2003 Feb 20;11(4):581-90. PMID 12538023
4. Pan LC, Carpino PA, Lefker BA, Ragan JA, Toler SM, Pettersen JC, Nettleton DO, Ng O, Pirie CM, Chidsey-Frink K, Lu B, Nickerson DF, Tess DA, Mullins MA, MacLean DB, DaSilva-Jardine PA, Thompson DD. Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine growth hormone secretagogue. Endocrine. 2001 Feb;14(1):121-32. PMID 11322494
5. Thompson DD. Aging and sarcopenia. Journal of Musculoskeletal and Neuronal Interactions. 2007 Oct-Dec;7(4):344-5. PMID 18094505
6. Heidi K. White, Charles D. Petrie, William Landschulz, David MacLean, Ann Taylor, Kenneth Lyles, Jeanne Y. Wei, Andrew R. Hoffman, Roberto Salvatori, Mark P. Ettinger, Miriam C. Morey, Marc R. Blackman, George R. Merriam for the Capromorelin Study Group. Effects of an Oral Growth Hormone Secretagogue in Older Adults. Journal of Clinical Endocrinology & Metabolism. April 2009, Vol. 94, No. 4 1198-1206. doi:10.1210/jc.2008-0632. PMID 19174493
7. Hersch EC, Merriam GR. Growth hormone (GH)-releasing hormone and GH secretagogues in normal aging: Fountain of Youth or Pool of Tantalus? Clinical Interventions in Aging. 2008;3(1):121-9. PMID 18488883

Researchers

• Pfizer
• Merck
• University of Washington/VA Puget Sound Health Care System: Dr. George Merriam
• University of Poland: Dr. Agnieszka Baranowska-Bik

• Capromorelin
• Clinical Trials
• Capromorelin Information

Carpino, P.A.; Lefker, B.A.; Toler, S.M.; et al.
Design, synthesis and biological evaluation of a novel series of pyrazolidone-piperidine growth hormone secretagogues
216th ACS Natl Meet (August 23-27, Boston) 1998, Abst MEDI 276

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Fidaxomicin

873857-62-6 

3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one

C₅₂H₇₄Cl₂O₁₈   Molecular Weight: 1058.03916 

US FDA:link         Launched – 2011   Clostridium difficile-associated diarrhea

OPT-80  
PAR-101

Using Astellas’ Dificlir (fidaxomicin) as a first-line treatment for clostridium difficile infection (CDI) is not only clinically effective but could also save the National Health Service thousands of pounds compared to the standard of care, according to data from a late-stage study

Read more at: http://www.pharmatimes.com/Article/14-05-14/Astellas_Dificlir_could_save_NHS_thousands_of_pounds.aspx#ixzz31qrtFXlT

Fidaxomicin (trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrummacrocyclic antibiotic drugs.^[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.^[3][4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species ofbacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.^[5] [6]

It is marketed by Cubist Pharmaceuticals after acquisition of its the originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection. Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient’s clinical status. It is currently one of the most expensive antibiotics approved for use. A 20 tab pack costs upwards of £1350.^[7]

Fidaxomicin works by inhibiting the bacterial enzyme RNA polymerase, resulting in the death of Clostridium difficile.^[8] It is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.^[3]

Approvals and indications

For the treatment of CDAD (Clostridium difficile-Associated diarrhea), the drug won an FDA advisory panel’s unanimous approval on April 5, 2011.^[14] and full FDA approval on May 27, 2011.^[15]

Fidaxomicin is an antibiotic approved and launched in 2011 in the U.S. for the treatment of Clostridium difficile-associated diarrhea (CDAD) in adults 18 years of age and older. In September 2011, the product received a positive opinion in the E.U. and final approval was assigned in December 2011. First E.U. launch took place in the U.K. in June 2012. Optimer Pharmaceuticals is conducting phase III clinical trials for the prevention of Clostridium difficile-associated diarrhea in patients undergoing hematopoietic stem cell transplant. Preclinical studies are ongoing for potential use in the prevention of methicillin-resistant Staphylococcus (MRS) infection. Early clinical studies had been under way for the prevention and treatment of vancomycin-resistant enterococcal (VRE) infection; however, no recent development has been reported for this indication.

The compound is a novel macrocyclic antibiotic that is produced by fermentation. Its narrow-spectrum activity is highly selective for C. difficile, thus preserving gut microbial ecology, an important consideration for the treatment of CDAD.

In May 2005, Par Pharmaceutical and Optimer entered into a joint development and collaboration agreement for fidaxomicin. However, rights to the compound were returned to Optimer in 2007. The compound was granted fast track status by the FDA in 2003. In 2010, orphan drug designation was assigned to fidaxomicin in the U.S. by Optimer Pharmaceuticals for the treatment of pediatric Clostridium difficile infection (CDI). In 2011, the compound was licensed by Optimer Pharmaceuticals to Astellas Pharma in Europe and certain countries in the Middle East, Africa, the Commonwealth of Independent States (CIS) and Japan for the treatment of CDAD. In 2011, fidaxomicin was licensed to Cubist by Optimer Pharmaceuticals for comarketing in the U.S. for the treatment of CDAD. In July 2012, the product was licensed by Optimer Pharmaceuticals to Specialised Therapeutics Australia in AU and NZ for the treatment of Clostridium difficile-associated infection. OBI Pharma holds exclusive commercial rights in Taiwan, where the compound was approved for the treatment of CDAD in September 2012, and in December 2012, the product was licensed to AstraZeneca in South America with commercialization rights also for the treatment of CDAD. 

Clinical trials

Good results were reported in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment ofClostridium difficile infection (CDI)^[9][10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).^[11] Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next 4 weeks.^[12]

Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.^[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

References

http://www.pharmatimes.com/Article/14-05-14/Astellas_Dificlir_could_save_NHS_thousands_of_pounds.aspx

(RTTNews.com) – BioCryst Pharmaceuticals Inc. ( BCRX ) will be reporting results from OPuS-1, a phase IIa trial of orally-administered BCX4161 in patients with hereditary angioedema, on Tuesday, May 27, 2014 at 8:30 a.m. Eastern Time.

The OPuS-1 clinical trial is testing 400 mg of BCX4161 administered three times daily for 28 days in up to 25 hereditary angioedema patients who have a high frequency of attacks (≥ 1 per week), in a randomized, placebo-controlled, two-period cross-over design.
Read more: http://www.nasdaq.com/article/bcrx-to-watch-out-for-gtiv-adopts-poison-pill-teva-qgen-drtx-get-fda-nod-20140527-00005#ixzz335Khl0sk

BCX-4161 is a novel, selective inhibitor of plasma kallikrein in development for prevention of attacks in patients with hereditary angioedema (HAE). By inhibiting plasma kallikrein, BCX-4161 suppresses bradykinin production. Bradykinin is the mediator of acute swelling attacks in HAE patients.

……………………………….

old article

Active pharmaceutical ingredients (APIs) are frequently delivered to the patient in the solid state as part of such dosage forms as tablets, capsules, etc.In this context the ability to deliver the drug to the patient in a safe, efficacious and cost-effective way depends largely on the physicochemical properties of the APIs in the solid state, and ……..read more

http://www.allfordrugs.com/cocrystals/

SAFINAMIDE

cas  202825-46-5 (mesylate)

N²-{4-[(3-fluorobenzyl)oxy]benzyl}-L-alaninamide

Newron Pharmaceuticals and fellow Italy-headquartered partner Zambon have filed their investigational Parkinson’s disease treatment safinamide with regulators in the USA.

The submission to the US Food and Drug Administration is for safinamide as add-on therapy in early and mid-to late stage PD patients. Newron said the filing was based on “completion of activities agreed upon during meetings” with the FDA, noting that a marketing authorisation application was submitted to the European Medicines Agency in December.

Read more at: http://www.pharmatimes.com/Article/14-05-30/Italy_s_Newron_files_Parkinson_s_drug_with_FDA.aspx#ixzz33LlGLEt7

Safinamide (EMD 1195686) is a candidate drug against Parkinson’s disease with multiple methods of action.^[1] In 2007, a Phase III clinical trial was started. It was scheduled to run until 2011.^[2] The compound was originally discovered at Farmitalia-Carlo Erba and developed by Newron Pharmaceuticals, which sold the rights to Merck-Serono in 2006. In October 2011 Merck-Serono announced that they would give all rights to develop the compound back to Newron.^[3]

Potential additional uses might be restless legs syndrome (RLS) and epilepsy.^[4] They were being tested in Phase II trials in 2008, but no results are available.

Adverse effects

Common adverse events in clinical trials were nausea, dizziness, tiredness, headache and backache. There was no significant difference in the occurrence of these effects between safinamide and placebo treated patients.^[5]

Methods of action

Parkinson and RLS relevant mechanisms

Safinamide is a reversible and selective monoamine oxidase B inhibitor, reducing degradation of dopamine, and a glutamate release inhibitor.^[6][5] It also seems to inhibit dopamine reuptake.^[7] Additionally, safinamide blocks sodium and calcium channels.^[6]

References

1.  Fariello, RG (2007). “Safinamide”. Neurotherapeutics 4 (1): 110–116. doi:10.1016/j.nurt.2006.11.011. PMID 17199024.
2.  Study of Safinamide in Early Parkinson’s Disease as Add-on to Dopamine Agonist (MOTION)
3.  Merck Returns Rights for Safinamide to Newron, 21 October 2011.
4.  Chazot, PL (2007). “Drug evaluation: Safinamide for the treatment of Parkinson’s disease, epilepsy and restless legs syndrome”. Current Opinion in Investigational Drugs 8 (7): 570–579. PMID 17659477.
5.  H. Spreitzer (14 April 2014). “Neue Wirkstoffe – Safinamid”. Österreichische Apothekerzeitung (in German) (8/2014): 30.
6.  Caccia, C; Maj, R; Calabresi, M; Maestroni, S; Faravelli, L; Curatolo, L; Salvati, P; Fariello, RG (2006). “Safinamide: From molecular targets to a new anti-Parkinson drug”. Neurology 67 (7 Suppl 2): S18–23. PMID 17030736.
7.  Merck Serono: Vielversprechende Daten zur kognitiven Wirkung von Safinamid bei Parkinson im Frühstadium.(German) 8 June 2007.

US2012010225	1-13-2012	PHARMACEUTICAL COMPOSITION
US8034820	10-12-2011	Pharmaceutical composition
US2004209960	10-22-2004	Methods of treating lower urinary tract disorders using sodium channell modulators
WO9935125	7-16-1999	ALPHA-AMINOAMIDE DERIVATIVES USEFUL AS ANALGESIC AGENTS

 

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AMUVATINIB

Amuvatinib (MP-470) is an orally bioavailable synthetic carbothioamide with potential antineoplastic activity. Multitargeted receptor tyrosine kinase inhibitor MP470 binds to mutant forms of the stem cell factor receptor (c-Kit; SCFR), inhibiting clinically relevant mutants of this receptor tyrosine kinase that may be associated with resistance to therapy. In addition, MP470 inhibits activities of other receptor tyrosine kinases, such as c-Met, Ret oncoprotein, and mutant forms of Flt3 and PDGFR alpha, which are frequently dysregulated in variety of tumors. This agent also suppresses the induction of DNA repair protein Rad51, thereby potentiating the activities of DNA damage-inducing agents. Mutant forms of c-Kit are often associated with tumor chemoresistance.

http://www.google.co.in/patents/EP1678166A2?cl=en

Scheme 1

EXAMPLE 34 Synthesis and Analysis of Further Illustrative Compounds Compound (111-1-3), also referred to herein as HPK56/MP-470, is an illustrative compound of the present invention having the following structure:

 

Analogues of (111-1 -3) were designed and synthesized in order to evaluate and optimize kinase selectivity, aqueous solubility, and to improve pharmacokinetic and pharmacodynamic profiles. Illustrative synthesis approaches for generating (111-1 -3) analogues are depicted in the synthesis schemes below. Synthesis of R-i substituted benzofuranopyrimidines was undertaken. The methyl 3-guanidinobenzofuran-2-carboxylate is prepared from methyl 3-aminobenzofuran-2-carboxylate by reacting with cyanoacetamide in presence of dioxane and dry HCI gas. The obtained guanidine is cyclized in the presence of aqueous NaOH. Similar procedures were utilized for preparing 2- substituted (111-1-3) and its analogues as depicted in the Schemes 8-10 set forth below. Introduction of -NH₂ at the 2 position was utilized for various sulfonic, inorganic and hydroxyacid salts. Illustrative compounds are shown in Table 4 below.Table 4

 

Scheme 1 

Scheme 2 Scheme 3

,-NH_{2 /}N Cl S

EXAMPLE 35 Analysis of Compound Binding and Inhibitory Activity against c-kit Mutants

The published crystal structure of c-kit kinase (pdb code:1 PKG) and its mutated structure were used to study the mode of binding of compound (111-1-3) (HPK56/MP-470), a benzofuranopyrimidine compound, its 2-substituted analogs, and quinazoline derivatives.

 

(Ill- 1-3)

According to news published on 15 Apr 2008;  Research data build upon previous results showing that MP-470 exhibits anti-tumor activity in breast and http://www.medicalnewstoday.com/articles/150086.php”>prostate cancer cells. The fact that MP-470 in combination with erlotinib effectively suppressed the HER pathway suggests that concurrent administration of both compounds could represent a new treatment for prostate and breast cancers.

1. Kreidberg, Jordan A.; Qin, Shan. Method using a cMET inhibitor for the treatment of polycystic kidney disease. PCT Int. Appl. (2009), 43pp. CODEN: PIXXD2 WO 2009111529 A2 20090911 CAN 151:350826 AN 2009:1107388

2. Fujiwara, Masahiro; Fujita, Masayuki. Curing agents, adhesive curable compositions, articles and coating materials therefrom, and optical materials formed by using the compositions. Jpn. Kokai Tokkyo Koho (2008), 39pp. CODEN: JKXXAF JP 2008260894 A 20081030 CAN 149:472741 AN 2008:1303932

3. Janne, Pasi A.; Engelman, Jeffrey; Cantley, Lewis C. Methods for treating cancer resistant to ErbB therapeutics. PCT Int. Appl. (2008), 96pp. CODEN: PIXXD2 WO 2008127710 A2 20081023 CAN 149:486836 AN 2008:1282443

4. Nakagawa, Kiyoshi; Kurushima, Yoshiaki; Mizuma, Masahiro. Fabric with highly-expanded layer and process for production thereof. PCT Int. Appl. (2007), 44pp. CODEN: PIXXD2 WO 2007083641 A1 20070726 CAN 147:213021 AN 2007:815020

5. Mahadevan, D.; Cooke, L.; Riley, C.; Swart, R.; Simons, B.; Della Croce, K.; Wisner, L.; Iorio, M.; Shakalya, K.; Garewal, H.; Nagle, R.; Bearss, D. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene (2007), 26(27), 3909-3919. CODEN: ONCNES ISSN:0950-9232. CAN 147:226484 AN 2007:613908

6. Gong, QingJie; Han, DongYu; Wang, YuRong. Experimental determination of scheelite solubility in 4.0% NaCl solution in critical region. Yanshi Xuebao (2006), 22(12), 3052-3058. CODEN: YANXEU ISSN:1000-0569. CAN 147:34728 AN 2007:301330

7. Tokunaga, Koji; Mukai, Takashi; Kishigami, Akira. Two-component weak solvent-based coating compositions with no curing interference by dewing. Jpn. Kokai Tokkyo Koho (2005), 15 pp. CODEN: JKXXAF JP 2005239815 A 20050908 CAN 143:249850 AN 2005:979155

8. Lauer, S. J.; Shuster, J. J.; Mahoney, D. H., Jr.; Winick, N.; Toledano, S.; Munoz, L.; Kiefer, G.; Pullen, J. D.; Steuber, C. P.; Camitta, B. M. A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: A pediatric oncology group phase III randomized trial. Leukemia (2001), 15(7), 1038-1045. CODEN: LEUKED ISSN:0887-6924. CAN 135:338846 AN 2001:586045

9. Sen, Ayusman; Hennis, April. Palladium (II) catalyzed polymerization of norbornene and acrylates. PCT Int. Appl. (2001), 22 pp. CODEN: PIXXD2 WO 2001021670 A1 20010329 CAN 134:252774 AN 2001:228935

10. Patel, Raman; Mallin, Dan; Saunders, Keith; Tiberio, Patrick; Andries, John. Polymer compositions containing polyolefins, polar polymers and block or graft copolymer compatibilizers and their preparation. PCT Int. Appl. (1999), 25 pp. CODEN: PIXXD2 WO 9950350 A1 19991007 CAN 131:272658 AN 1999:640932

11. Koehler, Burkhard; Imai, Seisaku; Doering, Joachim; Ruesseler, Wolfgang; Dorf, Ernst Ullrich. Mixtures of polyarylene sulfides, glass fibers, and polymaleimides with good mechanical properties. Ger. Offen. (1992), 4 pp. CODEN: GWXXBX DE 4105913 A1 19920827 CAN 118:82122 AN 1993:82122

12. Itoh, Michiya; Fuke, Kiyokazu; Kobayashi, Sachiko. Direct observation of intramolecular anthracene excimer in 1,3-dianthrylpropane. Journal of Chemical Physics (1980), 72(2), 1417-18. CODEN: JCPSA6 ISSN:0021-9606. CAN 92:155340 AN 1980:155340

13. Tomillero A; Moral M A Gateways to clinical trials. Methods and findings in experimental and clinical pharmacology (2009), 31(9), 597-633. Journal code: 7909595. ISSN:0379-0355. PubMed ID 20094643 AN 2010048694

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15. Gorrand Jean-Marie; Doly Michel; Bacin Franck Macular pigment density assessed by directional fundus reflectance. Journal of the Optical Society of America. A, Optics, image science, and vision (2009), 26(8), 1847-54. Journal code: 9800943. ISSN:1084-7529. PubMed ID 19649122 AN 2009529589

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ABT 199
4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

1257044-40-8 [RN]

2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

ABT 199

• Molecular Formula: C₄₅H₅₀ClN₇O₇S
• Average mass: 868.439209 Da
• Monoisotopic mass: 867.318115 Da

• 4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide

NORTH CHICAGO, Ill., May 31, 2014/NEWS.GNOM.ES/ — AbbVie (NYSE: ABBV) released interim results from a Phase Ib clinical trial of ABT-199/GDC-0199, an investigational B-cell lymphoma 2 (BCL-2) selective inhibitor, in combination with rituximab (Abstract 7013). Results showed anoverall response rate (ORR) of 84 percent, in patients with relapsed/refractory chronic lymphocytic leukemia(CLL), the most common leukemia in the UnitedStates. These results were presented at the 50^thAnnual Meeting of the American Society of ClinicalOncology (ASCO), May 30 – June 3 in Chicago.

http://news.gnom.es/pr/abbvie-presents-new-results-from-studies-of-investigational-oncology-compound-abt-199gdc-0199-at-the-2014-american-society-of-clinical-oncology

ABT-199 is a so-called BH3-mimetic drug, which is designed to block the function of the protein Bcl 2. In 1988, it was discovered that Bcl-2 allowed leukaemia cells to become long-lived, a discovery made at the Walter and Eliza Hall Institute by Professors David Vaux, Suzanne Cory and Jerry Adams. Subsequent research led by them and other institute scientists, including Professors Andreas Strasser, David Huang, Peter Colman and Keith Watson, has explained much about how Bcl-2 and related molecules function to determine if a cell lives or dies. These discoveries have contributed to the development of a new class of drugs called BH3-mimetics that kill, and thereby rapidly remove, leukaemic cells by blocking Bcl-2. (source:http://www.wehi.edu.au).

GDC-0199 (RG7601) is a novel small molecule Bcl-2 selective inhibitor designed to restore apoptosis, also known as programmed cell death, by blocking the function of a pro-survival Bcl-2 family protein. The Bcl-2 family proteins, which are expressed at high levels in many tumors, play a central role in regulating apoptosis and, consequently, are thought to impact tumor formation, tumor growth and resistance.

 1: Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2
inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Jan 6. doi: 10.1038/nm.3048. [Epub ahead of print] PubMed PMID: 23291630.

Glenmark Pharmaceuticals inaugurates new Antibody Manufacturing Facility in La Chaux-de-Fonds, Switzerland

• State of the art manufacturing facility for supply of clinical trial material
• With the facility Glenmark has end-to-end capabilities for the development of novel, state-of-the-art monoclonal antibodies including bi-specific antibodies
La Chaux-de-Fonds, Switzerland, June 4, 2014 – Glenmark Pharmaceuticals S.A (GPSA), a wholly owned subsidiary of Glenmark Pharmaceuticals Limited, India (GPL), announced the opening of its new cGMP compliant monoclonal antibody manufacturing facility in La Chaux-de-Fonds, Switzerland. This manufacturing facility supplements Glenmark’s existing in-house discovery and development capabilities and will supply material for clinical development.

The manufacturing facility has been designed for use of single use bioreactor systems and also houses a suite for manufacturing cell banks. The facility is fully compliant with quality, environmental and safety standards for manufacturing clinical trial material.

http://www.moneycontrol.com/stocks/stock_market/corp_notices.php?autono=813829