Keryx Biopharmaceuticals has announced that its new drug application (NDA) for Zerenex (ferric citrate coordination complex) has been accepted for filing by the US FDA.
Keryx’s NDA for kidney drug accepted for filing by US FDA
Zerenex aims to lower blood levels of phosphorous in patients undergoing kidney dialysis.
An experimental drug being developed by Regeneron Pharmaceuticals Inc. (REGN) and Sanofi SA (SNY) showed promising results during a small, mid-stage clinical trial in treating a subset of patients with moderate to severe asthma, but some physicians cautioned that it was too early to say how effective the treatment may ultimately be.
The drug, dupilumab, is considered one of Regeneron’s most promising pipeline drugs and could eventually reach $750 million in annual U.S. sales if it gains U.S. approval to treat asthma, according to Barclays. Regeneron and Sanofi, which have a partnership to co-develop certain experimental drug programs, are also testing the drug to treat a type of eczema, the itchy skin condition, and have said dupilumab could eventually be applied to other allergic conditions.
Results from the trial, published online Tuesday in the New England Journal of Medicine, showed that dupilumab reduced asthma attacks by 87% in patients taking the drug compared to those receiving a placebo. Side effects of the drug appeared to be relatively consistent with those of patients taking placebos.
“It really raises the possibility that we’ve hit upon a fundamental pathway that’s driving the allergic reaction in asthma,” said George D. Yancopoulos, Regeneron’s chief scientific officer, in an interview.
However, the trial was relatively small, enrolling 52 patients in each of the study’s two treatment groups. An editorial accompanying the study results said the trial design, in which patients were gradually weaned off of standard therapies for asthma, did not reflect a “real world” environment.
It’s also unclear how large a swath of asthma patients will benefit from the drug, because only those with higher-than-normal disease-fighting white blood cells were admitted to the study, Michael E. Wechsler, director of the asthma program at National Jewish Health, a Denver-based research hospital that specializes in respiratory conditions, wrote in the editorial. Just 21% of patients screened for the trial met the inclusion criteria, Dr. Wechsler wrote.
Asthma affects more than 24 million people in the U.S., but existing therapies are unable to control the condition for as many as 10% to 20% of patients, according to the study’s authors.
The drug will advance into a larger phase-two trial, which will have four to five times as many patients as the trial published Tuesday, said Regeneron’s Mr. Yancopoulos.
Dupilumab is a monoclonal antibody designed for the treatment of atopic diseases.[1] It binds to the alpha subunit of the interleukin-4 receptor.[2] Through blockade of IL-4R alpha, dupilumab modulates signaling of both the IL-4 and IL-13 pathway, which have been implicated in the pathophysiology of allergic disease.[3]
This drug was developed by Regeneron Pharmaceuticals.
On May 21/2013 mid-stage data was presented at the American Thoracic Society meeting and published in the NEJM demonstrating a 87% reduction in asthma exacerbations in patients with moderate-to-severe allergic asthma.[2]
Researchers have developed a new drug to treat the underlying pathology associated with asthma, reducing flare-ups by nearly 87%, according to results of a new trial. Some experts view this as a potential game changer if the drug lives up to its early performance in a smallstudy of 104 patients, recently presented at theAmerican Thoracic Society InternationalConference in Philadelphia.
Dupilumab, an injectable medication developed by Regeneron Pharmaceuticals REGN -3.76% Inc. and Sanofi , has sparked the interest of many pulmonologists and as well as critical care physicians, and represents a new class of drug to treat this disabling, as well as costly disease. It is estimated that approximately 25 million people in the United States are known to have asthma. The worldwide estimates are between 235-300 million people, with 180,000 deaths annually.
Asthma is a chronic inflammatory disease of the airways associated with airway sensitivity with multiple triggers leading to acute and chronic narrowing of the airway with increased mucus production. Patients with asthma exacerbations experience wheezing, chest tightness, shortness of breath, and coughing. In severe cases, these symptoms can be life-threatening. For the majority of asthma patients, standard treatments can control the disease.
However, an estimated 10% to 20% of asthmatic patients are less than optimally controlled despite existing therapies. Moderate-to-severe asthma is generally recognized as a so called heterogeneous disease; the Th2 (Type 2 helper T cell) inflammation pathway is believed to play a role in disease pathogenesis in approximately 50% of these patients.
Based on results of this small study, Dupilumab helped to improve symptoms and standard measures of lung function and reduced the need for standard drugs such as long acting beta agonists (LABA) and anti-inflammatory medications such as steroids.
Dupilumab works by simultaneously blocking proteins that have been linked to inflammation, interleukin-4 (IL-4) and interleukin-13 (IL-13). In the past, other pharmaceutical companies have investigated medications that block one or both of the proteins, but without success.
On May 21, Sanofi and Regeneron Pharmaceuticals, Inc. jointly announced publication online in the New England Journal of Medicine of positive results from a Phase 2a study of dupilumab in patients with moderate-to-severe allergic-type asthma. The study results were presented at the American Thoracic Society 2013 International Conference.
Dupilumab is a monoclonal antibody targeting the alpha subunit of the interleukin 4 receptor (IL-4R alpha), which regulates signaling of both IL-4 and IL-13, drivers of Th2 (Type 2 helper T cell) immune response.
The proof-of-concept study enrolled 104 patients with moderate-to-severe, chronic asthma that was not well controlled with inhaled glucocorticosteroids (ICS) and long-acting beta agonist (LABA) therapy, and who had elevated blood or sputum eosinophils (immune cells used as a marker of Th2 asthma in this study).
The primary objective of the trial was to assess the effect of subcutaneous dupilumab, administered weekly at a dose of 300 milligrams (mg) for twelve weeks. Patients were treated with dupilumab (N=52) or placebo (N=52) in addition to ICS and LABA therapy for the first four weeks of the study. The LABA was withdrawn at week four and the ICS was tapered to withdrawal between the sixth and ninth week.
Patients were treated for 12 weeks or until they experienced a protocol-defined asthma exacerbation, the primary endpoint of the study. 23 patients (44.2%) receiving placebo experienced an asthma exacerbation compared to three patients (5.8%) receiving dupilumab, resulting in an 87% reduction in the incidence of asthma exacerbations for the dupilumab arm compared to placebo (p<.001).
Statistically and clinically significant improvements were observed for measures of lung function and other asthma control parameters, such as forced expiratory volume over one second (FEV1) (difference from baseline to week 12 between dupilumab and placebo of 0.27 L)
Adverse events (AEs) were reported by a similar proportion of patients in both groups (76.9% placebo; 80.8% dupilumab). AEs were generally non-specific and of mild-to-moderate intensity. The most common AEs for dupilumab were injection-site reaction (28.8%), nasopharyngitis (13.5%), upper respiratory tract infection (13.5%), headache (11.5%) and nausea (7.7%).
A fair number of patients with moderate-to-severe, persistent allergic type asthma are not well controlled despite standard therapy placing them at risk for repeated exacerbations hospitalizations and negative outcomes.
It is estimated that standard drugs are typically unable to control asthma well in about 10% to 20% of patients. The inflammation caused by Th2 cells, the type of inflammation among patients they tested, is a factor in nearly half of these moderate to severe cases, representing nearly 2.5 million people in the US and up to 30 million throughout the world.
Dupilumab, through blockade of IL-4R alpha, modulates signaling of both the IL-4 and IL-13 pathways, which have been implicated in the pathophysiology of Th2 mediated diseases such as asthma and atopic dermatitis.
Along with previously reported positive proof-of-concept clinical results of dupilumab in atopic dermatitis presented at the recent Amercian Academy of Dermatology (AAD), data from the present study supports the concept that blocking the IL-4/IL-13 pathway is encouraging as an method to treat multiple allergic conditions. Phase 2b trials with dupulimab in both asthma and atopic dermatitis will be forthcoming.
Data from asthma patients as well as those with atopic dermatitis suggests that this new antibody may affect a common pathway shared by these two allergic diseases.
If Dupilumab is approved, it may be a significant advance for patients with moderate to severe persistent asthma that is not well controlled by standard drugs.
Dupilumab is a drug that can treat the root cause of asthma.Strategies to treat asthma have, for the most part, dealt with only the symptoms, without addressing the underlying mechanism or ultimate cause.
Solid form screening is commonly performed to find a candidate with optimal properties for early development or to find a form with different properties to improve a formulation in later development. A variety of screens can be performed including polymorph, salt, co-crystal, amorphous, and amorphous dispersion. X-ray powder diffraction (XRPD) is commonly used at various stages of screening to identify and characterize new forms. It is also used to help evaluate other properties, such as physical stability and manufacturability, in order to choose the best form for development. This paper discusses the use of XRPD during screening and form selection of pharmaceutical materials.
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efinaconazole
str credit kegg
http://www.ama-assn.org/resources/doc/usan/efinaconazole.pdf
1-Piperidineethanol, α-(2,4-difluorophenyl)-β-methyl-4-methylene-α-(1H-1,2,4-triazol-1- ylmethyl)-, (αR,βR)-
(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol
MOLECULAR FORMULA C18H22F2N4O
MOLECULAR WEIGHT 348.39
SPONSOR Dow Pharmaceutical Sciences, Inc.
CODE DESIGNATION KP-103
CAS REGISTRY NUMBER 164650-44-6
Efinaconazole is a topical triazole antifungal in development for the treatment of onychomycosis.
Valeant Pharmaceuticals International Inc. announced that the New Drug Submission for Jublia has been approved from the Canadian regulatory authority, Health Canada, for the treatment of mild to moderate onychomycosis, a common and destructive nail infection caused predominantly by dermatophyte fungi.
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US FDA STATUS
NOT APPROVED
May 28, 2013 Valeant Pharmaceuticals International, Inc. today announced that it has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for efinaconazole for the treatment of onychomycosis. A CRL is issued by the FDA’s Center for Drug Evaluation and Research when the review of a file is completed and questions remain that preclude the approval of the NDA in its current form. The questions raised by the FDA pertain only to Chemistry, Manufacturing and Controls (CMC) related areas of the container closure apparatus. As no efficacy or safety issues were raised by the FDA, Valeant believes that these items can be addressed and is working for a timely response to the FDA as soon as possible. Valeant remains committed to bringing efinaconazole to market as a potential new treatment for onychomycosis.
Valeant Pharmaceuticals International, Inc. is a multinational specialty pharmaceutical company that develops, manufactures and markets a broad range of pharmaceutical products primarily in the areas of dermatology, neurology and branded generics. More information about Valeant Pharmaceuticals International, Inc. can be found at www.valeant.com.
NON-PATENT DOCUMENTS
(where HX signifies the acid in the acid addition salt)
cilnidipine
西尼地平
CAS 132203-70-4
Cilnidipine (INN) is a calcium channel blocker. It is sold as Atelec in Japan, asCilaheart, Cilacar in India, and under various other trade names in East Asian countries.
Cilnidipine is a dual blocker of L-type voltage-gated calcium channels in vascular smooth muscle and N-type calcium channels in sympathetic nerve terminals that supply blood vessels. However, the clinical benefits of cilnidipine and underlying mechanisms are incompletely understood.
Clinidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. It was jointly developed by Fuji Viscera Pharmaceutical Company, Japan and Ajinomoto, Japan and approved to come into market for the first time and used for high blood pressure treatment in 1995. in india j b chemicals & pharmaceuticals ltd and ncube pharmaceutical develope a market of cilnidipine.
Hypertension is one of the most common cardiovascular disease states, which is defined as a blood pressure greater than or equal to 140/90 mm Hg. Recently, patients with adult disease such as hypertension have rapidly increased. Particularly, since damages due to hypertension may cause acute heart disease or myocardial infarction, etc., there is continued demand for the development of more effective antihypertensive agent.
Meanwhile, antihypertensive agents developed so far can be classified into Angiotensin II Receptor Blocker (ARB), Angiotensin-Converting Enzyme Inhibitor (ACEI) or Calcium Chanel Blocker (CCB) according to the mechanism of actions. Particularly, ARB or CCB drugs manifest more excellent blood pressure lowering effect, and thus they are more frequently used.
However, these drugs have a limit in blood pressure lowering effects, and if each of these drugs is administered in an amount greater than or equal to a specific amount, various side-effects may be caused. Therefore, there have been many attempts in recent years to obtain more excellent blood pressure lowering effect by combination therapy or combined preparation which combines or mixes two or more drugs.
Particularly, since side-effect due to each drug is directly related to the amount or dose of a single drug, there have been active attempts to combine or mix two or more drugs thereby obtaining more excellent blood pressure lowering effect through synergism of the two or more drugs while reducing the amount or dose of each single drug.
For example, US 20040198789 discloses a pharmaceutical composition for lowering blood pressure combining lercanidipine, one of CCB, and valsartan, irbesartan or olmesartan, one of ARB, etc. In addition, a combined preparation composition which combines or mixes various blood pressure lowering drugs or combination therapy thereof has been disclosed.
cilnidipine Compared with other calcium antagonists, clinidipine can act on the N-type calcium-channel that existing sympathetic nerve end besides acting on L-type calcium-channel that similar to most of the calcium antagonists. Due to its N-type calcium-channel blocking properties, it has more advantages compared to conventional calcium-channel blockers. It has lower incidence of Pedal edema, one of the major adverse effects of other calcium channel blockers. Cilnidipine has similar blood pressure lowering efficacy as compared to amlodipine. One of the distinct property of cilnidipine from amlodipine is that it does not cause reflex tachycardia.
In recent years, cardiovascular disease has become common, the incidence increased year by year, about a patient of hypertension in China. 3-1. 500 million, complications caused by hypertension gradually increased, and more and more young patients with hypertension technology. In recent years, antihypertensive drugs also have great development, the main first-line diuretic drug decompression 3 – blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, ar blockers and vascular angiotensin II (Ang II) receptor antagonist.
In the anti-hypertensive drugs, calcium antagonists are following a – blockers after another rapidly developing cardiovascular drugs, has been widely used in clinical hypertension, angina and other diseases, in cardiovascular drugs in the world, ranked first.
Cilnidipine for the long duration of the calcium channel blockers, direct relaxation of vascular smooth muscle, dilation of peripheral arteries, the peripheral resistance decreased, with lower blood pressure, heart rate without causing a reflex effect.
Cilnidipine is a dihydropyridine CCB as well as an antihypertensive. Cilnidipinehas L- and N-calcium channel blocking actions. Though many of the dihydropyridine CCBs may cause an increase in heart rate while being effective for lowering blood pressure, it has been confirmed that cilnidipine does not increase the heart rate and has a stable hypotensive effect. (Takahiro Shiokoshi, “Medical Consultation & New Remedies” vol. 41, No. 6, p. 475-481)
Cilnidipine (CAS NO.: 132203-70-4), with its systematic name of (+-)-(E)-Cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate, could be produced through many synthetic methods.
Following is one of the synthesis routes: By cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 °C.
MORE
NMR
CARBOHYDRATE POLYMERS 90 PG 1719-1724 , YR2012
Numerous peaks were found in the spectrum of cilnidipine: 2.3555 (3H, s, CH3), 2.3886(3H, s, CH3), 3.2843(CD3OD), 3.3292(3H, s, OCH3), 3.5255–3.5623(2H, m, CH3OCH2CH2 ), 4.1224–4.1597(2H, m, CH3OCH2CH2 ), 4.6695–4.7293(2H, m, CH2 CH CH ), 4.8844(D2O), 5.1576(1H, s, CH), 6.2609(1H, dt, CH2 CH CH ), 6.5518(1H, d, CH2 CH CH ), 7.2488–7.3657(6H, m, ArH), 7.7002(1H, dd, ArH), 7.9805(1H, dd, ArH), 8.1548(1H, s, ArH)
References:
Dihydropyridine calcium channel blocker. Prepn: T. Kutsuma et al., EP 161877; eidem, US 4672068(1985, 1987 both to Fujirebio).
Pharmacology: K. Ikeda et al., Oyo Yakuri 44, 433 (1992).
Mechanism of action study: M. Hosonoet al., J. Pharmacobio-Dyn. 15, 547 (1992).
LC-MS determn in plasma: K. Hatada et al., J. Chromatogr. 583, 116 (1992). Clinical study: M. Ishii, Jpn. Pharmacol. Ther. 21, 59 (1993).
Acute toxicity study: S. Wada et al., Yakuri to Chiryo 20, Suppl. 7, S1683 (1992), C.A. 118, 32711 (1992).
U.S Patent No. 4,572,909 discloses amlodipine; U.S Patent No. 4,446,325 discloses aranidipine; U.S Patent No. 4,772,596 discloses azelnidipine; U.S Patent No. 4,220,649 discloses barnidipine; U.S Patent No. 4,448,964 discloses benidipine; U.S Patent No. 5,856,346 discloses clevidipine; U.S Patent No. 4,466,972 discloses isradipine; U.S Patent No. 4,885,284 discloses efonidipine; and U.S Patent No. 4,264,61 1 discloses felodipine.
U.S Patent No. 5,399,578 discloses Valsartan; European Patent No. 0 502 314 discloses Telmisartan; U.S Patent No. 5,138,069 discloses Losartan; U.S Patent No. 5,270,317 discloses Irbesartan; U.S Patent No. 5,583,141 and 5,736,555 discloses Azilsartan; U.S Patent No. 5,196,444 discloses Candesartan; U.S Patent No. 5,616,599 discloses Olmesartan; and U.S Patent No. 5,185,351 discloses Eprosartan.
U.S Patent No. 4,374,829 discloses enalapril; U.S Patent No. 4,587,258 discloses ramipril; U.S Patent No. 4,344,949 discloses quinapril; U.S Patent No. 4,508,729 discloses perindopril; U.S Patent No. 4,374,829 discloses lisinopril; U.S Patent No. 4,410,520 discloses benazepril; U.S Patent No. 4,508,727 discloses imidapril; U.S Patent No. 4,316,906 discloses zofenopril; U.S Patent Nos. 4,046,889 and 4,105,776 discloses captopril; and U.S Patent No. 4,337,201 discloses fosinopril.
sumanirole
179386-43-7
179386-44-8 (maleate)
Sumanirole maleate, U-95666 (free base), U-95666E, PNU-95666E
| Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives | |
| Council Of Scientific & Industrial Research | |
| The present invention relates to novel and concise process for the construction of chiral 3-substituted tetrahydroquinoline derivatives based on proline catalyzed asymmetric α-functionalization of aldehyde, followed by in situ reductive cyclization of nitro group under catalytic hydrogenation condition with high optical purities. Further the invention relates to conversion of derived chiral 3-substituted tetrahydroquinoline derivatives into therapeutic agents namely (-)-sumanirole (96% ee) and 1-[(S)-3-(dimethylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]propanone[(S)-903] (92% ee). | |
| Process,sumanirole | |
| Indications | Restless legs syndrome; Parkinsons disease |
| Target-based Actions | Dopamine D2 receptor agonist |
| Other Actions | Anxiolytic; Antiparkinsonian |
|
|
| Inventors | Boopathi, Senthil, Kumar; Arumugam, Sudalai; Rawat, Varun |
| IPC Codes | C07D 215/20; C07D 471/06; C07D 215/38 |
| DRUG | sumanirole |
| Publication Date | 26-Sep-2013 WO-2013140419-A1 |
Sumanirole (PNU-95,666) is a highly selective D2 receptor full agonist, the first of its kind to be discovered. It was developed for the treatment of Parkinson’s disease andrestless leg syndrome. While it has never been approved for medical use it is a highly valuable tool compound for basic research to identify neurobiological mechanisms that are based on a dopamine D2-linked (vs. D1, D3, D4, and D5-linked) mechanism of action
sumanirole
OTHER INFO
D-Phenylalanine (I) was protected as the methyl carbamate (II) by acylation with methyl chloroformate under Schotten-Baumann conditions. The N-methoxy amide (III) was then prepared by coupling of (II) with O-methyl hydroxylamine in the presence of EDC. Cyclization of (III) to the N-methoxy quinolinone (IV) was accomplished by treatment with bis(trifluoroacetoxy)iodobenzene in the presence of trifluoroacetic acid. Simultaneous reduction of the N-methoxy lactam and carbamate functions of (IV) by means of borane-methyl sulfide complex provided diamine (V). The aliphatic amino group of (V) was then selectively protected as the benzyl carbamate (VI) by using N-(benzyloxycarbonyloxy)succinimide at -40 C. Reaction of (VI) with phosgene, followed by treatment of the intermediate carbamoyl chloride with O-methyl hydroxylamine gave rise to the N-methoxy urea derivative (VII). This was cyclized with bis(trifluoroacetoxy)iodobenzene to the imidazoquinolinone (VIII). The N-methoxy and N-benzyloxycarbonyl groups of (VIII) were then removed by hydrogenolysis in the presence of Pearlman’s catalyst, and the title compound was finally converted to the corresponding maleate salt.
JOC 1997,62,(19):6582
