MELOGLIPTIN

Melogliptin

Phase III

A DP-IV inhibitor potentially for treatment of type II diabetes.

EMD-675992; GRC-8200

CAS No. 868771-57-7

4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile
4(S)-Fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile

Note………The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

MELOGLIPTIN




GRC 8200; 868771-57-7, EMD-675992
4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile
4(S)-Fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile
GRC-8200, a dipeptidyl peptidase IV inhibitor (DPP-IV), is currently undergoing phase II clinical trials at Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes. In 2006, the compound was licensed by Glenmark Pharmaceuticals to Merck KGaA in Europe, Japan and N. America for the treatment of type 2 diabetes, however, these rights were reaquired by Glenmark in 2008.
.

ALTERNATE……….



- See more at: http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html#sthash.21wvMwlT.dpuf

MELOGLIPTIN




GRC 8200; 868771-57-7, EMD-675992
4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile
4(S)-Fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile
GRC-8200, a dipeptidyl peptidase IV inhibitor (DPP-IV), is currently undergoing phase II clinical trials at Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes. In 2006, the compound was licensed by Glenmark Pharmaceuticals to Merck KGaA in Europe, Japan and N. America


.

ALTERNATE……….







P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

MELOGLIPTIN




GRC 8200; 868771-57-7, EMD-675992
4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile
4(S)-Fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile
GRC-8200, a dipeptidyl peptidase IV inhibitor (DPP-IV), is currently undergoing phase II clinical trials at Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes. In 2006, the compound was licensed by Glenmark Pharmaceuticals to Merck KGaA in Europe, Japan and N. America for the treatment of type 2 diabetes, however, these rights were reaquired by Glenmark in 2008.
.

ALTERNATE……….



- See more at: http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html#sthash.21wvMwlT.dpuf

////////

Iptakalim Hydrochloride 盐酸埃他卡林

Iptakalim Hydrochloride  盐酸埃他卡林

NDA Filed china

A K(ir) 6.1/SUR2B activator potentially for the treatment of pulmonary arterial hypertension.

179.7, C9H21N.HCl

CAS No. 642407-44-1(Iptakalim)

642407-63-4(Iptakalim Hydrochloride)

N-(1-methylethyl)-2,3-dimethyl-2-butylamine

Catholic Healthcare West (D/B/A/ St. Joseph's Hospital And Medical Center)

 

 

Hypertension is a multifactorial disorder, and effective blood pressure control is not achieved in most individuals. According to the most recent report of the American Heart Association, for 2010, the estimated direct and indirect financial burden for managing hypertension is estimated to be $76.6 billion. Overall, almost 75% of adults with cardiovascular diseases/comorbidities have hypertension, which is associated with a shorter overall life expectancy. Alarmingly, rates of prehypertension and hypertension are increasing among children and adolescents due, in part, to the obesity epidemic we currently face. There is also the problem of an aging population and the growing rates of diabetes and obesity in adults, all factors that are associated with high blood pressure.Thus, the need is great for novel drugs that target the various contributing causes of hypertension and the processes leading to end organ damage.

Iptakalim (IPT), chemically 2, 3–dimethyl-N-(1-methylethyl)-2-butanamine hydrochloride, is novel adenosine triphosphate–sensitive potassium (K_ATP) channel opener. K_ATP channels are composed of discrete pore-forming inward rectifier subunits (Kir6.1s) and regulatory sulphonylurea subunits (SUR).IPT shows high selectivity for cardiac K_ATP (SUR2A/Kir6.2) and vascular K_ATP (SUR2B/Kir6.1 or SUR6B/Kir6.2). Because of this high selectivity, IPT does not exhibit the adverse side effects associated with the older nonspecific K⁺ channel openers, which limit their use to the treatment of severe or refractory hypertension. IPT produces arteriolar and small artery vasodilatation, with no significant effect on capacitance vessels or large arteries. Vasodilatation is induced by causing cellular hyperpolarization via the opening of K⁺ channels, which in turn decreases the opening probability of L-type Ca²⁺ channels. Of particular note, IPT is very effective in lowering the blood pressure of hypertensive humans but not of those with normal blood pressure.

 

• The present compd relates generally to a novel method for decreasing a human's cravings for cigarettes and reducing instances of relapse during detoxification once smoking abstinence has been achieved, and more specifically, to a method for decreasing nicotine use by treating a human with a novel type of nicotinic acetylcholine receptor antagonist, iptakalim hydrochloride (IPT).

• Cigarette smoking is a prevalent, modifiable risk factor for increased morbidity and mortality in the United States, and perhaps in the world. Smokers incur medical risks attributable to direct inhalation. Bystanders, termed passive smokers, also incur medical risks from second-hand smoke. Society, as a whole, also bears the economic costs associated with death and disease attributable to smoking. Although the majority of smokers have tried repeatedly to quit smoking, eighty percent of smokers return to tobacco in less than two years after quitting. Therefore, tobacco dependence is a health hazard for millions of Americans.
•  
  Nicotine is the biologically active substance that is thought to promote the use of tobacco products by approximately one-quarter of the world populations. Tobacco-related disease is personally and economically costly to the any nation. Unfortunately, once use of tobacco has begun, it is hard for a smoker to quit because of nicotinic dependence and addiction.
•  
  The initiation and maintenance of tobacco dependence in a human is due to certain bio-behavioral and neuromolecular mechanisms. Nicotinic acetylcholine receptors (nAChRs) in humans are the initial binding sites for nicotine. The binding of nicotine to nAChRs is thought to modulate the brain's “reward” function by triggering dopamine release in the human brain. The nAChRs exist as a diverse family of molecules composed of different combinations of subunits derived from at least sixteen genes. nAChRs are prototypical members of the ligand-gated ion channel superfamily of neurotransmitter receptors. nAChRs represent both classical and contemporary models for the establishment of concepts pertaining to mechanisms of drug action, synaptic transmission, and structure and function of transmembrane signaling molecules.
•  
  Basic cellular mechanisms of nicotinic dependence also involve the functional state changes during repeated nicotinic agonists exposure and receptor changes in the number of receptors during chronic nicotinic exposure. nAChRs can exist in many different functional states, such as resting, activated, desensitized or inactivated The activation and/or desensitization of nAChRs plays an important role in initiating nicotinic tolerance and dependence. Recovery from receptor activation and/or desensitization contributes to nicotinic withdrawal symptoms.
•  
  The most abundant form of nAChRs in the brain contains α4 and β2 subunits. α4β2-nAChRs bind nicotine with high affinity and respond to levels of nicotine found in the plasma of smokers. α4β2-nAChR also have been implicated in nicotine self-administration, reward, and dependence. Therefore, selective drug action at nAChRs, especially at those containing α4 subunits, is thought to be an ideal way for nicotine cessation and reducing nicotine withdrawal syndrome. Unfortunately, thus far, no optimal compound can meet this purpose. The brain-blood-barrier permeable nAChR antagonist, mecamylamine is popularly used systemically but exhibits much less nAChR subtype selectivity.
•  
  Although a variety of psychopharmacological effects contribute to drug reinforcement, actions on the mesolimbic dopaminergic pathway is the predominant hypothesis for mechanisms of nicotinic reward. The mesolimbic dopaminergic pathway originates in the ventral tegmental area (VTA) of the midbrain and projects to forebrain structures including the prefrontal cortex and to limbic areas such as the olfactory tubercle, the amygdala, the septal region, and the nucleus accumbens. Many studies have indicated that dopamine release in the nucleus accumbens of the human brain is “rewarding” or signals an encounter with a “reward” from the environment. Other substances, such as alcohol, cocaine, and opiates, operate in the same manner, resulting in a cycle of substance or alcohol abuse.
•  
  Therefore, a considerable need exists for a novel compound that can selectively block α4 subtypes of nAChRs to prevent smoking-induced “reward”, to limit increasing nicotine-induced dopamine release, and/or to diminish nicotinic withdrawal symptoms.

 

 

Patent

https://www.google.com/patents/US20040266822
Example 1

•  
  Production of N-(1-methylethyl)-2,3-dimethyl-2-butylamine (Compound 1): Method 1. The solution of 7.6 g (0.0745 mole) 2,3-dimethyl-2-butanol in 3.24 mL glacial acetic acid was cooled and maintained at −5 to −8 degree of centigrade (° C.), then was added 7.3 g (0.49 mole) of powdered potassium cyanide in several times under stirring. 32.4 mL concentrated sulfuric acid was added dropwise while keeping the temperatue below 20° C., after which, the reaction mixture was stirred for 3.5 hours below 20° C. and another 6 hours at room temperature, then stood overnight. After poured into ice colded water, the mixture was adjusted to pH10 with 20% aqueous sodium hydroxide solution, and extracted with ether (×4). The extract was dried over anhydrous sodium sulfate. After filtration on the next day, the dessicator was removed, and the filtrate was evaporated off the ether, then distilled in vacuum to give 8.8 g (yield 91.6%) N-[2-(2,3-dimethylbutyl)]-fomide; bp 105-108° C./5 mmHg.
•  
  To the mixture of 7.7 g (0.0597 mole) N-[2-(2,3-dimethylbutyl)]-formide, 6.2 mL ethanol and 51.6 mL wate, 17.4 mL concentrated hydrochloric acid was added. The reaction mixture was refluxed for 4 hours in the oil bath, then distilled off ethanol in vacuum. The residue was adjusted to above pH12 with 40% aqueous sodium hydroxide solution, and extracted with ether. The extract was dried over anhydrous potassiun carbonate. After recovering the ether, The residue was distilled at atmosphere to give 3.75 g (yield 62.2%) 2,3-dimethyl-2-butylamine, bp 97-104° C.
•  
  The mixture of 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45 g (0.0524 mole) 2-bromopropane, 3.0 mL glycol and 22.0 mL toluene was added into an autoclave, and heated with stirring for 17 hours at temperature of 170° C., after which, the organic layer was separated and extracted with 6N hydrochloric acid (15 mL×4). The extract was combined and washed once with toluene, then adjusted to pH 12-13 with 4% aqueous sodium hydroxide in the ice bath. The mixture was extracted with ether and then dried over anhydrous potassium carbonate. After recovering the ether, The filtrate was distilled to yield the fraction of bp 135-145° C. (yield 68.8%). The hydrochloride's Mp is 228-230° C. (1-PrOH-Et₂O). Elemental analysis for C₉H₂₂ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C, 60.14; H, 12.48; N, 7.31, Cl 19.67.
•  
  ¹H-NMR(D₂O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M+), 100(B).
•  
  Method 2. To the mixture of 288 mL glacial acetic acid, 412 g (6.86 mole) urea and 288 g (3.43 mole) 2,3-dimethyl-2-butene, the solution of 412 mL concentrated sulfuric acid and 412 mL of glacial acetic acid was added dropwise under stirring, while maintaining the reaction temperature at the range of 45° C. to 50° C., then stirred for 5 hours at the temperature of 50-55° C. The mixture stood overnight. Next day, the mixture was reacted for another 7 hours at the temperature of 50-55° C., then poured into the solution of 1200 g (30 mole) sodium hydroxide in 8L glacial water. The resulting solid was filtered, washed with water (200 mL×5) and dried to give 404 g (yield 81.8%) N-(2,3-dimethyl-2-butyl)urea as white solid, mp 175-176° C. Elemental analysis for C₇H₁₆N₂O(%): Calculated C 58.30, H 11.18, N 19.42; Found C, 58.70; H, 11.54; N, 19.25, ¹H-NMR(CDCl₃, ppm) 0.88-0.91(d, 6H, 2×CH₃), 1.26(s, 6H, 2×CH₃), 2.20-2.26(m, 1H, CH), 4,45(br, 2H), 4.65(br, 1H). MS(m/z) 145.0, 144.0(M⁺), 143.0, 129.1, 101.0, 86.1, 69.1, 58.0(B).
•  
  To the mixture of 196 g (1.36 mole) N-(2,3-dimethyl-2-butyl)urea and 392 mL glycol or tri-(ethanol)amine, a solution of 118 g (2.95 mole) sodium hydroxide in 118 mL water was added. The reaction mixture was heated for 8 hours in an oil bath at temperature of 120° C., then distilled at atmosphere to collect the fraction of bp 95-102° C. To the fraction, 75 g anhydrous potassium carbonate and. 40 g sodium hydroxide were added. The resulting mixture was distilled to give 88.5 g (yield 64.3%) 2,3-dimethyl-2-butylamine as colorless liquid, bp 99-101° C.
•  
  ¹H-NMR(CDCl₃, ppm) 0.88-0.91(d, 6H, 2×CH₃), 1.04 (s, 6H, 2×CH₃), 1.53(m, 1H, CH).
•  
  To a 50.0 ml autoclave, 10.6 g (0.15 mole) 2,3-dimethyl-2-butylamine, 6.45 g (0.0524 mol) 2-bromopropane, 3.0 ml glycol and 22.0 ml toluene were added, and heated with stirring for 17 hours at 170° C., after which the organic layer was seperated and extracted with 6N hydrochloric acid (15 ml×4). The extract was combined and washed once with toluene, then adjusted to pH 12-13 with 4% aqueous sodium hydroxide in the ice bath. The mixture was extracted with ether and then dried over anhydrous potassium carbonate the ether was recovered, and distilled to give the fraction of bp 135-145° C. (yield 68.8%). mp of the hydrochloride is 228-230° C., (i-PrOH: Et₂O). Elemental analysis for C₉H₂₂ClN(%): Calculated C, 60.14; H, 12.34; N, 7.79, Cl 19.73; Found C 60.14, H 12.48, N 7.31, Cl 19.67. ¹H-NMR(D₂O, ppm) 0.98(d, J=6.75H, 6H), 1.33(s, 6H), 1.37(d, J=6.46, 6H), 2.10(m, 1H), 3.70(m, 1H). MS(m/z) 143 (M⁺), 100(B).
•  
  Method 3. a solution of 0.10 mole enamine (prepared from the condensation of methyl iso-propyl ketone and iso-propylamine) in 20 mL hexane was filled with N₂ and added dropwise to a solution containing 0.10 mole lithium methide with stirring in ice bath. After the reaction is complete, the mixture was poured into 500 g glacial water, and stirred. The aqueous layer was extracted with ether (×2). The resulting organic layer was concentrated. 3N hydrochloric acid was added to acified the organic layer to pH<1. The mixture was kept for ten minutes and adjusted to pH>11 with 10% aqueous sodium hydroxide, then extracted with ether (×3). The extract was dried over anhydrous potassium carbonate and filtered. The filtrate was distilled at atmosphere to give a fraction of bp 140-145° C. with a yield of 80%.

REF
http://www.google.com/patents/US20060293393



//////Iptakalim Hydrochloride,  盐酸埃他卡林 , K(ir) 6.1/SUR2B activator,  pulmonary arterial hypertension, nda

//////////////
see.........http://newdrugapprovals.org/2015/12/04/iptakalim-hydrochloride-%E7%9B%90%E9%85%B8%E5%9F%83%E4%BB%96%E5%8D%A1%E6%9E%97/

Tesmilifene , Antagonist of intracellular histamine

Tesmilifene

BMS-217380; BMY-33419; DPPE

CAS No. 98774-23-3(Tesmilifene),  92981-78-7(Tesmilifene hydrochloride)

Tesmilifene

CAS  98774-23-3

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine

DPPE

MFC19H25NO

MW 283.41

Percent Composition: C 80.52%, H 8.89%, N 4.94%, O 5.65%

 Hydrochloride

CAS 92981-78-7

 BMS-217380-01; BMY-33419

MF C19H25NO.HCl

MF 319.87

Percent Composition: C 71.34%, H 8.19%, N 4.38%, O 5.00%, Cl 11.08%

Properties: White crystals from isopropanol + acetone (3:1), mp 156-158°. pKa 10.9.

Melting point: mp 156-158°

pKa: pKa 10.9

 

Therap-Cat: Antineoplastic adjunct (chemosensitizer).

AT YM BIOSCIENCES, GILEAD

Tesmilifene is a novel potentiator of chemotherapy which, when added to doxorubicin, achieved an unexpected and very large survival advantage over doxorubicin alone in a randomized trial in advanced breast cancer.
PHASE 23 FOR An estrogen receptor antagonist potentially for the treatment of advanced breast cancer, gastric cancer
Tesmilifene is a novel agent that augments cytotoxicity of various chemotherapeutic agents both in vitro and in vivo. It binds selectively to the high-affinity microsomal antiestrogen binding site (Ki=50nm) but has no affinity for estrogen receptors. Inhibits concanavalin-A-induced histamine release in mast cells and acts as a novel antagonist of intracellular histamine.
US 4803227

 

The target product can be prepared by reacting para-benzylphenol (I) with 2-diethylaminoethylchloride hydrochloride (II) either by means of NaOH in H2O or with K2CO3 in DMF/acetone (at 60 C in both cases), followed by treatment with HCl to obtain the corresponding hydrochloride salt.

EP 0153160; JP 1985190742; US 4803227

 US 4803227
http://www.google.com/patents/US4803227

Tesmilifene is a small molecule chemopotentiator under development by YM BioSciences, a Candian pharmaceutical company that specialises in the development of cancer treatments. It is indicated for use in combination with standard cytotoxic drugs, such as taxanes and anthracyclines, which are widely used in the treatment of metastatic disease – when cancers spread to distant sites in the body.
Tesmilifene, the company's lead investigational compound, is currently in phase III development for patients with metastatic breast cancer. At the end of January 2007, an independent safety monitoring board advised the company that its ongoing registration trial should be stopped; it was considered unlikely that significant differences in overall survival (primary endpoint) between treatment arms would emerge over time. The company had hoped that the addition of tesmilifene to standard epirubicin/cyclophosphamide therapy would confer a survival benefit similar to that seen in its earlier phase III trial.
In light of these disappointing results, YM BioSciences plans a detailed analysis of its phase III data in advanced breast cancer to see if it can identify why tesmilifene failed to add clinical benefit in this trial.

DRUG RESISTANCE LIMITS EFFECTIVENESS OF CHEMOTHERAPY

Cytotoxic drugs have proved potent weapons in the fight against malignant tumours and are considered first-line therapy for the treatment of many cancers. However, while patients often respond well to a first course of chemotherapy over time the response to drug treatment diminishes and the tumour may eventually become drug resistant. In some cases resistance can develop across several classes of anti-cancer drugs, leading to multidrug resistance. The development of drug resistance limits the effectiveness of many anti-cancer agents and is an important contributor to cancer deaths.
The development of agents that can overcome drug resistance is seen as one of the most important areas of cancer research and for which there is significant unmet need. Various approaches are being explored to boost the use of cytotoxic agents including chemopotentiators, chemoprotectants and liposomal formulations.
Clearly any agent that can prevent or reverse drug resistance would have a major impact on treatment strategies, enhancing the benefits of standard cytotoxic drugs.

TESMILIFENE MAY BOOST CYTOTOXIC EFFECTS OF ANTHRACYCLINES

Anthracyclines are a class of cytotoxic agents with proven efficacy in the treatment of breast cancer. They include agents such as doxorubicin and epirubicin among others. Because patients with metastatic breast cancer may have received anthracycline therapy for earlier stage breast cancer (adjuvant therapy) or following disease recurrence, there is a risk that they will fail to respond to continued treatment.
A phase III trial in 305 patients with advanced breast cancer has shown that when tesmilifene is combined with doxorubicin it appears to improve survival over treatment with doxorubicin alone. In this trial approximately half the patients were treated with both tesmilifene and doxorubicin, while the other half received doxorubicin alone. Although there were no significant differences in tumour response rates, progression-free survival, or average duration of response between treatment arms at endpoint, overall survival was significantly improved in the combination arm. Among patients treated with tesmilifene and doxorubicin overall survival was 23.6 months compared with 15.6 months for those treated with doxorubicin alone.
Researchers have suggested that tesmilifene may enhance the anti-tumour effects of anthracyclines in several ways:

• Reducing the cancer cell's ability to become resistant
• Decreasing the metabolism or "break-down" of doxorubicin
• Disrupting the cancer cell's energy source

TESMILIFENE REGISTRATION TRIAL

In March 2004 YM BioSciences began its pivotal international phase III trial of tesmilifene in metastatic breast cancer. By September 2005, 723 patients had been enrolled in the trial, which was designed once again to compare the efficacy and safety of tesmilifene and an antrhacycline (epirubicin) with epirubicin alone.

"At the end of January 2007, an independent safety monitoring board advised the company that its ongoing registration trial should be stopped."

Given the survival benefit seen in the earlier trial, which was carried out by the Canadian National Cancer Institute, the company was optimistic about outcome in its pivotal registration trial. However, an interim analysis of 351 events suggested that significant differences in overall survival were unlikely to be seen between the two treatment arms as the data matured and the trial was brought to a premature end.
In addition to its work on anthracyclines, YM BioSciences has also been exploring the potential of tesmilifene to enhance the efficacy of taxanes, also standard chemotherapy for metastatic breast cancer. Other potential applications include:

• Adjuvant therapy for breast cancer, i.e. immediately post-surgery and before the cancer has recurred or metastasised
• Hormone-refractory prostate cancer
• Lung cancer
• Non-Hodgkin's lymphoma

MARKETING COMMENTARY
Although there have been major advances in the treatment of breast cancer in the last 10 to 15 years, it remains a disease for which improved treatments are still urgently needed. Estimates from the WHO suggest that metastatic breast cancer will claim the lives of over 40,000 patients a year.
Current treatments for metastatic breast cancer are rarely curative but can nonetheless do much to improve patients' quality of life or duration of survival. . By boosting the cytotoxic effects of standard chemotherapy agents such as anthracyclines, while protecting healthy cells, tesmilifene was thought to have potential to extend the benefits of cytotoxic therapy to more patients. This is now in doubt following premature ending of its pivotal registration trial in advanced breast cancer.

Literature References: Intracellular histamine antagonist with chemopotentiating and cytoprotective activity. Structurally similar to tamoxifen, q.v., although binds anti-estrogen binding site (AEBS) with no affinity for the estrogen receptor.
Prepn: L. J. Brandes, M. W. Hermonat, Biochem. Biophys. Res. Commun. 123, 724 (1984); and use as antineoplastic: eidem, US 4803227 (1989 to Univ. Manitoba); and study of binding affinity: M. Poirot et al., Bioorg. Med. Chem. 8, 2007 (2000). Spectral analysis of interaction with P450 isozymes: L. J. Brandes et al., Cancer Chemother. Pharmacol. 45, 298 (2000).
Clinical evaluation in combination with cyclophosphamide in prostate cancer: L. J. Brandes et al., J. Clin. Oncol. 13, 1398 (1995); in combination with doxorubicin in breast cancer: L. Reyno et al., J. Clin. Oncol. 22, 269 (2004).
Bioorg Med Chem 2000,8(8),2007

Patent	Submitted	Granted
Neoadjuvant treatment of Breast Cancer [US2008318880]	2008-12-25
Selective androgen receptor modulators for treating diabetes [US2007281906]	2007-12-06
Nuclear receptor binding agents [US8158828]	2007-11-15	2012-04-17
Treatment of hormone-refractory prostate cancer [US2004220281]	2004-11-04
METABOLITES OF SELECTIVE ANDROGEN RECEPTOR MODULATORS AND METHODS OF USE THEREOF [US8003689]	2010-01-07	2011-08-23
Treatment of metastatic breast cancer with anthracyclines, and taxanes [US2006089317]	2006-04-27
Serm reduction of lipid profiles [US2007135407]	2007-06-14
TREATMENT OF HORMONE-UNRESPONSIVE METASTATIC PROSTATE CANCER [EP0737067]	1996-10-16	2003-09-10
Use of a combination of dppe with other chemotherapeutic agents for the treatment of breast cancer [US2006142287]	2006-06-29
Neoadjuvant treatment of breast cancer [US2006160755]	2006-07-20

Product Literature References

Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene.: P. J. Ferguson, et al.; Cancer Lett. 274, 279 (2009), Abstract;

Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group St: L. Reyno, et al.; J. Clin. Oncol. 22, 269 (2004), Abstract;

Synergy between tamoxifen and cisplatin in human melanoma cells is dependent on the presence of antiestrogen-binding sites.: J.A. Jones, et al.; Cancer Res. 57, 2657 (1997), Abstract;

Influence of DPPE on histamine release from isolated rat mast cells.: N. Grosman; Agents Actions 41, 1 (1994), Abstract;

Histamine is an intracellular messenger mediating platelet aggregation.: S.P: Saxena, et al.; Science 243, 1596 (1989), Abstract;

///////Tesmilifene, Antineoplastic Adjunct, Chemosensitizer, PHASE 3, Tesmilifene hydrochloride, BMY-33419, BMS-217380, DPPE, N,N-DPPE, Antagonist of intracellular histamine

CCN(CC)CCOC1=CC=C(C=C1)CC2=CC=CC=C2



see............http://newdrugapprovals.org/2015/12/04/tesmilifene/

Zucapsaicin for osteoarthritis

Zucapsaicin (珠卡赛辛)

cis-Capsaicin; (Z)-Capsaicin

Zucapsaicin; Civamide; Cis-Capsaicin; 25775-90-0; (Z)-Capsaicin; (Z)-N-(4-Hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide;

(Z)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide

CAS No. 25775-90-0

MF C18H27NO3
Molecular Weight:	305.41188 g/mol

WINSTON INNOVATOR

SANOFI

(Zuacta^®/Civanex^®

A medication used to treat osteoarthritis of the knee and other neuropathic pain.TRPV1 CHANNEL AGONIST

 


Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. It is applied three times daily for a maximum of three months. It reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use (patch and cream).^[1]
Zucapsaicin has been tested for treatment of a variety of conditions associated with ongoing nerve pain. This includes herpes simplex infections; cluster headaches and migraine; and knee osteoarthritis.^[2]

Civanex (zucapsaicin) cream is a TRPV-1 modulator in development for the treatment of signs and symptoms of osteoarthritis of the knee.
Zucapsaicin, the cis-isomer of the natural product capsaicin, is a
topical analgesic that was initially developed by Winston Pharmaceuticals
and approved in Canada in July 2010 for the treatment of
severe pain in adults with osteoarthritis of the knee.
Bronson, J.; Dhar, M.; Ewing, W.; Lonberg, N. In Annual Reports in MedicinalChemistry; John, E. M., Ed.; Academic Press, 2011; Vol. 46, p 433.
The advantagesof zucapsaicin compared with naturally-occurring capsaicin, are reported to be a lesser degree of local irritation (stinging, burning,
erythema) in patients and a greater degree of efficacy in preclinical
animal models of pain.
Bernstein, J. E. U.S. 5063060, 1991.
Bernstein, J. E. U.S. 20050084520 A1, 2005.
The analgesic action of both
zucapsaicin and capsaicin is mediated through the transient receptor
potential vanilloid type 1 (TRPV1) channel, a ligand-gated ion
channel expressed in the spinal cord, brain, and localized on neurons
in sensory projections to the skin, muscles, joints, and
gut.
Westaway, S. M. J. Med. Chem. 2007, 50, 2589.
The scale preparation of zucapsaicin likely parallels the original
approach described by Gannett and co-workers involving the
coupling of vanillylamine with (Z)-8-methylnon-6-enoyl chloride.
Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.; Sharpe, J.; Toth, B. J. Org.Chem. 1988, 53, 1064.
Orito and co-workers elaborated this original approach in
an effort to prepare both capsaicin and zucapsaicin on gram-scale,
Kaga, H.; Miura, M.; Orito, K. J. Org. Chem. 1989, 54, 3477.

References

 

• 1 Winston Pharmaceuticals website http://www.winstonlabs.com/productdevelopment/civamide.asp
• 2 Zucapsaicin information from the National Library of Medicine http://druginfo.nlm.nih.gov/drugportal

Janusz, John M.; Buckwalter, Brian L.; Young, Patricia A.; LaHann, Thomas R.; Farmer, Ralph W.; et al. Journal of Medicinal Chemistry, 1993 , vol. 36, # 18 p. 2595 - 2604
Journal of Organic Chemistry, , vol. 53, # 5 p. 1064 - 1071

Zucapsaicin

Systematic (IUPAC) name
(Z)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide
Clinical data
Trade names	Civanex
Routes of administration	Topical
Identifiers
CAS Number	25775-90-0
ATC code	M02AB02
PubChem	CID: 1548942
ChemSpider	1265956
UNII	15OX67P384
Synonyms	Civamide; (Z)-Capsaicin; cis-Capsaicin
Chemical data
Formula	C18H27NO3
Molecular mass	305.41188 g/mol

////Zucapsaicin
Oc1ccc(cc1OC)CNC(CCCC\C=C/C(C)C)=O



see......http://newdrugapprovals.org/2015/12/05/zucapsaicin-for-osteoarthritis/