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Cortendo AB: First Patient Enrolled into NormoCort Phase 3 SONICS Trial Following a Successful EU Investigator Meeting

August 13, 2014 7:37 am / Leave a comment

KETOCONAZOLE 2S 4R

ALSO

142128-57-2
228850-16-6 (tartrate)

(-)-cis-1-Acetyl-4-[4-[2(S)-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4(R)-ylmethoxy]phenyl]piperazine

531.431, C26 H28 Cl2 N4 O4

COR-003
DIO-902
LDKTZ

CORTENDO

licensee DiObex

Biological Role(s):	antifungal agent An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.

Application(s):	antifungal agent An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce. Antifungal agents differ from industrial fungicides in that they defend against fungi present in human or animal tissues.

Ketoconazole, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3– dioxolan-4-yl]methoxy]phenyl]piperazine, is a racemic mixture of the cis enantiomers (-)-(2S,4R) and (+)-(2R,4S) marketed as an anti-fungal agent. Ketoconazole inhibits fungal growth through the inhibition of ergosterol synthesis.(-)-Ketoconazole, the (2S,4R) enantiomer contained in the racemate of ketoconazole, is in phase III clinical trials at Cortendo for the treatment of endogenous Cushing’s syndrome. The company and licensee DiObex had also been developing the drug candidate for the treatment of type 2 diabetes; however, no recent development has been reported for this research.Preclinical studies have demonstrated the drug candidate’s ability to inhibit the synthesis of cortisol, resulting in substantial clinical benefits including lowering both blood pressure and cholesterol in addition to controlling glucose levels. It has also been shown that (-)-ketoconazole is responsible for virtually all of the cortisol synthesis inhibitory activity present in the racemate. Rights to the compound are shared with Cortendo.In 2012, orphan drug designation was assigned in the U.S. for the treatment of endogenous Cushing’s syndrome.

August 12, 2014 02:30 AM Eastern Daylight Time

GÖTEBORG, Sweden.–(BUSINESS WIRE)–Cortendo AB (OSE:CORT) today announced that the first patient has been enrolled into the Phase 3 SONICS trial, i.e., “Study Of NormoCort In Cushing’s Syndrome.”

“The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”

The patient was enrolled by one of the trial’s lead principal investigators at a Pituitary Center from a prestigious institution in Baltimore, Maryland. “The enrollment of the first patient into the SONICS trial represents a significant milestone for Cortendo”, said Dr. Theodore R Koziol. ”The SONICS clinical trial team is acutely focused on the implementation of the trial following a successful EU Investigator’s meeting in Barcelona in July, which we believe further solidified the foundation for the trial.”

Cortendo successfully completed its European Investigator meeting supporting SONICS held in Barcelona, Spain on July 17-18. More than 35 investigators/study coordinators, including many of the world’s leading Cushing’s experts from 24 study sites, were in attendance and received training for the trial. Based on the positive feedback from the meeting, Cortendo has gained further confidence that NormoCort (COR-003) has the potential to be an important future treatment option for patients afflicted with Cushing’s Syndrome. A second US Investigator meeting is also being planned for later this year.

”It was gratifying to participate in the NormoCort SONICS trial investigator meeting in my home town of Barcelona with so many esteemed colleagues dedicated to treating patients with Cushing’s Syndrome”, said Susan Webb M.D. Ph.D. Professor of Medicine Universitat Autonoma de Barcelona. ”There remains a significant unmet medical need for patients, and I am delighted to be part of the development of this new therapy”.

Cortendo has also further strengthened its internal as well as external teams to support the study and to position the trial for an increased recruitment rate. In July, Cortendo added both an experienced physician and internal Clinical Operations Director to the NormoCort development team. Cortendo, working in concert with its CROs supporting the SONICS trial, now has a team of approximately 20 personnel on the NormoCort development program.

Cortendo has previously communicated its plan to meet the recruitment goal by increasing the number of study sites from 38 to 45 worldwide. The company is at various levels of activation with more than 30 study sites to date. Therein, Cortendo expects a large proportion of the sites to be activated by the end of the third quarter this year and remains confident that essentially all sites will be open by the end of 2014.

Risk and uncertainty

The development of pharmaceuticals carries significant risk. Failure may occur at any stage during development and commercialization due to safety or clinical efficacy issues. Delays may occur due to requirements from regulatory authorities not anticipated by the company.

About Cortendo

Cortendo AB is a biopharmaceutical company headquartered in Göteborg, Sweden. Its stock is publicly traded on the NOTC-A-list (OTC) in Norway. Cortendo is a pioneer in the field of cortisol inhibition and has completed early clinical trials in patients with Type 2 diabetes. The lead drug candidate NormoCort, the 2S, 4R-enantiomer of ketoconazole, has been re-focused to Cushing’s Syndrome, and has entered Phase 3 development. The company’s strategy is to primarily focus its resources within orphan drugs and metabolic diseases and to seek opportunities where the path to commercialization or partnership is clear and relatively near-term. Cortendo’s business model is to commercialize orphan and specialist product opportunities in key markets, and to partner non-specialist product opportunities such as diabetes at relevant development stages.

Cortendo AB (publ)

Sweden: Box 47 SE-433 21 Partille Tel. / Fax: +46 (0)31-263010

USA: 555 East Lancaster Ave Suite 510 Radnor, PA 19087 Tel: +1 610-254-9200 Fax: +1 610-254-9245

This information was brought to you by Cision http://news.cision.com

Contacts

Alexander Lindström
Chief Financial Officer Office
+1 610 254 9200
Mobile : +1 917 349 7210
E-mail : alindstrom@cortendo.com

Ketoconazole, 1-acetyl-4- [4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolan-4-yl] methoxy] phenyl] piperazine, is a racemic mixture of the cis enantiomers (-)-(2S, 4R) and (+)-(2R, 4S) marketed as an anti-fungal agent. Ketoconazole inhibits fungal growth through the inhibition of ergosterol synthesis. Ergosterol is a key component of fungal cell walls.
More recently, ketoconazole was found to decrease plasma cortisol and to be useful, alone and in combination with other agents, in the treatment of a variety of diseases and conditions, including type 2 diabetes, Metabolic Syndrome (also known as the Insulin Resistance Syndrome, Dysmetabolic Syndrome or Syndrome X), and other medical conditions that are associated with elevated cortisol levels. SeeU.S. Patent Nos. 5,584,790 ; 6,166,017 ; and 6,642,236 , each of which is incorporated herein by reference. Cortisol is a stress-related hormone secreted from the cortex of the adrenal glands. ACTH (adenocorticotropic hormone) increases cortisol secretion. ACTH is secreted by the pituitary gland, a process activated by secretion of corticotropin releasing hormone (CRH) from the hypothalamus.
Cortisol circulates in the bloodstream and activates specific intracellular receptors, such as the glucocorticoid receptor (GR). Disturbances in cortisol levels, synthetic rates or activity have been shown to be associated with numerous metabolic complications, including insulin resistance, obesity, diabetes and Metabolic Syndrome. Additionally, these metabolic abnormalities are associated with substantially increased risk of cardiovascular disease, a major cause of death in industrialized countries. See Mårin P et al., “Cortisol secretion in relation to body fat distribution in obese premenopausal women.” Metabolism 1992; 41:882-886, Bjorntorp, “Neuroendocrine perturbations as a cause of insulin resistance.” Diabetes Metab Res Rev 1999; 15(6): 427-41, and Rosmond, “Role of stress in the pathogenesis of the metabolic syndrome.” Psychoneuroendocrinology 2005; 30(1): 1-10, each of which is incorporated herein by reference.
While ketoconazole is known to inhibit some of the enzymatic steps in cortisol synthesis, such as, for example, 17α hydroxylase (Wachall et al., “Imidazole substituted biphenyls: a new class of highly potent and in vivo active inhibitors of P450 17 as potential therapeutics for treatment of prostate cancer.” Bioorg Med Chem 1999; 7(9): 1913-24, incorporated herein by reference) and 11b-hydroxylase (Rotstein et al., “Stereoisomers of ketoconazole: preparation and biological activity.” J Med Chem 1992; 35(15): 2818-25) and 11β-hydroxy steroid dehydrogenase (11β-HSD) (Diederich et al., “In the search for specific inhibitors of human 11β-hydroxysteroid-dehydrogenases (11β-HSDs): chenodeoxycholic acid selectively inhibits 11β-HSD-L” Eur J Endocrinol 2000; 142(2): 200-7, incorporated herein by reference) the mechanisms by which ketoconazole decreases cortisol levels in the plasma have not been reported. For example, there is uncertainty regarding the effect of ketoconazole on the 11β-hydroxy steroid dehydrogenase (11β-HSD) enzymes. There are two 11β-HSD enzymes. One of these, 11β-HSD-I, is primarily a reductase that is highly expressed in the liver and can convert the inactive 11-keto glucocorticoid to the active glucocorticoid (cortisol in humans and corticosterone in rats). In contrast, the other, 11β-HSD-II, is primarily expressed in the kidney and acts primarily as an oxidase that converts active glucocorticoid (cortisol in humans and corticosterone in rats) to inactive 11-keto glucocorticoids. Thus, the plasma concentration of active glucocorticoid is influenced by the rate of synthesis, controlled in part by the activity of adrenal 11β-hydroxylase and by the rate of interconversion, controlled in part by the relative activities of the two 11β-HSD enzymes. Ketoconazole is known to inhibit these three enzymes (Diederich et al., supra) and the 2S,4R enantiomer is more active against the adrenal 11β-hydroxylase enzyme than is the 2R,4S enantiomer (Rotstein et al., supra). However, there are no reports describing the effect of the two ketoconazole enantiomers on either of 11β-HSD-I or 11β-HSD-II, so it is not possible to predict what effects, if any, the two different ketoconazole enantiomers will each have on plasma levels of the active glucocorticoid levels in a mammal.
Ketoconazole has also been reported to lower cholesterol levels in humans (Sonino et al. (1991). “Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients.” Clin Endocrinol (Oxf). 35(4): 347-52; Gylling et al. (1993). “Effects of ketoconazole on cholesterol precursors and low density lipoprotein kinetics in hypercholesterolemia.” J Lipid Res. 34(1): 59-67) each of which is incorporated herein by reference). The 2S,4R enantiomer is more active against the cholesterol synthetic enzyme 14 αlanosterol demethylase than is the other (2R,4S) enantiomer (Rotstein et al infra). However, because cholesterol level in a human patient is controlled by the rate of metabolism and excretion as well as by the rate of synthesis it is not possible to predict from this whether the 2S,4R enantiomer of ketoconazole will be more effective at lowering cholesterol levels.
The use of ketoconazole as a therapeutic is complicated by the effect of ketoconazole on the P450 enzymes responsible for drug metabolism. Several of these P450 enzymes are inhibited by ketoconazole (Rotsteinet al., supra). This inhibition leads to an alteration in the clearance of ketoconazole itself (Brass et al., “Disposition of ketoconazole, an oral antifungal, in humans.” Antimicrob Agents Chemother 1982; 21(1): 151-8, incorporated herein by reference) and several other important drugs such as Glivec (Dutreix et al., “Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects.” Cancer Chemother Pharmacol 2004; 54(4): 290-4) and methylprednisolone (Glynn et al., “Effects of ketoconazole on methylprednisolone pharmacokinetics and cortisol secretion.” Clin Pharmacol Ther 1986; 39(6): 654-9). As a result, the exposure of a patient to ketoconazole increases with repeated dosing, despite no increase in the amount of drug administered to the patient. This exposure and increase in exposure can be measured and demonstrated using the “Area under the Curve” (AUC) or the product of the concentration of the drug found in the plasma and the time period over which the measurements are made. The AUC for ketoconazole following the first exposure is significantly less than the AUC for ketoconazole after repeated exposures. This increase in drug exposure means that it is difficult to provide an accurate and consistent dose of the drug to a patient. Further, the increase in drug exposure increases the likelihood of adverse side effects associated with ketoconazole use.
[0008]

Rotstein et al. (Rotstein et al., supra) have examined the effects of the two ketoconazole cis enantiomers on the principal P450 enzymes responsible for drug metabolism and reported “…almost no selectivity was observed for the ketoconazole isomers” and, referring to drug metabolizing P450 enzymes: “[t]he IC50 values for the cis enantiomers were similar to those previously reported for racemic ketoconazole”. This report indicated that both of the cis enantiomers could contribute significantly to the AUC problem observed with the ketoconazole racemate.
One of the adverse side effects of ketoconazole administration exacerbated by this AUC problem is liver reactions. Asymptomatic liver reactions can be measured by an increase in the level of liver specific enzymes found in the serum and an increase in these enzymes has been noted in ketoconazole treated patients (Sohn, “Evaluation of ketoconazole.” Clin Pharm 1982; 1(3): 217-24, and Janssen and Symoens, “Hepatic reactions during ketoconazole treatment.” Am J Med 1983; 74(1B): 80-5, each of which is incorporated herein by reference). In addition 1:12,000 patients will have more severe liver failure (Smith and Henry, “Ketoconazole: an orally effective antifungal agent. Mechanism of action, pharmacology, clinical efficacy and adverse effects.” Pharmacotherapy 1984; 4(4): 199-204, incorporated herein by reference). As noted above, the amount of ketoconazole that a patient is exposed to increases with repeated dosing even though the amount of drug taken per day does not increase (the “AUC problem”). The AUC correlates with liver damage in rabbits (Ma et al., “Hepatotoxicity and toxicokinetics of ketoconazole in rabbits.” Acta Pharmacol Sin 2003; 24(8): 778-782 incorporated herein by reference) and increased exposure to the drug is believed to increase the frequency of liver damage reported in ketoconazole treated patients.
Additionally, U.S. Patent No. 6,040,307 , incorporated herein by reference, reports that the 2S,4R enantiomer is efficacious in treating fungal infections. This same patent application also reports studies on isolated guinea pig hearts that show that the administration of racemic ketoconazole may be associated with an increased risk of cardiac arrhythmia, but provides no data in support of that assertion. However, as disclosed in that patent, arrhythmia had not been previously reported as a side effect of systemic racemic ketoconazole, although a particular subtype of arrhythmia, torsades de pointes, has been reported when racemic ketoconazole was administered concurrently with terfenadine. Furthermore several published reports (for example, Morganroth et al. (1997). “Lack of effect of azelastine and ketoconazole coadministration on electrocardiographic parameters in healthy volunteers.” J Clin Pharmacol. 37(11): 1065-72) have demonstrated that ketoconazole does not increase the QTc interval. This interval is used as a surrogate marker to determine whether drugs have the potential for inducing arrhythmia. US Patent Number 6,040,307 also makes reference to diminished hepatoxicity associated with the 2S,4R enantiomer but provides no data in support of that assertion. The method provided in US Patent Number 6,040,307 does not allow for the assessment of hepatoxicity as the method uses microsomes isolated from frozen tissue.

…………………………

http://www.google.com/patents/EP1853266B1?cl=en

DIO-902 is the single enantiomer 2S,4R ketoconazole and is derived from racemic ketoconazole. It is formulated using cellulose, lactose, cornstarch, colloidal silicon dioxide and magnesium stearate as an immediate release 200 mg strength tablet. The chemical name is 2S,4R cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl] methoxyl]phenyl] piperazine, the formula is C₂₆H₂₈Cl₂N₄O₄, and the molecular weight is 531.44. The CAS number is 65277-42-1, and the structural formula is provided below. The chiral centers are at the carbon atoms 2 and 4 as marked.

[0132]

Ketoconazole is an imidazole-containing fungistatic compound. DIO-902 is an immediate release tablet to be taken orally and formulated as shown in the table below.

Component	Percentage
2S,4R ketoconazole; DIO-902	50%
Silicified Microcrystalline Cellulose, NF (Prosolv HD 90)	16.5
Lactose Monohydrate, NF (316 Fast-Flo)	22.4
Corn Starch, NF (STA-Rx)	10
Colloidal Silicon Dioxide, NF (Cab-O-Sil M5P)	0.5
Magnesium Stearate, NF	0.6

The drug product may be stored at room temperature and is anticipated to be stable for at least 2 years at 25° C and 50% RH. The drug is packaged in blister packs.

ketoconazole 2S,4R enantiomer

ketoconazole 2S,4S enantiomer

ketoconazole 2R,4R enantiomer

ketoconazole 2R,4S enantiomer

……………………..

Journal of Medicinal Chemistry (Impact Factor: 5.61). 08/1992; 35(15):2818-25. DOI: 10.1021/jm00093a015

http://pubs.acs.org/doi/abs/10.1021/jm00093a015

…………………….

Enantioselective separation of ketoconazole enantiomers by membrane extraction

http://www.sciencedirect.com/science/article/pii/S1383586611001638

A new process has been developed to separate ketoconazole (KTZ) enantiomers by membrane extraction, with the oppositely preferential recognition of hydrophobic and hydrophilic chiral selectors in organic and aqueous phases, respectively. This system is established by adding hydrophobic l-isopentyl tartrate (l-IPT) in organic strip phase (shell side) and hydrophilic sulfobutylether-β-cyclodextrin (SBE-β-CD) in aqueous feed phase (lumen side), which preferentially recognizes (+)-2R,4S-ketoconazole and (−)-2S,4R-ketoconazole, respectively. The studies performed involve two enantioselective extractions in a biphasic system, where KTZ enantiomers form four complexes with SBE-β-CD in aqueous phase and l-IPT in organic phase, respectively. The membrane is permeable to the KTZ enantiomers but non-permeable to the chiral selector molecules. Fractional chiral extraction theory, mass transfer performance of hollow fiber membrane, enantioselectivity and some experimental conditions are investigated to optimize the separation system. Mathematical model of I/II = 0.893e^0.039NTU for racemic KTZ separation by hollow fiber extraction, is established. The optical purity for KTZ enantiomers is up to 90% when 9 hollow fiber membrane modules of 30 cm in length in series are used.

Full-size image (10 K)

I, (−)-2S,4R-ketoconazole;
II, (+)-2R,4S-ketoconazole;
CDs, cyclodextrin derivatives;
l-IPT, l-isopentyl tartrate;
d-IPT, d-isopentyl tartrate;
HP-β-CD, hydroxypropyl-β-cyclodextrin;
Me-β-CD, methyl-β-cyclodextrin;
β-CD, β-cyclodextrin;
NTU, number of transfer units;
HTU, height of a transfer unit;
PVDF,polyvinylidene fluoride

…………………….

Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-

Stereoselective synthesis of both enantiomers of ketoconazole from (R)- and (S)-epichlorohydrin

Original Research Article
Pages 1283-1294
Pelayo Camps, Xavier Farrés, Ma Luisa García, Joan Ginesta, Jaume Pascual, David Mauleón, Germano Carganico
Bromobenzoates (2R,4R)- and (2S,4S)-18, prepared stereoselectively from (R)- and (S)-epichlorohydrin, were transformed into (2R,4S)-(+)- and (2S,4R)-(−)-Ketoconazole, respectively, following the known synthetic protocols for the racemic mixture.

Tetrahedron Asymmetry 1995, 6(6): 1283

Stereoselective syntheses of both enantiomers of ketoconazole (1) from commercially available (R)- or (S)-epichlorohydrin has been developed. The key-step of these syntheses involves the selective substitution of the methylene chlorine atom by benzoate on a mixture of and or of their enantiomers, followed by crystallization of the corresponding cis-benzoates, (2S,4R)-18 or(2S,4S)-18, from which (+)- or (−)-1 were obtained as described for (±)-1. The ee’s of (+)- and (−)-ketoconazole were determined by HPLC on the CSP Chiralcel OD-H.

………………..

WO 1996029325

http://www.google.com/patents/WO1996029325A1?cl=en

The incidence of fungal infections has considerably increased over the last decades. Notwithstanding the utility of the antifungal compounds commercialized in the last 15 years, the investigation in this field is however very extensive. During this time, compounds belonging to the azole class have beer, commercialized for both the topical and oral administrations, such a class including imidazoles as well as 1,2,4-triazoles. Some of these compounds car. show m some degree a low gastrointestinal tolerance as well as hepatotoxycity.

A large number of pharmaceutically active compounds are commercialized as stereoisomeric mixtures. On the other hand, the case in which only one of said stereoisomers is pharmaceutically active is frequent.

The undesired enantiomer has a lower activity and it sometimes may cause undesired side-effects.

Ketoconazole (1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine), terconazole (1-[4-[[2(2,4-dichlorophenyl)-2-[(1H-1 , 2 ,4-triazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]-4-(1-methylethyl)piperazine) and other related azole antifungal drugs contain in their structure a substituted 1,3-dioxolane ring, in which carbon atoms C2 and C4 are stereogenic centres, therefore four possible stereoisomers are possible. These compounds are commercialized in the form or cis racemates which show a higher antifungal activity than the corresponding trans racemates.

The cis homochiral compounds of the present invention, which are intermediates for the preparation of enantiomerically pure antifungal drugs, have been prepared previously in the racemic form and transformed into the different azole antifungal drugs in the racemic form [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979). J . Med . Chem . , 26, 611 (1983), J . Med . Chem . , 27 , 894 (1984) and US 4,144,346, 4,223,036, 4,358,449 and 4,335,125].

Scheme 1 shows the synthesis described for racemic ketoconazole [J. Heeres et al., J . Med . Chem . , 22 , 1003 (1979)]. Scheme 1

)

The synthesis of racemic terconazole [J. Heeres et al., J. Med . Chem . , 26 , 611 11983)] is similar. differing in the introduction of a 1 H- 1 , 2,4-triazol-1-yl substituent in place of 1H-imidazol-1-yl and in the nature of the phenol used in the last step of the synthetic sequence, which phenol is 1-methylethyl-4-(4- hydroxyphenyl)piperazme instead of 1-acetyl-4-(4-nydroxyphenyl)piperazine.

The preparation of racemic itraconazole [J. Heeres et al., J. Med . Chem. , 27 , 894 (1984)] is similar to that of terconazole, differing only in the nature of the phenol used in the last step of the synthetic sequence.

In the class of azoles containing a 1,3-dioxolane ring and a piperazine ring and moreover they are pure enantiomers, only the preparation of (+)- and (-)-ketoconazole has been described [D. M. Rotstein et al., J. Med . Chem . , 35, 2818 (1992)] (Scheme 2) starting from the tosylate of (+)- and (-) 2,2-dimethyl-1,3-dioxolane-4-methanol.

Scheme 2

This synthesis suffers from a series of drawbacks, namely: a) the use of expensive, high molecular weight starting products which are available only on a laboratory scale, and b) the need for several chromatographies during the process in order to obtain products of suitable purity, which maKes said synthesis economically unattractive and difficult to apply industrially.

Recently (N. M. Gray, WO 94/14447 and WO 94/14446) the use of (-)-ketoconazole and (+)-ketoconazole as antifungal drugs causing less side-effects than (±)-ketoconazole has been claimed.

The industrial preparation of enantiomerically pure antifungal drugs with a high antifungal activity and less side-effects is however a problem in therapy. The present invention provides novel homochiral compounds which are intermediates for the industrial preparation of already known, enantiomerically pure antifungal drugs such as ketoconazole enantiomers, or of others which have not yet been reported in literature, which are described first in the present invention, such as (+)-terconazole and (-)-terconazoie, which show the cited antifungal action, allowing to attain the same therapeutical effectiveness using lower dosages than those required for racemic terconazole

Example 14 : (2S,4R)-(-)-1-acetyl-4-[4-[ [2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)-methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine, (2S,4R) -(- )-ketoconazole.

This compound is prepared following the process described above for (2R,4S)-(+)-ketoconazole. Starting from HNa (60-65% dispersion in paraffin, 32 mg, 0.80 mmol), 1-acetyl-4-(4-hydroxyphenyl)piperazine (153 mg, 0.69 mol) and (2S,4S)-(-)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH₃) (250 mg, 0.61 mmol), upon crystallization from an acetone:ethyl acetate mixture, (2S,4R) -(-)-ketoconazole is obtained [(2S,4R)-V Ar = 2,4-dichlorophenyl, Y = CH, Z = COCH₃] (196 mg, 61% yield) as a solid, m.p. 153-155ºC (lit. 155-157ºC); [α]_D ²⁰ = -10.50 (c = 0.4, CHCl₃) (lit. [α]_D ²⁵ = -10.58. c = 0.4, CHCl₃) with e.e. > 99% (determined by HPLC using the chiral stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1 % diethylamine as the eluent).

Figure imgf000007_0001

+ KETOCONAZOLE…. UNDESIRED

Example 7: (2 R ,4S)-(+)-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane-4-yl]methoxy]phenyl]piperazine (22, 4 S)-(+)-ketoconazole.

To a suspension of NaH (dispersed in 60-65% paraffin, 19.2 mg, 0.48 mmol) in anhydrous DMSO (3 ml),

1-acetyl-4-(hydroxyphenyl)piperazine (102 mg, 0.46 mmol) is added and the mixture is stirred for 1 hour at room temperature. Then, a solution of (2R,4R) – (+)-IV (Ar = 2,4-dichlorophenyl, Y = CH, R = CH₃) (160 mg, 0.39 mmol) in anhydrous DMSO (5 ml) is added, and the mixture is heated at 80ºC for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with water

(20 ml) and extracted with CH₂Cl₂ (3 × 25 ml). The combined organic phases are washed with water (3 × 25), dried with Na₂SO₄ and the solvent is evaporated off under vacuum. The oily residue thus obtained is crystallized from an acetone:ethyl acetate mixture to give (2R,4S)-(+)-ketoconazole ( (2R, 4 S) -V , Ar 2,4-dichlorophenyl, Y = CH , Z = COCH₃ ) ( 110 mg , 5 3 % yie ld ) as a white solid, m.p. 155-156°C (lit. 154-156ºC), [α]_D ²⁰ = + 8.99 (c = 0.4, CHCl₃) (lit. [α]_D ²⁵ = + 8.22, c = 0.4, CHCl₃), with e.e. > 99% (determined by HPLC using the chirai stationary phase CHIRALCEL OD-H and ethanol:hexane 1:1 mixtures containing 0.1% of diethylamine, as the eluent; (+)-Ketoconazole retention time 73,28 min. (-)-Ketoconazole, retention time 79.06 min).

IR (KBr), ʋ : 2875, 1645, 1584, 1511, 1462, 1425, 1250, 103S, 313 cm^-1.

¹H NMR (500 MHz, CDCl₃), δ : 2.12 (s, 3H, COCH₃),

3.02 (m, 2H, 3-H₂), 3.05 (m, 2H, 5-H₂), 3.27 (dd, J= 9.5

Hz, J’=7.0 Hz, 1H) and 3.70 (dd, J=9.5 Hz, J’=5.0 Hz, 1 H) (4″-CH₂), 3.60 (m, 2H, 6-H₂), 3.76 (m, 2H, 2-H₂), 3.73 (dd, J=8.0 Hz, J’=5.0 Hz, 1H) and 3.86 (dd, J=8.0 Hz, J’=6.5 Hz, 1H) (5″-H₂), 4.34 (m, 1H, 4″-H), 4.40 (d, J=15.0 Hz, 1H) and 5.00 (d, J=15.0 Hz, 1H) (CH₂-N), 4.34

(m, 1H, 4″-H), 6.76 [d, J = 9.0 Hz, 2H, 2′(C6′ )-H], 6.88

[d, J=9.0 Hz, 2H, C3′(C5)-H], 6.96 (s, 1H, imidazole 5- H), 6.99 (s, 1H, imidazole 4-H), 7.25 (dd, J=8.5 Hz, J’=2.0 Hz, 1H, 5″‘-H), 7.46 (d, J=2.0 Hz, 1H, 3″‘-H),

7.53 (s, 1H, imidazole 2-H), 7.57 (d, J=8.5 Hz, 1H,

6″‘-H).

¹³C NMR (75.4 MHz, CDCI₃), δ : 21.3 (CH₃, COCH₃), 41.4 (CH₂, C₂), 46.3 (CH₂, C6), 50.6 (CH₂, C3), 51.0 (CH₂, C5), 51.2 (CH₂, CH₂-N), 67.6 [CH₂, C5″ and 4″-CH₂), 74.7 (CH, C4″), 108.0 (C, C2″), 115.2 [CH, C2′(6′)], 118.8 [CH, C3′(5′)], 121.2 (CH, imidazole C5), 127.2 (CH, C5″‘), 128.5 (CH, imidazole C4), 129.5 (CH, C6′”), 131.3 (CH, C3″‘), 133.0 (C, C2″‘), 134.6 (C, C1′”), 135.8 (C, C4″‘), 138.8 (CH, imidazole C2), 145.6 (C, C1′), 152.8 (C, C4’), 168.9 (C, CO).

…………………………

Experimental and theoretical analysis of the interaction of (+/-)-cis-ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid
J Pharm Sci 1999, 88(6): 599

Experimental and theoretical analysis of the interaction of (±)-cis-ketoconazole with β-cyclodextrin in the presence of (+)-l-Tartaric acid (pages 599–607)

Enrico Redenti, Paolo Ventura, Giovanni Fronza, Antonio Selva, Silvia Rivara, Pier Vincenzo Plazzi and Marco Mor

Article first published online: 12 JUN 2000 | DOI: 10.1021/js980468o

http://onlinelibrary.wiley.com/doi/10.1021/js980468o/pdf

¹H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using β-cyclodextrin in the presence of (+)-l-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by ¹H and ¹³C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.

WO1993019061A1 *	Mar 10, 1993	Sep 30, 1993	Janssen Pharmaceutica Nv	Itraconazole and saperconazole stereoisomers
WO1994025452A1 *	Apr 28, 1994	Nov 10, 1994	Ashit K Ganguly	Process for preparing intermediates for the synthesis of antifungal agents
EP0050298A2 *	Oct 13, 1981	Apr 28, 1982	Hoechst Aktiengesellschaft	1-(1,3-Dioxolan-2-ylmethyl) azoles, process for their preparation and their use
EP0052905A1 *	Nov 19, 1981	Jun 2, 1982	Janssen Pharmaceutica N.V.	Novel (2-aryl-4-phenylthioalkyl-1,3-dioxolan-2-yl-methyl)azole derivatives
US5208331 *	Jun 18, 1992	May 4, 1993	Syntex (U.S.A.) Inc.	Process for preparing 1,3-dioxolane derivatives

New drug discovery: Where are we heading to?

August 12, 2014 1:06 pm / 1 Comment on New drug discovery: Where are we heading to?

To start with the simplest one is Quantitative structure-activity relationship (QSAR) which is also referred to as 2D-QSAR sometimes. 3D-QSAR involving Comparative Molecular Field Analysis (CoMFA) and Comparative molecular similarity index analysis (CoMSIA) are extension of QSAR. QSAR is not able to take the three dimensional structure of a molecule into consideration due to absence of three-dimensional parameterization of structures. 3D-QSAR scores over QSAR in this respect. Docking studies throw more light on the binding modes of drugs with their target proteins but it is feasible only when the crystal structure of the target enzyme/protein is known with good resolution. Docking studies are also used for virtual screening of databases. But the ideal technique for virtual screening of compounds is through pharmacophore mapping and screening, especially when the structure of the target is not known. Very large databases can be first screened by pharmacophorebecause the technique is quite fast followed by screening of the positive hits using docking studies. Insilico designing of novel compounds can also be performed using deNovodesigning techniques subject to the condition that the target structure in known.

Yadav M R. New drug discovery: Where are we heading to?. J Adv Pharm Technol Res 2013;4:2-3

URL:
Yadav M R. New drug discovery: Where are we heading to?. J Adv Pharm Technol Res [serial online] 2013 [cited 2014 Aug 12];4:2-3. Available from: http://www.japtr.org/text.asp?2013/4/1/2/107493

http://www.japtr.org/article.asp?issn=2231-4040;year=2013;volume=4;issue=1;spage=2;epage=3;aulast=Yadav

Mirati Therapeutics Receives Orphan Designation from U.S. FDA for Mocetinostat in Diffuse Large B-Cell Lymphoma

August 12, 2014 3:48 am / Leave a comment

Mocetinostat

CAS 726169-73-9;

MGCD0103; MGCD-0103; MGCD 0103;

N-(2-AMINOPHENYL)-4-([[4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL]AMINO]METHYL)BENZAMIDE

N-(2-Amino-phenyl)-4-[(4-pyridin-3-pyrimidin-2-ylamino)-methyl]-benzamide

Molecular Formula: C₂₃H₂₀N₆O

Molecular Weight: 396.4445

SAN DIEGO, Aug. 11, 2014 /PRNewswire/ — Mirati Therapeutics, Inc. (NASDAQ: MRTX) today announced that the U.S. FDA has granted Orphan Drug Designation to mocetinostat, a spectrum selective HDAC inhibitor, for diffuse large B-cell lymphoma (DLBCL). In June, mocetinostat was granted Orphan Drug Designation as a treatment for myelodysplastic syndrome (MDS). Orphan drug designation is also being sought for bladder cancer patients with specific genetic alterations.

http://www.prnewswire.com/news-releases/mirati-therapeutics-receives-orphan-designation-from-us-food–drug-administration-for-mocetinostat-in-diffuse-large-b-cell-lymphoma-270737161.html

Identifiers
IUPAC name N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide
CAS number	726169-73-9
PubChem	9865515
ChemSpider	8041206
ChEMBL	CHEMBL272980
Jmol-3D images	Image 1


Properties
Molecular formula	C₂₃H₂₀N₆O
Molar mass	396.44 g mol⁻¹

Chemical structure for Mocetinostat

Mocetinostat (MGCD0103) is a benzamide histone deacetylase inhibitor undergoing clinical trials for treatment of various cancers including follicular lymphoma, Hodgkin’s lymphoma and acute myelogenous leukemia.^[1]^[2]^[3]

One clinical trial (for refractory follicular lymphoma) was temporarily put on hold due to cardiac problems but resumed recruiting in 2009.^[4]

In 2010 favourable results were announced from the phase II trial for Hodgkin’s lymphoma.^[5]

MGCD0103 has also been used as a research reagent where blockage of members of the HDAC-family of histone deacetylases is required.^[6]

Mechanism of action

It works by inhibiting mainly histone deacetylase 1 (HDAC1), but also HDAC2, HDAC3, and HDAC11.^[7]

About Mocetinostat

Mocetinostat is an orally-bioavailable, spectrum-selective HDAC inhibitor. Mocetinostat is enrolling patients in a Phase 2 dose confirmation study in combination with Vidaza as treatment for intermediate and high-risk MDS. Mirati also plans to initiate Phase 2 studies of mocetinostat as a single agent in patients with mutations in histone acetyl transferases in bladder cancer and DLBCL. Initial data from the Phase 2 studies is expected by the end of 2014. In addition to the ongoing Phase 2 clinical trials, mocetinostat has completed 13 clinical trials in more than 400 patients with a variety of hematologic malignancies and solid tumors.

About Mirati Therapeutics

Mirati Therapeutics is a targeted oncology company developing an advanced pipeline of breakthrough medicines for precisely defined patient populations. Mirati’s approach combines the three most important factors in oncology drug development – drug candidates with complementary and compelling targets, creative and agile clinical development, and a highly accomplished precision medicine leadership team. The Mirati team is using a proven blueprint for developing targeted oncology medicines to advance and maximize the value of its pipeline of drug candidates, including MGCD265 and MGCD516, which are orally bioavailable, multi-targeted kinase inhibitors with distinct target profiles, and mocetinostat, an orally bioavailable, spectrum-selective histone deacetylase inhibitor. More information is available at www.mirati.com.

In eukaryotic cells, nuclear DNA associates with histones to form a compact complex called chromatin. The histones constitute a family of basic proteins which are generally highly conserved across eukaryotic species. The core histones, termed H2A, H2B, H3, and H4, associate to form a protein core. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin.

Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones are subject to posttranslational acetylation of the α,ε-amino groups of N-terminal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HAT1). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin structure. Indeed, Taunton et al., Science, 272: 408-411 (1996), teaches that access of transcription factors to chromatin templates is enhanced by histone hyperacetylation. Taunton et al. further teaches that an enrichment in underacetylated histone H4 has been found in transcriptionally silent regions of the genome.

Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed histone deacetylases (HDACs). Grozinger et al., Proc. Natl. Acad. Sci. USA, 96: 4868-4873 (1999), teaches that HDACs are divided into two classes, the first represented by yeast Rpd3-like proteins, and the second represented by yeast Hda1-like proteins. Grozinger et al. also teaches that the human HDAC1, HDAC2, and HDAC3 proteins are members of the first class of HDACs, and discloses new proteins, named HDAC4, HDAC5, and HDAC6, which are members of the second class of HDACs. Kao et al., Genes & Dev., 14: 55-66 (2000), discloses HDAC7, a new member of the second class of HDACs. More recently, Hu et al. J. Bio. Chem. 275:15254-13264 (2000) and Van den Wyngaert, FEBS, 478: 77-83 (2000) disclose HDAC8, a new member of the first class of HDACs.

Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998), discloses that HDAC activity is inhibited by trichostatin A (TSA), a natural product isolated from Streptomyces hygroscopicus, and by a synthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida and Beppu, Exper. Cell Res., 177: 122-131 (1988), teaches that TSA causes arrest of rat fibroblasts at the G₁and G₂phases of the cell cycle, implicating HDAC in cell cycle regulation. Indeed, Finnin et al., Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cell growth, induce terminal differentiation, and prevent the formation of tumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905, EP 0847992, JP 258863/96, and Japanese Application No. 10138957, disclose benzamide derivatives that induce cell differentiation and inhibit HDAC. Delorme et al., WO 01/38322 and PCT/IB01/00683, disclose additional compounds that serve as HDAC inhibitors.

The molecular cloning of gene sequences encoding proteins with HDAC activity has established the existence of a set of discrete HDAC enzyme isoforms. Some isoforms have been shown to possess specific functions, for example, it has been shown that HDAC-6 is involved in modulation of microtubule activity. However, the role of the other individual HDAC enzymes has remained unclear.

These findings suggest that inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation and that HDAC inhibitors have great therapeutic potential in the treatment of cell proliferative diseases or conditions. To date, few inhibitors of histone deacetylase are known in the art.

………………..

http://www.google.com/patents/WO2011112623A1?cl=en

Mocetinostat (MGCD-0103)

N-(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl^^

…………………………

http://www.google.co.in/patents/US6897220

Example 426 Synthesis of N-(2-Amino-phenyl)-4-[(4-pyridin-3-pyrimidin-2-ylamino)-methyl]-benzamide

Step 1: Synthesis of 4-Guanidinomethyl-benzoic acid methyl ester Intermediate 1

The mixture of 4-Aminomethyl-benzoic acid methyl ester HCl (15.7 g, 77.8 mmol) in DMF (85.6 mL) and DIPEA (29.5 mL, 171.2 mmol) was stirred at rt for 10 min. Pyrazole-1-carboxamidine HCl (12.55 g, 85.6 mmol) was added to the reaction mixture and then stirred at rt for 4 h to give clear solution. The reaction mixture was evaporated to dryness under vacuum. Saturated NaHCO₃solution (35 mL) was added to give nice suspension. The suspension was filtered and the filter cake was washed with cold water. The mother liquid was evaporated to dryness and then filtered. The two solids were combined and re-suspended over distilled H₂O (50 ml). The filter cake was then washed with minimum quantities of cold H₂O and ether to give 12.32 g white crystalline solid intermediate 1 (77% yield, M+1: 208 on MS).

Step 2: Synthesis of 3-Dimethylamino-1-pyridin-3-yl-propenone Intermediate 2

3-Acetyl-pyridine (30.0 g, 247.6 mmol) and DMF dimethyl acetal (65.8 mL, 495.2 mmol) were mixed together and then heated to reflux for 4 h. The reaction mixture was evaporated to dryness and then 50 mL diethyl ether was added to give brown suspension. The suspension was filtered to give 36.97 g orange color crystalline product (85% yield, M+1: 177 on MS).

Step 3: Synthesis of 4-[(4Pyridin-3-pyrimidin-2-ylamino)-methyl]benzoic acid methyl ester Intermediate 3

Intermediate 1 (0.394 g, 1.9 mmol) and intermediate 2 (0.402 g, 2.3 mmol) and molecular sieves (0.2 g, 4A, powder, >5 micron) were mixed with isopropyl alcohol (3.8 mL). The reaction mixture was heated to reflux for 5 h. MeOH (50 mL) was added and then heated to reflux. The cloudy solution was filtrated over a pad of celite. The mother liquid was evaporated to dryness and the residue was triturated with 3 mL EtOAc. The suspension was filtrated to give 0.317 g white crystalline solid Intermediate 3 (52%, M+1: 321 on MS).

Step 4: Synthesis of N-(2-Amino-phenyl)-4-[(4-pyrymidin-2-ylamino)-methyl]-benzamide

Intermediate 3 (3.68 g, 11.5 mmol) was mixed with THF (23 mL), MeOH (23 mL) and H₂O (11.5 mL) at rt. LiOH (1.06 g, 25.3 mmol) was added to reaction mixture. The resulting reaction mixture was warmed up to 40° C. overnight. HCl solution (12.8 mL, 2N) was added to adjust pH=3 when the mixture was cooled down to rt. The mixture was evaporated to dryness and then the solid was washed with minimum quantity of H₂O upon filtration. The filter cake was dried over freeze dryer to give 3.44 g acid of the title compound (95%, M+1: 307 on MS).

Acid (3.39 g, 11.1 mmol) of the title compound, BOP (5.679 g, 12.84 mmol) and o-Ph(NH₂)₂(2.314 g, 21.4 mmol) were dissolved in the mixture of DMF (107 mL) and Et₃N (2.98 mL, 21.4 mmol). The reaction mixture was stirred at rt for 5 h and then evaporated to dryness. The residue was purified by flash column (pure EtOAc to 5% MeOH/EtOAc) and then interested fractions were concentrated. The final product was triturated with EtOAc to give 2.80 g of title product

(66%, MS+1: 397 on MS).

¹H NMR (400 MHz, DMSO-D₆) δ (ppm): 9.57 (s, 1H), 9.22 (s, 1H), 8.66 (d, J=3.5 Hz, 1H), 8.39 (d, J=5.1 Hz, 2H), 8.00 (t, J=6.5 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.50 (m, 3H), 7.25 (d, J=5.1 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 6.94 (dd, J=7.0, 7.8 Hz, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.57 (dd, J=7.0, 7.8 Hz, 1H), 4.86 (s, 2H), 4.64 (d, J=5.9 Hz, 2H).

References

“Pharmion Corporation (PHRM) Release: Clinical Data On Oncology HDAC Inhibitor MGCD0103, Presented At The American Society of Clinical Oncology 42nd Annual Meeting” (Press release). Colorado, United States: BioSpace. June 6, 2006.
Gelmon, K.; Tolcher, A.; Carducci, M.; Reid, G. K.; Li, Z.; Kalita, A.; Callejas, V.; Longstreth, J. et al. (2005). “Phase I trials of the oral histone deacetylase (HDAC) inhibitor MGCD0103 given either daily or 3x weekly for 14 days every 3 weeks in patients (pts) with advanced solid tumors”. J. Clin. Oncol. 2005 ASCO Annual Meeting. 23 (16S). 3147.
MethylGene to Resume Development of its HDAC Inhibitor, MGCD0103 (Mocetinostat), Sept 2009
“METHYLGENE TO RESUME DEVELOPMENT OF ITS HDAC INHIBITOR, MGCD0103 (MOCETINOSTAT)”. 21 Sep 2009.
“Final Phase 2 Clinical Data for Mocetinostat (MGCD0103) in Relapsed/Refractory Hodgkin Lymphoma Patients”. 6 Dec 2010.
Pfefferli, Catherine; Müller, Fritz; Ja¿wi¿ska, Anna; Wicky, Chantal (2014). “Specific NuRD components are required for fin regeneration in zebrafish”. BMC Biol. 12 (30). doi:10.1186/1741-7007-12-30. PMID 24779377.
MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

US2009076021	3-20-2009	THERAPEUTIC COMBINATIONS AND METHODS FOR CARDIOVASCULAR IMPROVEMENT AND TREATING CARDIOVASCULAR DISEASE
US2008242648	10-3-2008	COMBINATION OF ERa+ LIGANDS AND HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF CANCER
US2007292351	12-21-2007	Assay for efficacy of histone deacetylase inhibitors
US6897220	5-25-2005	Inhibitors of histone deacetylase

US8110550	2-8-2012	HDAC INHIBITORS AND HORMONE TARGETED DRUGS FOR THE TREATMENT OF CANCER
US2011129456	6-3-2011	Sequential Administration of Chemotherapeutic Agents for Treatment of Cancer
US2011104256	5-6-2011	METHODS FOR TREATING OR PREVENTING COLORECTAL CANCER
US7868204	1-12-2011	Inhibitors of histone deacetylase
US7868205	1-12-2011	Inhibitors of Histone Deacetylase
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US2010056522	3-5-2010	INTRAOCULAR PRESSURE-LOWERING AGENT COMPRISING COMPOUND HAVING HISTONE DEACETYLASE INHIBITOR EFFECT AS ACTIVE INGREDIENT
US2009149511	6-12-2009	Administration of an Inhibitor of HDAC and an mTOR Inhibitor
US2009131367	5-22-2009	Combinations of HDAC Inhibitors and Proteasome Inhibitors
US2009124631	5-15-2009	Combination Therapy

SEE COMPILATION ON SIMILAR COMPOUNDS AT …………..http://drugsynthesisint.blogspot.in/p/nostat-series.html

EMA grants orphan drug designations to Alnylam’s ALN-AT3 for haemophilia treatment

August 11, 2014 3:21 am / Leave a comment

EMA grants orphan drug designations to Alnylam’s ALN-AT3 for haemophilia treatment
Biopharmaceutical company Alnylam Pharmaceuticals has received orphan drug designations for ALN-AT3 from the European Medicines Agency (EMA) Committee to treat haemophilia A and B

SEE

http://www.pharmaceutical-technology.com/news/newsema-grants-orphan-drug-designations-alnylams-aln-at3-hemophilia-treatment-4338904?WT.mc_id=DN_News

May 13,2014

Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced today positive top-line results from its ongoing Phase 1 trial of ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD). These top-line results are being presented at the World Federation of Hemophilia (WFH) 2014 World Congress being held May 11 – 15, 2014 in Melbourne, Australia. In Part A of the Phase 1 study, human volunteer subjects received a single subcutaneous dose of ALN-AT3 and, per protocol, the maximum allowable level of AT knockdown was set at 40%. Initial results show that a single, low subcutaneous dose of ALN-AT3 at 0.03 mg/kg resulted in an up to 28-32% knockdown of AT at nadir that was statistically significant relative to placebo (p < 0.01 by ANOVA). This led to a statistically significant (p < 0.01) increase in peak thrombin generation, that was temporally associated and consistent with the degree of AT knockdown. ALN-AT3 was found to be well tolerated with no significant adverse events reported. With these data, the company has transitioned to the Multiple Ascending Dose (MAD) Part B of the study in moderate-to-severe hemophilia subjects. Consistent with previous guidance, the company plans to present initial clinical results from the Phase 1 study, including results in hemophilia subjects, by the end of the year. These human study results are the first to be reported for Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency, durability, and a wide therapeutic index. Further, these initial clinical results demonstrate a greater than 50-fold potency improvement with ESC-GalNAc conjugates relative to standard template chemistry conjugates.

“We are excited by these initial positive results for ALN-AT3 in the human volunteer ‘Part A’ of our Phase 1 study. Indeed, within the protocol-defined boundaries of single doses that provide no more than a 40% knockdown of AT in normal subjects, we were able to demonstrate a statistically-significant knockdown of AT of up to 28-32% and an associated increase in thrombin generation. Remarkably, this result was achieved at the lowest dose tested of 0.03 mg/kg, demonstrating a high and better than expected level of potency for ALN-AT3, our first ESC-GalNAc conjugate to enter clinical development,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “With these results in hand, we are now proceeding to ‘Part B’ of the study, where we will administer multiple ascending doses to up to 18 patients with moderate-to-severe hemophilia A or B. Patients will receive three weekly doses, and we fully expect to achieve robust levels of AT knockdown as we dose escalate. In addition, we will aim to evaluate a once-monthly dosing regimen in future clinical studies, as we believe this could provide a highly attractive prophylactic regimen for patients. We look forward to sharing our detailed Phase 1 results, including data in hemophilia subjects, later this year, consistent with our original guidance.”

“There are several notable implications of these exciting initial results with ALN-AT3. First, ALN-AT3 now becomes the fourth program in our ‘Alnylam 5×15’ pipeline to demonstrate clinical activity. As such, these results increase our confidence level yet further across the entirety of our pipeline efforts, where we remain focused on genetically defined, liver-expressed disease targets with a modular and reproducible delivery platform. Moreover, these results with ALN-AT3 establish human proof of concept for our ESC-GalNAc conjugate technology, extending and broadening the human results we have previously shown with ALN-TTRsc which employs our standard template chemistry. Our ESC-GalNAc conjugate technology enables subcutaneous dosing with increased potency and durability and a wide therapeutic index, and has now become our primary approach for the delivery of RNAi therapeutics,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Finally, the achievement of target knockdown at such a low dose of 0.03 mg/kg is unprecedented. Based on our evaluation of datasets from non-human primate (NHP) and human studies, these results demonstrate a 10-fold improved potency for ALN-AT3 as compared with NHP and a 50-fold improved potency in humans as compared with ALN-TTRsc. Based on data we announced earlier this week at TIDES, we believe that this increased potency is the combined result of enhanced stability for ESC-GalNAc conjugates and an attenuated nuclease environment in human tissue compared with other species. If these results extend to other ESC-GalNAc-siRNA conjugates, such as those in our complement C5 and PCSK9 programs, we believe we can expect highly potent clinical activities with very durable target knockdown effects.”

The ongoing Phase 1 trial of ALN-AT3 is being conducted in the U.K. as a single- and multi-dose, dose-escalation study comprised of two parts. Part A – which has now been completed – was a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, intended to enroll up to 24 healthy volunteer subjects. The primary objective of this part of the study was to evaluate the safety and tolerability of a single dose of ALN-AT3, with the potential secondarily to show changes in AT plasma levels at sub-pharmacologic doses. This part of the study evaluated only low doses of ALN-AT3, with a dose-escalation stopping rule at no more than a 40% level of AT knockdown. Based on the pharmacologic response achieved in this part of the study, only the lowest dose cohort (n=4; 3:1 randomization of ALN-AT3:placebo) was enrolled. Part B of the study is an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate-to-severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses, specifically three doses, of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3; thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia (Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)). In this part of the study, dose-escalation will be allowed to proceed beyond the 40% AT knockdown level.

In addition to reporting positive top-line results from the Phase 1 trial with ALN-AT3, Alnylam presented new pre-clinical data with ALN-AT3. First, in a saphenous vein bleeding model performed in hemophilia A (HA) mice, a single subcutaneous dose of ALN-AT3 that resulted in an approximately 70% AT knockdown led to a statistically significant (p < 0.0001) improvement in hemostasis compared to saline-treated HA mice. The improved hemostasis was comparable to that observed in HA mice receiving recombinant factor VIII. These are the first results in what can be considered a genuine bleeding model showing that AT knockdown with ALN-AT3 can control bleeding. Second, a number of in vitro studies were performed in plasma from hemophilia donors. Stepwise AT depletion in these plasma samples was shown to achieve stepwise increases in thrombin generation. Furthermore, it was shown that a 40-60% reduction of AT resulted in peak thrombin levels equivalent to those achieved with 10-15% levels of factor VIII in HA plasma and factor IX in hemophilia B (HB) plasma. These levels of factor VIII or IX are known to significantly reduce bleeding in hemophilia subjects. As such, these results support the hypothesis that a 40-60% knockdown of AT with ALN-AT3 could be fully prophylactic. Finally, a modified Activated Partial Thromboplastin Time (APTT) assay – an ex vivomeasure of blood coagulation that is significantly prolonged in hemophilia – was developed, demonstrating sensitivity to AT levels. Specifically, depletion of AT in HA plasma led to a shortening of modified APTT. This modified APTT assay can be used to routinely and simply monitor functional activity of AT knockdown in further ALN-AT3 clinical studies.

“The unmet need for new therapeutic options to treat hemophilia patients remains very high, particularly in those patients who experience multiple annual bleeds such as patients receiving replacement factor ‘on demand’ or patients who have developed inhibitory antibodies. Indeed, I believe the availability of a safe and effective subcutaneously administered therapeutic with a long duration of action would represent a marked improvement over currently available approaches for prophylaxis,” said Claude Negrier, M.D., head of the Hematology Department and director of the Haemophilia Comprehensive Care Centre at Edouard Herriot University Hospital in Lyon. “I continue to be encouraged by Alnylam’s progress to date with ALN-AT3, including these initial data reported from the Phase 1 trial showing statistically significant knockdown of antithrombin and increased thrombin generation, which has been shown to correlate with bleeding frequency and severity in hemophilia. I look forward to the advancement of this innovative therapeutic candidate in hemophilia subjects.”

About Hemophilia and Rare Bleeding Disorders

Hemophilias are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Hemophilia A is defined by loss-of-function mutations in Factor VIII, and there are greater than 40,000 registered patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function mutations in Factor IX, affects greater than 9,500 registered patients in the U.S. and E.U. Other Rare Bleeding Disorders (RBD) are defined by congenital deficiencies of other blood coagulation factors, including Factors II, V, VII, X, and XI, and there are about 1,000 patients worldwide with a severe bleeding phenotype. Standard treatment for hemophilia patients involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of people with severe hemophilia A will develop an antibody to their replacement factor – a very serious complication; these ‘inhibitor’ patients become refractory to standard replacement therapy. There exists a small subset of hemophilia patients who have co-inherited a prothrombotic mutation, such as Factor V Leiden, antithrombin deficiency, protein C deficiency, and prothrombin G20210A. Hemophilia patients that have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for Factor VIII or Factor IX treatment as part of their disease management. There exists a significant need for novel therapeutics to treat hemophilia patients.

About Antithrombin (AT)

Antithrombin (AT, also known as “antithrombin III” and “SERPINC1″) is a liver expressed plasma protein and member of the “serpin” family of proteins that acts as an important endogenous anticoagulant by inactivating Factor Xa and thrombin. AT plays a key role in normal hemostasis, which has evolved to balance the need to control blood loss through clotting with the need to prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss of certain procoagulant factors (Factor VIII and Factor IX, in the case of hemophilia A and B, respectively) results in an imbalance of the hemostatic system toward a bleeding phenotype. In contrast, in thrombophilia (e.g., Factor V Leiden, protein C deficiency, antithrombin deficiency, amongst others), certain mutations result in an imbalance in the hemostatic system toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines a novel strategy for improving hemostasis.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in several of Alnylam’s genetic medicine programs, including programs in clinical development.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15TM” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. As part of its “Alnylam 5×15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. Alnylam is also developing ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

Cefuroxime Axetil

August 9, 2014 7:48 am / Leave a comment

Figure 1 :Chemical structure of Cefuroxime Axetil

Cefuroxime Axetil

[6R- [6alpha, 7beta (Z)]] – 3 – [[(Aminocarbonyl) oxy] methyl] -7 – [[2-furanyl (methoxyimino) acetyl] amino] -8-oxo-5-thia-1- azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 1- (acetyloxy) ethyl ester

64544-07-6, 55268-75-2 (free acid), 56238-63-2 (Na salt)

Ceftin; Zinnat; Elobact; Zinat; Cefuroxime 1-acetoxyethyl ester; Bioracef; CXM-AX; Coliofossim; Celocid

CCI-15641

Trademarks: Ceftin (GSK); Cefurax (Betapharm); Cepazine (Sanofi-Synthelabo); Elobact (Cascan); Oraxim (Menarini); Zinat (GSK); Zinnat (GSK)

Percent Composition: C 47.06%, H 4.34%, N 10.98%, O 31.34%, S 6.28%

Antibacterial (Antibiotics); ?Lactams; Cephalosporins.

Molecular Formula: C₂₀H₂₂N₄O₁₀S Molecular Weight: 510.47448

Cefuroxime Axetil (1-(acetyloxy) ethyl ester of cefuroxime, is (RS)-1-hydroxyethyl (6R,7R)-7-[2-(2-furyl)glyoxyl-amido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylate, 7 ² -(Z)-(O-methyl-oxime), 1-acetate 3-carbamate.

Its molecular formula is C ₂₀ H ₂₂ N ₄ O ₁₀S, and it has a molecular weight of 510.48.

Cefuroxime Axetil is used orally for the treatment of patients with mild-to-moderate infections, caused by susceptible strains of the designated microorganisms.

Cefuroxime axetil is a second generation oral cephalosporin antibiotic. It was discovered by Glaxo now GlaxoSmithKline and introduced in 1987 as Zinnat.^[1] It was approved by FDA on Dec 28, 1987.^[2] It is available by GSK as Ceftin in US^[3] and Ceftum in India.^[4]

It is an acetoxyethyl ester prodrug of cefuroxime which is effective orally.^[5] The activity depends on in vivo hydrolysis and release of cefuroxime.

Cefuroxime is chemically (6R, 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-iminoacetamido] ceph-3-em-4-carboxylic acid and has the structural Formula II:

Cefuroxime axetil having the structural Formula I:

is the 1-acetoxyethyl ester of cefuroxime, a cephalosporin antibiotic with a broad spectrum of activity against gram-positive and gram negative micro-organisms.

This compound as well as many other esters of cefuroxime, are disclosed and claimed in U.S. Pat. No. 4,267,320. According to this patent, the presence of an appropriate esterifying group, such as the 1-acetoxyethyl group of cefuroxime axetil, enhances absorption of cefuroxime from the gastrointestinal tract, whereupon the esterifying group is hydrolyzed by enzymes present in the human body.

Because of the presence of an asymmetric carbon atom at the 1-position of the 1-acetoxyethyl group, cefuroxime axetil can be produced as R and S diastereoisomers or as a racemic mixture of the R and S diastereoisomers. U.S. Pat. No. 4,267,320 discloses conventional methods for preparing a mixture of the R and S isomers in the crystalline form, as well as for separating the individual R and S diastereoisomers.

The difference in the activity of different polymorphic forms of a given drug has drawn the attention of many workers in recent years to undertake the study on polymorphism. Cefuroxime axetil is the classical example of amorphous form exhibiting higher bioavailability than the crystalline form.

U.S. Pat. No. 4,562,181 and the related U.S. Pat. Nos. 4,820,833; 4,994,567 and 5,013,833, disclose that cefuroxime axetil in amorphous form, essentially free from crystalline material and having a purity of at least 95% aside from residual solvents, has a higher bioavailability than the crystalline form while also having adequate chemical stability.

These patents disclose that highly pure cefuroxime axetil can be recovered in substantially amorphous form from a solution containing cefuroxime axetil by spray drying, roller drying, or solvent precipitation. In each case, crystalline cefuroxime axetil is dissolved in an organic solvent and the cefuroxime axetil is recovered from the solution in a highly pure, substantially amorphous form.

Another U.S. Pat. No. 5,063,224 discloses that crystalline R-cefuroxime axetil which is substantially free of S-isomer is readily absorbed from the stomach and gastrointestinal tract of animals and is therefore ideally suited to oral therapy of bacterial infections.

According to this patent, such selective administration of R-cefuroxime axetil results in surprisingly greater bioavailability ability of cefuroxime, and thus dramatically reduces the amount of unabsorbable cefuroxime remaining in the gut lumen, thereby diminishing adverse side effects attributable to cefuroxime.

British Patent Specification No. 2,145,409 discloses a process for obtaining pure crystalline cefuroxime axetil and is said to be an improvement over British Patent Specification No. 1,571,683. Sodium cefuroxime is used as the starting material in the disclosed specification, which in turn, is prepared from either 3-hydroxy cefuroxime or cefuroxime.

Said process involves an additional step of preparing sodium cefuroxime, and therefore is not economical from commercial point of view.

CEFTIN (cefuroxime axetil) Tablets and CEFTIN (cefuroxime axetil) for Oral Suspension contain cefuroxime as cefuroxime axetil. CEFTIN (cefuroxime axetil) is a semisynthetic, broad-spectrum cephalosporin antibiotic for oral administration.

Chemically, cefuroxime axetil, the 1-(acetyloxy) ethyl ester of cefuroxime, is (RS)-1-hydroxyethyl (6R,7R)-7-[2-(2-furyl)glyoxyl-amido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylate, 7²-(Z)-(O-methyl-oxime), 1-acetate 3-carbamate. Its molecular formula is C₂₀H₂₂N₄O₁₀S, and it has a molecular weight of 510.48.

Cefuroxime axetil is in the amorphous form and has the following structural formula:

CEFTIN (cefuroxime axetil tablets) Structural Formula Illustration

CEFTIN (cefuroxime axetil) Tablets are film-coated and contain the equivalent of 250 or 500 mg of cefuroxime as cefuroxime axetil. CEFTIN (cefuroxime axetil) Tablets contain the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hydrogenated vegetable oil, hypromellose, methylparaben, microcrystalline cellulose, propylene glycol, propylparaben, sodium benzoate, sodium lauryl sulfate, and titanium dioxide.

CEFTIN (cefuroxime axetil) for Oral Suspension, when reconstituted with water, provides the equivalent of 125 mg or 250 mg of cefuroxime (as cefuroxime axetil) per 5 mL of suspension. CEFTIN (cefuroxime axetil) for Oral Suspension contains the inactive ingredients acesulfame potassium, aspartame, povidone K30, stearic acid, sucrose, tutti-frutti flavoring, and xanthan gum.

Cefuroxime axetil
Systematic (IUPAC) name

1-Acetoxyethyl (6R,7R)-3-[(carbamoyloxy)methyl]-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
Clinical data

Identifiers

PubChem	CID 6321416
ChemSpider	4882027
ChEMBL	CHEMBL1095930
Synonyms	Cefuroxime 1-acetoxyethyl ester
Chemical data
Formula	C₂₀H₂₂N₄O₁₀S
Mol. mass	510.475 g/mol

Table 2 :FT-IR peaks of pure Cefuroxime Axetil, urea, and physical mixture of Cefuroxime Axetil and urea

dsc

Figure 2 :Differential scanning calorimetry of Cefuroxime Axetil

http://www.google.com/patents/US5013833

Chemical structure for cefuroxime axetil

http://www.google.com/patents/US6833452

EXAMPLE 1

Dicyclohexylamine (17.2 g) in N,N-dimethylacetamide (50 ml) was added to a solution of cefuroxime acid (42.4 g) in N,N-dimethylacetamide (300 ml) at about −10° C. (R,S)1-Acetoxethylbromide (33.4 g) in N,N-dimethylacetamide (50 ml) was added to the above solution and the reaction mixture was stirred for 45 minutes at about −3 to 0° C. Potassium carbonate (1.1 g) was added to the reaction mixture and it was further stirred at that temperature for about 4 hours. The reaction mixture was worked up by pouring into it ethyl acetate (1.0 It), water (1.2 It) and dilute hydrochloric acid (3.5% w/w, 200 ml). The organic layer was separated and the aqueous layer was again extracted with ethyl acetate. The combined organic extracts were washed with water, dilute sodium bicarbonate solution (1%), sodium chloride solution and evaporated in vacuo to give a residue. Methanol was added to the residue and the crude product was precipitated by adding water.

The resulting precipitate was filtered off and recrystallized from the mixture of ethylacetate, methanol and hexane. The precipitated product was filtered, washed and dried to give pure crystalline cefuroxime axetil (42.5 g).

Assay (by HPLC on anhydrous basis)-98.2% w/w; Diastereoisomer ratio-0.53; Total related substances-0.48% w/w.

…………………………………

http://www.google.com/patents/EP1409492B1?cl=en

The present invention relates to an improved method for synthesis of cefuroxime axetil of formula (I) in high purity substantially free of the corresponding 2-cephem(Δ²)-ester of formule (II) and other impurities. The compound produced is valuable as a prodrug ester of the corresponding cephalosporin- 4-carboxylic acid derivative i. e. cefuroxime, particularly suitable for oral administration in various animal species and in man for treatment of infections caused by gram-positive and gram-negative bacteria.

BACKGROUND OF THE INVENTION

[0002]

One of the ways to improve the absorption of cephalosporin antibiotics which are poorly absorbed through the digestive tract is to prepare and administer the corresponding ester derivatives at the 4-carboxylic acid position. The esters are then readily and completely hydrolysed in vivoby enzymes present in the body to regenerate the active cephalosporin derivative having the free carboxylic acid at the 4-position.
[0003]

Among the various ester groups that can be prepared and administered only a selected few are biologically acceptable, in addition to possessing high antibacterial activity and broad antibacterial spectrum. Clinical studies on many such potential “prodrug esters” such as cefcanel daloxate (Kyoto), cefdaloxime pentexil tosilate (Hoechst Marion Roussel) and ceftrazonal bopentil (Roche), to name a few have been discontinued, while ceftizoxime alapivoxil ((Kyoto) in under Phase III clinical studies. The cephalosporin prodrug esters which have been successfully commercialised and marketed include cefcapene pivoxil (Flomox^® , Shionogi), cefditoren pivoxil (Spectracef^®, Meiji Seika), cefetamet pivoxil (Globocef^®, Roche), cefotiam hexetil (Taketiam^®, Takeda), cefpodoxime proxetil (Vantin^®, Sankyo), cefteram pivoxil (Tomiron^®, Toyama) and cefuroxime axetil (Ceftin^® and Zinnat^®, Glaxo Wellcome).
[0004]

Typically, such (3,7)-substituted-3-cephem-4-carboxylic acid esters represented by formula (I A) are synthesised by reacting the corresponding (3,7)-substituted-3- cephem-4-carboxylic acid derivative of formula (III A), with the desired haloester compound of formula (IV A) in a suitable organic solvent. The synthesis is summarised in Scheme-I, wherein in compounds of formula (I A), (II A), (III A) and (IV A) the groups R¹ and R² at the 3- and 7-positions of the β-lactam ring are substituents useful in cephalosporin chemistry ; R³ is the addendum which forms the ester function and X is halogen.

[0005]

However, the esterification reaction which essentially involves conversion of a polar acid or salt derivative to a neutral ester product invariably produces the corresponding (3,7)-substituted-2-cephem (Δ²)-4-carboxylic acid ester derivative of formula (II A) in varying amounts, arising out of isomerisation of the double bond from the 3-4 position to the 2-3 position as well as other unidentified impurities.
[0006]

It has been suggested [D. H. Bentley, et. al., Tetrahedron Lett., 1976, 41, 3739] that the isomerisation results from the ability of the 4-carboxylate anion of the starting carboxylic acid to abstract a proton from the 2-position of the 3-cephem-4-carboxylic acid ester formed, followed by reprotonation at 4-position to give the said Δ²-ester. It has also been suggested [R. B. Morin, et. al., J. Am. Chem. Soc., 1969, 91, 1401 ; R. B. Woodward, et. al., J. Am. Chem. Soc., 1966, 88, 852] that the equilibrium position for isomerisation is largely determined by the size of the ester addendum attached at the 4-carboxylic acid position.
[0007]
The 2-cephem-4-carboxylic acid esters of formula (II A) are not only unreactive as antibacterial agents but are undesired by-products. Pharmacopoeias of many countries are very stringent about the presence of the 2-cephem analogues in the finished sample of (3,7)-substituted-3-cephem-4-carboxylic acid esters and set limits for the permissible amounts of these isomers. Due to the structural similarity of the 2-cephem and 3-cephem analogues it is very difficult to separate the two isomers by conventional methods, such as chromatography as well as by fractional crystallisation. In addition to this removal of other unidentified impurities formed in the reaction, entails utilisation of tedious purification methods, thus overall resulting in,
1. a) considerable loss in yield, increasing the cost of manufacture and
2. b) a product of quality not conforming to and not easily amenable for upgradation to pharmacopoeial standards.
[0008]
Several methods are reported in the prior art for synthesis of cefuroxime axetil of formula (I) and various (3,7)-substituted-3-cephem-4-carboxylic acid esters of formula (I A), with attempts to minimise the unwanted Δ²-isomers formed in such reactions as well as conversion of the Δ²-isomer thus formed back to the desired Δ³– isomer. The prior art methods can be summarised as follows:
- i) US Patent No, 4 267 320 (Gregson et. al.) describes a method for synthesis of cefuroxime axetil comprising reaction of cefuroxime acid or its alkali metal salts or onium salts with (R,S)-1-acetoxyethyl bromide in an inert organic solvent selected from N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile and hexamethylphosphoric triamide at a temperature in the range of -50 to +1150° C. The patent mentions that when alkali metal salts, specially potassium salt of cefuroxime acid are employed the reaction can be carried out in a nitrile solvent in the presence of a crown ether. When cefuroxime acid is employed the reaction is carried out in the presence of a weak inorganic base such as sodium carbonate or potassium carbonate, which is added prior to the addition of the haloester. The patent further mentions that the use of potassium carbonate in conjunction with the haloester, specially the bromo or iodo ester is preferred since it helps to minimise the formation of the Δ²-isomer. Ideally, substantially equivalent amounts of cefuroxime acid and the base is employed.
  The US Patent No. 4 267 320 also describes methods, wherein the said esterification is carried out in the presence of an acid binding agent, which serve to bind hydrogen halide liberated in the reaction, thereby controlling the formation of the Δ²-isomer. The acid binding agents that are utilised include a tertiary amine base such as triethylamine or N, N-dimethylamine ; an inorganic base such as calcium carbonate or sodium bicarbonate and an oxirane compound such as ethylene oxide or propylene oxide.
  However, from the examples provided in the above patent the yield of cefuroxime axetil and other (3,7)-substituted-3-cephem-4-carboxylic acid esters obtained is found to be only of about 50%, implying formation of substantial amounts of impurities in the reaction. Indeed, when cefuroxime acid is reacted with (R,S)-1-acetoxyethyl bromide in the presence of 0.55 molar equivalents of sodium carbonate or potassium carbonate in N,N-dimethylacetamide as solvent, as per the process disclosed in this patent, it is found that substantial amounts of the Δ²-isomer in a proportion ranging from 10-22% is formed, in addition to other unknown impurities. Also, substantial amounts of the starting cefuroxime acid remains unreacted even after 5 hrs of reaction. Isolation of the product generally affords a gummy material, which resists purification even after repeated crystallisations.
  Moreover, the use of the acid binding agents mentioned in the above patent, specially tertiary amines and inorganic bases lead to cleavage of the β-lactam ring and also promote the undesired Δ²-isomerisation, thereby enhancing the level of impurities formed in the reaction.
- ii) GB Patent No. 2 218 094 describes a method by which the Δ²-isomers formed during esterification can be converted back to the desired Δ³-isomers. The method comprises of oxidation of the dihydrothiazine ring in the mixture of Δ²– and Δ³– cephalosporin acid esters to the corresponding sulfoxide derivatives with suitable oxidising agents, whereby the Δ²-isomer gets isomerised to the corresponding Δ³-isomer during oxidation and the Δ³– cephalosporin acid ester sulfoxide is isolated. The sulfide group is regenerated back by reduction of the sulfoxide function with suitable reducing agents.
  Typically, the oxidation is carried out using m-chloroperbenzoic acid and the reduction achieved by use of an alkali metal halide in presence of acetyl chloride in presence of an inert organic solvent or by use of a phosphorous trihalide.
  Although, this method provides the desired Δ³-isomers in good purity, it cannot be considered as an industrially feasible method since it involves a two step process of oxidation and reduction, isolation of the intermediate products at each stage and necessary purifications, all resulting in considerable loss of the desired product and increase in the cost of manufacture. Moreover, the use of acetyl halide and phosphorous trihalide in the reduction step cannot be applied to cephalosporin derivatives that are sensitive to these reagents.
  A similar method has been reported by Kaiser et. al. in J. Org. Chem., 1970, 35, 2430.
- (iii)Mobasherry et. al. in J. Org. Chem., 1986, 51, 4723 describe preparation of certain Δ³-cephalosporin-4-carboxylic acid esters by reaction of the corresponding 3-cephem-4-carboxylic acids (in turn prepared form the corresponding carboxylic acid alkali metal salts) with an haloester in presence of 1.1 eq of sodium carbonate in the presence 1.2-1.5 eq of an alkyl halide and in presence of a solvent comprising of a mixture of N,N-dimethylformamide and dioxane. The authors claim that the method provides of Δ³– cephalosporin-4-carboxylic acid esters unaccompanied by the corresponding Δ²-isomer.
  However, the method involves an additional step in that the starting 3-cephem-4-carboxylic acid ester derivatives are obtained from the corresponding alkali metal salts prior to reaction. In addition, longer reaction times of about 24 hrs coupled with the fact that it utilises dioxane, a potent carcinogen, not recommended by International Conference on Harmonisation (ICH) on industrial scale renders the method unattractive commercially.
  Moreover, on duplication of the method exactly as described in the article it is found that about 3-4% of the corresponding Δ²-isomer is indeed formed in the reaction in addition to other unidentified impurities. Also, substantial amounts of the starting cephalosporin carboxylic acid is recovered unreacted.
- (iv)Shigeto et. al. in Chem. Pharm. Bull., 1995, 43(11), 1998 have carried out the esterification of certain 7-substituted-3-cephem-4-carboxylic acid derivatives with 1-iodoethyl isopropyl carbonate in a solvent system containing a mixture of N, N-dimethylformamide and dioxane in a 3:5 ratio. A conversion to the corresponding 3-cephem- 4-carboxylate ester was achieved in only 34%, out of which the Δ²-isomer amounted to about 8%.
  Esterification of 7-formamido-3-(N,N-dimethylcarbamoyloxy)methyl-3-cephem-4-carboxylic acid sodium salt with a suitable haloester in presence of solvents such as N, N-dimethylacetamide and N, N-dimethylformamide, with formation of about 0.8 to 3.0% of the Δ²-isomer is also reported in the above article by Shigeto et. al. The 7-formamido group was cleaved under acidic conditions to give the corresponding 7-amino derivative contaminated with only about 0.4% of the corresponding Δ²-isomer. The minimisation of the percentage of Δ²-isomer is attributed to the relative unstability of 7-amino-2-cephem-4-carboxylic acid esters in acidic conditions, facilitating isomerisation of the 2-cephem intermediate to the 3-cephem derivative.
  However, the method does not have a general application, especially for synthesis of commercially valuable cephalosporin derivatives containing hydroxyimino or alkoxyimino substituents in the 7-amino side chain addendum, since these oxyimino functions exhibit a tendency to isomerise from the stable (Z)-configuration to the relatively undesirable(E)-configuration under acidic conditions. This would render separation of the two isomers cumbersome. Moreover, longer reaction times of about 18-20 hrs to effect the isomerisation of the double bond from the 2- position to the 3-position and use of toxic dioxane as solvent impose further limitations on the method.
  (v) Demuth et. al. in J. Antibiotics, 1991, 44, 200 have utilised the N, N-dimethylformamide-dioxane system in the coupling of 1-iodocephem-4-nitrobenzyl ester with naldixic acid sodium salt and recommend use of dioxane since it reduces the basicity of the quinolone carboxylate and lowers the polarity of the reaction medium.
  However, low yields of about 35% and use of toxic dioxane makes the method of little industrial application.
- (vi) Wang et. al. in US Patent No. 5 498 787 claim a method for preparation of certain (3,7)-substituted-3-cephem-4-carboxylic acid prodrug esters, unaccompanied by the analogous 2-cephem esters comprising reaction of the corresponding (3,7)-substituted-3-cephem-4-carboxylic acid alkali metal salts with suitable haloesters in the presence of catalytic amounts of a quaternary ammonium or quarternary phosphonium salt. Among the prodrug esters covered in this patent is cefuroxime axetil.
  US Patent No. 5 498 787 claims that among the quarternary ammonium salts, such salts with acid counter ion, specially tetrabutyl ammonium sulfate (TBA⁺HSO₄ ^–) is the most preferred. When the molar ratio of TBA⁺HSO₄ ^–/cefuroxime sodium was above 0.40 no Δ²-isomer was detected, when the said molar ratio was below 0.40 and near about 0.20 the molar ratio of Δ²/Δ³ isomers formed was about 2.0%. When no TBA⁺HSO₄ ^– was added the molar ratio of Δ²/Δ³ isomers formed was about 10.0%. Examples 1 and 2 of this patent illustrate the esterification of cefuroxime sodium in presence of TBA⁺HSO₄ ^– and indicate that the Δ²-isomer was not detected after 3-12 hours of reaction. The same patent also establishes the superiority of TBA⁺HSO₄ ^– over other salts, specially tetrabutyl ammonium iodide (TBA⁺I^–) since use of the latter salt resulted in considerable isomerisation of the double bond giving the undesired Δ²-isomer in predominant amounts.
  The present inventors have, however, found that when cefuroxime sodium is reacted with (R,S)- 1-acetoxyethyl bromide in the presence of tetrabutylammonium sulfate (TBA⁺HSO₄ ^–) as per the method covered in US Patent No. 5,498 787 the same did not necessarily result in the production of the desired Δ³isomer free of the undesired Δ² isomer and other impurities. Also, such process had limitations in that the reaction could not be completed at times even at the end of 5.0hrs. Moreover, the separation of the impurities; from the product proved cumbersome and could not be removed from the product even after successive crystallisations.
- (vii) H. W. Lee et. al., Syntheic Communications, 1998, 28(23), 4345-4354 have demonstrated a method essentially similar to that claimed in US Patent No. 5 498 787 . The method of preparation of various esters of cefotaxime consists of reacting cefotaxime sodium with the requisite haloester compound in a suitable solvent and in presence of quarternary ammonium salts as phase transfer catalysts. It is claimed that when no quarternary ammonium salts are added the molar ratio (%) of Δ²/Δ³ isomers formed is about 10%. The formation of Δ²– isomer is minimised when quarternary ammonium salts are added and particularly when the molar ratio of TBA⁺HSO₄ ^–/cefotaxime sodium employed is 0.80 the formation of the Δ²– isomer is completely inhibited.
  However, this method requires long hours (~18-24 hrs) and is carried out at higher temperatures (40-45° C) and as such may not be suitable for cephalosporin derivatives that are sensitive to heat.
- (viii)H. W. Lee et. al. in Synthetic Communications, 1999, 29(11), 1873-1887 demonstrate a method for preparation of number of (3,7)-substituted-3-cephem-4-carboxylic acid esters comprising reacting the corresponding (3,7)-substituted-3-cephem-4-carboxylic acid derivatives with a base selected form cesium carbonate or cesium bicarbonate either used alone or in combination with potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate. The authors established that the formation of Δ²– isomers could be minimised by utilisation of a solvent combination ofN, N-dimethyl formamide and dioxane. The use of the latter mentioned solvent i. e. dioxane was expected to lower polarity of the reaction medium and thereby reduce the basicity of the transient 3-cephem-4-carboxylate anion formed in the reaction and thus preventing the isomerisation of the double bond from the 3-4 position to the 2-3 position.
  The formation of the Δ²– isomer was found to be dependent on the amount of dioxane in the solvent mixture, the more the proportion of dioxane lesser the degree of isomerisation.
  However, yields of representative esters obtained by the method are in the range of 45-85 %, implying that the reaction is accompanied by formation of substantial amounts of impurities and that the isomerisation is dependent on the nature of the substituent at 3α-position of the cephalosporin nucleus as well as on the nature of the haloester employed. Moreover, the method utilises dioxane, not desirable for reasons mentioned herein earlier and expensive cesium salts. This method, therefore, also has limited application.
- (ix) Y.S. Cho et. al., in Korean J. Med. Chem., 1995, 5(1), 60-63 describe synthesis of several cephalosporin prodrug esters and their efficacy on oral administration. The esters were synthesised by reacting the corresponding cephalosporin-4-carboxylic acid derivative with the respective haloester derivative in presence of cesium carbonate and N, N-dimethylacetamide. The yields of the ester derivatives obtained are in the range of only 25-56%, indicating formation of substantial amounts of impurities in the reaction.

Example – 1

Preparation of (R, S -1-Acetoxyethyl-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (Cefuroxime axetil, I) :

Without use of GrouplI

II metal phosphate and C_1-4 alcohol

[0045]

(R, S)-1-Acetoxyethyl bromide (1.6gms; 0.0094moles) was added to a mixture of cefuroxime acid (2gms; 0.0047moles) and potassium carbonate (0.326gms; 0.00235moles) in N,N-dimethylacetamide (10 ml) at 5°C and stirred at 0 to 20° C for 180 minutes Ethyl acetate was added to the reaction mixture, followed by 3% aqueous sodium bicarbonate solution (15ml). The organic layer containing the title product, Δ² isomer (8.51%) and unidentified impurities (X₁-1.86% and X₂ – 3.54%) was separated and washed with 10% aqueous NaCl solution. The organic solvent was evaporated off under vacuum to give 1.08gms (44.90%) of the title compound as a gummy solid.
[0046]

HPLC analysis : Purity (compound I) – 89.11% ; Impurities : Δ² isomer (II) – 8.51%, X₁ – 1.86% and X₂ – 3.54%

………………………………..

The reaction of 3-hydroxymethyl-7- [2- (2-furyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid (I) with chlorosulfonyl isocyanate (II) and then with sodium 2-ethylhexanoate gives sodium cefuroxime (III), which is then treated with 1-bromoethyl acetate (IV) in DMA.

References

“Our history – About GSK”. GlaxoSmithKline.
http://www.drugs.com/monograph/cefuroxime-axetil.html
https://www.gsksource.com/gskprm/en/US/adirect/gskprm?cmd=ProductsByName#C
“Our products”. GlaxoSmithKline.
Walter Sneader. Drug Discovery: A History. John Wiley, Chichester, UK. ISBN 0-471-89979-8.

Literature References:

Prepn: M. C. Cook et al., DE 2439880; eidem, US 3974153 (1973, 1976 both to Glaxo).

Prepn of the 1-acetoxyethyl ester: M. Gregson, B. Sykes, DE 2706413; eidem, US 4267320 (1977, 1981 both to Glaxo).

In vitro studies: C. H. O’Callaghan et al., Antimicrob. Agents Chemother. 9, 511 (1976); R. N. Jones et al., ibid. 12, 47 (1977).

In vitro antibacterial activity, human pharmacokinetics: C. H. O’Callaghan et al., J. Antibiot. 29, 29 (1976).

Pharmacology: H. Freiesleben et al., Proc. 10th Int. Congr. Chemother., Zürich, 1977 (Am. Soc. for Microbiol., Washington, 1978) II, pp 873-874.

Pharmacokinetics: P. E. Gower, ibid. 877-878; J. Kosmidis et al., ibid. 875-876.

Clinical studies: P. F. Wood et al., ibid. 1042-1044; R. Norrby et al., J. Antimicrob. Chemother. 3, 355 (1977).

Review of antibacterial activity, pharmacology and therapeutic efficacy: R. N. Brogden et al., Drugs 17, 233-266 (1979).

Comprehensive description: T. J. Wozniak, J. R. Hicks, Anal. Profiles Drug Subs. 20, 209-236 (1991).

US6894162	5-18-2005	Intermediates in cephalosporin production
US6833452	12-22-2004	Process for the preparation of highly pure crystalline (R,S)-cefuroxime axetil

Cefuroxime

Title: Cefuroxime

CAS Registry Number: 55268-75-2

CAS Name: (6R,7R)-3-[[(Aminocarbonyl)oxy]methyl]-7-[[(2Z)-2-furanyl(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Additional Names: (6R,7R)-3-carbamoyloxymethyl-7-[2-(2-furyl)-2-(methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; (6R,7R)-3-carbamoyloxymethyl-7-[2-(2-furyl)-2-(methoxyimino)acetamido]ceph-3-em-4-carboxylic acid

Molecular Formula: C16H16N4O8S

Molecular Weight: 424.39

Percent Composition: C 45.28%, H 3.80%, N 13.20%, O 30.16%, S 7.56%

Properties: White crystalline solid. [a]D20 +63.7° (c = 1.0 in 0.2M pH 7 phosphate buffer). uv max (pH 6 phosphate buffer): 274 nm (e 17600).

Optical Rotation: [a]D20 +63.7° (c = 1.0 in 0.2M pH 7 phosphate buffer)

Absorption maximum: uv max (pH 6 phosphate buffer): 274 nm (e 17600)

Citing Patent	Filing date	Publication date	Applicant	Title
US5847118 *	Jul 25, 1997	Dec 8, 1998	Apotex, Inc.	Methods for the manufacture of amorphous cefuroxime axetil
US6060599 *	Jun 17, 1998	May 9, 2000	Ranbaxy Laboratories Limited	Process for the preparation of cefuroxime axetil in an amorphous form
US6107290 *	Sep 16, 1999	Aug 22, 2000	Hammi Pharm Co., Ltd.	Non-crystalline cefuroxime axetil solid dispersant, process for preparing same and composition for oral administration thereof
US6323193	Aug 21, 2000	Nov 27, 2001	Ranbaxy Laboratories Limited	Bioavailable oral dosage form of cefuroxime axetil
US6384213	May 19, 2000	May 7, 2002	Ranbaxy Laboratories Limited	Process for preparing a pure, pharmacopoeial grade amorphous form of cefuroxime axetil
US6534494	Jan 27, 1999	Mar 18, 2003	Ranbaxy Laboratories Limited	Process for the preparation of cefuroxime axetil in an amorphous form
US6833452	Jul 16, 2001	Dec 21, 2004	Ranbaxy Laboratories Limited	Process for the preparation of highly pure crystalline (R,S)—cefuroxime axetil
US6911441 *	Dec 16, 2002	Jun 28, 2005	Akzo Nobel N.V.	Prolonged release pharmaceutical composition
US7507813	Jul 22, 2005	Mar 24, 2009	Nanomaterials Technology Pte Ltd.	Amorphous cefuroxime axetil and preparation process therefore
CN1909889B	Jan 10, 2005	Jun 2, 2010	韩美药品株式会社	Cefuroxime axetil granule and process for the preparation thereof
EP1619198A1 *	Jul 14, 2005	Jan 25, 2006	Nanomaterials Technology Pte Ltd	Amorphous cefuroxime axetil and preparation process therefore
WO1999065919A1 *	Jan 27, 1999	Dec 23, 1999	Ranbaxy Lab Ltd	Process for the preparation of cefuroxime axetil in an amorphous form
WO2001010410A1 *	Jul 25, 2000	Feb 15, 2001	Hanmi Pharm Ind Co Ltd	Non-crystalline cefuroxime axetil solid dispersant, process for preparing same and composition for oral administration thereof
WO2003014126A1 *	Aug 1, 2002	Feb 20, 2003	Marco Alpegiani	Process for the preparation of highly pure cefuroxime axetil
WO2005065658A1 *	Jan 10, 2005	Jul 21, 2005	Hee Chul Chang	Cefuroxime axetil granule and process for the preparation thereof

Derivative Type: Sodium salt

CAS Registry Number: 56238-63-2

Trademarks: Anaptivan (Help); Biociclin (Del Saz & Filippini); Biofurex (Lenza); Bioxima (Ital. Suisse); Cefamar (Firma); Cefoprim (Esseti); Cefumax (Locatelli); Cefurex (Sarm); Cefurin (Magis); Curocef (GSK); Curoxim (Elan); Duxima (Dukron); Gibicef (Metapharma); Ipacef (IPA); Kefurox (Lilly); Kesint (Proter); Lampsporin (Von Boch); Medoxim (Medici); Novocef (Pliva); Spectrazole (Mallinckrodt); Ultroxim (Duncan Flockhart); Zinacef (GSK)

Molecular Formula: C16H15N4NaO8S

Molecular Weight: 446.37

Percent Composition: C 43.05%, H 3.39%, N 12.55%, Na 5.15%, O 28.67%, S 7.18%

Properties: White solid. [a]D20 +60° (c = 0.91 in water). uv max (water): 274 nm (e 17400). Freely sol in water and buffered solutions; sol in methanol; very slightly sol in ethyl acetate, diethyl ether, octanol, benzene and chloroform. Soly in water: 500 mg/2.5 ml. pKa (water): 2.5; (DMF): 5.1. Solns are stable at room temp for 13 hrs; <10% decompn in 48 hrs at 25° (O’Callaghan,J. Antibiot.).

pKa: pKa (water): 2.5; (DMF): 5.1

Optical Rotation: [a]D20 +60° (c = 0.91 in water)

Absorption maximum: uv max (water): 274 nm (e 17400)

The pharmacovigilance system in the European Union (EU)

August 9, 2014 3:25 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The pharmacovigilance system in the European Union (EU) operates with the management and involvement of regulatory authorities in Member States, the European Commission and the European Medicines Agency. In some Member States, regional centres are in place under the coordination of the national competent authority.

Within this system, the Agency’s role is to coordinate the EU pharmacovigilance system and to ensure the provision of advice for the safe and effective use of medicines.

More information

Pharmacovigilance (PV or PhV), also known as Drug Safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention ofadverse effects with pharmaceutical products.^[1] The etymological roots for the word “pharmacovigilance” are:

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World Hepatitis Day – European Medicines Agency uses regulatory tools to facilitate patient access to innovative medicines

August 9, 2014 3:12 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

25/07/2014

World Hepatitis Day – European Medicines Agency uses regulatory tools to facilitate patient access to innovative medicines

According to the World Health Organization External link icon (WHO), viral hepatitis kills 1.4 million people worldwide every year. That is as many as are killed by AIDS/HIV infections.

Viral hepatitis is caused by five different types of hepatitis viruses, hepatitis A, B, C, D and E, which can lead to the development of acute or chronic inflammation of the liver.

In Europe, hepatitis C virus (HCV) infection is a major public-health challenge. It occurs in between 0.4% and 3.5% of the population in different European Union (EU) Member States and is the most common reason for liver transplantation in the EU.

The treatment paradigm for chronic hepatitis C is currently shifting rapidly with the development of several new classes of direct-acting antivirals. These new medicines display high efficacy rates allowing patients with chronic HCV…

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Concept paper on good genomics biomarker practices

August 9, 2014 3:01 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Document details

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/08/WC500170682.pdf

Download document	Concept paper on good genomics biomarker practices
Reference number	EMA/CHMP/PGWP/415990/2014
Status	draft: consultation open
First published	04/08/2014
Last updated	04/08/2014
Consultation start date	04/08/2014
Consultation end date	04/11/2014
Email address for submissions	pgwpsecretariat@ema.europa.eu

Summary

Genomic data have become important to evaluate efficacy and safety of a drug for regulatory approval. As a result, genomic information has been increasingly included in drug labels relevant for the benefit/risk evaluation of a drug and consequently as guidance for patient treatment.

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Europe to boost cooperation with international partners on generics

August 9, 2014 2:54 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

07/08/2014

Europe to boost cooperation with international partners on generics

European system to be used as model to facilitate assessment of medicines

The European Union’s decentralised procedure is being used as a model to accelerate the assessment of applications for generic medicines as part of theInternational Generic Drug Regulators Pilot External link icon (IGDRP).

The European Union (EU) is leading an international pilot project through which, upon request from a generic pharmaceutical company, it will share the assessment reports generated as part of the decentralised procedure in real time with collaborating regulatory agencies outside the EU.

By offering to share its assessment reports, the EU aims to reinforce collaboration and information-sharing between regulatory authorities across the world, contributing to facilitating and strengthening the scientific assessment process for medicines. This should enable medicines to be authorised in different territories in a coordinated way at approximately the same time.

The first phase of the…

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Female viagra……….UK-414,495 is a drug developed by Pfizer for the treatment of female sexual arousal disorder

August 8, 2014 4:45 am / 1 Comment on Female viagra……….UK-414,495 is a drug developed by Pfizer for the treatment of female sexual arousal disorder

UK-414,495

Molecular Formula: C₁₆H₂₅N₃O₃S

Molecular Weight: 339.453

UK 414495

CAS 388630-36-2

(-)-(2R)-2-[[1-[[(5-Ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl]cyclopentyl]methyl]pentanoic acid;

AND

Cyclopentanepropanoic acid, 1-[[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl]-α-propyl-, (αR)-

((R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl) carbamoyl]cyclopentyl}methyl) valeric acid)

(2R)-2-[(1-{[(5-Ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl) methyl]pentanoic acid

…………………………………………………

Cas 337962-93-3 RACEMIC…………2-[[1-[[(5-Ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl]cyclopentyl]methyl]pentanoic acid

…………………………………………………………………..

ITS ENANTIOMER

(+)-(2S)-2-[[1-[[(5-Ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl]cyclopentyl]methyl]pentanoic acid……………337962-74-0

Pfizer Inc.

CAS SUMMARY

Cas number

388630-36-2
337962-74-0 (enantiomer)
337962-93-3 (racemate)
388630-59-9 (sodium salt)

desired

UK-414,495 is a drug developed by Pfizer for the treatment of female sexual arousal disorder.^[1] UK-414,495 acts as a potent, selective inhibitor of the enzyme neutral endopeptidase, which normally serves to break down the neuropeptide VIP. The consequent increase in VIP activity alters blood flow to the genital region leading to increased lubrication and muscle relaxation.^[2]^[3]^[4]

Female sexual arousal consists of a number of physiological responses resulting from increased genital blood. Vasoactive intestinal peptide (VIP), neuropeptide Y and to a lesser extent nitric oxide are neurotransmitters found in the vasculature of the genitalia. Neutral endopeptidase (NEP) modulates the activity of neuropeptides including VIP.

The aim of this study was to investigate the control of genital blood flow by VIP and endogenous neuropeptides using a selective NEP inhibitor [UK-414,495, ((R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl) carbamoyl]cyclopentyl}methyl) valeric acid)].

A female equivalent of Viagra could soon be available to help women increase their sexual arousal, scientists claim.

For years they have endeavoured to create an alternative for women that mimics the effects of the male Viagra pill.

Now, the pharmaceutical company behind the original pill has created a prototype which increases blood flow to the genitalia in a similar way to Viagra.

Pfizer have come up with a prototype version of the female equivalent of Viagra

More than half of women experience sexual dysfunction at some point in their lives.

They may suffer a lack of desire, emotional or mental health problems and physical problems that mean they avoid having sex.

Pharmaceutical giant Pfizer has developed a drug, so far called only UK-414,495, which is supposed to increase sexual arousal, but will not affect desire, mood or emotional problems.

Some women take Viagra with mixed results and the drug has been used in fertility treatment to increase blood flow to the pelvis and encourage an embryo to implant in the womb.

But this is the first pill that claims to be an equivalent of the male Viagra.

The research, which involved animals, is published by the British Journal of Pharmacology, though Pfizer say they won’t develop the drug and warn that the chemical may not work the same way in humans, according to the Telegraph.

Chris Wayman, the lead researcher, said: ‘Before this work, we knew surprisingly little about the processes that control all of these changes.

Pfizer claim the tablets may help overcome female sexual arousal disorder

‘Now that we are beginning to establish the pathways involved in sexual arousal, scientists may be able to find ways of helping women who would like to overcome female sexual arousal disorder.

‘While the particular chemical compound in this research did not prove appropriate for further developments, the implications of the research could lead to the development of a product in the future.’

Viagra was originally developed as a treatment for high blood pressure and the heart condition angina, but men who took part in early trials realised the drug had an interesting side effect.

Clinical trials suggested the drug had little effect on angina and instead induced erections in men.

The drug first went on sale in 1998 and has since been prescribed to 25million men, creating a multi-billion pound global market.

The name Viagra has become so associated with men’s erectile problems that many cures are marketed as ‘herbal viagra’.

It is known by many nicknames, including Vitamin V and the Blue Pill.

Read more: http://www.dailymail.co.uk/health/article-1265842/Female-Viagra-help-women-increase-sexual-arousal.html#ixzz39lkmpSik
…………………………………

scheme

http://www.google.com/patents/US20020052370

Figure US20020052370A1-20020502-C00014

Figure US20020052370A1-20020502-C00015

Figure US20020052370A1-20020502-C00017

Figure US20020052370A1-20020502-C00018

Ex	Prec	n	Y	Data







4³	Prep 37	0		¹H NMR (CDCl₃, 400 MHz) δ: 0.92 (t, 3H), 1.35 (t, 3H), 1.25-1.80 (m, 11H), 2.20-2.50 (m, 4H), 2.95 (q, 2H), 12.10 (bs, 1H); LRMS: m/z 339.8 (MH⁺) Anal. Found: C, 56.46; H, 7.46; N, 12.36. C₁₆H₂₅N₃O₃S requires C, 56.62; H, 7.44; N, 12.37%.

Example 29 (2R)-2-[(1-{[(5-Ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl) methyl]pentanoic acid

[0354]

desired

[0355] and

Example 30 (2S)-2-[(1-{[(5-Ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl) methyl]pentanoic acid

[0356]

undesired

[0357] The acid from Example 4 (824 mg) was further purified by HPLC using an AD column and using hexane:iso-propanol:trifluoroacetic acid (85:15:0.2) as eluant to give the title compound of example 29 as a white foam, 400 mg, 99.5% ee, ¹H NMR (CDCl₃, 400 MHz) δ: 0.90 (t, 3H), 1.36 (m, 6H), 1.50-1.80 (m, 9H), 2.19 (m, 1H), 2.30 (m, 1H), 2.44 (m, 1H), 2.60 (m, 1H), 2.98 (q, 2H), 12.10-12.30 (bs, 1H), LRMS: m/z 338 (MH⁻), [α]_D=−9.0°(c=0.1, methanol),

and

the title compound of example 30 as a white foam, 386 mg, 99% ee, ¹H NMR (CDCl₃, 400 MHz) δ: 0.90 (t, 3H), 1.38 (m, 6H), 1.50-1.79 (m, 9H), 2.19 (m, 1H), 2.30 (m, 1H), 2.44 (m, 1H), 2.60 (m, 1H), 2.98 (q, 2H), 12.10-12.27 (bs, 1H);

[0358] LRMS: m/z 338 (MH⁻); and [α]_D=+3.8°(c=0.1, methanol).

[0359] Alternatively, Example 29 may be prepared as follows:

[0360] To a solution of the product from Preparation 51a (574 g, 1.45 mol) in dichloromethane (2.87 L) was added trifluoroacetic acid (1.15 L) over a period of 50 minutes with cooling at 10° C. After addition was complete, the reaction was allowed to warm to ambient temperature with stirring under a nitrogen atmosphere for 24 hours. Deionised water (2.6 L) was then added. The reaction mixture was then washed with deionised water (3×2.6 L). The dichloromethane layer was concentrated to a volume of approximately 1 L to give the crude title compound (439 g, 1.29 mol, 96% yield) as a solution in dichloromethane. A purified sample of the title compound was obtained using the following procedure. To a dichloromethane solution (2.34 L) of the crude product, that had been filtered to remove any particulate contamination, was added isopropyl acetate (1.38 L). The resultant mixture was distilled at atmospheric pressure whilst being simultaneously replaced with isopropyl acetate until the solution temperature reached 87° C. The heating was stopped and the solution was allowed to cool to ambient temperature with stirring for 14 hours to give a cloudy brown solution. The agitation rate was then increased and crystallisation commenced. The suspension was then allowed to granulate for 12 hours at ambient temperature. The resultant suspension was then cooled to 0° C. for 3.5 hours and the solid was then collected by filtration. The filter cake was then washed with isopropyl acetate (2×185 ml, then 2×90 ml) and the solid was dried under vacuum at 40-45° C. for 18 hours to give the title compound (602 g, 0.18 mol, 70% yield) as a cream coloured, crystalline solid;

m.p.: 130-136° C.;

LRMS (negative APCI): m/z [M−H]⁻ 338;

¹H-NMR (CDCl₃, 300 MHz) δ: 0.92 (t, 3H), 1.27-1.52 (m, 7H), 1.52-1.89 (m, 8H), 2.11-2.27 (m, 1H), 2.27-2.37 (m, 1H), 2.42-2.55 (m, 1H), 2.65 (dd, 2H), 3.00 (q, 2H), 12.25 (bs, 1H).

[0361] Example 29 may be purified as follows:

[0362] The title product from Example 29 was disolved in methanol. To this solution was added sodium methoxide (1 equivalent) in methanol (1 ml/g of Example 29) and the mixture was stirred at room temperature for 20 minutes. The solvent was removed in vacuo and the residue was azeotoped with ethyl acetate to give a brown residue. Ethyl acetate was added and the solution filtered to give a brown solid which was washed with tert-butylmethyl ether to give the crude sodium salt of Example 29. This crude product (35 g) was partitioned between water (200 ml) and ethyl acetate (350 ml). Concentrated hydrochloric acid (˜7 ml) was added until the pH of the aqueous layer was pH2. The aqueous phase was washed with ethyl acetate (2×100 ml). The combined layers were dried using magnesium sulphate. The solvent was removed in vacuo to give a light brown solid (31 g). Ethyl acetate (64 ml, 2 ml/g) and diisopropyl ether (155 ml, 5 ml/g) were added and the mixture heated to 68° C. until a clear solution was obtained (˜30 min). Upon cooling to room temperature, crystallisation of the free acid occurred. After 30 minutes stirring at room temperature the product was collected by filtration and washed with diisopropyl ether. The product was dried in a vacuum oven at 50° C. overnight. (20.2 g, 61% recovery from the sodium salt.); m.p. 135 degC (determined using a Perkin Elmer DSC7 at a heating rate of 20° C./minute).

[0372] The title compound of Example 29 metabolysed to form (2R)-1-(2-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}pentyl)cyclopentanecarboxylic acid.

[0373] This compound was prepared as follows:

[0374] The product from Preparation 102 (430 mg, 1 mmol) was taken up in ethanol (5 mls) and methanol (1 ml) and hydrogenated at 30 psi hydrogen pressure at room temperature for 2 h. The mixture was then filtered through a plug of Arbocel®) and evaporated to a yellow oil. This oil was purified by column chromatography using firstly 19:1, then 9:1 DCM:MeOH as eluant to provide the product as a clear oil (120 mg, 35%); ¹HNMR (400 MHz, CDCl₃) 0.88 (t, 3H), 1.20-1.88 (m, 13H), 1.90-2.03 (m, 1H), 2.24-2.38 (m, 1H), 2.43-2.72 (m, 2H), 2.95 (q, 2H); LRMS m/z 340.2 (M+H).

Example 31 (R)-2-{[1-({[2-(Hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)-cyclopentyl]methyl}pentanoic acid

[0375] and

Example 32 (S)-2-{[1-({[2-(Hydroxymethyl)-2.3-dihydro-1H-inden-2-yl]amino}carbonyl)-cyclopentyl]methyl}pentanoic acid

[0376]

[0377] 2-{[1-({[2-(Hydroxymethyl)-2,3-dihydro-1H-inden-2-yl]amino}carbonyl)-cyclopentyl]methyl}pentanoic acid (WO 9110644, Example 8) was further purified by HPLC using an AD column and hexane:isopropanol:trifluoroacetic acid (90:10:0.1) as eluant, to give the title compound of Example 31, 99% ee, [α]_D=+10.40 (c=0.067, ethanol) and the title compound of Example 32, 99% ee, [α]_D=−10.9° (c=0.046, ethanol).

………………..

http://www.google.com/patents/US6734186

Example 7 (+)-2-[(1-{[(5-Ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic Acid (F63)

The acid from Preparation 18 (18/ex4) (824 mg) was further purified by HPLC using an AD column and using hexane:iso-propanol:trifluoroacetic acid (85:15:0.2) as eluant to give the title compound of example 7 as a white foam, 386 mg, 99% ee,¹H NMR (CDCl₃, 400 MHz) δ: 0.90 (t, 3H), 1.38 (m, 6H), 1.50-1.79 (m, 9H), 2.19 (m, 1H), 2.30 (m, 1H), 2.44 (m, 1H), 2.60 (m, 1H), 2.98 (q, 2H), 12.10-12.27 (bs, 1H); LRMS: m/z 338 (MH-); and [α]_D=+3.80°(c=0.1, methanol)

……………………………………….

Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides
J Med Chem 2006, 49(14): 4409

Novel Selective Inhibitors of Neutral Endopeptidase for the Treatment of Female Sexual Arousal Disorder. Synthesis and Activity of Functionalized Glutaramides

David C. Pryde, Graham N. Maw, Simon Planken, Michelle Y. Platts, Vivienne Sanderson, Martin Corless, Alan Stobie, Christopher G. Barber, Rachel Russell, Laura Foster, Laura Barker, Christopher Wayman, Piet Van Der Graaf, Peter Stacey, Debbie Morren, Christopher Kohl, Kevin Beaumont, Sara Coggon, and Michael Tute

pp 4409–4424

Publication Date (Web): June 15, 2006 (Article)

DOI: 10.1021/jm060133g

http://pubs.acs.org/doi/abs/10.1021/jm060133g

Supporting Info

http://pubs.acs.org/doi/suppl/10.1021/jm060133g/suppl_file/jm060133gsi20060510_083156.pdf

Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R–13, for which detailed pharmacology and pharmacokinetic parameters are presented.

ACID ENTRY 13

δH(CDCl3, 400 MHz) 0.92 (3H, t), 1.35 (3H, t), 1.25-

1.80 (11H, m), 2.20-2.50 (4H, m), 2.95 (2H, q),

12.10 (1H, b s); MS

m/z

(TS+) 340 (M+H+

…………………………………………..

WO 2002002513

http://www.google.com/patents/WO2002002513A1?cl=en

…………………..

WO 2002003995

http://www.google.com/patents/WO2002003995A2?cl=en

Scheme 12

LiAIHψ THF, 6hr at reflux

Example 1

( f?)-2-r(1 r(5-ethyl-1.3.4-thiadiazol-2-yl)aminolcarbonyl)cvclopentyl) methyllpentanoic acid

and

Example 2

( S)-2-r(1-fr(5-Ethyl-1.3.4-thiadiazol-2-vnaminolcarbonyl)cvclopentyl)- methyllpentanoic acid

The title product from stage c) below (824mg) was further purified by HPLC using an AD column and using hexane:/sσ-propanol:trifluoroacetic acid (85:15:0.2) as elutant to give the title product from Example 1 , 400mg, 99.5% ee, ¹H NMR (CDCI₃, 400MHz) δ: 0.90 (t, 3H), 1.36 (m, 6H), 1.50-1.80 (m, 9H), 2.19 (m, 1 H), 2.30 (m, 1 H), 2.44 (m, 1 H), 2.60 (m, 1 H), 2.98 (q, 2H), 12.10-12.30 (bs, 1 H), LRMS : m/z 338 (MH^“ ), [α]_D = -9.0° (c = 0.1 , methanol), and the title product from Example 2, 386mg, 99% ee, ¹H NMR (CDCl₃, 400MHz) δ: 0.90 (t, 3H), 1.38 (m, 6H), 1.50-1.79 (m, 9H), 2.19 ( , 1 H), 2.30 ( , 1H), 2.44 (m, 1 H), 2.60 (m, 1 H), 2.98 (q, 2H), 12.10-12.27 (bs, 1H); LRMS: m/z 338 (MH^“); and [α]_D = +3.8° (c = 0.1 , methanol)

Preparation of Starting Materials a) 1 -r2-(tø/t-Butoxycarbonyl)-4-pentvπ-cvclopentane carboxylic acid

A mixture of 1 -[2-(tø t-butoxycarbonyl)-4-pentenyl]-cyclopentane carboxylic acid (EP 274234) (23g, 81.5mmol) and 10% palladium on charcoal (2g) in dry ethanol (200ml) was hydrogenated at 30psi and room temperature for 18 hours. The reaction mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure to give a yellow oil. The crude product was purified by column chromatography on silica gel, using ethyl acetate:pentane (40:60) as the eluant, to provide the desired product as a clear oil, 21 g, 91%; ¹H NMR (CDCI₃, 0.86 (t, 3H), 1.22-1.58 (m, 15H), 1.64 (m, 4H), 1.78 (dd, 1H), 2.00-2.18 ( , 3H), 2.24 ( , 1H); LRMS : m/z 283 (M-HV b) tert-Butyl 2-1Ϊ1 -flT5-ethyl-1.3.4-thiadiazol-2-vnaminolcarbonyl)- cvclopentvDmethyllpentanoate.

1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 mmol), 1 – hydroxybenzotriazole hydrate (0.2mmol), N-methylmorpholine (0.31 mmol) and 2-amino-5-ethyl-1 ,3,4-thiadiazole (0.22mmol) were added to a solution of the product from stage a) above (150mg, 0.53mmol) in N,N- dimethylformamide (3ml), and the reaction stirred at 90°C for 18 hours. The cooled solution was diluted with ethyl acetate (90ml), washed with water

(3x25ml), and brine (25ml), then dried (MgSO ) and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel, using ethyl acetate:pentane (30:70) as the eluant to afford the title compound, 92%; ¹H NMR (CDCI₃, 300MHz) δ: 0.82 (t, 3H), 1.20-1.80 (m, 22H), 1.84 (m, 1 H), 2.20 (m, 4H), 3.04 (q, 2H), 9.10 (bs, 1 H); LRMS : m/z

396.2 (MH⁺).

c) . 2-r(1-H^,(5-ethyl-1.3.4-thiadiazol-2-yl)amino1carbonyl)cvclopentyl) methyllpentanoic acid.

Trifluoroacetic acid (5ml) was added to a solution of the title product from stage b) above (0.31 mmol) in dichloromethane (5ml), and the solution stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue azeotroped with toluene and dichloromethane to afford the title compound as a clear oil, 81 %, ¹H NMR

(CDCI₃, 400MHz) δ: 0.92 (t, 3H), 1.35 (t, 3H), 1.25-1.80 (m, 11 H), 2.20-2.50 (m, 4H), 2.95 (q, 2H), 12.10 (bs, 1 H); LRMS : m/z 339.8 (MH⁺); Anal. Found: C, 56.46; H, 7.46; N, 12.36. Cι₆H₂₅N₃O₃S requires C, 56.62; H, 7.44; N, 12.37%.

………………………………………

Cyclization of the Acyl Glucuronide Metabolite of a Neutral Endopeptidase Inhibitor to an Electrophilic Glutarimide: Synthesis, Reactivity, and Mechanistic Analysis

Xiaoli Meng, James L. Maggs, David C. Pryde, Simon Planken, Rosalind E. Jenkins, Torren M. Peakman, Kevin Beaumont, Christopher Kohl, B. Kevin Park, and Andrew V. Stachulski

pp 6165–6176

Publication Date (Web): November 07, 2007 (Article)

DOI: 10.1021/jm0706766

http://pubs.acs.org/doi/abs/10.1021/jm0706766

Supporting Info

………………………………..

Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder

Original Research Article
Pages 142-159
David C. Pryde, Andrew S. Cook, Denise J. Burring, Lyn H. Jones, Stephanie Foll, Michelle Y. Platts, Vivienne Sanderson, Martin Corless, Alan Stobie, Donald S. Middleton, Laura Foster, Laura Barker, Piet Van Der Graaf, Peter Stacey, Christopher Kohl, Sara Coggon, Kevin Beaumont
http://www.sciencedirect.com/science/article/pii/S0968089606008212
Graphical abstract

References

‘Female Viagra’ will help women increase their sexual arousal. Daily Mail Online 14th April 2010
Armer R, Warne P, Witherington J (2006). “Recent disclosures of clinical drug candidates”. Drug News & Perspectives 19 (1): 65–72.PMID 16550257. ISSN 0214-0934
Angulo, J. (2010). “Neutral endopeptidase inhibition: could it have a role in the treatment of female sexual arousal disorder?”. British Journal of Pharmacology 160: 48. doi:10.1111/j.1476-5381.2010.00693.x.
Wayman, C.; Baxter, D.; Turner, L.; Van Der Graaf, P.; Naylor, A. (2010). “UK-414,495, a selective inhibitor of neutral endopeptidase, potentiates pelvic nerve-stimulated increases in female genital blood flow in the anaesthetized rabbit”. British Journal of Pharmacology160 (1): 51–59. doi:10.1111/j.1476-5381.2010.00691.x. PMC 2860206. PMID 20412068.

SEE

The discovery of small molecule inhibitors of neutral endopeptidase. Structure-activity studies on functionalized glutaramides
Chem Biol Drug Des 2006, 67(1): 74

Optimization of oral pharmacokinetics in the discovery of clinical candidates for the treatment of sexual dysfunction
237th ACS Natl Meet (March 22-26, Salt Lake City) 2009, Abst MEDI 173

Novel selective inhibitors of neutral endopeptidase for the treatment of female sexual arousal disorder. Synthesis and activity of functionalized glutaramides
J Med Chem 2006, 49(14): 4409

Bioorganic & Medicinal Chemistry (2007), 15(1), 142-159

Journal of Medicinal Chemistry (2007), 50(24), 6165-6176.

US2004087561	5-7-2004	Treatment of sexual dysfunction
US2002169101	11-15-2002	Treatment of sexual dysfunction
US2002052370	5-3-2002	Cyclopentyl-substituted glutaramide derivatives as inhibitors of neutral endopeptidase

UK-414,495
Systematic (IUPAC) name

(R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl)carbamoyl]cyclopentyl}methyl)valeric acid
Clinical data
Legal status	?
Identifiers
CAS number	337962-93-3
ATC code	?
PubChem	CID 9949799
Chemical data
Formula	C₁₆H₂₅N₃O₃S
Mol. mass	339.452 g/mol

Citing Patent	Filing date	Publication date	Applicant	Title
US6734186 *	Nov 8, 2000	May 11, 2004	Pfizer Inc.	Phosphodiesterase 2 inhibitor
US7956195 *	Dec 21, 2007	Jun 7, 2011	Abbott Laboratories	reacting arylboronic acids with a cycloalkanone, in the presence of a rhodium catalyst or BINAP, to form a substituted arylcycloalkanone, then formin of a hydantoin, alkylation of the hydantoin, resolution, hydrolysis of the hydantoin to the amino acids and esterification of acids; chemical intermediates
WO2005007166A1 *	Jul 12, 2004	Jan 27, 2005	Alasdair Mark Naylor	Treatment of sexual dysfunction

Female Sexual Response

The female sexual response phase of arousal is not easily distinguished from the phase of desire until physiological changes begin to take place in the vagina and clitoris as well as other sexual organs. Sexual excitement and pleasure are accompanied by a combination of vascular and neuromuscular events which lead to engorgement of the clitoris, labia and vaginal wall, increased vaginal lubrication and dilatation of the vaginal lumen (Levin, 1980; Ottesen, 1983; Levin, 1991; Levin, 1992; Sjoberg, 1992; Wagner, 1992; Schiavi et al., 1995; Masters et al., 1996; Berman et al., 1999).

Vaginal engorgement enables transudation to occur and this process is responsible for increased vaginal lubrication. Transudation allows a flow of plasma through the epithelium and onto the vaginal surface, the driving force for which is increased blood flow in the vaginal capillary bed during the aroused state. In addition engorgement leads to an increase in vaginal length and luminal diameter, especially in the distal ⅔ of the vaginal canal. The luminal dilatation of the vagina is due to a combination of smooth muscle relaxation of its wall and skeletal muscle relaxation of the pelvic floor muscles. Some sexual pain disorders such as vaginismus are thought to be due, at least in part, by inadequate relaxation preventing dilatation of the vagina; it has yet to be ascertained if this is primarily a smooth or skeletal muscle problem. (Levin, 1980; Oltesen, 1983; Levin, 1991; Levin, 1992; Sjoberg, 1992; Wagner, 1992; Schiavi et al., 1995; Master et al., 1996; Berman et al., 1999).

The vasculature and micro vasculature of the vagina are innervated by nerves containing neuropeptides and other neurotransmitter candidates. These include calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY; Sequence No. 4), nitric oxide synthase (NOS), substance P and vasoactive intestinal peptide (VIP; Sequence No. 8) (Hoyle et al., 1996). Peptides that are present in the clitoris are discussed infra. Nitric oxide synthase, which is often colocalised with VIP (Sequence No. 8), displays a greater expression, immunologically, in the deep arteries and veins rather than in the blood vessels of the propria (Hoyle et al., 1996).

Female Sexual Dysfunction

It is known that some individuals can suffer from female sexual dysfunction (FSD). FSD is best defined as the difficulty or inability of a woman to find satisfaction in sexual expression. FSD is a collective term for several diverse female sexual disorders (Leiblum, 1998, Berman et al., 1999). The woman may have lack of desire, difficulty with arousal or orgasm, pain with intercourse or a combination of these problems. Several types of disease, medications, injuries or psychological problems can cause FSD.

Studies investigating sexual dysfunction in couples reveals that up to 76% of women have complaints of sexual dysfunction and that 30-50% of women in the USA experience FSD.

Sub-types of FSD include hypoactive sexual desire disorder, female sexual arousal disorder, orgasmic disorder and sexual desire disorder.

Treatments in development are targeted to treat specific subtypes of FSD, predominantly desire and arousal disorders.

The categories of FSD are best defined by contrasting them to the phases of normal female sexual response: desire, arousal and orgasm (Leiblum 1998). Desire or libido is the drive for sexual expression—and manifestations often include sexual thoughts either when in the company of an interested partner or when exposed to other erotic stimuli. In contrast, sexual arousal is the vascular response to sexual stimulation, an important component of which is vaginal lubrication and elongation of the vagina. Thus, sexual arousal, in contrast to sexual desire, is a response relating to genital (e.g. vaginal and clitoral) blood flow and not necessarily sensitivity. Orgasm is the release of sexual tension that has culminated during arousal. Hence, FSD typically occurs when a woman has an inadequate or unsatisfactory response in any of these phases, usually desire, arousal or orgasm. FSD categories include hypoactive sexual desire disorder, sexual arousal disorder, orgasmic disorders and sexual pain disorders.

Hypoactive sexual desire disorder is present if a woman has no or little desire to be sexual, and has no or few sexual thoughts or fantasies. This type of FSD can be caused by low testosterone levels, due either to natural menopause or to surgical menopause. Other causes include illness, medications, fatigue, depression and anxiety.

Female sexual arousal disorder (FSAD) is characterised by inadequate genital response to sexual stimulation. The genitalia (e.g. the vagina and/or the clitoris) do not undergo the engorgement that characterises normal sexual arousal. The vaginal walls are poorly lubricated, so that intercourse is painful. Orgasms may be impeded. Arousal disorder can be caused by reduced oestrogen at menopause or after childbirth and during lactation, as well as by illnesses, with vascular components such as diabetes and atherosclerosis. Other causes result from treatment with diuretics, antihistamines, antidepressants eg SSRIs or antihypertensive agents. FSAD is discussed in more detail infra.

Sexual pain disorders (which include dyspareunia and vaginismus) are characterised by pain resulting from penetration and may be caused by medications which reduce lubrication, endometriosis, pelvic inflammatory disease, inflammatory bowel disease or urinary tract problems.

The prevalence of FSD is difficult to gauge because the term covers several types of problem, some of which are difficult to measure, and because the interest in treating FSD is relatively recent. Many women’s sexual problems are associated either directly with the female ageing process or with chronic illnesses such as diabetes and hypertension.

There are wide variations in the reported incidence and prevalence of FSD, in part explained by the use of differing evaluation criteria, but most investigators report that a significant proportion of otherwise healthy women have symptoms of one or more of the FSD subgroups. By way of example, studies comparing sexual dysfunction in couples reveal that 63% of women had arousal or orgasmic dysfunction compared with 40% of men have erectile or ejaculatory dysfunction (Frank et al., 1978).

However, the prevalence of female sexual arousal disorder varies considerably from survey to survey. In a recent National Health and Social Life Survey 19% of women reported lubrication difficulties whereas 14% of women in an outpatient gynaecological clinic reported similar difficulties with lubrication (Rosen et al., 1993).

Several studies have also reported dysfunction with sexual arousal in diabetic women (up to 47%), this included reduced vaginal lubrication (Wincze et al., 1993). There was no association between neuropathy and sexual dysfunction.

Numerous studies have also shown that between 11-48% of women overall may have reduced sexual desire with age. Similarly, between 11-50% of women report problems with arousal and lubrication, and therefore experience pain with intercourse. Vaginismus is far less common, affecting approximately 1% of women.

Studies of sexually experienced women have detailed that 5-10% have primary anorgasmia. Another 10% have infrequent orgasms and a further 10% experience them inconsistently (Spector et al., 1990).

Because FSD consists of several subtypes that express symptoms in separate phases of the sexual response cycle, there is not a single therapy. Current treatment of FSD focuses principally on psychological or relationship issues. Treatment of FSD is gradually evolving as more clinical and basic science studies are dedicated to the investigation of this medical problem. Female sexual complaints are not all psychological in pathophysiology, especially for those individuals who may have a component of vasculogenic dysfunction (eg FSAD) contributing to the overall female sexual complaint. There are at present no drugs licensed for the treatment of FSD. Empirical drug therapy includes oestrogen administration (topically or as hormone replacement therapy), androgens or mood-altering drugs such as buspirone or trazodone. These treatment options are often unsatisfactory due to low efficacy or unacceptable side effects.

Since interest is relatively recent in treating FSD pharmacologically, therapy consists of the following:- psychological counselling, over-the-counter sexual lubricants, and investigational candidates, including drugs approved for other conditions. These medications consist of hormonal agents, either testosterone or combinations of oestrogen and testosterone and more recently vascular drugs, that have proved effective in male erectile dysfunction. None of these agents has been demonstrated to be very effective in treating FSD.

Female Sexual Arousal Disorder (FSAD)

The sexual arousal response consists of vasocongestion in the pelvis, vaginal lubrication and expansion and swelling of the external genitalia. The disturbance causes marked distress and/or interpersonal difficulty. Studies investigating sexual dysfunction in couples reveals that there is a large number of females who suffer from sexual arousal dysfunction; otherwise known as female sexual arousal disorder (FSAD).

The Diagnostic and Statistical Manual (DSM) IV of the American Psychiatric Association defines Female Sexual Arousal Disorder (FSAD) as being:

“a persistent or recurrent inability to attain or to maintain until completion of the sexual activity adequate lubrication-swelling response of sexual excitement. The disturbance must cause marked distress or interpersonal difficulty.”

FSAD is a highly prevalent sexual disorder affecting pre-, peri- and post menopausal (±HRT) women. It is associated with concomitant disorders such as depression, cardiovascular diseases, diabetes and UG disorders.

The primary consequences of FSAD are lack of engorgement/swelling, lack of lubrication and lack of pleasurable genital sensation. The secondary consequences of FSAD are reduced sexual desire, pain during intercourse and difficulty in achieving an orgasm.

It has recently been hypothesised that there is a vascular basis for at least a proportion of patients with symptoms of FSAD (Goldstein et al., 1998) with animal data supporting this view (Park et al., 1997).

Drug candidates for treating FSAD, which are under investigation for efficacy, are primarily erectile dysfunction therapies that promote circulation to the male genitalia. They consist of two types of formulation, oral or sublingual medications (Apomorphine, Phentolamine, Sildenafil), and prostaglandin (PGE₁-Alprostadil) that are injected or administered transurethrally in men, and topically to the genitalia in women.

The present invention seeks to provide an effective means of treating FSD, and in particular FSAD.

SUMMARY

The present invention is based on findings that FSAD is associated with reduced genital blood flow—in particular reduced blood flow in the vagina and/or the clitoris. Hence, treatment of women with FSAD can be achieved by enhancement of genital blood flow with vasoactive agents. In our studies, we have shown that cAMP mediates vaginal and clitoral vasorelaxation and that genital (e.g. vaginal and clitoral) blood flow can be enhanced/potentiated by elevation of cAMP levels. This is a seminal finding.

In this respect, no one has previously proposed that FSAD can be treated in such a way—i.e. by direct or indirect elevation of cAMP levels. Moreover, there are no teachings in the art to suggest that FSAD was associated with a detrimental modulation of cAMP activity and/or levels or that cAMP is responsible for mediating vaginal and clitoral vasorelaxation. Hence, the present invention is even further surprising.

In addition, we have found that by using agents of the present invention it is possible to increase genital engorgement and treat FSAD—e.g. increased lubrication in the vagina and increased sensitivity in the vagina and clitoris. Thus, in a broad aspect, the present invention relates to the use of a cAMP potentiator to treat FSD, in particular FSAD.

The present invention is advantageous as it provides a means for restoring a normal sexual arousal response—namely increased genital blood flow leading to vaginal, clitoral and labial engorgement. This will result in increased vaginal lubrication via plasma transudation, increased vaginal compliance and increased genital (e.g. vaginal and clitoral) sensitivity. Hence, the present invention provides a means to restore, or potentiate, the normal sexual arousal response.

More particularly, the present invention relates to:

A pharmaceutical composition for use (or when in use) in the treatment of FSD, in particular FSAD; the pharmaceutical composition comprising an agent capable of potentiating cAMP in the sexual genitalia of a female suffering from FSD, in particular FSAD; wherein the agent is optionally admixed with a pharmaceutically acceptable carrier, diluent or excipient.

The use of an agent in the manufacture of a medicament (such as a pharmaceutical composition) for the treatment of FSD, in particular FSAD; wherein the agent is capable of potentiating cAMP in the sexual genitalia of a female suffering from FSD, in particular FSAD.

A method of treating a female suffering from FSD, in particular FSAD; the method comprising delivering to the female an agent that is capable of potentiating cAMP in the sexual genitalia; wherein the agent is in an amount to cause potentiation of cAMP in the sexual genitalia of the female; wherein the agent is optionally admixed with a pharmaceutically acceptable carrier, diluent or excipient.

An assay method for identifying an agent that can be used to treat FSD, in particular FSAD, the assay method comprising: determining whether an agent can directly or indirectly potentiate cAMP; wherein a potentiation of cAMP in the presence of the agent is indicative that the agent may be useful in the treatment of FSD, in particular FSAD.

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Frespaciguat CAS 2101645-33-2 MF C27H22ClF5N6O3 MW 608.9 g/mol 3-[4-[(5S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)indazol-3-yl]-5-methyl-6-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanoic acid 3-{4-[(5S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic acidguanylate cyclase activator, MK5475, MK 5475, sGC activator 1, 6DXN080KGB Frespaciguat (development code MK-5475) is an experimental…
Fosrolapitant
Fosrolapitant CAS 2573694-38-7 MF C27H29F6N2O8P MW654.5 g/mol phosphonooxymethyl (5S,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-2-oxo-8-phenyl-1,9-diazaspiro[4.5]decane-9-carboxylate (phosphonooxy)methyl (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)-2-oxo-8-phenyl-1,7-diazaspiro[4.5]decane-7-carboxylateneurokinin 1 (NK1) receptor antagonist, HR20013, HR 20013, M5QGY92X8B Fosrolapitant (HR20013) is a novel, intravenous, highly selective neurokinin-1…
Filricianine
Filricianine CAS 2140857-94-7 MF C45H52N2O12S3, 909.1 3H-Indolium, 3-(3-carboxypropyl)-2-[2-[3-[2-[1,3-dihydro-3,3-dimethyl-1-(3-sulfopropyl)-2H-indol-2-ylidene]ethylidene]-2-(4-sulfophenoxy)-1-cyclohexen-1-yl]ethenyl]-3-methyl-1-(3-sulfopropyl)-, inner salt 3-[(2Z)-3-(3-carboxypropyl)-2-[(2E)-2-[3-[(E)-2-[3,3-dimethyl-1-(3-sulfopropyl)indol-1-ium-2-yl]ethenyl]-2-(4-sulfophenoxy)cyclohex-2-en-1-ylidene]ethylidene]-3-methylindol-1-yl]propane-1-sulfonate 3-[(3RS)-3-(3-carboxypropyl)-2-{(1Ξ)-2-[(3Ξ)-3-{(2Ξ)-2-[3,3-dimethyl-1-(3-sulfopropyl)- 1,3-dihydro-2H-indol-2-ylidene]ethylidene}-2-(4-sulfophenoxy)cyclohex-1-en-1-yl]ethen-1-yl}-3-methyl-3H-indol-1-ium-1-yl]propane-1-sulfonatediagnostic imaging agent, CI4MD9KLX8 AS ON OCT2025 4.511 LAKHS VIEWS ON BLOG WORLDREACH…
Fanregratinib
Fanregratinib CAS 1628537-44-9 MF C27H33ClN6O2, 509.0 g/mol 4-chloro-3-[2-[2-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]pyrimidin-5-yl]ethyl]-5-methoxy-N-methylbenzamide fibroblast growth factor receptor tyrosine kinase inhibitor, antineoplastic, 8RWL2B2CLS FANREGRATINIB is a small molecule drug with a maximum…
Evetifator
Evetifator CAS 2278265-85-1 MF C20H19ClF3N3O4 MW457.8 g/mol 2-(4-chlorophenoxy)-N-[3-[5-[3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]-1-bicyclo[1.1.1]pentanyl]acetamide 2-(4-chlorophenoxy)-N-(3-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}bicyclo [1.1.1]pentan-1-yl)acetamideeukaryotic translation initiation factor 2B (eIF2B) activator, DNL-343, DNL 343, FYL3Y9D7SK Evetifator (also known as DNL343) is…
Evategrel
Evategrel CAS 2760609-74-1 MF C21H26ClNO7S MW 472.0 g/mol (2Z)-2-[(4R)-1-[(1S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-(propan-2-yloxycarbonyloxymethylsulfanyl)piperidin-3-ylidene]acetic acid (Z)-[(4R)-1-[(1S)-1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-{[({[(propan-2-yl)oxy]carbonyl}oxy)methyl]sulfanyl}piperidin-3-ylidene]acetic acidplatelet aggregation inhibitor, CG-0255, CG 0255, 9FKJ76ZX22 Evategrel (CG-0255) is a promising new antiplatelet drug,…
Enrupatinib
Enrupatinib CAS 2222689-47-4 MF C27H26N6O3 MW 482.5 g/mol 6-[3-methoxy-4-[(6-methyl-3-pyridinyl)methoxy]anilino]-3-morpholin-4-ylquinoxaline-5-carbonitrile colony-stimulating factor 1 receptor (CSF1R) inhibitor, antineoplastic, EI 1071, EI-1071, 9L35RVQ9J6 ENRUPATINIB is a small molecule drug…
Emestedastat
Emestedastat CAS 1346013-80-6 MF C19H19N5O2S MW381.5 g/mol [(1R,3r,5S)-3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan-8-yl][5-(1H-pyrazol-4-yl)thiophen-3-yl]methanone11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, UE-2343, UE 2343, 106ELK29GH Emestedastat (proposed brand name Xanamem; developmental code name UE-2343) is a steroidogenesis inhibitor which…
Direclidine
Direclidine CAS 1803346-98-6 MF C19H30N4O2 MW346.5 g/mol ethyl 2-[4-(2-methylpyrazol-3-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate 6-Azaspiro[3.4]octane-6-carboxylic acid, 2-[4-(1-methyl-1H-pyrazol-5-yl)-1-piperidinyl]-, ethyl ester, cis- ethyl (2r,4s)-2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylatemuscarinic M4 receptor positive allosteric modulator, TXB4V44U24, NBI-1117568, NBI 1117568…
Dezecapavir
Dezecapavir CAS 2570323-59-8 MF C37H29ClF9N9O5S MW918.19 1H-Cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-acetamide, N-[(1S)-1-[(3S)-3-[4-chloro-1-methyl-3-[(methylsulfonyl)amino]-1H-indazol-7-yl]-3,4-dihydro-4-oxo-7-(3,3,3-trifluoropropoxy)pyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-, (3bS,4aR)- N-[(1S)-1-[(3P)-3-[4-chloro-3-(methanesulfonamido)-1-methyl-1H-indazol-7-yl]-4-oxo-7-(3,3,3-trifluoropropoxy)-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1Hcyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamideinhibitor of viral replication, antiviral, SEK9LN2LSM, VH 4011499, VH4011499, VH-4011499, VH 499, GSK2838232, GSK 2838232 Dezecapavir…

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Enantioselective separation of ketoconazole enantiomers by membrane extraction

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May 13,2014

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World Hepatitis Day – European Medicines Agency uses regulatory tools to facilitate patient access to innovative medicines

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Europe to boost cooperation with international partners on generics

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The aim of this study was to investigate the control of genital blood flow by VIP and endogenous neuropeptides using a selective NEP inhibitor [UK-414,495, ((R)-2-({1-[(5-ethyl-1,3,4-thiadiazol-2-yl) carbamoyl]cyclopentyl}methyl) valeric acid)].

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