- The process development of a scaleable route to the PDE5 inhibitor UK-357,903
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A case history is outlined for the development of a scaleable route to the drug candidate UK-357,903. Despite the partial structural similarities to those of sildenafil (Viagra), the introduction of the central pyridine moiety within UK-357,903 had a significant impact on the commercial process. In particular, the triply activated 2-alkoxypyridyl moiety of UK-357,903 is much more susceptible to nucleophilic attack than the 2-ethoxyphenyl moiety of sildenafil, necessitating the development of new chemistry. Particular items of note are (i) the new six-step route to the advanced 2-ethoxy-5-(4-ethylpiperazinylsulfonyl)nicotinic acid intermediate and the subsequent telescoping to a two-pot process, (ii) the telescoping of the two steps from N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl)nicotin-amide to UK-357,903 to a single step, with the additional use of a hydroxide trapping agent to give an ambient pressure process yielding clinical quality product, and (iii) the introduction of process modifications to allow for the use of teratogenic 2-methoxyethanol, as both reagent and solvent, in the penultimate process step.
- Dale, David J.,Draper, John,Dunn, Peter J.,Hughes, Michael L.,Hussain, Farhat,Levett, Philip C.,Ward, Gordon B.,Wood, Albert S.
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Read Online
- The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics
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This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.2,3.
- Rawson, David J.,Ballard, Stephen,Barber, Christopher,Barker, Laura,Beaumont, Kevin,Bunnage, Mark,Cole, Susan,Corless, Martin,Denton, Stephen,Ellis, David,Floc'H, Marion,Foster, Laura,Gosset, James,Holmwood, Frances,Lane, Charlotte,Leahy, David,Mathias, John,Maw, Graham,Million, William,Poinsard, Cedric,Price, Jenny,Russel, Rachel,Street, Stephen,Watson, Lesa
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p. 498 - 509
(2012/03/08)
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- Pyrazolopyrimidine derivatives
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The present invention provides a compound of formula (I): where Q is a group of formula: These compounds inhibit cyclic guanosine 3',5'-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds are potent and selective inhibitors of the type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases and have utility therefore in a variety of therapeutic areas. In particular, the present compounds are of value for the curative or prophylactic treatment of mammalian sexual disorders.
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- Novel process for the preparation of pyrazolopyrimidinones
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There is provided a process for the production a compound of general formula I: wherein A, R1, R2, R3 and R4 have meanings given in the description, which process comprises the reaction of a compound of formula II, wherein Rx is a group substitutable by an aminopyrazole, with a compound of general formula III
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- Novel process for the preparation of pyrazolopyrimidinones
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There is provided a process for the production a compound of general formula I: 1wherein A, R1, R2, R3 and R4 have meanings given in the description, which process comprises the dehydrogenation of a compound of general formula II, 2
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- Crystalline therapeutic agent
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A polymorph of 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl}-4-ethylpiperazine.
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- Therapeutic agents
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The invention relates anhydrous para-toluenesulphonic acid salts of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one having the formula (I): a process for
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Page column 13
(2010/11/30)
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- Pyrazolopyrimidinone CGMP PDE5 inhibitors for the treatment of sexual dysfunction
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There is provided compounds of formula IA and of formula IB, wherein R1, R2, R3, R4and A have meanings given in the description, which are useful in the curative and prophylactic treatment of a medical condition for which inhibition of a cyclic guanosine 3′,5′-monophosphate phosphodiesterase (e.g. cGMP PDE5) is desired.
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Page column 32
(2010/02/05)
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- Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction
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Compounds of the formulae (IA) and (IB): wherein R1is C1to C3alkyl optionally substituted with phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted by one or more substitutents selected from C1to C4alkoxy; halo; CN; CF3; OCF3or C1to C4alkyl wherein said C1to C4alkyl group is optionally substituted by C1to C4haloalkyl or haloalkoxy either of which is substituted by one or more halo atoms; R2is C1to C6alkyl and R13is OR3or NR5R6, or pharmaceutically or veterinarily acceptable salts thereof, or pharmaceutically or veterinarily acceptable solvates of either entity are potent and selective inhibitors of type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP PDE5) and have utility in the treatment of, inter alia, male erectile dysfunction (MED) and female sexual dysfunction (FSD).
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- Process for the preparation of pyrazolo [4,3-d] pyrimidin-7-ones-3-pyridylsulphonyl compounds and intermediates thereof
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A process is provided for the preparation of compounds of formula (I) herein comprising reacting a compound of formula (II), (III) or (IV) in the presence of -OR and a hydroxide trapping agent or in the case of compounds of formula (IV) reacting in the presence of an auxiliary base and a hydroxide trapping agent (i.e. -OR is substituted by the auxiliary base), wherein X is a leaving group and R1 to R4 are as defined above.
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