Tracks information on drugs on worldwide basis by Dr Anthony Melvin Crasto, helping millions with websites, 9 million hits on google, 2.5 lakh connections worldwide, P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
Friday, 31 January 2014
Thursday, 30 January 2014
Mirodenafil 米罗那非 标准品 ………..An erectogenic agent.
Mirodenafil, 米罗那非 标准品
SYNTHESIS WILL BE UPDATED SOON
SK-3530
UNII-504G362H0H
862189-96-6 DIHYDROCHLORIDE
862189-95-5 (free base)
862189-95-5 (free base)
5-Ethyl-3,5-dihydro-2-[5-([4-(2-hydroxyethyl)-1-piperazinyl]sulfonyl)-2-propoxyphenyl]-7-propyl-4H-pyrrolo[3,2-d]pyrimidin-4-one
5-ethyl-2-f-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-phenylg -7-propoxypropyl-3,5-dihydropyrrolo-[3,2-d]-pyrimidin-4-one
5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one
2-(5-(4-(3-hydroxypropyl)piperazin-1-ylsulfonyl)-2-n-propoxyphenyl)-5-ethyl-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one;
Launched – 2007
In2Gen (Originator)
SK Chemicals (Originator)
SK Chemicals (Originator)
Treatment of
Treatment of Erectile Dysfunction , hypertention
Treatment of Erectile Dysfunction , hypertention
Mirodenafil belongs to a class of drugs called PDE5 inhibitors, which many other erectile dysfunction drugs such as sildenafil, tadalafil, andvardenafil also belong to. It was developed by SK Chemicals Life Science and is marketed under the trade name of Mvix tab which comes in different doses (50 mg, 100 mg).
Mirodenafil is also available under the name of Mvix S ODF 50 mg as an orally dissolving film (ODF) which dissolves on the tongue without water. It is the first licensed medicine for the treatment of erectile dysfunction as a dosage form of film.
Mirodenafil is a newly developed oral phosphodiesterase type 5 inhibitor, currently under investigation as a treatment for erectile dysfunction (ED).
MIRODENAFIL米罗那非 标准品
Mirodenafil hydrochloride is a high selective PDE5 inhibitor commercialized by SK Chemicals which had been in early clinical development for the treatment of erectile dysfunction (ED). Early clinical studies had also been ongoing for the treatment of hypertension in patients taking amlodipine; however, no recent development has been reported for this research. The development of compound started in 1998 jointly by SK Chemicals and a bio-venture In2Gen.
Several clinical trials were conducted,[1][2][3] but mirodenafil has not been approved for use in the United States by the U.S. Food and Drug Administration.
CLINICAL STUDIES
Mirodenafil dihydrochloride
|
The introduction of oral phosphodiesterase type 5 inhibitor therapy in 1998 revolutionized the treatment of erectile dysfunction. Erectile dysfunction is the most common sexual problem in men. It often has a profound effect on intimate relationships and quality of life. The analysis of pharmaceuticals is an important part of the drug development process as well as for routine analysis and quality control of commercial formulations. Whereas the determination of sildenafil citrate, vardenafil and tadalafil are well documented by a variety of methods, there are few publications about the determination of udenafil, lodenafil carbonate, mirodenafil and avanafil. The paper presents a brief review of the action mechanism, adverse effects, pharmacokinetics and the most recent analytical methods that can determine drug concentration in biological matrices and pharmaceutical formulations of these four drugs.
European patent applications EP-A-0463756 and EP-A-0526004 disclose certain pyrazolo 4,3-dpyrimidin-7-ones as cGMP PDE inhibitors, useful in the treatment of cardiovascular disorders such as angina, hypertension and heart failure. International application WO 94/28902 discloses their use for the treatment of impotence. 0017The present inventors have recently disclosed a series of pyrazolo4,3-dpyrimidin-7-one derivatives as PDE V inhibitors (Appln. No. KR 98-60436 and KR 99-7580). Herein a new series of pyrrolo4,33,2d-pyrimidin-74-one derivatives are prepared as PDE V inhibitors
Korean Patent No. 358083 discloses pyrrolopyrimidinone derivatives having good inhibition activity against PDE-5, a method of its preparation thereof, an intermediate compound used to prepare the same and their use for prevention and treatment of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive pulmonary disease, benign prostatic hypertrophy and lower urinary tract diseases.
Of the pyrrolopyrimidinone derivatives disclosed in Korean Patent No. 358083, 5-ethyl-2-{5-[4- (2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl}-7-n-propyl-l-3,5-dihydro-4 H-pyrrolo[3,2-d]pyrimidin-4-one (hereinafter, “SK-3530″) represented by the following formula (1 ) is an excellent selective inhibitor PDE-5 over other PDEs and is under clinical trial for the treatment of erectile dysfunction after passing through the preclinical stage.
The dihydrochloride salt (2HCI) of SK-3530 has been under investigation through the preclinical and clinical stages.
The SK-3530 dihydrochloride salt has good solubility and can be easily stabilized for pharmaceutical preparation. But, it has the following drawbacks.
First, because the SK-3530 dihydrochloride salt is hygroscopic, it easily absorbs moisture from the atmosphere and becomes discolored when the moisture content is high. And, due to the hygroscopic property, an anhydrous solvent condition and a dry air condition have to be provided to obtain a stable product. Second, the SK-3530 dihydrochloride salt should be kept at a temperature lower than room temperature because it does not show enough stability at room temperature. In particular, the SK-3530 dihydrochloride salt is labile to heat or light, and thus any prolonged exposure to heat or light results in various impurities.
Third, the SK-3530 dihydrochloride salt could corrode the punch during tablet ting due to its somewhat corrosive properties. This is because the SK-3530 dihydrochloride salt is a simple amorphous salt rather than being a stable crystalline acid addition salt or hydrate form. Thus, one of the two hydrochloric acid groups with a relatively weak ionic bond character may leave the molecule under severe conditions. As aforementioned, the SK-3530 dihydrochloride salt may be endowed with a sufficient stability for pharmaceutical preparation. But, some additional techniques and costs are needed due to the deficiency in intrinsic physicochemical property and stability of the compound.
MIRODENAFIL米罗那非 标准品
…………………………
The invention relates to a series of pyrrolopyrimidinone derivatives of the formula (1):
R1 ETHYL
R2=H
R3= PROPYL
R4 = PROPYL
R5=R5=SO2NR6R7, NR6R7 is 4-(3-hydroxypropyl)piperazinyl) IS MIRODENAFIL
ANALOGOUS METHOD
BELOW IS CUT PASTE OF R1 METHYL ANALOGUE ……………..R1 =METHYL AND NOT ETHYL ….CAUTION
Example 39 Preparation of
5-(5-(4-(2-hydroxyethyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one hydrochloride (a compound of the formula (1) wherein R5=SO2NR6R7, R1=CH3, R2=H, R3=CH2CH2CH3, R4=CH2CH2CH3; NR6R7 is 4-(2-hydroxyethyl)piperazinyl)
The titled compound was prepared as described in Example 2 by using 5-(5-(4-(2-hydroxyethyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one in place of 5-(2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one.
yield: 99%
mp 66.5° C. dec;
IR (neat) 3332 (NH and OH), 1676 (C═O), 1166 (SO2) cm−1;
1H NMR (DMSO-d6) δ 0.92 (t, J=7.2 Hz, 3H, CH2CH2CH3), 0.96 (t, J=7.2 Hz, 3H, OCH2CH2CH3), 1.56-1.80 (m, 4H, 2 CH2CH2CH3), 2.59 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.91 (br t, J=11.7 Hz, 2H, 2 SO2NCHax), 3.12-3.27 (m, 4H, NCH2CH2 and 2 SO2NCHeq), 3.58 (br d, J=11.7 Hz, 2H, 2 +HNCHax), 3.68-3.85 (m, 4H, CH2CH2OH and 2 +HNCHeq), 4.00 (s, 3H, NCH3), 4.15 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.66 (br s, 1H, OH), 7.28 (s, 1H, H-2), 7.44 (d, J=9.0 Hz, 1H, H-3′), 7.89 (dd, J=9.0 Hz, 2.4 Hz, 1H, H-4′), 8.01 (d, J=2.4 Hz, 1H, H-6′), 10.85 (br s, 1H, NH+), 12.01 (br s, 1H, NH).
Example 42 Preparation of
5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one (a compound of the formula (1) wherein R5=SO2NR6R7, R1=CH3, R2=H, R3=CH2CH2CH3, R4=CH2CH2CH3; NR6R7 is 4-(3-hydroxypropyl)piperazinyl)
The titled compound was prepared as described in Example 1 by using 5-(5-chlorosulfonyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one and 1-(3-hydroxypropyl)piperazine in place of 5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one and 1-methylpiperazine.
yield: 94%
mp 162.5° C. dec (EtOAc/hexanes);
IR (neat) 3484, 3302 (NH and OH), 1669 (C═O), 1170 (SO2) cm−1;
1H NMR (CDCl3/TMS) δ 1.00 (t, J=7.5 Hz, 3H, CH2CH2CH3), 1.20 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.64-1.80 (m, 4H, CH2CH2CH2OH and CH2CH2CH3), 1.99-2.11 (m, 2H, OCH2CH2CH3), 2.58-2.64 (m, 6H, NCH2CH2 and 2 NCH2), 2.71 (t, J=7.5 Hz, 2H, CH2CH2CH3), 3.08 (br s, 4H, 2 SO2NCH2), 3.71 (t, J=5.4 Hz, 2H, CH2CH2OH), 4.08 (s, 3H, NCH3), 4.26 (t, J=6.3 Hz, 2H, OCH2CH2CH3), 4.28 (br s, 1H, OH), 6.88 (s, 1H, H-2), 7.14 (d, J=8.7 Hz, 1H, H-3′), 7.77 (dd, J=8.7 Hz, 2.7 Hz, 1H, H-4′), 8.87 (d, J=2.7 Hz, 1H, H-6′), 10.69 (br s, 1H, NH); MS (FAB) m/z 532 (MH+).
Example 43 Preparation of
5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one hydrochloride (a compound of the formula (1) wherein R5=SO2NR6R7, R1=CH3, R2=H, R3=CH2CH2CH3, R4=CH2CH2CH3; NR6R7 is 4-(3-hydroxypropyl)piperazinyl)
The titled compound was prepared as described in Example 2 by using 5-(5-(4-(3-hydroxypropyl)piperazinylsulfonyl)-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one in place of 5-(2-ethoxy-5-(4-methylpiperazinylsulfonyl)phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrrolo[4,3-d]pyrimidin-7-one.
yield: 99%
mp 62.5° C. dec;
IR (neat) 3347, 3321 (NH and OH), 1689 (C═O), 1168 (SO2) cm−1;
1H NMR (DMSO-d6) δ 0.93 (t, J=7.5 Hz, 3H, CH2CH2CH3), 0.96 (t, J=7.5 Hz, 3H, OCH2CH2CH3), 1.57-1.87 (m, 6H, CH2CH2CH2OH and 2 CH2CH2CH3), 2.59 (t, J=7.5 Hz, 2H, CH2CH2CH3), 2.89 (br t, J=11.7 Hz, 2H, 2 SO2NCHax), 3.01-3.19 (m, 4H, NCH2CH2 and 2 SO2NCHeq), 3.44 (t, J=6.0 Hz, 2H, CH2CH2OH), 3.52 (br d, J=11.7 Hz, 2H, 2 +HNCHax), 3.79 (br d, J=11.7 Hz, 2H, 2 +HNCHeq), 4.00 (s, 3H, NCH3), 4.15 (t, J=6.6 Hz, 2H, OCH2CH2CH3), 4.71 (br s, 1H, OH), 7.29 (s, 1H, H-2), 7.44 (d, J=8.7 Hz, 1H, H-3′), 7.89 (dd, J=8.7 Hz, 2.4 Hz, 1H, H-4′), 8.02 (d, J=2.4 Hz, 1H, H-6′), 11.13 (br s, 1H, NH+), 12.05 (br s, 1H, NH).
……………………………
Synthesis from patent and some construction by me
you can synthesize as follows, A CHEMIST CAN PICK THIS UP, this is not available clearly anywhere
Chlorosulfonation of the methyl salicylate with ClSO3H in SOCl2 affords the Methyl 3-Chlorosulfonyl-6-hydroxybenzoate described below
THESE INTERMEDIATES FROM PATENT MAY HELP YOU
methyl salicylate
X=CL, R8=ME
- Methyl 3-Chlorosulfonyl-6-hydroxybenzoate
Example 1 EP1362858A1
- To a cooled solution of SOCl2 (156 g, 1. 31 mol) and ClSO3H (460 g, 3.94 mol) at 0°C was added slowly methyl salicylate (200 g, 1.31 mol) for 30 minutes, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was poured slowly into the ice (2 kg) and H2O (3 L) mixture, and the resulting white precipitates were collected by filtration. The filtered solid was washed with H2O (3 L), air-dried for 2 days and then dried under vacuum at 40°C for 2 days to afford the titled product (232 g, 93%) as a white solid.
mp 76.5-77.5 °C (toluene/hexanes);
IR (neat) 1699 (C=O) cm-1;
1H NMR (CDCl3/TMS) δ 3. 90 (s, 3 H, OCH3), 6. 93 (d, J= 8. 7 Hz, 1 H, H-3), 7. 70 (dd, J= 8. 7 Hz, 2. 4 Hz, 1 H, H-4), 8. 03 (d, J= 2. 4 Hz, 1 H, H-6).
- Methyl 3-Chlorosulfonyl-6-hydroxybenzoate
Example 2 EP1362858A1
- 1-(2-hydroxyethyl)piperazine
- R8=ME, W=N, n=2
- Methyl 2-Hydroxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]benzoate
- To a mixture of 1-(2-hydroxyethyl)piperazine (27 mg, 0. 21 mmol) and K2CO3 (33 mg, 0. 24 mmol) in DMF (5 mL) was added methyl 3-chlorosulfonyl-6-hydroxybenzoate (50 mg, 0. 20 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with H2O (10 mL), and the aqueous layer was further extracted with 5% MeOH in CH2Cl2 (20 mL). The combined organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (5% MeOH in CH2Cl2) to afford the titled compound (59 mg, 86%) as white solid.
mp 152 °C (dec) (CH2Cl2/ether);
IR (neat) 1685 (C=O) cm-1;
1H NMR (CDCl3/TMS) δ 2. 30 (br s, 1 H, CH2OH), 2. 63 (t, J = 5. 4 Hz, 2 H, NCH 2CH2O), 2. 70 (m, 4 H, 2 NCH2), 3. 12 (m, 4 H, 2 SO2NCH2), 3. 64 (t, J= 5. 4 Hz, 2 H, NCH2CH 2O), 4. 01 (s, 3 H, OCH3), 7. 12 (d, J= 8. 7 Hz, 1 H, H-3), 7. 81 (dd, J= 8. 7 Hz, 2. 4 Hz, 1 H, H-4), 8. 26 (d, J = 2. 4 Hz, 1 H, H-6), 11. 26 (br s, 1 H, OH);
MS (FAB) m/z 345 (MH+).
- Methyl 2-Hydroxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]benzoate
Example 3 EP1362858A1
Methyl 3-[4-(2-Hydroxyethyl)piperazin-1-ylsulfonyl]-6-n-propoxybenzoate
- To a mixture of methyl 2-hydroxy-5-(4-(2-hydroxyethyl)piperazin-1-ylsulfonyl)benzoate (800 mg, 2. 32 mmol) and K2CO3 (482 mg, 3. 49 mmol) in DMF (5 mL) was added 1-bromopropane (253 µL, 2.79 mmol), and the mixture was stirred at 60°C overnight. The reaction mixture was evaporated to dryness under reduced pressure, washed with H2O (10 mL), and the aqueous layer was further extracted with CH2Cl2 (50 mL x 2). The combined organic layer was dried (MgSO4), filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude residue was purified by MPLC on silica gel (3% MeOH in CHCl3) to afford the titled compound (309 mg, 80%) as a white solid.
mp 88-89 °C (EtOAc/hexanes);
IR (neat) 3242 (OH), 1741 (C=O) cm-1;
1H NMR (CDCl3/TMS) δ 1. 09 (t, J = 7. 5 Hz, 3 H, OCH2CH2CH 3), 1. 84-1. 95 (m, 2 H, OCH2CH 2CH3), 2. 23 (br s, 1 H, CH2OH), 2. 54 (t, J= 5. 4 Hz, 2 H, NCH 2CH2O), 2. 60 (m, 4 H, 2 NCH2), 3. 04 (m, 4 H, 2 SO2NCH2), 3. 58 (t,J = 5. 4 Hz, 2 H, NCH2CH 2O), 3. 91 (s, 3 H, OCH3), 4. 08 (t, J= 6. 6 Hz, 2 H, OCH 2CH2CH3), 7. 07 (d, J = 9. 0 Hz, 1 H, H-3), 7. 82 (dd, J = 9. 0 Hz, 2. 4 Hz, 1 H, H-4), 8. 15 (d, J = 2. 4 Hz, 1 H, H-6);
MS (FAB) m/z 387 (MH+).
- FURTHER INFO OTHER THAN ABOVE PATENT
- HYDROLYSE Methyl 3-[4-(2-Hydroxyethyl)piperazin-1-ylsulfonyl]-6-n-propoxybenzoate TO -COOLi SALT using LiOH
- CONDENSE WITH 3-amino-1-ethyl-4-propyl-1H-pyrrole-2-carboxamide USING HOBt AND DMAP/ PYRIDINE
9……….Methyl 3-[4-(2-Hydroxyethyl)piperazin-1-ylsulfonyl]-6-n-propoxybenzoate R8= ME, R4=PROPYL, W=N, n=2
10……….3-amino-1-ethyl-4-propyl-1H-pyrrole-2-carboxamide R1=ETHYL, R2=H, R3=PROPYL, IN ABOVE
YOU WILL GET A COMPD
R1 ETHYL
R2=H
R3= PROPYL
R4 = PROPYL
W=N
n=2
IS MIRODENAFIL precursor ie n-1 compund
- CYCLIZE THIS WITH BuOK/tBuOH AND USE ACID TO GET FINAL PRODUCT MIRODENAFIL
- A cyclization reaction is generally carried out by heating at an elevated temperature, for example 50-150° C., in the presence of an acid or a base in a suitable solvent such as an aqueous C1-C4 alkanol, water, a halogenated hydrocarbon, or acetonitrile. Thus, for example, the cyclization may be affected by treatment of a compound with an inorganic or organic base such as sodium hydroxide, potassium carbonate or potassium tert-butoxide, in an alcoholic aqueous medium, preferably potassium tert-butoxide in tert-butanol at 60° C. to reflux temperature.
SYNTHESIS OF 1-(2-hydroxyethyl)piperazine needed for MIRODENAFIL SYNTHESIS
Compounds of the formula (29) can be prepared from the compounds of the formula (30):
wherein X and P are as previously defined.
note X=N ATOM, n = 2
…………………………….
MIRODENAFIL
Two methods were published for the determination of mirodenafil in biological fluids. Choi et al. (2009) describe an isocratic reversed-phase liquid chromatographic method for simultaneous analysis of mirodenafil and its two main metabolites, SK3541 and SK3544, in rat plasma, urine, and tissue homogenates. The authors used a simple deproteinization procedure for sample preparation, and the compounds were separated on a C18 column (250 mm x 4.6 mm, i.d.; 5 µm particle size; Shiseido, Tokyo, Japan). The mobile phase was constituted with 0.02 M ammonium acetate buffer (pH 6):acetonitrile (52:48, v/v) at a flow rate of 1.4 mL/min. UV detection was at 254 nm.
Lee et al. (2009) developed a study with the proposed method to determine sildenafil and mirodenafil in the plasma and corpus cavernosum tissue of rats using LC–MS/MS. A CapcellPak phenyl column (2.1mm x 150 mm, 5µm) maintained constant at 40 ºC was used for the separation. The mobile phase consisted of 90% acetonitrile in 5 mM ammonium formate (pH 6.0). A gradient program was used for the LC separation with a flow rate of 0.2 mL/min.
References
- Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC, Kim SW, Lee SW, Min KS, Moon KH, Park JK, Park K, Park NC, Suh JK, Yang DY, Jung HG (November 2008). “Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction”. The Journal of Sexual Medicine 5 (11): 2672–80. doi:10.1111/j.1743-6109.2008.00945.x. PMID 18638004.
- Kim BH, Yi S, Kim J, Lim KS, Kim KP, Lee B, Shin SG, Jang IJ, Yu KS (June 2009). “Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: a single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea”.Clinical Therapeutics 31 (6): 1234–43. doi:10.1016/j.clinthera.2009.06.008. PMID 19695390.
- Shin KH, Kim BH, Kim TE, Kim JW, Yi S, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (December 2009). “The effects of ketoconazole and rifampicin on the pharmacokinetics of mirodenafil in healthy Korean male volunteers: an open-label, one-sequence, three-period, three-treatment crossover study”.Clinical Therapeutics 31 (12): 3009–20. doi:10.1016/j.clinthera.2009.12.012. PMID 20110038.
- Synthesis of 5-ethyl-2-[5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]-2-n-propoxyphenyl]-7-n-propyl-3,5-dihydro-4H-pyrrolo[3,2-d]-[2-14C]pyrimidin-4-one·2 HCl (14C-SK3530·2 HCl)J Label Compd Radiopharm 2006, 49(13): 1141
- More information about mirodenafil can be found at Paick J S et al., (2008) The Journal of Sexual Medicine, 5 (11): 2672-80.
- PDE-5 inhibitor that came into the market recently (Choi et al., 2009; Lee et al., 2009).not currently approved for use in the United States but clinical trials are being conducted.
- Crystal forms of SK-3530.
Song HO, Sohn YT.Arch Pharm Res. 2010 Dec;33(12):2033-6. doi: 10.1007/s12272-010-1220-3. Epub 2010 Dec 30. - Looking to the future for erectile dysfunction therapies.Hatzimouratidis K, Hatzichristou DG.Drugs. 2008;68(2):231-50. Review.
- Paick JS, Ahn TY, Choi HK, Chung WS, Kim JJ, Kim SC, Kim SW, Lee SW, Min KS, Moon KH, Park JK, Park K, Park NC, Suh JK, Yang DY, Jung HG (November 2008). “Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction”. The Journal of Sexual Medicine 5 (11): 2672–80. doi:10.1111/j.1743-6109.2008.00945.x. PMID 18638004.
- Kim BH, Yi S, Kim J, Lim KS, Kim KP, Lee B, Shin SG, Jang IJ, Yu KS (June 2009). “Influence of alcohol on the hemodynamic effects and pharmacokinetic properties of mirodenafil: a single-dose, randomized-sequence, open-label, crossover study in healthy male volunteers in Korea”. Clinical Therapeutics 31 (6): 1234–43.doi:10.1016/j.clinthera.2009.06.008. PMID 19695390.
- Shin KH, Kim BH, Kim TE, Kim JW, Yi S, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (December 2009). “The effects of ketoconazole and rifampicin on the pharmacokinetics of mirodenafil in healthy Korean male volunteers: an open-label, one-sequence, three-period, three-treatment crossover study”. Clinical Therapeutics 31 (12): 3009–20.doi:10.1016/j.clinthera.2009.12.012. PMID 20110038.
- Matheny, C., et al., Drug Metab. Dispos., 32, 1008 (2004)
Gupta, M., et al., J. Clin. Pharmacol., 45, 987 (2005)
Ek, M., et al., Biochem. Pharmacol., 74, 496 (2007)
Lee, H., et al., Xenobiotica, 38, 21 (2008)
PATENTS
1 WO 2001060825
2.WO 2013085276
3 KR 2013086771
4 WO2008/4796 A1
WO2006018088A1 * | Jul 15, 2005 | Feb 23, 2006 | Switch Biotech Ag | Use of a pde 5 inhibitor for treating and preventing hypopigmentary disorders |
KR20010083637A * | Title not available |
US6962911 * | Feb 15, 2001 | Nov 8, 2005 | Sk Chemicals Co., Ltd. | Pyrrolopyrimidinone derivatives, process of preparation and use |
US20100069632 * | Jul 3, 2007 | Mar 18, 2010 | Sk Chemicals Co., Ltd | Salts of pyrrolopyrimidinone derivatives and process for preparing the same |
EP2038282A1 * | Jul 3, 2007 | Mar 25, 2009 | SK Chemicals, Co., Ltd. | Salts of pyrrolopyrimidinone derivatives and process for preparing the same |
Wednesday, 29 January 2014
Sweet success for bio-battery
An enzyme cascade strips electrons from glucose and turns it into electricity that could be used to power a mobile phone © NPG
Sugar is an excellent source of energy. Most living cells generate their energy from glucose by passing it down an enzymatic chain that converts it into different sugars. This enzymatic cascade provides the necessary energy to create an electrochemical gradient. This, in turn, can be used to power an enzyme that synthesises adenosine triphosphate (ATP) – the universal biological energy currency. However, extracting this energy from a sugar if you’re not a biological organism is tricky – short of combustion, which is impractical to power handheld electronics.
To fuel their battery the team used maltodextrin – a polymer made up of glucose subunits. They then created an entirely new synthetic enzymatic pathway to extract energy from the sugar. Using 13 different enzymes they were able to strip, on average, 24 electrons from a single glucose molecule, which can then be harnessed to power an electrical device.
Tuesday, 28 January 2014
Gisadenafil for erectile dysfunction
GISEDENAFIL
GISEDENAFIL BESYLATE
334826-98-1 free form
334827-98-4 (as besylate)
334827-98-4 (as besylate)
- UK 369003
- UK-369,003
- UK0369,003
- UNII-S6G4R7DI1C
THERAPEUTIC CLAIM Treatment of lower urinary tract
symptoms associated with BPH
symptoms associated with BPH
CHEMICAL NAMES FREE FORM
1. ........7H-Pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[(4-ethyl-1-
piperazinyl)sulfonyl]-3-pyridinyl]-3-ethyl-2,6-dihydro-2-(2-methoxyethyl)-
piperazinyl)sulfonyl]-3-pyridinyl]-3-ethyl-2,6-dihydro-2-(2-methoxyethyl)-
2. .......5-{2-ethoxy-5-[(4-ethylpiperazin-1-yl)sulfonyl]pyridin-3-yl}-3-ethyl-2-(2-
methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
3.........1-(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine
MOLECULAR FORMULA C23H33N7O5S
MOLECULAR WEIGHT 519.6
CODE DESIGNATION UK-369,003
CAS REGISTRY NUMBER 334826-98-1
5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-(2-methoxyethyl)-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-7-one
Phosphodiesterase PDE5A Inhibitors , Treatment of Erectile Dysfunction
Pfizer (Originator)
UK-369003 is a phosphodiesterase V (PDE V) inhibitor which had been under development for the treatment of erectile dysfunction, pulmonary hypertension and for the treatment of lower urinary tract symptoms, but no recent development has been reported for these indications. Trials for the treatment of benign prostatic hyperplasia were discontinued.
Gisadenafil besylate (USAN)
D09622, 334827-98-4
M.Wt:677.79
5-(2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl)-3-ethyl-2-(2-methoxyethyl)-2H-pyrazolo[4,3-d]pyrimidin-7(6H)-one benzenesulfonate
1-[[6-Ethoxy-5-[3-ethyl-4,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridinyl]sulfonyl]-4-ethylpiperazine Monobenzenesulfonate
Formula:C23H33N7O5S.C6H6O3S
Certificate of Analysis |
|
Biological Activity:Potent and selective PDE5 inhibitor (IC50: 1.23 nM) with improved selectivity over PDE6(PDE5/6 selectivity value 117 and >3000-fold selectivity over other PDEs).Gisadenafil has the potential for oral bioavailability and dose-proportional pharmacokinetics. Close analogue of Sildenafil (Viagra; Axon 2046) |
Gisadenafil besylate is a PDE5 inhibitor. Inhibition of PDE5 prevents the breakdown of cyclic phosphodiester secondary messenger molecules. This has the effect of prolonging and enhancing signal transduction.
CLINICAL TRIALS
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PAPERS
Bioorganic and Medicinal Chemistry, 2012 , vol. 20, 1 p. 498 - 509
Scheme 1.
Reagents and conditions: (i) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, hydroxybenzotriazole, di-isopropylethylamine, THF, 20 °C, 20 h; (ii) caesium carbonate, alkyl mesylate or alkyl chloride, DMF, 20 °C, 20 h; (iii) KHMDS, R1OH, 120 °C, 20 h.
Scheme 2.
Reagents and conditions: (i) KHMDS, nBuOH, 120–130 °C, pressure vessel (ii) TFA, CH2Cl2; (iii) methanesulphonyl chloride, NEt3, CH2Cl2; (iv) HOAc, NaCNBH3, CH2O (v) KHMDS, nBuOH, reflux.
Scheme 3.
Reagents and conditions: (i) caesium carbonate, RCl, DMF; (ii) 50 psi H2, 10% Pd/C (iii) 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, HOBT, di-isopropylethylamine, THF, 20 °C, 20 h; (iv) KHMDS, ethanol, 120 °C, pressure vessel; (v) TFA, CH2Cl2; (vi) CH2O, HOAc, NaCNBH3; (vii) R1OH, KHMDS, 120 °C.
Scheme 4.
Reagents and conditions: (i) NaNO2, HCl, H2O; (ii) TFAA, Et2O; (iii) ethyl propynoate, xylene, reflux, 2 h; (iv) NaOH, H2O, dioxan; (v) HNO3/H2SO4, 40–55 °C; (vi) (COCl)2, CH2Cl2, DMF; (vii) NH3, THF; (viii) 10% Pd/C, EtOH, 60 psi H2, 20 °C, 14 h; (ix) acid chloride of 3, NEt3, CH2Cl2; (x) KHMDS, EtOH, 130 °C, 14 h, pressure vessel; (xi) methoxyethanol, KHMDS, reflux, 14 h.
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PAPERS
Org. Proc. Res. Dev., 2004, 8 (4), pp 674–679
DOI: 10.1021/op0300241
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PAPERS
Yousef Hajikarimian, Steve Yeo, Robert W. Ryan, Philip Levett, Christopher Stoneley and Paul Singh
Org Process Res Dev 2010, 14(4): pp 1027–1031
Publication Date (Web): June 25, 2010 (Article)
DOI: 10.1021/op100141g
UK-369,003 was nominated for development as the lead candidate for treatment of benign prostatic hyperplasia (BPH). The free base was found to be moderately crystalline with a melting point of 168 °C. Solubility of the free base at physiological pH was found to be poor hence necessitating a comprehensive screen for a suitable salt form of the API. Benzenesulfonic acid was found to form the most suitable counterion for the API with a melting point of 248 °C and satisfied all our requirements for primary and secondary processing. The process for the formation of the benzenesulfonic acid salt involved the use of water/methyl ethyl ketone (4% water by volume) as the reaction medium. The water level at 4% ensured an optimum balance between product quality (purging of impurities) and the reaction yield. The cyclisation reaction (step 2/Scheme 01) involves the use of ethanol as the reaction media. Any residual amount of ethanol in the isolated step 2 product was therefore considered to be a considerable risk factor in the potential formation of ethyl besylate during the final step processing (step 3/Scheme 01).
Scheme 1. Manufacturing route to UK-369,003-26a
aCDI = carbonyl diimidazole; MEK = methyl ethyl ketone; EtOAc = ethyl acetate; KOtBu = potassium tertiary butoxide; EtOH = ethanol.
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SYNTHESIS
Compound 1E is also known as 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, or alternatively as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridyl sulphonyl}-4-ethylpiperazine (the compound of Example 103 of WO 01/27113 and exemplified hereinafter as Example 1).
Preparation 1
2,2-dimethoxybutane:
Methyl ethyl ketone (672 mL) was charged to a 2 L round bottomed flask and stirred at room temperature before being treated with, trimethylorthoformate (763 mL) and para-toluenesulphonic acid (6.65 g, 0.5 mol %). Over a 15 min period the internal temperature rose to 46° C., so the reaction was cooled to 0° C. for 30 min. The reaction was then stirred at room temperature for 2 h. The reaction was then neutralised by pouring onto sodium carbonate (ca. 750 g) with constant stirring. The resultant slurry was filtered under vacuum and the resultant filtrate was distilled at atmospheric pressure. The fraction boiling in the range 118° C.-124° C. was collected as a colourless liquid, 582 g, 70%.
1H NMR (CDCl3): δ=0.88 (3H, t), 1.24 (3H, s), 1.61 (2H, q), 3.17 (6H, s).
Example 1 N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide
(a) Ethyl 3-ethyl-1H-pyrazole-5-carboxylate (IIA) from (IlI) and (V)
To a stirred solution of 2,2-dimethoxybutane (10 g, 84.7 mMol) in CH2Cl2 (50 mL) under a nitrogen atmosphere at 0° C. was added pyridine (13.7 mL, 169.5 mMol). The reaction mixture was maintained at 0° C. and a solution of trichloroacetyl chloride (18.9 mL, 169.5 mMol) in CH2Cl2 (35 mL) was added over 1 hour with constant stirring. The yellow-orange solution begins to precipitate a white solid as the reaction progresses. The reaction mixture is allowed to warm to room temperature over 20 h. The reaction mixture was diluted with ethanol (150 mL) and re-cooled to 0° C. before treatment with hydrazine hydrate (8.2 mL, 169.5 mMol) as a solution in ethanol (35 mL) over 30 min. The reaction was heated to 50° C. and solvent was distilled at atmospheric pressure. The temperature was increased until the head temperature reached 78° C. Reflux was maintained for a further 2 h, before cooling to room temperature. The reaction mixture was diluted with water (250 mL) and ethanol was removed by evaporation at reduced pressure. The resultant mixture was extracted with CH2Cl2 (3×200 mL). The combined organics were dried (MgSO4), filtered and evaporated at reduced pressure to afford the title compound as a brown oil, 12.05 g, 85%.
1H NMR (300 MHz, CDCl3): δ=1.20 (3H, t), 1.28 (3H, t), 2.67 (2H, q), 4.29 (2H, q), 6.55 (1H, s), 12.56 (1H, s).
LRMS m/z=167.1 [M-H]+, C8H12N2O2 requires 168.2.
(b) Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid (IIA) from (IIA) via route 1
Aqueous sodium hydroxide solution (10M; 100 ml, 1.0 mol) was added dropwise to a stirred suspension of the title compound of Example (a) (66.0 g, 0.39 mol) in methanol and the resulting solution heated under reflux for 4 hours. The cool reaction mixture was concentrated under reduced pressure to ca. 200 ml, diluted with water (200 ml) and this mixture washed with toluene (3×100 ml). The resulting aqueous phase was acidified with concentrated hydrochloric acid to pH 4 and the white precipitate collected and dried by suction to provide the title compound (34.1 g). δ (DMSOd6): 1.13 (3H,t), 2.56 (2H,q), 6.42 (1H,s).
(c) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxylic acid
Fuming sulphuric acid (17.8 ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0 ml), the resulting solution heated to 50° C., then 3-n-propyl-1H-pyrazole-5-carboxylic acid (Chem. Pharm. Bull., 1984, 32,1568; 16.4 g, 0.106 mol) added portionwise over 30 minutes whilst maintaining the reaction temperature below 60° C. The resulting solution was heated for 18 hours at 60° C., allowed to cool, then poured onto ice. The white precipitate was collected, washed with water and dried by suction to yield the title compound (15.4 g), m.p. 170-172° C. Found: C, 42.35; H, 4.56; N, 21.07. C7H9N3O4requires C, 42.21; H, 4.55; N, 21.10%. δ (DMSOd6): 0.90 (3H,t), 1.64 (2H,m), 2.83 (2H,m), 14.00 (1 H,s).
(d) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid (IIA) to (AA) via route 2
Obtained from the title compound of Example (b), by analogy with the process of Example (c), as a brown solid (64%). δ (DMSOd6): 1.18 (3H,t), 2.84 (2H,m), 13.72 (1 H,s).
(e) 4-Nitro-3-n-propyl-1H-pyrazole-5-carboxamide
A solution of the title compound of Example (c) (15.4 g, 0.077 mol) in thionyl chloride (75 ml) was heated under reflux for 3 hours and then the cool reaction mixture evaporated under reduced pressure. The residue was azeotroped with tetrahydrofuran (2×50 ml) and subsequently suspended in tetrahydrofuran (50 ml), then the stirred suspension ice-cooled and treated with gaseous ammonia for 1 hour. Water (50 ml) was added and the resulting mixture evaporated under reduced pressure to give a solid which, after trituration with water and drying by suction, furnished the title compound (14.3 g).
m.p. 197-199° C. Found: C, 42.35; H, 5.07; N, 28.38. C7H10N4O3 requires C, 42.42; H, 5.09; N, 28.27%. δ (DMSOd6): 0.90 (3H,t), 1.68 (2H,m), 2.86 (2H,t), 7.68 (1 H,s), 8.00 (1 H,s).
(f) 3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide BA from AA via route 3
Obtained from the title compound of Example (d), by analogy with Example (e), as a white solid (90%). δ (DMSOd6): 1.17 (3H,t), 2.87 (2H,m), 7.40 (1H,s), 7.60 (1H,s), 7.90 (1H,s). LRMS: m/z 185 (M+l)+.
(g)(i) 5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide CA from BA via route 4
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (2.5 kg, 13.6 Mol), sodium carbonate (1.8 Kg, 17.0 Mol) and 2-bromoethyl methyl ether (1.98 kg, 14.2 Mol) in THF (22.5 L) and water (2.5 L) was heated under reflux and stirred for 20 hours. The mixture was cooled to ambient temperature and CH2Cl2 (67.5 L) and water (22.5 L) were added. The resultant organic and aqueous layers were separated. The aqueous phase was extracted with CH2Cl2 (22.5 L) and the combined organic solution was distilled under atmospheric pressure and replaced with ethyl acetate (33 L) to a final volume of 17 L. The cooled mixture was granulated at ambient temperature for 2 hours, filtered and washed with ethyl acetate (2.5 L). This afforded 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a white crystalline solid, 2.10 kg, 57%. m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4O4 requires C, 44.63; H, 5.79; N, 23.14%.
δ (CDCl3): 1.18 (3H, t), 2.98 (2H, q), 3.22 (3H, s), 3.77 (2H, t), 4.28 (2H, q), 6.03 (1H, s), 7.36 (1H, s).
LRMS: m/z=243 (M+1)+
(g)(ii) 5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide.
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25 g, 0.136 Mol), sodium carbonate (18 g, 0.17 Mol) and sodium iodide (20.4 g, 0.136 Mol) were suspended in ethyl methyl ketone (125 mL) at room temperature. 2-bromoethyl methyl ether (12.8 mL, 0.142 Mol) was added and the mixture was heated to reflux and stirred for 70 hours. The mixture was cooled to ambient temperature and water (250 mL) was added. The resultant slurry was warmed to reflux and held at that temperature for 30 min before cooling to room temperature. The resultant precipitate was granulated at room temperature for 3 h, filtered and vacuum dried to afford 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a yellow crystalline solid 24.3 g, 74%. Data as reported for Example (g)(i).
(h) 4-Amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (IA) from CA via route 5
A mixture of 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide (20 g, 82.6 mMol) and 5% Pd/C (1 g) in methanol (200 mL) was pressurised at 50psi/25° C. in a sealed vessel and stirred for 15 hours. At the end of the reaction the mixture was filtered through arbocel and the filter cake was washed with methanol. The methanolic solution was distilled at atmospheric pressure and replaced with ethyl acetate to a final volume of 100 mL. The cooled mixture was granulated at ambient temperature for 2 h filtered and washed with ethyl acetate (20 mL) to afford 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide as a white crystalline solid, 15 g, 88%. m.p.=131° C. Found: C, 50.75; H, 7.62; N, 26.38. C9H16N4O2 requires C, 50.94; H, 7.55; N, 26.42%. δ (CDCl3): 1.20 (3H, t), 2.63 (2H, q), 3.32 (3H, s), 3.74 (2H, t), 3.95 (2H, s), 4.15 (2H, t), 5.27 (1H, s), 6.59 (1H, s).
LRMS: m/z=213 (M+1)+
(i) N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide.
2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinic acid (2.31 kg, 6.73 Mol) was suspended in ethyl acetate (16.2 L) and 1,1-carbonyldimidazole (1.09 kg, 6.73 Mol) was added at room temperature. The reaction mixture was heated at 45° C. for 40 minutes and then the reaction was stirred for a further 40 minutes at reflux. After cooling to ambient temperature 4-amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide (1.5 kg, 7.06 Mol) was added to the cooled mixture, and the reaction stirred for a further 15 hours under reflux. The mixture was cooled filtered and the filter cake was washed with 90% water/10% ethyl acetate, (2 mL /g) to afford N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide as an off white crystalline solid, 3.16 kg, 88%. m.p.=156° C. Found: C, 51.33; H, 6.56; N, 18.36. C23H35N7O6S requires C, 51.40; H, 6.53; N, 18.25%.
δ (CDCl3): 1.04 (3H, t), 1.22 (3H, t), 1.60 (3H, t), 2.44 (2H, q), 2.54 (4H, m), 2.96 (2H, q), 3.12 (4H, m), 3.36 (3H, s), 3.81 (2H, t), 4.27 (2H, t), 4.80(2H, q), 5.35(1H, s), 6.68 (1H, s), 8.66 (1H, d), 8.86 (1H, d), 10.51 (1H, s).
LRMS: m/z=539 (M+1)+
(i) 1-(6-Ethoxy-5-[3-ethyll-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine•ethyl acetate solvate.
GISADENAFIL
A mixture of N-[3-carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide (1.18 kg, 2.2 Mol), potassium tert-butoxide (500 g, 4.4 moles) and ethyl acetate (193 g) in ethanol (11.8 L) was heated at 120° C. for 20 hours. The reaction mixture was then concentrated under reduced pressure, in total approx. 10 L of solvent were distilled. To the residue water (2.9 L) was added and the mixture stirred at room temperature while aqueous HCl was added until pH 7.5 was obtained. Ethyl acetate (7.5 L) was added and the two phase mixture was warmed to 55° C. The organic phase was separated and the aqueous phase was extracted with further ethyl acetate (3.0 L). The combined organic phases were distilled at atmospheric pressure to a final volume of 4 L. The precipitated solids were granulated at 5° C. for 1 h, filtered and washed with ethyl acetate (1.2 L) and dried under vacuum. This afforded 1-(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazole[4,3-d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine as a light yellow crystalline solid, 877 g, 78%. m.p.=157° C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5CO2CH3 requires C, 53.21; H, 6.49; N, 18.25%.
δ (CDCl3): 1.07 (3H, t), 1.42 (3H, t), 1.61 (3H, t), 2.44 (2H, q), 2.57 (4H, m), 3.08 (2H, q), 3.15 (4H, m), 3.32 (3H, s), 3.92 (2H, q), 4.48 (2H, q), 4.77 (2H, q), 8.65 (1H, d), 9.06 (1H, d). The spectrum also has signals that correspond to a solvate with ethyl acetate.
LRMS: m/z=520 (M+1)+
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Example 102
1-(6-Ethoxy-5-f3-ethyll-6,7-dihvdro-2-(2-methoxyethvn-7-oxo-2r7-pyrazoler4.3- cf1pyrimidin-5-vn-3-pyridylsulfonyl)-4-ethylpiperazine»ethyl acetate solvate.
To prepare the compound of Example 8 a mixture of Λ/-[3-carbamoyl-5-ethyl- 1 -(2-methoxyethyl)-1 /-/-pyrazol-4-yl}-2-ethoxy-5-(4-ethyl-1 -piperazinyl sulfonyl) nicotinamide (1.18 kg, 2.2 Mol), potassium tert-butoxide (500 g, 4.4 moles) and ethyl acetate (193 g) in ethanol (11.8 L) was heated at 120°C for 20 hours. The reaction mixture was then concentrated under reduced pressure, in total approx. 10 L of solvent were distilled. To the residue water (2.9 L) was added and the mixture stirred at room temperature while aqueous HCl was added until pH 7.5 was obtained. Ethyl acetate (7.5 L) was added and the two phase mixture was warmed to 55°C. The organic phase was separated and the aqueous phase was extracted with further ethyl acetate (3.0 L). The combined organic phases were distilled at atmospheric pressure to a final volume of 4L. The precipitated solids were granulated at 5°C for 1 h, filtered and washed with ethyl acetate (1.2 L) and dried under vacuum. This afforded 1 -(6-Ethoxy-5-[3-ethyl]-6,7-dihydro-2-(2-methoxyethyl)-7-oxo- 2H-pyrazole[4,3-o pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine as a light yellow crystalline solid, 877 g, 78%. m.p. = 157°C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5C02CH3 requires C, 53.21 ; H, 6.49; N, 18.25%.
δ(CDCI3): 1.07 (3H, t), 1.42 (3H, t), 1.61 (3H, t), 2.44 (2H, q), 2.57 (4H, m), 3.08 (2H, q), 3.15 (4H, m), 3.32 (3H, s), 3.92 (2H, q), 4.48 (2H, q), 4.77 (2H, q), 8.65 (1 H, d), 9.06 (1 H, d). The spectrum also has signals that correspond to a solvate with ethyl acetate.
LRMS: m/z = 520 (M+1)+
Example 103
1-(6-ethoxy-5-r3-ethyl-6.7-dihvdro-2-(2-methoxyethvn-7-oxo-2H-pyrazolor4.3- dlpyrimidin-5-vn-3-pyridylsulfonyl)-4-ethylpiperazine
GISADENAFIL
10g (0.019 mol) of the compound of Example 8 and Example 102, 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 ethyl acetate solvate, was charged followed by 12ml/g (120mls) of 16% water in ethyl alcohol. The slurry was heated to reflux to yield a solution and 6ml/g (60mls) distilled off at atmospheric pressure. The solution was then cooled to room temperature with crystallisation occurring at 40°C. The slurry was then cooled to 5-10°C and granulated for 30 minutes following which it was filtered and washed with 2ml/g ethyl alcohol (20 mis). The damp solid was dried in vacuo overnight at 55-60 °C to yield a white crystalline solid. (Yield 7.6g, 76%). Melting Point 162- 165°C.
δ (CDCI3): 1.05 (3H,t), 1.42 (3H,t), 1.58 (3H,t), 2.43 (2H,q), 2.57 (4H,t), 3.09 (2H, t), 3.15 (4H,t), 3.30 (3H,s), 3.93 (2H,t), 4.48 (2H,t), 4.90 (2H,q), 8.65 (1 H,d), 9.05 (1 H,d), 10.65 (1 H,s).
In the process of Example 103, water and pharmaceutically acceptable alcohols such as methanol, ethanol, propanol, butanol and mixtures thereof can be used to prepare the compound of Examples 8 and 102.
BESYLATE SALT
Example 104 1-(6-ethoxy-5-r3-ethyl-6,7-dihvdro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolor4.3- d]pyrimidin-5-yl]-3-pyridylsulfonyl)-4-ethylpiperazine benzene-sulfonate salt.
170g (0.33 mol) of the compound of Example 103, 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, was charged followed by a water/ 2- butanone (4% v/v) at 10 ml/g (1.7 litres) and warmed to reflux. 53g (0.33 mol) of benzene sulfonic acid dissolved in water (23mls, resulting in 70 % w/w solution) was added to the refluxing solution over 30 minutes.5.3ml/g (0.9 litres) of 2-butanone were striped and replaced and the slurry cooled. The slurry was cooled to 5-10°C and granulated for 2 hours after which it was filtered and washed with 2ml/g (0.3 litres) of 2-butanone. The salt was dried overnight in vacuo at 55-60°C to yield a white crystalline solid. Yield 215g, 96.4%. Mpt 242-244°C. δ (DMSO): 1.17 (3H, t), 1.28 (3H, t), 1.35 (3H, t), 2.73 (2H, q), 2.97 (2H, q), 3.2 (3H, s), 3.58 (2H, t), 3.78 (3H, t), 3.81 (2H, t), 4.49 (2H, t) 4.51 (2H, q), 7.29-7.33 (3H, m), 7.57-7.60 (2H, m), 8.28 (1 H, d), 8.73 (1 H, d), 9.13 (1 H,s), 11.90(1 H,s).
The powder X-ray diffraction (PXRD) pattern for this salt, having Mpt 242- 244°C, was determined using a Siemens D5000 powder X-ray diffractometer fitted with a theta-theta goniometer, automatic beam divergence slits, a secondary monochromator and a scintillation counter. The specimen was rotated whilst being irradiated with copper K-alpha1 X-rays (Wavelength = 1.5046 Angstroms) filtered with a graphite monochromator (λ = 0.15405nm) with the X-ray tube operated at 40 kV/mA. The main peaks (in degrees θ) of the PXRD pattern are illustrated in Table I.
Table
The same besylate salt, as defined by the XRD pattern described in Table 1 , when made via alternative routes can have a melting point in the range of from 235-246°C (measured using a Perkin Elmer DSC7 at a heating rate of 20°C/minute).
References
1 The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics
Bioorg Med Chem 2012, 20(1): 498.............MP 161 - 162 °C
Bioorg Med Chem 2012, 20(1): 498.............MP 161 - 162 °C
2. Hajikarimian, Y.; Yeo, S.; Ryan, R.W.; Levett, P.; Stoneley, C.; Singh, P.
Investigation into the formation of the genotoxic impurity ethyl besylate in the final step manufacturing process of UK-369,003-26, a novel PDE5 inhibitor
Org Process Res Dev 2010, 14(4): 1027
Investigation into the formation of the genotoxic impurity ethyl besylate in the final step manufacturing process of UK-369,003-26, a novel PDE5 inhibitor
Org Process Res Dev 2010, 14(4): 1027
3. Bentham; Dawson; Dunn; Papadopoulos; Taylor; Mitchell; Snowden; Taylor
Organic Process Research and Development, 2004 , vol. 8, 4 PG. 674 - 679 .............AS ENTRY B
Organic Process Research and Development, 2004 , vol. 8, 4 PG. 674 - 679 .............AS ENTRY B
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PATENTS
1. WO 2010062366
2. WO 2007072156
3 WO 2007072156
4.US2002/22732 A1,
5.US2002/28799 A1,
6.
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WO1999054333A1 * | Mar 25, 1999 | Oct 28, 1999 | Mark Edward Bunnage | Pyrazolopyrimidinone cgmp pde5 inhibitors for the treatment of sexual dysfunction |
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EP0995750A1 | 15 окт 1999 | 26 апр 2000 | Pfizer Inc. | Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction |
WO1998049166A1 | 10 апр 1998 | 5 ноя 1998 | Mark Edward Bunnage | PYRAZOLOPYRIMIDINONES WHICH INHIBIT TYPE 5 CYCLIC GUANOSINE 3',5'-MONOPHOSPHATE PHOSPHODIESTERASE (cGMP PDE5) FOR THE TREATMENT OF SEXUAL DYSFUNCTION |
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WO2001027112A1 | 4 окт 2000 | 19 апр 2001 | Charlotte Moira Norfo Allerton | 5-(2-substituted-5-heterocyclylsulphonylpyrid-3-yl)-dihydropyrazolo[4,3-d]pyrimidin-7-ones as phosphodiesterase inhibitors |
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PDE5 inhibitors mirodenafil
sildenafil
tadalafil
udenafil 3-(l-methyl-7-oxo-3-propyl-4H-pyrazolo[5,4-e]pyrimidin-5-yl)-N- [2-(l -methylpyrrolidin-2-yl)ethyl] -4-propoxybenzenesulfonamide
vardenafil 4-[2-ethoxy-5-(4-ethylpiperazin-l-yl)sulfonyl-phenyl]-9-methyl-7- propyl- 3,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one
avanafil 4-[(3-chloro-4-methoxy-phenyl)methylamino]-2-[(2S)-2- (hydroxymethyl)pyrrolidin- 1 -yl] -N-(pyrimidin-2- ylmethyl)pyrimidine-5-carboxamide
dasantafil 7-[(3-bromo-4-methoxyphenyl)methyl]-l-ethyl-8-[[(lR,2R)-2- hydroxycyclopentyl]amino]-3-(2-hydroxyethyl)purine-2,6-dione
NM 702 (Nissan Chemical Industries)
SLX 101 (Surface Logix) - Structure Not Available
UK 369003 (Pfizer) - Gisadenafil besylate
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