UDENAFIL

An oral phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction.

268203-93-6 CAS NO

LAUNCHED 2005 MEZZION DA-8159  ME-3113 Udzire  Zydena MEZZION …INNOVATOR

POWERPOINT PRESENTATION BY INNOVATOR.. CLICK HERE

3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide

(5- [2-propyloxy-5- (1- methyl-2-pyrolidinylethylamidosulfonyl) phenyl] -1-methyl- propyl-1, β-dihydro-7H-pyrazolo (4 , 3-d) pyrimidin-7-one)

A pyrazolo-pyrimidinone similar to sildenafil; phosphodiesterase type 5 inhibitor. Udenafil is a new phosphodiesterase type 5 (PDE5) inhibitor used to treat erectile dysfunction (ED). It has been approved in South Korea and will be marketed under the brand name Zydena.

It is not yet approved for use in the U.S., E.U., or Canada. Udenafil (Zydena^®) is also a potent and selective PDE5i developed by Dong-A Pharmaceutical Company in Korea (Kim et al., 2008; Han et al., 2010).

It has not yet been approved by FDA or the European Medicines Agency (EMEA) and was only approved by the Korean Food and Drug Administration (KFDA), being currently used in Korea and Russia (Alwaal et al., 2011; Cho et al., 2012).

• DA 8159
• DA-8159
• Udenafil
• UNII-L5IB4XLY36
• Zydena

Udenafil is a drug used in urology to treat erectile dysfunction. It belongs to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafil, tadalafil, and vardenafil also belong to. It was developed by Dong-A Pharmaceutical Co., Ltd. and is marketed under the trade name Zydena™.^[2] With a T max of 1.0-1.5 h and a T 1/2 of 11-13 h (a relatively rapid onset and a long duration of action), both on-demand and once-daily use of udenafil have been reported.^[3] Typical doses are 100 and 200 mg. It is not approved for use in the United States by theU.S. Food and Drug Administration. Udenafil (DA-8159), a pyrazolopyramidinone derivative that acts as a phosphodiesterase 5 (PDE5) inhibitor, was launched by Dong-A Pharmtech (currently Mezzion Pharma) in late 2005 in Korea for the oral treatment of erectile dysfunction (ED). The company is currently conducting phase III clinical trials in the U.S. for this indication.

Dong-A Pharmatech is conducting phase III clinical trials for the treatment of patients with portal hypertension resulting from liver disease and for the treatment of benign prostatic hyperplasia (BPH). Phase II/III clinical studies at Dong-A Pharmatech for the treatment of secondary Raynaud phenomenon have been completed. Meiji Seika Pharma is developing the compound in phase I clinical trials for the treatment of BPH in Japan.

Phosphodiesterases regulate the tissue concentration of cyclic guanosine monophosphate (cGMP), which in turn triggers smooth muscle relaxation, allowing blood to flow into the penis and resulting in erection. PDE5 is the most abundant phosphodiesterase in the human corpus cavernosum, and as such its inhibition by DA-8159 enhances erectile function by increasing the concentration of cGMP. Results from phase I studies indicate that udenafil has a unique pharmacokinetic profile with a relatively rapid onset and sufficiently long duration to make it effective for up to 24 hours. In 2009, the compound was licensed to Warner Chilcott (acquired by Actavis in 2013) by Dong-A Pharmatech for development and marketing in the U.S. for the oral treatment of erectile dysfunction.

In 2011, udenafil was licensed to Meiji Seika Pharma by Dong-A ST in Japan for the treatment of benign prostatic hyperplasia. Udenafil is a potent novel phosphodiesterase-5 inhibitor approved for use in Korea. Udenafil has unique properties, with a T max of 1.0–1.5 h and a T 1/2 of 11–13 h (a relatively rapid onset and a long duration of action). Therefore, both on-demand and once-daily use of udenafil have been reported. Udenafil’s efficacy and tolerability have been evaluated in several studies, and recent and continuing studies have demonstrated udenafil’s promise in both dosing regimens. Presently, tadalafil is the only FDA-approved drug for daily dosing, but udenafil can be used as a once-daily dose for erectile dysfunction patients who cannot tolerate tadalafil due to phosphodiesterase subtype selectivity. Udenafil as an on-demand or once-daily dose is effective and tolerable, but more studies are needed in patients of other ethnicities and with comorbid conditions such as diabetes mellitus, hypertension, and benign prostate hyperplasia.

Erectile dysfunction (ED) is defined as the inability to achieve and maintain a sufficient erection to permit satisfactory intercourse [Montorsi et al. 2010]. Numerous strategies have been used to overcome ED. Therapies for ED include intracavernosal injection, vacuum erection devices, intraurethral suppositories, penile prosthesis surgery and oral phosphodiesterase-5 (PDE5) inhibitors [Dinsmore and Evans, 1999]. Oral PDE5-inhibitor medications have revolutionized the treatment of ED. Men prefer oral medications as the first-line therapeutic option in the absence of a specific contraindication to their use [Ding et al. 2012].

There are currently four PDE5 inhibitors (sildenafil, vardenafil, tadalafil, and avanafil) approved worldwide for the treatment of male erectile dysfunction, with two other agents (udenafil and mirodenafil) currently approved only in Korea [Bell and Palmer, 2011]. The choice of PDE5 inhibitor for each patient should be determined after physician and patient discuss the characteristics of different drugs and the individual patient’s sexual habits, preferences, and expectations [Hatzimouratidis et al. 2010]. There are two types of treatment usage of PDE5 inhibitors according to their pharmacological characteristics. On-demand treatment of ED with PDE5 inhibitors allows the patient to have intercourse within 1 hour, but can remove spontaneity from sexual activity and be burdensome to patients and their partners [Hanson-Divers et al. 1998]. Once-daily dosing of a PDE5 inhibitor is an alternative for couples that prefer spontaneous sexual activities.

A new oral selective PDE5 inhibitor, udenafil (Zydena, Dong-A, Seoul, Korea), has recently been developed for the treatment of ED. Udenafil is a novel pyrazolopyrimidinone compound developed by Dong-A Pharmaceutical Co., Ltd (Seoul, Korea) for the treatment of ED which has the same mechanism of action as sildenafil [Kim et al. 2008]. Udenafil is rapidly absorbed, reaching peak plasma concentrations at 0.8–1.3 h, then declining monoexponentially with a terminal half-life (T 1/2) between 7.3 and 12.1 hours, giving it the unique pharmacokinetics of both relatively rapid onset and long duration [Salem et al. 2006]. Thus, both on-demand treatment and once-daily dosing have been reported in the literature. The purpose of this review is to evaluate the efficacy and tolerability of udenafil for patients with ED according to the currently available literature.

Udenafil” refers to the chemical compound, 3-(1-methyl-7-oxo-3-propyl-4,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide and has the following chemical formula:

More information about udenafil can be found at Kouvelas D. et al., (2009) Curr Pharm Des, 15(30):3464-75. Udenafil is marketed under the trade name Zydena® but not approved for use in the United States. TRADE NAME IN INDIA – UDEZIRE Erectile dysfunction (ED) is an inability to achieve or sustain an erection suitablefor sexual intercourse.

Sexologists say at least 10% men in India may have to use these drugs at some point. Studies have shown that 40% of men up to the age of 40 years have ED andit goesup 70% by 60 years. The commonly prescribed drugs for the disorder in India are sildenafil(Viagra) and tadalafil,which belong to a category called phosphodiesterasetype5 drugs.

Now, Zydus, a pharmaceutical company, has got exclusive permission to sell udenafil. It’s not always that the release of a drug is celebrated by many, particularly men. A drug that was released in India last week is the recent in the list of drugs that has a cure for erectile dysfunction. The manufacturers say udenafil, which will be marketed under the brand name Udezire, will be long-acting, but with minimal side effects. Erectile dysfunction (ED) is an inability to achieve or sustain an erection suitable for sexual intercourse. Sexologists say at least 10% men in India may have to use these drugs at some point. Studies have shown that 40% of men up to the age of 40 years have ED and it goes up 70% by 60 years

Udenafil like Sildenafil, Tadalafil, Avanafil,  and Vardenafil (Viagra®, Cialis®, Stendra ® and Levitra® respectively) is an orally taken PDE-5 inhibitor. Its function is very similar in that it blocks the action of phosphodiesterase type 5 and relieves erectile dysfunction in men.

UDENAFIL

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INTRODUCTION

Udenafil (Zydena®) is a therapeutic agent hypothesized to improve erectile function endpoints through interaction with the phosphodiesterase type 5 (PDE5) enzyme. As such, udenafil belongs to the class of such agents that includes tadalafil (Clalis®), sildenafil (Viagra®), and vardenafil (Levitra®). These agents are purported to promote erectile response through inhibition of PDE5, the predominant PDE within the penis, which leads to higher intracellular levels of cyclic guanylate cyclase (cGMP). cGMP is a second messenger for the smooth-muscle relaxing effects of nitric oxide within the penis. The various agents differ in pharmacology primarily based on 1) onset and duration of action and 2) selectivity profiles vs. other PDEs. All three marketed agents have proven remarkably safe. These agents should not be taken by patients with unstable cardiovascular disease. Udenafil has been shown to exhibit greater selectivity against the known PDE homologues, than other PDE5 inhibitors. Udenafil is comparable to tadalafil in many respects, such as duration of action and high selectivity for PDE6, but udenafil has greater selectivity for PDE11 than tadalafil.

Tadalafil, with a half life of 17.5 hours, has a much longer duration of action and improved exercise tolerance than either sildenfail or vardenafil, which have half lives of 4-5 hours. Consequently, tadalafil is associated with less planning or pressure to have sexual intercourse after dosing. Dissociation of the sexual activity from the time of dosing is associated with higher rates of patient and partner satisfaction. In prospective, randomized crossover clinical studies, patients preferred tadalafil over sildenafil by margins ranging from 7:3 to 9:1. Sildenafil and vardenafil both modulate PDE6 at higher rate than tadalafil. PDE6 modulation has been associated with chromatopsia. The side effects of chromatopsia, such as sensitivity to light and blurred vision, are therefore higher in patients taking sildenafil or vardenafil, about 2-3%, than patients taking tadalafil, about <0.1%. Tadalafil is less selective than sildenafil and vardenafil for PDE5 and for PDE11a. Activity at PDE11a is suspected to have a causal relationship with myalgia and testicular toxicity. The selectivity profile for udenafil is similar to sildenafil, which should impart greater safety for this agent.

The benefits and shortcomings of these drugs have been reviewed. Some of these shortcomings can be traced to metabolism-related phenomena. Udenafil is converted in vivo by oxidative and conjugative degradation to multiple metabolites. Phase I metabolism leads to demethylation of the pyrazole, hydroxylation of the pyrazole propyl group, and dealkylation alpha to the sulfonamide nitrogen to afford an active metabolite. Because udenafil is metabolized primarily by cytochrome P₄₅₀ subtype 3A4 (CYP3A4), exposure to udenafil can influence polypharmacy. For example, CYP3A4 inhibitors such as HIV protease inhibitors, azole antifungals, and erythromycin can lead to higher than otherwise expected blood levels of udenafil. Conversely, co-administration of CYP3A4 inducers such as rifampin can decrease the otherwise expected blood levels of udenafil. Thus, the polypharmacy of udenafil is necessarily complex and has potential for adverse events. In addition, there may be increased inter-patient variability in response to polypharmacy.

Analogs of udenafil as described herein have the potential to alleviate the problems associated with the commercially available PDE5 inhibitors while maintaining or improving efficacy. It is believed that the reduction in CYP3A4 clearance of udenafil analogs will be expected to increase the proportion of clearance via mechanisms less susceptible to polypharmaceutical complications. In addition, analogs of udenafil having an attenuated rate of oxidative metabolism will have an increased half-life, further augmenting their advantages vs. tadalafil, sildenafil and vardenafil. Potentially, a single dose of an udalafil analog, described herein, having an increased half-life may provide therapeutic coverage for an entire weekend or beyond while increasing safety parameters by reducing the likelihood of drug-drug interactions and by increasing safety as a result of the increased selectivity.

The compounds of formula 1 may contain asymmetric centers and thus they can exist as enantiomers. The present invention includes both mixtures and separate individual isomers . Male erectile dysfunction is one of the most common sexual dysfunctions in men. Although erectile dysfunction can be primarily psychogenic in origin, it often accompanies chronic illnesses, such as diabetes mellitus, heart disease, hypertension, and a variety of neurological diseases. Its prevalence is strongly related to age, with a estimated prevalence of 2% at age 40 years rising to 25-30% by age of 65. Although no data are available on the prevalence of erectile dysfunction in men aged over 75, it is probably over 50%. Various treatment options for erectile dysfunction are available, such as counseling, hormonal therapy, self-injection or transurethral application of vasodilator agents, vacuum devices, prosthesis implantation, and venous/arterial surgery. However, these therapeutic options have several limitations such as side effects, high-cost and low efficacy.

Therefore it has called for research efforts to develop new, high effective and simple to use treatment methods, potentially oral medication. Recently, sildenafil has been developed as a therapeutic agent for male erectile dysfunction by oral administration. Sildenafil is the first in a new class of drugs known as inhibiting phosphodiesterase-5 enzyme distributed specifically in corpus cavernosal tissues and induces relaxation of the corpus cavernosal smooth muscle cells, so that blood flow to the penis is enhanced, leading to an erection.

Sildenafil has shown a response rate of around 80% in men with erectile dysfunction of organic cause. On the other hand, USP 3,939,161 discloses that 1 , 3 -dimethyl -lH-pyrazolopyrimidinone derivatives exhibit anticonvulsant and sedative activiity, and also exhibit anti-inflammatory activity and gastric antisecretory activity; EP 201,188 discloses that 5-substituted pyrazolopyrimidinone derivatives have effects of antagonizing adenosine receptor and of inhibiting phosphodiesterase enzymes and can be used for the treatment of cardiovascular disorders such as heart failure or cardiac insufficiency; EP 463,756, EP 526,004, WO 93/6,104 and WO 93/7,149 disclose that pyrazolopyrimidinone derivatives which inhibit c-GMP phosphodiesterase more selectively than c-AMP phosphodiesterase have efficacy on cardiovascular disorders such as angina pectoris, hypertension, heart failure, atherosclerosis, chronic asthma, etc.; and WO 94/28,902, WO 96/16,644, WO 94/16,657 and WO 98/49,166 disclose that the known inhibitors of c-GMP phosphodiesterase including the pyrazolopyrimidinone derivatives of the above mentioned patents can be used for the treatment of male erectile dysfunction Since sildenafil has been developed, various compounds for inhibiting phosphodiesterase-5 have been reported.

Among them, pyrazolopyrimidinone compounds of formula 1 (KR Pat. No. 99-49384) were reported having better potency than that of sildenafil, based on the mechanism of inhibiting phosphodiesterase-5 and having better selectivity over phosphodiesterase-6 distributed in retina and phosphodiesterase-3 distributed in heart to reduce the side effects. Further, the pyrazolopyrimidinone compounds of formula 1 were said to be improved the solubility and the metabolism in the liver, which are very important factor affecting the rate of the absorption when administered orally.

The KR patent No. 99-49384 also disclosed a process for preparing the pyrazolopyrimidinone compounds of formula , comprising the steps of: a) reacting chlorosulfonated alkoxy bonzoic acid with a primary amine to obtain sulfonamide-substituted benzoic acid; b) reacting the obtained sulfonamide-substituted benzoic acid with pyrazolamine in the presence of activating reagent of carboxylic group or coupling agent of carboxylic group with amine group to obtain corresponding amide compound; and, c) performing an intramolecular cyclization of the obtained amide compound to obtain the pyrazolopyrimidinone compound of formula 1. This reaction is represented in scheme 1 Scheme 1

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SYNTHESIS

WO2007114534A1

The present invention provides an agent comprising a pyrazolopyrimidinone compound (5- [2-propyloxy-5- (1- methyl-2-pyrolidinylethylamidosulfonyl) phenyl] -1-methyl- propyl-1, 6-dihydro-7H-pyrazolo (4, 3-d) pyrimidin-7-one) expressed as formula 1 as an effective ingredient for preventing and treating benign prostatic hyperplasia (BPH) . Formula 1

The pyrazolopyrimidinone compound represented as formula 1 is one of the PDE-5 inhibitors and has characteristics in that it has a strong inhibitive activity and an excellent selectivity for PDE-5; it is readily absorbed as its solubility is improved; it has a good bioavailability and a large volume of distribution; and it has an in vivo half-life longer three times than sildenafil or vardenafil, a drug of the same mechanism. Physicochemical properties of the pyrazolopyrimidinone compound of formula 1 are as follows: it is hardly dissolved in water; however, it is readily dissolved in acetic acid, methanol, chloroform and the like; and it is a white or pale yellow powder, not a hydrate or a solvate, having a melting point of 158 to 161 “Q and having pKal and pKa2 of about 6.5 and 12.5, respectively. The pyrazolopyrimidinone compound represented as formula 1 is prepared via a synthetic process consisting of roughly three steps. The inventors of the present invention have disclosed a method for preparing the same in WO2000/027847 (Corresponding Korean Patent No.0353014), which will now be described roughly as follows. First, in the first step, 4- [2-propyloxy-5- (chlorosulfonyl) benzamido] -l-methyl-3-propyl-5-carbamoyl pyrazole is prepared.

For such preparation, a specified amount of 4- [2-propyloxybenzamido] -l-methyl-3-propyl-5- carbamoyl pyrazole is added to a specified amount of chlorosulfonic acid cooled to 0 ^°Q then, the resultant mixture is stirred, filtered, washed and dried to obtain 4- [2-propyloxy-5- (chlorosulfonyl) benzamido] -l-methyl-3- propyl-5-carbomoyl pyrazole. In the second step, from the pyrazole compound prepared in the first step, 4- [2-propyloxy-5- ( l-methyl-2- pyrolidinylethylamidosulfonyl) benzamido] -l-methyl-3- propyl-5-carbomoyl pyrazole is prepared. For such preparation, a specified amount of 2- (2-aminoethyl) -1- methyl pyrolidine is added in dichloromethane solution of the specified amount of 4- [2-propyloxy-5- (chlorosulfonyl) benzamido] -l-methyl-3-propyl-5-carbamoyl pyrazole prepared in the first step to be stirred. Then, the reactant solution is diluted with dichloromethane. The organic layer is washed, dried, concentrated and filtered to obtain 4- [2-propyloxy-5- (l-methyl-2- pyrolidinylethylamidosulfonyl) benzamido] -l-methyl-3- propyl-5-carbomoyl pyrazole is obtained.

Last, in the third step, the pyrazolopyrimidinone compound of the present invention (5- [2-propyloxy-5- (1- methyl-2-pyrolidinylethylamidosulfonyl) phenyl] -1-methyl- propyl-1, β-dihydro-7H-pyrazolo (4 , 3-d) pyrimidin-7-one) is prepared from the compound obtained in the second step. For such preparation, the specified amount of pyrazole compound prepared in the second step is dissolved in t- butanol . A specified amount of potassium t-butoxide is added in the resultant solution and, then, reflux-stirred for a predetermined time. After the resultant solution is cooled, diluted, washed and dried, distillation under reduced pressure, solvolysis and silica gel column chromatography are carried out, thus obtaining a specified amount of pure pyrazolopyrimidinone compound of the present invention

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SYNTHESIS WO2000027848A1

REACTION SCHEME 2

The process for preparation according to the present invention comprises the steps of : 1) reacting the chlorosulfonated compound of formula ( 2 ) and primary amine (3_) under the condition of suitable temperature and suitable solvent to give sulfonamide (4.) (step 1) ; 2) reacting the carboxylic acid (4.) prepared in step 1 and pyrazoleamine (5) to give an amide (6.) by the known method preparing amide from carboxylic acid and amine (step 2) ; and 3) cyclizing the amide (6.) prepared in step 2 to give the desired compound of formula 1 by the known cyclization method used for preparation of pyrimidinone (step 3) .

In step 1, a little excess of 2 equivalents of amine may be used, or a little excess of 1 equivalent of amine and 1 equivalent of acid scavenger such as tertiary amine are may be used together. The reaction temperature is preferred below 20 °C. The known method preparing amide from carboxylic acid and amine in step 2 is the process, for example, in which carboxyl group is transformed into activated acid chloride or acid anhydride by using thionyl chloride, pivaloyl chloride, trichlorobenzoyl chloride, carbonyldiimidazole, diphenylphosphinic chloride, etc. and followed by reacting with amine group, or the process using coupling agents such as DCC (1,3-dicyclo hexylcarbodiimide) or EEDQ (N-ethoxycarbonyl -2 -ethoxy- 1, 3-dihydroquinoline) .

The cyclization process in step 3 may be carried out in the presence of a suitable base and a suitable solvent. Preferred bases which are employed in step 3 are metal alkoxides; metal salts of ammonia; amine; hydrides of alkali metal or alkaline earth metal; hydroxides; carbonates; bicarbonates ; and bicyclic amidines such as DBU (1 , 8-diazabicyclo [5.4.0] undec -7-ene) and DBΝ (1 , 5-diazabicyclo [4.3.0] non-5-ene) . Preferred solvents which are employed in step 3 are alcohols such as methanol, ethanol, isopropanol, t-butanol, etc.; ethers such as tetrahydrofuran, dimethoxyethane, dioxane, etc.; aromatic – hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc.; acetonitrile; dimethylsulfoxide; dimethylformamide; N-methylpyrrolidin-2 -one ; and pyridine.

SEE   ENTRY no  68

5- [2-propyloxy-5- ( 1-methyl-2-pyrrolidinylethyl amidosulfonyl) phenyl] -l-methyl-3 -propyl-1 , 6-dihydro-7 H-pyrazolo (4 , 3-d) yrimidin-7-one (compound of example68)

ACCORDING TO ME ENTRY IS 68  ANY ERROR, amcrasto@gmail.com

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Synthesis WO2001098304A1

The present invention relates to a process for preparing pyrazolopyrimidinone derivatives of formula 1 and pharmaceutically acceptable salts thereof which have an efficacy on impotence, comprising the steps of chlorosulfonation of pyrazolamide compounds of formula 2, followed by amination with a primary amine and intramolecular cyclization. Formula 1

Formula 2

The compounds of formula 1 may exist in tautomeric equilibrium as shown below.

The compounds of formula 1 may also contain asymmetric centers and thus they can exist as enantiomers. The present invention includes both racemic mixture and separate individual enantiomers. Scheme 2

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SYNTHESIS WO2010013925A2

INTERMEDIATES

4-[2-propyloxy benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole

CHLOROSULPHONIC ACID

4-[2-propyloxy-5-(chlorosulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole

2-(2-aminoethyl)-l-methylpyrrolidine 4-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl amido- sulfonyl)benzamido]-l-methyl-3-propyl-5-carbamoyl pyrazole

potassium t-butoxide

3, 5-[2-propyloxy-5-(l-methyl-2-pyrrolidinylethyl amido- sulfonyl)phenyl]-l-methyl-3-propyl-l,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one UDENAFIL

The present invention provides a pharmacological compound containing 5- [2-propyloxy-5-( 1 -methyl-2-pyrolidinylethylamidosulphonyl)phenyl] – 1 -methyl-prop yl- 1 ,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, a pyrazolopyrimidinone compound, represented by the following Chemical Formula 1 or pharmaceutically acceptable salts thereof, as an active ingredient for prevention and treatment of respiratory diseases. [14] [Chemical Formula 1]

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SYNTHESIS

US20080194529,

EXAMPLE 2 3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-4-propoxy-benzenesulfonamide

Step 1

2,4-Dioxo-heptanoic acid methyl ester: Sodium (25.3 g, 1.1 mol) was proportionally added to ethanol (350 mL) at ambient temperature with vigorous stirring, and the solution was cooled to 0° C. Pentan-2-one (86 g, 1.0 mol) and diethyl oxalate (146 g, 1.0 mol) were added sequentially at 0° C., and stirring was continued for 1 hour at 0° C., and overnight at ambient temperature. The solvent was removed under reduced pressure, diethyl ether (200 mL) and cold dilute hydrochloric acid (500 mL) were added. Following standard extractive work up, the solvent was evaporated under reduced pressure to yield the title compound (141 g, 76%). ¹H-NMR (300 MHz, CDCl3) δ 14.51 (broad s, 1H), 6.37 (s, 1H), 4.35 (q, 2H, J=6.6 Hz), 2.47 (t, 2H, J=7.2 Hz), 1.76-1.66 (m, 2H), 1.38 (t, 3H, J=7.2 Hz), 0.97 (t, 3H, J=7.5 Hz); GC-MS: 186 (M)⁺, 113 (M-73)⁺

Step 2

5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester: Hydrazine hydrate (41.4 g, 827 mmol) was slowly added to a solution of 2,4-dioxo-heptanoic acid methyl ester (140 g, 753 mmol) in 280 mL of acetic acid at 0° C. The mixture was heated to reflux for 8 hours and cooled. The solvent was removed under reduced pressure; the residue was diluted with diethyl ether (300 mL). Following standard extractive work up, the solvent was evaporated under reduced pressure to yield the title compound as a white solid (131 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 9.27 (broad s, 1H), 6.61 (s, 1H), 4.37 (q, 2H, J=7.2 Hz), 2.68 (t, 2H, J=7.5 Hz), 1.75-1.62 (m, 2H), 1.37 (t, 3H, J=6.6 Hz), 0.96 (t, 3H, J=7.2 Hz); LC-MS: m/z=183 (MH)⁺;

Step 3

2-Methyl-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester: A mixture of 5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester (32.8 g, 180 mmol) and dimethyl sulfate (24.9 g, 198 mmol) was heated at 90° C. for 3 hours. The reaction was cooled and diluted with dichloromethane (200 mL). Following standard extractive work up, the solvent was evaporated under reduced pressure to yield a crude residue which was purified by flash chromatography on silica gel to give the title compound as a colorless oil (23 g, 65%). ¹H NMR (300 MHz, CDCl₃) δ 6.59 (s, 1H), 4.37 (q, 2H, J=7.2 Hz), 2.58 (t, 2H, J=7.2 Hz), 1.76-1.64 (m, 2H), 1.40 (t, 3H, J=6.6 Hz), 1.01 (t, 3H, J=7.2 Hz), 4.40 (q, 2H), 3.89 (s, 3H), 2.59 (t, 2H), 1.69 (2H), 1.37 (t, 3H), 1.01 (t, 3H); LC-MS: m/z=197 (MH)⁺.

Step 4

2-Methyl-5-propyl-2H-pyrazole-3-carboxylic acid: 2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester (29.4 g, 150 mmol) was suspended in 6N sodium hydroxide (120 mL, 720 mmol) and heated to 80° C. for 2 hours, cooled, diluted with water (100 mL) and acidified with 5N hydrochloric acid (200 mL) to give a precipitate which was filtered off and dried to give the title compound as a white solid (24.2 g, 96%). ¹H NMR (300 MHz, CDCl₃) δ 6.76 (s, 1H), 4.17 (s, 3H), 2.63 (t, 2H, J=7.2 Hz), 1.70-1.68 (m, 2H), 0.98 (t, 3H, J=7.2 Hz); LC-MS: m/z=169 (M+H)⁺;

Step 5

2-Methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid: A solution of 2-methyl-5-propyl-2H-pyrazole-3-carboxylic acid (22 g, 131 mmol) in concentrated sulfuric acid (98%, 85 mL) was heated to 50° C. and treated with a mixture of fuming nitric acid (95%, 7.7 mL) and concentrated sulfuric acid (98%, 18 mL), while keeping the reaction temperature between 50 and 55° C. The reaction mixture was kept for 8 hours at 50° C., cooled to ambient temperature, and slowly added to cold water (600 mL, 4° C.), keeping the temperature below 25° C. The precipitate was collected by filtration, and dried below 80° C. to give the title compound as a white solid (25 g, 90%). ¹H NMR (300 MHz, CDCl₃) δ 4.25 (s, 3H), 2.92 (t, 2H, J=7.5 Hz), 1.77-1.70 (m, 2H), 1.03 (t, 3H, J=7.2 Hz); LC-MS: m/z=214 (M+H)⁺

Step 6

2-Methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxamide: To a suspension of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid (17.0 g, 79.8 mmol) in dry toluene (85 mL) was added a catalytic quantity of dimethylformamide (0.6 mL). The mixture was heated to 50° C. and thionyl chloride (17.1 g, 143.7 mmol) was added over 30 minutes. The reaction was stirred and heated at 55-60° C. for 6 hours. The solvent was removed, dry toluene (80 mL) was added and the mixture was cooled to 20° C. and cold (5° C.) concentrated ammonium hydroxide (100 mL) was added. The precipitate was filtered, washed with water and dried to give the title compound as an off-white solid (14.8 g, 87%). LC-MS: m/z=213 (M+H)⁺, 235 (M+Na)⁺.

Step 7

4-Amino-2-methyl-5-propyl-2H-pyrazole-3-carboxamide: To a suspension of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxamide (14.7 g, 69.3 mmol) in ethyl acetate (130 mL), was added 10% palladium on carbon (3.3 g). The mixture was reacted at 50° C. and 4 atm hydrogen pressure overnight. The reaction mixture was cooled, and the catalyst was filtered off and washed with ethyl acetate and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (13.8 g, 98%). ¹H NMR (300 MHz, CDCl₃) δ 4.12 (s, 3H), 2.84 (s, 2H), 2.55 (t, 2H, J=7.2 Hz), 1.71-1.61 (m, 2H), 0.99 (t, 3H, J=7.2 Hz); LC-MS: m/z=183 (MH)⁺

Step 8

2-Methyl-4-(2-propoxybenzoylamino)-5-propyl-2H-pyrazole-3-carboxamide: A solution of 2-propoxybenzoic acid (13.7 g, 76.1 mmol) and thionyl chloride (36.2 g, 304.4 mmol) in dry dichloromethane (80 mL) was heated for 3 hours at reflux. The solvent and excess thionyl chloride were distilled off under reduced pressure. The residue was taken up in dry dichloromethane (60 mL) and reacted with a solution of 4-amino-2-methyl-5-propyl-2H-pyrazole-3-carboxamide (12.6 g, 69.2 mmol), dry triethylamine (7 g, 69.2 mmol) and 4-(N,N-dimethylamino)pyridine (84.5 mg, 0.7 mmol) in dry dichloromethane (200 mL) at 0° C. Stirring was maintained for 1 hour, and the reaction mixture was successively washed with water (150 mL), saturated aqueous sodium carbonate solution (200 mL) and saturated brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 60 mL, and then hexane (150 mL) was added to give precipitate product as a white solid (22 g, 92%). ¹H NMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 8.28 (d, 1H, J=7.8 Hz), 7.87 (br.s, 1H), 7.57-7.52 (m, 1H), 7.16-7.05 (m, 2H), 5.53 (s, 1H), 4.20 (t, 2H, J=6.6 Hz), 4.09 (s, 3H), 2.54 (t, 2H, J=7.5 Hz), 1.97-1.85 (m, 2H), 1.69-1.26 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.95 (t, 3H, J=7.5 Hz). LC-MS: m/z=345 (M+H)⁺

Step 9

3-(5-Carbamoyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-4-propxy-benzenesulfonyl chloride: 2-Methyl-4-(2-propoxybenzoylamino)-5-propyl-2H-pyrazole-3-carboxamide (20 g, 58.1 mmol) was added to chlorosulfonic acid (81.3 g, 698 mmol) at 0° C. and the reaction was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was poured into ice water (800 g) and mechanically stirred for 1 hour to give a white solid, which was filtered and washed with water. Following standard extractive work up, the solvent was evaporated under reduced pressure to yield the title compound (8 g, 31%). ¹H NMR (300 MHz, CDCl₃) δ 9.19 (s, 1H), 8.97 (s, 1H), 8.19 (t, 1H, J=8.9 Hz), 7.56 (br. s, 1H), 4.35 (t, 2H, J=6.6 Hz), 4.07 (s, 3H), 2.53 (t, 2H, J=7.5 Hz), 2.06-1.94 (m, 2H), 1.78-1.60 (m, 2H), 1.18 (t, 3H, J=7.5 Hz), 0.95 (t, 3H, J=7.2 Hz); LC-MS: m/z=443.1 (M+H)⁺

Step 10

2-Methyl-4-{5-[2-(1-methyl-pyrrolidin-2-yl)-ethylsulfamoyl]-2-propoxy-benzoylamino}-5-propyl-2H-pyrazole-3-carboxamide: To a solution of 3-(5-carbamoyl-1-methyl-3-propyl-1H-pyrazol-4-ylcarbamoyl)-4-propoxy-benzenesulfonyl chloride (2.12 g, 4.8 mmol) and dry triethylamine (0.5 g, 4.8 mmol) in dichloromethane (20 mL), was added 2-(2-aminoethyl)-1-methylpyrrolidine (0.6 g, 4.8 mmol) at 0° C. The reaction was warmed to ambient temperature, stirred for 1 hour at ambient temperature, and diluted with dichloromethane (40 mL). Following standard extractive work up, the solvent was evaporated under reduced pressure to yield the title compound (2.2 g) which was used directly in the next step. LC-MS: m/z=535 (M+H)⁺

Step 11

3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-4-propoxy-benzenesulfonamide: Potassium tert-butoxide (0.9 g, 8.0 mmol) was added to a solution of crude 2-methyl-4-{5-[2-(1-methyl-pyrrolidin-2-yl)-ethylsulfamoyl]-2-propoxy-benzoylamino}-5-propyl-2H-pyrazole-3-carboxamide (2.14 g, 4.0 mmol) in dry tert-butanol (50 mL), and the mixture was heated to reflux for 8 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (300 mL). Following standard extractive work up, the solvent was evaporated under reduced pressure to yield a crude residue which was purified by flash chromatography to give the title compound (1.1 g, 53%).

¹H NMR (300 MHz, CDCl₃) δ 10.90 (broad s, 1H), 8.93 (s, 1H), 7.96 (d, 1H, J=8.7 Hz), 7.15 (d, 1H, J=8.7 Hz), 4.28-4.24 (m, 3H), 4.24 (s, 2H), 3.13 (t, 3H, J=6.9 Hz), 2.93 (t, 3H, J=7.8 Hz), 2.56 (s, 1H), 2.40 (s, 3H), 2.26-2.24 (m, 1H), 2.10-1.99 (m, 2H), 1.89-1.80 (m, 4H), 1.67 (s, 3H, J=7.2 Hz), 1.56-1.52 (m, 1H), 1.22 (t, 3H, J=7.5 Hz), 1.03 (t, 3H, J=7.2 Hz);

LC-MS: m/z=517 (MH)⁺

…………………….

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