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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Yonkenafil


 

Yonkenafil

Mw 487.61, MF C₂₄H₃₃N₅O₄S,

Cas 804518-63-6

4H-Pyrrolo[2,3-d]pyrimidin-4-one, 2-[2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]phenyl]-3,7-dihydro-5-methyl-7-propyl-,

2- [2-ethoxy –5- (4 – ethylpiperazine -1– sulfonyl) phenyl] -5 – methyl – 7 – n-Propyl-3 7 – PYRROLINE [2, 3 – d] pyrimidin – 4 – one

Phase2  Erectile dysfunction

扬子江药业 (Originator), 天士力制药 (Originator)

phosphodiesterase type 5 (PDE5) inhibitor

  • Originator Tasly Pharmaceutical Group; Yangtze River Pharmaceutical Group
  • Class Erectile dysfunction therapies
  • Mechanism of Action Type 5 cyclic nucleotide phosphodiesterase inhibitors

str1.jpg

Yonkenafil Hydrochloride

  Molecular Weight 524.08
Formula C24H33N5O4S • HCl

804518-63-6 (Yonkenafil);
804519-64-0 (Yonkenafil Hydrochloride);

4H-Pyrrolo[2,3-d]pyrimidin-4-one, 2-[2-ethoxy-5-[(4-ethyl-1-piperazinyl)sulfonyl]phenyl]-3,7-dihydro-5-methyl-7-propyl-, hydrochloride (1:1)

2- [2-ethoxy –5- (4 – ethylpiperazine -1– sulfonyl) phenyl] -5 – methyl – 7 – n-Propyl-3 7 – PYRROLINE [2, 3 – d] pyrimidin – 4 – one

   
   

Yonkenafil hydrochloride, useful for treating erectile dysfunction and other PDE-5 mediated diseases eg female sexual dysfunction, benign prostatic hyperplasia, hypertension, allergic asthma, bronchitis, glaucoma, gastrointestinal motility disorders or Alzheimer’s Ydisease.

Yangtze River Pharmaceutical, under license from Jilin University, is developing yonkenafil (appears to be first disclosoed in WO2004108726), a PDE-5 inhibitor, for treating male erectile dysfunction.

In June 2016, yonkenafil was reported to be in phase 2 clinical development.

Yonkenafil hydrochloride is in phase II clinical trials for the treatment of erectile dysfunction (ED).

The compound was co-developed by Yangtze River Pharmaceutical and Tianjin Tasly Pharm.

Yonkenafil is a novel phosphodiesterase type 5 (PDE5) inhibitor. Here we evaluated the effect of yonkenafil on ischemic injury and its possible mechanism of action. Male Sprague-Dawley rats underwent middle cerebral artery occlusion, followed by intraperitoneal or intravenous treatment with yonkenafil starting 2h later. Behavioral tests were carried out on day 1 or day 7 after reperfusion. Nissl staining, Fluoro-Jade B staining and electron microscopy studies were carried out 24h post-stroke, together with an analysis of infarct volume and severity of edema. Levels of cGMP-dependent Nogo-66 receptor (Nogo-R) pathway components, hsp70, apaf-1, caspase-3, caspase-9, synaptophysin, PSD-95/neuronal nitric oxide synthases (nNOS), brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) and nerve growth factor (NGF)/tropomyosin-related kinase A (TrkA) were also measured after 24h. Yonkenafil markedly inhibited infarction and edema, even when administration was delayed until 4h after stroke onset. This protection was associated with an improvement in neurological function and was sustained for 7d. Yonkenafil enlarged the range of penumbra, reduced ischemic cell apoptosis and the loss of neurons, and modulated the expression of proteins in the Nogo-R pathway. Moreover, yonkenafil protected the structure of synapses and increased the expression of synaptophysin, BDNF/TrkB and NGF/TrkA. In conclusion, yonkenafil protects neuronal networks from injury after stroke.

Erectile dysfunction (Erectile dysfunction, ED) refers to the duration can not be achieved, and (or) maintain an erection sufficient for satisfactory sexual life. ED can be divided according to different causes psychogenic, organic and mixed three categories, which are closely related to the aging process, but it is not inevitable disease with age.

The primary risk factors for ED include: high blood pressure, high cholesterol, diabetes, coronary and peripheral vascular disease, spinal cord injury or pelvic organs or surgery. According to statistics worldwide about 150 million men suffer from varying degrees of ED, 2025 the number of patients will double. More ED treatment options, such as oral medications phosphodiesterase 5 (PDE5) inhibitors, dopaminergic activator, a receptor blocker, intracavernous injection therapy, vacuum devices treatment, penile prosthesis treatment Wait. Wherein the selective phosphodiesterase 5 (PDE5) inhibitors are the most sophisticated study based on ED treatment, clinical treatment for ED is the first-line drugs. Has now approved the listing of these drugs were five sildenafil (Sildenafil), Tadalafil (Tadalafil), vardenafil (Vardenafil), to that of non-black (Udenafil) and Miro that non-( Mirodenafil).

In 2004 the Chinese patent CN03142399. X discloses a series pyrrolopyrimidine ketone compound of the structure and for the treatment of sexual dysfunction in animals, including humans, in particular male erectile dysfunction and TOE5 function-related diseases use; wherein the compound 1-HC1, i.e. 2- [2_ ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) phenyl] -5-methyl-7-n-propyl -3 , 7-dihydro-pyrrolo [2, 3-d] pyrimidine-4-one monohydrochloride salt has been used as CN03142399. X Example features are disclosed compound named hydrochloride that non-gifted grams. This patent only to the preparation of the compounds have been described

PATENT

WO2004108726

http://www.google.co.in/patents/WO2004108726A1?cl=en

Example 1

Preparation of 2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl] -5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one, its monohydrochloride and dihydrochloride

Route of synthesis

    • Figure imgb0011
      Figure imgb0012
      • (1a)2-amino-3-cyano-4-methylpyrrole;
      • (1b)N-propyl-2-amino-3-cyano-4-methylpyrrole;
      • (2)2-ethoxylbenzoyl chloride;
      • (3a)N-(3-cyano-4-methyl-1H-pyrrol-2-yl)-2-ethoxylbenzamide;
      • (3b)N-(3-cyano-4-methyl-1-n-propyl-1H-pyrrol-2-yl)-2-ethoxylbenzami de;
      • (4a) 2-(2-ethoxylbenzamido)-4-methyl-1H-pyrrolo-3-formamide;
      • (4b) 2-(2-ethoxylbenzamido)-4-methyl-1-n-propyl-1H-pyrrolo-3-formamide;
      • (5) 2-(2-ethoxylphenyl)-5-methyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin -4-one;
      • (6)2-(2-ethoxylphenyl)-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d ]pyrimidin-4-one;
      • (7)4-ethoxyl-3-(5-methyl-4-oxy-7-n-propyl-3,7-dihydropyrrolo[2,3-d] pyrimidin-2-yl)benzenesulfonyl chloride;
      • (8)2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7 -n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one.

Preparation 1N-(3-cyano-4-methyl-1H-pyrrol-2-yl)-2-ethoxylbenzamide (3a) and N-(3-cyano-4-methyl-1-n-propyl-1H-pyrrol-2-yl)-2-ethoxylbenzamide (3b)

2-ethoxyl benzoic acid (10.0g, 60.2mmol) was added into thionyl chloride (20ml), and the mixture was refluxed with agitation for 40 minutes, and the excess amount of thionyl chloride was evaporated under reduced pressure. The residual was dissolved into dichloromethane (150ml). Within 30 minutes and being stirred on ice bath, the afore-obtained solution of 2-ethoxyl benzoyl chloride was dropped into the compound (1a) (7.0g, 56.8mmol) dissolved in tetrahydrofuran (80ml) and triethylamine (8.5ml, 61.0mmol). After completion, the mixture was stirred for 1 hour at 0°C . After being washed with water and filtrated with diatomaceous earth, the reaction solution was mixed with 20g of silica gel and evaporated to dryness. The resulting residual was eluted with dichloromethane by using silica gel(80g) column to obtain 7.5g of solid product (3a) with the yield of 48%. Furthermore, the sample for analysis was prepared by column chromatography (developing agent: dichloromethane: n-hexane=1:2) and recrystallization (dichloromethane: n-hexane=1:5).

mp 183~184°C (sublimation 162°C);\

IR (cm-1) : 3326, 3309, 2981, 2938, 2915, 2854, 2208, 1647, 1593, 1471, 1309, 1302, 1232, 1039, 923, 727, 655, 648;1H NMR (CDCl3) : δ 1.70 (t, J=7.0Hz, 3H), 2.15 (s, 3H), 4.32 (q, J=7.0Hz, 2H), 6.24 (s, 1H), 7.04 (d, 1H), 7.10 (m, 1H), 7.51 (dd, 1H), 8.20 (dd, J=7.9 and 1.8Hz, 1H), 10.69 (brs, 1H), 10.80 (s, 1H);13CNMR (CDCl3) : δ (CH3) 10.6, 15.0; (CH2) 65.7; (CH) 110.3, 112.3, 121.4132.1, 134.2; (C) 78.7, 115.6, 119.2, 119.4, 136.7, 157.0, 163.2;

MS (ES+) : m/z 287 (M+NH4) .

Elemental analysis (C15H15N3O2) : C 66.90%; H 5.61%; N 15.60%; 0 11.88%. The compound (3b) was prepared from compound (1b) according to the above-mentioned method with the yield of 41%.

mp 58~61°C;

IR (cm-1) : 3596, 3336, 2969, 2937, 2877, 2216, 1676, 1658, 1603, 1571, 1537, 1475, 1431, 1292, 1232, 1122, 1037, 927, 789, 752, 577;1H NMR (CDCl3): δ 0.88 (t, J=7.4Hz, 3H), 1.58 (t, J=7.0Hz, 3H), 1.75(m, 2H), 2.16 (s, 3H), 3.73 (t, J=7.4Hz, 2H),4.30 (q, J=7.0Hz, 2H), 6.36 (s, 1H), 7.04 (d, 1H), 7.11 (m, 1H), 7.48 (dd, 1H), 8.23 (dd, J=7.9 and 1.8Hz, 1H), 9.62 (brs, 1H) ;13C NMR (CDCl3) : δ (CH3) 11.1, 14.8; (CH2) 23.6, 48.3, 65.2; (CH) 112.5,117.0, 121.3, 132.5, 134.1; (C) 89.2, 115.6, 119.8, 120.5, 131.2, 157.1, 165.0;MS (ES+): m/z 329 (M+NH4).

Preparation 2

2-(2-ethoxylbenzamido)-4-methyl-1H-pyrrolo-3-formamide (4a) and 2-(2-ethoxylbenzamido)-4-methyl-1-n-propyl-1H-pyrrolo-3-formamide(4 b);

A mixture of N-(3-cyano-4-methyl-1H-pyrrol-2-yl)-2-ethoxylbenzamide(3a) (2.00g, 7.44mmol) or N-(3-cyano-4-methyl-1-n-propyl-1H-pyrrol-2-yl)-2 -ethoxylbenzamide(3b) (2.30g, 7.44mmol) of preparation 1 and 85% phosphoric acid (14.8ml) was stirred for 20 minutes at 130°C, cooled and poured into crushed ice (80g). The precipitations were filtrated and dried to give dark red solid of compound (3a) or (3b) with the yield of 80%. The product(3a) and (3b) of this step may be directly used for the next step without further purification.

Preparation 32-(2-ethxoylphenyl)-5-methyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one(5) and 2-(2-ethoxylphenyl)-5-methyl-7-n-propyl -3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one(6)

A mixture of 2-(2-ethoxylbenzamido)-4-methyl-1H-pyrrolo-3-formamide (4a) (7.0g, 25.5mmol) of preparation 2 and dimethyl cyclohexylamine (20ml) was refluxed with agitation for 11 hours in N,N-dimethyl formamide (100ml). After evaporation the solvent by distillation under reduced pressure, the residual was extracted with dichloromethane, and the dichloromethane extraction was washed with water. the resultant extraction was dried with anhydrous sodium sulfate. n-hexane (80ml) was added into the residual and ground to give product (5) (6.0g) by filtration with the yield of 91%.

mp 219~221°C

IR (cm-1) : 3187, 3114, 3062, 2978, 2923, 1658, 1587, 1460, 1321, 1292, 1250, 1044, 771, 763;

1H NMR (DMSO-d6) : δ 1.35 (t, J=6.9Hz, 3H), 2.29 (s, 3H), 4.13 (q, J=7.0Hz, 2H), 6.79 (s, 1H), 7.05 (t, 1H), 7.14 (d, 1H), 7.45 (dd, 1H), 7.76 (dd, 1H), 11.35 (brs, 1H), 11.54 (brs, 1H);

13C NMR (DMSO-d6) : δ (CH3) 11.2, 14.5; (CH2) 64.2; (CH) 113.0, 118.0, 120.6, 130.1, 131.9, (C) 105.0, 113.6, 121.9, 148.5, 149.8, 156.5, 159.2; MS(ES+) : m/z 287 (M+NH4) .

The compound (6) was prepared from compound(4b) according to the above-mentioned method with the yield of 85%

mp 124~127°C

IR (cm-1) : 3234, 3184, 3141, 3103, 3056, 2956, 2943, 2869, 1654, 1595, 1567, 1468, 1311, 1267, 1243, 1191, 1118, 1047, 758;

1H NMR (CDCl3) : δ 0.88 (t, J=7.5Hz, 3H), 1.23 (t, 3H), 1 . 80 (q, 2H), 2. 42 (s, 3H), 4.08 (t, J=7.2Hz, 2H), 4.22 (q, 2H), 6.60 (s, 1H), 7.01 (d, J=8.3Hz, 1H), 7.08 (t, 1H), 7.40 (m, 1H), 8.35 (dd, J=8.0 and 1.9 Hz, 1H), 11.02 (brs, 1H).

Preparation 42-(2-ethxoylphenyl)-5-methyl-7-n-propyl-3,7-dihydro-pyrrolo[2,3-d] pyrimidin-4-one(6):

A mixture of compound (5) (1.5g, 5.57mmol) of preparation 3, n-propyl bromide (2.0g, 16.3mmol) and potassium carbonate (5g, 36.2mmol) was dissolved in acetone (15ml), refluxed with agitation by heating for 15 hours, after the solids were filtrated out, the filtrate was dried under reduced pressure. The resultant was developed by column chromatography, using dichloromethane as mobile phase to obtain 0.6g of product (6) with yield of 35%. The physical/chemical data were identical with that of the above-mentioned.

Preparation 54-ethoxyl-3-(5-methyl-4-oxy-7-n-propyl-4,7-dihydropyrrolo[2,3-d] pyrimidin-2-yl)benzenesulfonyl chloride(7):

2-(2-ethxoylphenyl)-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d] pyrimidin-4-one(6) (1.25g, 4.01mmol) of preparation 4 was added into chlorosulfonic acid (4ml) that was dissolved in acetic ether (20ml), stirred at 0°C by two batches. The obtained solution was stirred at 0 °C for 30 minutes, and then reacted with agitation at room temperature for 3 hours. The resultant solution was poured into the a mixture of icy water (50ml) and acetic ether (50ml) . The organic layer was separated, washed with cold water (5ml), desiccated with anhydrous sodium sulfate and concentrated to dryness to afford 1.33g of product as yellow foam. The yield was 81%. The product was used directly for the next reaction.

Compound 1:

BASE

2-[2-ethoxyl-5-(4-ethyl-piperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n -propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one (8):

4-ethoxyl-3-(5-methyl-4-oxy-7-n-propyl-4,7-dihydro-3H-pyrrolo[2,3-d ]pyrimidin-2-yl)benzenesulfonyl chloride(7) (1.00g, 2.44mmol) of Preparation 5 was dissolved into dichloromethane (20ml), stirred at 0 °C, into which 1-ethyl piperazine (0.78ml, 6.10mmol) was added slowly. Reactant solution was stirred at 0°C for 5 minutes, and then sequentially stirred at room temperature for 5 hours. The crude product was washed with water and dried with anhydrous sodium sulfate to give 1. 2g of product as yellow foam. Continuously, the product was refined by column chromatography (acetic ether: methanol=20:1) to afford 0.89g of product as a yellow solid with yield of 75%.

mp: 174~176°C (EtOAc);

IR (cm-1) : 3324, 2960, 2923, 2869, 2862, 2767, 1682, 1560, 1458, 1355, 1282, 1247, 1172, 1149, 739, 615, 588, 555;

1H NMR(CDCl3) : δ 0.89(t,J=7.4Hz, 3H), 0.99(t, J=7.2Hz, 3H), 1.61(t,J=7.0Hz,3H),1.77-1.86(m, 2H), 2.35(m, 2H), 2.41(s, 3H), 2.50(brs, 4H), 3.05(brs,4H), 4.08(t, J=7.0Hz, 2H), 4.29-4.37(q, 2H), 6.61(s, 1H), 7.11(d, J=8.8Hz,1H), 7.77(dd, J=8.7 and2.2Hz, 1H), 8.74(d, J=2.2, 1H), 10.63(brs, 1H);

13C NMR(CDCl3) : δ (CH3) 11.0, 11.3, 11.8, 14.3; (CH2)23.8, 45.9, 46.1, 51.6, 51.7, 65.8; (CH)112.9, 121.1, 130.6, 131.3;(C)105.7,114.6, 121.4, 127.8, 146.8, 147.3, 159.3, 159.6;MS(ES+): m/z 505(M+NH4).

Elemental analysis (C24H33N5O4S) : theoretical value C 59.12%; H 6.82%; N 14.36%; practically measured value C59.38%; H 7.10%; N 14.12%.

Compound 1-HCl:

2-[2-ethoxyl-5-(4-ethylpiperazinyl-1-sulfonyl)phenyl]-5-methyl-7-n-propyl-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one monohydrochloride (9) :

The free alkali (compound 1) (1.00g, 2.05mmol) was dissolved into ether (10ml) and dichloromethane (10ml), into which the solution of 4M hydrochloric acid (HC1)- dioxane (0.51ml, 2.04mmol) diluted with ethyl ether (10ml) was dropped with agitation. After completion, the resulting solution was continued to stir at room temperature for 20 minutes, filtrated and dried to give 1.01g of monohydrochloride with yield of 94%.

mp: 147~150°C;

IR(cm-1): 2964, 2931, 2675, 2599, 2462, 1668, 1574, 1456, 1348, 1167, 933, 588;

1H NMR(D2O): δ 0.72(m, 3H),1.24(t, J=7.3Hz, 3H), 1.45(m, 3H), 1.59(m, 2H), 2.04(s, 3H), 2.77-3.81(all brs, 8H), 3.20(q, 2H), 3.75(m, 2H), 4.20(m, 2H), 6.62(m, 1H), 7.17(m, 1H), 7.73(m, 1H), 8.22(s, 1H).

Elemental analysis (C24H33N5O4S. HCl) : theoretical value C 55.00%; H 6.54%; N 13.36%; practically measured value C55.28%; H 6.41%; N 13.07%.

PATENT

WO 2016095650

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016095650&redirectedID=true

Example 1:
At room temperature, preferably hydrochloride grams that non-B polymorph (1.0g, prepared as described in its comparative) and 95% by volume aqueous ethanol (6mL) added to the flask and stirred for 2h, isolated by filtration, and the resulting solid dried under reduced pressure to give hydrochloride gifted grams that non-A type polymorph (0.8g). Its X-RD diffraction as shown in Figure 1, as shown in Figure 2. DSC.

SEE

https://www.google.com/patents/CN1552714A?cl=en

Spectral Analysis

str2 STR3

STR3

13C NMR PREDICT

str2

str2

COSY PREDICT

str2

CN1552714A * Jun 6, 2003 Dec 8, 2004 天津倍方科技发展有限公司 2-substituted benzyl-5,7-dihydrocarbyl-3,7-dihydro pyrroline [2,3-d] pyromidine-4-one derivative ,its preparation and medicinal use
CN102970965A * Apr 4, 2011 Mar 13, 2013 Sk化学公司 Composition containing PDE5 inhibitor for relieving skin wrinkles
WO2007067570A1 * Dec 5, 2006 Jun 14, 2007 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of disease

//////////yonkenafil, Phase 2,  Erectile dysfunction , phosphodiesterase type 5 (PDE5) inhibitor, Tasly Pharmaceutical Group; Yangtze River Pharmaceutical Group

Cc4cn(CCC)c1c4N/C(=N\C1=O)c2cc(ccc2OCC)S(=O)(=O)N3CCN(CC3)CC

Gisadenafil

Erectile dysfunction can be reversed without medication


Lyra Nara Blog

Men suffering from sexual dysfunction can be successful at reversing their problem, by focusing on lifestyle factors and not just relying on medication, according to new research at the University of Adelaide.

In a new paper published in the Journal of Sexual Medicine, researchers highlight the incidence of erectile dysfunction and lack of sexual desire among Australian men aged 35-80 years.

Over a five-year period, 31% of the 810 men involved in the study developed some form of erectile dysfunction.

“Sexual relations are not only an important part of people’s wellbeing. From a clinical point of view, the inability of some men to perform sexually can also be linked to a range of other health problems, many of which can be debilitating or potentially fatal,” says Professor Gary Wittert, Head of the Discipline of Medicine at the University of Adelaide and Director of the University’s Freemasons Foundation Centre for…

View original post 254 more words

Lodenafil Carbonate … an Erectile Dysfunction Drug in Phase III


 

Lodenafil carbonate

UNII-29X84F932D, CRIS-031

bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate

5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one. IS THE NAME OF MONOMER

398507-55-6  CAS

Cristalia (Originator)

C47 H62 N12 O11 S2= MF
 Molecular Weight 1035.199

Lodenafil is a drug belonging to a class of drugs called PDE5 inhibitor, which many other erectile dysfunction drugs such as sildenafiltadalafil, and vardenafil also belong to. Like udenafil and avanafil it belongs to a new generation of PDE5 inhibitors.

Lodenafil is formulated as a dimerlodenafil carbonate, which breaks down in the body to form two molecules of the active drug lodenafil. This formulation has higher oral bioavailability than the parent drug.[1]

It is manufactured by Cristália Produtos Químicos e Farmacêuticos in Brazil and sold there under the brand-name Helleva.[2]

Helleva (Lodenafil Carbonate) - 80mg (4 Tablets)

Helleva (Lodenafil Carbonate) is an oral PDE5 inhibitor prescribed to treat men suffering from erectile dysfunction. It operates by relaxing muscles and dilating blood vessels in the penis to increase circulation making it easier to attain and maintain an erection.

It has undergone Phase III clinical trials,[3][4][5] but is not yet approved for use in the United States by the U.S. Food and Drug Administration.

lodenafil

………..

SYNTHESIS

WO 2002012241 OR US7148350

MONOMER synthesis

PIPERAZINE

AND

ETHYL CHLORO ACETATE

WILL GIVE

Ethyl 1-piperazinylacetateChemSpider 2D Image | Ethyl 1-piperazinylacetate | C8H16N2O2

SEE RXN 1 BELOW

Reaction 1:

Synthesis of Piperazine Ethyl Acetate

To a reaction blend containing 100 g (3 Eq, 0.515 mol, MW=194) of piperazine, 26.3 mL (1.1 Eq, 0.189 mol, MW=101, d=0.726) of triethylamine in 200 mL of isopropanol, add to a solution previously prepared of 18.4 mL (1 Eq., 0.172 mol, MW=122.55, d=1.15) of chloroacetate of ethyl in 140 mL of isopropanol under stirring, at room temperature. Keep the reaction medium under stirring, monitoring the reaction termination by means of a chromatography of the thin layer (about 2–3 hours). Add a solution of 40.6 g (0.344 mol) of succinic acid in 140 mL of isopropanol. Keep the system under stirring for about 30 minutes to assure total precipitation of the succinate salt of piperazine formed. Filter this salt and concentrate the filtrate containing the mono and dialkyled derivatives. We obtain a slightly yellowish oil, which is used in later phases without purification.

Mass obtained=33 g

GC/MS: Monoalkylated derivative 72%, and dialkylated 22%.

NEXT

ChemSpider 2D Image | Ethyl 1-piperazinylacetate | C8H16N2O2Piperazine Ethyl Acetate

AND

5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one Structure

5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one

WILL REACT TO GIVE… 5-{2-ethoxy-5-[(4-ethyl acetate 1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-di-hydro-7H-pyrazole[4,3-d]pyrimidin-7-one AS IN RXN 4 BELOW

Reaction 4:

Synthesis of 5-{2-ethoxy-5-[(4-ethyl acetate 1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-di-hydro-7H-pyrazole[4,3-d]pyrimidin-7-one.

Suspend 24.6 g (60 mmol, MW=410.9) of 5-(5-chlorosulfonyl-2-etoxyphenyl)-1-methyl-3n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one in 900 mL of ethanol absolute. Under stirring and at room temperature, add at only one time, a solution containing 31.0 g (3 Eq., 180 mmol MW=172) of N-piperazine ethyl acetate (Reaction 1) dissolved in 150 mL of ethanol absolute. In an interval of 2–10 minutes, all solid is consumed, forming a clean and homogeneous solution, and after that starts the precipitation of the expected product. At the end of the reaction, which lasts 2–3 hours (monitored by chromatography of thin layer), the product is vacuum filtered and the solid is washed with two portions of 50 mL of iced absolute ethanol. 29 g are obtained (yielding=89%) from the product as a white solid of MP=165.5–166.5° C.

Reaction 7:

Intermediate 1

5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one.  IS MONOMER

please note during LAH redn  …………. the PIP CH2-C=O-O CH2 CH3     BECOMES        PIP-CH2CH2-OH

To a suspension of lithium aluminum hydride (0.74 g 2.2 Eq. MW=37.9) in 25 mL of THF, slowly add, under stirring and at room temperature, a suspension of 5.0 g (9.1 mmol, MW=546.6) of 5-{2-ethoxy-5-[(4-ethyl acetate 1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-di-hydro-7H-pyrazole[4,3-d]pyrimidin-7-one in 50 mL of THF. The system is maintained under stirring, monitoring the consumption of the product by chromatography of thin layer, until the complete consumption of the starting reagent (about 5–6 hours). Slowly add water to the reaction medium and, when there is no longer release of H2, add HCl 1M regulating pH for 7. Extract the product with 3 200 mL-portions of chloroform, dry with anhydrous sodium sulfate and vacuum concentrate the product. It is obtained 3.8 g of the product as a cream solid MP=183–187° C. yielding 83%. The same was crystallized from methanol and DMF yielding a slightly yellowish solid with melting point at 189–192° C.

 

note …………. the PIP CH2-C=O-O CH2 CH3 BECOMES  PIP-CH2CH2-OH

 

HOMODIMER CARBONATE

 

EXAMPLE 1B

Homodimer Carbonate of Intermediate 1—Alternative Method

A phosgene solution (3.5 g, 35 mmol) dissolved in 20 mL of toluene was added dropwise to a solution of 2.02 g (4 mmol) of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one, suspended in 44 mL of toluene. The reaction mixture resulting is stirred and followed by chromatography analysis of thin layer every hour until the reagent conversion in its chloroformate was completed. When the analysis indicates the complete consumption of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one, the volatile compounds of the reaction are vacuum removed (solvents and phosgene), yielding the esther chloroformate raw derivative of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one.

The raw chloroformate obtained above (4.0 mmol, 2.27 g) is dissolved in about 30 mL of dichloromethane, to which is added 2.07 g (4.1 mmol) of 5-{2-ethoxy-5-[(4-hydroxyethyl-1-piperazinyl)sulfonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one, followed by the addition of 4 mL of dichloromethane containing 450 mg of triethylamine. The reaction mixture is maintained under stirring, being followed by chromatography of thin layer every hour until this indicates the end of the reaction (disappearing of chloroformate derivative). The reaction mixture is then diluted with 60 mL of dichloromethane, washed with NaCl saturated solution, after with sodium bicarbonate saturated solution and again with NaCl saturated solution. Organic phase is separated and dry with anhydrous sodium sulfate. The solvent is then evaporated to dry, yielding the dimer carbonate as a slightly yellowish solid.

This compound is re-crystallized from ethanol:DMF, yielding a pale white solid. Yielding m=3.2 g (76%)

Microanalysis: Theoretical C, (54.53%); H, (6.04%); N, (16.24%);

Obtained C, (54.45%); H, (6.02%); N, (16.17%).

 

INFO ABOUT INTERMEDIATE

5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one Structure

5-(5-chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidin-7-one

CAS No. 139756-22-2
Chemical Name: 5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one
Synonyms: Sildenafil Chlorosulfone IMpurity;Sildenafil Chlorosulfonyl IMpurity;5-(5-CHLOROSULFONYL-2-ETHOXY PHENYL)-1-METHYL-3-N-PROPYL-1;3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo-(4-3-d)-pyrimidine-5;5-(5-Chlorosulfonyl-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;3-(4,7-Dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxy-benzenesulfonyl Chloride;4-Ethoxy-3-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyriMidin-5-yl)benzene-1-sulfonyl chloride
CBNumber: CB11175931
Molecular Formula: C17H19ClN4O4S

http://www.chemicalbook.com/ChemicalProductProperty_EN_CB11175931.htm

…………..

SYNTHESIS OF

Figure US06362178-20020326-C00096

http://www.google.co.in/patents/US6362178

2-butyrylamino-propionic acid
EXAMPLE 1A 2-Butyrylaminopropionic acid

Figure US06362178-20020326-C00052

 

22.27 g (250 mmol) of D,L-alanine and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and for 1 hour at 40° C. After cooling to −10° C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred for 2 hours at −10° C. and for one hour at room temperature.

With ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous phase is evaporated to dryness, the residue is titrated with acetone and the mother liquor is filtered off with suction. The solvent is removed and the residue is chromatographed. The resulting product is dissolved in 3N aqueous sodium hydroxide solution and the resulting solution is evaporated to dryness. The residue is taken up in conc. HCl and once more evaporated to dryness. The residue is stirred with acetone, precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. This gives 28.2 g (71%) of a viscous oil which crystallizes after some time.

200 MHz 1H-NMR (DMSO-d6): 0.84, t, 3H; 1.22, d, 3H; 1.50, hex, 2H; 2.07, t, 2H; 4.20, quin., 1H; 8.09, d, 1H.

EXAMPLE 3A 2-Ethoxybenzonitrile

Figure US06362178-20020326-C00054

 

25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 30.0 g (97%) of a colourless liquid.

200 MHz 1H-NMR (DMSO-d6): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H; 7.51, dt, 2H.

 2-ethoxybenzamidine hydrochloride
EXAMPLE 4A 2-Ethoxybenzamidine hydrochloride

Figure US06362178-20020326-C00055

 

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene, and the suspension is cooled to 0° C. 200 ml of a 2M solution of trimethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reaction mixture is stirred at 80° C. (bath) overnight.

With ice-cooling, the cooled reaction mixture is added to a suspension of 100 g of silica gel and 950 ml of chloroform, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered off with suction, and the filter residue is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is stirred with a mixture of dichloromethane and methanol (9:1), the solid is filtered off with suction and the mother liquor is concentrated. This gives 30.4 g (76%) of a colourless solid.

200 MHz 1H-NMR (DMSO-d6): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, 1H; 7.21, d, 1H; 7.52, m, 2H; 9.30, s, broad, 4H.

EXAMPLE 10A 2-(2-Ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

 

Figure US06362178-20020326-C00061

 

7.16 g (45 mmol) of 2-butyrylamino-propionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF and, after addition of a spatula tip of DMAP, heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are added dropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The ethanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70° C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography using ethyl acetate and crystallization afford 4.00 g (28%) of a colourless solid, Rf=0.42 (dichloromethane/methanol=95:5)

200 MHz 1H-NMR (CDCl3): 1.02, t, 3H; 1.56, t, 3H; 1.89, hex, 2H; 2.67, s, 3H; 3.00, t, 2H; 4.26, quart., 2H; 7.05, m, 2H; 7.50, dt, 1H; 8.17, dd, 1H; 10.00, s, 1H.

EXAMPLE 15A 4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride

 

Figure US06362178-20020326-C00066

 

At 0° C., 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred ovemight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a colourless foam.

200 MHz 1H-NMR (CDCl3): 1.03, t, 3H; 1.61, t, 2H; 1.92, hex, 2H; 2.67, s, 3H; 3.10, t, 2H; 4.42, quart., 2H; 7.27, t, 1H; 8.20, dd, 1H; 8.67, d, 1H; 10.18, s, 1H.

Example 22 2-[2-Ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

 

Figure US06362178-20020326-C00096

 

By the same method, starting with 0.04 g (0.097 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 0.04 g (0.29 mmol) of 1-amino-4-hydroxyethylpiperazine, 46 mg (91%) of 2-[2-ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.

Rf=0.08 (dichloromethane/methanol=19:1)

200 MHz 1H-NMR (CDCl3): 1.02, t, 3H; 1.59, t, 3H; 1.90, sex., 2H; 2.49, m, 6H; 2.62, s, 3H; 2.71, m, 4H; 3.00, t, 2H; 3.55, t, 2H; 4.31, quart., 2H; 7.14, d, 1H; 8.05, dd, 1H; 8.60, d, 1H.

…………..

Methods of analysis

The development of lodenafil carbonate was reported by Toque et al. (2008). They observed the effects of lodenafil carbonate on rabbit and human corpus cavernosum relaxation, activity of PDE5 in human platelets, stability and metabolic studies in comparison with sildenafil and lodenafil, as well as the pharmacological evaluation of lodenafil carbonate after intravenous and oral administration in male beagles.

The determination of PDE activity, stability of lodenafil carbonate in human, dog and rat plasma and the pharmacokinetic parameters after a single intravenous or oral dose was carried out by LC-MS/MS analysis

Codevilla et al. (2011a) developed a stability-indicating reversed-phase liquid chromatography method using ultraviolet (UV) detection for the quantitative determination of lodenafil carbonate in tablets. The method can be useful for routine quality control assay and stability studies.

Another study for the determination of lodenafil carbonate in tablets was developed by Codevilla et al. (2011b). As an alternative to the LC method the authors suggested a UV-spectrophotometric method for the analysis of lodenafil carbonate in pharmaceutical form. The UV method offers advantages over other analytical methods due to its rapidity, simplicity, and lower cost. Recently, Codevilla et al. (2012) developed and validated a capillary zone electrophoresis (CZE) method for determination of lodenafil carbonate in drug products. There are some advantages to use the CZE method, such as rapid analysis, small sample and reagent consumption, high separation efficiency (Furlanetto et al., 2001; Yang et al., 2010). The results obtained from the UV-spectrophotometric method and CZE method were compared statistically with the LC method (Codevilla et al., 2011a) and the results showed no significant difference between these methods.

 

References

  1.  Toque HA, Teixeira CE, Lorenzetti R, Okuyama CE, Antunes E, De Nucci G (September 2008). “Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum”. European Journal of Pharmacology 591 (1–3): 189–95. doi:10.1016/j.ejphar.2008.06.055PMID 18593576.
  2.  Cristália Product page. Retrieved on September 16, 2009.
  3.  ukmedix Lodenafil article. Retrieved on September 16, 2009.
  4.  Glina S, Toscano I, Gomatzky C, de Góes PM, Júnior AN, Claro JF, Pagani E (February 2009). “Efficacy and tolerability of lodenafil carbonate for oral therapy in erectile dysfunction: a phase II clinical trial”. The Journal of Sexual Medicine 6 (2): 553–7. doi:10.1111/j.1743-6109.2008.01079.x.PMID 19040623.
  5.  Glina S, Fonseca GN, Bertero EB, Damião R, Rocha LC, Jardim CR, Cairoli CE, Teloken C, Torres LO, Faria GE, da Silva MB, Pagani E (February 2010). “Efficacy and Tolerability of Lodenafil Carbonate for Oral Therapy of Erectile Dysfunction: A Phase III Clinical Trial”. The Journal of Sexual Medicine 7 (5): 1928–1936. doi:10.1111/j.1743-6109.2010.01711.xPMID 20214718.
  6. Toque H A et al., (2008) European Journal of Pharmacology, 591(1-3):189-95.
  7. Exploring the role of PDE5 inhibition in the treatment of muscular dystrophy
    Drugs Fut 2011, 36(4): 321

 

Mirodenafil 米罗那非 标准品 ………..An erectogenic agent.


Figure US20120269898A1-20121025-C00007
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)
Formula C26H37N5O5S 
Mol. mass 531.666 g/mol
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)
Treatment of
Treatment of Erectile Dysfunction , hypertention

Mirodenafil belongs to a class of drugs called PDE5 inhibitors, which many other erectile dysfunction drugs such as sildenafiltadalafil, 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

CAS No:
862189-96-6
Synonyms:

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 hydrochloride
Chemical Formula:
C26H39Cl2N5O5S
Molecular Weight:
604.59
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.

Figure imgf000003_0001

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

…………………………

Links

US6962911

The invention relates to a series of pyrrolopyrimidinone derivatives of the formula (1):

Figure US06962911-20051108-C00001

R1 ETHYL

R2=H

R3= PROPYL

R4 = PROPYL

R5=R5=SO2NR6R7,  NR6Ris 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; NR6Ris 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, NCH2CHand 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; NR6Ris 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, NCH2CHand 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; NR6Ris 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, NCH2CHand 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).

……………………………

Links

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

Links

EP1362858A1

THESE INTERMEDIATES FROM PATENT MAY HELP YOU

Skeletal formulamethyl salicylate

Figure 00130002X=CL, R8=ME

      Methyl 3-Chlorosulfonyl-6-hydroxybenzoate

Example 1 EP1362858A1

      Methyl 3-Chlorosulfonyl-6-hydroxybenzoate

    • 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).

Example 2 EP1362858A1

      Methyl 2-Hydroxy-5-[4-(2-hydroxyethyl)piperazin-1-ylsulfonyl]benzoate

    • 1-(2-Hydroxyethyl)piperazine 98%1-(2-hydroxyethyl)piperazine
    • Figure 00130001R8=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+).

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

Figure 00120001

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

Figure 00110001

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-Calkanol, 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):

Figure US06962911-20051108-C00016

wherein X and P are as previously defined.

note X=N ATOM, n = 2

…………………………….

Links

MIRODENAFIL

METHODS OF ANALYSIS

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.

Links

References

  1.  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.xPMID 18638004.
  2.  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.2009.06.008PMID 19695390.
  3.  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.2009.12.012PMID 20110038.
  4. 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
  5. More information about mirodenafil can be found at Paick J S et al., (2008) The Journal of Sexual Medicine, 5 (11): 2672-80.
  6. 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.
  7. 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.
  8. 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)
shark
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

EP2038282A1

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

DASANTAFIL


Figure imgf000081_0001Dasantafil

569351-91-3 CAS NO

405214-79-1 (racemate)

UNII-48P711MI2G, SCH 446132, D03657,
Molecular Formula: C22H28BrN5O5
Molecular Weight: 522.39222
Merck & Co. (Originator) IN PHASE 2

THERAPEUTIC CLAIM       treatment of erectile dysfunction (phosphodiesterase (PDE) 5 isoenzyme inhibitor)

read all at

ALL ABOUT DRUGS

CLICK BELOW

http://www.allfordrugs.com/2014/01/29/dasantafil-for-treatment-of-erectile-dysfunction/

 

Gisadenafil for erectile dysfunction


GISEDENAFIL

Gisadenafil besylate C23H33N7O5S.C6H6O3S [334827-98-4]GISEDENAFIL BESYLATE

334826-98-1 free form
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

LEARN SPECTROSCOPY USING GISADENAFIL INTERMEDIATES

CLICK HERE

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)-

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

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
Download
 
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

http://clinicaltrials.gov/search/intervention=UK-369,003

………………………….

PAPERS

Links

Bioorganic and Medicinal Chemistry, 2012 ,  vol. 20,  1  p. 498 – 509

http://www.sciencedirect.com/science/article/pii/S0968089611008303

Full-size image (6 K)

Full-size image (36 K)

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.

Full-size image (20 K)

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.

Full-size image (37 K)

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.

Full-size image (28 K)

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.

……………………………

PAPERS

Links

Org. Proc. Res. Dev., 2004, 8 (4), pp 674–679
DOI: 10.1021/op0300241

http://pubs.acs.org/doi/abs/10.1021/op0300241

Abstract Image

………………………….

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

Figure

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).

Figure

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.

……………………

SYNTHESIS

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US6407259

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)

Figure US06407259-20020618-C00033

To a stirred solution of 2,2-dimethoxybutane (10 g, 84.7 mMol) in CH2Cl(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 CH2Cl(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 CH2Cl(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]+, C8H12N2Orequires 168.2.

(b) Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid (IIA) from (IIA) via route 1

Figure US06407259-20020618-C00034

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

Figure US06407259-20020618-C00035

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. C7H10N4Orequires 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

Figure US06407259-20020618-C00036

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

Figure US06407259-20020618-C00037

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 CH2Cl(67.5 L) and water (22.5 L) were added. The resultant organic and aqueous layers were separated. The aqueous phase was extracted with CH2Cl(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. C9H14N4Orequires 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

Figure US06407259-20020618-C00038

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. C9H16N4Orequires 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.

Figure US06407259-20020618-C00039

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.

Figure US06407259-20020618-C00040
 

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 C2H5CO2CHrequires 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)+

……………..

WO2001027113A2

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.

Figure imgf000150_0001

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

Figure imgf000151_0001
 

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.

Figure imgf000152_0001

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

Figure imgf000154_0001
Figure imgf000155_0002

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).

Links

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

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

3. Bentham; Dawson; Dunn; Papadopoulos; Taylor; Mitchell; Snowden; Taylor
Organic Process Research and Development, 2004 ,  vol. 8,   4  PG. 674 – 679 ………….AS ENTRY B

  • Bloch, W., et al.: Prostate, 33, 1 (1997)
  • • Glowienke, S., et al.: Mutat. Res., 581, 23 (1997)
  • • Chapple, C., et al.: Eur. Urol., 54, 563 (1997)
  • • Elder, D., et al.: J. Pharm. Pharmacol., 61, 269 (1997)

PATENTS

1. WO 2010062366

2. WO 2007072156

3  WO 2007072156

4.US2002/22732 A1,

5.US2002/28799 A1,

6.

WO1998049166A1 * Apr 10, 1998 Nov 5, 1998 Mark Edward Bunnage PYRAZOLOPYRIMIDINONES WHICH INHIBIT TYPE 5 CYCLIC GUANOSINE 3′,5′-MONOPHOSPHATE PHOSPHODIESTERASE (cGMP PDE5) FOR THE TREATMENT OF SEXUAL DYSFUNCTION
WO1999054333A1 * Mar 25, 1999 Oct 28, 1999 Mark Edward Bunnage Pyrazolopyrimidinone cgmp pde5 inhibitors for the treatment of sexual dysfunction
US4666921 * 15 окт 1985 19 май 1987 Ludwig Heumann & Co. Gmbh Pyrazole derivatives, processes for their preparation and pharmaceutical preparations containing these compounds
US5808092 * 15 окт 1997 15 сен 1998 Ube Industries, Ltd. Process for preparing-1-ethyl-5-hydroxypyrazole
US6015911 * 24 мар 1998 18 янв 2000 Dow Agrosciences Llc Process for preparing 1-alkyl-4-(2-chloro-3-alkoxy-4-alkylsulfonylbenzoyl)-5-hydroxypyrazole and related compounds
EP0463756A1 7 июн 1991 2 янв 1992 Pfizer Limited Pyrazolopyrimidinone antianginal agents
EP0812845A1 4 июн 1997 17 дек 1997 Pfizer Limited Process for preparing sildenafil
EP0994115A2 11 окт 1999 19 апр 2000 Pfizer Limited Process for preparation of pyrazolo-(4,3-d)pyrimidin-7-ones and intermediates thereof
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
WO1999054333A1 25 мар 1999 28 окт 1999 Mark Edward Bunnage Pyrazolopyrimidinone cgmp pde5 inhibitors for the treatment of sexual dysfunction
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
WO2001027113A2 11 окт 2000 19 апр 2001 Mark Edward Bunnage PYRAZOLO `4,3-d! PYRIMIDINE DERIVATIVES

PDE5 inhibitors mirodenafil

Figure imgf000078_0002

sildenafil

Figure imgf000078_0003

tadalafil

Figure imgf000079_0001

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

Figure imgf000080_0001

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

Figure imgf000080_0002

avanafil 4-[(3-chloro-4-methoxy-phenyl)methylamino]-2-[(2S)-2- (hydroxymethyl)pyrrolidin- 1 -yl] -N-(pyrimidin-2- ylmethyl)pyrimidine-5-carboxamide

Figure imgf000080_0003

dasantafil 7-[(3-bromo-4-methoxyphenyl)methyl]-l-ethyl-8-[[(lR,2R)-2- hydroxycyclopentyl]amino]-3-(2-hydroxyethyl)purine-2,6-dione

Figure imgf000081_0001

NM 702 (Nissan Chemical Industries)

Figure imgf000081_0002

SLX 101 (Surface Logix) – Structure Not Available

UK 369003 (Pfizer) – Gisadenafil besylate

Figure imgf000081_0003
 
 
 
 
Cut paste from my blog on  organic spectroscopy international
SEE  BELOW OR FOLLOW LINK
 
GISEDENAFIL
Gisadenafil besylate C23H33N7O5S.C6H6O3S [334827-98-4]GISEDENAFIL BESYLATE
334826-98-1 free form

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

 break dancer animation
LEARN NMR STEP BY STEP
can can  animation1…………..
Ethyl 3-ethyl-1H-pyrazole-5-carboxylate
 
Figure US06407259-20020618-C00033
1H NMR (300 MHz, CDCl3):
δ=1.20 (3H, t), METHYL OF  -CH2-CH3
1.28 (3H, t),  METHYL OF  -C=O-O-CH2-CH3
 2.67 (2H, q), CH2 OF  OF  -CH2-CH3
4.29 (2H, q),  CH2  OF  -C=O-O-CH2-CH3
6.55 (1H, s), LONE PYRAZOLE PROTON ON RING
12.56 (1H, s). NH PROTON
LRMS m/z=167.1 [M-H]+, C8H12N2Orequires 168.2.
dancer  animation

 
2………. Ethyl 3-ethyl-1H-pyrazole-5-carboxylic acid
 
Figure US06407259-20020618-C00034
 
 δ (DMSOd6):
1.13 (3H,t), METHYL OF  -CH2-CH3
2.56 (2H,q), CH2 OF-CH2-CH3
6.42 (1H,s).LONE PYRAZOLE PROTON ON RING
VERY EASY..FEELING HAPPY..1H NMR IS EASY
dancer  animation

shark

3………..
3-Ethyl-4-nitro-1H-pyrazole-5-carboxylic acid
Figure US06407259-20020618-C00035
 δ (DMSOd6):
1.18 (3H,t), METHYL OF  -CH2-CH3
2.84 (2H,m), CH2  OF  -CH2-CH3
13.72 (1 H,s). NH PROTON
ALERT……….LONE PYRAZOLE PROTON ON RING LOST DUE TO NITRO SUBSTITUTION
hula dancing  animation

 
4………..
3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide
Figure US06407259-20020618-C00036
 
 δ (DMSOd6):
1.17 (3H,t), METHYL OF  -CH2-CH3
2.87 (2H,m),CH2 OF  -CH2-CH3
7.40 (1H,s),
7.60 (1H,s),
7.90 (1H,s).
ALL NH AND NH2 SIGNALS
DO IT YOURSELF………….NMR IS EASY
LRMS: m/z 185 (M+l)+.
liz hurlley dancing  animation
5………..
5-Ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide
Figure US06407259-20020618-C00037
m.p.=140° C. Found: C, 44.46; H, 5.79; N, 23.01. C9H14N4Orequires C, 44.63; H, 5.79; N, 23.14%.
δ (CDCl3):
1.18 (3H, t), METHYL OF  -CH2-CH3
2.98 (2H, q),CH2 OF  -CH2-CH3
 3.22 (3H, s), METHYL OF -OCH3
3.77 (2H, t), CH2 OF NCH2-CH2-O-CH3
4.28 (2H, q), CH2 OF NCH2 –CH2-O-CH3
6.03 (1H, s), NH2
7.36 (1H, s).NH2
 
LRMS: m/z=243 (M+1)+
african carnival dancing  animation
 art    animation
 
 
 
6……
4-Amino-5-ethyl-1-(2-methoxyethyl)-1H-pyrazole-3-carboxamide
Figure US06407259-20020618-C00038
 m.p.=131° C. Found: C, 50.75; H, 7.62; N, 26.38. C9H16N4Orequires 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), NH2 OF PYRAZOLE
4.15 (2H, t),
5.27 (1H, s),C=0-NH2
 6.59 (1H, s).C=O-NH2
NITRO IS CONVERTED TO AMINO….DO IT YOURSELF
 
LRMS: m/z=213 (M+1)+
ballerina  animation
 




7…………………
 
N-[3-Carbamoyl-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinyl sulfonyl) nicotinamide.
Figure US06407259-20020618-C00039
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), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING
1.22 (3H, t), METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN
1.60 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING
2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING
2.54 (4H, m), 4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM
2.96 (2H, q), CH2 OF  –CH2-CH3 ON PYRAZOLE SIDE CHAIN
3.12 (4H, m), 4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP
3.36 (3H, s), METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN
3.81 (2H, t), CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.27 (2H, t), CH2 OF NCH2 –CH2-O-CH3 ON PYRAZOLE SIDECHAIN
4.80(2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING
5.35(1H, s), C=0–NH2
6.68 (1H, s), C=O-NH2
8.66 (1H, d) ,PYRIMIDINE AROM H …..AWAY/PARA TO C=O-NH -PYRAZOLE GP
 8.86 (1H, d), PYRIMIDINE AROM H …..CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift to delta 9.06 after cyclization in next step ie formation of GISADENAFIL
10.51 (1H, s). NH
LRMS: m/z=539 (M+1)+
 
modern dancers  animation


shark



FINAL
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.
Figure US06407259-20020618-C00040
 
 m.p.=157° C. Found: C, 52.65; H, 6.46; N, 17.76. C23H33N705S. 0.2 C2H5CO2CHrequires C, 53.21; H, 6.49; N, 18.25%.
δ (CDCl3):

1.07 (3H, t), METHYL  OF  -N CH2-CH3 ON PIPERAZINE RING

1.42 (3H, t),  METHYL OF  -CH2-CH3 ON PYRAZOLE SIDE CHAIN

1.61 (3H, t), METHYL OF  -O-CH2-CH3 ON PYRIMIDINE RING

2.44 (2H, q), CH2  OF  -N CH2-CH3 ON PIPERAZINE RING

2.57 (4H, m),4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM

3.08 (2H, q), CH2 OF  –CH2-CH3 ON PYRAZOLE SIDE CHAIN

3.15 (4H, m),4H OF –NCH2 ON PIPERAZINE RING BOTH SIDE OF N ATOM CLOSE TO SO2 GP

3.32 (3H, s),METHYL OF -OCH3 ON PYRAZOLE SIDE CHAIN

3.92 (2H, q),  CH2 OF NCH2-CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.48 (2H, q), CH2 OF NCH2 –CH2-O-CH3 ON PYRAZOLE SIDECHAIN

4.77 (2H, q), CH2 OF O-CH2 CH3 ON PYRIMIDINE RING

8.65 (1H, d), PYRIMIDINE AROM H …..AWAY/PARA TO C=O-NH -PYRAZOLE GP

9.06 (1H, d). PYRIMIDINE AROM H …..CLOSER/ORTHO TO C=O-NH -PYRAZOLE GP, reason this signal will shift from 8,86 delta to  9.06 after cyclization in this step ie formation of GISADENAFIL

The spectrum also has signals that correspond to a solvate with ethyl acetate.

 
LRMS: m/z=520 (M+1)+

SILDENAFIL, VIAGRA REVIEW


ANTHONY MELVIN CRASTO Ph.D

Sildenafil by Anthony Crasto

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AYURVEDA- ERECTILE DYSFUNTION AND ASSOCIATED MEDICINES


sildanafil

Erection of the penis in males is often a result of a state of sexual arousal. Erectile dysfunction occurs when it becomes difficult to produce erection even in a state of adequate arousal. Erectile dysfunction can occur at any age to any one and at any point of time. It can be due to a vast array of reasons, ranging from fatigue to serious diabetic or heart conditions. While causes like fatigue can be taken care of by simple rest and a good night’s sleep, serious causes like diabetes and cardiovascular diseases can be a little difficult to deal with. Erectile dysfunction does not necessarily mean that there is something physically wrong within the body, as it can also be a result of a vast number of psychological reasons. The loss of erection in itself can give rise to a vast number of psychological problems like loss of self respect and confidence and, hence, requires immediate medical assistance.

File:Vardenafil.svg

vardenafil

You can characterize erectile dysfunction (also known as the problem of male impotency) into two broad categories: firstly, when sometimes full erections are obtained, like when the person under consideration is in deep sleep. This condition is due to the failure of getting an erection due to a psychological reason and can be solved with professional psychological assistance. Secondly, when no erection is obtained. This is generally when the physical structure is not working properly.

File:Tadalafil skeletal.svg

tadalafil

Erectile dysfunction takes place when a man fails to get a proper erection or is not able to sustain it to indulge in sexual intercourse. There is no formal means of detecting and diagnosing an erectile dysfunction. However, blood tests are conducted in such cases as they generally give a fair idea of the underlying diseases such as prolactinoma, diabetes and hypogonadism. Impotency is generally a result of poor health conditions and can be a result of obesity or malnutrition. There are a number of tests along with the blood tests that are undertaken to determine the nature and extent of an erectile dysfunction problem. These are duplex ultrasound to evaluate the blood flow, penile nervous function test such as bulbocavernosus reflex, nocturnal penile tumescence, penile biothesiometry, Magnetic Resonance Angiography (MRA), etc.

avanafil

Avanafil can be synthesized from a benzylamine derivative and a pyrimidine derivative:

Avanafil synthesis.png

Some patients have trouble discussing problems relating to erectile dysfunction with their doctors, but it is important to step forward as erectile dysfunction can also be a symptom of other health problems such as clogged arteries or nerve damage. A doctor can offer a number of treatments for erectile dysfunction depending on the reason and underlying conditions.

While some treatments may involve a steady intake of medicines over a period of time, others can be as simple as taking a few pills for some days and getting more exercise and physical activity. The treatment generally lasts for about a month, but can also be of shorter or longer duration, depending on the severity of the disorder. If the erectile dysfunction is due to some other major ailment, then the problem generally subsides after complete recovery.

When a patient is suffering from erectile dysfunction, he generally has a very low self esteem and, hence, it becomes important that he get professional help and doesn’t try to deal with the situation all by himself. Becoming a part of a support group and taking psychological help from a psychiatrist often helps.

The most common medicines prescribed for erectile dysfunctions are sildanafil or viagra, vardenafil or levitra, and tadalafil or cialis. These medicines can cause side effects such as dizziness and headaches, and should be only taken under expert medical supervision. Some of the other side effects of these medicines may include an increased blood pressure and, thus, are not recommended for heart patients.

Remedies for Erectile Dysfunction

Here are several natural remedies that are used for erectile dysfunction.

L-Arginine

L-arginine is an amino acid that the body uses to make nitric oxide, a substance signals smooth muscle surrounding blood vessels to relax, which dilates the blood vessels and increases blood flow. Relaxation of smooth muscle in the penis allows for enhanced blood flow, leading to an erection.

L-arginine is found naturally in foods such as meat, dairy, poultry and fish. It is also available as oral L-arginine supplements, which some product manufacturers market as a “natural Viagra”).

There have only been two studies to date, however, evaluating the effectiveness of L-arginine for erectile dysfunction.

One study involved 50 men who took L-arginine (5 grams a day) or a placebo. After six weeks, significantly more men taking L-arginine experienced an improvement in sexual function compared with men taking the placebo. Interestingly, it only benefited men who had initially low levels of nitric oxide.

Another study using a smaller dose of L-arginine and a shorter treatment duration found no benefit with L-arginine use. The study involved 32 men with erectile dysfunction who took oral L-arginine supplements (500 milligrams three times per day) or a placebo for 17 days. Oral L-arginine was no better than the placebo.

Side effects may include digestive complaints. High dosees of L-arginine may stimulate the body’s production of gastrin, a hormone that increases stomach acid. For this reason, L-arginine may be harmful for individuals with ulcers and people taking drugs that are hard on the stomach.

L-arginine may also alter potassium levels in the body, especially in people with liver disease. It should not be taken by people who are on medications that alter potassium levels, such as potassium sparing diuretics and ACE inhibitors

Propionyl-L-Carnitine

One study examined the use of two forms of carnitine, propionyl-L-carnitine and acetyl-L-carnitine in 96 men who with erectile dysfunction after prostate surgery. One group were given a placebo, another group took propionyl-L-carnitine (2 grams per day) plus acetyl-L-carnitine (2 grams per day) and sildenafil (Viagra) when needed, and the third group used Viagra alone.

Propionyl-L-carnitine and acetyl-L-carnitine were found to enhance the effectiveness of sildenafil, and result in improved erectile function, sexual intercourse satisfaction, orgasm, and general sexual well-being compared to Viagra alone.

Another study examined the effectiveness of propionyl-L-carnitine supplements plus sildenafil in men with erectile dysfunction and diabetes who were previously unresponsive to Viagra alone. Participants in the study received either propionyl-L-carnitine (two grams per day) plus Viagra (50 milligrams twice a week) or Viagra alone. After 24 weeks, propionyl-L-carnitine plus Viagra was significantly more effective than Viagra alone.

Gingko

The herb ginkgo is used for erectile dysfunction, particularly in people who experience sexual dysfunction as a side effect of antidepressant drugs. It appears to relax smooth muscle and enhance blood flow in the penis.

In one study of 60 men with erectile dysfunction, there was a 50 percent success rate after six months of ginkgo treatment. Two additional studies, however, found that ginkgo was no better than a placebo.

Zinc

Siginificant depletion of the mineral zinc, associated with long-term use of diuretics, diabetes, digestive disorders, and certain kidney and liver diseases, has been shown to lead to erectile dysfunction.

Ashwagandha

The herb ashwagandha (Withania somnifera) is sometimes called Indian Ginseng because it is thought to have similar effects on the body. It is thought to increase energy, stamina, and sexual function. No studies, however, have examined whether it is effective for erectile dysfunction in humans.

Side effects of ashwagandha may include drowsiness. It should not be combined with sedative drugs.

Yohimbe

The bark of the west African yohimbe tree is a source of yohimbine, a compound that has been found to stimulate blood flow to the penis, increase libido, and decrease the period between ejaculations.

Yohimbe is not recommended, however, because it is potentially dangerous, even in small doses. Side effects may include dizziness, anxiety, nausea, a severe drop in blood pressure, abdominal pain, fatigue, hallucinations, and paralysis.

Tongkat Ali

Tongkat Ali was dubbed the “Asian Viagra” in a May 1999 report in the New Sunday Times.

It has been used in Malaysia for many years by men to increase sexual desire, libido, sexual performance and to treat erectile dysfunction.

Tongkat ali appears to work by increasing levels of the hormone testosterone. Testosterone is primarily responsible for the growth and development of male reproductive organs, including the penis, testicles, scrotum, prostate, and seminal vesicles. Normal testosterone levels maintain energy level, mood, fertility, and sexual desire.

Because of its testosterone-enhancing properties, tongkat ali is also used by bodybuilders to increase muscle mass and strength

…………………………………………………………………………………………………..

Tribulus terrestris

Tribulus terrestris, also known as puncture vine, is a herb that has been used in the traditional medicine of China and India for centuries.

In the mid-1990s, tribulus terrestris became known in North America after Eastern European Olympic athletes said that taking tribulus helped their performance.

The active compounds in tribulus are called steroidal saponins. Two types, called furostanol glycosides and spirostanol glycosides, appear to be involved with the effects of tribulus. These saponins are found primarily in the leaf.

Tribulus is most often used for infertility, erectile dysfunction, and low libido. In the last decade, it has become popular to improve sports performance.

Tribulus has been marketed these conditions because research performed in Bulgaria and Russia indicates that tribulus increases levels of the hormones testosterone (by increasing luteinizing hormone), DHEA, and estrogen. The design of these research studies, however, has been questioned.

A more recent study found that four weeks of tribulus supplements (at 10 to 20 milligrams per kg of body weight daily) had no effect on male sex hormones testosterone, androstenedione, or luteinizing hormone compared to people who did not take tribulus.

Preliminary animal studies found that tribulus heightened sexual behavior and increased intracavernous pressure. This was attributed to increases in testosterone. There haven’t been any well-designed human studies to confirm these early findings.

…………………………………………………………………………………………………………………….

Maca

Maca (Lepidium meyenii) is a root plant consumed as a food and for medicinal purposes. Maca is also known as “Peruvian ginseng” (despite the fact that it is not a member of the ginseng family), because it is used as a folk remedy to increase stamina, energy, and sexual function. It is typically taken as a pill or liquid extract or as powdered maca root.

Long used to enhance energy and boost stamina, maca is often touted as an aphrodisiac and a natural means of improving sexual performance and fertility. Although few scientific studies have tested maca’s medicinal effects, some research suggests that maca may offer certain health benefits.

Proponents claim that maca may help with these health concerns:

  • fatigue
  • infertility
  • symptoms of menopause
  • sexual dysfunction in women
  • sexual dysfunction in men (including erectile dysfunction)

Maca is also said to aid in the treatment of cancer.

Here’s a look at the available research on maca and its potential health benefits:

There is “limited evidence” for maca’s effectiveness in improving sexual function in men and women, according to a 2010 report published in BMC Complementary and Alternative Medicine. The report’s authors analyzed four clinical trials, two of which found that maca may have positive effects on sexual dysfunction or sexual desire in healthy menopausal women or healthy adult men. However, the other two trials found that maca failed to produce any positive effects on sexual function.

In a 2008 study from CNS Neuroscience & Therapeutics, researchers found that maca may help alleviate sexual dysfunction caused by use of selective-serotonin reuptake inhibitors (or SSRIs, a class of medications used in treatment of depression). The study involved 20 people with depression, all of whom were experiencing SSRI-induced sexual dysfunction. Results revealed that maca may also help improve libido.

………………………………………………………………………………………………………………

Muira Palma

Muira puama is a small Brazilian tree that grows across the Amazon river basin. It has a long history of use in Brazilian folk medicine as an aphrodisiac.

The root and stem of the tree are used medicinally.

Muira puama is used mainly as a herbal remedy for erectile dysfunction and sexual dysfunction in women.

……………………………………………………………………………………………………………..

Damiana

Other Names: Turnera diffusa, Turnera aphrodisiacaDamiana is a plant native to Mexico and the southern United States. The dried leaves are used medicinally.Damiana has been widely used as an aphrodisiac in Mexico for men and women.The use of damiana as an aphrodisiac is somewhat controversial because there is no scientific evidence that it works and yet it has been widely promoted as a sexual stimulant.One study suggests that damiana may have plant compounds with effects similar to those of progesterone. Over 150 herbs were tested for their ability to bind with estrogen and progesterone receptors in breast cancer cells and found that the damiana was among the six highest progesterone-binding herbs and spices.Damiana is also used for asthma, anxiety, depression, headache, and menstrual disorders, however, there is no scientific evidence that it works for these conditions.

Damiana is found in various forms, including capsule, liquid extract, and tea form. A typical dosage is a 400 mg capsule taken once or twice a day.

Damiana may cause mild indigestion.

Damiana contains a glycoside compound called arbutin. In the urinary tract, arbutin is converted into a chemical called hydroquinone. In large amounts, hydroquinone can cause nausea, vomiting, tinnitus (ringing in the ears, convulsions, and eventually, collapse and death.

Although damiana contains about 1/10 of the arbutin as the herb uva ursi, a maximum safe dose of damiana has not been established.

The safety of damiana in children, pregnant or nursing women, or people with liver or kidney disease has not been established.

…………………………………………………………………………………………………………..

Fo-Ti

Other Names: Polygonum multiflorum, He shou wu

Fo-ti is a plant native to China that is also found in Japan and Taiwan. The medicinal part of the plant is the root. In traditional Chinese medicine, it is often boiled in a liquid made with black beans — this is known as red fo-ti. White fo-ti is the unprocessed root.

Fo-ti is called He shou wu, which means “black-haired Mr. He” in Chinese. This name refers to a legend of an older villager named Mr. He who took fo-ti and restored his black hair, youthful appearance and vitality.

……………………………………………………………………………………………………………….

Horny Goat Weed

Horny goat weed is a leafy plant that is native to Asia and the Mediterranean region. It is also known as Epimedium and Yin Yan Huo.

Horny goat weed has a long history of use in traditional Chinese medicine.

According to folklore, horny goat weed’s reputed aphrodisiac qualities were discovered when a Chinese goat herder noticed increased sexual activity in his flock after they ingested the weed.

Animal studies indicate that horny goat weed may work by increasing nitric oxide levels, which relaxes smooth muscle and lets more blood flow to the penis or clitoris.

Horny goat weed also appears to act by inhibiting the PDE-5 enzyme, which is the same way that the popular drug Viagra works.

Some evidence suggests horny goat weed may modulate levels of the hormones cortisol, testosterone, and thyroid hormone, bringing low levels back to normal.

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