RQ 00000010
CAS 907607-22-1
| Molecular Formula: | C22H27F3N2O6 |
|---|---|
| Molecular Weight: | 472.45479 g/mol |
RaQualia Pharma Inc
Raqualia Pharma Inc.
PFIZER INNOVATOR
RQ-00000010; RQ-10
4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid
4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid
ΦirΦfff^fΣ^^-TrifluoroethoxyVi.a-benzisoxazol-S-vnoxylmethvπpiperidin-i-vπmethylltetrahydro-2H-pyran-4-carboxylic acid
4-[[4-[[4-(2,2,2-trifluoroethoxy)-1,2-benzoxazol-3-yl]oxymethyl]piperidin-1-yl]methyl]oxane-4-carboxylic acid
PHASE 1 for the treatment of GERD, functional dyspepsia and chronic constipation.
Useful for treating diseases mediated by 5-HT4 receptor activity eg such as gastroesophageal reflux disease (GERD), gastric motility disorder, dyspepsia, constipation, esophagitis, diabetes, CNS and cardiovascular diseases.
RaQualia, following its spin-out from Pfizer, is developing RQ-00000010, a 5-HT4 receptor partial agonist, for the treatment of gastric motility disorders, including gastroparesis associated with Parkinson's disease.
In November 2015, the drug was reported to be in phase 1 clinical development. RaQualia and licensee CJ CheilJedang are investigating the drug for the treatment of GERD, functional dyspepsia and chronic constipation.
4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid is disclosed in PL1 as a 5-HT4 receptor agonist, which is useful in the treatment or alleviation of disease conditions mediated by 5-HT4 receptor activity; in particular 5-HT4 receptor agonistic activity, such as gastroesophageal reflux disease (GERD), gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia (FD), irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageal disease, gastritis, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders, cardiac failure, heart arrhythmia, diabetes, and apnea syndrome (See NPL 1 to 13 and PL 2 to 7).
Simply an white solid has been produced in the previously known methods of preparing 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid, described in PL 1. A generic disclosure of pharmaceutically-acceptable salts of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid of the instant application is disclosed, and the free base of the compound of the instant invention is disclosed and claimed, in PL 1 having an international filing date of December 6, 2006, assigned to the assignee hereof. Thus any salts of the compound have been neither pacifically described nor synthesized in prior art.
It has been found that HCl-salt, HBr-salt, pTSA-salt and EDSA-salt of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid shown below, can be isolated as a crystalline form which has advantageous properties such as ease of making a formulation, high solubility, and good stability. In addition the salts of the present invention are more easily purified than a non-crystalline form disclosed in PL 1 (WO2006/090224) and crystalline form disclosed in PL 3 (WO2012/157288).
Patent Literature
{PL 1} WO2006/090224.
{PL 2} US Patent No. 6,106,864.
{PL 3} WO2012/157288
{PL 4} WO00/35298.
{PL 5} WO91/11172.
{PL 6} WO94/02518.
{PL 7} WO98/55148.
Non Patent Literature
{NPL 1} Bockaert J. et al., TiPs 13; 141-145, 1992.
{NPL 2} Ford A. P et al., Med. Res. Rev. 13: 633-662, 1993.
{NPL 3} Gullikson G. W. et al., Drug Dev. Res. 26; 405-417, 1992.
{NPL 4} Richard M. Eglen et al., TiPs 16; 391-398, 1995.
{NPL 5} Bockaert J. et al., CNS Drugs 1; 6-15, 1994.
{NPL 6} Romanelli M. N. et al., Arzheim Forsch./Drug Res., 43; 913-918, 1993.
{NPL 7} Kaumann A. J. et al., Naunyn-Schmiedebergs Arch Pharmacol., 344; 150-159, 1991.
{NPL 8} Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).
{NPL 9} Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001).
{NPL 10} Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
{NPL 11} Pharmaceutical Technology On-line, 25(2), 1-14, by Verma et al. (2001).
{NPL 12} J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
{NPL 13} Evrard, B., et al., Journal of Controlled Release 96 (3), pp. 403-410, 2004.
{NPL 14} Byrn S. R. et al., Solid-State Chemistry of Drugs 2nd ed., pp 3-43 and 461-503, 1999, SSCI, Inc.
PATENT
WO2006090224| PFIZER JAPAN INC. |
EXAMPLE 1 :
ΦirΦfff^fΣ^^-TrifluoroethoxyVi.a-benzisoxazol-S-vnoxylmethvπpiperidin-i-vπmethylltetrahydro-2H-pyran-4-carboxylic acid
Step 1. Methyl 2-hvdroxy-6-(2,2,2-trifluoroethoxy)benzoate
A mixture of 5-hydroxy-2,2-dimethyl-4tø-1 ,3-benzodioxin-4-one (123 g, 633 mmol, Synth. Commun.
1994, 24t 1025), potassium carbonate (262 g, 1.9 mol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (95.8 mL, 665 mmol) in Λ/,Λ/-dimethylformamide (600 mL) was stirred at 50 0C for 30 min. Then methanol (300 ml_) was added to the mixture, and stirring was continued for 5 h at that temperature. After cooling to room temperature, the mixture was diluted with water (500 ml_) and neutralized with 2Λ/ hydrochloric acid. Product was extracted with a mixture of ethyl acetate-hexane (5:1 , 500 mL x 3). Combined organic layers were washed with water (500 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was recrystallized from methanol-water to afford 125 g (79%) of the desired product as colorless crystals.
1H-NMR (CDCI3) δ: 11.47 (1 H, s), 7.36 (1 H, t, J = 8.4 Hz), 6.72 (1 H, dd, J = 1.1 , 8.4 Hz), 6.38 (1 H, q, J = 8.1 Hz), 4.36 (2 H, q, J= 8.0 Hz), 3.96 (3 H, s).
MS (ESI) m/z: 251 (M+H) +, 249 (M-H) \
Step 2. 4-(2,2,2-Trifluoroethoxy)-1 ,2-benzisoxazol-3-ol
To a solution of hydroxylamine sulfate (120 g, 732 mmol) in water (360 mL) was added potassium carbonate (121 g, 875 mmol) at 0 0C. After 30 min of stirring, sodium sulfite (3.74 g, 29.7 mmol) and a methanolic solution of methyl 2-hydroxyl-6-(2,2,2-trifluoroethoxy)benzoate (36.4 g, 146 mmol, EXAMPLE 1 , step 1 , in 360 mL of methanol) were added to the mixture. Then the mixture was warmed to 50 °C and stirred for 30 h. After cooling to room temperature, reaction mixture was partially concentrated to approx. 2/3 volume and acidified with 2Λ/ hydrochloric acid. Product was extracted three times with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford the desired product as a crystalline solid. Crude product (36.3 g) was used for the next step without further purification.
The described above crude product (5.56 g, 22.14 mmol) was suspended in tetrahydrofuran (22.0 mL) and heated at 50 °C. 1 ,1 '-carbonyldiimidazole (7.54 g, 46.48 mmol) was added to the suspension at 50 °C. After addition, the mixture was stirred at 50 0C for 14 h, the mixture was cooled to room temperature. 2Λ/ hydrochloric acid was added to the mixture and extracted with ethyl acetate. The organic layer was extracted with 10% aq. potassium carbonate (100 mL x 5). The water layers were acidified with 2Λ/ hydrochloric acid and extracted with ethyl acetate (200 mL x 2). The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give brown solid. The residual solid was recrystallized from ethyl acetate/hexane to give 3.21 g (61 %) of the title compound as colorless needles.
1H-NMR (CDCl3) δ: 7.53 (1 H1 1, J = 8.5 Hz), 7.14 (1 H, d, J= 8.5 Hz), 6.73 (1 H, d, J = 7.9 Hz), 4.63 (2 H, q, J= 8.0 Hz), 3.83 (1 H, br).
MS (ESI) m/z: 234 (M+H) +, 232 (M-H) ".
Step 3. rMethoxy(tetrahydro-4H-pyran-4-ylidene)methoxyKtrimethyl)silane
To a stirred solution of diisopropylamine (5.2 mL, 37 mmol) in tetrahydrofuran (15 mL) was added dropwise n-butyllithium (1.6 M in hexane, 21 mL, 34 mmol) at 0 0C and stirred for 20 min. A mixture of methyl tetrahydro-2W-pyran-4-carboxylate (4.5 g, 31 mmol) and trimethylsilyl chloride (4.3 mL, 34 mmol) was added to the mixture at -40 0C, then trimethylsilyl chloride (0.4 mL, 0.3 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The volatile components were removed by evaporation and the residual mixture was filtered through a pad of celite washing with hexane. The filtrate was evaporated to give 6.9 g (quant.) of the title compound as a clear yellow oil.
1H-NMR (CDCI3) δ: 3.64-3.59 (4 H, m), 3.52 (3 H, s), 2.24 (2 H, t, J = 5.6 Hz), 2.15 (2 H, t, J = 5.4 Hz), 0.22 (9 H, s).
Step 4. Methyl 4-{f4-(hvdroxymeth'vDpiperidin-1 -yllmethylltetrahvdro^rt-pyran^-carboxylate
To a stirred mixture of piperidin-4-ylmethanol (5.0 g, 43.4 mmol), f-butyldimethylsilylchloride (7.2 g, 47.8 mmol), and triethylamine (7.3 ml_, 52.1 mmol) in dichloromethane (50 mL) was added 4-dimethylaminopyridine (530 mg, 4.3 mmol) at 0 0C. After being stirred at 0 0C for 2 h, 50 mL of water was added to the mixture. The mixture was extracted with dichloromethane (50 mL x 3) and the extracts were combined, dried over sodium sulfate, and concentrated in vacuo to give 10.2 g of a crude oil. The residual oil was dissolved with 86 mL of ethanol, and potassium carbonate (7.2 g, 52.1 mmol) and paraformaldehyde (1.56 g, 52.1 mmol) were added to the solution. After being stirred at room temperature for 2 days, the mixture was filtered and the filtrate was concentrated in vacuo to give a yellow oil. The residual oil was dissolved with 45 mL of acetonitrile and magnesium chloride (414 mg, 4.3 mmol) was added to the solution. [methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane (11.3 g, 52.1 mmol, EXAMPLE 1 , step 3) was added to the mixture at 0 0C. After being stirred at 0 0C for 20 h, 100 mL of 2Λ/ hydrochloric acid was added to the mixture. The mixture was stirred for 30 min and washed with diethyl ether (100 mL x 2). The water layer was neutralized with aq. ammonia and extracted with ethyl acetate (100 mL x 2). The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The residual oil was purified by silica gel column chromatography (dichloromethane/methanol/aq. ammonia 400: 10: 1 ) to give 6.8 g (41%) of the title compound as a colorless waxy solid.
1H-NMR (CDCI3) δ: 3.75-3.90 (2 H, m), 3.71 (3 H, s), 3.40-3.55 (4 H, m), 2.73 (2 H, m), 2.49 (2 H, m), 2.10-2.25 (2 H, m), 1.95-2.10 (2 H, m), 1.50-1.70 (4 H, m), 1.30-1.50 (2 H, m), 1.10-1.30 (2 H, m).
MS (ESI) m/z: 272 (M+H) +.
Step 5. Methyl 4-{r4-((r4-(2,2,2-trifluoroethoxy)-1 ,2-benzisoxazol-3-vπoxy)methyl)piperidin-1 -yllmethyll-tetrahydro-2H-pyran-4-carboxylate
A mixture of 4-(2,2,2-trifluoroethoxy)-1 ,2-benzisoxazol-3-ol (230 mg, 1 mmol, EXAMPLE 1 , step
2), methyl 4-{[4-(hydroxymethyl)piperidin-1 -yl]methyl}tetrahydro-2/-/-pyran-4-carboxylate (270 mg, 1 mmol, EXAMPLE 1 , step 4), and cyanomethyltributylphosphorane (400 mg, 1.5 mmol) in toluene (1.0 mL) was stirred at 100 0C for 16 h. After cooling, the mixture was concentrated in vacuo to give a dark brown oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 2 : 1 ) to give 250 mg (51 %) of the title compound as a white solid.
1H-NMR (CDCl3) δ: 7.44 (1 H, dd, J= 7.9, 8.4 Hz), 7.12 (1 H, d, J= 8.4 Hz), 6.61 (1 H, d, J= 7.9 Hz), 4.49 (2 H, q, J= 8.1 Hz), 4.24 (2 H, d, J= 6.4 Hz), 3.88-3.78 (2 H, m), 3.72 (3 H, s), 3.54-3.41 (2 H, m), 2.83-2.71 (2 H, m), 2.52 (2 H, s), 2.35-1.29 (11 H, m).
MS (ESI) m/z: 487 (M+H) +.
Step 6. 4-(r4-(ir4-(2,2,2-Trifluoroethoxy)-1 ,2-benzisoxazol-3-vπoxy)methyl)piperidin-1 -ylimethylltetrahydro-2H-pyran-4-carboxylic acid
A mixture of methyl 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1 ,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2/+pyran-4-carboxylate (89 mg, 0.18 mmol, EXAMPLE 1 , Step 5) in tetrahydrofuran (1 mL), methanol (1 ml_) and 2 Λ/ aq. sodium hydroxide (1 ml_) was stirred at 70 °C for 17 h. The mixture was neutralized with 2 N hydrochloric acid (1 mL) and formed precipitate was filtered.
The precipitate was triturated with diethylether to give 50 mg (58%) of the title compound as a white solid.
1H-NMR (DMSO-d6) δ: 7.59 (1 H1 dd, J= 8.1 , 8.4 Hz), 7.25 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.1 Hz), 4.93 (2 H, q, J= 8.7 Hz), 4.19 (2 H, d, J= 5.9 Hz), 3.75-3.62 (2 H, m), 3.48-3.30 (2 H, m), 2.90-2.74 (2 H, m), 2.50 (2 H, s), 2.29-2.13 (2 H, m), 1.94-1.23 (9 H, m).
A signal due to CO2H was not observed.
MS (ESI) m/z: 473 (M+H) +, 471 (M-H) ".
m.p.: 171.7 °C.
IR (KBr) v: 2950, 1617, 1527, 1188, 1113 cm"1.
Anal. Calcd for C22H27N2O6F3: C, 55.93; H, 5.76; N, 5.93. Found: C, 55.72; H, 5.78; N, 5.80.
PATENT
WO2015174098https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015174098
PATENT
WO2014080633http://www.google.com/patents/WO2014080633A1?cl=en
PATENT
WO 2015178020https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015178020&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText
The present invention relates to novel salts of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid. More particularly, the invention relates to salt forms (HCl-salt, HBr-salt, p-toluenesulfonate salt and ethanedisulfonate salt), and to processes for the preparation of, compositions containing and to uses of, such salt forms.
EXAMPLE 1
Preparation of
4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid according to the conventional process
A slurry of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-methyl}tetrahydro-2H-pyran-4-carboxylic acid (1.326 kg, 2.807 mol, a white solid) in ethyl acetate (18.564 L) is dissolved at 70 oC. The solution is cooled to 64 oC during 35 min and 200 mg of seed crystal (0.423 mmol) is seeded to the mixture. The mixture is cooled to 40 oC over 5 h period and stirred at this temperature for 14.5 h. The slurry is gradually cooled to 19 oC during 6 h period and the mixture is stirred at this temperature for 46 h. The formed precipitate is collected by filtration and the filter cake is washed with 2.0 L of ethyl acetate. The filter cake is dried under reduced pressure at 50 oC to afford 1.140 kg of the desired crystalline form of 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]-
methyl}tetrahydro-2H-pyran-4-carboxylic acid (86%).
1H-NMR (DMSO-d6) delta: 7.59 (1 H, dd, J = 8.1, 8.4 Hz), 7.25 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.1 Hz), 4.93 (2 H, q, J = 8.7 Hz), 4.19 (2 H, d, J = 5.9 Hz), 3.75-3.62 (2 H, m), 3.48-3.30 (2 H, m), 2.90-2.74 (2 H, m), 2.50 (2 H, s), 2.29-2.13 (2 H, m), 1.94-1.23 (9 H, m).
A signal due to CO2H is not observed.
m.p. (DSC onset): 169 oC.
The temperature has a margin of error of +/- 1 oC.
Crystallinity by PXRD: Crystal (Figure 1): Main peaks at 2-Theta: 5.9, 9.3, 9.8, 11.9, 13.7, 14.3, 15.0, 17.8, 18.2-19.3, 19.7, 22.6, 23.4-24.5 and 24.9 (o ). Each peak has a margin of error of +/- 0.2.
IR nu (diffuse reflection) (Figure 6): 4389-4383, 3426, 2943-2937, 2120, 1904, 1724, 1614, 1535, 1508, 1437, 1420, 1287, 1261, 1221, 1180, 1121, 1094, 1059, 1022, 991, 974, 957, 934, 918, 868, 827, 783, 746, 731, 654, 638, 615, 588, 554, 542 and 507 cm-1. Each peak has a margin of error of +/- 2 cm-1.
Anal. Calcd for C22H27N2O6F3: C, 55.93; H, 5.76; N, 5.93. Found: C, 55.76; H, 5.74; N, 5.85.
PATENT
WO2012/157288http://www.google.co.in/patents/WO2012157288A1?cl=pt-PT
EXAMPLE 1
Preparation of
4-{[4-({[4-(2,2,2-Trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylic acid according to the conventional process
A mixture of methyl 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylate (89 mg, 0.18 mmol, PCT WO2006090224 EXAMPLE 1, Step 5) in tetrahydrofuran (1 mL), methanol (1 mL) and 2 N aq. sodium hydroxide (1 mL) is stirred at 70 oC for 17 h. The mixture is neutralized with 2 N hydrochloric acid (1 mL) and formed precipitate is filtered. The precipitate is triturated with diethylether to give 50 mg (58%) of the title compound as a white solid.
1H-NMR (DMSO-d6) delta: 7.59 (1 H, dd, J = 8.1, 8.4 Hz), 7.25 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.1 Hz), 4.93 (2 H, q, J = 8.7 Hz), 4.19 (2 H, d, J = 5.9 Hz), 3.75-3.62 (2 H, m), 3.48-3.30 (2 H, m), 2.90-2.74 (2 H, m), 2.50 (2 H, s), 2.29-2.13 (2 H, m), 1.94-1.23 (9 H, m).
A signal due to CO2H is not observed.
MS (ESI) m/z: 473 (M+H) +, 471 (M-H) -.
| Patent | Submitted | Granted |
|---|---|---|
| Benzisoxazole Derivatives [US2008207690] | 2008-08-28 | |
| 5-HT4 Receptor Agonist as a Prokinetic Agent [US2014051726] | 2012-03-23 | 2014-02-20 |
| Polymorph Form of 4-methyl)piperidin-1-yl]methyl}-tetrahydro-2H-pyran-4-carboxylic acid [US2014187583] | 2012-05-18 | 2014-07-03 |
| Publication Number | Publication Date | IPCR Assignee/Applicant | Structure hits | Tools | |
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WO-2015178020-A1 | 2015-11-26 |
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WO-2015174098-A1 | 2015-11-19 |
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US-9187463-B2 | 2015-11-17 | ||||
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US-20150322055-A1 | 2015-11-12 | ||||
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EP-2710002-A4 | 2014-10-01 |
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US-8816090-B2 | 2014-08-26 | ||||
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EP-1856114-B1 | 2014-08-20 |
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US-20140187583-A1 | 2014-07-03 | ||||
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WO-2014080633-A1 | 2014-05-30 |
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EP-2710002-A1 | 2014-03-26 |
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US-20140051726-A1 | 2014-02-20 | ||||
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EP-2688648-A1 | 2014-01-29 |
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WO-2012157288-A1 | 2012-11-22 |
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WO-2012127878-A1 | 2012-09-27 |
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US-20080207690-A1 | 2008-08-28 | ||||
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EP-1856114-A1 | 2007-11-21 |
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WO-2006090224-A1 | 2006-08-31 |
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/////c12c(cccc1onc2OCC3CCN(CC3)CC4(CCOCC4)C(=O)O)OCC(F)(F)F
C1CN(CCC1COC2=NOC3=C2C(=CC=C3)OCC(F)(F)F)CC4(CCOCC4)C(=O)O
//////////
see
http://newdrugapprovals.org/2015/12/03/rq-00000010-for-the-treatment-of-gerd-functional-dyspepsia-and-chronic-constipation/
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I’m here to testify about what Dr James did for me. I have been suffering from (GENITAL HERPES VIRUS) disease for the past 4 years and had constant pain and itching, especially in my private part. During the first year.This disease started circulating all over my body and I have used Oregano oil, Coconut oil, Acyclovir, Valacyclovir, Famciclovir, and some other products and it really helped during my outbreaks but I totally got cured! from my HSV with a strong and active herbal medicine ordered from Dr James herbal mix and it completely fought the virus from my nervous system and I was tested negative after 15 days of using Dr James herbal mix medicine. I'm here to let y'all know that herpes virus has a complete cure, I got rid of mine with the help of Dr James herbal medicine. I came across a testimony of Kasha, on the internet testifying about Dr James , on how he cured Her from 7 years HSV 2. And she also gave the email address of Dr James... [drjamesherbalmix@gmail.com]..., advising anybody to contact him for help on any kind of diseases that he would be of help with, so I emailed him telling him about my (HSV 2) he told me not to worry that I'm going to be cured!! Well, I never doubted him. I have faith he can cure me too,, Dr James prepared and sent me his herbal mix medicine made of roots and herbs which I took. In the first one week, I started experiencing changes all over me, after 15 days I drank his herbal mix medicine, I was totally cured. no more itching , pain on me anymore as Dr James assured me. After some time I went to my doctor to do another test. the result came out negative. So friends my advice is if you have such disease or know anyone who suffers from it or any other disease like Alzheimer's Disease, Warts,Moles, Bipolar disorder, Shingles, HPV, HBV, HIV/AIDS, ALS, HBP, CANCER,NEPHROTIC SYNDROME HIV / AIDS, herpes cancer,Ovarian Cancer,Pancreatic cancers, bladder cancer, bladder cancer, prostate cancer, Glaucoma., Cataracts,Macular degeneration,Cardiovascular disease,Autism,Lung disease.Enlarged prostate,Osteoporosis.Alzheimer's disease,psoriasis ,Tach Diseases,Lupus,Backache,dementia.kidney cancer, lung cancer, skin cancer, skin cancer and skin cancer.testicular Cancer, , LEUKEMIA, VIRUSES, HEPATITIS, INFERTILITY . , etc. you can contact Dr James directly on his.... [drjamesherbalmix@gamil.com]... He is a good man,and He will help you.
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