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The FDA has published a supplementing Guide on Quality Metrics. This is a very unusual step as the contents of the guide are planned to be integrated into the Guideline on Quality Metrics which hasn’t been finalised yet. Read more about the Technical Quality Metrics Guide.

see http://www.gmp-compliance.org/enews_05437_FDA-publishes-Technical-Guide-on-Quality-Metrics_15515,S-QSB_n.html

The so-called FDA Quality Metrics Technical Conformance Guide should supplement the Guidance for Industry: Request for Quality Metrics published on 28 July 2015 which is currently still in the draft version. We have recently published a GMP News about a Quality Metrics Case Study at Aenovaregarding a possible implementation. Now, the Technical Guide defines how the industry should submit Quality Metrics to the…

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Yonkenafil

June 29, 2016 10:39 am / Leave a comment

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

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

- (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

13C NMR PREDICT

COSY PREDICT

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

Tenatoprazole, テナトプラゾール

June 23, 2016 12:35 pm / 1 Comment on Tenatoprazole, テナトプラゾール

Tenatoprazole

テナトプラゾール

泰妥拉唑

Tenatoprazole; 113712-98-4; Ulsacare; Protop; TU 199; TU-199;
Molecular Formula:	C₁₆H₁₈N₄O₃S
Molecular Weight:	346.40412 g/mol

2-[2-(3,5-Dimethyl)pyridylmethylsulfinyl]-5-methoxyimidazo[4,5-b]pyridine

PHASE 1 FOR ………..A proton pump inhibitor potentially for the treatment of gastroesophageal reflux disease.

Research Code TU-199

CAS No. 113712-98-4

Mitsubishi Tanabe Pharma and was licensed to Negma Laboratories

Tenatoprazole is a proton pump inhibitor drug candidate that was undergoing clinical testing as a potential treatment for refluxoesophagitis and peptic ulcer as far back as 2003.^[1] The compound was invented by Mitsubishi Tanabe Pharma and was licensed to Negma Laboratories (part of Wockhardt as of 2007^[2]).^[3]^:22

Mitsubishi reported that tenatoprazole was still in Phase I clinical trials in 2007^[4]^:27 and again in 2012.^[3]^:17

Tenatoprazole has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, and has a half-life about seven times longer than other PPIs.^[5]

Tenatoprazole is a novel imidazopyridine derivative and has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors. It is activated more slowly than other proton pump inhibitor, but its inhibition is resistant to reversal.Tenatoprazole has an extended plasma half-life in comparison with those of all other proton pump inhibitors; this makes it more potent in the treatment of nocturnal acid breakthrough than esomeprazole, one of the most popular proton pump inhibitors.

Tenatoprazole belongs to the class of covalent proton pump inhibitors (PPIs), which is converted to the active sulfenamide or sulfenic acid by acid in the secretory canaliculus of the stimulated parietal cell of the stomach.This active species binds to luminally accessible cysteines of the gastric H⁺,K⁺-ATPase, resulting in disulfide formation and acid secretion inhibition.Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg⁻¹ of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg⁻¹of the enzyme at 2 h after intravenous (IV) administration.

Tenatoprazole, or (+)-5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} imidazo-[4,5-b] pyridine, is described in Patent No. EP 254,588. It belongs to the group of drugs considered as proton pump inhibitors, which inhibit the secretion of gastric acid and are useful in the treatment of gastric and duodenal ulcers. It can also be used to treat gastro-oesophageal reflux, digestive bleeding and dyspepsia, because of its relatively long elimination half-life, as described in the application for French patent No. FR 02. 13113.

The first known derivative of this series of proton pump inhibitors was omeprazole, described in Patent No. EP 001,529, which is endowed with properties which inhibit the secretion of gastric acid and is widely employed as an anti-ulcerative in human therapeutics.

In addition to omeprazole, other proton pump inhibitors are well known, and particular mention can be made of rabeprazole, pantoprazole and lansoprazole, which all exhibit structural analogy and lansoprazole, which all exhibit structural analogy and belong to the group of pyridinyl methyl sulfinyl benzimidazoles. These compounds are sulfoxides presenting with asymmetry at the level of the sulphur atom, and therefore generally take the form of a racemic mixture of two enantiomers.

Like omeprazole and other sulfoxide with an analogue structure, tenatoprazole has an asymmetric structure and may therefore be present in the form of a racemic mixture or of its enantiomers. Thus it may exist in the form of its two enantiomers with R and S configurations, or (+) or (−), respectively.

Recent studies have shown that, unlike all the other proton pump inhibitors such as, for example, omeprazole or lansoprazole, and unexpectedly, tenatoprazole is endowed with a markedly prolonged duration of action, resulting from a plasma half-life which is about seven times longer. Thus the clinical data collected have shown that tenatoprazole enables a degree of symptom relief and healing of gastric lesions which is superior to that achieved by other drugs belonging to the same therapeutic category of proton pump inhibitors, which thus allows its effective use in the treatment of atypical and oesophageal symptoms of gastro-oesophageal reflux, digestive bleeding and dyspepsia, as indicated above.

Studies performed by the application have made it possible to show that the two enantiomers contribute differently to the properties of tenatoprazole, and that the two enantiomers, (+) and (−) exhibit significantly different pharmacokinetic properties. Thus it is possible to prepare medicinal products with specific activity by isolating the enantiomers, and these enantiomers themselves exhibit a different pharmacokinetic profile from that of the known racemic mixture. It then becomes possible to use each of these enantiomers more effectively in precise indications for the treatment of perfectly identified pathologies.

Anti-ulcer drug
tenatoprazole (tenatoprazole) is a new proton pump inhibitor, by the Japanese company Tokyo Tanabe, Japan’s Mitsubishi Corporation and Japan’s Hokuriku pharmaceutical companies jointly developed, has passed Phase II clinical trials. It acts on gastric parietal cells, reducing treatment of gastric ulcer, duodenal ulcer, reflux wall cell H + / K + -ATP activity, inhibition of gastric acid secretion, and H. pylori antibacterial activity, mainly for esophagitis and Zhuo – Ellison syndrome and gastric acid secretion disorders related diseases. Compared with the same types of drugs, Tenatoprazole suppress H + / K + -ATP enzyme activity is stronger, more stable, its efficacy than similar products currently widely used in clinical omeprazole strong 7 times. It has not been in the domestic market, nor ratified the production, with broad market prospects and development potential.
Proton pump inhibitors (proton pump inhibitors) for the treatment of acid-related diseases, the past ten years a wide range of clinical applications, better effect of the drug. It can quickly pass through the stomach wall membrane, gathered in a strongly acidic secretory tubules, and H + / K + -ATP enzyme (proton pump) thiol groups covalently bonded to form a disulfide bond, proton pump inactivation, inhibition of the enzyme H + / K + transport, so as to achieve the effect of acid suppression. Proton pump inhibitors and conventional clinical application of gastric acid suppression drugs H2 receptor antagonists compared with different sites of action and have different characteristics, namely acid-suppressing effect at night is good, rapid onset of acid inhibition strong and long time, easy to take these drugs can quickly and efficiently inhibit gastric acid secretion and clearance of Helicobacter pylori, it is widely used gastric ulcer, duodenal ulcer, reflux esophagitis and Zhuo – Ellison syndrome and other diseases treatment. Currently, proton pump inhibitors has been listed on the main omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole.Physical and

chemical properties ofwhite or white crystalline powder, melting point 174 ~ 175 ℃. Soluble in chloroform, insoluble in alcohol and water.
This product and other proton pump inhibitors as compared to chemically stable. China had 34 omeprazole preparations from Portugal, Brazil, India, China and other 13 countries, the stability of the measurements were made. The results showed that only six products (18%) during the trial showing good physical and chemical stability of. 27 products (79%) less (including Chinese product), the active ingredient a significant chemical decomposition, color and physical properties such as dissolution, are also a corresponding change. The results of a stability test designed to compare the various proton pump inhibitors show investigated eight days at 60 ℃, relative humidity of 75%, after omeprazole decomposition only 3% of the active ingredient, the tenatoprazole 77% of the data, said Alpha pantoprazole stability far superior to omeprazole, is already developed similar products in the most promising products.

Synthesis

Matsuishi, N.; Takeda, H.; Iizumi, K.; Murakami, K.; Hisamitsu, A. US Patent 4,808,596, 1989

Synthesis of Tenatoprazole 1 commences with the coupling of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 in the presence of potassium hydroxide affords 4 with 73% yield in ethanol and chloroform. The oxidation of the penultimate sulfide intermediate4 with m-CPBA in chloroform (100 vol) afforded 1

Syn 2

Org. Process Res. Dev., 2009, 13 (4), pp 804–806

DOI: 10.1021/op800173u

http://pubs.acs.org/doi/full/10.1021/op800173u

synthesis of 1 begins with the solvent-free condensation of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to deliver the sulfide intermediate4 with 98% yield.

The final step of the synthesis is the oxidation of the sulfide intermediate with m-CPBA to form tenatoprazole 1. The sulfide intermediate 4 on treatment with 0.9 equiv of m-chloroperbenzoic acid (m-CPBA) at −10 to −15 °C afforded the crude tenatoprazole which was isolated as its sodium salt. The sodium salt of tenatoprazole 5 was purified by recrystallsation using dimethyl formamide and ethyl acetate (2:1 ratio) to yield the pure crystalline tenatoprazole sodium 5. Treatment of tenatoprazole sodium 5 with dil. HCl in the presence of acetone and water afforded the pure tenatoprazole 1

PATENT

CN 1861600

CN 1982311

WO 2009116072

CN 101429192

WO 2010043601

IN 2010CH00462

IN 251400

CN 102304127

WO 2012004802

CN 102703922

IN 2009DE01392

WO 2014111957

IN 2013MU00181

IN 2014CH01419

PAPER

Dai, Liyan; Synthetic Communications 2008, V38(4), P576-582

Advanced Materials Research (Durnten-Zurich, Switzerland) (2011), 233-235(Pt. 1, Fundamental of Chemical Engineering), 160-164.

Organic Process Research & Development (2013), 17(10), 1293-1299

Enantiomeric separation of proton pump inhibitors on new generation chiral columns using LC and supercritical fluid chromatography
Journal of Separation Science (2013), 36, (18), 3004-3010………http://onlinelibrary.wiley.com/doi/10.1002/jssc.201300419/abstract

PATENT

CN 102304127

https://www.google.com/patents/CN102304127A?cl=en

Tenatoprazole is a new type of gastric H + / K + -ATP enzyme inhibitors (proton pump inhibitor PPI), the chemical name 5-methoxy-2- (4-methoxy-3, 5-dimethyl-2-methylsulfinyl) imidazole and W, 5-b] pyridine, useful in the treatment of gastric ulcer, duodenal ulcer, reflux esophagitis and Zhuo – Ai syndrome and gastric acid secretion disorders related diseases. The drug was developed by Japan’s Tokyo Tanabe, Japan’s Mitsubishi Corporation and Japan’s Hokuriku pharmaceutical companies. Compared with other varieties of the same type, which inhibit H + / K + -ATP enzyme activity is stronger, ulcers of various tests are effective, and significantly improve the stability compared with other proton pump inhibitors.

US patent US4808596 “hidazo [4,5_b] pyridine compounds and pharmaceutical compositions containing same)) synthesis process disclosed Tenatoprazole the below formula:

By The route of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride with 2-mercapto-5-methoxy-imidazole, 5-b] pyridine under basic conditions condensation of Intermediate 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine, and then oxidizing the Thai duly omeprazole. This route for the synthesis of pull azole classic line, many pull azoles such as omeprazole can be synthesized by a similar route, this route mild condition, simple operation. But the route condensation, oxidation treatment after use of large amounts of toxic solvent chloroform, is not conducive to industrial scale; lower oxidation yields, the resulting Tenatoprazole containing unreacted starting materials 2- [2_ (3,5 – dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine, further comprising a sulfone by-product, N- oxide, N- oxide sulfone, These by-products may interfere with purification of tenatoprazole.

Japanese Patent invention Wo 丨 J JP05222038 “5_methoxy-2- [[(4_methoxy-3, 5-dimethyl-2-pyridyl) methyl] thio] imidazo [4,5 ~ b] pyridine and intermediates)) male

Synthesis open Tenatoprazole the below formula:

4-chloro-2-chloromethyl-3,5-dimethylpyridine -N- oxide 2_ mercapto _5_ methoxy-imidazo – [4, 5-b] pyridine in alkaline under condensation of Intermediate 5-Methoxy-2- (4-chloro-3,5-dimethyl-2-methylthio Bi) imidazo W, 5-b] pyridine-oxide -N- ( yield 82%), then refluxed in a solution of sodium methoxide in methanol to give 5-methoxy-2- (4-oxo-3,5-dimethyl-2-methyl sulfide) imidazo W , 5-b] pyridine -N- oxide (income ¥ 71%), and then at room temperature in methylene chloride, phosphorus trichloride treated with deoxy (yield 95%), and finally oxidation in Tenatoprazole (income Rate not reported). The novel synthetic route, mild reaction conditions, simple operation, the yield of each step is higher, but the route is too long resulting in a total yield is not high, prolonged and rising production costs.

Reaction route is as follows:

Example 1:

] a) 2- [2- (3,5-dimethyl) -4-methoxy-picolyl thioether _5_ methoxy] imidazo [4,5_b] pyridine:

To a reaction flask was added 2-mercapto-5-methoxy-imidazole, 5-b] pyridine 18. lg, 12g of sodium hydroxide and water 144. 8g, stirred and dissolved at 25 ° C, was added dropwise within Ih 20g of the 2-chloromethyl-dimethyl-4-methoxy _3,5- pyridine hydrochloride and 60g of water were mixed solution dropwise at 25 ° C the reaction 2h, the reaction is completed, filtered, washed with water 144. 8g, 36. 2mL ethanol and washed to obtain a wet powder; wet powder was dried at 50 ° C in vacuo to constant weight to give 2- [2_ (3,5-dimethyl) -4-methoxy-pyridylmethyl sulfide -5 – methoxy] imidazo [4,5-b] pyridine 32. Og;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5-b] pyridine 30g, dichloromethane 300g, methanol 15g, and dissolved with stirring; cooled to -10 ° C, was added dropwise the 15g and 485g m-chloroperbenzoic acid in methylene chloride mixed solution, dropwise addition the reaction temperature was controlled at -10 ° C, the dropping time of the pool; the dropwise addition, the temperature control at -10 ° C, the reaction 30min; completion of the reaction, at 10 ° C by the dropwise addition of lithium hydroxide and 135g water 15g mixed solution, drip complete, insulation stirred Ih; filtered cake was washed with acetone 60mL, get wet powder; wet powder was dried at 35 ° C under vacuum to constant weight to give Tenatoprazole lithium salt ^ g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, acetone 63mL, water IOOmL, cooling M0 ° C, dropping lmol within lh / L hydrochloric pH7 0, drops. Albert, stirring 30min; the filter cake washed with water 50mL, washed with acetone and 50mL, wet powder was dried at 35 ° C under vacuum to constant weight to give Tenatoprazole 19. Sg.

Example 2:

a) 2- [2- (3,5-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5_b] pyridine (4) Preparation: To the reaction flask was added 2-mercapto-5-methoxy-imidazo 44,5-b] pyridine 18. lg, 11. 2g of potassium hydroxide and water 217mL, stirred and dissolved at! 35 ° C, was added dropwise within 2h by the 33. 3g of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride and 133. 2mL water mixed solution, dropwise at 35 ° C the reaction 4h, the reaction is completed, filtration, water 217mL, 72. 4mL ethanol and washed to obtain a wet powder; wet powder was dried at 60 ° C in vacuo to constant weight to give 2- [2- (3,5-dimethyl) -4-methoxy-pyridylmethyl sulfide -5-methoxy-yl] imidazo W, 5-b] pyridine 33. Ig;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 400mL, methanol 50mL, stirring to dissolve; cooled to _15 ° C, was added drop by the m-chloroperoxybenzoic acid 16g of mixed solution of dichloromethane and 400mL , the process reactor temperature control was added dropwise at -20 ° C, the dropping time 2. 5h; the dropwise addition, the temperature control _15 ° C, the reaction 35min; completion of the reaction, at 15 ° C by the dropwise addition of 20g of hydrogen Lithium oxide and 200mL water mixed solution, drip completed, insulation mixing 1. 5h; filtration, the filter cake washed with acetone 90mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 6g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, ethanol 75mL, water 150mL, cooled to 10 ° C, dropping 6mol / L hydrochloric pH8 0 within 2h,. drops Albert, stirring 40min; the filter cake washed with water 100mL, washed with acetone IOOmL, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 5g.

Example 3:

a) 2- [2- (3,5-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazo W, 5_b] pyridine (4) Preparation: To the reaction flask was added 2-mercapto-5-methoxy-imidazo 44,5-b] pyridine 18. lg, 8.4g of lithium hydroxide and water 180ml, stirred and dissolved at 30 ° C, was added dropwise within 1. 5h by the Guang .6g 2-chloro-3,5-dimethyl-4-methoxy-pyridine hydrochloride and 90mL water mixed solution, drop end at 30 ° C reaction 3h, the reaction is complete, filtration, water 217mL , washed with 85mL ethanol to obtain a wet powder; wet powder was dried at 55 ° C in vacuo to constant weight to give 2- [2- (3,5-dimethyl) -4-methoxy-5-pyridylmethyl sulfide oxy] imidazo [4,5-b] pyridine 32. 4g;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 600mL, methanol 60mL, stirring to dissolve; cooled to -20 ° C, was added drop by the m-chloroperoxybenzoic acid 18g of mixed solution of dichloromethane and 600mL , dropwise addition the reaction temperature is controlled at _20 ° C, the dropping time of the pool; the dropwise addition, the temperature control at _20 ° C, the reaction 40min; completion of the reaction, at 20 ° C by the dropwise addition of lithium hydroxide and 300mL 30g water mixed solution, drip complete insulation mixing tank; filter, the filter cake washed with acetone and 120mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 7g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, methanol 75mL, water 120mL, cooled to 5 ° C, dropping dilute hydrochloric acid within 1 5h tune pH7 5,.. drops Albert, stirring 35min; the filter cake washed with water 75mL, 75mL acetone washed, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 6g.

Example 4:

a) 2- [2- (3,5-dimethyl) -4-methoxy-picolyl thioether _5_ methoxy] imidazo [4,5_b] pyridine ⑷ Preparation of: To a solution The reaction flask was added 2-mercapto-5-methoxy imidazole -½, 5-b] pyridine 18. lg, IOg sodium hydroxide and water 150ml, stirred and dissolved at 30 ° C, the 1. 5h dropwise added from 21 . 5g of 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride and 90mL water mixed solution, dropwise at 30 ° C the reaction 3h, completion of the reaction, was filtered, washed with water 217mL, The wet powder was washed with ethanol to give 85mL; wet powder was dried at 55 ° C in vacuo to constant weight to give 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide ] imidazo [4,5-b] pyridine 32. 3g;

2) Preparation of tenatoprazole lithium salt: To a reaction flask was added 2- [2- (3,5_-dimethyl) -4-methoxy-5-methoxy-pyridylmethyl sulfide] imidazole and W, 5-b] pyridine 30g, dichloromethane 500mL, methanol 60mL, stirring to dissolve; cooled to -20 ° C, was added drop by the m-chloroperoxybenzoic acid 18g of mixed solution of dichloromethane and 500mL , the process reactor temperature control was added dropwise at -20 ° C, the dropping time pool; the dropwise addition, the temperature control in -20 ° C, the reaction 40min; completion of the reaction, at 20 ° C by the dropwise addition of lithium hydroxide 30g and 300mL water mixed solution, drip complete insulation mixing tank; filter, the filter cake washed with acetone and 120mL, get wet powder; wet powder was dried at 40 ° C under vacuum to constant weight to give Tenatoprazole lithium salt 28. 6g;

3) Preparation Tenatoprazole: To a reaction flask 加入泰 pantoprazole lithium salt 25g, isopropanol 75mL, water 120mL, cooled to 5 ° C, dropping 3mol / L hydrochloric within 1 5h. . pH7 5, drops Albert, stirring 35min; the filter cake washed with water 75mL, 75mL acetone washed, wet powder was dried at 40 ° C under vacuum to constant weight, yield powder was Tenatoprazole 19. 7g.

PAPER

An Improved Synthesis of Antiulcerative Drug: Tenatoprazole

http://pubs.acs.org/doi/full/10.1021/op800173u

Somaiah Sripathi^†, Ramachandra Reddy Bojja^†, Venugopal Reddy Karnati*^‡, V. V. N. K. V. Prasada Raju^§ andMayur D. Khunt^§

Department of Research and Development, Srini Pharmaceuticals Ltd., Plot No. 10, Type-C, Road No. 8, Film Nagar, Jubilee Hills, Hyderabad-500033, Andhra Pradesh, India, Department of Chemistry, Osmania University, Tarnaka, Hyderabad-500007, Andhra Pradesh, India and Research and Development, Integrated Product Development Organization, Innovation Plaza, Dr. Reddy’s Laboratories Ltd., Bachupally, Qutubullapur, R. R. Dist. 500 072, Andhra Pradesh, India

Org. Process Res. Dev., 2009, 13 (4), pp 804–806

DOI: 10.1021/op800173u

Publication Date (Web): November 12, 2008

* To whom correspondence should be addressed. Telephone: +91 9490783736. E-mail: drkvr_ou@yahoo.com;kvgr1951@rediffmail.com., †Srini Pharmaceuticals Ltd.
, ‡Osmania University.
, §Dr. Reddy’s Laboratory Ltd.

An efficient, cost-effective and multikilogram-scale process for the synthesis of tenatoprazole 1, an antiulcerative drug, is described. The key steps in this synthesis involve the coupling of 2-mercapto-5-methoxyimidazo[4,5-b]pyridine 2 with 2-chloromethyl-4-methoxy-3,5-dimethyl pyridine hydrochloride 3 to yield 4 and its subsequent oxidation with m-CPBA to produce sulfoxide 1. The process has been scaled up for the multikilogram-scale of compound 1 with an overall yield of 72%. The new process requires no purification process and affords the target compound 1 with 99.8% purity by HPLC.

2-[2-(3,5-dimethyl)pyridylmethylsulfinyl]-5-methoxyimidazo[4,5-b]pyridine (1, 15.5 kg, 74%). Purity by HPLC 99.8%; ¹H NMR (200 MHz, DMSO) δ 2.2 (s, 6H), 3.8 (s, 6H), 4.8 (s, 2H), 6.6 (d, 1H), 7.8 (d, 1H), 8.2 (s, 1H), 13.0 (s, 1H).

PATENT

http://www.google.co.in/patents/US7507746

the (+) enantiomer of tenatoplazole can be obtained by using chloroform, an industrially acceptable solvent, in accordance with the method proposed by Umemura et al. (J. Org. Chem. 1993, 58, 4592) as follows:

Example 1 (−)-5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridineThe conditions for preparative chromatography, shown as an example, are as follows:

Column: 265×110 mm ChiralPak®

Chiral Stationary Phase selector of the Amylose tris type [(S)-a methylbenzylcarbamate]

Flow rate: 570 ml/min

Detection: UV 240 nm

Temperature: Ambient temperature

These conditions are implemented on a liquid preparative chromatography apparatus.

Introduce approximately 2 g of the racemic mixture if tenatoprazole exhibiting purity higher than 99.5%. The (−) enantiomer is identified by measuring the angle of optical rotation, which must be laevogyre. This measurement can be performed directly on the column, the product being dissolved in the solvent (acetonitrile).

Example 2 (+)-5-methoxy-2-{(4-methoxy-3, 5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridine(R)-(+)-binaphthol 85 g (0.311 mol, 0.2 equivalence), ortho titanic acid isopropyl 42 g (0.148 mol, 0.1 equivalence), water 55 g (3.06 mol) and chloroform 7.5 L were stirred for 1 hour at room temperature. To the resultant, 5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio}imidazo[4,5-b]pyridine (MPI), 0.5 kg, was added and stirred for 0.5 hours at room temperature. The thus-prepared mixture was cooled to 5° C. and then 70% aqueous solution of tert-butylhydroperoxide, 0.4 L (approx. 3.0 mol, 2.0 equivalence) was added and stirred for 72 hours at the same temperature as above. After the reaction endpoint was confirmed by HPLC, an aqueous solution of sodium hydroxide was added thereto to separate the aqueous layer, thus removing foreign matter. Then, the resultant was concentrated. Ethyl acetate was added to concentrated residues, which were then heated and suspended. The thus-prepared crude crystalline substances were dissolved in water and neutralized to pH 6.8 with a diluted sulfuric acid solution which was chilled with ice. Deposited crystals were filtered, dried and recrystallized by addition of ethanol to obtain (+)-5-methoxy-2-{(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl}-1H-imidazo[4,5-b]pyridine {(+)-TU-199}

Yield: 77%

Optical purity: 96.6% ee

Chemical purity: 94.5%

Melting point: 135° C.

Optical rotation: +184° (conditions: C=1.0, N,N-dimethylformaldehyde solution)

Ultraviolet absorption spectrum: (10 μg/mL)λmax (nm): 316, 273, 206

When measurements were carried out, for a solubility of (+), (−) forms and a racemic form (±) of tenatoprazole in relation to water, it was found that the (+) form dissolved almost 3 times greater than the racemic body and (−) form dissolved over 2 times greater than the racemic form, exhibiting favorable physical properties in preparing drugs (refer to Table 2 below).

TABLE 2
(+) form	(−) form	(±)racemic form
Solubility (water) μg/mL	93.0	74.4	34.6

CLIPS

Tenatoprazole is a pyridinylmethylsulfinyl imidazopyridine compound, which is a weak base. This compound has three pKas. One is the pyridine pKa of pyridinylmethyl moiety and the others are the imidazole pKa and the pyridine pKa of the imidazopyridine moiety. The pyridine pKa1 enables tenatoprazole accumulation in the acidic canaliculus of the parietal cell. Protonation of the imidazopyridine ring enhances electron deficiency at the C-2 position, allowing intramolecular rearrangement to the active form. The active form is the sulfenic acid and/or cyclic sulfonamide, and reacts with luminal cysteine thiols of the enzyme to inhibit the enzyme activity

Synthesis route
from 2-mercapto-5-methoxy-imidazo [4,5-b] pyridine (2) and 2-chloro-3,5-dimethyl-4-methoxypyridine hydrochloride ( 3) by nucleophilic substitution synthesis of 2- (4-methoxy-3,5-dimethyl-2-methylthio) -5-methoxy-imidazo [4,5-b] pyridine (4) the oxidation of 4 1. Figure 1 is a synthesis route of tenatoprazole

References

DataMonitor. March 2003. Gastrointestinal Disease Update: Digestive Disease Week 2003
Economic Times. 3 March, 2011. Investors unwilling to forgive Wockhardt, promoter for failings
Mitsubishi Tanabe Pharma State of New Product Development (as of May 8, 2012)
Mitsubishi Tanabe Pharma FY2007 Interim Financial Results
Li H et al. H+/K+-ATPase inhibitors: a patent review. Expert Opin Ther Pat. 2013 Jan;23(1):99-111. PMID 23205582

US4808596 *	24 Jul 1987	28 Feb 1989	Tokyo Tanabe Company, Ltd.	Imidazo[4,5-b]pyridine compounds and pharmaceutical compositions containing same
US5753265 *	7 Jun 1995	19 May 1998	Astra Aktiebolag	Multiple unit pharmaceutical preparation
US5798120 *	6 Oct 1994	25 Aug 1998	Tokyo Tanabe Company Limited	Enteric granule-containing tablets
EP0124495A2	28 Feb 1984	7 Nov 1984	Aktiebolaget Hässle	Omeprazole salts
EP0254588A1	24 Jul 1987	27 Jan 1988	Tokyo Tanabe Company Limited	Imidazo[4,5-b] pyridine compounds, process for preparing same and pharmaceutical compositions containing same

Reference
1	*	Andersson et al., Pharmacology & Therapeutics, 2005, vol. 108, pp. 294-307.
2	*	Anon et al., Drugs in R&D, 2002, vol. 3, pp. 276-277.
3	Kakinoki et al., Methods and Findings in Experimental and Clinical Pharmacology, 21(3): 179-187 (1999).
4	Komatsu et al., J. Org. Chem., 58(17): 4529-4533 (1993).
5	Uchiyama et al., Journal of Pharmacy and Pharmacology, 51(4): 457-464 (1999).
6	Uchiyama et al., Methods and Findings in Experimental and Clinical Pharmacology, 21(2): 115-122 (1999).

Citing Patent	Filing date	Publication date	Applicant	Title
US20120220623 *	30 Aug 2012	Mitsubishi Tanabe Pharma Corporation	The enantiomer of tenatoprazole and the use thereof in therapy

CN1453278A *	May 10, 2002	Nov 5, 2003	中国人民解放军军事医学科学院放射医学研究所	Omprazole compound and its prepn and application
CN1861600A *	Jun 14, 2006	Nov 15, 2006	浙江大学	Preparation process of taytrolazole

Reference
1	*	《Organic Process Research & Development》 20081112 Somaiah Sripathi et al. An Improved Synthesis of Antiulcerative Drug:Tenatoprazole 第804-806页 1-6 第13卷,
2	*	《Synthetic Communication》 20080101 Liyan Dai et al. Improved Synthetic Approach to Tenatoprazole 第576-582页 1-6 第38卷,
3	*	《中国药物化学杂志》 20061231 赵冬梅等抗溃疡药泰妥拉唑的合成第360-362页 1-6 第16卷, 第6期

Tenatoprazole
Systematic (IUPAC) name

5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine
Clinical data
Routes of administration	Oral
Pharmacokinetic data
Metabolism	Hepatic (CYP2C19-mediated)
Biological half-life	4.8 to 7.7 hours
Identifiers
CAS Number	113712-98-4
ATC code	none
PubChem	CID 636411
ChemSpider	552196
UNII	RE0689TX2K
Chemical data
Formula	C₁₆H₁₈N₄O₃S
Molar mass	346.405 g/mol
Chirality	Racemic mixture

テナトプラゾール
Tenatoprazole

C16H18N4O3S : 346.4
[113712-98-4]

/////////////Tenatoprazole, 113712-98-4, TU-199, proton pump inhibitor, treatment of gastroesophageal reflux disease, Mitsubishi Tanabe Pharma, Negma Laboratories, PHASE 1, テナトプラゾール

CC1=CN=C(C(=C1OC)C)CS(=O)C2=NC3=C(N2)C=CC(=N3)OC

Roxadustat

June 21, 2016 2:38 pm / Leave a comment

ROXADUSTAT

ASP1517; ASP 1517; ASP-1517; FG-4592; FG 4592; FG4592; Roxadustat.

Fibrogen, Inc.

CAS 808118-40-3
Chemical Formula: C19H16N2O5
Exact Mass: 352.10592

THERAPEUTIC CLAIM
Treatment of anemia

Roxadustat nonproprietary drug name

CHEMICAL NAMES

(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)glycine

1. Glycine, N-[(4-hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl)carbonyl]-

2. N-[(4-hydroxy-1-methyl-7-phenoxyisoquinolin-3-yl)carbonyl]glycine

MF C19H16N2O5
MW 352.3
SPONSOR FibroGen
CODE FG-4592; ASP1517
CAS 808118-40-3
WHO NUMBER 9717

Roxadustat, also known as ASP1517 and FG-4592, is an HIF α prolyl hydroxylase inhibitor in a cell-free assay. It stabilizes HIF-2 and induces EPO production and stimulates erythropoiesis. Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin

FG-4592 (also known as ASP1517), 2-(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxamido)acetic acid, is a potent small molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH), an enzyme up-regulating the expression of endogenous human erythropoietin (Epo). It is currently being investigated as an oral treatment for anemia associated with chronic kidney disease (CKD). Unlike other anemia treating agents, erythropoiesis-stimulating agents (ESAs), FG-4592 inhibits HIF, through a distinctive mechanism, by stabilization of HIF. According to previous studies, FG-4592 is capable of correcting and maintaining hemoglobin levels in CKD patients not receiving dialysis and in patients of end-stage renal disease who receives dialysis but do not need intravenous iron supplement. Reference 1. Luis Borges. Different modalities of erythropoiesis stimulating agents. Port J Nephrol Hypert 2010; 24(2): 137-145 2. “FibroGen and Astellas announce initiation of phase 3 trial of FG-4592/ASP1517 for treatment of anemia of chronic kidney disease” Fibrogen Press Release. Dec 11 2012 3. “FibroGen announces initiation of phase 2b studies of FG-4592, an oral HIF prolyl hydroxylase inhibitor, for treatment of anemia”

Originator FibroGen
Developer Astellas Pharma; AstraZeneca; FibroGen
Class Amides; Antianaemics; Carboxylic acids; Isoquinolines; Small molecules
Mechanism of Action Basic helix loop helix transcription factor modulators; Hypoxia-inducible factor-proline dioxygenase inhibitors

Phase III Anaemia
Discontinued Sickle cell anaemia

Most Recent Events

09 Jun 2016 Phase-III clinical trials in Anaemia in Japan (PO)
20 May 2016 In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In chronic kidney disease patients undergoing peritoneal dialysis) in Japan (PO) (NCT02780726)
19 May 2016 In collaboration with FibroGen, Astellas Pharma plans a phase III trial for Anaemia (In erythropoiesis stimulating agent-naive, chronic kidney disease patients undergoing haemodialysis) in Japan (PO) (NCT02780141)

Roxadustat (FG-4592) is a novel new-generation oral hypoxia-induciblefactor (HIF) prolyl hydroxylase inhibitor (PHI) for the treatment of ane-mia in patients with chronic kidney disease (CKD). HIF is a cytosolic tran-scription factor that induces the natural physiological response to lowoxygen conditions, by stimulating erythropoiesis and other protectivepathways. Roxadustat has been shown to stabilize HIF and induce ery-thropoiesis. Consequently, it corrects anemia and maintains hemoglo-bin levels without the need for intravenous iron supplementation in CKDpatients not yet receiving dialysis and in end-stage renal disease pa-tients receiving dialysis. There are many concerns about the use of ery-thropoiesis-stimulating agents (ESA) to treat anemia as they causesupra-physiologic circulating erythropoietin (EPO) levels and are asso-ciated with adverse cardiovascular effects and mortality. Available clin-ical data show that modest and transient increases of endogenous EPOinduced by HIF-PHI (10- to 40-fold lower than ESA levels) are sufficientto mediate erythropoiesis in CKD patients. Evidence suggests that rox-adustat is well tolerated and, to date, no increased risk of cardiovascu-lar events has been found. This suggests that roxadustat provides adistinct pharmacological and clinical profile that may provide a saferand more convenient treatment of CKD anemia

FG-4592 is a new-generation hypoxia-inducible factor prolyl hydroxylase inhibitor in early clinical trials at FibroGen for the oral treatment of iron deficiency anemia and renal failure anemia. Preclinical studies are ongoing for the treatment of sickle cell anemia.

The investigational therapy is designed to restore balance to the body’s natural process of erythropoiesis through mechanisms including: natural EPO production, suppression of the effects of inflammation, downregulation of the iron sequestration hormone hepcidin, and an upregulation of other iron genes, ensuring efficient mobilization and utilization of the body’s own iron stores. In April 2006, FG-4592 was licensed to Astellas Pharma by originator FibroGen in Asia, Europe and South Africa for the treatment of anemia. FibroGen retains rights in the rest of the world. In 2007, the FDA put the trial on clinical hold due to one case of death by fulminant hepatitis during a phase II clinical trial for patients with anemia associated with chronic kidney disease and not requiring dialysis. However, in 2008, the FDA informed the company that clinical trials could be resumed. Phase II/III clinical trials for this indication resumed in 2012. In 2013, the compound was licensed to AstraZeneca by FibroGen for development and marketing in US, CN and all major markets excluding JP, Europe, the Commonwealth of Independent States, the Middle East and South Africa, for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).
PATENTS
WO 2004108681
WO 2008042800
WO 2009058403
WO 2009075822
WO 2009075824
WO 2012037212
WO 2013013609
WO 2013070908

PATENT

CN 104892509

MACHINE TRANSLATED

Connaught orlistat (Roxadustat) by the US company Phibro root (FibroGen) R & D, Astellas AstraZeneca and licensed by a hypoxia-inducible factor (HIF) prolyl hydroxylase small molecule inhibitors, codenamed FG-4592.As a first new oral drug, FG-4592 is currently in Phase III clinical testing stage, for the treatment of chronic kidney disease and end-stage renal disease related anemia. Because the drug does not have a standard Chinese translation, so the applicant where it is transliterated as “Connaught Secretary him.”

Connaught orlistat (Roxadustat, I) the chemical name: N_ [(4- hydroxy-1-methyl-7-phenoxy-3-isoquinolinyl) carbonyl] glycine, its structural formula is:

The original research company’s international patent W02004108681 Division provides a promise he was prepared from the intermediate and intermediate Connaught Secretary for his synthetic route:

Zhejiang Beida company’s international patent W02013013609 preparation and acylation of core intermediate was further optimized synthesis route is:

n PhO. eight XOOH

original research company’s international patent W02014014834 and W02014014835 also provides another synthetic route he Connaught Secretary prepared:

Analysis of the above synthetic route, although he continued to Connaught Division to improve and optimize the synthesis, but its essence rings manner that different form quinoline ring is basically the same mother. Especially methyl isoquinoline replaced either by way of introducing the Suzuki reaction catalyzed by a noble metal element, either through amine reduction achieved. Moreover, the above reaction scheme revelation raw materials are readily available, many times during the reaction need to be protected and then deprotected. Clearly, the preparation process is relatively complicated, high cost, industrial production has brought some difficulties.

Example One:

tyrosine was added to the reaction flask and dried (18. lg, 0.1 mmol) and methanol 250mL, cooling to ice bath 0_5 ° C, was added dropwise over 1 hour a percentage by weight of 98% concentrated sulfuric acid 10g. Drops Albert, heating to reflux. The reaction was stirred for 16-20 hours, TLC the reaction was complete. Concentrated under atmosphere pressure, the residue was added water 100mL, using 10% by weight sodium hydroxide to adjust the pH to 6. 5-7.0, precipitated solid was filtered, washed with methanol and water chloro cake (I: 1) and dried in vacuo tyrosine methyl ester as a white solid (11) 15.38, yield 78.5% out 1–] \ ^ 111/2: 196 [] \ 1 + 1] +!.

Example Two:

[0041] a nitrogen atmosphere and ice bath, was added to the reaction flask tyrosine methyl ester (II) (9. 8g, 50mmol), potassium methoxide (3. 5g, 50mmol) and methanol 50mL, until no gas generation after, was heated to reflux, the reaction was stirred for 2 hours. Concentrated under atmosphere pressure to remove the solvent, the residue was added dimethylsulfoxide 25mL, freshly prepared copper powder (0.2g, 3. Lmmol), was slowly warmed to 150-155 ° C, for about half an hour later, a solution of bromobenzene ( 7. 9g, 50mmol), continue to heat up to 170-175 ° C, the reaction was stirred for 3 hours, TLC detection of the end of the reaction. Was cooled to 60 ° C, and methanol was added to keep micro-boiling, filtered while hot, the filter cake washed three times with hot ethanol, and the combined organic phases, was cooled to square ° C, filtered, and dried in vacuo to give a white solid of 2-amino-3- ( 4-phenoxyphenyl) propanoate (111) 8 11.5, yield 84.9% as 1 -] \ ^ 111/2:! 272 [] \ 1 + 1] +.

Example Three:

in the reaction flask was added 2-amino-3- (4-phenoxyphenyl) propionic acid methyl ester (III) (10. 8g, 40mmol), 40% by weight acetaldehyde (20g, 0. 2mol ) and the percentage by weight of 35% concentrated hydrochloric acid 50mL, refluxed for 1 hour. Continue 40% by weight was added acetaldehyde (10g, 0.1mol), and the percentage by weight of 35% concentrated hydrochloric acid 25mL, and then the reaction was refluxed for 3-5 hours. Was cooled to 4-7 ° C, ethyl acetate was added, and extracted layers were separated. The aqueous layer was adjusted with sodium hydroxide solution to pH 11-12, extracted three times with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid of 1-methyl-3-carboxylate -7- phenoxy-1,2,3,4-tetrahydroisoquinoline (IV) 8 4g, 70.7% yield; Mass spectrum (EI): EI-MS m / z: 298 [M + H] + .

Example Four:

Under ice bath, the reaction flask was added methyl 3-carboxylate I- -7- phenoxy-1,2, 3,4-tetrahydro-isoquinoline (IV) (5. 9g, 20mmol) and dichloromethane 100mL, 0 ° C and under stirring added potassium carbonate (13. 8g, 0. lmol), p-toluenesulfonyl chloride (11. 4g, 60mmol), the addition was completed, the ice bath was removed and stirred at room temperature 3 hour. Water was added 30mL, after stirring standing layer, the organic phase was washed with dilute hydrochloric acid, water and saturated brine, and concentrated, the resulting product was added a 30% by weight sodium hydroxide solution (8. 0g, 60mmol) and dimethyl sulfoxide 60mL, gradually warming to 120-130 ° C, the reaction was stirred for 2-4 hours to complete the reaction by TLC. Cooled to room temperature, water was added lOOmL, extracted three times with ethyl acetate, the combined organic phase was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated, the resulting oil was treated with ethyl acetate and n-hexane (1: 3) recrystallization, vacuum dried to give an off-white solid 1-methyl-3-carboxylate 7-phenoxyheptanoic isoquinoline (V) 5. 25g, yield 89. 6%; EI-MS m / z: 294 [M + H] VH NMR (DMS0-d6) δ 2. 85 (s, 3H), 3 · 97 (s, 3H), 7 · 16-7. 24 (m, 3H), 7 · 49-7. 60 (m, 4Η), 8 · 35 (d, J = 9 · 0,1Η), 8 · 94 (s, 1Η).

Example five:

[0047] added 1-methyl-3-carboxylic acid methyl ester 7-phenoxyheptanoic isoquinoline (V) (2. 93g, IOmmol) and glacial acetic acid 50mL reaction flask, stirring solution of 30% by weight hydrogen peroxide 5mL, warmed to 60-70 ° C, was slowly added dropwise within 10 hours the percentage by weight of a mixture of 30% hydrogen peroxide 2mL and 12mL of glacial acetic acid, a dropping was completed, the reaction was continued for 20-24 hours. Concentrated under reduced pressure, ethanol was added, distillation is continued to be divisible remaining glacial acetic acid. The residue was dissolved with dichloromethane, washed with 5% by weight of sodium bicarbonate, the organic phase was separated, dried over anhydrous sodium sulfate. Filtered and the resulting solution was added p-toluenesulfonyl chloride (3. 8g, 20mmol), was heated to reflux, the reaction was stirred for 3-4 hours, TLC detection completion of the reaction. The solvent was distilled off under reduced pressure, cooled to room temperature, methanol was added, the precipitated solid, cooled to square ° C, allowed to stand overnight. Filtered, the filter cake washed twice with cold methanol and vacuum dried to give an off-white solid 1- methyl-3-methyl-4-hydroxy-phenoxy-isoquinoline -7- (VI) I. 86g, yield 60.2 %; EI-MS m / z:.. 310 [M + H] +, 1H NMR (DMS0-d6) δ 2.90 (s, 3H), 4.05 (s, 3H), 7 17-7 26 (m, 3H ), 7. 49-7. 61 (m, 4H), 8. 38 (d, J = 9. 0,1H), 11. 7 (s, 1H) 〇

Example VI:

in the reaction flask with magnetic stirring and pressure to join I- methyl-3-methyl-4-hydroxy-7-phenoxyheptanoate isoquinoline (VI) (1.55g, 5mmol), glycine (I. 13g, 15mmol) and sodium methoxide (3. 25g, 6mmol) in methanol (30mL).Sealed, slowly heated to 120 ° C, the reaction was stirred for 8-10 hours to complete the reaction by TLC. Cooled to room temperature, solid precipitated. Filtration, and the resulting solid was recrystallized from methanol, acetone and then beating the resulting solid was dried under vacuum to give a white solid Connaught orlistat 1.40g, yield 79.5%;

EI-MS m / z: 353 [M + H] +,

1H NMR (DMS0-d6) S2.72 (s, 3H), 3 · 99 (d, J = 6 · 0, 2H), 7 · 18-7. 28 (m, 3H), 7 · 49-7. 63 (m, 4H), 8 · 31 (d, J = 8 · 8,1H), 9 · 08 (s, lH), 13.41 (brs, lH).

PATENT

WO 2014014835

Example 10. Preparation of Compound A

a) 5-Phenoxyphthalide

[0200] A reactor was charged with DMF (68 Kg), and stirring was initiated. The reactor was then charged with phenol (51 Kg), acetylacetone (8 Kg), 5-bromophthalide (85 Kg), copper bromide (9 Kg), and potassium carbonate (77 Kg). The mixture was heated above 85 °C and maintained until reaction completion and then cooled. Water was added. Solid was filtered and washed with water. Solid was dissolved in dichloromethane, and washed with aqueous HCl and then with water. Solvent was removed under pressure and methanol was added. The mixture was stirred and filtered. Solid was washed with methanol and dried in an oven giving 5- phenoxyphthalide (Yield: 72%, HPLC: 99.6%). b) 2-Chloromethyl-4-phenoxybenzoic acid methyl ester

[0201] A reactor was charged with toluene (24 Kg), and stirring was initiated. The reactor was then charged with 5-phenoxyphthalide (56 Kg), thionyl chloride (41 Kg), trimethyl borate (1

Kg), dichlorotriphenylphosphorane (2.5 Kg), and potassium carbonate (77 Kg). The mixture was heated to reflux until reaction completion and solvent was removed leaving 2-chloromethyl-4- phenoxybenzoyl chloride. Methanol was charged and the mixture was heated above 50 °C until reaction completion. Solvent was removed and replaced with DMF. This solution of the product methyl 2-chloromethyl-4-phenoxybenzoic acid methyl ester in DMF was used directly in the next step (HPLC: 85%). c) 4-Hydroxy-7-phenoxyisoquinoline-3-carboxylic acid methyl ester (la)

[0202] A reactor was charged with a solution of 2-chloromethyl-4-phenoxybenzoic acid methyl ester (~68 Kg) in DMF, and stirring was initiated. The reactor was then charged with p- toluenesulfonylglycine methyl ester (66 Kg), potassium carbonate (60 Kg), and sodium iodide (4 Kg). The mixture was heated to at least 50 °C until reaction completion. The mixture was cooled. Sodium methoxide in methanol was charged and the mixture was stirred until reaction completion. Acetic acid and water were added, and the mixture was stirred, filtered and washed with water. Solid was purified by acetone trituration and dried in an oven giving la (Yield from step b): 58%; HPLC: 99.4%). 1H NMR (200 MHz, DMSO-d6) δ 11.60 (s, 1 H), 8.74 (s, 1H),

8.32 (d, J = 9.0 Hz, 1 H), 7.60 (dd, J = 2.3 & 9.0 Hz, 1H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.96 (s, 3 H); MS-(+)-ion M+l = 296.09 d) Methyl l-((dimethylamino)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate

(lb)

[0203] A flask was charged with la (29.5 g) and acetic acid (44.3 g ± 5%), and then stirred. Bis-dimethylaminomethane (12.8 g ± 2%) was slowly added. The mixture was heated to 55 ± 5 °C and maintained until reaction completion. The reaction product was evaluated by MS, HPLC and 1H NMR. 1H NMR (200 MHz, DMSO-d6) δ 11.7 (s, 1 H), 8.38 (d, J = 9.0 Hz, 1 H), 7.61 (dd, J = 9.0, 2.7 Hz, 1 H), 7.49 (m, 3 H), 7.21 (m, 3 H), 5.34 (s, 2 H), 3.97 (s, 3 H), 1.98 (s, 3 H); MS-(+)-ion M+l = 368.12. e) Methyl l-((acetoxy)methyl)-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (lc)

[0204] The solution of lb from a) above was cooled below 25 °C, at which time acetic anhydride (28.6 g ± 3.5 %) was added to maintain temperature below 50 °C. The resulting mixture was heated to 100 ± 5 °C until reaction completion.

[0205] The solution of lc and Id from above was cooled to less than 65 ± 5 °C. Water (250 mL) was slowly added. The mixture was then cooled to below 20 ± 5 °C and filtered. The wet cake was washed with water (3 x 50 mL) and added to a new flask. Dichloromethane (90 mL) and water (30 mL) were added, and the resulting mixture was stirred. The dichloromethane layer was separated and evaluated by HPLC.

[0206] The organic layer was added to a flask and cooled 5 ± 5 °C. Morpholine was added and the mixture was stirred until reaction completion. Solvent was replaced with acetone/methanol mixture. After cooling, compound lc precipitated and was filtered, washed and dried in an oven (Yield: 81%, HPLC: >99.7%). 1H NMR (200 MHz, DMSO-d6) δ 11.6 (S, 1 H), 8.31 (d, J = 9.0 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.49 (m, 3 H), 7.24 (m, 3 H), 3.95 (s, 3 H), 3.68 (s, 2H), 2.08 (s, 6 H); MS-(+)-ion M+l = 357.17. f) Methyl 4-hydroxy-l-methyl-7-phenoxyisoquinoline-3-carboxylate (le)

[0207] A reactor was charged with lc (16.0 g), Pd/C (2.08 g), anhydrous Na₂C0₃ (2.56 g) and ethyl acetate (120 mL). The flask was vacuum-purged with nitrogen (3X) and vacuum-purged with hydrogen (3X). The flask was then pressurized with hydrogen and stirred at about 60 °C until completion of reaction. The flask was cooled to 20-25 °C, the pressure released to ambient, the head space purged with nitrogen three times and mixture was filtered. The filtrate was concentrated. Methanol was added. The mixture was stirred and then cooled. Product precipitated and was filtered and dried in an oven (Yield: 90%, HPLC: 99.7%). g) [(4-Hydroxy-l-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid

(Compound A)

[0208] A pressure flask was charged with le (30.92 g), glycine (22.52 g), methanol (155 mL), sodium methoxide solution (64.81 g) and sealed (as an alternative, sodium glycinate was used in place of glycine and sodium methoxide). The reaction was heated to about 110 °C until reaction was complete. The mixture was cooled, filtered, washed with methanol, dried under vacuum, dissolved in water and washed with ethyl acetate. The ethyl acetate was removed and to the resulting aqueous layer an acetic acid (18.0 g) solution was added. The suspension was stirred at room temperature, filtered, and the solid washed with water (3 x 30 mL), cold acetone (5-10 °C, 2 x 20 mL), and dried under vacuum to obtain Compound A (Yield: 86.1%, HPLC: 99.8%). Example 11. Biological Testing

[0209] The solid forms provided herein can be used for inhibiting HIF hydroxylase activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF), and can be used to treat and prevent HIF-associated conditions and disorders (see, e.g., U.S. Patent No. 7,323,475, U.S. Patent Application Publication No. 2007/0004627, U.S. Patent Application Publication No. 2006/0276477, and U.S. Patent Application Publication No. 2007/0259960, incorporated by reference herein).

SYNTHESIS……..http://zliming2004.lofter.com/post/1cc9dc55_79ad5d8

FG-4592 - zliming2004 - zliming2004的博客

Condensation of 5-bromophthalide (I) with phenol (II) in the presence of K2CO3, CuBr and acetylacetone in DMF gives 5-phenoxyphthalide (III), which upon lactone ring opening using SOCl2, Ph3PCl2, B(OMe)3 and K2CO3 in refluxing toluene yields 2-chloromethyl-4-phenoxybenzoyl chloride (IV). Esterification of acid chloride (IV) with MeOH at 50 °C furnishes the methyl ester (V), which is then condensed with methyl N-tosylglycinate (VI) in the presence of K2CO3 and NaI in DMF at 50 °C to afford N-substituted aminoester (VII). Cyclization of the intermediate diester (VII) using NaOMe in MeOH leads to methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (VIII), which is submitted to Mannich reaction with bis-dimethylaminomethane (IX) in the presence of AcOH at 57 °C to provide the dimethylaminomethyl compound (X). Treatment of amine (X) with Ac2O at 103 °C, followed by selective hydrolysis of the phenolic acetate with morpholine leads to methyl 1-acetoxymethyl-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (XI). Hydrogenolysis of the benzylic acetate (XII) in the presence of Pd/C and Na2CO3 in EtOAc yields methyl 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboylate (XII), which finally couples with glycine (XIII) in the presence of NaOMe in MeOH at 110 °C to afford the target roxadustat (1-3).

FG-4592 - zliming2004 - zliming2004的博客

Cyclization of 4-phenoxyphthalic acid (I) with glycine (II) at 215 °C gives the phthalimide (III), which upon esterification with MeOH and H2SO4 at reflux yields methyl ester (IV). Subsequent rearrangement of phthalimidoacetate (IV) by means of Na in BuOH at 97 °C, followed by flash chromatography provides the isoquinoline-2-carboxylate (V). Bromination of intermediate (V) using POBr3 and NaHCO3 in acetonitrile leads to butyl 8-bromo-3-hydroxy-6-phenoxy-isoquinoline-2-carboxylate (VI), which upon hydrolysis with NaOH in refluxing H2O/EtOH furnishes carboxylic acid (VII). Substitution of bromine in intermediate (VII) using MeI and BuLi in THF at -78 °C, followed by alkylation with PhCH2Br in the presence of K2CO3 in refluxing acetone affords the 2-methyl isoquinoline (VIII). Ester hydrolysis in intermediate (VIII) using KOH in MeOH gives the corresponding carboxylic acid (IX), which is then activated with i-BuOCOCl and Et3N in CH2Cl2, followed by coupling with benzyl glycinate hydrochloride (X) to yield benzylated roxadustat (XI). Finally, debenzylation of intermediate (XI) with H2 over Pd/C in EtOAc/MeOH provides the title compound (1).

FG-4592 - zliming2004 - zliming2004的博客

Condensation of 4-nitro-ortho-phthalonitrile (I) with phenol (II) in the presence of K2CO3 in DMSO gives 4-phenoxy-ortho-phthalonitrile (III) (1), which upon hydrolysis with NaOH (1) or KOH (2) in refluxing MeOH yields 4-phenoxyphthalic acid (IV) (1,2). Dehydration of dicarboxylic acid (IV) using Ac2O and AcOH at reflux furnishes the phthalic anhydride (V), which is then condensed with methyl 2-isocyanoacetate (VI) using DBU in THF to provide oxazole derivative (VII). Rearrangement of intermediate (VII) with HCl in MeOH at 60 °C leads to isoquinoline derivative (VIII), which is partially chlorinated by means of POCl3 at 70 °C to afford 1-chloro-isoquinoline derivative (IX). Substitution of chlorine in intermediate (IX) using Me3B, Pd(PPh3)4 and K2CO3 in refluxing dioxane gives methyl 4-hydroxy-1-methyl-7-phenoxy-3-carboxylate (X), which is then hydrolyzed with aqueous NaOH in refluxing EtOH to yield the carboxylic acid (XI). Coupling of carboxylic acid (XI) with methyl glycinate hydrochloride (XII) by means of PyBOP, (i-Pr)2NH and Et3N in CH2Cl2 yields roxadustat methyl ester (XII), which is finally hydrolyzed with aqueous NaOH in THF to afford the target roxadustat (1).

CLIPS

SAN FRANCISCO, Nov 12, 2013 (BUSINESS WIRE) — FibroGen, Inc. (FibroGen), today announced that data from a China-based Phase 2 study of roxadustat (FG-4592), a first-in-class oral compound in late stage development for the treatment of anemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD), were presented in an oral session at the 2013 American Society of Nephrology (ASN) Kidney Week in Atlanta, Georgia.

Roxadustat is an orally administered, small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase. HIF is a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced and iron is incorporated into hemoglobin (Hb).

The randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy, safety, and tolerability of roxadustat in the correction of anemia in patients (N=91) with chronic kidney disease who had not received dialysis treatment, were not receiving erythropoiesis-stimulating agents (ESAs), and had Hb levels less than 10 g/dL. The correction study randomized patients 2:1 between roxadustat and placebo for 8 weeks of dosing, and included a low-dose cohort (n=30) and high-dose cohort (n=31). Intravenous (IV) iron was not allowed. The study also evaluated iron utilization, changes in serum lipids, and other biomarkers during treatment with roxadustat.

Data from this study suggest that roxadustat effectively corrected hemoglobin levels in anemic CKD patients in a dose-dependent manner as compared to placebo, and did so in the absence of IV iron supplementation regardless of degree of iron repletion at baseline. At the end of the 8-week treatment period, subjects showed mean maximum Hb increases from baseline of 2.6 g/dL in the high dose cohort and 1.8 g/dL in the low dose cohort, as compared to 0.7 g/dL in the placebo group (p < 0.0001) from mean baseline Hb of 8.8 g/dL, 8.8 g/dL, and 8.9 g/dL in the high dose, low dose, and placebo groups, respectively. 87% of patients in the high-dose cohort, 80% of patients in the low-dose cohort, and 23% of patients in the placebo group experienced a hemoglobin increase of 1 g/dL or greater from baseline (p < 0.0001). Similarly, 71% of patients in the high-dose cohort, 50% of patients in the low-dose cohort, and 3% of patients in the placebo group achieved target hemoglobin of 11 g/dL or greater (p < 0.0001). Serum iron levels remained stable in subjects randomized to roxadustat while the subjects underwent brisk erythropoiesis.

Study data also suggest that roxadustat may lower cholesterol. Dyslipidemia is highly prevalent in chronic kidney disease patients and a major cardiovascular risk factor in this population. Patients treated with roxadustat experienced a statistically significant reduction in total cholesterol (p <0.0001) and low-density lipoprotein (LDL) cholesterol (p <0.0001) at the end of the treatment period. The relative proportion of high density lipoprotein (HDL) cholesterol to LDL cholesterol increased significantly (p <0.02). Overall LDL cholesterol levels declined by a mean of 26% and median of 23% from a mean baseline value of 103 mg/dL.

Roxadustat was well tolerated by patients in the study with incidence of adverse events similar across all groups. In contrast to the exacerbation of hypertension observed in studies in which patients received currently available ESA therapies, subjects who received roxadustat in the present study showed small decreases in blood pressure that were similar to blood pressure changes in the placebo group. No cardiovascular serious adverse events were reported in patients treated with roxadustat.

The efficacy and safety of roxadustat are currently being investigated in a global pivotal Phase 3 development program.

“There is a global need for effective, safe, and accessible anemia therapies,” said Thomas B. Neff, Chief Executive Officer of FibroGen. “Side effects associated with current treatments include exposure to supra-physiological levels of erythropoietin and depletion of iron stores. Preliminary clinical findings show that oral administration of roxadustat (FG-4592) is able to correct anemia and maintain hemoglobin levels in patients with chronic kidney disease, to do so with peak erythropoietin levels within physiological range, and to achieve these effects without the administration of intravenous iron. These results suggest roxadustat, as an oral agent, has the potential to overcome the treatment barriers and inconveniences of current ESA therapies, including administration by injection and IV iron supplementation, in treating anemia in CKD patients.”

About Chronic Kidney Disease (CKD) and Anemia

Diabetes, high blood pressure, and other conditions can cause significant damage to the kidneys. If left untreated, those can result in chronic kidney disease and progress to kidney failure. Such deterioration can lead to patients needing a kidney transplant or being placed on dialysis to remove excess fluid and toxins that build up in the body. The progression of CKD also increases the prevalence of anemia, a condition associated with having fewer of the red blood cells that carry oxygen through the body, and/or lower levels of hemoglobin, the protein that enables red blood cells to carry oxygen. As hemoglobin falls, the lower oxygen-carrying capacity of an anemic patients’ blood results in various symptoms including fatigue, loss of energy, breathlessness, and angina. Anemia in CKD patients has been associated with increased hospitalization rates, increased mortality, and reduced quality of life.

Chronic kidney disease is a worldwide critical healthcare problem that affects millions of people and drives significant healthcare cost. In the US, prevalence of CKD has increased dramatically in the past 20 years, from 10 percent of the adult population (or approximately 20 million U.S. adults) as stated in the National Health and Nutrition Evaluation Survey (NHANES) 1988-1994, to 15 percent (or approximately 30 million U.S. adults) in NHANES 2003-2006. In 2009, total Medicare costs for CKD patients were $34 billion. China has an estimated 145 million CKD patients, or approximately five times the number of CKD patients in the U.S. (Lancet April 2012).

About Roxadustat / FG-4592

Roxadustat (FG-4592) is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity, in development for the treatment of anemia in patients with chronic kidney disease (CKD). HIF is a protein transcription factor that induces the natural physiological response to conditions of low oxygen, “turning on” erythropoiesis (the process by which red blood cells are produced) and other protective pathways. Roxadustat has been shown to correct anemia and maintain hemoglobin levels without the need for supplementation with intravenous iron in CKD patients not yet receiving dialysis and in end-stage renal disease patients receiving dialysis. An Independent Data Monitoring Committee has found no signals or trends to date to suggest that treatment with roxadustat is associated with increased risk of cardiovascular events, thrombosis, or increases in blood pressure requiring initiation or intensification of antihypertensive medications.

About FibroGen

FibroGen is a privately-held biotechnology company focused on the discovery, development, and commercialization of therapeutic agents for treatment of fibrosis, anemia, cancer, and other serious unmet medical needs. FibroGen’s FG-3019 monoclonal antibody is in clinical development for treatment of idiopathic pulmonary fibrosis and other proliferative diseases, including pancreatic cancer and liver fibrosis. Roxadustat (FG-4592), FibroGen’s small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase, is currently in clinical development for the treatment of anemia. FibroGen is also currently pursuing the use of proprietary recombinant human type III collagens in synthetic corneas for treatment of corneal blindness. For more information please visit: www.fibrogen.com .

References

1: Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, Leong R, Hemmerich S, Yu KH, Neff TB. Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients. Nephrol Dial Transplant. 2015 Oct;30(10):1665-73. doi: 10.1093/ndt/gfv302. Epub 2015 Aug 3. PubMed PMID: 26238121; PubMed Central PMCID: PMC4569392.

2: Forristal CE, Levesque JP. Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl Med. 2014 Feb;3(2):135-40. doi: 10.5966/sctm.2013-0134. Epub 2013 Dec 26. PubMed PMID: 24371328; PubMed Central PMCID: PMC3925058.

3: Bouchie A. First-in-class anemia drug takes aim at Amgen’s dominion. Nat Biotechnol. 2013 Nov;31(11):948-9. doi: 10.1038/nbt1113-948b. PubMed PMID: 24213751.

4: Flight MH. Deal watch: AstraZeneca bets on FibroGen’s anaemia drug. Nat Rev Drug Discov. 2013 Oct;12(10):730. doi: 10.1038/nrd4135. PubMed PMID: 24080688.

5: Beuck S, Schänzer W, Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Test Anal. 2012 Nov;4(11):830-45. doi: 10.1002/dta.390. Epub 2012 Feb 24. Review. PubMed PMID: 22362605.

6: Cases A. The latest advances in kidney diseases and related disorders. Drug News Perspect. 2007 Dec;20(10):647-54. PubMed PMID: 18301799.

//////////ASP1517, ASP 1517, ASP-1517, FG-4592, FG 4592, FG4592, Roxadustat, PHASE 3, ASTELLAS, FibroGen, 808118-40-3

O=C(O)CNC(C1=C(O)C2=C(C(C)=N1)C=C(OC3=CC=CC=C3)C=C2)=O

Novartis, Torrent drug for diabetes, NVP-LBX192, LBX-192

June 19, 2016 10:38 am / Leave a comment

Figure US07750020-20100706-C00023

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

(3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide)

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

cas 866772-52-3

Novartis Ag

NVP-LBX192

LBX-192

R(−) 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

R(−)17c BELOW

Inventors	Gregory Raymond Bebernitz, Ramesh Chandra Gupta, Vikrant Vijaykumar Jagtap, Appaji Baburao Mandhare, Davinder Tuli,
Original Assignee	Novartis Ag

Inventors

Gregory Raymond Bebernitz, Ramesh Chandra Gupta, Vikrant Vijaykumar Jagtap, Appaji Baburao Mandhare, Davinder Tuli,

Original Assignee

Novartis Ag

Molecular Formula:	C₂₆H₃₃N₅O₄S₂
Molecular Weight:	543.70132 g/mol

LBX192, also known as NVP-LBX192, is a Liver Targeted Glucokinase Activator. LBX192 activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice. A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen.

SYNTHESIS BY WORLDDRUGTRACKER

54 Discovery and Evaluation of NVP-LBX192, a Liver Targeted Glucokinase Activator

Thursday, October 8, 2009: 10:30 AM

Nathan Hale North (Hilton Third Floor)

Gregory R. Bebernitz, PhD , Global Discovery Chemistry, Novartis Institute for Biomedical Research, Cambridge, MA

Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen. We will describe our efforts to generate liver selective GK activators which culminated in the discovery of NVP-LBX192 (3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide). This compound activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice.

https://acs.confex.com/acs/nerm09/webprogram/Paper75087.html

Sulfonamide-Thiazolpyridine Derivatives, Glucokinase Activators, Treatment Of Type 2 Diabetes

2009 52 (19) 6142 – 6152
Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes
Journal of Medicinal Chemistry
Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao JP, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang JS, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, Denny IS, Taslimi PM, Vash B, Caplan SL

2010 240th (August 22) Medi-198
Glucokinase activators with improved physicochemicalproperties and off target effects
American Chemical Society National Meeting and Exposition
Kirman LC, Schuster HF, Grondine MS et al

2010 240th (August 22) Medi-197
Investigation of functionally liver selective glucokinase activators
American Chemical Society National Meeting and Exposition
Schuster HF, Kirman LC, Bebernitz GC et al

PATENT

http://www.google.com/patents/US7750020

EXAMPLE 1 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A. Phenylacetic Acid Ethyl Ester

A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) is treated with catalytic amount of sulfuric acid (4 mL). The reaction mixture is refluxed for 4 h. The reaction is then concentrated in vacuo. The residue is dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100 mL). The organic layer dried over sodium sulfate filtered and concentrated in vacuo to give phenylacetic acid ethyl ester as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 1.2 (t, J=7.2, 3H), 3.6 (s, 2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]⁺.

B. (4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester

To a cooled chlorosulfonic acid (83.83 g, 48 mL, 0.71 mol) under nitrogen is added the title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol) over a period of 1 h. Reaction temperature is brought to RT (28° C.), then heated to 70° C., maintaining it at this temperature for 1 h while stirring. Reaction is cooled to RT and poured over saturated aqueous sodium chloride solution (200 mL) followed by extraction with DCM (2×200 mL). The organic layer is washed with water (5×100 mL), followed by saturated aqueous sodium chloride solution (1×150 mL). The organic layer dried over sodium sulfate, filtered and concentrated in vacuo to give crude (4-chlorosulfonyl-phenyl)acetic acid ethyl ester. Further column chromatography over silica gel (60-120 mesh), using 100% hexane afforded pure (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester as a colorless oil.

C. [4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester

A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: ¹H NMR (400 MHz, CDCl₃) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]⁺.

D. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester

A solution of the title C compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (15 g, 0.046 mol) in a mixture of THF (60 mL) and DMTP (10 mL) is cooled to −78° C. under nitrogen. The resulting solution is stirred at −78° C. for 45 min and to this is added LDA (25.6 mL, 6.40 g, 0.059 mol, 25% solution in THF/Hexane). A solution of iodomethylcyclopentane (11.60 g, 0.055 mol) in a mixture of DMTP (12 mL) and THF (20 mL) is added over a period of 15 min at −78° C. and reaction mixture stirred at −78° C. for 3 h further, followed by stirring at 25° C. for 12 h. The reaction mixture is then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) and is concentrated in vacuo. The residue is diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic solution is washed with a saturated aqueous sodium chloride (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography over silica gel (60-120 mesh), using 50% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 0.9-2.1 (m, 11H), 1.2 (t, J=7.1, 3H), 2.3 (s, 3H), 2.5 (br s, 4H), 3.0 (br s, 4H), 3.6 (m, 1H), 4.1 (q, J=7.1, 2H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H); MS 409 [M+1]⁺.

E. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid

A solution of the title D compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester (14 g, 0.034 mol) in methanol:water (30 mL:10 mL) and sodium hydroxide (4.11 g, 0.10 mol) is stirred at 60° C. for 8 h in an oil bath. The methanol is then removed in vacuo at 45-50° C. The residue is diluted with water (25 mL) and extracted with ether (1×40 mL). The aqueous layer is acidified to pH 5 with 3 N aqueous hydrochloric acid solution. The precipitated solid is collected by vacuum filtration, washed with water (20 mL), followed by isopropyl alcohol (20 mL). Finally, solid cake is washed with 100 mL of hexane and dried under vacuum at 40° C. for 6 h to give 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 1.1-2.0 (m, 11H), 2.4 (s, 3H), 2.7 (br s, 4H), 3.1 (br s, 4H), 3.6 (m, 1H), 7.5 (d, J=8.3, 2H), 7.6 (d, J=8.3, 2H); MS 381 [M+l]⁺.

F. 5-Methoxy-thiazolo[5,4-b]pyridin-2-ylamine

A solution of 6-methoxy-pyridin-3-ylamine (5.0 g, 0.0403 mol) in 10 mL of acetic acid is added slowly to a solution of potassium thiocyanate (20 g, 0.205 mol) in 100 mL of acetic acid at 0° C. followed by a solution of bromine (2.5 mL, 0.0488 mol) in 5 mL of acetic acid. The reaction is stirred for 2 h at 0° C. and then allowed to warm to RT. The resulting solid is collected by filtration and washed with acetic acid, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The insoluble material is removed by filtration and the organic layer is evaporated and dried to afford 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a tan solid.

G. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A solution of the title E compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (5 g, 0.013 mol) in DCM (250 mL) is cooled to 0° C. and then charged HOBt hydrate (2.66 g, 0.019 mol), followed by EDCI hydrochloride (6 g, 0.031 mol). The reaction mixture is stirred at 0° C. for 5 h. After that the solution of the title F compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.36 g, 0.013 mol) and D1EA (8 mL, 0.046 mol) in a mixture of DCM (60 mL) and DMF (20 mL) is added dropwise over 30 min. Reaction temperature is maintained at 0° C. for 3 h, then at RT (28° C.) for 3 days. Reaction is diluted with (60 mL) of water and the organic layer is separated and washed with saturated sodium bicarbonate solution (2×50 mL) followed by water washing (2×50 mL) and saturated sodium chloride aqueous solution (1×150 mL). Finally the organic layer is dried over sodium sulfate, filtered, and evaporated under vacuo. The crude product is purified using column chromatography over silica gel (60-120 mesh), using 40% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 0.9-2.1 (m, 11H), 2.2 (s, 3H), 2.5 (br s, 4H), 3.1 (br s, 4H), 3.7 (m, 1H), 4.0 (s, 3H), 6.8 (d, J=8.8, 1H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H), 7.8 (d, J=8.8, 1H), 8.6 (s, 1H); MS 617 [M+1]⁺.

H. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride

The title G compound, 3-cyclopentyl-2-(4-methyl piperazinyl sulfonyl)phenyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)propionamide (2.8 g, 0.0051 mol) is added to a cooled solution of 10% hydrochloric acid in isopropanol (3.75 mL). The reaction mixture is stirred at 0° C. for 1 h and then at RT for 2 h. The solid is separated, triturated with 10 mL of isopropanol and collected by vacuum filtration and washed with 50 mL of hexane. The solid is dried at 70° C. for 48 h to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride as an off white solid.

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4° C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

EXAMPLE 3 (S)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is prepared analogously to Example 2.

J MED CHEM 2009, 52, 6142-52

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Gregory R. Bebernitz*†, Valerie Beaulieu†, Bethany A. Dale†, Richard Deacon†, Alokesh Duttaroy†, Jiaping Gao†, Melissa S. Grondine†, Ramesh C. Gupta‡, Mesut Kakmak†, Michael Kavana†, Louise C. Kirman†, Jinsheng Liang†, Wieslawa M. Maniara†, Siralee Munshi‡, Sunil S. Nadkarni‡, Herbert F. Schuster†, Travis Stams†, Irene St. Denny†, Paul M. Taslimi†, Brian Vash† and Shari L. Caplan†

^† Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139

^‡ Torrent Research Centre, Village Bhat, Gujarat, India

J. Med. Chem., 2009, 52 (19), pp 6142–6152

DOI: 10.1021/jm900839k

http://pubs.acs.org/doi/abs/10.1021/jm900839k

Abstract Image

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10−15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the β-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (αK_a = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

PATENT

EP-1735322-B1

Example 2(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Image loading...

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4°C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250 x 20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min / %B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

REFERENCES

US 7750020

WO-2005095418-A1

US-20080103167-A1

1 to 2 of 2

Patent ID	Date	Patent Title
US2015218151	2015-08-06	NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020	2010-07-06	Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

^† Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139

^‡ Torrent Research Centre, Village Bhat, Gujarat, India

J. Med. Chem., 2009, 52 (19), pp 6142–6152

DOI: 10.1021/jm900839k

Publication Date (Web): September 11, 2009

*To whom correspondence should be addressed. Phone: (617) 871 7302. Fax: (617) 871 7042. E-mail: greg.bebernitz@novartis.com.

http://pubs.acs.org/doi/abs/10.1021/jm900839k

https://www.google.com/patents/US7750020

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
Flow rate: 6.0 mL/min; and
Detection: by UV at 305 nm.

Patent ID	Date	Patent Title
US2015218151	2015-08-06	NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020	2010-07-06	Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

Torrent Research Centre, Village Bhat, Gujarat, India

Mr. Samir Mehta, 52, is the Vice Chairman of the USD 2.75 billion Torrent Group and Chairman of Torrent Pharma

Mr. Sudhir Mehta - Executive Chairman

Shri Sudhir Mehta – Chairman Emeritus ::

Dr. Chaitanya Dutt – Director (Research & Development) ::

Born in the year 1950, Dr. Chaitanya Dutt holds an MD in Medicine. He practiced as a consulting physician before joining the company in 1982. Since then he has been associated with the Company. His rich experience spans in the areas of Pharma R&D, clinical research, manufacturing, quality assurance, etc. He is one of the key professionals in the top management team of the Company. He has been instrumental in setting up the Torrent Research Centre (TRC), the research wing of the Company. Under his prudent guidance and leadership, TRC has achieved tremendous progress in the areas of discovery research as well as development work on formulations. He does not hold any directorship in any other company.

///NOVARTIS, DIABETES, Sulfonamide-Thiazolpyridine Derivatives, Glucokinase Activators, Treatment Of Type 2 Diabetes, 866772-52-3, Novartis Molecule, functionally liver selective glucokinase activators, treatment of type 2 diabetes , NVP-LBX192, LBX-192

c1(sc2nc(ccc2n1)OC)NC(C(c3ccc(cc3)S(=O)(=O)N4CCN(CC4)C)CC5CCCC5)=O

Supporting Info

Final WHO Guidance Document on Good Data and Record Management Practices

June 16, 2016 1:48 pm / 1 Comment on Final WHO Guidance Document on Good Data and Record Management Practices

DRUG REGULATORY AFFAIRS INTERNATIONAL

The WHO has just released the the final version of the important guideline “Good Data and Record Management Practices“.

http://www.gmp-compliance.org/enews_05418_Final-WHO-Guidance-Document-on-Good-Data-and-Record-Management-Practices_15488,15637,Z-COVM_n.html

We recently informed you about the WHO Draft Guidance on Good Data and Record Management Practices. Now, the WHO has just released the the final version of this important guideline “Good Data and Record Management Practices”.

The final version is sectioned rather similar to the draft version:

– Introduction
– Aims and objectives of this guidance
– Glossary
– Principles
– Quality risk management to ensure good data management
– Management governance and quality audits
– Contracted organizations, suppliers and service providers
– Training in good data and record management
– Good documentation practices
– Designing and validation systems to assure data quality and reliability
– Managing data and records throughout the data lifecycle
– Addressing data reliability issues
– References and further reading

Although the individual chapters were…

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Revision of the general Chapter on Pharmaceutical Water in the US Pharmacopoeia

June 16, 2016 1:45 pm / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The 2nd supplement of USP39 NF34 comprises the revised version of the chapter on pharmaceutical water of the US Pharmacopoeia <1231> Water for pharmaceutical purposes.

http://www.gmp-compliance.org/enews_05410_Revision-of-the-general-Chapter-on-Pharmaceutical-Water-in-the-US-Pharmacopoeia_15160,15266,15221,15612,Z-PEM_n.html

The 2nd supplement of USP39 NF34 comprises the revised version of the chapter on pharmaceutical water of the US Pharmacopoeia <1231> Water for pharmaceutical purposes. The first draft version had already been published in September 2015 in the USP Pharmacopeial Forum 41(5).

First of all: there are no new or revised specifications of individual test parameters or new requirements. But the chapter has been revised structurally to ensure better readability. In addition there are now also details regarding feed water as well as for the validation and on action and warning limits. With a chapter number greater than 1000 the Chapter <1231> is not binding, but has a recommending character. The recommended temperature for hot sanitising was changed. So far temperatures of 80…

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Indian API Manufacturers remain in the Focus of European GMP Inspectors

June 16, 2016 1:44 pm / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Some time ago three Non-Compliance Reports have been published in quick succession in the EudraGMDP database. Those reports deal with inspections performed at pharmaceutical APIs production sites located in India. Read more about the fundamental violations of the requirements for GMP-compliant API manufacturing in those facilities.

http://www.gmp-compliance.org/enews_05414_Indian-API-Manufacturers-remain-in-the-Focus-of-European-GMP-Inspectors_15339,15332,S-WKS_n.html

The EudraGMDP database contains more and more frequently Non-Compliance Reports of API facilities located in India. Three of these reports were published in April and May this year. The companies inspected (Krebs Biochemicals & Industries Ltd, J P Laboratories Private Ltd and Dhanuka Laboratories Ltd) were accused of major violations of the GMP rules (in one case even a critical violation was observed). All in all, the GMP inspectors came to the conclusion that – in their current states – those facilities are not able to manufacture APIs in a GMP-compliant way.

At all three companies, deficiencies against the fundamental requirements for GMP-compliant…

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Amneal Pharma’s, 4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidine containing phenothiazines as antitubercular agents

June 15, 2016 7:43 am / Leave a comment

Cas 1580464-40-9

MW458.97, C₂₄ H₁₉ Cl N₆ S,

1H-Pyrazolo[3,4-d]pyrimidin-6-amine, 4-(4-chlorophenyl)-4,7-dihydro-3-methyl-1-(10H-phenothiazin-2-yl)-

4-(4-chlorophenyl)-3-methyl-1-(10H-phenothiazin-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

4-(4-chlorophenyl)-3-methyl-1-(10H-Phenothiazin-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-d] pyrimidin-6-amine

Yield 79%, m.p.: 186-188 ^ºC.

IR (KBr): 3328 (NH), 1648 (C-N), 640 (C-S-C). ¹H NMR (300 MHz, CDCl₃): d 2.32 (s, 3H, CH₃), 4.95 (s, 1H, CH), 7.36-7.38 (dd, 2H, J=8.10 Hz), 7.84-7.87 (dd, 2H, J=7.80 Hz), 7.90-8.05 (m, 7H, Ar-H), 8.46 (s, 1H, NH), 8.56 (s, 2H, NH₂), 9.11 (s, 1H, NH):

¹³C NMR (75 MHz, CDCl₃): d 26.1, 41.2, 52.5, 59.8, 103.6, 104.2, 105.3, 114.2, 116.6, 122.7, 127.1, 127.9, 128.2, 128.6, 129.2, 132.5, 134.6, 142.4, 143.7, 155.3, 162.5. Mass (m/z): 459. Anal. (%) for C₂₄H₁₉ClN₆S, Calcd. C, 62.81; H, 4.17; N, 18.31. Found: C, 62.75; H, 4.15; N, 18.26.

Mass spectrum of 4g

¹H NMR spectrum of 4g

Tuberculosis (TB) is a highly infectious airborne disease caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb). ¹According to the latest World Health Organization (WHO) report, an estimated 8.6 million people developed TB and 1.3 million died from the disease (including 320,000 deaths among HIV-positive people) in 2012. The majority of cases worldwide in 2012 were in the South-East Asia (29%), African (27%) and western Pacific (19%) regions. India and China alone accounted for 26% and 12% of total cases, respectively.² The standard antitubercular treatment regimen, termed DOTS (Directly Observed Therapy, Short-course), is based on the co-administration of age-old drugs like isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) for the first two months, followed by a prolonged treatment with INH and RMP for additional 4–7 months with no guarantee of complete sterilization from the infection. ^4 and 5 Furthermore, emergence of new virulent forms of TB such as multi drug resistant (MDR-TB) and extremely drug resistant (XDR-TB), and its synergy with human immunodeficiency virus (HIV) has fuelled its epidemic nature. These reasons make a compelling case for an urgent need for new and effective antitubercular agents with improved properties such as enhanced activity against MDR strains, reduced toxicity, rapid mycobactericidal mechanism of action and the ability to penetrate host cells and exert antimycobacterial effects in the intracellular environment.

Phenothiazines are important classes of compounds which have increasingly attracted attention, owing to their remarkable biological and pharmacological properties, such as antibacterial, antifungal, anticancer, antiviral, anti-inflammatory, antimalarial, antifilarial, trypanocidal, anticonvulsant, analgesic, immunosuppressive and multidrug resistance reversal. These activities are the results of the actions exerted by phenothiazines on biological systems via the interaction of the pharmacophoric substituent (in some cases of strict length), via the interaction multicyclic ring system (π–π interaction, intercalation in DNA) and via the lipophilic character permitting the penetration through the biological membranes to reach its site of action. Further, Phenothiazines have been shown to exhibit in vitro and in vivo activity against Mtb and multidrug-resistant Mtb. Some of the phenothiazine derived antipsychotic agents such as chlorpromazine, trifluoperazine (TPZ) and thioridazine are found to be effective inhibitors of Mtb.Phenothiazines are predicted to target the genetically validated respiratory chain component type II NADH:quinone oxidoreductase (Ndh)

Chintu Patel, RPh

Co-Chief Executive Officer and
Co-Chairman, Co-Founder

Chirag Patel

Co-Chief Executive Officer and
Co-Chairman, Co-Founder

Paper

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 6, 15 March 2014, Pages 1493–1495

4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidine containing phenothiazines as antitubercular agents

^a Amneal Pharmaceuticals India Pvt Ltd, 882/1-871, Village Rajoda, Tal.: Bavla Dist.: Ahmedabad 382220, Gujarat, India
^b Division of Medicinal Chemistry, Department of Chemistry (DST-FIST Sponsored), Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364002, Gujarat, India
^c Department of Chemistry, Saurashtra University, Kalawad Road, Rajkot 360005, Gujarat, India

doi:10.1016/j.bmcl.2014.02.012

A series of novel dihydropyrazolo[3,4-d]pyrimidine derivatives bearing a phenothiazine nucleus were synthesized in excellent yields via a modified Biginelli multicomponent reaction. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, Mass spectra and elemental analysis followed by antimycobacterial screening. Among all the screened compounds, compound 4g showed most pronounced activity against Mycobacterium tuberculosis (Mtb) with minimum inhibitory concentration (MIC) of 0.02 μg/mL, making it more potent than first line antitubercular drug isoniazid.

Scheme 1.

Synthetic protocol of title compounds 4a–k. Reagents and conditions: (a) NH₂NH₂, reflux; (b) ethyl acetoacetate, sodium ethoxide, reflux; (c) guanidine hydrochloride, aldehyde (R-CHO), P₂O₅, EtOH, reflux.

Vipul Kataria

Saurashtra University

https://www.linkedin.com/in/vipul-kataria-3aa37950

Experience

Assistant professor of chemistry

V P & R P T P science college

August 2013 – Present (2 years 11 months)

please send other authors pic at amcrasto@gmail.com

Amneal Pharmaceuticals’ co-CEO Chirag Patel

Chirag Patel and Chintu Patel

Chintu Patel, owner of Amneal Pharmaceuticals,

///////Dihydropyrazolo[3,4-d]pyrimidine, Phenothiazines, Biginelli multicomponent reaction, Cytotoxicity, Antitubercular activity, 4,5-Dihydro-1H-pyrazolo[3,4-d]pyrimidine, phenothiazines, antitubercular agents, amneal, 1580464-40-9

Clc1ccc(cc1)C2N=C(N)Nc3c2c(C)nn3c4cc5Nc6ccccc6Sc5cc4

GSK-2881078

June 14, 2016 7:50 am / Leave a comment

GSK-2881078

(R)-1-[1-(Methylsulfonyl)propan-2-yl]-4-(trifluoromethyl)-1H-indole-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

A selective androgen receptor modulator potentially for the treatment of cachexia.

Inventors	Philip Stewart Turnbull, Rodolfo Cadilla
Applicant	Glaxosmithkline Intellectual Property (No.2) Limited

CAS Number	1539314-06-1
Chemical Name	GSK-2881078
Synonyms	GSK-2881078
Molecular Formula	C14H13NF3N2O2S
Formula Weight	330.33

Originator GlaxoSmithKline
Mechanism of Action Selective androgen receptor modulators

Phase I Cachexia

Most Recent Events

03 Sep 2015 GlaxoSmithKline initiates enrolment in a phase I trial for Cachexia (In volunteers) in USA (NCT02567773)
01 Mar 2015 GlaxoSmithKline completes a phase I trial in Cachexia (In volunteers) in USA (NCT02045940)
31 Jan 2014 Phase-I clinical trials in Cachexia (In volunteers) in USA (PO)

GSK2881078 is a selective androgen receptor modulator (SARM) that is being evaluated for effects on muscle growth and strength in subjects with muscle wasting to improve their physical function. Part A of this study will evaluate the safety, efficacy and pharmacokinetics of GSK2881078 in healthy, older men and post-menopausal women who will take daily dosing for 28 days and be followed for a total of 70 days. Part B of this study will characterize the effect of Cytochrome P450 3A4 (CYP3A4) inhibition on the GSK2881078 pharmacokinetics. Part B will only be conducted if safe and efficacious dose is identified in Part A. Part A will include healthy older males and post-menopausal females; and randomize approximately 60 subjects (about 15 per cohort [4 cohorts]) to complete approximately 48 (about 12 per cohort). Part B will enroll one cohort of approximately 15 healthy male subjects to complete approximately 12. The study duration will be approximately 115 days for Part A and 122 days for Part B.

Steroidal nuclear receptor (NR) ligands are known to play important roles in the health of both men and women. Testosterone (T) and dihydrotestosterone (DHT) are endogenous steroidal ligands for the androgen receptor (AR) that appear to play a role in every tissue type found in the mammalian body. During the development of the fetus, androgens play a role in sexual differentiation and development of male sexual organs. Further sexual development is mediated by androgens during puberty. Androgens play diverse roles in the adult, including stimulation and maintenance of male sexual accessory organs and maintenance of the musculoskeletal system. Cognitive function, sexuality, aggression, and mood are some of the behavioral aspects mediated by androgens. Androgens have a physiologic effect on the skin, bone, and skeletal muscle, as well as blood, lipids, and blood cells (Chang, C. and Whipple, G. Androgens and Androgen Receptors. Kluwer Academic Publishers: Boston, MA, 2002)

Many clinical studies with testosterone have demonstrated significant gains in muscle mass and function along with decreases in visceral fat. See, for example,

Bhasin (2003) S. J. Gerontol. A Biol. Sci. Med. Sci. 58:1002-8, and Ferrando, A. A. et al. (2002) Am. J. Phys. Endo. Met. 282: E601-E607. Androgen replacement therapy (ART) in men improves body composition parameters such as muscle mass, strength, and bone mineral density (see, for example, Asthana, S. et al. (2004) J. Ger, Series A: Biol. Sci. Med. Sci. 59: 461 -465). There is also evidence of improvement in less tangible parameters such as libido and mood. Andrologists and other specialists are increasingly using androgens for the treatment of the symptoms of androgen deficiency. ART, using T and its congeners, is available in transdermal, injectable, and oral dosage forms. All current treatment options have contraindications (e.g., prostate cancer) and side-effects, such as increased hematocrit, liver toxicity, and sleep apnoea. Side-effects from androgen therapy in women include: acne, hirsutism, and lowering of high-density lipoprotein (HDL) cholesterol levels, a notable side-effect also seen in men.

Agents that could selectively afford the benefits of androgens and greatly reduce the side-effect profile would be of great therapeutic value. Interestingly, certain NR ligands are known to exert their action in a tissue selective manner (see, for example, Smith et al. (2004) Endoc. Rev. 2545-71 ). This selectivity stems from the particular ability of these ligands to function as agonists in some tissues, while having no effect or even an antagonist effect in other tissues. The term “selective receptor modulator” (SRM) has been given to these molecules. A synthetic compound that binds to an intracellular receptor and mimics the effects of the native hormone is referred to as an agonist. A compound that inhibits the effect of the native hormone is called an antagonist. The term “modulators” refers to compounds that have a spectrum of activities ranging from full agonism to partial agonism to full antagonism.

SARMs (selective androgen receptor modulators) represent an emerging class of small molecule pharmacotherapeutics that have the potential to afford the important benefits of androgen therapy without the undesired side-effects. Many SARMs with demonstrated tissue-selective effects are currently in the early stages of development See, for example, Mohler, M. L. et al. (2009) J. Med. Chem. 52(12): 3597-617. One notable SARM molecule, Ostarine™, has recently completed phase I and II clinical studies. See, for example, Zilbermint, M. F. and Dobs, A. S. (2009) Future Oncology 5(8):121 1-20. Ostarine™ appears to increase total lean body mass and enhance functional performance. Because of their highly-selective anabolic properties and demonstrated androgenic-sparing activities, SARMs should be useful for the prevention and/or treatment of many diseases in both men and women, including, but not limited to sarcopenia, cachexias (including those associated with cancer, heart failure, chronic obstructive pulmonary disease (COPD), and end stage renal disease (ESRD), urinary incontinence, osteoporosis, frailty, dry eye and other conditions associated with aging or androgen deficiency. See, for example, Ho et al. (2004) Curr Opin Obstet Gynecol. 16:405-9; Albaaj et al. (2006) Postgrad Med J 82:693-6; Caminti et al. (2009) J Am Coll Cardiol. 54(10):919-27; lellamo et al. (2010) J Am Coll Cardiol. 56(16): 1310-6; Svartberg (2010) Curr Opin Endocrinol Diabetes Obes. 17(3):257-61 , and Mammadov et al. (201 1 ) Int Urol Nephrol 43:1003-8. SARMS also show promise for use in promoting muscle regeneration and repair (see, for example, Serra et al. (Epub 2012 Apr 12)

doi:10.1093/Gerona/gls083),in the areas of hormonal male contraception and benign prostatic hyperplasia (BPH), and in wound healing (see, for example, Demling (2009) ePIasty 9:e9).

Preclinical studies and emerging clinical data demonstrate the therapeutic potential of SARMs to address the unmet medical needs of many patients. The demonstrated advantages of this class of compounds in comparison with steroidal androgens (e.g. , tissue-selective activity, oral administration, AR selectivity, and lack of androgenic effect) position SARMs for a bright future of therapeutic applications.

Although amorphous forms of SARMs may be developed for some uses, compounds having high crystallinity are generally preferred for pharmaceutical use due to their improved solubility and stability. Accordingly, there remains a need in the art for crystalline form of SARMs for therapeutic use.

Patent

WO 2015110958

EXAMPLES

Example 1 – Synthesis of (R)-1 -(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)- -indole-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)^-(trifluoromethyl)-1 H-indole-5-carbonitrile

Method 1 :

A. (R)-1 -(Methylthio)propan-2 -amine

Step 1

To a solution of commercially available (R)-2-aminopropan-1 -ol (5 g, 66.6 mmol) in MeCN (20 mL), in an ice bath, is added very slowly, dropwise, chlorosulfonic acid (4.46 mL, 66.6 mmol) (very exothermic). The reaction mixture is kept in the cold bath for ~10 min, and then at rt for ~ 30 min. After stirring for another ~ 10 minutes, the solids are collected by filtration, washed sequentially with MeCN (40 mL) and hexanes (100 mL), and dried by air suction for ~ 40 min. to produce the intermediate ((R)-2-aminopropyl hydrogen sulfate.

Step 2:

To a solution of sodium thiomethoxide (5.60 g, 80 mmol) in water (20 mL) is added solid NaOH (2.66 g, 66.6 mmol) in portions over ~ 10 min. Then the intermediate from step 1 is added as a solid over ~ 5 min. The mixture is then heated at 90 °C for ~10 h. The reaction mixture is biphasic. Upon cooling, MTBE (20 mL) is added, and the organic phase (brownish color) is separated. The aqueous phase is extracted with MTBE (2 x 20 mL). The original organic phase is washed with 1 N NaOH (15 mL). The basic aqueous phase is re-extracted with MTBE (2 x 20 mL). All the ether phases are combined, dried over Na₂S0₄, filtered, and concentrated (carefully, since the product is volatile) to afford the crude product as a light yellow oil.

Method 2

(R)-1-(methylthio)propan-2 -amine hydrochloride

A. (R)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

Step 1

Commercially available (R)-2-aminopropan-1 -ol (135 g, 1797 mmol) is dissolved in MeOH 1350 mL). The solution is cooled to 5°C with an icebath, then Boc₂0 (392 g, 1797 mmol) is added as a solution in MeOH (1000 mL). The reaction temperature is kept below 10°C. After the addition, the cooling bath is removed, and the mixture is stirred for 3 h. The MeOH is removed under vacuum (rotavap bath: 50°C). This material is used as is for the next step.

Step 2

The residue is dissolved in CH₂CI₂ (1200 mL) and NEt₃ (378 mL, 2717 mmol) is added, then the mixture is cooled on an ice bath. Next, MsCI (166.5 mL, 2152 mmol) is added over ~2 h, while keeping the reaction temperature below 15°C. The mixture is stirred in an icebath for 1 h then the bath was removed. The mixture is stirred for 3 d, then washed with a 10% NaOH solution (500 mL 3 x), then with water. The organic phase is dried with MgS0₄, filtered, then stripped off (rota, 50°C waterbath. The impure residue is dissolved in a mix of 500mL EtOAc (500 mL) and MTBE (500 mL) and then extracted with water to remove all water-soluble salts. The organic phase is dried with MgS0₄, filtered, then stripped off to afford a white solid residue.

B. (R)-tert-Butyl (1 -(methylthio)propan-2-yl)carbamate

NaSMe (30 g, 428 mmol) is stirred with DMF (200 mL) to afford a suspension. Next, (R)-2-((tertbutoxycarbonyl)amino)propyl methanesulfonate (97 g, 383 mmol) is added portionwise while the temperature is kept below 45°C (exothermic). After the addition, the mixture is stirred for 2 h, then toluene (100 mL) is added. The mixture is washed with water (500 mL, 4 x), then dried with MgS0₄, and filtered. The filtrate is stripped off (rotavap) to a pale yellow oil.

C. (R)-1 -(Methylthio)propan-2 -amine hydrochloride

Acetyl chloride (150 mL,) is added to a stirred solution of MeOH (600 mL) cooled with an icebath. The mixture is stirred for 30 min in an icebath, then added to (R)-tert-butyl (1 -(methylthio)propan-2-yl)carbamate (78 g, 380 mmol). The mixture is stirred at rt for 2 h, (C0₂, (CH₃)₂C=CI-l2 evolution) and then stripped off to a white solid.

D. 4-Fluoro-3-iodo-2-(trifluoromethyl)benzonitrile

To a freshly prepared solution of LDA (1 19 mmol) in anhyd THF (250 mL) at -45°C is added a solution of commercially available 4-fluoro-2-(trifluoromethyl)benzonitrile (21 .5 g, 1 14 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained < -40°C (became dark brown during addition). The mixture is stirred 30 min at -45°C, cooled to -70°C and iodine (31 .7 g, 125 mmol) is added in one portion (-70°C→ -52°C). The mixture is stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na₂S₂0₃ (ca. 250 mL) and 1 N HCI (ca. 125 mL). The mixture is extracted with EtOAc (x3). Combined organics are washed (water, brine), dried over Na₂S0₄ and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc / hexanes, gradient elution) followed by

recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (15.79 g, 50.1 mmol, 44.1 % yield) as a pale yellow solid.

E. 4-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile

A 20 mL vial is charged with 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile,(0.315 g, 1 .00 mmol), Pd(PPh₃)₂CI₂ (0.014 g, 0.020 mmol) and Cul (0.0076 g, 0.040 mmol), and sealed with a rubber septum. Anhyd PhMe (5 mL) and DIPA (0.210 mL, 1 .500 mmol) are added via syringe and the mixture is degassed 10 min by sparging with N₂while immersed in an ultrasonic bath. Ethynyltrimethylsilane (0.155 mL, 1 .100 mmol) is added dropwise via syringe and the septum is replaced by a PTFE-faced crimp top. The mixture is stirred in a heating block at 60°C. Upon cooling the mixture is diluted with EtOAc and filtered through Celite. The filtrate is washed (satd NH₄CI, water, brine), dried over Na₂S0₄ and concentrated in vacuo. The residue is purified by low pressure liquid chromatography (silica gel, EtOAc / hexanes, gradient elution) affording 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile .

F. (R)-1 -(1 -(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

A mixture of 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (1 .16 g, 4.07 mmol), (R)-1 -(methylthio)propan-2-amine (0.599 g, 5.69 mmol) and DIEA (1 .42 mL, 8.13 mmol) in DMSO (7 mL) is heated (sealed tube) at 100°C for 50 min. Upon cooling, the reaction mixture is diluted with EtOAc (50 mL) and washed with water (30 mL). The organic phase is washed with water and brine, dried over Na₂S0₄, filtered and concentrated to give the intermediate aniline. This intermediate is dissolved in NMP (7 mL), treated with KOtBu (1 M in THF) (5.69 mL, 5.60 mmol) and heated at 50°C. The reaction is monitored by LCMS, and deemed complete after 40 min. Upon cooling, the reaction mixture is diluted with EtOAc (40 mL) and washed with water (30 mL). The organic phase is washed with more water and brine, dried over Na₂S0₄, filtered and concentrated. The residue is chromatographed over silica gel using a 5-40% EtOAc-hexane gradient to give the thioether intermediate:

G. (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

To an ice-cold solution of (R)-1 -(1 -(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (0.560 g, 1.88 mmol) in MeOH (10 mL) is added a solution of Oxone (4.04 g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture is diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase is washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue is chromatographed over silica gel using 100% CH₂CI₂ to give (R)-1-(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-l H-indole-5-carbonitrile as a white foam that is crystallized from

CH₂CI₂/hexanes to afford a white solid.

Example 2- Preparation of crystalline form 1 of (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .74kg, 1wt) was dissolved in ethyl acetate (12.0 Kg, 6.9 wt) at 20-30°C. The solution was transferred into a clean reaction vessel via an in-line cartridge filter. The solution was concentrated to ~3.0-5.0 volumes under reduced pressure, keeping the temperature below 50°C. The solution was cooled to 20-30°C, and n-heptane (23.0 Kg, 13.2 wt) was added slowly over ~1 hour. The solution was stirred 1 -2 hrs at 20-30°C, heated to 50-55°C for 2-3 hours, cooled back to 20-30°C and stirred for 1 -2 hours. The slurry was sampled and analyzed by XRPD. The solid was collected by filtration, washed with n-heptane (1 .4 Kg, 0.8 wt), and dried in vacuo at 40-50 °C to provide crystalline

(R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .54 Kg, Form 1 ; 88.5 % yield, 99.5% purity) as a slightly colored solid.

Example 3- Preparation of crystalline form 2 of (R)-1 -(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile

Crude (R)-1 -(1 -(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)indoline-5-carbonitrile (1 .54 g [theoretical], 1 wt) was dissolved in dichloromethane (5mL, 3.25 vol) and loaded onto a 12-g ISCO column (Si0₂). The column was eluted with DCM (-500 mL, 325 vol) and the product-containing fractions were combined and concentrated in vacuo. The resulting residue was triturated in n-heptane. The solid was collected by filtration, air-dried, and placed under high vacuum for 3 h to provide GSK2881078A (1 .009 g, Form 2; 65.1 % yield, 100% AUC HPLC-UV) as a white solid.

PATENT

https://www.google.com/patents/WO2014013309A1?cl=en22

Example 26

1-(1-(Methylsulfonyl)propan-2-yl)-4-(trifiuoromethyl)-1H-indole-5-carbonitrile Synthesized in a manner similar to Example 9 using 1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (Example 25): MS (ESI): m/z 331 (MH+).

Example 27

(R)-1 -(1 -(Methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile

A. (R)-1-(Methylthio)propan-2-amine

Step l

To a solution of commercially available (R)-2-aminopropan-1-ol (5 g, 66.6 mmol) in MeCN (20 mL), in an ice bath, was added very slowly, dropwise, chlorosulfonic acid (4.46 mL, 66.6 mmol) (very exothermic). A gummy beige precipitate formed. The reaction mixture was kept in the cold bath for -10 min, and then at rt for ~ 30 min. The reaction mixture was scratched with a spatula to try to solidify the gummy precipitate. After a few minutes, a beige solid formed. After stirring for another ~ 10 minutes, the solids were collected by filtration, washed sequentially with MeCN (40 mL) and hexanes (100 mL), and dried by air suction for ~ 40 min. The intermediate ((R)-2-aminopropyl hydrogen sulfate, weighed 0.46 g (~ 96% yield).

Step 2:

To a solution of sodium thiomethoxide (5.60 g, 80 mmol) in water (20 mL) was added solid NaOH (2.66 g, 66.6 mmol) in portions over – 10 min. Then the intermediate from step 1 was added as a solid over ~ 5 min. The mixture was then heated at 90 °C for -10 h. The reaction mixture was biphasic. Upon cooling, MTBE (20 mL) was added, and the organic phase (brownish color) was separated. The aqueous phase was extracted with MTBE (2 x 20 mL). The original organic phase is washed with 1 NaOH (15 mL) (this removes most of the color). The basic aqueous phase was re-extracted with MTBE (2 x 20 mL). All the ether phases are combined, dried over Na₂S0₄, filtered, and

concentrated (carefully, since the product is volatile) to afford the crude product as a light yellow oil: ¹H NMR (400 MHz, DMSO-cf₆) δ 2.91-2.87 (m, 1 H), 2.43-2.31 (m, 2 H), 2.04 (s, 3 H), 1.50 (bs, 2 H), 1.01 (d, J = 6.3 Hz, 3 H).

Alternative synthesis of example 27A:

(R)-1 -(Methylthio)propan-2 -amine hydrochloride

A. (R)-2-((tert-Butoxycarbonyl)amino)propyl methanesulfonate

Step 1

Commercially available (R)-2-aminopropan-1-ol (135 g, 1797 mmol) was dissolved in MeOH 1350 mL). The solution was cooled to 5°C with an icebath, then Boc₂0 (392 g, 1797 mmol) was added as a solution in MeOH (1000 mL). The reaction temperature was kept below 10°C. After the addition, the cooling bath was removed, and the mixture was stirred for 3 h. The MeOH was removed under vacuum (rotavap bath: 50°C). The resulting residue was a colorless oil that solidified overnight to a white solid. This material was used as is for the next step.

Step 2

The residue was dissolved in CH₂CI₂ (1200 mL) and NEt₃ (378 mL, 2717 mmol) was added, then the mixture was cooled on an ice bath. Next, MsCI (166.5 mL, 2152 mmol) was added over ~2 h, while keeping the reaction temperature below 15°C. The mixture was stirred in an icebath for 1 h then the bath was removed. The mixture was stirred for 3 d, then washed with a 10% NaOH solution (500 mL 3 x), then with water. The organic phase was dried with MgS0 , filtered, then stripped off (rota, 50°C waterbath. The impure residue was dissolved in a mix of 500mL EtOAc (500 mL) and MTBE (500 mL) and then, extracted with water to remove all water-soluble salts.The organic phase was dried with MgS0₄, filtered, then stripped off to afford a white solid residue: ¹H NMR (400 MHz, DMSO-d_s) δ 6.94-6.92 (m, 1 H), 4.02 (d, J = 5.8 Hz, 2 H), 3.78-3.71 (m, 1 H), 3.16 (s, 3 H), 1.38 (s, 9 H), 1.06 (d, J = 6.8 Hz, 3 H).

B. (R)-tert-Butyl (1-(methylthio)propan-2-yl)carbamate

NaSMe (30 g, 428 mmol) was stirred with DMF (200 mL) to afford a suspension. Next, (R)-2-((tertbutoxycarbonyl)amino)propyl methanesulfonate (97 g, 383 mmol) was added

portionwise while the temperature was kept below 45°C (exothermic).. After the addition, the mixture was stirred for 2 h, then toluene (100 ml_) was added. The mixture was washed with water (500 ml_, 4 x), then dried with MgS0₄, and filtered. The filtrate was stripped off (rotavap) to a pale yellow oil: ¹H NMR (400 MHz, DMSO-d₆) δ 6.77-6.75 (m, 1 H), 3.60-3.54 (m, 1 H), 2.54-2.50 (m, 1 H), 2.43-2.38 (m, 1 H), 2.05 (s, 3 H), 1.38 (s, 9 H), 1.08 (d, J = 7.8 Hz, 3 H).

C. (R)-1-(Methylthio)propan-2-amine hydrochloride

Acetyl chloride (150 mL,) was added to a stirred solution of MeOH (600 mL) cooled with an icebath. The mixture was stirred for 30 min in an icebath, then added to (R)-tert-butyl (1-(methylthio)propan-2-yl)carbamate (78 g, 380 mmol). The mixture was stirred at rt for 2 h, (C0₂, (CH₃)₂C=CH₂ evolution) and then stripped off to a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (bs, 3 H), 3.36-3.29 (m, 1 H), 2.80-2.75 (m, 1 H), 2.64-2.59 (m, 1 H (d, J = 6.6 Hz, 3 H).

D. (R)-1 -(1 -(Methylthio)propan-2-yl)-4-(trif luoromethy l)-1 H-indole-5-carbonitrile

A mixture of 4-fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (Example 21 D,1.16 g, 4.07 mmol), (R)-1-(methylthio)propan-2-amine (0.599 g, 5.69 mmol) and DIEA (1.42 mL, 8.13 mmol) in DMSO (7 mL) was heated (sealed tube) at 100°C for 50 min. Upon cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL). The organic phase was washed with water and brine, dried over Na₂S0₄, filtered and concentrated to give the intermediate aniline. This intermediate was dissolved in NMP (7 mL), treated with KOtBu (1 M in THF) (5.69 mL, 5.60 mmol) and heated at 50°C. The reaction was monitored by LCMS, and deemed complete after 40 min. Upon cooling, the reaction mixture was diluted with EtOAc (40 mL) and washed with water (30 mL). The organic phase was washed with more water and brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed over silica

gel using a 5-40% EtOAc-hexane gradient to give the thioether intermediate: MS (ESI):

E. (R)-1-(1-(Methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile

To an ice-cold solution of (R)-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1 H-indole-5-carbonitrile (0.560 g, 1.88 mmol) in MeOH (10 mL) was added a solution of Oxone (4.04 g, 6.57 mmol) in water (10 mL). After 50 min, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed over silica gel using 100% CH₂CI₂ to give (R)-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-l H-indole-5-carbonitrile as a white foam that was crystallized from CH₂CI₂/hexanes to afford a white solid (0.508 g, 79% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J = 8.6 Hz, 1 H), 8.12 (d, J = 3.5 Hz, 1 H), 7.81 (d, J – 8.5 Hz, 1 H), 6.87-6.84 (m, 1 H), 5.43-5.35 (m, 1 H), 4.01 (dd, J = 14.8, 8.6 Hz, 1 H), 3.83 (dd, J = 14.8, 4.9 Hz, 1 H), 2.77 (s, 3 H), 1.59 (d, J = 6.8 Hz, 3 H); MS (ESI): m/z 331 (M+H).

Philip Turnbull

Director of Chemistry

https://www.linkedin.com/in/philip-turnbull-21266a8

Education

The Scripps Research Institute

post doc, Organic chemistry

1996 – 1998

University of California, Irvine

Doctor of Philosophy (Ph.D.), Organic synthesis

1991 – 1996

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