Yonkenafil

phase 2 Comments Off

Jun 292016

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

Chidamide (Epidaza), A New Cancer Drug, Made in China

Uncategorized Comments Off

Jun 292016

Figure CN103833626AD00031

Chidamide (Epidaza)

CS055; HBI-8000

CAS 743438-44-0 CORRECT

C₂₂ H₁₉ F N₄ O_2,Benzamide, N-(2-amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]-

Molecular Weight, 390.41

Benzamide, N-(2-amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propenyl]amino]methyl]-
N-(2-Amino-4-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]benzamide
CS 055
Chidamide
Epidaza

Activity: HDAC Inhibitor; Cancer Drug; Histone Deacetylase Inhibitor; HDAC-1, 2,3,10 Inhibitor; Treatment for Peripheral T-cell Lymphomas; Treatment for PTCL

Status: Launched 2014 (China)

Originator: Shenzhen Chipscreen Biosciences Ltd

Shenzhen Chipscreen Biosciences, Ltd.

SHENZHEN CHIPSCREEN BIOSCIENCES LTD. [CN/CN]; Research Institute of Tsinghua University, Suite C301, P.O. Box 28, High-Tech Industrial Park Nanshan District, Shenzhen, Guangdong 518057

ERROR IN STRUCTURE

FLUORO IN WRONG POSITION

CAS Registry Number: 743420-02-2

CN103833626A

As described for Example 2 according to the patent ZL03139760.3 obtained chidamide poor purity (about 95%). LC / MS analysis results shown in Figure 1, show that the product contains N- (2- amino-5-fluorophenyl) -4- (N- (3- pyridin-acryloyl group of 4.7% of the structure shown in formula II) aminomethyl) benzamide. 1H NMR analysis of the results shown in Figure 2, show that the product contains 1.80% of tetrahydrofuran, far beyond the technical requirements for people with drug registration International Conference on Harmonization (ICH, International Conference of Harmonizition) provided 0.072% residual solvent limits. Therefore, the solid

Body not for pharmaceutical manufacturing.

WRONG COMPD….https://www.google.com/patents/CN103833626A?cl=en

Chidamide (Epidaza) is an HDAC inhibitor (HDI) developed wholly in China.^[1] It was originally known as HBI-8000.^[2]

It is a benzamide HDI) and inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10.^[3]

It is approved by the Chinese FDA for relapsed or refractory peripheral T-cell lymphoma (PTCL), and having orphan drug status in Japan.^[2]

As of April 2015 it is only approved in China.^[1]

It shows potential in treating pancreatic cancer.^[4]^[5]^[6]

Is NOT approved for the treatment of pancreatic cancer.

Chidamide drug administration and clinical milestone

November 2005: China declared IND

November 2006: eligible for Phase I clinical documents of approval

November 2006: completion of the International Patent Licensing, China entered the international fray original new drug development

May 2008: completed Phase I clinical, showing international mechanism similar drugs have the potential to become the best

February 2009: eligible lymphoma indications II / III of this document

March 2009: Start of the Phase II clinical trial for the NDA to ①CTCL goal of clinical trials and ②PTCL

March 2009: IND by the FDA application is eligible to start Phase I clinical in the United States

July 2009: eligible for non-small cell lung cancer, breast cancer and prostate cancer clinical documents of approval

December 2010: of PTCL by a conventional phase II directly into Phase II clinical trial registered drug trial center and by recognition

March 2011: combination chemotherapy for non-small cell lung cancer clinical trials enter phase Ib

September 2012: of PTCL indication test deadline

December 2012: of PTCL clinical summary will be held

January 2013: Chidamide declare China NDA

December 2014: the State Food and Drug Administration (CFDA) approved the listing

Chidamide overview, location and clinical significance

Chidamide (Chidamide, love spectrum sand ® / Epidaza®) Shenzhen microchip biotechnology limited liability company developed a new subtype selective histone having a chemical structure and is eligible for a global patent licensing deacetylase inhibitor, belong to the new mechanisms of epigenetic regulation new class of targeted anticancer drugs, has now completed with relapsed or refractory peripheral T-cell lymphoma clinical trial study registered indications, was in March 2013 to the SFDA reporting new drug certificate (NDA) and the marketing authorization (MAA). While a number of Chinese Cancer clinical trials undertaken Chidamide is also China’s first approved by the US FDA clinical studies in the United States of Chinese chemical original new drug trials in the United States Phase I has been completed. Chidamide has won the national “Eleventh Five-Year” 863 major projects (project number: 2006AA020603) and the national “Eleventh Five-Year”, “significant Drug Discovery” science and technology and other major projects funded project (project number: 2009ZX09401-003), was chosen the Ministry of Science and one of the “Eleventh five-Year” major national scientific and technological achievements.

Relapsed or refractory peripheral T-cell lymphoma (PTCL) is Chidamide first approvedclinical indications, PTCL belongs to the category of rare diseases, the lack of standard drug currently recommended clinical treatment, conventional chemotherapy response rate is low, recur, 5-year overall survival rate was about 25%. The world’s first PTCL treatment Folotyn (intravenous drug use) is eligible for FDA clearance to market in 2009, the second drugs Istodax (intravenous drug use) approved by the FDA in 2011. Add a new drug information for these drugs is very expensive, and were listed in China. Chidamide album clinical trial results showed that the primary endpoint of objective response rate was 28%, reaching the intended target research and development; sustained remission rate of 24% three months; drug safety was significantly better than the international similar drugs, and oral medication.
Chidamide is a completely independent intellectual property rights China originator of innovative medicines, has been multi-national patent. In China, for patients with relapsed or refractory PTCL to carry out effective drug treatment is urgent clinical need, Chidamide expected to bring new treatment options for patients with PTCL, prolong survival and improve quality of life of patients.

In China, for the effective treatment of patients with relapsed or refractory PTCL has undertaken urgent clinical need

Chidamide is a completely independent intellectual property rights China originator of innovative medicines

Chidamide (Chidamide) has been multi-national invention patents

In October 2006, the US HUYA biological microchip company formally signed the International Patent Chidamide licensing and international clinical cooperative development agreement; the United States in the ongoing Phase I clinical

Chidamide (Epidaza), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I , as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.

Chidamide, the English called Chidamide, by the Shenzhen-core biotechnology limited liability company independent design and synthesis of a novel anti-cancer drugs with new chemical structures and global intellectual property, and its chemical name N- (2-amino-_4_ fluorophenyl) -4_ (N- (3- topiramate Li acryloyl) aminomethyl) benzamide, its chemical structure of the structural formula I

The patent ZL03139760.3 and said US7,244,751, Chidamide have histone deacetylase inhibitory activity can be used to treat the differentiation and proliferation-related diseases such as cancer and psoriasis, especially for leukemia and solid tumors with excellent results.

Patent No. ZL03139760.3 and US7,244,751 discloses a method for preparing chidamide, but did not specify whether the resulting product is a crystalline material, nor did the presence or absence of the compound polymorphism. In the above patent, the activity of the compound for evaluation is not conducted in a solid state and, therefore, does not disclose any description about characteristics of the crystal.

Chipscreen grabs CFDA approval for chidamide

Posted on 2015/01/10

Chipscreen BioSciences announced that the CFDA had approved chidamide for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in December 2014. The drug and Hengrui’s apatinib were the only two NCEs launched by domestic drug makers last year.

Chidamide (CS055/HBI-8000) is a HDAC1/2/3/10 inhibitor derived from entinostat (MS-27-275)[1] which was first discoved by Mitsui Pharmaceuticals in 1999. Chipscreen holds worldwide IP rights to chidamide (patents: WO2004071400, WO2014082354).

Syndax Pharmaceuticals (NASDAQ: SNDX) is testing entinostat in breast cancer and NSCLC in pivotal trials. The FDA granted Breakthrough Therapy Designation to entinostat for advanced breast cancer in 2013. Eddingpharm in-licensed China rights to entinostat from Syndax in September 2013.

Chipscreen disclosed positive results from Phase II study of chidamide in relapsed or refractory PTCL at 2013 ASCO Annual Meeting[2]. Out of 79 evaluable patients in the trial, 23 patients (29.1%) had confirmed responses (8 CR, 3 CRu, and 12 PR). The most common grade 3/4 AEs were thrombocytopenia (24%), leucocytopenia (13%), neutropenia(10%).

The FDA has approved three HDAC inhibitors, known as Zolinza (vorinostat), Istodax (romidepsin) and Beleodaq (belinostat), for the treatment of PTCL. Celgene priced Istodax at $12000-18000/month and reported annual sales of $54 million in 2013. The efficacy and safety profile of chidamide compares favorably with romidepsin.

Although a dozen of companies are developing generic vorinostat and romidepsin, no chemical 3.1 NDA has been submitted to the CFDA so far. Chipscreen will be the only domestic maker of HDAC inhibitor in the coming two years. Moreover, the company is testing chidamide in NSCLC and breast cancer in early clinical studies.

CLIP

Chiamide synthesis: US7244751B2

Procedure:

Step a: To a suspension of 0.33 g (2.01 mmol) of N,N’-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0 °C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid (0.46 g, 82%). HRMS calcd for C16H14N2O3: 282.2988. Found: 282.2990. MA calcd for: C16H14N2O3: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.

Step b: To a suspension of 0.29 g (1.78 mmol) of N,N’-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45 °C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give N-(2-amino-4-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzamide (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d6): dppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C22H19N4O2F: 390.4170. Found: 390.4172. MA calcd for C22H19N4O2F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.

http://www.google.co.in/patents/US7244751

EXAMPLE 1

Preparation of 4-[N-(Pyridin-3-ylacryloyl)aminomethyl]benzoic acid

To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of 3-pyridineacrylic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 5. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.46 g, 82%). HRMS calcd for C₁₆H₁₄N₂O₃: 282.2988. Found: 282.2990. MA calcd for: C₁₆H₁₄N₂O₃: C, 68.07%; H, 5.00%; N, 9.92%. Found: C, 68.21%; H, 5.03%; N, 9.90%.EXAMPLE 2

Preparation of N-(2-amino-4-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide

To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofiman (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.40 g, 57%). ¹H NMR (300 MHz, DMSO-d₆): δppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (1H, t), 6.80 (2H, m),696 (1H, t), 7.18 (1H, d), 7.42 (2H, d), 7.52 (1H, d), 7.95 (2H, d), 8.02 (1H, d), 8.56 (1H, d), 8.72 (1H, br. t), 8.78 (1H, s), 9.60 (1H, br.s). IR (KBr) cm¹: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C₂₂H₁₉N₄O₂F: 390.4170. Found: 390.4172. MA calcd for C₂₂H₁₉N₄O₂F: C, 67.68%; H, 4.40%; N, 14.35%. Found: C, 67.52%; H, 4.38%; N, 14.42%.EXAMPLE 3

Preparation of 4-[N-cinnamoylaminomethyl]benzoic acid

To a suspension of 0.33 g (2.01 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (10 ml) is added drop-wise a solution of 0.30 g (2.01 mmol) of cinnamic acid at 0° C. Then, the mixture is stirred at room temperature for 3 hours and added drop-wise to a separately prepared 2.0 ml (2.00 mmol) of 1N aqueous sodium hydroxide solution including 0.30 g (2.00 mmol) of 4-aminomethylbenzoic acid, followed by stirring at room temperature for 8 hours. The reaction mixture is evaporated under vacuum. To the residue is added a saturated solution of sodium chloride (2 ml), then the mixture is neutralized with concentrated hydrochloric acid to pH 7. The deposited white solid is collected by filtration, washed with ice-water, and then dried to give the title compound (0.51 g, 91%). HRMS calcd for C₁₇H₁₅NO₃: 281.3242. Found: 281.3240. MA calcd for C₁₇H₁₅NO₃: C, 72.58%; H, 5.38%; N, 4.98. Found: C, 72.42%; H, 5.37%; N, 4.98%.

EXAMPLE 4

Preparation of N-(2-amino-4-fluorophenyl)-4-[N-cinnamoylaminomethyl]benzamide

To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-cinnamoylaminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofunan (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 16 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.45 g, 64%). ¹H NMR (300 MHz, DMSO-d₆): δppm: 4.42 (2H, d), 4.92 (2H, br.s), 6.62 (1H, t), 6.78 (2H, m), 7.01 (1H, t), 7.32 (5H, m), 7.54 (5H, m), 8.76 (1H, br.t), 9.58 (1H, br.s). IR (KBr) cm⁻¹: 3306, 1618, 1517, 1308, 745. HRMS calcd for C₂₃H₂₀N₃O₂F: 389.4292. Found: 389.4294. MA calcd for C₂₃H₂₀N₃O₂F: C, 70.94%; H, 5.18%; N, 10.79%. Found: C, 70.72%; H, 5.18%; N, 10.88%.

PATENT

https://www.google.com/patents/US20150299126

FIG. 2 is the ¹H NMR spectrum of the solid prepared according to Example 2 of patent ZL 03139760.3;

NMR, MS ETC CLICK TO VIEW

CLIP

Chidamide (Epidaza), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I 1–3, as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.74

This agent also inhibits the expression of signaling kinases in the PI3K/ Akt and MAPK/Ras pathways and may result in cell cycle arrest and the induction of tumor cell apoptosis.75

Currently, phases I and II clinical trials are underway for the treatment of non-small cell lung cancer and for the treatment of breast cancer, respectively.76 The scalable synthetic approach to chidamide very closely follows the discovery route,77–79 and is described in Scheme 10. The sequence began with the condensation of commercial nicotinaldehyde (52) and malonic acid (53) in a mixture of pyridine and piperidine. Next, activation of acid 54 with N,N0-carbonyldiimidazole (CDI) and subsequent reaction with 4-aminomethyl benzoic acid (55) under basic conditions afforded amide 56 in 82% yield.

Finally, activation of 56 with CDI prior to treatment with 4-fluorobenzene- 1,2-diamine (57) and subsequent treatment with TFA and THF yielded chidamide (VIII) in 38% overall yield from 52. However, no publication reported that mono-N-Boc-protected bis-aniline was used to approach Chidamide.

74. Ning, Z. Q.; Li, Z. B.; Newman, M. J.; Shan, S.; Wang, X. H.; Pan, D. S.; Zhang, J.;
Dong, M.; Du, X.; Lu, X. P. Cancer Chemother. Pharmacol. 2012, 69, 901.
75. Liu, L.; Chen, B.; Qin, S.; Li, S.; He, X.; Qiu, S.; Zhao, W.; Zhao, H. Biochem.
Biophys. Res. Commun. 2010, 392, 190.
76. Gong, K.; Xie, J.; Yi, H.; Li, W. Bio. Chem. J. 2012, 443, 735.
77. Lu, X. P.; Li, Z. B.; Xie, A. H.; Shi, L. M.; Li, B. Y.; Ning, Z. Q.; Shan, S.; Deng, T.;
Hu, W. M. US Patent 2004224991A1, 2004.
78. Lu, X. P.; Li, Z. B.; Xie, A. H.; Shi, L. M.; Li, B. Y.; Ning, Z. Q.; Shan, S.; Deng, T.;
Hu, W. M. CN Patent 1513839A, 2003.
79. Yin, Z. H.; Wu, Z. W.; Lan, Y. K.; Liao, C. Z.; Shan, S.; Li, Z. L.; Ning, Z. Q.; Lu, X.
P.; Li, Z. B. Chin. J. New Drugs 2004, 13, 536.

see CN 105457038

CN 1513839

WRONG COMPD

WO2004071400

Example 2. Preparation of
N-(2-amino-5-fluorophenyl)-4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzamide

To a suspension of 0.29 g (1.78 mmol) of N, N’-carbonyldiimidazole in tetrahydrofunan (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-(Pyridn-3-ylacryloyl)aminomethyl]benzoic acid, followed by stirring at 45°C for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofunan (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 24 hours, the deposited white solid is collected by filtration, washed with tetrahydrofunan, and then dried to give the title compound (0.40 g, 57%). 1H NMR (300 MHz, DMSO-d₆): δppm: 4.49 (2H, d), 4.84 (2H, br.s), 6.60 (IH, t), 6.80 (2H, m), 6.96 (IH, t), 7.18 (IH, d), 7.42 (2H, d), 7.52 (IH, d), 7.95 (2H, d), 8.02 (IH, d), 8.56 (IH, d), 8.72 (IH, br. t), 8.78 (IH, s), 9.60 (IH, br.s). IR (KBr) cm^“1: 3310, 1655, 1631, 1524, 1305, 750. HRMS calcd for C₂₂Hι₉N₄O₂F: 390.4170. Found: 390.4172. MA calcd for C₂₂Hι₉N₄O₂F: C, 67.68%; H, 4.40%; N, 14.35. Found: C, 67.52%; H, 4.38%; N, 14.42%.

Photo taken on May 22, 2015 shows a box of Chidamide in Shenzhen, south China’s Guangdong Province. Chidamide is the world’s first oral HDAC inhibitor …

A New Cancer Drug, Made in China

After 14 years, Shenzhen biotech’s medicine is one of the few locally developed from start to finish

HONG KONG— Xian-Ping Lu left his job as director of research at drug maker Galderma R&D in Princeton, N.J., to co-found a biotech company to develop new medicines in his native China.

It took more than 14 years but the bet could be paying off. In February, Shenzhen Chipscreen Biosciences’ first therapy, a medication for a rare type of lymph-node cancer, hit the market in China.

The willingness of veterans like Dr. Lu and others to leave multinational drug companies for Chinese startups reflects a growing optimism in the industry here. The goal, encouraged by the government, is to move the Chinese drug industry beyond generic medicines and drugs based on ones developed in the West.

Chipscreen’s drug, called chidamide, or Epidaza, was developed from start to finish in China. The medicine is the first of its kind approved for sale in China, and just the fourth in a new class globally. Dr. Lu estimates the research cost of chidamide was about $70 million, or about one-tenth what it would have cost to develop in the U.S.

“They are a good example of the potential for innovation in China,” said Angus Cole, director at Monitor Deloitte and pharmaceuticals and biotechnology lead in China.

China’s spending on pharmaceuticals is expected to top $107 billion in 2015, up from $26 billion in 2007, according to Deloitte China. It will become the world’s second-largest drug market, after the U.S., by 2020, according to an analysis published last year in the Journal of Pharmaceutical Policy and Practice.

China has on-the-ground infrastructure labs, a critical mass of leading scientists and interested investors, according to Franck Le Deu, head of consultancy McKinsey & Co.’s pharmaceuticals and medical-products practice in China. “There’re all the elements for the recipe for potential in China,” he said.

But there are obstacles to an industry where companies want big payoffs for a decade or more of work and tremendous costs it takes to develop a drug.

While the protection of intellectual property has improved, China’s cumbersome rules for drug approval and a government effort to cut health-care costs, particularly spending on drugs, could hurt the Chinese drug companies’ efforts, said Mr. Cole of Deloitte.

“Will you start to see success? Of course you will,” said Mr. Cole. However, “I’ve yet to see convincing or compelling evidence that it’s imminent.”

To date, many of the Chinese companies that are flourishing in the life sciences are contract research organizations that help carry out clinical trials, as well as providers of related services.

Some companies, like Shanghai-based Hua Medicine, are buying the rights to develop new compounds in China from multinational drug companies, what some experts consider more akin to an intermediate step to innovation.

Late last year, Hua Medicine completed an early-stage human clinical trial of a diabetes drug in China and in March filed an application to the Food and Drug Administration to develop it in the U.S. as well. The company has raised $45 million in venture funding to date.

Li Chen, who left an 18-year career at Roche Holding AG as head of research and development in China to help start Hua Medicine, said the company’s goal is to “create a game-changer of drug discovery.”

At Chipscreen Biosciences, Dr. Lu and his co-founders set up the company in 2001 in Shenzhen, a city that was quickly growing into a technology and research hub, just over the border from Hong Kong. They created a lab of 10 scientists to use a new analytic technique known as “chemical genomics” to examine the relationships between molecular structures of the existing and failed drugs, how they act on different targets in the body and what genes were being activated or repressed. Now they have more than 60 scientists.

By better predicting how chemicals would act on the body before entering human testing, they hoped they would be more likely get a drug to market.

“How can a small company compete with a multinational?” said Dr. Lu. “The only thing we can compete with is the scientific brain.”

The biggest challenges for the company have been financing and the Chinese regulatory system, said Dr. Lu. The company has raised a total of 300 million yuan ($48 million) over five rounds of venture funding, said Dr. Lu. Chipscreen also receives grant money from the Chinese government.

The company filed its application for approval of chidamide to the Chinese Food and Drug Administration, or CFDA, in early 2013. It had to wait nearly two years for approval, receiving the OK only in December.

Chidamide now is on the market in China for 26,500 yuan ($4,275) a month, a price far lower than patients in the U.S. pay for some of the newest cancer medicines but much more than the typical Chinese patient pays for drugs. Dr. Lu said the price reflects a balance between affordability for patients and return for shareholders. Some investors wanted to price the drug higher.

PAPER

Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment

De-Si Pan,^a Qian-Jiao Yang,^a Xin Fu,^a Song Shan,^a Jing-Zhong Zhu,^a Kun Zhang,^a Zhi-Bin Li,^a Zhi-Qiang Ning^a and Xian-Ping Lu*^a

Corresponding authors

^aShenzhen Chipscreen Biosciences Ltd., BIO-Incubator, Suit 2-601, Shenzhen Hi-Tech Industrial Park, Shenzhen, P. R. China
E-mail: xplu@chipscreen.com

Med. Chem. Commun., 2014,5, 1789-1796

DOI: 10.1039/C4MD00350K, http://pubs.rsc.org/en/content/articlelanding/2014/md/c4md00350k#!divAbstract

Tumorigenesis is maintained through a complex interplay of multiple cellular biological processes and is regulated to some extent by epigenetic control of gene expression. Targeting one signaling pathway or biological function in cancer treatment often results in compensatory modulation of others, such as off-target drivers of cell survival. As a result, overall survival of cancer patients is still far from satisfactory. Epigenetic-modulating agents can concurrently target multiple aberrant or compensatory signaling pathways found in cancer cells. However, existing epigenetic-modulating agents in cancer treatment have not yet fully translated into survival benefits beyond hematological tumors. In this article, we present a historical rationale for use of chidamide (CS055/Epidaza), an orally active and subtype-selective histone deacetylase (HDAC) inhibitor of the benzamide chemical class. This compound was discovered and successfully developed as mono-therapy for relapsed and refractory peripheral T cell lymphoma (PTCL) in China. We discuss the evidence supporting chidamide as a durable epigenetic modulator that allows cellular reprogramming with little cytotoxicity in cancer treatments.

Graphical abstract: Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment

CLIPS

Chinese scientists develop world’s 1st oral HDAC inhibitor

Lu Xianping works in a lab at Shenzhen Chipscreen Biosciences Ltd. in Shenzhen, south China’s Guangdong Province, May 20, 2015. Lu Xianping, together with other four returned overseas scientists, spent 14 years to develop Chidamide, the world’s first oral HDAC inhibitor, which was given regulatory approval in January. (Xinhua/Mao Siqian)

GNT Biotech and Medicals Corporation Licenses Novel Cancer Molecule from Shenzhen Chipscreen Biosciences Ltd.

PR Newswire

SHENZHEN, China, Oct. 10, 2013

SHENZHEN, China, Oct. 10, 2013 /PRNewswire/ — GNT Biotech and Medicals Corporation announces the grant of an exclusive license from Shenzhen Chipscreen Biosciences Ltd.for the development and commercialization of Chidamide in Taiwan. Chidamide, an oral, selective histone deacetylase (HDAC) inhibitor, is currently being evaluated in Phase II trials by Chipscreen Biosciences in Peripheral T-Cell Lymphoma (PTCL), Cutaneous T-Cell Lymphoma (CTCL) and Non-Small Cell Lung Cancer patients (NSCLC). GNTbm will develop and commercialize Chidamide primarily in PTCL, NSCLC and will also retain the rights to develop and commercialize Chidamide in other oncology indications in Taiwan.

About Chidamide

Chidamide is a selective HDAC inhibitor against subtype 1, 2, 3 and 10, and being studied in multiple clinical trials as a single agent or in combination with chemotherapeutic agents for the treatment of various hematological and solid cancers. Its anticancer effects are thought to be mediated through epigenetic modulation via multiple mechanisms of action, including the inhibition of cell proliferation and induction of apoptosis in blood derived cells, inhibition of epithelial to mesenchymal transition (EMT, a process that is highly relevant to tumor cell metastasis and drug resistance), induction of tumor specific antigen and antigen-specific T cell cytotoxicity, enhancement of NK cell anti-tumor activity, induction of cancer stem cell differentiation, and resensitization of tumor cells that have become resistant to anticancer agents such as platinums, taxanes and topoisomerase II inhibitors. Chidamide has demonstrated clinical efficacy in pivotal phase II trials on Cutaneous T-Cell Lymphoma (CTCL) and Peripheral T-Cell Lymphoma (PTCL) conducted in China, and is currently undergoing phase II trial in NSCLC together with first line PC therapeutic treatment. Due to its superior pharmacokinetic properties and selectivity, Chidamide may offer better clinical profile over the other HDAC inhibitors currently under development or being marketed.

About GNTbm

GNTbm is a subsidiary of GNT Inc, a Taiwanese company focused on the manufacture of nano-scale metallic particles for food and medical purposes. Founded in 1992 by a team of electronic professionals, GNT has successfully developed the innovative technology of physical metal miniaturization based on the patent of MBE (Molecular Beam Epitaxy). Further information about GNT Inc is available at www.gnt.com.tw.

GNTbm was established in August 2013, and housed in the Nankang Biotech Incubation Center, (NBIC), in Nankang, Taipei. Lead by Dr. Chia-Nan Chenalong with an experienced team of scientists, GNTbm will explore development and commercialization of novel drug delivery systems, Innovative biomedical and diagnostic tools based on gold nanoparticles.

About Shenzhen Chipscreen Biosciences Ltd.

Chipscreen is a leading integrated biotech company in China specialized in discovery and development of novel small molecule pharmaceuticals. The company has utilized its proprietary chemical genomics-based discovery platform to successfully develop a portfolio of clinical and preclinical stage programs in a number of therapeutic areas. Chipscreen’s business strategy is to generate differentiated drug candidates across multiple therapeutic areas. Drug candidates are either developed by Chipscreen or co-developed and commercialized in a partnership at the research, preclinical and clinical stages. The company was established as Sino-foreign joint venture in 2001. Further details about Chipscreen Bioscience is available atwww.chipscreen.com.

GNT Biotech and Medicals Corporation

Ekambaranellore Prakash, PhD

Director of International Department

GNT Biotech and Medicals Corporation

TEL: +886-2-7722-0388 #303

E-mail: prakash@gntbm.com.tw

Web site: www.gnt.com.tw

Shenzhen Chipscreen Biosciences Ltd.

Rebecca Hai

Investor Relations

Shenzhen Chipscreen Biosciences Ltd.

TEL: +86-755-26957317

E-mail: rebeccai_hai@chipscreen.com

Web site: www.chipscreen.com

SOURCE GNT Biotech and Medicals Corporation

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Chidamide
Systematic (IUPAC) name

N-(2-Amino-5-fluorophenyl)-4-[[[1-oxo-3-(3-pyridinyl)-2-propen-1-yl]amino]methyl]-benzamide
Clinical data
Trade names	Epidaza
Identifiers
CAS Number	743420-02-2
PubChem	CID 9800555
ChemSpider	7976319
UNII	87CIC980Y0
Chemical data
Formula	C₂₂H₁₉FN₄O₂
Molar mass	390.4 g/mol

Patent ID	Date	Patent Title
US2015299126	2015-10-22	CRYSTAL FORM OF CHIDAMIDE, PREPARATION METHOD AND USE THEREOF
US2010222379	2010-09-02	NOVEL HISTONE DEACETYLASE INHIBITORS
US7244751	2007-07-17	Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity

References

“China’s First Homegrown Pharma.”. April 2015.
^ Jump up to:^a ^b [1]
HUYA Bioscience International Grants An Exclusive License For HBI-8000 In Japan And Other Asian Countries To Eisai. Feb 2016
Qiao, Z (2013-04-26). “Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells.”. Biochem Biophys Res Commun. 434 (1): 95–101. doi:10.1016/j.bbrc.2013.03.059. PMID 23541946.
Guha, Malini (2015-04-01). “HDAC inhibitors still need a home run, despite recent approval”. Nature Reviews Drug Discovery 14: 225–226. doi:10.1038/nrd4583.
Wang, Shirley S. (2015-04-02). “A New Cancer Drug, Made in China”. The Wall Street Journal. Retrieved 13 April 2015.
References:
1. Ning, Z. Q.; et. al. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother Pharmacol2012, 69(4), 901-909. (activity)
2. Gong, K.; et. al. CS055 (Chidamide/HBI-8000), a novel histone deacetylase inhibitor, induces G1 arrest, ROS-dependent apoptosis and differentiation in human leukaemia cells. Biochem J 2012, 443(3), 735-746. (activity)

3. Hu, W.; et. al. N-(2-amino-5-fluorophenyl)-4-[N-(Pyridin-3-ylacryloyl) aminomethyl ]benzamide or other derivatives for treating cancer and psoriasis. US7244751B2
4. Lu, X.; et. al. Crystal form of chidamide, preparation method and use thereof. WO2014082354A1
5. Yin, Z.-H.; et. al. Synthesis of chidamide,a new histone deacetylase (HDAC) inhibitor. Chin J New Drugs 2004, 13(6), 536-538. (starts with basic raw materials)
Zhongguo Xinyao Zazhi (2004), 13(6), 536-538.

/////////Chidamide, Epidaza, CS055, HBI-8000, orally active subtype-selective HDAC inhibitor, epigenetic modulator, cancer treatment

Fc3ccc(NC(=O)c1ccc(cc1)CNC(=O)/C=C/c2cccnc2)c(N)c3

Selectbio’s 4th International conference on Drug Discovery India 2016, 29-30 Sept 2016, Bengaluru, India

Uncategorized Comments Off

Jun 292016

Drug Discovery India 2016

Selectbio’s Drug Discovery India 2016, 29 – 30 September 2016, Bengaluru, India

see

https://selectbiosciences.com/conferences/index.aspx?conf=DDI16&se=india

Overview

SELECTBIO is delighted to announce its 4^th International Drug Discovery India 2016 Conference and Exhibition. This conference will be held in Le Méridien Bangalore Hotel, Bengaluru on September 29-30, 2016. The theme of the conference is “Deriving Best Out of Chemistry, Biotechnology and Natural Products“.

The event aims to expand knowledge by providing insights into the latest developments and innovations in the field of drug discovery, medicinal chemistry, natural products and chemical biology. Every year this event bring together about 200 drug discovery scientists together at a platform to discuss and share drug discovery related research and facilitates collaborations amongst scientists from across the globe.

This meeting will be co-located with our 2^nd International Conference Antibodies and Antibody Drug Conjugates. Registered delegates will have unrestricted access to all co-located meetings ensuring a comprehensive learning and sharing experience as well as being financially beneficial for attendees.

Running alongside the Drug Discovery India 2016 conference will be an Exhibition covering the latest technological advances within these fields. We look forward to welcoming you at the Drug Discovery India 2016 Conference and Exhibition and hope that the two days will be both informative and enjoyable.

Who Should Attend

Drug Discovery Scientists, Medicinal Chemists, Biotechnologists & Researchers from Pharmaceutical Industry R&D and Academic institutions working in the area of New Drug Discovery Research, Discovery and Development of New Chemical entities, Biomolecular Screening Technologies, Drug Target Identification, Structure-based and Target-based, Drug Design, Protein-Protein Interactions, Drug Repurposing, Orphan Drugs, Chemical Biology, Stem Cell, Epigenetics as well as Natural Products.

Conference Chair

Dr. Rathnam Chaguturu

Dr Rathnam Chaguturu
Founder & CEO, iDDPartners

Dr. Sanjay Bajaj, Ph.D.

Managing Director

Unit 21, Level 2, Berkeley Square, Plot 24,

Industrial Area Phase I, Chandigarh 160002, India

Phone: +91 172 5025050, M: +91 9814412082

Email: s.bajaj@selectbio.com; Website: www.selectbiosciences.com; www.selectbioindia.net

Upcoming Events in India

Show Calender 2016

3for2_emailsig .

https://selectbiosciences.com/conferences/index.aspx?conf=DDI16&se=india

//////////Sanjay Bajaj, Selectbio, Drug Discovery India 2016, 29 – 30 September 2016, Bengaluru, India

Copper(I)/N-Heterocyclic Carbene (NHC)-Catalyzed Addition of Terminal Alkynes to Trifluoromethyl Ketones for Use in Continuous Reactors.

flow synthesis Comments Off

Jun 272016

Thumbnail image of graphical abstract

A copper(I)/N-heterocyclic carbene complex-catalyzed addition of terminal alkynes to trifluoromethyl ketones at low loading is described. The developed process functions well using a range of terminal alkynes but functions best when an aryl trifluoromethyl ketone is used. This substrate scope is well-suited for the production of active pharmaceutical ingredients (APIs) such as efavirenz. In this vein, we demonstrate that the described method can be translated into a flow process laying the framework for a completely continuous synthesis of efavirenz in the future.

Advanced Synthesis & Catalysis

Volume 355, Issue 18, pages 3517–3521, December 16, 2013

Adv. Synth. Catal. 2013, 355, 3517−3521.

Copper(I)/N-Heterocyclic Carbene (NHC)-Catalyzed Addition of Terminal Alkynes to Trifluoromethyl Ketones for Use in Continuous Reactors

Camille A. Correia¹,
D. Tyler McQuade^1,3,* and
Peter H. Seeberger^1,2

DOI: 10.1002/adsc.201300802, http://onlinelibrary.wiley.com/doi/10.1002/adsc.201300802/abstract

Correia, C. A., McQuade, D. T. and Seeberger, P. H. (2013), Copper(I)/N-Heterocyclic Carbene (NHC)-Catalyzed Addition of Terminal Alkynes to Trifluoromethyl Ketones for Use in Continuous Reactors. Adv. Synth. Catal., 355: 3517–3521. doi: 10.1002/adsc.201300802

Author Information

1Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany
2Institute for Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany
3Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, USA

Email: D. Tyler McQuade (tyler.mcquade@mpikg.mpg.de; mcquade@chem.fsu.edu)

^*Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany

/////////

タバルマブ（遺伝子組換え) Tabalumab

MONOCLONAL ANTIBODIES, Uncategorized Comments Off

Jun 272016

Tabalumab

タバルマブ（遺伝子組換え)
Tabalumab (Genetical Recombination)

[1143503-67-6]

Tabalumab (LY 2127399) is an anti-B-cell activating factor (BAFF) human monoclonal antibody designed for the treatment of autoimmune diseases and B cell malignancies.^[1]^[2] Tabalumab was developed by Eli Lilly and Company.

A phase III clinical trial for rheumatoid arthritis was halted in Feb 2013.^[3] In September 2014, a second phase III trial focussing on treating systemic lupus erythematosus, was terminated early as the study failed to meet its primary endpoint.^[4]

References

abalumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	BAFF
Identifiers
CAS Number	1143503-67-6
ATC code	none
ChemSpider	none
Chemical data
Formula	C₆₅₁₈H₁₀₀₀₈N₁₇₂₄O₂₀₃₂S₃₈
Molar mass	146.25 kg/mol

////////////タバルマブ , 遺伝子組換え, Tabalumab, 1143503-67-6, antibody, Monoclonal antibody

Review, Continuous Processing

PROCESS, spectroscopy, SYNTHESIS, Uncategorized Comments Off

Jun 272016

Continuous Processing

Continuous production is a flow production method used to manufacture, produce, or process materials without interruption. Continuous production is called a continuous process or a continuous flow process because the materials, either dry bulk or fluids that are being processed are continuously in motion, undergoing chemical reactions or subject to mechanical or heat treatment. Continuous processing is contrasted with batch production.

Continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. Some chemical plants can operate for more than one or two years without a shutdown. Blast furnaces can run four to ten years without stopping.^[1]

Production workers in continuous production commonly work in rotating shifts.

Processes are operated continuously for practical as well as economic reasons. Most of these industries are very capital intensive and the management is therefore very concerned about lost operating time.

Shutting down and starting up many continuous processes typically results in off quality product that must be reprocessed or disposed of. Many tanks, vessels and pipes cannot be left full of materials because of unwanted chemical reactions, settling of suspended materials or crystallization or hardening of materials. Also, cycling temperatures and pressures from starting up and shutting down certain processes (line kilns, boilers, blast furnaces, pressure vessels, etc.) may cause metal fatigue or other wear from pressure or thermal cycling.

In the more complex operations there are sequential shut down and start up procedures that must be carefully followed in order to protect personnel and equipment. Typically a start up or shut down will take several hours.

Continuous processes use process control to automate and control operational variables such as flow rates, tank levels, pressures, temperatures and machine speeds.^[2]

Semi-continuous processes

Many processes such as assembly lines and light manufacturing that can be easily shut down and restarted are today considered semi-continuous. These can be operated for one or two shifts if necessary.

History

The oldest continuous flow processes is the blast furnace for producing pig iron. The blast furnace is intermittently charged with ore, fuel and flux and intermittently tapped for molten pig iron and slag; however, the chemical reaction of reducing the iron and silicon and later oxidizing the silicon is continuous.

Semi-continuous processes, such as machine manufacturing of cigarettes, were called “continuous” when they appeared.

Many truly continuous processes of today were originally batch operations.

The Fourdrinier paper machine, patented in 1799, was one of the earliest of the industrial revolution era continuous manufacturing processes. It produced a continuous web of paper that was formed, pressed, dried and reeled up in a roll. Previously paper had been made in individual sheets.

Another early continuous processes was Oliver Evans‘es flour mill (ca. 1785), which was fully automated.

Early chemical production and oil refining was done in batches until process control was sufficiently developed to allow remote control and automation for continuous processing. Processes began to operate continuously during the 19th century. By the early 20th century continuous processes were common.

Shut-downs

In addition to performing maintenance, shut downs are also when process modifications are performed. These include installing new equipment in the main process flow or tying-in or making provisions to tie-in sub-processes or equipment that can be installed while the process is operating.

Shut-downs of complicated processes may take weeks or months of planning. Typically a series of meetings takes place for co-ordination and planning. These typically involve the various departments such as maintenance, power, engineering, safety and operating units.

All work is done according to a carefully sequenced schedule that incorporates the various trades involved, such as pipe-fitters, millwrights, mechanics, laborers, etc., and the necessary equipment (cranes, mobile equipment, air compressors, welding machines, scaffolding, etc.) and all supplies (spare parts, steel, pipe, wiring, nuts and bolts) and provisions for power in case power will also be off as part of the outage. Often one or more outside contractors perform some of the work, especially if new equipment is installed.

Safety

Safety meetings are typically held before and during shutdowns. Other safety measures include providing adequate ventilation to hot areas or areas where oxygen may become depleted or toxic gases may be present and checking vessels and other enclosed areas for adequate levels of oxygen and insure absence of toxic or explosive gases. Any machines that are going to be worked on must be electrically disconnected, usually through the motor starter, so that it cannot operate. It is common practice to put a padlock on the motor starter, which can only be unlocked by the person or persons who is or are endangered by performing the work. Other disconnect means include removing couplings between the motor and the equipment or by using mechanical means to keep the equipment from moving. Valves on pipes connected to vessels that workers will enter are chained and locked closed, unless some other means is taken to insure that nothing will come through the pipes.

Continuous processor (equipment)

Continuous Production can be supplemented using a Continuous Processor. Continuous Processors are designed to mix viscous products on a continuous basis by utilizing a combination of mixing and conveying action. The Paddles within the mixing chamber (barrel) are mounted on two co-rotating shafts that are responsible for mixing the material. The barrels and paddles are contoured in such a way that the paddles create a self-wiping action between themselves minimizing buildup of product except for the normal operating clearances of the moving parts. Barrels may also be heated or cooled to optimize the mixing cycle. Unlike an extruder, the Continuous Processor void volume mixing area is consistent the entire length of the barrel ensuring better mixing and little to no pressure build up. The Continuous Processor works by metering powders, granules, liquids, etc. into the mixing chamber of the machine. Several variables allow the Continuous Processor to be versatile for a wide variety of mixing operations:^[3]

Barrel Temperature
Agitator speed
Fed rate, accuracy of feed
Retention time (function of feed rate and volume of product within mixing chamber)

Continuous Processors are used in the following processes:

Compounding
Mixing
Kneading
Shearing
Crystallizing
Encapsulating

The Continuous Processor has an unlimited material mixing capabilities but, it has proven its ability to mix:

Plastics
Adhesives
Pigments
Composites
Candy
Gum
Paste
Toners
Peanut Butter
Waste Products

EXAMPLE…………….

In the development of a new route to bendamustine hydrochloride, the API in Treanda, the key benzimidazole intermediate 5 was generated via catalytic heterogeneous hydrogenation of an aromatic nitro compound using a batch reactor. Because of safety concerns and a site limitation on hydrogenation at scale, a continuous flow hydrogenation for the reaction was investigated at lab scale using the commercially available H-Cube. The process was then scaled successfully, generating kilogram quantities on the H-Cube Midi. This flow process eliminated the safety concerns about the use of hydrogen gas and pyrophoric catalysts and also showed 1200-fold increase in space–time yield versus the batch processing.

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

Org. Process Res. Dev., 2014, 18 (11), pp 1427–1433

DOI: 10.1021/op400179f, http://pubs.acs.org/doi/full/10.1021/op400179f

EXAMPLE…………….

Correia et al. have published a three-step flow synthesis of rac-Effavirenz. This short synthetic route begins with cryogenic trifluoroacetylation of 1,4-dichlorobenzene. After quench and removal of morpholine using silica gel, this intermediate could either be isolated, or the product stream could be used directly in the next alkynylation step. Nucleophilic addition of lithium cyclopropylacetylide to the trifluoroacetate gave the propargyl alcohol intermediate in 90% yield in under 2 min residence time. This reaction was temperature-sensitive, and low temperatures were required to minimize decomposition. Again silica gel proved effective in the quench of the reaction. However, residual alkyne and other byproducts were difficult to remove. Thus, isolation of this intermediate was performed to minimize the impact of impurities on the final copper catalyzed cyanate installation/cyclization step to afford Effavirenz. Optimization of this step in batch mode for both copper source and ligand identified Cu(NO₃)₂ and CyDMEDA in a 1:4 molar ratio (20 mol % and 80 mol %, respectively) produced the product in 60% yield. Adaptation of this procedure to flow conditions resulted in poor conversion due to slow in situ reduction of the Cu(II) to Cu(I). Thus, a packed bed reactor of NaOCN and Cu(0) was used. Under these conditions, the ligand and catalyst loading could be reduced without compromising yield. Due to solubility limitations of Cu(NO₃)₂, Cu(OTf)₂ was used with CyDMEDA in 1:2 molar ratio (5 mol % and 10 mol % loading, respectively). Under these optimized conditions, rac-Effavirenz was obtained in 62% isolated yield in reaction time of 1 h. This three-step process provides 45% overall yield of rac-Effavirenz and represents the shortest synthesis of this HIV drug reported to date

1H NMR (400 MHz, CDCl3, ppm) δ9.45 (s, 1H), 7.49 (s, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 1.43-1.36 (m, 1H); 0.93-0.85 (m, 4H);

13C NMR (100 MHz, CDCl3, ppm) δ 149.2, 133.2, 131.7, 129.2, 127.8, 122.1 (q, JC-F = 286 Hz), 116.3, 115.1, 95.9, 79.6 (q, JC-F = 35 Hz), 66.1, 8.8, 0.6;

19F NMR (376 MHz, CDCl3, ppm) δ -80.98.

1 T. J. Connolly; A. W.-Y Chan; Z. Ding; M. R. Ghosh; X. Shi; J. Ren, E. Hansen; R. Farr; M. MacEwan; A. Alimardanov; et al, PCT Int. Appl. WO 2009012201 A2 20090122, 2009.

2 (a) Z. Dai, X. Long, B. Luo, A. Kulesza, J. Reichwagen, Y. Guo, (Lonza Ltd), PCT Int. Appl. WO2012097510, 2012; (b) D. D. Christ; J. A. Markwalder; J. M. Fortunak; S. S. Ko; A. E. Mutlib; R. L. Parsons; M. Patel; S. P. Seitz, PCT Int. Appl. WO 9814436 A1 19980409, 1998 (c) C. A. Correia; D. T. McQuade; P. H. Seeberger, Adv. Synth. Catal. 2013, 355, 3517−3521.

A Concise Flow Synthesis of Efavirenz^†

DOI: 10.1002/anie.201411728

http://onlinelibrary.wiley.com/doi/10.1002/anie.201411728/abstract

SUPP INFO

http://onlinelibrary.wiley.com/store/10.1002/anie.201411728/asset/supinfo/anie_201411728_sm_miscellaneous_information.pdf?v=1&s=e1b253efab4a6f4cd5bd245694623e2459700ff5

NEXT EXAMPLE…………….

Wang et al. developed a flow process that uses metal catalyzed hydrogenation of NAB (2-nitro-2′-hydroxy-5′-methylazobenzene) to BTA (2-(2′-hydroxy-5′-methylphenyl)benzotriazole), a commonly used ultraviolet absorber. The major challenge in this process was to optimize the reduction of the diazo functionality over the nitro group and control formation of over reduction side products. The initial screen of metals adsorbed onto a γ-Al₂O₃ support indicated Pd to be superior to the other metals and also confirmed that catalyst preparation plays an important role in selectivity. To better understand the characteristics of the supported metal catalyst systems, the best performing were analyzed by TEM, XRD, H₂-TPR, and N₂ adsorption–desorption. Finally, solvents and bases were screened ultimately arriving at the optimized conditions using toluene, 2 equiv n-butylamine over 1% Pd/Al₂O₃, which provided 90% yield BTA in process with 98% conversion. The process can run over 200 h without a decrease in performance

( ACS Sustainable Chem. Eng. 2015, 3,1890−1896)

The synthesis of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole from 2-nitro-2′-hydroxy-5′-methylazobenzene over Pd/γ-Al₂O₃ in a fixed-bed reactor was investigated. Pd/γ-Al₂O₃ catalysts were prepared by two methods and characterized by XRD, TEM, H₂-TPR, and N₂ adsorption–desorption. Employed in the above reaction, the palladium catalyst impregnated in hydrochloric acid exhibited much better catalytic performance than that impregnated in ammonia–water, which was possibly attributed to the better dispersion of palladium crystals on γ-Al₂O₃. This result demonstrated that the preparation process of the catalyst was very important. Furthermore, the reaction parameters were optimized. Under the optimized conditions (toluene, NAB/triethylamine molar ratio 1:2, 60 °C, 2.5 MPa hydrogen pressure, 0.23 h^–1 liquid hourly space velocity), about 90% yield of 2-(2′-hydroxy-5′-methylphenyl)benzotriazole was obtained. Finally, the time on stream performance of the catalyst was evaluated, and the reaction could proceed effectively over 200 h without deactivation of the catalyst.

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al₂O₃ by a Continuous Process

ACS Sustainable Chem. Eng., 2015, 3 (8), pp 1890–1896

DOI: 10.1021/acssuschemeng.5b00507

Publication Date (Web): July 06, 2015

http://pubs.acs.org/doi/abs/10.1021/acssuschemeng.5b00507

NEXT EXAMPLE…………….

Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

continuous flow processing of organometallic reagents

A new enabling technology for the pumping of organometallic reagents such as n-butyllithium, Grignard reagents, and DIBAL-H is reported, which utilises a newly developed, chemically resistant, peristaltic pumping system. Several representative examples of its use in common transformations using these reagents, including metal–halogen exchange, addition, addition–elimination, conjugate addition, and partial reduction, are reported along with examples of telescoping of the anionic reaction products. This platform allows for truly continuous pumping of these highly reactive substances (and examples are demonstrated over periods of several hours) to generate multigram quantities of products. This work culminates in an approach to the telescoped synthesis of (E/Z)-tamoxifen using continuous-flow organometallic reagent-mediated transformations.

https://www.vapourtec.com/flow-chemistry-resource-centre/publications-citing-vapourtec/continuous-flow-processing-of-organometallic-reagents-using-an-advanced-peristaltic-pumping-system-and-the-telescoped-flow-synthesis-of-ez-tamoxifen/

NEXT EXAMPLE…………….

Multi-step Continuous Flow Pyrazole Synthesis via a Metal-free Amine-redox Process

A versatile multi-step continuous flow synthesis for the preparation of substituted pyrazoles is presented.

The automated synthesis utilises a metal-free ascorbic acid mediated reduction of diazonium salts prepared from aniline starting materials followed by hydrolysis of the intermediate hydazide and cyclo-condensation with various 1,3-dicarbonyl equivalents to afford good yields of isolated functionalised pyrazole products.

The synthesis of the COX-2 selective NSAID was demonstrated using this approach.

J.-S. Poh, D. L. Browne, S. V. Ley, React. Chem. Eng., 2016, DOI: 10.1039/C5RE00082C

NEXT EXAMPLE…………….

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

Continuous flow methodologyhas been used to enhance several steps in the synthesis of a precursor to Sacubitril.

In particular, a key carboethoxyallylation benefited from a reducedprocessing time and improved reproducibility, the latter attributable toavoiding the use of a slurry as in the batch procedure. Moreover, in batchexothermic formation of the organozinc species resulted in the formation ofside products, whereas this could be avoided in flow because heat dissipationfrom a narrow packed column of zinc was more efficient

S.-H. Lau, S. L. Bourne, B. Martin, B. Schenkel, G. Penn, S. V. Ley, Org. Lett., 2015, 17 (21), pp 5436–5439

NEXT EXAMPLE…………….

RAFT RAFT (Reversible Addition Fragmentation chain Transfer), a type of controlled radical polymerization, was invented by CSIRO in 1998 but developed in partnership with DuPont over a long term collaboration. Conventional polymerisation is fast but gives a wide distribution of polymer chain lengths. (known as a high polydispersity index ). RAFT is more versatile than other living polymerization techniques, such as atom transfer radical polymerization (ATRP) or nitroxide-mediated polymerization (NMP), it not only leads to polymers with a low polydispersity index and a predetermined molecular weight, but it permits the creation of complex architectures, such as linear block copolymers, comblike, star, brush polymers and dendrimers. Monomers capable of polymerizing by RAFT include styrenes, acrylates, acrylamides, and many vinyl monomers. CSIRO is the owner of the RAFT patents and is actively commercialising the technology. There are 12 licences in force and CSIRO is pursuing interest in a number of fields including human health, agriculture, animal health and personal care. RAFT is the dominant polymerization technique for the creation of polymer-protein or polymer-drug conjugates, permitting (for example) the combination of a polymer exhibiting high solubility with a drug molecule with poor solubility.. Though RAFT can be carried out in batch, it also lends itself to continuous flow processing, as this processing method offers an easy and reproducible scale-up route of the oxygen sensitive RAFT process. The possibility to effectively exclude oxygen using continuous flow reactors in combination with inline degassing methods offers advantages over batch processing at scales beyond the laboratory environment. Challenges associated with the high viscosity of the polymer product solution can be controlled using pressuriseable continuous flow reactor systems. http://www.csiro.au/products/RAFT.html

Examples………..

Cyclohexaneperoxycarboxylic acid (6, has been developed as a safe, inexpensive oxidant, with demonstrated utility in a Baeyer−Villiger rearrangement.³⁴ Solutions of cyclohexanecarboxylic acid in hexane and 50% aqueous H₂O₂ were continuously added to 45% H₂SO₄ at 50−70 °C and slightly reduced pressure. The byproduct H₂O was removed azeotropically, and the residence time in the reactor was 3 h. Processing was adjusted to maintain a concentration of 6 at 17−19%, below the detonable level, and the product was kept as a stable solution in hexane. These operations enhanced the safety margin in preparing 6.

Scheme . Generation of cyclohexaneperoxycarboxylic acid

Examples………..

The conversion of a batch process to continuous (flow) operation has been investigated. The manufacture of 4,d-erythronolactone at kilogram scale was used as an example. Fully continuousprocessing was found to be impracticable with the available plant because of the difficulty in carrying out a multiphase isolation step continuously, so hybrid batch–continuous options were explored. It was found that very little additional laboratory or process safety work other than that required for the batch process was required to develop the hybrid process. A hybrid process was chosen because of the difficulty caused by the precipitation of solid byproduct during the isolation stage. While the project was a technical success, the performance benefits of the hybrid process over the batch were not seen as commercially significant for this system.

Multikilogram Synthesis of 4-d-Erythronolactone via Batch andContinuous Processing

Org. Process Res. Dev., 2012, 16 (5), pp 1003–1012

DOI: 10.1021/op200352k, http://pubs.acs.org/doi/full/10.1021/op200352k

Examples………..

Abstract Image

Continuous Biocatalytic Processes

Org. Process Res. Dev., 2009, 13 (3), pp 607–616

DOI: 10.1021/op800314f, http://pubs.acs.org/doi/full/10.1021/op800314f

Scheme . Biotransformation of sodium l-glutamate to γ-aminobutyric acid (GABA) by single-step α-decarboxylation with glutamate decarboxylase

PICS…………..

References

American Iron and Steel Institute
Benett, Stuart (1986). A History of Control Engineering 1800-1930. Institution of Engineering and Technology. ISBN 978-0-86341-047-5.
Ziegler, Gregory R.; Aguilar, Carlos A. (2003). “Residence Time Distribution in a Co-rotating, Twin-screw Continuous Mixer by the Step Change Method”. Journal of Food Engineering(Elsevier) 59 (2-3): 1–7.

Sources and further reading

R H Perry, C H Chilton, C W Green (Ed), Perry’s Chemical Engineers’ Handbook (7th Ed), McGraw-Hill (1997), ISBN 978-0-07-049841-9
Major industries typically each have one or more trade magazines that constantly feature articles about plant operations, new equipment and processes and operating and maintenance tips. Trade magazines are one of the best ways to keep informed of state of the art developments.

/////////////

A Review on the Applications of Self Regenerating Catalysts

SYNTHESIS Comments Off

Jun 272016

Page Header

A Review on the Applications of Self Regenerating Catalysts

Ronak Upadhyay, Shaaz Khatib, Atmin Parekh\

http://www.bombaytechnologist.org/index.php/bt/article/view/59

Abstract

Metallic catalysts have a tendency to lose their activity over time due to various reasons such as change in oxidation state of the metal, deposition of material on the catalyst or structural rearrangement of the catalysts. Metallic catalysts (such as Pt based catalysts) are often rare and expensive. Therefore, there is currently an interest in developing self-regenerating catalysts which independently recover their activity after deactivation without human intervention and which thus have a high turnover number. Our aim is to review the applications of these catalysts and study their mechanism of regeneration in various systems. Perovskites based catalyst systems have shown indication that they can be used instead of the conventional catalyst used in the automobiles to treat exhaust gases, in a cost effective manner. A modification of the crystallographic structure has enhanced the regenerative ability of cobalt nanoparticles, have found application in the Fischer Tropsch Synthesis. Self-healing non precious metal-based catalyst provides an economic alternative in hydrogen production by water splitting with sunlight as the main energy source. Palladium based self-healing catalysts are used in CO detection devices. ‘Kearby’ Catalyst, a self-regenerating catalyst used in the preparation of the vinyl monomers via catalytic dehydrogenation.

more……….

////////////self-regenerating, Perovskites, Kearby catalyst, Fischer Tropsch Synthesis, CO detection, Vinyl monomers

WO 2016092561, Ivacaftor, New patent, Laurus Labs Pvt Ltd

PATENTS Comments Off

Jun 272016

WO-2016092561, Ivacaftor, NEW PATENT

https://www.google.com/patents/WO2016092561A2?cl=en

Novel polymorphs of ivacaftor, process for its preparation and pharmaceutical composition thereof

Laurus Labs Pvt Ltd

LAURUS LABS PRIVATE LIMITED [IN/IN]; Plot No. DS1, IKP Knowledge Park, Genome Valley Turkapally, Shameerpet Mandal, Ranga District Hyderabad 500078 (IN)

Ram Thaimattam, Venkata Srinivasa Rao DAMA, Venkata Sunil Kumar Indukuri, Seeta Rama Anjaneyulu GORANTLA,Satyanarayana Chava,
Applicant	Laurus Labs Private Limited

THAIMATTAM, Ram; (IN).
DAMA, Venkata Srinivasa Rao; (IN).
INDUKURI, Venkata Sunil Kumar; (IN).
GORANTLA, Seeta Rama Anjaneyulu; (IN).
CHAVA, Satyanarayana; (IN)

Novel crystalline forms of ivacaftor (designated as forms L1 to L14), processes for their preparation and composition comprising them are claimed.

Vertex, in research collaboration with Cystic Fibrosis Foundation Therapeutics, had developed and launched ivacaftor.

Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula I:

Formula I

Ivacaftor was approved by FDA and marketed by Vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO^® in the form of 150 mg oral tablets.

WO2006/002421 publication discloses modulators of ATP-binding cassette transporters such as ivacaftor. This patent generally discloses a process for the preparation of modulators of ATP-binding cassette transporters such as quinoline compounds; however, specific process for the preparation of ivacaftor and its solid state details were not specifically disclosed.

WO2007/079139 publication discloses Form A, Form B and amorphous form of ivacaftor characterized by PXRD, DSC and TGA and process for their preparation. Further this publication discloses ethanol crystalate of ivacaftor in example part.

WO2009/038683 publication discloses the solid forms of ivacaftor, which are designated as Form-I (2-methylbutyric acid), Form-II (propylene glycol), Form-HI (PEG400.KOAc), Form-IV (lactic acid), Form-V (isobutyric acid), Form-VI (propionic

acid), Form- VII (ethanol), Form- VIII (2-propanol), Form-IX (monohydrate), Form-X (besylate Form A), Form-XI (besylate Form B), Form-XII (besylate Form D), Form-XIII (besylate Form E), Form-XIV (besylate Form F), Form-XV (besylate (2: 1)), Form-XVI (besylate mono hydrate). This publication also discloses the characterization details like PXRD, DSC and TGA for the above forms and process for their preparation.

WO201 1/1 16397 publication discloses crystalline Form C of ivacaftor, process for its preparation and pharmaceutical composition comprising the same. Also discloses characterization details of Form C, such as PXRD, IR, DSC and ¹³CSSNMR.

WO2013/158121 publication discloses solvated forms of ivacaftor, which are designated as Form D (acetonitrile or acetonitrile/water (75/25) solvate), Form E (Methyl ethyl ketone (MEK), MEK/water (90/1), MEK/water (90/10), MEK/water (80/20) solvate), Form F (acetonitrile/water (75/25) solvate), Form G (isopropyl acetate solvate), Form H (isopropyl acetate/water (95/5) solvate), Form I (MEK solvate), Form J (MEK/water (99/1) solvate), Form K (MEK or MEK/water (99/1) or MEK/water (90/10) or MEK/water (80/20) solvate), Form L (isopropyl acetate/water (95/5) solvate), Form M (MEK or MEK/water (99/1) solvate), Form N (MEK water (90/10) or MEK/water (80/20) solvate), Form O (MEK or MEK/water (99/1) solvate), Form P (MEK water (90/10) or MEK water (80/20) solvate), Form Q (MEK/water (80/20) solvate), Form R (acetonitrile solvate), Form S (MEK/water (80/20) solvate), Form T (isopropyl acetate/water (95/5) solvate), Form W (acetonitrile/water (90/10) solvate), Form XX (from 10% water/ acetonitrile) and hydrate B (hydrated form). This patent further discloses characterization details like PXRD and TGA for the above forms and process for their preparation.

WO2014/118805 publication discloses crystalline forms of ivacaftor designated as Form D, Form E, Form El, Form G and Form G’; amorphous ivacaftor designated as Form I and Form II; crystalline ivacaftor solvates such as n-butanol solvate, methanol solvate, propylene glycol solvate, DMF solvate, THF solvate, DMF:ethylacetate solvate. This publication further discloses the process for the preparation of said forms along with their characterization details.

WO2015/070336 publication discloses polymorphic form APO-I and MIBK solvate of ivacaftor along with its characteristic PXRD details, process for its preparation and pharmaceutical composition comprising them.

CN 104725314A publication discloses ivacaftor new polymorph D, which is obtained by crystallization of ivacaftor from acetonitrile/water. This publication further discloses characteristic details such PXRD, IR and DSC of ivacaftor new polymorph D.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.

Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound, like ivacaftor, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. New polymorphic forms of the ivacaftor have now been discovered and have been designated as ivacaftor Form-Ll, Form-L2, Form-L3, Form-L4, Form-L5, Form-L6, Form-L7, Form-L8, Form-L9, Form-LlO, Form-Ll 1, Form-Ll 2 A, Form-Ll 2B, Form-Ll 3 and Form-Ll 4.

EXAMPLE 1 : Preparation of Ivacaftor Form-Ll

A suspension of ivacaftor ethanolate (5 g) in n-heptane (200 mL) was heated to 95-100°C and stirred for 5 hrs at the same temperature. Then the reaction mixture was cooled to 25-35°C and stirred for an hour. The solid obtained was filtered, washed with n-heptane and suck dried. The wet solid was further dried at 60-65°C for 16 hrs under vacuum yielded ivacaftor Form-Ll . The XRPD is set forth in Figure- 1.

In a similar manner, ivacaftor Form-Ll was prepared from different solvates of ivacaftor in place of ivacaftor ethanolate as input using the following conditions;

Ivacaftor cyclopentyl methyl ether (0.5 g) n-heptane (20 mL) 50°C/8 hr

Ivacaftor methyltertiarybutyl ether (0.5 g) n-heptane (20 mL) 50°C/8 hr

Laurus Labs: A hot startup in the pharma sector

Dr Satyanarayana Chava

Chief executive officer (CEO)

Laurus Labs Private Limited

When Dr Satyanarayana Chava started Laurus Labs in 2007, he invested nearly Rs 60 crore of his own money into it. His confidence in its success was neither bravado nor bluster, but defined by his knowledge of the pharmaceutical industry. Eight years on, the Hyderabad-based company is on track to reach revenues of Rs 2,000 crore by the end of FY2016.

Chava, now 52, has more than two decades of experience in the pharmaceutical industry; in his last job, he was chief operating officer (COO) of the successful startup, Matrix Laboratories. Of his 10 years there, he says with pride, “I never skipped a promotion and got to work in all departments.” His dedication, coupled with a sound understanding of what it takes to start a pharmaceutical company, is what makes Laurus Labs among the hottest startups in this sector.

Initially, Chava planned the business around research and development (R&D). He wanted Laurus Labs to focus on contract research and make money from royalties. “In India, companies start with manufacturing and then get into R&D,” he explains. “I did it the other way round.” He focussed his fledgling company’s resources on developing formulations for medicines, and licensed them to other pharmaceutical players. In the early months, Laurus Labs had 10 people in manufacturing and 300 in R&D.

In June 2007, Aptuit, a US-based contract research organisation (CRO), signed it on for a $20 million (then Rs 80 crore) contract. But despite this injection of funds, Chava was unable to sustain his original idea of developing technologies for other companies. At the time of the Aptuit deal, Laurus Labs’s annual revenues were not even $20,000 (Rs 8 lakh at the time). In 2008, Chava decided to start manufacturing active pharmaceutical ingredients (API), which, as the name suggests, are chemicals or key ingredients in drugs required to make the medication work. His early investment into R&D benefitted Laurus Labs; it maintains a large repository of research-based knowledge that forms the bedrock of any successful pharmaceutical business.

Today, it is a key manufacturer supplier of APIs and holds its own against better-known competitors like US generic drug giant Mylan, which, incidentally, acquired a controlling stake in Matrix around the time Chava founded Laurus Labs. It has also carved a niche for itself by supplying antiretroviral or ARVs (used to fight infections caused by retroviruses like HIV) and oncology drugs. And despite being a relatively new player, its clients include giants like Pfizer, Teva Pharmaceutical Industries and Merck.

The person behind it
A Master’s degree in chemistry was never on the cards for Chava. In the early 1980s, the best students usually studied physics, and he had planned to do the same. But when he went to his college in Amravati (Andhra Pradesh) to enroll, his elder sister’s friend suggested he study chemistry too. Chava took up the subject on a whim. He ended up liking chemistry so much so that in his final year he topped his batch despite not having written one out of the four required papers. He went on to complete his PhD in the subject in 1991.

Upon graduating, he was hired by Ranbaxy Laboratories in Delhi as a researcher. In those early years itself Chava knew he’d spend a lifetime in the industry. He enjoyed the work and gained valuable experience as a young researcher in what was then India’s finest pharmaceutical company.

But through his years in the industry, Chava was conscious of the fact that he needed to broaden his experience outside of research. His stint at Matrix Laboratories afforded him that opportunity. As it was a startup, he was able to rise through the ranks quickly and got the opportunity to work in key departments from sales and marketing to finance and accounts. Within eight years of joining Matrix, he became its COO.

This experience was to come in handy when, due to differences with the board—he refused to elaborate on this—he decided to leave Matrix and set up Laurus Labs. And though he is the company’s chief executive officer (CEO), Chava remains true to his calling as a chemist. He has strived to build an organisation that is not very hierarchical. It is not uncommon to see him interacting with the chemists in the company and discussing formulations with them—something unheard of in an industry where most CEOs are from a sales and marketing background.

Chandrakanth Chereddi

VP Synthesis Business Unit

Prior to his current assignment at Laurus Labs India, Chandra headed the Project Management division for all scientific projects at the Laurus R&D center. Chandra previously worked for McKinsey & Company in India as a member of the healthcare practice and at Google Inc. as a software engineer in Google’s Mountain View, CA office. Chandra holds a BE from the College of Engineering, Osmania University, Hyderabad, and MS from University of Illinois at Urbana-Champaign, and an MBA from Indian School of Business, Hyderabad.

///////WO 2016092561, Ivacaftor, New patent, Laurus Labs Pvt Ltd

EP 03031800, New patent, Miglustat, Navinta LLC

PATENTS, Uncategorized Comments Off

Jun 272016

MIGLUSTAT

Gauchers disease type I; Niemann Pick disease type C

EP-03031800, Process for the preparation of high purity miglustat

Navinta, LLC ; Shah, Shrenik K. ; Kharatkar, Raju Mahadev ; Bhatt, Chiragkumar Anilkumar ; Kevat, Jitendra Bhagwandas

The present invention provides a process for the preparation and isolation of crystalline miglustat without the use of a column chromatography or ion exchange purification. The crystalline miglustat has a high purity and a melting point of 128 °C and an endothermic peak is 133 °C.

Process for preparing and isolating crystalline form of miglustat with a high purity is claimed. Represents a first PCT filing from the inventors on miglustat. Actelion, under license from Oxford GlycoSciences (OGS; then Celltech, now UCB), which licensed the compound from GD Searle & Co, has developed and launched miglustat.

Product patent WO9426714, will expire in the US in 2018.

Kharatkar is affiliated with Sterling Biotech, Bhatt is affiliated with Intas and Kevat is affiliated with Orchid Chemicals & Pharmaceuticals.

INVENTORS Shah, Shrenik K.; Kharatkar, Raju Mahadev; Bhatt, Chiragkumar Anilkumar; Kevat, Jitendra Bhagwandas

About Navinta

Navinta, LLC in Ewing, N.J. is a technology driven Pharmaceutical Company that focuses on novel routes of synthesis of new and existing drug molecules, complex pharmaceutical ingredients, novel formulations of liquid dosage form, novel oral dosage form, novel injectable dosage form and implantable drug delivery devices. Navinta has currently at least fifteen (15) patents granted or pending with the United States Patent and Trademark Office.

EP-03031800 LINK EMBEDDED

Miglustat is a potent inhibitor of glycosyltransferase. It is primarily used in the treatment of Gaucher’s disease. Miglustat is chemically known as N-butyl-1,5-dideoxy-1,5-imino-D-glucitol of formula (I) and is sometimes referred as N-butyl-1-deoxynojirimycin. Miglustat is a white to off-white crystalline solid with a melting point of 125-126° C. Its empirical formula is C₁₀H₂₁NO₄and has a molecular weight of 219.28 g/mol.

(MOL) (CDX)

Miglustat belongs to the class of azasugars or iminosugars. Ever since the discovery of iminosugars in the 1960s, iminosugars have been subject of extensive studies in both the organic chemistry and biochemistry fields. Iminosugars are polyhydroxylated alkaloids, which may be described as monosaccharide analogues with nitrogen replacing oxygen in the ring. A well-known member of this extensive family of compounds is 1-deoxynojirimycin of formula (II).

(MOL) (CDX)

1-Deoxynojirimycin was initially synthesized in a laboratory. Subsequently, 1-deoxynojirimycin was isolated from natural sources, such as from leaves of mulberry trees and certain species of bacteria. 1-Deoxynojirimycin was shown to be an enzyme inhibitor.

Further research on 1-deoxynojirimycin analogs revealed that N-alkylated derivatives of 1-deoxynojirimycin exhibited greater biological activity than 1-deoxynojirimycin. Among them, N-butyl-1-deoxynojirimycin or miglustat of formula (I), was identified as a very potent inhibitor of glycosyltransferase. Miglustat was later approved by the FDA for human use.

Preparation of azasugars has been a very active area of research for a long time. A seminal synthesis of the compounds of formulas (I) and (II) by double reductive aminations of 5-keto-D-glucose was developed by Baxter and Reitz (J. Org. Chem. 1994, 59, 3175). This method was later refined by Matos and Lopes (Synthesis 1999, 571), in which tetra-O-benzyl-glucose was used as a starting material. Synthesis of miglustat can be traced back to 1977, when chemists from Bayer reported a synthesis of miglustat from 1-deoxynojirimycin and patented in U.S. Pat. No. 4,639,436. Other variations of this general scheme have also appeared in patents and non-patent literature, for example, U.S. Pat. No. 8,802,155 and U.S. Application Publication No. 2014/0243369.

A major drawback of those protocols is that all of them require the use of ion-exchange resins for purification of miglustat. In those protocols, an aqueous solution of miglustat obtained after running an ion-exchange column was concentrated to isolate miglustat. Due to the presence of four hydroxyl groups and a tertiary amine moiety in its chemical structure, miglustat is extremely hydrophilic. Thus, isolation of miglustat from an aqueous solution is quite challenging. In particular, it was very difficult to remove diastereomers and inorganic impurities formed during the reactions from miglustat by those protocols. Sometimes a second chromatographic purification was required to separate these impurities from miglustat. As a result, the yields of miglustat were generally low. The requirement to use a column purification (e.g. ion exchange column, flash column chromatography) further limits the scale of miglustat that could be prepared.

Scheme 1 is a synthetic scheme of miglustat in accordance with one embodiment of the invention:

(MOL) (CDX)

As depicted in scheme 1, the method of preparing miglustat may include the steps of: (1) providing or synthesizing a compound of formula (V); (2) conducting a reductive amination to provide a compound of formula (VI); (3) performing a hydrogenation reaction; and (4) isolating a free base miglustat.

The starting material, 2,3,4,6-tetra-O-benzyl-1-deoxynojirimycin hydrochloride of formula (V) may be prepared by following the methods described in Organic Process Research and Development, 2008, 12, 414-423.

Example 1

Synthesis of 2, 3, 4, 6-tetra-O-benzyl-N-butyl-1-deoxynojirimycin hydrochloride of Formula (VI)

To a solution of 2, 3, 4, 6-tetra-O-benzyl-1-deoxynojirimycin hydrochloride (V) (prepared as in Organic Process Research & Development, 2008, 12, 414-423) (45 g, 0.08 mol) in 1575 mL of methanol, n-butyraldehyde (21.6 g, 0.24 mol) and sodium cyanoborohydride (25.2 g, 0.4 mol) were added and stirred. The reaction was maintained under stirring at a temperature from about 25.degree. C. to about 30.degree. C. After the completion of the reaction, the reaction was quenched by adding 765 ml of 10% HCl in methanol, while keeping the temperature between 25.degree. C. to 30.degree. C. The reaction mass was cooled to 0.degree. C. to 5.degree. C. and the resulting precipitate solids were filtered. The filtrate was treated with aqueous HCl and the solid formed was filtered, suspended in 1 N HCl, stirred for 1 hour and filtered. The collected solid was washed with diisopropylether and dried under vacuum to furnish 46.2 g of compound (IV) (46.2 g, 0.075 mol, 94% yield) of high chemical purity based on HPLC analysis (>99.0%).

Example 2

Synthesis of Miglustat Hydrochloride of Formula (III)

A solution of 2, 3, 4, 6-tetra-O-benzyl-N-butyl-1-deoxynojirimycin hydrochloride (VI) (100 g, 0.16 mol) in methanol (1000 mL), 10% HCl solution in methanol (100 mL), and 10% Pd/C (50% wet) (10 g) were mixed and stirred under hydrogen atmosphere at a temperature of about 25.degree. C. to about 30.degree. C. until completion of the reaction. The reaction mass was filtered and the solvent was removed from the filtrate by rotary evaporation. Ethyl acetate (1000 mL) was added to the residue from the rotary evaporation to precipitate the solid. The solid was filtered and dried to isolate Miglustat hydrochloride (III) (42 g, 0.16 mol, 100% yield) of >99.5% purity as measured by HPLC analysis. The DSC thermogram of this product is provided as FIG. 3, and the FTIR spectrum of this product is provided as FIG. 4.

Example 3

Synthesis of Miglustat of Formula (I)

Miglustat hydrochloride (III) (42 g, 0.16 mol) obtained from Example 2 was dissolved in 420 mL of methanol and DBU (1,8-diazabicycloundec-7-ene) (34.1 mL) was added. The reaction mass was warmed slightly and stirred for about 2 hours. The reaction was concentrated by removal of methanol. Dichloromethane (900 mL) was added to the residue. The resulting solid was filtered and dried to obtain crystalline miglustat (I) (27 g, 0.12 mol, 75% yield) of >99.5% purity as measured by HPLC analysis. The melting point of the crystalline miglustat (I) is 128.degree. C. The DSC thermogram and FTIR spectrum of the product are provided as FIG. 1 and FIG. 2, respectively. The crystalline miglustat (I) contained <0.05% of the 5R isomer (IV) as measured by HPLC.

////////////EP 03031800, new patent, miglustat, Kharatkar, Sterling Biotech, Bhatt, Intas , Kevat, Orchid Chemicals & Pharmaceuticals.

Billion-Dollar Products Coming Off Patent in 2016

PATENTS Comments Off

Jun 262016

2016 Patent Expirations .

READ AT

http://lab.express-scripts.com/lab/insights/drug-options/2016-drug-pipeline-full-of-blockbuster-potential

CUBICIN OFF PATENT IN 2016 IN US

JAPAN 2016

Blopress

BARACLUDE IN JAPAN IN 2016

ENTECAVIR, BARACLUDE

Vfend (Voriconazole) IN UK

According to a report by DCAT, based on IMS analysis, the following are some of the key patent expiries between 2014 and 2018.

Nexium (esomeprazole): This patent expired in May 2014. Innovator AstraZeneca granted a license to Teva (TEVA) to produce the generic form in the United States.
Celebrex (celecoxib): This patent expired in 2014. Pfizer conceded the drug to generic drug makers Actavis (ACT) and Teva after a prolonged lawsuit.
Symbicort (budesonide/formoterol fumarate dihydrate): Some of AstraZeneca’s 13 patents have expired, but all won’t expire until 2023. No generic version of the drug exists.
Crestor (rosuvastatin): AstraZeneca will lose its patent protection for Crestor in 2016.
Cialis (tadalafi): Eli Lilly (LLY) is set to lose patent protection in the United States and Europe in 2017.

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

Ranking (by highest sales forecasts for 2020)

	Drug	Disease	Pharmaceutical Company	2020 Forecast Sales (US $ billions)
1	Obeticholic acid	Chronic liver diseases, primarily primary biliary cirrhosis	Intercept Pharmaceuticals and Sumitomo Dainippon Pharma	2.621
2	Emtricitabine + tenofovir alafenamide (F/TAF)	HIV-1 infection	Gilead Sciences and Japan Tobacco	2.006
3	Tenofovir alafenamide + emtricitabine + rilpivirine (R/F/TAF)	HIV-1 infection	Gilead Sciences and Janssen R&D	1.572
4	MK-5172A (grazoprevir + elbasvir)	HCV infection	Merck & Co	1.537
5	Venetoclax	Chronic lymphocytic leukemia	Abbvie	1.477
6	Nuplazid (pimavanserin)	Parkinson’s disease psychosis	ACADIA Pharmaceuticals	1.409
7	Uptravi (selexipag)	Pulmonary arterial hypertension	Nippon Shinyaku Co and Actelion	1.268

2016 DRUGS-TO-WATCH FORECAST SALES RANKINGS

Analysis based on data accessed on January 08, 2016.

(SOURCE: Thomson Reuters Cortellis)

SOME SELECTED STRUCTURES

Obeticholic acid

2Grazoprevir

3 Venetoclax

4 Pimavanserin

New Blockbuster Drugs to Watch in 2016

Each of these new drugs could rake in $2 billion in sales.

Blockbuster drugs, those medicines that bring in more than $1 billion in sales every year, are the holy grail of drug development. They can make a pharmaceutical company and send them to rock-star status among investors, as evidenced by the rise of Gilead Sciences after the launch of its hepatitis C treatments. This year’s slate of new drug launches features at least seven drugs expected to hit blockbuster status within the next five years, according to a study by Thomson Reuters.

The line-up also reveals key trends within the pharmaceutical industry for this year and beyond, including an increasing focus on rare diseases, the development of more convenient single-dose regimens, and more affordable treatments.

Here are the seven drugs set to launch this year and reach blockbuster status by 2020.

1. Intercept Pharmaceuticals and Sumitomo Dainippon Pharma

Drug: Obeticholic acid

Indication: Chronic liver diseases, primarily primary biliary cirrhosis

2020 Forecast Sales: $2.62 billion

Intercept Pharmaceuticals’ ICPT -7.35% obeticholic acid has proved very effective in treating non-alcoholic steatohepatitis, a type of liver inflammation caused by fat build-up in the organ. This condition has no approved treatment and a potentially large market, which is expected to push the drug to blockbuster status, if approved. About 2% to 3% of the global population has non-alcholoic steatohepatitis and the share will likely increase due to rising rates of pre-disposing factors like obesity and insulin resistance.

2. Gilead Sciences and Japan Tobacco

Drug: Emtricitabine and tenofovir alafenamide (F/TAF)

Indication: HIV-1 infection

2020 Forecast Sales: $2 billion

Gilead’s GILD -3.48% two HIV-1 infection drugs in development are both expected to be big money-makers, and the company is hoping the new daily single-dosage options will be able to replace sales of its existing HIV treatments that are set to lose patent protections in 2017. The new TAF-based therapies show evidence that they are potentially a safer replacement for some current therapies, including Gilead’s own Truvada.

3. Gilead Sciences and Janssen R&D

Drug: Tenofovir alafenamide and emtricitabine and rilpivirine (R/F/TAF)

Indication: HIV-1 infection

2020 Forecast Sales: $1.57 billion

Like the No. 2 drug on this list, Gilead’s secondary TAF-based combination therapy in partnership with Johnson & Johnson’s JNJ -1.49% Janssen unit is expected to improve renal and bone mineral density measurements compared with some existing drugs. Those results combined with the improved longevity of HIV patients and increasing numbers of those eligible for antiretroviral drugs means a large and lucrative market for the two new TAF-based drugs.

Tenofovir alafenamide

4. Merck & Co.

Drug: MK-5172A

Indication: Hepatitis C virus

2020 Forecast Sales: $1.54 billion

Merck MRK -3.12% is getting ready to enter the heated market for hepatitis C treatments, going up against Gilead’s Harvoni and Abbvie’s Viekira Pak. Following a significant setback when theFood and Drug Administration withdrew its “breakthrough drug” status, Merck’s treatment could finally launch this year to give another safe and high-quality treatment for the disease. A recent warning by the FDA concerning Viekira Pak has dampened sales of Abbvie’s drug, which could give Merck a leg up when it eventually brings its hepatitis C drug to market. It could also pursue an aggressive pricing strategy to gain market share, given the currently high price tags on current treatments.

5. Abbvie

Drug: Venetoclax

Indication: Chronic lymphocytic leukemia

2020 Forecast Sales: $1.48 billion

Abbvie’s ABBV -2.37% Venetoclax is a potential oral treatment for cancer, primarily focused on a type of chronic lymphocytic leukemia that is resistant to chemotherapy. The drug was a leading therapy at last year’s annual meeting of the American Society of Hematology after a clinical trial showed an overall response rate of 79.4% in patients with relapsed chronic lymphocytic leukemia. The drug is also being tested as a potential treatment for other hematological cancers like non-Hodgkin’s lymphoma, as well as in combination with tamoxifen in patients with metastatic breast cancer.

6. ACADIA Pharmaceuticals

Drug: Nuplazid

Indication: Parkinson’s disease psychosis

2020 Forecast Sales: $1.41 billion

ACADIA’s ACAD -6.18% nuplazid could be the first and only drug on the market to help treat Parkinson’s disease psychosis, which affects up to 40% of Parkinson’s patients. Clinical trials have shown that the drug does not worsen motor symptoms, a vital factor for these patients, while improving night-time sleep, daytime wakefulness, and caregiver burden. Nuplazid may also work in other psychosis settings, such as schizophrenia and Alzheimer’s disease psychosis. The combination of those three diseases means ACADIA’s drug has a potentially massive and therefore lucrative market.

7. Nippon Shinyaku and Actelion

Drug: Uptravi

Selexipag

Indication: Pulmonary arterial hypertension

2020 Forecast Sales: $1.27 billion

Nippon Shinyaky’s Uptravi is able to both delay the progression of pulmonary arterial hypertension, a type of high blood pressure that affects arteries in the lungs and heart, as well as reduce the risk of hospitalization. The drug is the only one on this list that’s already available. It entered the market in the first week of January 2016 and is expected to bring in $189 million in its first year, with sales increasing to $1.27 billion by 2020. Uptravi is being promoted as an additional therapy once baseline treatment has been started. A massive clinical trial showed that Uptravi reduced the risk of death from pulmonary arterial hypertension by 39% versus placebo.

2015

Opdivo, Bristol-Myers Squibb, $5.684 billion
Praluent, Regeneron Pharmaceuticals and Sanofi, $4.414 billion
LCZ-696, Novartis, $3.731 billion
Ibrance, Pfizer, $2.756 billion
Iumacaftor plus ivacaftor, Vertex Pharmaceuticals, $2.737 billion
Viekira Pak, AbbieVie, $2.500 billion
Evolocumab, Amgen and Astellas Pharma, $1.862 billion
Gardasil 9, Merck & Co., $1.637 billion
Brexpiprazole, Ostuka Pharmaceutical and Lundbeck, $1.353 billion
Toujeo, Sanofi, $1.265 billion
Cosentyx, Novartis, $1.082 billion

SOME MORE STRUCTURES

Rilpivirine

Elbasvir

Opdivo

Quetiapine

The pharmaceuticals losing patent protection in 2016

A review of the drugs to watch in 2016 identifies several key areas of continued focus in the pharmaceutical industry: rare diseases, FDC regimens and pricing. The year ahead is anticipated to be a very interesting, and challenging, one for the pharmaceutical industry.

THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India

Older Entries Newer Entries

AUTHOR OF THIS BLOG

Yonkenafil Hydrochloride

PATENT

Compound 1:

BASE

Compound 1-HCl:

ERROR IN STRUCTURE

November 2005: China declared IND

November 2006: eligible for Phase I clinical documents of approval

November 2006: completion of the International Patent Licensing, China entered the international fray original new drug development

May 2008: completed Phase I clinical, showing international mechanism similar drugs have the potential to become the best

February 2009: eligible lymphoma indications II / III of this document

March 2009: Start of the Phase II clinical trial for the NDA to ①CTCL goal of clinical trials and ②PTCL

March 2009: IND by the FDA application is eligible to start Phase I clinical in the United States

July 2009: eligible for non-small cell lung cancer, breast cancer and prostate cancer clinical documents of approval

December 2010: of PTCL by a conventional phase II directly into Phase II clinical trial registered drug trial center and by recognition

March 2011: combination chemotherapy for non-small cell lung cancer clinical trials enter phase Ib

September 2012: of PTCL indication test deadline

December 2012: of PTCL clinical summary will be held

January 2013: Chidamide declare China NDA

December 2014: the State Food and Drug Administration (CFDA) approved the listing

In China, for the effective treatment of patients with relapsed or refractory PTCL has undertaken urgent clinical need

Chidamide is a completely independent intellectual property rights China originator of innovative medicines

Chidamide (Chidamide) has been multi-national invention patents

In October 2006, the US HUYA biological microchip company formally signed the International Patent Chidamide licensing and international clinical cooperative development agreement; the United States in the ongoing Phase I clinical

WRONG COMPD

Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment

GNT Biotech and Medicals Corporation Licenses Novel Cancer Molecule from Shenzhen Chipscreen Biosciences Ltd.

References

Overview

Advanced Synthesis & Catalysis

Author Information

References

Continuous Processing

Semi-continuous processes

History

Shut-downs

Safety

Continuous processor (equipment)

EXAMPLE…………….

Improved Continuous Flow Processing: Benzimidazole Ring Formation via Catalytic Hydrogenation of an Aromatic Nitro Compound

EXAMPLE…………….

NEXT EXAMPLE…………….

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al2O3 by a Continuous Process

NEXT EXAMPLE…………….

Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen

NEXT EXAMPLE…………….

Multi-step Continuous Flow Pyrazole Synthesis via a Metal-free Amine-redox Process

NEXT EXAMPLE…………….

Synthesis of a Precursor to Sacubitril Using Enabling Technologies

NEXT EXAMPLE…………….

Examples………..

Examples………..

Multikilogram Synthesis of 4-d-Erythronolactone via Batch andContinuous Processing

Examples………..

Continuous Biocatalytic Processes

PICS…………..

References

Sources and further reading

A Review on the Applications of Self Regenerating Catalysts

Abstract

3 Venetoclax

4

Pimavanserin

New Blockbuster Drugs to Watch in 2016

Each of these new drugs could rake in $2 billion in sales.

Construction of 2-(2′-Hydroxy-5′-methylphenyl)benzotriazole over Pd/γ-Al₂O₃ by a Continuous Process