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WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

January 8, 2018 10:09 am / Leave a comment

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WO-2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

(WO2018001353) METHOD FOR PREPARING APREMILAST

ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

DU, Xiaoqiu; (CN).
ZHOU, Lianchao; (CN).
LIU, Jiegen; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018001353&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

EN)Method one: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L-leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an aprotic solvent to produce the compound of formula I; method two: (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl-L- leucine salt of formula II is reacted with 3-acetylaminophthalic anhydride of formula III in an organic solvent in the presence of an organic alkaline or an alkali metal hydride to produce the compound of formula I. The method for preparing apremilast requires inexpensive raw materials and reagents , is suitable for industrialized production, and has great economic effects.

Apremilast is a PDE4 inhibitor developed by Celgene. Currently, there are clinical indications such as rheumatoid arthritis, psoriatic arthritis, Behcet’s disease and ulcerative colitis. March 21, 2014 FDA approves first indication – adult active psoriatic arthritis (PsA). Name of Product:

(FDA, as a post-marketing requirement, will evaluate the effect of this drug on pregnant women through a pregnancy registry study.) Three clinical trials evaluated the safety and efficacy of Asprate in the treatment of PsA, The response rates to ACR20 in the prest and placebo groups were 32-41% and 18-19%, respectively.

Aspast’s oral anti-rheumatic drug, a new mechanism of action, distinguishes itself from currently available anti-TNF monoclonal antibodies. Thomson Pharma predicts rapid sales growth of 201.2 million U.S. dollars in 2015 with sales of US $ 516 million in 2015 . Upstall’s sales are expected to reach a maximum of 2 billion U.S. dollars. Compared with its counterparts, Actuate has the following advantages: It inhibits the production of various proinflammatory mediators (PDE-4, TNF-α, IL-2, interferon γ, leukotriene, NO synthase) Inflammation; selective inhibitor of phosphodiesterase 4 (PDE4), approved for use in psoriatic arthritis in September 2014 FDA approved mid-to-severe treatment of plaque psoriasis for phototherapy or systemic therapy Patient, the first and only PDE4 inhibitor approved for the treatment of plaque psoriasis; clinical trials have shown that OTEZLA reduces erythema, thickening and scaling in patients with moderate to severe plaque psoriasis; clinical trials have demonstrated Painstrept was well tolerated and had minimal adverse reactions. Patients in the Otezla-treated and placebo clinical trials showed signs and symptoms of PsA improvement including tenderness, joint swelling and physical function.

The original patent CN 101683334A reports the synthesis of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- ) And 3-acetylaminophthalic anhydride (3) Prepared with acetic acid as solvent (1), and the synthetic route is as follows:

The method has low yield, needs lower than 50 DEG C to distill the high-boiling acetic acid, and produces one deacetyl impurity (4) during the reflux reaction and the acetic acid distillation, which affects the product purity. Acetic acid will corrode the equipment at high temperatures. Distillation of high-boiling acetic acid will also increase plant production time. Acetic acid, which is not distilled away, consumes a large amount of lye to neutralize and increases the amount of wastes and production costs, which is not conducive to industrialized production.

Example one

10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- 4.6g (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, then add 50mL of acetonitrile, heating 75 ~ 80 ℃, the reaction incubated for 18 hours and cooled to room temperature. After the reaction mixture was evaporated to dryness, 60 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 25 mL of water was added to the organic layer and stirred for 10-30 minutes. The layers were evaporated to dryness to give a light yellow solid, then add 30mL absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.4 g of a white powder in 91.2% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.

Example two

10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- A solution of 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride in a 250 mL three-necked flask was charged with 80 mL of toluene and 10 mL of N, N-dimethylformamide. The mixture was heated to 100 ° C and the reaction was incubated for 12 hours and then cooled to room temperature. After the reaction solution was evaporated to dryness, 80 mL of methylene chloride was added, 25 g of 10% sodium carbonate solution was added thereto and the mixture was stirred for 10 to 30 minutes. The mixture was allowed to stand for further delamination and then 50 mL of water was added to the organic layer and stirred for 10 to 30 minutes. Evaporated to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. Cooled to 0 ~ 5 ℃ and stirred for 1 ~ 2 hours, filtered and drained, the filter cake was dried in vacuo to give 9.2g white powder, yield 89.2%, HPLC: 99.9%, wherein the deacetyl impurities (4 ) Has an HPLC area of 0.03%.

Example three:

10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- To a 250 mL three-necked flask was added 4.6 g (0.0224 mol) of 3-acetamidophthalic anhydride followed by 50 mL of ethyl acetate and 1.81 g (0.8 eq) of triethylamine. The mixture was heated at 75-80 ° C and incubated for 18 hours. The reaction was stopped, 100 mL of ethyl acetate was further added and the mixture was cooled to 20-30 ° C. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was heated to 0-5 ° C for 1 to 2 hours, filtered and drained. The filter cake was vacuum dried to give 9.8 g of a white powder in 95.1% yield. HPLC: 99.9% ) Had an HPLC area of 0.04%.

Example 4:

10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine N-acetyl- (0.0224mol) 3-acetamidophthalic anhydride into a 250mL three-necked flask, followed by the addition of 120mL of isopropyl acetate and 30mL of acetonitrile and 1.81g (0.8eq) of triethylamine, heating 75 ~ 80 ℃, incubated reaction 16 hours. Stop the reaction, cooled to 20 ~ 30 ℃. The reaction solution was added 30g of 8% sodium carbonate solution, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred for 10 to 30 minutes, allowed to stand layered, the organic layer was added 30mL of water, stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. The mixture was hot beaten with ethanol, cooled to 0-5 ° C, stirred for 1-2 hours, filtered and drained. The filter cake was vacuum dried to give 9.6 g of a white powder in 93.1% yield. HPLC: 99.9% ) Has an HPLC area of 0.03%.

Comparative Example:

According to the preparation example of Compound A in original patent CN 101683334A, 10.0 g (0.0224 mol) of (S) -1- (3-ethoxy-4- methoxyphenyl) -2- (methylsulfonyl) N-acetyl-L-leucinate and 4.6 g (0.0224 mol) of 3-acetylaminophthalic anhydride were placed in a 250 mL three-necked flask and 50 mL of acetic acid was added thereto. The mixture was heated at 75 to 80 ° C and the reaction was incubated for 18 hours. The reaction mixture was cooled to 40-50 ° C and the temperature of the water bath was controlled to 40-50 ° C. The reaction mixture was vortexed to glacial acetic acid without any significant fraction. 150 mL of ethyl acetate was added and the mixture was stirred to dissolve. 100 mL of water was added and the mixture was stirred 10 ~ 30 minutes, standing stratification, the organic layer was added 100mL water, stirred for 10 to 30 minutes, allowed to stand for stratification, the organic layer was added 100g 8% sodium bicarbonate solution, stirred for 10 to 30 minutes, The organic layer was added with 100g of 8% sodium bicarbonate solution and stirred for 10-30 minutes. The layers were separated and the organic layer was added with 100 mL of water. The mixture was stirred for 10-30 minutes, and the layers were separated. The organic layer was further added with 100 mL of water and stirred 10 ~ 30 minutes, standing stratification, the organic layer was evaporated to dryness to a pale yellow solid, then add 30mL of absolute ethanol, evaporated again. 68mL of anhydrous ethanol and 34mL of acetone were added to the solid, heated to 60-65 ° C, stirred to make it fully dissolved, and then cooled to 0-5 ° C and stirred for 1 to 2 hours, filtered and drained, and the filter cake was dried under vacuum to give 8.6 Class g white powder, yield 83.4%, HPLC: 99.7% with an HPLC area of deacetylated impurity (4) of 0.22%.

////////////WO 2018001353, APREMILAST, NEW PATENT, ZHEJIANG HUAHAI PHARMACEUTICAL CO., LTD

IMIGLIPTIN, NEW PATENT, WO 2017211293, XUANZHU PHARMA CO., LTD.

December 18, 2017 10:28 am / Leave a comment

(WO2017211293) CRYSTALLINE FORM OF SUCCINATE USED AS DIPEPTIDYL PEPTIDASE-4 INHIBITOR

WO-2017211293,

XUANZHU PHARMA CO., LTD. [CN/CN]; 2518, Tianchen Street, National High-Tech Development Zone Jinan, Shandong 250101 (CN)

SHU, Chutian; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017211293&recNum=1&tab=PCTDocuments&maxRec=&office=&prevFilter=&sortOption=&queryString=

The present invention relates to a crystalline form of a succinate used as a dipeptidyl peptidase-4 inhibitor, and a manufacturing method, pharmaceutical composition, and application thereof. The invention specifically relates to a dipeptidyl peptidase-4 inhibitor compound as represented by formula (1), a crystalline form of a succinate, wherein the succinate is an (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)methyl)benzonitrile, and a manufacturing method, pharmaceutical composition, and application thereof.

Example 1: Preparation of the succinate salt form I of the compound of formula (1)

[0056]

[0057]

The compound of formula (1) (44.6 g, 0.12 mol) was added to a 2 L round bottom flask and suspended in 1593 mL of acetonitrile. The mixture was heated to 80 ° C. and dissolved in free form. Immediately after the addition of 15.4 g A white solid precipitated, maintained at 80 ℃ for 1 hour and then cooled to room temperature, filtered and the filter cake was dried in vacuo at 40 ℃ for 10 hours, weighed 57.6g, yield 98.3%. The succinate salt Form I was tested by XRPD.

[0058]

Example 2: Preparation of the succinate salt form I of the compound of formula (1) II

[0059]

A quantity of succinate salt of the compound of formula (1) was weighed into glass vials in a total of 26 parts. A total of 26 vials of methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, toluene, Isopropyl acetate, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, 1,4-dioxane, n-butanol, pentane, heptane, cyclohexane, Ketone, xylene, isobutyl acetate, diethyl ether). After stirring, ultrasound and other means to make the sample fully dissolved. Subsequently, about 2 mL of liquid was removed from each bottle and filtered into 26 reagent tubes numbered 1-26. The resulting 26 filtrates were distributed in two 96-well plates. One or two of the above 1-13 solvents are sequentially added into the first 96-well plate, one or two of the above-mentioned 14-26 kinds of solvents are sequentially added into the second 96-well plate, Zha Kong sealing film sealed, placed in a fume hood, the natural environment to dry. Wherein Form I is obtained in the following mixed solvent, and Form I is also precipitated in the methyl isobutyl ketone in the remaining solution after plating.

[0060]

The solvent used to prepare succinate salt Form I was prepared

[0061]

[Table 0001]

Mixed solvents	Solvent 1	Solvent 2
1	Methyl isobutyl ketone	Ether
2	Xylene	Ether
3	Isobutyl acetate	Ether
4	Ether	Ether
5	1,4-dioxane	Pentane
6	1,4-dioxane	Heptane
7	1,4-dioxane	Cyclohexane
8	1,4-dioxane	Methyl isobutyl ketone
9	1,4-dioxane	Xylene
10	1,4-dioxane	Isobutyl acetate
11	Butyl acetate	Ether
12	Butyl acetate	1,4-dioxane

[0062]

Example 3: Preparation of the succinate salt form II of the compound of formula (1)

[0063]

Take 8 parts of the compound of formula (1), 200mg each, placed in a 10mL round bottom flask, add the solvent in the following table to each solvent, warmed until the solvent is refluxed, after dissolving it, add 69mg (1.1eq) succinic acid and cool to At room temperature, the solid precipitated and was filtered. The resulting solid was subjected to XRPD testing as succinate crystal form II.

[0064]

[Table 0002]

Feeding amount	Solvent and ratio
2mL	Tetrahydrofuran
3mL	acetone
5.5mL	Acetonitrile: water = 10: 1
2mL	Methanol
4mL	Ethanol
1mL	Ethanol: water = 10: 1
2mL	Isopropanol: water = 19: 1
2mL	Isopropyl alcohol: water = 9: 1

Sacubitril, WO 2016180275, New patent, SUZHOU PENGXU PHARMATECH CO., LTD

November 23, 2016 1:31 am / Leave a comment

Sacubitril, WO 2016180275, New patent, SUZHOU PENGXU PHARMATECH CO., LTD

AHU-377 INTERMEDIATES AND METHOD FOR PREPARING AHU-377 AND AHU-377 INTERMEDIATES PATENT

WO2016180275, new patent, SUZHOU PENGXU PHARMATECH CO., LTD. [CN/CN]; 3rd Floor Building 7, 2358 Chang An Road, Wujiang Suzhou, Jiangsu 215200 (CN)

WANG, Peng; (CN).

LI, Pixu; (CN).

GU, Xiangyong; (CN)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016180275&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

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Heart failure is a very high mortality syndrome, for patients with heart failure, so far no drug can significantly improve mortality and morbidity, and thus a new type of therapy is necessary. AHU-377 (CAS No. 149709-62-6) is an enkephalinase inhibitor, which is a prodrug ester groups can be lost through hydrolysis, converted to pharmaceutically active LBQ657, inhibit endorphin enzyme (NEP) the role of the main biological effects of NEP is to natriuretic peptides, bradykinin and other vasoactive peptide degradation failure. AHU-377 and angiotensin valsartan composition according to the molar ratio of 1 LCZ696. LCZ696 is an angiotensin receptor enkephalinase inhibitors, which can lower blood pressure, treat heart failure may become a new drug. Clinical data show, LCZ696 is more effective for the treatment of hypertension than valsartan alone.

Patents US 5,217,996 and US 5,354,892 reported the first synthesis of AHU-377, the synthetic route is as follows:

Reaction with unnatural D-tyrosine derivative as a substrate, more expensive, while the second step in the synthesis is necessary to use Pd-catalyzed Suzuki coupling reaction, whereby preparative route costs than the AHU-377 high.

Patent US 8,115,016 above routes also reported the departure from the pyroglutamate, through multi-step process for preparing a reaction AHU-377, which is more difficult methylation reaction, and the yield is not high. Patent US 8,580,974 also reported a carbonyl group of the a- introducing N, N- dimethyl enamine is converted to methyl, however, there are some problems in the route for constructing methyl chiral centers, are not suitable for scale-up synthesis route as follows:

About the latest AHU377 synthesis intermediates, Patent WO2014032627A1 reported using a Grignard reagent to react with epichlorohydrin, a quicker been important intermediates, synthetic route Compound AHU377 synthesized as follows:

However, the second step of the synthetic route use succinimide nitrogen atoms introduced by Mitsunobu reaction with hydrochloric acid hydrolysis to remove, then converted to Boc protected at the end of the synthesis process AHU377 Boc will have to take off protection, then any connection with succinic anhydride reaction product introduced into the structure of succinic acid portion, so that this method of atom economy and the economy of the steps are low.

Example 1

Synthesis of Compound 2

In inert atmosphere, a solution of three 500mL flask was added compound 1 (10g, 1eq), dissolved after 90mL THF, was added CuI (4.814g, 0.1eq), the system moves to the low temperature in the cooling bath to -20 ℃ when, biphenyl magnesium bromide dropwise addition, the internal temperature was controlled not higher than -10 ℃. Bi closed refrigeration drop, return to room temperature overnight. Completion of the reaction, the reaction solution was poured into saturated the NH ₄ of Cl (10vol, 100 mL) was stirred at room temperature for 0.5h. Suction filtered, the filter cake was rinsed with a small amount of EA, and the filtrate was transferred to a separatory funnel carved, and the aqueous phase was extracted with EA (10vol × 2,100mL × 2) and the combined organic phases with saturated NaHC [theta] ₃ , the NH ₄ of Cl, each Brine 150mL (15vol) washed once, dried over anhydrous over MgSO ₄ dried, suction filtered, and concentrated to give a white solid. Product obtained was purified by column 15.2g, yield 78%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.52 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.38-7.25 (m, 8H), 4.62-4.47 ( m, 2H), 4.09 (dd, J = 6.7,3.5Hz, 1H), 3.54 (dd, J = 9.5,3.5Hz, 1H), 3.43 (dd, J = 9.4 , 6.9Hz, 1H), 2.84 ( d, J = 6.6Hz, 2H), 2.38 (s, 1H).

Example 2

Synthesis of Compound 3

In an inert gas, at room temperature was added to the flask 500mL three Ph3P (18.54g, 2eq), 240mL DCM dissolution, butyryl diimide (of 6.44 g), compound 2 (15g), an ice-water bath cooling to 0 ℃ or so, was added dropwise DIAD (14mL) was complete, the reaction go to room temperature.Starting material the reaction was complete, the system was added to water (100 mL) quenched the reaction was stirred for 10min; liquid separation, the aqueous phase was extracted with DCM (100mL × 2), the combined organic phases with saturated Brine 100mL × 2), dried over anhydrous over MgSO ₄ dried , filtration, spin dry to give a white solid; product was purified by column 15.4g, yield 82%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.56 (D, J = 7.4Hz, 2H), 7.49 (D, J = 8.0Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.37-7.30 (m, 3H), 7.27 ( d, J = 6.7Hz, 3H), 7.22 (d, J = 8.0Hz, 2H), 4.75 (s, 1H), 4.56 (d, J = 12.0Hz, 1H), 4.45 (d, J = 12.0Hz, 1H ), 4.06 (t, J = 9.6Hz, 1H), 3.70 (dd, J = 10.0,5.2Hz, 1H), 3.23 (dd, J = 13.8,10.3Hz, 1H) , 3.14-3.00 (m, 1H), 2.48 (d, J = 4.0Hz.4H).

Example 3

Synthesis of Compound 4

Protection of inert gas, at room temperature was added to the flask 1L three compound 3 (18.81g), 470mL EtOH was dissolved, was added Pd / C, replaced the H ₂ three times, move heated on an oil bath at 60 ℃ reaction. Raw reaction was complete, the system was removed from the oil bath, the reaction solution was suction filtered through Celite and concentrated to give the crude product. It was purified by column pure 11.8g, a yield of 81.2%.

NMR data for the product are as follows:

₁ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.8Hz, 2H), 7.51 (D, J = 7.8Hz, 2H), 7.42 (T, J = 7.5Hz, 2H), 7.33 (T , J = 7.2Hz, 1H), 7.26 (d, J = 7.2Hz, 2H), 4.55 (d, J = 5.2Hz, 1H), 4.06-3.97 (m, 1H), 3.86 (dd, J = 12.0, 3.1Hz, 1H), 3.16 (dd , J = 8.1,2.9Hz, 2H), 2.58 (t, J = 7.0Hz, 4H), 1.26 (s, 2H).

Example 4

Synthesis of Compound 7

Protection of inert gas, at room temperature to a 25mL flask was added three Dess-Martin oxidant (767.7mg), 10mL DCM was dissolved, the system was cooled down to -10 deg.] C, was added 4 (500mg). Starting material the reaction was complete, to the system was added saturated NaHCO3 and Na2S2O3 each 5mL, quench the reaction stirred for 10min; aqueous phase was extracted with DCM (10mL × 3) and the combined organic phases with saturated NaHCO3, Brine 30mL each wash, dried over anhydrous MgSO4, filtration, spin dried to give the crude product used directly in the next reaction cast.

Example 5

Synthesis of Compound 8

Inert gas, at room temperature for three to 500mL flask 7 (497.5mg), 10mL DCM to dissolve an ice water bath to cool, added phosphorus ylide reagent (880.6mg), the system was removed from the ice water bath at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. Liquid separation, the aqueous phase was extracted with DCM (10mL × 2), organic phases were combined, washed with saturated Brine 20mL × 2, dried over anhydrous MgSO4, filtration, spin crude done. Product obtained was purified by column 563mg, 90% yield.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.60-7.53 (m, 2H), 7.51 (D, J = 8.1Hz, 2H), 7.42 (T, J = 7.6Hz, 2H), 7.33 (D, J = 7.3Hz, 1H), 7.23 (d , J = 8.1Hz, 2H), 7.13 (dd, J = 9.2,1.5Hz, 1H), 5.26 (td, J = 9.5,6.9Hz, 1H), 4.25-4.05 ( m, 2H), 3.40 (dd , J = 13.7,9.7Hz, 1H), 3.13 (dd, J = 13.8,6.7Hz, 1H), 2.53 (d, J = 2.2Hz, 4H), 1.85 (d, J = 1.4Hz, 3H), 1.30 ( t, J = 7.1Hz, 3H).

Example 6

Synthesis of Compound 9

Protection of inert gas, at room temperature to a 50mL flask was added three 8 (365mg, 1eq), 9mL of ethanol and stirred to dissolve, the system was replaced with hydrogen three times, was added Pd / C (25% w / w) at room temperature. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. The reaction mixture was suction filtered through Celite and concentrated to give the crude product. Product was purified by column, yield 80.2%, purity 97.2%.

Example 7

Synthesis of Compound 10

Equipped with Compound 9 (100mg) acetic acid A reaction flask (9mL), hydrochloric acid (1mL). The reaction was heated oil bath at 80 deg.] C. The reaction material completely stop the reaction, the system was added to water (5mL) to quench the reaction. After saturated NaHCO3 and extracted with EA and concentrated to give crude product. Product obtained was purified by column 90mg, yield 84%.

NMR data for the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.54 (m, 2H), 7.53-7.48 (m, 2H), 7.41 (dd, J = 10.5,4.9Hz, 2H), 7.31 (dd, J = 8.3 , 6.4Hz, 1H), 7.22 ( d, J = 8.2Hz, 2H), 5.93 (t, J = 9.7Hz, 1H), 4.34-4.00 (m, 3H), 2.91-2.71 (m, 2H), 2.68 -2.57 (m, 2H), 2.55 (ddd, J = 9.4,7.0,4.3Hz, 1H), 2.42 (dt, J = 13.3,6.8Hz, 2H), 1.97-1.74 (m, 1H), 1.64-1.46 (m, 1H), 1.23 ( td, J = 7.1,3.3Hz, 3H), 1.14 (dd, J = 7.1,3.9Hz, 3H)

Example 8

Synthesis of Compound 5

Example 8-1: The reaction flask was added compound 4 (1eq) was added water (2VOL), concentrated hydrochloric acid (2VOL), 110 ℃ reaction was heated in an oil bath overnight, complete conversion of starting material, the HPLC peak area 97%. 10% NaOH solution was added to adjust the pH to about 10, filtration products. Yield 85%.

Example 8-2: The reaction flask was added compound 4 (1eq) was added ethanol (5 vol), water (5 vol), potassium hydroxide (8 eq), was heated in an oil bath overnight at 110 ℃ reaction, complete conversion of the starting material, the HPLC peak area 99%. Water was added (5Vol), filtered to obtain the product. Yield 95%. Product was dissolved in toluene, was added ethanolic hydrochloric acid, the precipitated hydrochloride Compound 5.

NMR data for the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 8.31 (S, 3H), 7.70-7.61 (m, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.31 (m, 3H), 4.09 (the dq- , J = 42.6,7.1Hz, 1H), 3.62-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.11-3.00 (m, 1H), 2.95-2.84 (m, 1H), 1.30-1.10 (m, 1H).

EXAMPLE 9

Synthesis of Compound 6

To the reactor was added compound 5, was added absolute ethanol (3vol). Temperature of the outer set 30 ℃ heating, stirring was continued after the temperature reached 25 ℃ 20min. Was added 30% NaOH aqueous solution (1.1eq). External temperature 65 ℃ heating provided, after the internal temperature reached 60 deg.] C was slowly added (of Boc) ₂ O (1.1 eq). Stirring 0.5h, reaction monitoring. After completion of the reaction, water was added slowly dropwise (8vol), turn off the heating and natural cooling. The system temperature was lowered to 25 deg.] C and continue stirring for 2h. Filter cake at 50 ℃ blast oven drying to obtain the product.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) δ7.61-7.50 (m, 4H), 7.61-7.50 (m, 4H), 7.46-7.39 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.23 (m, 3H), 7.37-7.26 ( m, 3H), 4.82 (d, J = 7.9Hz, 1H), 4.82 (d, J = 7.9Hz, 1H), 3.91 (s, 1H), 3.70 (d, J = 11.0Hz, 1H), 3.77-3.54 (m, 2H), 3.65-3.47 (m, 1H), 2.88 (d, J = 7.0Hz, 2H), 2.88 (d, J = 7.0Hz, 2H), 2.51 (s, 1H), 2.51 (s, 1H), 1.42 (s, 9H), 1.42 (s, 9H).

Synthesis of Intermediate Compound 6 to Compound 10, i.e., the AHU-377, a synthetic route in the background of the present invention, the cited patent application WO2014032627A1 loaded in detail, not in this repeat.

Example 10

Synthesis of Compound 2

Benzyl glycidyl ether preparation (50g) in THF (200mL) was added. Under inert gas protection, the biphenyl magnesium bromide (365mmol) was added to THF (1020mL) was added the reaction flask is placed in a low temperature bath -40 ℃ cooling. Cuprous iodide (O.leq) when the internal temperature dropped to -9 ℃. Continued to decrease the temperature of -23 ℃ dropwise addition of benzyl glycidyl ether in THF was added dropwise to control the internal temperature process of not higher than -15 deg.] C, 47 min when used, the addition was completed the cooling off the reaction was stirred overnight. The cooling system to -20 ℃ quenched with 1N HCl aqueous solution, <10 ℃ Go stirred 30min at room temperature. Liquid separation, the aqueous phase was extracted with THF, the combined THF phases. Respectively saturated ammonium chloride (250mL), saturated brine (250mL) washed. Rotary evaporation to remove THF, and water (200 mL) Continue rotary evaporation 1h, cool to precipitate a solid. Suction crude. Crude n-heptane was added 2Vol beating, suction filtration to obtain the product in a yield of 90 ~ 95%, HPLC peak area 94%. In another column purification was pure, columned yield 88.6%, HPLC 99.1%.

Example 11

Synthesis of Compound 3

Preparation Example 9, said compound taking the embodiment 2 (5g) added to the reaction flask, the reaction flask was added toluene (80mL), phthalimide (2.55 g of) and triphenylphosphine (5.35g of), the nitrogen was replaced protection. An ice-salt bath cooling to -5 deg.] C, was added dropwise DIAD (4.12g), dropwise addition was exothermic, the temperature was raised to 5 ℃. The reaction was continued 1h sampling HPLC test material substantially complete reaction. Join 12g silica spin column done to collect the product (including DIEA derivative).

Example 12

Synthesis of Compound 11

Compound 3 (3g) was added to the reaction flask embodiment taken in Preparation Example 10, was added ethanol (30 mL), with stirring. Was added hydrazine hydrate (2g) was heated in an oil bath reflux 1h, when supplemented with 20mL ethanol was stirred difficulties, the reaction was continued to 2.5h, HPLC showed the starting material the reaction was complete. Add EA / H2O 100mL each liquid separation, the EA phase was washed with water (100mL) and the combined organic phases were washed with water (100mL) and saturated brine (100mL) washed. Anhydrous magnesium sulfate and filtered spin column was done product 1.88g, yield 88%, HPLC 94%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 7.64 (D, J = 7.2Hz, 2H), 7.57 (D, J = 8.1Hz, 2H), 7.45 (T, J = 7.6Hz, 2H), 7.39-7.32 ( m, 5H), 7.29 (d , J = 8.1Hz, 3H), 4.55-4.43 (m, 2H), 3.38-3.23 (m, 3H), 3.18-3.10 (m, 1H), 2.82-2.74 (m, 1H), 2.61-2.52 (m, 1H ).

Example 13

Synthesis of Compound 11

To the toluene solution of the compound 2 was added phthalimide (1.1 eq), triphenylphosphine (1.3 eq) with stirring. External bath set -10 ℃, to cool the system, the internal temperature dropped to 0 ~ 5 ℃, start dropping DIAD (1.3eq), control the internal temperature -5 ~ 5 ℃. Completion of the dropwise addition, the cooling bath was turned off outside the reaction was stirred at room temperature. The reaction was stirred for 1 to 4 hours. The reaction solution to give compound 3, administered directly in the next reaction. To the above reaction mixture was added hydrazine hydrate (6 eq), heated to 70 ~ 80 ℃, to complete the reaction, filtered hot, the filtrate. Aqueous sodium hydroxide solution (20vol 10%) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. Water was added (20vol) was stirred for 0.5h, allowed to stand for liquid separation from toluene phase. The toluene phase was added hydrochloric acid (20vol, 3N), stirred for 0.5h, to form a solid precipitate. Filtration and drying to obtain a product, i.e. compound 11, the hydrochloride salt, yield 60% in two steps.

NMR data of the product are as follows:

¹ the H NMR (400MHz, of DMSO) [delta] 8.46 (S, 3H), 7.63 (dd, J = 16.4,7.7Hz, 4H), 7.47 (T, J = 7.6Hz, 2H), 7.42-7.22 (m, 8H ), 4.56 (d, J = 12.1Hz, 1H), 4.48 (d, J = 12.1Hz, 1H), 3.58 (d, J = 7.9Hz, 2H), 3.47 (dd, J = 10.9,6.3Hz, 1H ), 3.11 (dd, J = 13.5,4.9Hz, 1H), 2.92 (dd, J = 13.4,9.1Hz, 1H).

Example 14

Synthesis of Compound 12

Weigh Compound 11 (1.38g) was added to the reaction flask. To the reaction flask plus DCM (14ml) and Et3N (462mg, 0.73ml). Weighed (of Boc) ₂O (1.23 g of) was added to DCM (5ml) was dissolved. Room temperature (8 ℃), a solution (of Boc) ₂ DCM solution O was added dropwise to the reaction, (2ml) rinsed with DCM. The reaction mixture was stirred at room temperature, detected by HPLC, the reaction ends 4h. Reaction mixture was washed (15ml) 3 times with Brine (15ml) The reaction solution was washed 1 times. Inorganic sulfate, concentrated and purified by column PE:EA = 15:1 give product 560mg, yield 30.8%, HPLC 99.92%.

NMR data of the product are as follows:

¹ the H NMR (400MHz, CDCl ₃ ) [delta] 7.57 (D, J = 7.6Hz, 2H), 7.49 (D, J = 7.4Hz, 2H), 7.43 (T, J = 7.3Hz, 2H), 7.39-7.28 (m, 5H), 7.24 ( d, J = 9.0Hz, 3H), 5.00-4.80 (br, 1H), 4.51 (q, J = 11.8Hz, 2H), 4.08-3.85 (br, 1H), 3.43 ( d, J = 2.9Hz, 2H) , 3.02-2.77 (m, 2H), 1.42 (s, 9H).

Example 15

Synthesis of Compound 6

Weigh Compound 12 (250mg) and methanol (9ml) was added to the reaction flask. Added Pd / C (138mg, 1 / 4w / w, water content 55%). The H ₂replaced 3 times, 50 ℃ stirred and heated. HPLC detection reaction, the reaction end 30h. Filtered off Pd / C, 40 ℃ concentrated under reduced pressure to remove methanol. PE:EA = 3:1 florisil column to give the product 196mg, 100% yield, 99.34% purity.

NMR data of the product are as follows:

Method for preparing the AHU-377, characterized by comprising the steps of: (a) Compound (1) S- benzyl glycidyl ether and biphenyl Grignard reagent produced by the reaction of the compound (2) in an organic solvent; ( b) compound (2) with a succinimide or phthalimide Mitsunobu reaction occurs in an organic solvent to form a compound (3); (C) compound (3) in an organic solvent in the role of a catalyst under removal debenzylation protected form compound (4); (D) compound (4) with an oxidizing agent oxidation reaction occurs in an organic solvent to form a compound (7); (E) compound (7) with a phosphorus ylide reagent in an organic solvent to give the compound (8); (F.) compound (8) in an organic solvent in the selective catalytic hydrogenation of the compound (9); and (g) of the compound (9) in an organic solvent in the hydrolysis reaction of the amide compound occurs in the presence of an acid ( 10), i.e., AHU-377;

HAO 472

July 8, 2016 4:08 am / Leave a comment

.CF3COOH

HAO 472

PHASE 1 CHINA

PRoject Name: HAO472 treatment Phase I clinical trial in relapsed / refractory AML, M2b type of AML

The main purpose: to determine HAO472 treatment of relapsed / refractory C the maximum tolerated dose (MTD). Secondary objectives: 1) evaluation of drug safety and tolerability; 2) study HAO472 in pharmacokinetic characteristics of the human body; 3) the effectiveness of HAO472 treatment of relapsed / refractory M2b type of AML.

Introduction Test

Acute myelogenous leukemia

HAO472

Phase I

Test Number: CTR20150246

Sponsor Name:

Jiangsu Hengrui Medicine Co., Ltd. 1/
2 Ruijin Hospital, Shanghai Jiaotong University School of Medicine /
3 Jiangsu Hengrui Medicine Co., Ltd. /
4 Shanghai Hengrui Medicine Co., Ltd. /

Natural products have historically been, and continue to be, an invaluable source for the discovery of various therapeutic agents. Oridonin, a natural diterpenoid widely applied in traditional Chinese medicines, exhibits a broad range of biological effects including anticancer and anti-inflammatory activities. To further improve its potency, aqueous solubility and bioavailability, the oridonin template serves as an exciting platform for drug discovery to yield better candidates with unique targets and enhanced drug properties. A number of oridonin derivatives (e.g. HAO472) have been designed and synthesized, and have contributed to substantial progress in the identification of new agents and relevant molecular mechanistic studies toward the treatment of human cancers and other diseases. This review summarizes the recent advances in medicinal chemistry on the explorations of novel oridonin analogues as potential anticancer therapeutics, and provides a detailed discussion of future directions for the development and progression of this class of molecules into the clinic.

Highlights

Oridonin displays significant anticancer activities via multi-signaling pathways.

Recent advances in medicinal chemistry of oridonin-like compounds are presented.

The article summarizes the SAR and mechanism studies of relevant drug candidates.

The milestones and future direction of oridonin-based drug discovery are discussed.

European Journal of Medicinal Chemistry

Volume 122, 21 October 2016, Pages 102–117

Review article

Discovery and development of natural product oridonin-inspired anticancer agents

^a Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555, United States
^b Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States

SEE http://www.sciencedirect.com/science/article/pii/S0223523416304937

doi:10.1016/j.ejmech.2016.06.015

Major milestones achieved in oridonin-inspired drug discovery and development.

////////Natural product, Oridonin, Diterpenoids, Anticancer agents, Drug discovery, Chemical biology, AML, HAO 472, relapsed / refractory AML. Jiangsu Hengrui Medicine Co., Ltd, PHASE1, LEUKEMIA

C[C@H](N)C(=O)O[C@]15OC[C@@]2([C@H](O)CCC(C)(C)[C@@H]2[C@H]1O)[C@H]3CC[C@@H]4C(=C)C(=O)[C@@]35C4O

FDA approves new diagnostic imaging agent FLUCICLOVINE F-18 to detect recurrent prostate cancer

May 28, 2016 5:28 am / Leave a comment

FLUCICLOVINE F-18

Cyclobutanecarboxylic acid, 1-amino-3-(fluoro-¹⁸F)-, trans- [

Molecular FormulaC₅H₈¹⁸FNO₂
Average mass132.124 Da

Axumin (fluciclovine F 18)

fluciclovinum (¹⁸F)

GE-148

NMK36

trans-1-Amino-3-(¹⁸F)fluorcyclobutancarbonsäure [German] [ACD/IUPAC Name]

trans-1-Amino-3-(¹⁸F)fluorocyclobutanecarboxylic acid [ACD/IUPAC Name]

UNII-38R1Q0L1ZE

anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid

cas 222727-39-1

FDA approves new diagnostic imaging agent to detect recurrent prostate cancer

05/27/2016 11:27 AM EDT

The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

May 27, 2016

Release

Prostate cancer is the second leading cause of death from cancer in U.S. men. In patients with suspected cancer recurrence after primary treatment, accurate staging is an important objective in improving management and outcomes.

“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, M.D., Ph.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Axumin is shown to provide another accurate imaging approach for these patients.”

Two studies evaluated the safety and efficacy of Axumin for imaging prostate cancer in patients with recurrent disease. The first compared 105 Axumin scans in men with suspected recurrence of prostate cancer to the histopathology (the study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. Radiologists onsite read the scans initially; subsequently, three independent radiologists read the same scans in a blinded study.

The second study evaluated the agreement between 96 Axumin and C11 choline (an approved PET scan imaging test) scans in patients with median PSA values of 1.44 ng/mL. Radiologists on-site read the scans, and the same three independent radiologists who read the scans in the first study read the Axumin scans in this second blinded study. The results of the independent scan readings were generally consistent with one another, and confirmed the results of the onsite scan readings. Both studies supported the safety and efficacy of Axumin for imaging prostate cancer in men with elevated PSA levels following prior treatment.

Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure to patients and healthcare providers during administration. Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.

The most commonly reported adverse reactions in patients are injection site pain, redness, and a metallic taste in the mouth.

Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom

Patent

http://www.google.com/patents/WO2014023775A1?cl=en

The non-natural amino acid [ F]-l-amino-3-fluorocyclobutane-l-carboxylic acid

([¹⁸F]-FACBC, also known as [¹⁸F]-Fluciclovine) is taken up specifically by amino acid transporters and has shown promise for tumour imaging with positron emission tomography (PET).

A known synthesis of [¹⁸F]-FACBC begins with the provision of the protected precursor compound 1 -(N-(t-butoxycarbonyl)amino)-3 –

[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester. This precursor compound is first labelled with [¹⁸F]-fluoride:

II before removal of the two protecting groups:

IT III

EP2017258 (Al) teaches removal of the ethyl protecting group by trapping the [¹⁸F]- labelled precursor compound (II) onto a solid phase extraction (SPE) cartridge and incubating with 0.8 mL of a 4 mol/L solution of sodium hydroxide (NaOH). After 3 minutes incubation the NaOH solution was collected in a vial and a further 0.8 mL 4 mol/L NaOH added to the SPE cartridge to repeat the procedure. Thereafter the SPE cartridge was washed with 3 mL water and the wash solution combined with the collected NaOH solution. Then 2.2 mL of 6 mol/L HCl was then added with heating to 60°C for 5 minutes to remove the Boc protecting group. The resulting solution was purified by passing through (i) an ion retardation column to remove Na⁺ from excess NaOH and Cl^~ from extra HCl needed to neutralise excess of NaOH to get a highly acidic solution before the acidic hydrolysis step, (ii) an alumina column, and (iii) a reverse-phase column. There is scope for the deprotection step(s) and/or the

purification step in the production of [¹⁸F]-FACBC to be simplified.

Example 1: Synthesis of f FIFACBC

No-carrier- added [¹⁸F]fluoride was produced via the ¹⁸0(p,n)¹⁸F nuclear reaction on a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo). Irradiations were performed using a dual-beam, 30μΑ current on two equal Ag targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6 ml of > 96% [¹⁸0]water (Marshall Isotopes). Subsequent to irradiation and delivery to a hotcell, each target was washed with 1.6 ml of [¹⁶0]water (Merck, water for GR analysis), giving approximately 2-5 Gbq in 3.2 ml of [¹⁶0]water. All radiochemistry was performed on a commercially available GE FASTlab™ with single-use cassettes. Each cassette is built around a one-piece-moulded manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connection with five prefilled vials, one water bag (100 ml) as well as various SPE cartridges and filters. Fluid paths are controlled with nitrogen purging, vacuum and the three syringes. The fully automated system is designed for single-step fluorinations with cyclotron-produced [¹⁸F]fluoride. The FASTlab was programmed by the software package in a step-by-step time-dependent sequence of events such as moving the syringes, nitrogen purging, vacuum, and temperature regulation. Synthesis of

[¹⁸F]FACBC followed the three general steps: (a) [¹⁸F]fluorination, (b) hydrolysis of protection groups and (c) SPE purification.

Vial A contained K₂₂₂ (58.8 mg, 156 μπιοΐ), K₂C0₃ (8.1 mg, 60.8 μπιοΐ) in 79.5% (v/v)

MeCN(a_q) (1105 μΐ). Vial B contained 4M HC1 (2.0 ml). Vial C contained MeCN

(4.1ml). Vial D contained the precursor (48.4 mg, 123.5 μιηοΐ) in its dry form (stored at -20 °C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml). The 30 ml product collection glass vial was filled with 200 mM trisodium citrate (10 ml). Aqueous

[¹⁸F]fluoride (1-1.5 ml, 100-200 Mbq) was passed through the QMA and into the ¹⁸0-

H₂0 recovery vial. The QMA was then flushed with MeCN and sent to waste. The trapped [¹⁸F]fluoride was eluted into the reactor using eluent from vial A (730 μΐ) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 μΐ, vial C). Approximately 1.7 ml of MeCN was mixed with precursor in vial D from which 1.0 ml of the dissolved precursor (corresponds to 28.5 mg, 72.7 mmol precursor) was added to the reactor and heated for 3 min at 85°C. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was washed with water, and then incubated with 2M NaOH (2.0 ml) for 5 min after which the 2M NaOH was sent to waste. The labelled intermediate (without the ester group) was then eluted off the tC18 cartridge into the reactor using water. The BOC group was hydrolysed by adding 4M HC1 (1.4 ml) and heating the reactor for 5 min at 60 °C. The reactor content with the crude [¹⁸F]FACBC was sent through the HLB and Alumina cartridges and into the 30 ml product vial. The HLB and Alumina cartridges were washed with water (9.1 ml total) and collected in the product vial. Finally, 2M NaOH (0.9 ml) and water (2.1 ml) was added to the product vial, giving a purified formulation of [¹⁸F]FACBC with a total volume of 26 ml. Radiochemical purity was measured by radio-TLC using a mixture of MeCN:MeOH:H₂0:CH₃COOH (20:5:5: 1) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [¹⁸F]FACBC fraction divided by the total used [¹⁸F]fluoride activity (decay corrected). Total synthesis time was 43 min.

The RCY of [¹⁸F]FACBC was 62.5% ± 1.93 (SD), n=4.

/////FDA, diagnostic imaging agent, recurrent prostate cancer, fda 2016, Axumin, marketed, Blue Earth Diagnostics, Ltd., Oxford, United Kingdom, fluciclovine F 18

C1[C@@](C[C@H]1[18F])(N)C(=O)O

UPDATE

FLUCICLOVINE

Image result for FLUCICLOVINE

LINK https://newdrugapprovals.org/2016/05/28/fda-approves-new-diagnostic-imaging-agent-fluciclovine-f-18-to-detect-recurrent-prostate-cancer/

SEE EMA

Axumin : EPAR – Summary for the public

EN = English

06/07/2017

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004197/human_med_002100.jsp&mid=WC0b01ac058001d124

Marketing-authorisation holder	Blue Earth Diagnostics Ltd
Revision	0
Date of issue of marketing authorisation valid throughout the European Union	22/05/2017

Contact address:

Blue Earth Diagnostics Ltd
215 Euston Road
London NW1 2BE
United Kingdom

Manufacture, characterisation and process controls

The active substance fluciclovine (18F) is prepared from the precursor AH113487 by nucleophilic substitution
of a triflate group by 18F-fluoride, followed by two deprotection steps. Due to the short half-life of the 18Ffluorine
radioisotope, each batch is prepared on the day of clinical use.
The active substance is prepared in a proprietary automated synthesiser unit. The synthesiser module is
computer-controlled. A fluid path for synthesis is provided in the form of a single use cassette (FASTlab). The
cassette contains 3 reagent vials and 3 solid phase cartridges. Two other reagent vials are supplied
separately as they have a recommended storage temperature of 2-8°C. These 2 vials are inserted into the
cassette on the day of production.
Assessment report
EMA/237809/2017 Page 13/90
Fluciclovine (18F) is produced in a continuous operation from the precursor AH113487. Due to the radioactive
nature of the process, and the short half-life of [18F] fluorine, intermediates are not isolated and there is no
opportunity for operator intervention or in-process testing. Control of the synthesis of fluciclovine (18F) from
the precursor is achieved through the automated synthesis platform, which is pre-programmed with
synthesis parameters optimised for the process. On-board detectors record transfers of radioactivity through
the fluid path at critical points and monitor temperature and pressure as appropriate so that the operator
may track the progress of the synthesis.
The active substance fluciclovine (18F) progressses immediately to purification, formulation and dispensing as
the finished product within a single, continuous operation. Validation of the manufacturing process for
fluciclovine (18F) is therefore described as part of finished product validation.
The characterisation of the active substance is in accordance with the EU guideline on chemistry of new
active substances.
As mentioned, the manufacture of the active substance and finished product takes place in a single,
continuous process. The active substance is not isolated at any point. Therefore, relevant information about
impurities is given only for the finished product.
For the same reason, information for the container closure system is provided only for the finished product.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004197/WC500230836.pdf

Cymipristone

April 29, 2016 1:19 pm / Leave a comment

ChemSpider 2D Image | Cymipristone | C34H43NO2

Cymipristone

(8S,11R,13S,14S,17S)-11-{4-[Cyclohexyl(méthyl)amino]phényl}-17-hydroxy-13-méthyl-17-(1-propyn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrén-3-one

Estra-4,9-dien-3-one, 11-[4-(cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propyn-1-yl)-, (11β,17β)-

11 β – [4- (Ν- -N- methyl-cyclohexylamino)] -17 α – (1- propynyl) -17 β – hydroxy estra-4,9-dien-3-one

Estra-4,9-dien-3-one, 11-[4-(cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-, (11β,17β)- (9CI)
(11β,17β)-11-[4-(Cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propyn-1-yl)estra-4,9-dien-3-one
Saimisitong

Shanghai Siniwest Pharmaceutical Chemical Technology Co., Ltd., Shanghai Zhongxi Pharmaceutical Co. Ltd., Xianju Pharmaceutical Co., Ltd,

A progesterone receptor antagonist potentially for termination of intrauterine pregnancy.

CAS No.329971-40-6

Molecular FormulaC₃₄H₄₃NO₂
Average mass497.711 Da
Steroid Compounds, a Method for Preparation thereof, Pharmaceutical Compositions Containing the Same and Use thereof

This invention relates to steroid compounds and pharmaceutical acceptable salts thereof, a method for preparation thereof, pharmaceutical compositions containing the same as active component, and their use in the preparation of medicines for treating diseases associated with progestogen dependence and for fertility control, abortion or contraception and for anticancer use.
Mifepristone (11β-[4-(N,N-dimethylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in French Patent No. 2,497,807 to Rousell-Uclaf, published May 31, 1983. It is the first progesterone receptor antagonist put into clinical application and is a new type of anti-progestin. It binds to progesterone receptor and glucocorticoid receptor, having an affinity with progesterone receptor in rabbit endometrium five-fold higher than that of progesterone and thereby having strong anti-progesterone effect. It causes degeneration of pregnant villus tissue and decidual tissue, endogenous prostaglandin (PG) release, luteinizing hormone decrease, corpus luteum dissolution, and necrosis of embryo sac whose development depends on corpus luteum, leading to abortion. Therefore, it can be used as a non-surgical medicine for stopping early pregnancy. It can also be used, inter alia, in contraception and as an antineoplastic. (The Antiprogestin Steroid Ru486 and Human Fertility Control, 1985, New York: Plenum Press) .
Onapristone (11β-[4-(N,N-diemthylamino)phenyl]-17α-hydroxy-17β-(3-hydroxypropyl)-13α-4,9-estradiene-3-one), is a steroid compound which is disclosed in German Patent No. 3,321,826 to Schering AG, published Dec. 20, 1984. It has a strong antiprogestin activity and can be used in abortion (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), anticancer (Breast Cancer Research and Treatment, 1989, 14:275-288), etc. It was reported that onapristone had toxicity to human liver (European Journal of Cancer, 1999, 35(2):214-218).
Lilopristone (11β-[4-(N,N-dimethylamino) phenyl]-17α-[3-hydroxy-1(Z)-propenyl]-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3,347,126 to Schering AG, published July 11, 1985. It has a strong antiprogestin activity and can be used in abortion, contraception (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), etc. It was reported that the clinical effect of lilopristone in stopping early pregnancy was only equivalent to that of mifepristone (Human Reproduction, 1994, 9(1):57-63).
ZK112993 (11β-(4-acetylphenyl)-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is as steroid compound which is disclosed in German Patent No. 3,504,421 to Schering AG, published Aug. 7, 1986. It has a potent antiprogestin activity and can be used in, inter alia, anticancer (Anticancer Res., 1990, 10:683-688).
In European Patent No. 321,010 to Akzo NV, The Netherland published June 21, 1989 are disclosed “11-arylsteroid compounds” having a strong antiprogestin activity.

PATENT

WO 2001018026

http://www.google.com/patents/EP1219632A1?cl=en

The preparation method of the present invention includes the following single- or multi-step procedures:

1. Method for the preparation of 11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (IV) which includes the following steps:

(1) Preparation of Grignard reagent (III)

4-bromo-N-methyl-N-cyclohexylaniline (II) is reacted with magnesium in tetrahydrofuran (THF) to obtain Grignard reagent of formula (III).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (III) prepared in step (1) are brought to an additive reaction to obtain compound of formula (V).

(3) Hydrolytic reaction

The compound of formula (V) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of form (VI).

2. Method for preparation of 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI) which includes the following steps:

(1) Preparation of Grignard reagent of formula (IX)

4-bromo-N-cyclohexylaniline (VII) is first protected by trimethylchlorosilane, then reacted with magnesium in THF to obtain Grignard reagent of formula (IX).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (IX) prepared in step (1) are brought to an additive reaction to obtain compound of formula (X).

(3) Hydrolytic reaction

The compound of formula (X) prepared in step (2) is subjects to a hydrolytic reaction to obtain compound of formula (XI).

Example 2:

9g 4-bromo-N-cyclohexylaniline (VII) (CA registration number [113388-04-8], see Synthetic Communications, 1986, 16(13): 1641-1645 for its preparation) was placed into a four-necked flask and 15 ml (1.5 mol/L) n-BuLi solution in n-hexane. The mixture was stirred for 30 min at room temperature. Then 8 g trimethylsilyl chloride (Me₃SiCl) was added and the mixture was stirred for 1 hour. Solvent and excessive Me₃SiCl was evaporated under reduced pressure to yield 4-bromo-(N-cyclohexyl-N-trimethylsilylaniline) (VIII) which was formulated into a solution with 7.5 ml anhydrous tetrahydrofuran for further use.
1.3 g magnesium was placed into a four-necked flask and a small amount of the above solution was added dropwise and slowly at 40°C. After completion of addition, the temperature was kept for 1 hour to yield a solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenylmagnesium bromide (IX) in tetrahydrofuran for further use.

(2) Preparation of 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cylohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

5g 3,3-ethylenedioxy-5,10-epoxy-17α-(1-propinyl)-17β-hydroxy-9(11)-estrene (IV) was placed into a four-necked flask and 10 ml anhydrous tetrahydrofuran and a catalytic amount of cuprous chloride (Cu2Cl2) added. Then solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenyl magnesium bromide (IX) in tetrahydrofuran was added dropwise and slowly while controlling the temperature below 5°C. After completion of addition, the mixture was allowed to react for 2 hours at room temperature and to stand overnight. Saturated ammonium chloride aqueous solution was added and the tetrahydrofuran layer separated which was washed with saturated ammonium chloride solution. The solution in tetrahydrofuran was washed with saturated saline and dried over anhydrous sodium sulfate. Evaporation of tetrahydrofuran under reduced pressure yielded a residual which was chromatographed on silica gel column using cyclohexane: acetone (5:1) as developing agent to yield 3 g 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

IR (KBr) cm^-1: 3420 (C₅, C₁₇-OH), 1610, 1510 (benzene backbone), 840, 808 (ArH).
¹H NMR (CDCl₃) δ ppm: 0.52(3H, S, C₁₃-CH₃), 2.72(3H, S, N-CH₃), 3.92(4H, m, -O-CH₂CH₂-O-), 4.24(1H, m, C₁₁-H), 6.65-7.00 (4H, ArH).

(3) Preparation of 11β- [4- (N-cyclohexylamino)phenyl] -17α- (1-propinyl) -17β-hydroxy-4,9-estradiene-3-one (XI).

1.5g 3,3-ethylenedioxy-5,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene (X) and 0.75 g para-toluenesulfonic acid (PTS) were dissolved in 15 ml 90 % ethanol (v/v). The mixture was stirred for 2 hours while controlling the temperature at 40°C-50°C. After completion of the reaction, the reactant was poured into diluted sodium hydroxide aqueous solution, extracted with dichloroethane, washed with water to neutrality, and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography on silica gel column using cyclohexane: ethyl acetate (5:1) as developing agent yielded 0.9 g 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI).

IR (KBr) cm^-1: 3400 (C₁₇-OH), 1658 (unsaturated ketone), 1613, 1514 (benzene backbone), 865, 810 (ArH).
¹H NMR (CDCl₃) δ ppm: 0.50 (3H, S, C₁₃-CH₃), 1.76 (3H, S, C≡C-CH₃), 4.32(1H, S, C₁₁-H), 5.75(1H, S, C₄-H), 6.9-7.10 (4H, ArH).

PATENT

WO 2006063526

PATENT

WO 2007009397

Example 1

Race meters mifepristone synthetic routes:

Epoxy adduct match rice mifepristone

(N- hexylamino methylcyclohexyl) phenyl magnesium bromide (1) 4-

In the four-necked flask, 1.4 g of magnesium into pieces (Mg) and 10 ml of anhydrous tetrahydrofuran (THF), no iodine or add a little change, at about 50 ° C, a solution of 10.86 g of 4-bromo-methyl -N- cyclohexyl aniline (dissolved in 24 ml of anhydrous tetrahydrofuran) dropwise Bi, incubation was continued for 1 hour with stirring to give 4- (N- methyl-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran solution (to be used in the next step an addition reaction ).

(2) 3,3-ethylenedioxy -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propyl block-yl) -9 (10) – Preparation of estra-ene (adduct) of

In the four-necked flask, into 5 g of 3,3-ethylenedioxy-5,10-epoxy -17 α – (1- propynyl) – 17 (3 – hydroxy – 9 (11) – estra-ene (epoxy), 29.1 ml anhydrous tetrahydrofuran (THF) and 0.1 g cuprous chloride (of Cu ₂ of Cl ₂ ), a solution of 4- (N- methyl -N-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran

Nan solution, temperature control 5. C, the drop was completed, the incubation was continued for 5 hours, the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, points to the water layer, the organic layer was washed with saturated ammonium chloride solution, the aqueous layer extracted with ethyl acetate number times, the organic layers combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, a silica gel column, eluent cyclohexane: acetone = (5: 1) to give 3,3-ethylene dioxo -5 α, 17 β – dihydroxy -11 β – [4- (- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – female steroidal women (adduct) solid 6 grams.

IR. ‘KBi cm- ^ SlS OI ^ ^ -OH lS jSlS benzene backbone), 819 (aromatic hydrogen). NMR Ή: (CDC1 ₃ ) ppm by [delta]: 0.47 (3H, the S, the C _IR CH ₃ ), 1.88 (3H, the S, the C ≡ the C-CH ₃ ), 2.72 (3H, the S, the N-CH ₃ ), 6.65- 7.03 (4H, ArH) _O

(3) 11 β – [4- (N- methyl -N- cyclohexylamino) phenyl] -17 α – (1- propynyl) -17 β – hydroxy-estra-4,9-diene – Preparation of 3-one (match rice mifepristone) of

‘2.5 g of p-toluenesulfonic acid (PTS) and 5 grams of 3,3-ethylenedioxythiophene -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – estra-ene (adduct) was dissolved in 50 ml of ethanol 90% (V / V), and at 5 ° C – 40 ° C the reaction was stirred 3 hours, the reaction solution was poured into dilute aqueous sodium hydroxide solution, the precipitated solid was suction filtered, washed with water until neutral, the filter cake was dissolved in 50 ml of ethyl acetate, then with saturated aqueous sodium chloride solution to the water layer was evaporated part of the solvent, the precipitated solid was suction filtered, and dried to give a pale yellow solid 11 β – [4- (Ν- -N- methyl-cyclohexylamino)] -17 α – (1- propynyl) -17 β – hydroxy estra-4,9-dien-3-one (match rice mifepristone) 3 grams.

^ Cm & lt IRCKB ¹ : 3447 (the C _{. 17} -OH), among 1655 (unsaturated ketone), 1607,1513 (benzene backbone), 865,819 (aromatic hydrogen).

NMR ¾: (CDC1 ₃ ) ppm by [delta]: 0.56 (3H, the S ₅ the C ₁₃ -CH ₃ ), 1.89 (3H, the S ₅ -C ≡ the C-the CH3), 2.74 (3H, the S, the N-the CH3), 4.34 ( lH, the S, the C _N -H), 5.75 (lH, the S, the C ₄ -H), 6.68-6.99 (4H, ArH).

PATENT

CN 102107007

PATENT

CN 102106805

PAPER

Journal of Chromatography B

Volume 878, Issues 7–8, 1 March 2010, Pages 719–723

Determination of cymipristone in human plasma by liquid chromatography–electrospray ionization-tandem mass spectrometry

doi:10.1016/j.jchromb.2010.01.027

Abstract

A rapid, specific and sensitive liquid chromatography–electrospray ionization-tandem mass spectrometry method was developed and validated for determination of cymipristone in human plasma. Mifepristone was used as the internal standard (IS). Plasma samples were deproteinized using methanol. The compounds were separated on a ZORBAX SB C₁₈ column (50 mm × 2.1 mm i.d., dp 1.8 μm) with gradient elution at a flow-rate of 0.3 ml/min. The mobile phase consisted of 10 mM ammonium acetate and acetonitrile. The detection was performed on a triple-quadruple tandem mass spectrometer by selective reaction monitoring (SRM) mode via electrospray ionization. Target ions were monitored at [M+H]⁺m/z 498 → 416 and 430 → 372 in positive electrospray ionization (ESI) mode for cymipristone and IS, respectively. Linearity was established for the range of concentrations 0.5–100 ng/ml with a coefficient correlation (r) of 0.9996. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.5 ng/ml. The validated method was successfully applied to study the pharmacokinetics of cymipristone in healthy Chinese female subjects.

CHEMICAL ABSTRACTS, vol. 115, no. 25, 23 December 1991 (1991-12-23) Columbus, Ohio, US; abstract no. 270851g, X. ZHAO ET AL.: “Synthesis and terminating early pregnancy effect of mifepristone derivatives” page 117; XP002219009 & ZHONGGUO YAOKE DAXUE XUEBAO, vol. 22, no. 3, 1991, pages 133-136,

//////////Cymipristone, Saimisitong, Shanghai Siniwest Pharmaceutical Chemical Technology Co., Ltd., Shanghai Zhongxi Pharmaceutical Co. Ltd., Xianju Pharmaceutical Co., Ltd,

WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, NEW PATENT

February 8, 2016 6:48 am / Leave a comment

(S) – propylene glycol and water, 1: 1 crystalline complex

PATENT

WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME

HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)

KIM, Ki Lim; (KR).
PARK, Chulhyun; (KR).
LEE, Jaeheon; (KR).
CHANG, Young-kil; (KR)

The present invention relates to a crystalline composite comprising dapagliflozin and a method for preparing the same. More specifically, the present invention provides a novel crystalline composite comprising dapagliflozin, which is an SGLT2 inhibitor, and a preparing method capable of economically preparing the novel crystalline composite at high purity.

long period of time, there is a problem with secretion of insulin in diabetes is a problem with the function of insulin, or the two compounds problems of the disease that is to say maintaining a high blood sugar. Insulin helps the one that sends glucose into cells in order to replace the nutrients such as glucose that is in a hormone secreted by the beta cells of the pancreas blood into energy. However, if there is insufficient action of insulin, glucose accumulates in the blood does not enter the cell and cause the muscles and blood sugar, sugar in the urine is out. When these two long-standing high blood sugar will cause a number of microvascular complications. Not cut due to such complications, such as may result in blindness.

Worldwide diabetes has become one of the major causes of death in adults, an increasing number of diabetes patients may sharply with the increase of obesity population.

In diabetic patients SGLT2 (Sodium-Glucose linked transporter 2) selective inhibition of significant gastrointestinal side effects without increasing the emissions of glucose in the urine, thereby improving insulin sensitivity and delay the onset of diabetes complications by the normalization of plasma glucose can be there.

Bristol-to US Patent No. 6,515,117 of Myers Squibb Company of formula It discloses a binary) to dapa glyphs.

[Formula 1]

While preparing the material of Formula 1 in the above patent, the desired compound was obtained as an oil form, here was added to the chloroform under vacuum to reprocess getting the desired compound as a solid in a viscous that contains ethyl acetate. Compounds of the formula I obtained by the above method of production must be carried out the purification using a column, etc. because it can not remove the impurities of the desired compound, which is not suitable as an industrial method.

In addition, Bristol-to the US Patent 7,919,598 of Myers Squibb Company No. discloses a compound of formula 2.

[Formula 2]

Compounds of Formula 2 are the compounds of formula 1, (S) – propylene glycol and water, 1: 1 crystalline complex: 1. The compound of Formula 2 can be conveniently used in medicine to use by crystallizing the compound of formula 1 with low crystallinity and are also useful in the purification of the compounds of formula (I).

However, the compound of formula 2 is (S), the price is very expensive – and the use of propylene glycol, which results in increasing the production cost. This is very disadvantageous In the eyes of people with diabetes need to take the long-term.

In addition, European Patent No. 2597090 of Sandoz is disclosed of the formula monohydrate. Of the formula monohydrate is then stirred as a compound of the sugar alcohol and the formula of the glycol, glycerol, arabitol, xylitol, etc. in water obtained the seed (seed), by using this discloses a method for preparing the monohydrate in water, and have.

However, the European patent is described that the hydrate should be obtained stirred for three days at low temperature in order to obtain after obtaining the actual seed crystals, although not yield is mentioned is expected to be very low. For this reason, because of the situation in the research and development of novel crystalline complexes THE dapa glyphs are continually required.

Best Mode for Carrying out the Invention

Hereinafter, the present invention will be described in detail.

Crystalline complex according to the invention is for lowering the production cost by obtaining a product of high purity without the need for further purification, it has the structure of formula (3).

[Formula 3]

The crystalline complex is in the X- ray diffraction pattern of 9.7, 17.3, 20.0, 20.4, and may comprise a characteristic peak at a 2θ of 21.4 ± 0.2 °, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and can include a peak at 2θ of teukjeongjik, it may be most preferably having a powder X-ray diffraction pattern is shown in Fig.

It was confirmed that the heat-absorption peak appears at about 163 ℃, to refer to the thermal analysis by; (DSC differential scanning calorimetr) The crystalline complex is differential scanning calorimetry of FIG.

The crystalline complex is the measured moisture content in accordance with the Karl-Fischer method can be 2-5%, preferably be 2.1 ~ 3.5%.

In addition, the present invention includes a mixture of 1), mannitol and the solvent to prepare a mannitol solution; 2) preparing an alcohol solution by mixing the alcohol with the glyph dapa gin; 3) mixing the mannitol solution and the alcohol solution, heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 ~ 15 ℃ provides a method for preparing the crystalline complex comprising the steps of obtaining a composite having a crystalline structure of Formula 3.

It describes a method for producing crystalline complex according to the present invention;

Step 1: Mannitol solution prepared

Step 1 of the manufacturing method according to the present invention is a step in which a mixture of mannitol and a solvent to prepare a mannitol solution.

The mannitol is suitable for the manufacture of a therapeutic agent for diabetes to be taking a long period of time as a material that is widely used like medicine, food, with high stability and low price. Furthermore, mannitol is used in reducing the edema by osmotic action, and thus the material to promote diuresis. This is mannitol is determined to be helpful to the action Qin dapa glyphs used as SGLT-2 inhibitors.

The mannitol is typically so long that can be purchased and / or synthesis is not particularly limited, preferably the D- mannitol, L- and D · mannitol may include one or more of the group consisting of L- mannitol , and it can be most preferably D- Magny-tolyl.

The solvent as long as it can dissolve the mannitol is not particularly limited, and may preferably be water.

The Mani mixing ratio of the toll and the solvent. If the amount that can be dissolve the mannitol, the solvent is not particularly restricted, the preferably mannitol and solvent 1: 8-20 weight ratio or 1: 1 may be mixed with 10 to 15 weight .

Step 2: Preparation of an alcohol solution

Step 2 of the manufacturing method according to the invention by mixing the alcohol with Jean dapa glyph is a step for preparing the alcoholic solution.

In the glyph binary dapa may be prepared by the method described in commercially available, and arc carried US Patent 6,515,117 example G.

The alcohol is long as it can dissolve the THE dapa glyph is not particularly limited, preferably the C ₁ ~ C ₄ alcohol may comprise at least one of (a lower alcohol), and most preferably ethanol .

The dapa If the mixing ratio of the pictures and alcohol as a glyph is content that can be dissolved in THE dapa glyph to alcohol is not particularly limited, preferably the gin alcohol dapa glyphs 1: 3-8 or 1: a volume ratio of 6-7 It may be mixed.

Step 3: heat-up phase

Step 3 of the manufacturing method according to the present invention is a step in which the mani mixing and heating the solution and the alcohol solution toll.

The step is a process for producing a crystalline complex containing THE dapa glyphs included in mannitol as an alcohol solution that is included in the mannitol solution, the mixing ratio of the mixed solution and the alcohol solution is mannitol and the pro pageul a binary 1: 0.5-2 or 1: it is preferable to mix in 1.0 to 1.5 molar ratio.

The heating may preferably be carried out at 50 ~ 100 70 ~ 90 ℃ or ℃.

Step 4: obtained crystalline complexes

Step 4 according to the present invention is by cooling the heated solution to obtain a crystalline complex having the structure of Formula 3.

The cooling is preferably at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃.

Further, according to the embodiment of the present invention, in order to improve the speed of determining the crystalline complex to be obtained, the cooling after seeding may further include a (seeding) and further comprising cooling. The further cooling can preferably be carried out at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃ for 5 to 24 hours, or 7 ~ 15 hours.

The production method of the present invention as described above, dapa glyphs to binary and mannitol for the crystalline complex has the advantage that can be produced in more than 99.0% pure without further purification, including, of high purity at a low manufacturing cost crystalline It has the advantage of producing the composite.

Mode for the Invention

Hereinafter the present invention will be described in more detail by examples. However, these examples are for the purpose of illustrating the invention by way of example, but the scope of the present invention is limited to these Examples.

Example 1. Preparation of the crystalline complex

The D- mannitol 0.98g (5.4mmol) was dissolved in purified water to prepare a mannitol 12㎖. On the other hand, amorphous THE dapa glyphs (purity:> 94%, U.S. Patent No. 6,515,117 prepared by the method described in of Example G) was dissolved in 2g (4.9mmol) in ethanol to give the alcohol 13 ㎖ solution. After the mannitol solution at room temperature to give the mixed solution is added to the alcohol solution. The mixed solution was heated under reflux for 3 hours so that the 80 ℃. After the cooling the solution obtained through the reflux slowly to 10 ℃ for 2 hours and then added to camp in the dapa glyph to 4 wt% solution total weight compared to the seeding (seeding) for 12 hours at 200 rpm at 4 ℃ cooling and stirring was added. After Buchner funnel (Buchner funnel) and filtered with a filter paper 55 ㎜ and dried for 8 hours under nitrogen and 20 ℃ to obtain a crystalline complex 1.3g (45%).

Experimental Example 1. Structural analysis

Nuclear magnetic resonance spectrum (NMR) (400MHz FT-NMR Spectrometer (Varian, 400-MR)) of a crystalline complex obtained in Example 1 by using ¹ yielded a H NMR spectrum, and the results, and in Fig. 1 It exhibited.

¹ H NMR (400㎒, DMSO-d ₆ ): δ 7.37-7.35 (d, 1H), 7.32-7.31 (d, 1H), 7.24-7.21 (dd, 1H), 7.10-7.08 (d, 2H), 6.83-6.81 (d, 2H), 4.97-4.95 (dd, 2H), 4.84-4.83 (d, 1H), 4.48-4.44 (t, 1H), 4.42-4.40 (d, 1H), 4.34-4.31 (t , 1H), 4.14-4.12 (d, 1H), 4.02-3.92 (m, 5H), 3.71-3.67 (m, 1H), 3.67-3.58 (m, 1H), 3.56-3.52 (t, 1H), 3.46 -3.35 (m, 3H), 3.28-3.07 (m, 4H), 1.31-1.27 (t, 3H)

The ^first through the results of 1 H NMR, and also, to the structure of a crystalline complex obtained in Example 1, it was confirmed that the formula (4).

[Formula 4]

Experimental Example 2. OK crystalline crystalline complexes

By performing an X-ray diffraction analysis and differential scanning calorimetry, it was confirmed that crystal form of the crystalline complex obtained in Example 1. More specifically, Diffraction Extensible Resource Descriptor (Brucker, USA) for use with X-ray diffraction (XRD) to perform, and differential scanning calorimetry (Differential scanning calorimeter; METTLER TOLEDO, Swiss) for use by differential scanning calorimetry (DSC) It was performed. Results of X-ray diffraction analysis results in Figure 1, the differential scanning calorimetry are shown in Fig.

Results of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention exhibited a characteristic peak at 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 2θ of 43.9 ° .

Experimental Example 3. HPLC analysis

To a crystalline complex obtained in Example 1 under the conditions of Table 1 and Table 2 it was carried out to HPLC (high performance liquid chromatography) analysis.

TABLE 1

column	Ascentis Express RP-Amide 4.6mm × 150mm (diameter × height), 2.7㎛ (Aldrich)
The mobile phase	_{A: Formic acid 1mL/1000mL in H 2 OB: Formic acid 1mL/1000mL in Acetonitrile (ACN)}
Test Solution	Acetonitrile Test specimen 5mg / 10mL in 50% (ACN)
Column temperature	25 ℃
Wavelength detector	UV, 220nm
Dose	3 ㎕
Flow rate	0.7 mL / min
Operating hours	40 min

Table 2

Gradient systems
Time (min)	Mobile phase A (%)	Mobile phase B (%)
0	75	25
0-25	35	65
25-26	30	70
26-29	30	70
29-35	75	25
35-40	75	25

As described above, the results of the HPLC analysis, the crystalline complex of Example 1, it was confirmed that the purity of 99% or more. In addition, the crystalline complex of Example 1, it was confirmed that the water content measured by Karl-Fischer method of 2.9%.

Claims

To a crystalline complex comprising a dapa THE glyph having the structure of formula 3: [Formula 3]

According to claim 1, wherein said crystalline complex is in the X- ray diffraction pattern of 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4, and the characteristic peaks at 2θ of 43.9 ± 0.2 ° containing crystalline complexes.

According to claim 1, wherein said crystalline complex is the measured moisture content in accordance with the Karl-Fischer method which is characterized in that 2 to 5%, the crystalline complex.

1) preparing a mannitol solution by mixing mannitol (mannitol) and the solvent 2) a mixture of binary (dapagliflozin) and alcohol in dapa glyph for preparing an alcohol solution; 3) wherein the mannitol solution and the alcohol mixing the solution and heated to 50 ~ 100 ℃; And 4) the production method to cool the heated solution to 0 ~ 15 ℃ comprising the step of obtaining a polycrystalline composite having a structure of formula (3), a crystalline complex: [Formula 3]

[Claim 5]

According to claim 4, wherein the solvent is the production of water, the crystalline complex.

According to claim 4, wherein the alcohol is a C ₁ ~ C _4, a method of producing a crystalline complex comprising at least one kind of alcohol.

According to claim 6, wherein the alcohol is ethanol, the method of the crystalline complex prepared.

According to claim 4, wherein the mixing ratio by the spirit and mannitol dapa glyph is 1: 0.5 to 2 mole ratio, the method of producing a crystalline complex.

FIGURES

Figure 1 illustrates a X- ray diffraction spectrum of the crystalline complex in accordance with an embodiment of the present invention.

2 is a result of the differential scanning calorimetry of the crystalline complexes (DSC) in accordance with an embodiment of the present invention.

3 is of the crystalline complex in accordance with an embodiment of the present invention ¹ shows the H-NMR measurement results.

[Figure 1]

[Figure 2]

[Figure 3]

CEO, YOUNG KIL CHANG

/////////WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, New patent

β-GLUCAN . Food Ingredient Sourced From Yeast, Shanghai Genon Biotech Co.,Ltd

October 25, 2013 3:43 am / Leave a comment

Diagram showing orientation and location of different beta-glucan linkages.

Examples of various β-glucan glycosidic linkages.

beta 1, 3- glucan and beta 1, 6- glucan.

Food Ingredient Sourced From Yeast

The shiitake mushroom contains beta-glucans.

β-Glucans (beta-glucans) are polysaccharides of D-glucose monomers linked by β-glycosidic bonds. β-glucans are a diverse group of molecules that can vary with respect to molecular mass, solubility, viscosity, and three-dimensional configuration. They occur most commonly as cellulose in plants, the bran of cereal grains, the cell wall of baker’s yeast, certain fungi, mushrooms and bacteria. Some forms of beta glucans are useful in human nutrition as texturing agents and as soluble fibersupplements, but can be problematic in the process of brewing.

Oat is a rich source of the water-soluble fibre (1,3/1,4) β-glucan, and its effects on health have been extensively studied the last 30 years. Oat β-glucans are the only dietary fiber currently recognized by the European Food Safety Authority (EFSA) to be able to reduce a disease risk. Oat β-glucans can be highly concentrated in different types of oat brans.

“Barley has more beta glucan fiber than any other grain” claims a report on DiabetesHealth website ; 11 sources are listed.

Yeast and medicinal mushroom derived β-glucans are notable for their ability to modulate the immune system. One study has shown that insoluble (1,3/1,6) β-glucan, has greater biological activity than that of its soluble (1,3/1,4) β-glucan counterparts.The differences between β-glucan linkages and chemical structure are significant in regards to solubility, mode of action, and overall biological activity.

I would like to thank amy of Shanghai Genon Biotech Co.,Ltd for motivating me to add this article

cut paste from Shanghai Genon Biotech Co.,Ltd

β-GLUCAN
‘Gecono’ β-Glucan (GNP80), derived from fresh food grade brewer’s yeast or baker’s yeast, is akind of ‘new resource food material’ developed by unique innovative biotechnologies. Its maincomponent is yeast sourced immunocompetent polysaccharide which has two isomers structured asbeta 1, 3- glucan and beta 1, 6- glucan. The former one which can greatly enhance human immunity isproved to have the anti-tumor, anti-radiation, anti-aging and free radical scavenging activities. It is animportant biological effect response agent.
Appearance: White or light yellow powder.

Features：
●A good Immune activator.
●A powerful free radical scavenger.
●Activate macrophages or neutrophil leukocyte to scavenge cell debris caused by radiation.
●Help the macrophages recognize and destroy the mutated cells.
●Help speed up the recovery of damaged tissue to produce cell factor( IL-1) .
●Enhance the activities of the other substances like antibiotics, antifungal and antiparasitic.
●Reduce the low-density lipoprotein( LDL) level and increase the high-density lipoprotein(HDL)
level in the blood to reduce the hyperlipidemiaoccurrence.
Applications：
●Health food supplements.
●Capsules and tablet health food.
●Beverages & functional oral liquid.
●Pharmaceutical & cosmetic ingredients.
●Other anti-aging，anti-radiation functional foods.
Package：25kg / bag, double-ply composite bag.
Shelf Life：24 months
Storage：Please store in dry condition and avoid explosion in open air. No shipment with noxious
chemicals.
Shanghai Genon Biotech Co.,Ltd
Address：No.88 Cailun Road Zhangjiang Hi-Tech Park, Shanghai, China Post Code：201210
Contact：Amy Tel：0086-21-5138 0613 Mobile: 15201937160 Fax：0086-21-58951012
Email: guyimei@hotmail.com ; amygoo@cngenon.com
Website：http://www.breweryeast.cn

cut paste of mail

Dear Sirs,

We got your info on line, and we are professional manufacturer of Beta 1,3,1,6-D-Glucan from 100% natural Brewer’s Yeast in Shanghai, China.

Beta-glucan can strengthen the immune system and in turn fend off cold,flu and even cancer. Additonally,beta-glucan increases the body`s denfense against the harmful effects of stress.

In additon to being available in food, beta-glucan supplements can help with following health problems:

·allergies ·asthma ·cancer

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·high cholesterol ·reheumatoid arthritis

·ulcerative colitis

Beta glucan 70%min / 80%min, the price is very competitive now.

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HAO 472

PRoject Name: HAO472 treatment Phase I clinical trial in relapsed / refractory AML, M2b type of AML

Introduction Test

Highlights

Oridonin displays significant anticancer activities via multi-signaling pathways.

Recent advances in medicinal chemistry of oridonin-like compounds are presented.

The article summarizes the SAR and mechanism studies of relevant drug candidates.

The milestones and future direction of oridonin-based drug discovery are discussed.

Discovery and development of natural product oridonin-inspired anticancer agents

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FLUCICLOVINE F-18

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Determination of cymipristone in human plasma by liquid chromatography–electrospray ionization-tandem mass spectrometry

Abstract

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Best Mode for Carrying out the Invention

Mode for the Invention

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