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

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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)

Image result for SUZHOU PENGXU PHARMATECH CO, LTD

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:

 

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).

 

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;


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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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