1R,2S-Methoxamine

1R,2S-methoxamine, also known as L-erythro-methoxamine

CAS 13699-29-1

Benzenemethanol, α-​[(1S)​-​1-​aminoethyl]​-​2,​5-​dimethoxy-​, (αR)​-

Benzenemethanol, α-(1-aminoethyl)-2,5-dimethoxy-, [R-(R*,S*)]-

(-)-Methoxamine

Molecular Weight, 211.26, C₁₁ H₁₇ N O₃

HYDROCHLORIDE

(1R,2S)-isomer HCl salt of 1 -(2,5-dimethoxyphenyl)-2-amino-1 -propanol also called as (1R, 2S)methoxamine hydrochloride

CAS  16122-04-6

Used as a pressor agent, as a vasoconstrictor, as a nasal decongestant, in ophthalmology and also found very effective in the treatment of faecal incontinence.

treatment of relief of fecal incontinence and anal itch (pruritis ani) , particularly for patients who have had a major bowel resection and reanastomosis .

Anal or fecal incontinence is the inability to voluntarily control the passage of feces or gas through the anus. It may occur either as fecal soiling or as rare episodes of incontinence for gas or watery stools. It is a very distressing condition that can result in self-inflicted social isolation and despair.

Conventional treatments for fecal incontinence include drug therapy to improve stool consistency, such as morphine, loperamide and codeine phosphate to reduce gut motility, and laxatives to soften stools and relieve constipation. Biofeedback training is another treatment which involves muscle strengthening exercises to improve anal canal resting pressure, and squeeze pressure, and to teach symmetry of anal canal function. The most common form of treatment however, is surgical repair, such as the creation of a neo-sphincter which involves grafting on muscle from other parts of the anus, or a colostomy. (Gastroenterology in Practice, Summer 1995, pl8- 21; Dig Dis 1990; 8:179-188; and The New England Journal of Medicine, April 1992, pl002-1004) . In mild cases of anal leakage, the patient will often try and plug the anus with a ball of cotton wall.

In Gut, 1991, 32, p.345-346 it was reported that two thirds of patients with idiopathic faecal incontinence had a decreased anal resting pressure resulting from an abnormal internal sphincter function. In many incontinent patients, the internal anal sphincter was found to be abnormally thin, while others had an external anal sphincter defect. It has also been reported that in vi tro contractile response of the internal anal sphincter to noradrenaline is decreased in incontinence, (Br. J. Surg. 1992, vol 79, August, p829-832; Digestive Diseases and Sciences, vol 38, no. 11, Nov. 1993, pl961-1969) . A further discussion of the innervation and control of the internal anal sphincter and drugs which can increase or decrease the normal anal resting pressure, is discussed in the text book Coloproctology and the Pelvic Floor (Butterworths) , second edition, 1992, at chapter 3 p37-53; Automic Control of Internal Anal Sphincter; and Journal of Clinical Investigation 1990, 86: p424-429.

In Surgery 1990; 107: p311-315 sodium valproate was found to be useful in the treatment of minor incontinence after ileoanal anastomosis.

It has now surprisingly been found that fecal incontinence and anal itch can be resolved by treatment with α adrenergic agonists, nitric oxide synthase inhibitors, prostaglandins F_2α, dopamine, morphine, β-blockers such as propranolol, and 5-Hydroxytryptamine (5-HT) .

This is surprising since it was always thought that once an anal sphincter began functioning abnormally, the patient would require major surgery.

In this way the anal leakage is reduced or eliminated without the patient having to undergo major surgery.

Accordingly in a first aspect of the invention there is provided use of a physiologically active agent selected from an α adrenergic agonist, nitric oxide synthase inhibitor, prostaglandin F_2α, dopamine, morphine, β-blockers, and 5- Hydroxytryptamine in the preparation of a medicament for the treatment or prophylaxis of fecal incontinence or anal itch.

The agents of the invention appear to at least partially treat the incontinence by increasing the resting pressure of the internal anal sphincter. Preferred agents are _λ adrenergic agonists, nitric oxide synthase inhibitors, and prostaglandins F_2α.

Examples of suitable a_λ adrenergic agonists are nor- adrenalin, methoxamine, but particularly preferred is phenylephrine .

Examples of suitable F_2α prostaglandin are dinoprost and carboprost.

Examples of suitable NO synthase inhibitors are

N^G-monnoommeetthhyyll--LL--aarrggiinn:ine (L-NMMA) , and N^G-nitro-L-arginine methyl ester ( -NAME)

The medicament can contain a single active agent or a combination of any of the above active agents.

Nitric Oxide (NO) synthase inhibitors such as LNMMA have previously been suggested for the therapeutic treatment of septic shock.

The prostaglandins, along with thromboxanes and leukotrienes are all derived from 20 -carbon polyunsaturated fatty acids and are collectively termed eicosanoids. F_2α prostaglandins are derived in vivo from the endoperoxide prostaglandin H₂which is in turn derived from leukotrienes. Clinically, F_2α prostaglandins such as dinoprost and carboprost are used as uterine stimulants in the termination of pregnancy, missed abortion or the induction of labour.

Phenylephrine (an α_x adrenergic agonist) is used as a mydriatic in ophthalmology, and as a decongestant , for example, in cold and flu remedies.

However there has been no suggestion to the inventors knowledge of using any of these active agents to treat fecal incontinence or anal itch. As used herein "fecal incontinence" includes all types of anal leakage from minor leakage or 'spotting' through moderate leakage, to major instances of faecal incontinence, and includes neurogenic, active, urge and passive incontinence.

More particularly the class of incontinent patients who will benefit most from the present invention are those with idiopathic incontinence and those whose incontinence is at least partly due to a weakness of either the internal or external anal sphincter, especially those with a normal or low maximum anal pressure and a structurally intact internal anal sphincter muscle, such as with an abnormally thin sphincter. However patients with minor structural damage such as a fragmented sphincter would still benefit from the invention. Not only incontinent patients with a damaged or abnormal internal sphincter can be treated, but also patients with a damaged or abnormal external sphincter since the increase in the internal anal resting tone induced by the invention will compensate for a poorly functioning external sphincter.

Another class of patients who particularly benefit from the invention are post-surgical patients who have had major bowel resection and reanastomosis . For example patients with ileoanal pouch (restorative proctocolectomy) , coloanal (with or without colonic pouch) anostomosis, lower anterior resection, and colectomy with ileorectal anastomosis.

The damage to the sphincter could be caused by trauma, such as experienced in child birth, surgical operations, or road traffic accidents. Furthermore it is also believed that incontinence caused by primary internal anal degeneration can also be relieved by the invention.

Anal leakage also often leads to pruritis of the anus and therefore by reducing or eliminating the leakage, the pruritis or anal itch is also relieved or prevented. Furthermore, as a result of the increased anal resting pressure, the patient no longer has the discomfort of distended anal sphincter muscles.

Methoxamine contains two chiral carbons and thus exists in four isomeric forms. Of all the isomeric forms, the studies revealed (1R,2S)- isomer to be therapeutically active.

US patent 2359707 describes the process for the synthesis of racemic β-(2,5-dimethoxy phenyl)-P-hydroxy-isopropyl amine in neutral, acid salt and its derivative from 2,5- dimethoxy propiophenone by treatment with methylnitrite in diethyl ether medium to obtain 2,5-dimethoxy-a-isonitrosopropiophenone hydrochloride. It is further reduced with palladium on carbon to yield β-(2,5-dimethoxyphenyl)-p-ketoisopropylamine hydrochloride and then with platinum black to get p-(2,5-dimethoxyphenyl)-β- hydroxyisopropyl amine hydrochloride. The described process for di-methoxamine HC1 is not cost-effective, due to the use of two expensive catalysts (platinum black and palladium carbon), solvent diethyl ether and involves more number of steps. The other drawback being it is racemic mixture and cannot be used directly as drug. The process described did not specify the quality of the product.

In US patent 3284490 the processes for racemic N-alkyl derivatives of methoxamine are described from dl-methoxamine.

JP 63165348 describes process for production of optically active l-(2,5- dimethoxyphenyl)-2-aminophenol by resolving racemic compound with the use of optically active L-N-acetylleucine as resolving agent. The disadvantages of the process are less yield, low quality and use of expensive naturally occurring amino acid, which prevents from employing this method on commercial scale.

WO 03/055474 A1 discloses mainly, the use of (1R, 2S)-methoxamine in the treatment of faecal incontinence at low doses without local or systemic side effects when used topically. The patent also described the synthesis of (1R, 2S)-methoxamine, from L- alanine, by protecting the amino group using methylchloroformate, converting carboxy
group of the N-protected alanine into an acid chloride insitu followed by reaction with an amine to produce an N-protected (S)-alanine amide and coupling that compound with a brominated 2,5-dimethoxybenzene in the presence of n-butyllithium or a magnesium based reagent to give (S)-amino-l-(2,5-dimethoxy-phenyl)-l-propanone, the amino group of which is protected .The reduction of the N-protected propanone was carried out using dimethylphenylsilane and the protecting group was removed by treatment with potassium hydroxide. Other method adopted in the patent to isolate (1R,2S)methoxamine is by separation of racemic methoxamine using chiral column.

The prior art suffers with some of the disadvantages like using n-butyllithium, which is pyrophoric, expensive and causes hazards to commercial scale. Also, the separation of racemic Methoxamine using chiral column mentioned in the patent can be considered for
isolating small quantities of the required isomer for analytical purposes but cannot be adopted on commercial scale for production of the drug.

US Patent 5962737 described stereospecific synthesis of the racemic threo isomers of 2- nitro-1 -phenylpropanols by reacting benzaldehyde derivative with nitroalkane in the presence of a tertiary amine and reducing 2-nitro-l-phenylpropanols with lithium aluminium hydride to 2-amino-l-phenylpropanols. Also described is phase transfer resolution of racemic mixtures of 2-amino-l-phenylpropanol and its derivatives into their optically pure isomers by reacting with the mono alkali metal salt of tartaric acid ester in a two phase system of a hydrocarbon and water. The specification further describes optically pure isomer D-threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by resolution of dl- threo 2-amino-( 1 -dialkoxy or alkoxy)phenylpropanol by using dibenzoyltartaric acid. The synthesis of the product (lS,2S)-threo 2-amino-(l-dialkoxy or alkoxy) phenyl propanol involves the use of expensive and hazardous chemicals like LAH making the process technically and commercially difficult for implementation.

Paper

Journal of the American Chemical Society (1984), 106(16), 4629-30

http://pubs.acs.org/doi/pdf/10.1021/ja00328a062

PATENT

http://www.google.com/patents/EP2275099A1?cl=en

EXAMPLE 3Synthesis of 1R,2S-Methoxamine(S)-N-Methoxycarbonyl alanine

To a stirred solution of L-alanine (300g, 3.37 mol sodium hydroxide (1N, 1800 cm³) at 0°C in an ice bath was added dropwise, over 2 hours, methyl chloroformate (274 cm³, 3.54 mol). The pH of the solution was maintained at 9 by the addition of sodium hydroxide (5N). The reaction mixture was stirred at 0°C for 3 hours whereupon it was acidified to pH 1 by the addition of phosphoric acid solution (15%) and extracted with diethyl ether (5 x 1000 cm³). The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure to yield the product as a viscous green oil (386 g, 78%). ¹H NMR (250 MHz; C²HCl₃) 1.48 (3H, d, J7.25, CH₃), 3.72 (3 H, s, COCH₃), 4.40 (1 H, quintet, J7.25, CH), 5.31 (1 H, bs, NH).

(S)-N-Methoxycarbonyl alaninedimethylamide

To a stirred solution of MeOC-alanine (227 g, 1.54 mol) and dimethylformamide (DMF) (25 cm³) in dry dichlorourethane (DCM) (2000 cm³) at 0°C was added dropwise oxalyl chloride (146 cm³, 1.62 mol) over a period of 2 hours. The solution was stirred at 0°C until the evolution of gasses ceased whereupon a basic solution of dimethylamine (676 g, 7.70 mol) in NaOH (3 N, 2000 cm³) was added. The aqueous layer was extracted with diethyl ether (2 x 500 cm³) and the combined organic layers dried (MgSO₄) and concentrated under reduced pressure to give the product as a white crystalline solid which required no further purification (230 g, 86%). ¹H NMR (250 MH_z; C²HCl₃) 1.33 (3 H, d, J6.75, CH₃), 2.99 3 H, s, OCH₃) 3.08, (3 H, s, OCH₃), 3.66 (3 H, s, COCH₃), 4.66 (H, quintet, J7.00, CH), 5.75 (1 H, d, J5.75, NH).

(S)-2-[(Methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone.

To a THF (1000 cm³) solution of bromo-2,5-dimethoxybenzene (55 g, 0.25 mol) at -20°C under nitrogen was addedn-butyl lithium (100 cm³, 2.5 M in hexanes, 0.25 mol). The mixture was stirred at -20°C for 0.75 hours, whereupon a THF (100 cm³) solution of amide (30 g, 0.17 mol) was added via cannula. The solution was stirred at -20°C for 2 hours and was then allowed to warm to room temperature over 1 hour and quenched by the addition of ammonium chloride solution (700 cm³). The solution was diluted with diethyl ether (1000 cm³) and the organic layer was dried (MgSO₄) and concentrated under reduced pressure to give a yellow oil. The product was purified by dry flash chromatography on silica (eluant 4:1 hexane/ethyl acetate then 3:2 hexane/ethyl acetate) to give the product as a white crystalline solid (45 g, 98%). ¹H NMR (250 MHz; C²HCl₃) 1.36 (3 H, d, J7.0, CH₃), 3.70 (3 H, s, COCH₃), 3.82 (3 H, s, OCH₃), 3.92 (3 H, s, OCH₃), 5.43 (1 H, quintet, J 7.3, H-2), 5.80 (1 H, bs, NH), 6.94 (1 H, d, J 9.0, ArH), 7.10 (1 H, dd, J 9.0, 3.3, ArH), 7.32 (1 H, d, J 3.3, ArH).

(1R,2S)-2-[(Methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol.

To a stirred solution of ketone i.e. (S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanone (20 g, 74.9 mmol) and dimethylphenyl silane (10.7 g, 78.6 mmol) in dry DCM (500 cm³) at 0°C in an ice bath was added dropwise trithioroacetic acid (TFA) (50 cm³). The solution was stirred at 0°C for 1 h and then quenched by the addition of sodium hydroxide (500 cm³, 1 N). The organic layer was dried and concentrated under reduced pressure to give a yellow oil which solidified on standing. This solid was crystallized from ether/hexane to give the product as a white crystalline solid (15.6 g, 75%).¹H NMR (250 MHz; C²HCl₃) 1.03 (3 H, d, J7.0, CH₃), 3.04 (1 H, d, J4.3, OH), 3.68 (3 H, s, COCH₃), 3.78 (3 H, s, OCH₃), 3.80 (3 H, s, OCH₃), 3.94-3.99 (1 H, m, H-2), 5.05-5.15 (2 H, m, H-1 and NH), 6.72-6.85 (2 H, m, ArH) 6.97 (1 H, d, J 2.0, ArH).

(1,R,2S)-Methoxamine.

To a stirred solution of methoxycarbonyl (MeOC) protected alcohol i.e. (1R,2S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol (4.0 g, 14.9 mmol) in methanol (175 cm³) was added a solution of KOH (4.06 g, 72.8 mmol in water (60 cm³). The solution was cooled and acidified with phosphoric acid (15% v/v). The solution was extracted with DCM (2 x 50 cm³) and the aqueous layer basified by the addition of K₂CO₃. The aqueous layer was extracted with diethyl ether (5 x 50 cm³) and the combined ethereal extracts dried (MgSO₄) and concentrated under reduced pressure to give the product as a clear yellow oil (1.9 g, 61%), ¹H NMR (250 MHz; C²HCl₃) 0.84 (3 H, d, J 7.0, CH₃), 3.19-3.22 (1 H, m, H-2), 3.71 (6 H, s, 2 x OCH₃), 4.67 (1 H, d, J 5.0, H-1), 6.66-6.72 (2 H, m, ArH), 6.92 (1 H, d, J 2.5, ArH).

(1R, 2S)-Methoxamine hydrochloride.

To an ice cooled solution of (1R,2S)-methoxamine (1.9 g, 9.00 mmol) in anhydrous diethyl ether (30 cm³) was passed a stream of dry HCl gas for 45 mins. The resultant precipitate was filtered by suction, washed with cold diethyl ether and dried under nitrogen to yield the title compound as a white solid. (1.5 g, 68%). ¹H NMR (250 MHz; [C²H₃]₂SO) 0.89 (3 H, d, J 6.8, CH₃), 3.37-3.42 (1 H,m,H-2), 3.71 (3 H, s, OCH₃), 3.75 (3 H, s, OCH₃), 5.12 (1 H, s, H-1), 5.92 (1 H, d, J 4.3, OH), 6.84 (1 H, dd, J 8.8, 3.0, ArH), 6.92-7.00 (2 H, m, ArH); HPLC.

Analytical Method for the Analysis of Methoxamine

The following method was used to analyse methoxamine samples.

Method

• Column :	Cyclobond I RSP 250 x 4.6 mm
  Column temperature :	23°C
  Mobile phase :	0.1% Tetraethylammonium pH 4.1*
  95%v/v
  :	Acetonitrile 5%v/v
  Flow rate :	0.6 ml/min
  Solution Concentration :	5 mg/l
  Injection volume :	2.5 µl to 20 µl
  Detection :	UV 230 nm
  *Tetraethylammonium acetate pH 4.1 was prepared fresh daily.

Example 2 above allows the complete assignment of the methoxamine isomers as shown below:

PATENT

INDIAN 1020/CHE/2011

BY

The Managing Director of Malladi Drugs & Pharmaceuticals, Prashant Malladi (left), with the Chief Executive Officer, V. N. Gopalakrishnan

V.N Gopalakrishnan

CEO at Malladi Drugs & Pharmaceuticals Ltd

Prabhakaran Ranganathan

Vice President (Operations) at Malladi Drugs and Pharmaceuticals Limited

The present invention further provides an improved process for the preparation of (JS, 2S)-Methoxamine HC1 of formula (6) from (1R, 2S)-methoxamine by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (IS, 2S)-Methoxamine base which is further acidified to form (1S,2S)- Methoxamine HC1 (6).

The present invention further provides an improved process for the preparation of (1R, 2R)-Methoxamine HC1 of formula (5) from its diastereomer (1S, 2R)-methoxamine HC1 of formula (2) by treating with acetic anhydride in toluene medium followed by acid hydrolysis and basification to obtain (1R, 2R)-Methoxamine base which is further acidified to form (1R, 2R)-Methoxamine HC1 (5).

The following examples illustrate the invention.

EXAMPLES

Example 1
Preparation of l-(2,5-Dimethoxyphenyl)propan-l-one (8)
Aluminium chloride (127.4 g; 0.955 mol) was added to dichloromethane (420 mL) in a round bottomed flask under nitrogen atmosphere. The reaction mixture was cooled to -5 °C; 1,4-dimethoxybenzene (100 g; 0.724 mol) was added slowly within 15-30 minutes. Propionic chloride (87 g; 0.94 mol) dissolved in dichloromethane (245 mL) was added slowly within 2 hours. The reaction mass was allowed to stir for 2 hours and then was quenched in crushed ice (1 kilo) and HC1 (75 mL) at 0 - 5 °C. Separated the layers and the organic layer was washed with 5% sodium hydroxide solution, dried and concentrated (140 g; colorless liquid); Purity by HPLC : 99.04%

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)propan-l-one was confirmed with the help of the following spectroscopic data.

a) IR (cm-1) (KBr)
Aromatic C-H stretch at 3071, aliphatic C - H stretch at 2938, C = O stretch at 1674, benzenoid bands at 1609 and 1584, C - O stretch at 1223, C - H out of plane bending of tri-substituted benzene ring at 814,719.

b) 1H NMR(CDCb, 300 MHz) (δH)
1.16 (3H, t, -CH2-CH3), 3.0 (2H, q, -CH2-CH3), 3.78 (3H, s, -OCH3), 3.85 (3H, s, -OCH3), 6.83 - 7.72 (3H, m, aromatic protons)

c) 13C NMR (CDCb, 300 MHz) (δC)
8.44 (-CH2-CH3), 37.03 (-CH2-CH3), 55.74 (-OCH3), 56.01 (-OCH3), 113.09 - 153.41 (aromatic carbons), 202.96 (C=O)

d) Mass spectrum (ESI, methanol)
[M+Na]+ at m/z 217 (9), [M+H]+ at m/z 195 (100).

Example 2
Preparation of l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one (9) l-(2,5-Dimethoxyphenyl)propan-l-one (100 g; 0.515 mol) was added to dichloromethane (660 mL) in a round bottomed flask under nitrogen atmosphere. Butylnitrite (46.6 g; 0.52 mol) was slowly added in about 30 minutes at 30 - 35 °C. Diethyl ether (60.2 mL) was added to the reaction mixture and dry HC1 gas was purged for about 4 hours at 30 - 35 °C. The reaction mass was maintained for 12 hours and then concentrated under vacuum The residue obtained (60 g; Pale yellow crystalline powder); Purity by HPLC: 99.81%; mp: 104-107 °C

Spectroscopic interpretation

The structure of the product, l-(2,5-Dimethoxyphenyl)-2-nitrosopropan-l-one was confirmed with the help of the following spectroscopic data

a) IR (cm1) (KBr)
O-H stretch at 3250 (broad), aromatic C-H stretch at 3024, aliphatic C - H stretch at 2934, C = O stretch at 1688, C = N stretch at 1645, benzenoid bands at 1589 and 1504, C-O stretch at 1231, C-H out of plane bending of tri-substituted benzene ring at 745,702.

b) 1H NMR(CDCb, 300 MHz) (δh)
2.07 (3H, s, -C-CH3), 3.72 (3H, s, -OCH3), 3.76 (3H, s, -OCH3), 6.84-6.99 (3H, m, aromatic protons), 8.89 (1H, bs, OH)

c) 13C NMR (CDCb, 300 MHz) (δC)
9.16 (-C-CH3), 55.81 (-OCH3), 56.34 (-OCH3), 113.09 - 153.27 (aromatic carbons), 157.07 (C=N-OH); 193.32 (CO)

d) Mass spectrum (ESI, methanol) [M+H]+ at m/z 224 (100)

Example 3
Preparation of dl-erythro-methoxamine HC1 (10)
Raney nickel (50 g); iso-propyl alcohol (250 mL) were added to the autoclave. l-(2,5- Dimethoxyphenyl)-2-nitrosopropan-1 -one (100 g; 0.448 mol) was added slowly at 50 - 55 °C by simultaneously purging the flask with hydrogen at 2-3 Kilo pressure. When hydrogen consumption ceases, the catalyst was filtered and the filtrate was concentrated. iso-Propyl alcohol (200 mL) was added to the concentrated mass followed by acidification with HC1 to obtaindl-erythro-methoxamine HC1 (70 g; white crystalline solid)

Spectroscopic interpretation
The structure of the product, dl-erythro-methoxaxmne HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3409, aromatic C-H stretch at 3010, aliphatic C - H stretch at 2914, HN-H str. at 2574 and 2467, benzenoid bands at 1615 and 1569, C-N stretch at 1279, C-O stretch at 1216, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6, 300 MHz) (δH)
1.0 (3H,d, -CH-CH3), 3.74 (3H, s, -OCH3), 3.77 (3H, s, -OCH3), 4.89 (1H, q, -CH-CH3),6.1 (1H, d, -CH-OH), 6.87-7.01 (3H, m, aromatic protons), 8.06 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δc)
14.75 (-CH-CH3), 52.12 (-OCH3), 55.70 (-OCH3), 55.70 (-CH-CH3), 67.25 (CH-OH), 111.89 - 153.16 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H)+ at m/z 212 (100), [M-H2O]+ at m/z 194 (56).

Example 4
Preparation of(JR,2S)-Metboxamine HC1 (1) and (1S, 2R)-Methoxamine HC1 (2) dl-erythro-methoxamine HC1 (117g; 0.47 mol) was dissolved in water (350 mL) at 30-35 °C. The clear solution obtained was basified using 50% sodium hydroxide solution. dl-erythro-Methoxaumne (3) was extracted into dichloromethane (150 mL) and concentrated. Mixture of methanol/DMSO (4:1; 1650 mL) was added and the mass was heated to 50 °C. L-(+)-Tartaric acid (71.1g; 0.47mol) was added slowly and the temperature of the mass was further raised to 70 °C for complete dissolution. The mass was cooled to 35 °C and maintained for 48 hours. (IR,2.S)-Methoxamine tartrate complex (80 g) precipitated was filtered. From the filtrate on concentration was obtained (1S,2R)- methoxamine tartrate complex (82 g) (IR,25)-Methoxamine tartrate complex was added to water (250 mL) at 35 °C, basified to 12 - 13 pH with 50% sodium hydroxide solution. Dichloromethane (200 mL) was added and stirred for 30 min. Separated the org layer, dried over sodium sulphate and concentrated completely under vacuum at 45° C. Iso-Propyl alcohol (150 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1R, 2S)-Methoxamine HC1 which was filtered and dried (48 g); White crystalline powder; Purity by HPLC : 100%; Chiral purity : 100 %; mp : 172-175 °C; [α]D: -47.94° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R,2S)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3300, aromatic C-H stretch at 3065, aliphatic C-H stretch at 2938, HN-H str. at 2693 and 2580, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.95 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.25 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
II. 44 (-CH-CH3), 49.22 (-OCH3), 55.24 (-OCH3), 55.70 (-CH-CH3), 66.49 (CH-OH),

III. 41 - 153.03 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).
(IS, 2i?)-Methoxamine tartrate complex was added to water (275 mL) at 35 °C, basified

to 12 - 13 pH with 50% sodium hydroxide solution. Dichloromethane (250 mL) was added and stirred for 30 min. Separated the organic layer, dried over sodium sulphate and concentrated completely under vacuum at 45 °C. Iso-Propyl alcohol (175 mL) was added, charcaolized and filtered. The clear filtrate was acidified with 20%IPA HC1 to yield (1S, 2R)-Methoxamine HC1 which was filtered and dried (51 g) White crystalline powder; Purity by HPLC : 99.99%; Chiral purity . 100 %; mp . 172-175 °C;[α]D : + 47.9° (c = 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1S, 2R)-Methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) m (cm1) (KBr)
O-H stretch at 3265, aromatic C-H stretch at 3059, aliphatic C-H stretch at 2997, HN-H str. at 2658 and 2567, benzenoid bands at 1611 and 1587,
C-N stretch at 1294, C-O stretch at 1217, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 818.

b) 1H NMR (DMSO-d6,300 MHz) (δH)
0.91 (3H,d, -CH-CH3), 3.71 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 5.14 (1H, m, -CH- NH3+), 5.97 (1H, d, -CH-OH), 6.83-7.01 (3H, m, aromatic protons), 8.19 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6,300 MHz) (δc)

II. 46 (-CH-CH3), 49.18 (-OCH3), 55.23 (-OCH3), 55.68 (-CH-CH3), 66.45 (CH-OH),

III. 42 - 153.02 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (15).

Example 5
Preparation of dl-threo-methoxamine HC1 (11)
dl-erythro-methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 - 35 °C and cooled to 10 - 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 - 70 °C. The reaction mass was maintained under stirring and further cooled to 10 - 20 °C. Conc.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 - 200 C. The reaction mass was heated to 35 - 400 C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10 - 15 °C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 - 15 °C.

The pH was adjusted to 12 - 13 using 50% sodium hydroxide solution and extracted the d/-threo-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude dl-threo-methoxamine HC1 was filtered. (85 g) Off white powder; Purity by HPLC: 99.4%; mp: 221-223 °C Spectroscopic interpretation

The structure of the product, di-threo-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm"1) (KBr)
O-H stretch at 3401, aromatic C-H stretch at 3005, aliphatic C-H stretch at 2924, HN-H str. at 2581 and 2490, benzenoid bands at 1609 and 1578, C-N stretch at 1277, C-0 stretch at 1215, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 802.

b) NMR (DMSO-d6,300 MHz) (δH)
1.2 (3H,d, -CH-CHs), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.87 (1H, q, -CH-CH3),6.3 (1H, d, -CH-OH), 6.83-6.99 (3H, m, aromatic protons), 8.03 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.76 (-CH-CH3), 52.15 (-OCH3), 55.89 (-OCH3), 67.34 (CH-OH), 111.96 - 153.21 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (52).

Example 6
Preparation of (1S,2S)- Methoxamine HC1 (6)
(IR, 2S)-Methoxamine HC1 (120 g; 0.48 mol) was dissolved in DM water (500 mL) at 30 -35 °C and cooled to 10 - 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17 mol) at 65 - 70 °C. The reaction mass was maintained under stirring and further cooled to 10 - 20 °C. Conc.sulphuric acid (57.6 g; 0.58 mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 - 20 °C. The reaction mass was heated to 35 - 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled to 10-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 - 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (1S, 2S)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol. Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (IS, 2S)-methoxamine HC1 was filtered. (86 g); White crystalline powder; Purity by HPLC . 99.8%; Chiral purity : 99.7%; mp : 172-175 °C; [α]D: + 30.739° (c = 2% in MeOH)

Spectroscopic interpretation
The structure of the product, (IS, 2S)-methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3080, aliphatic C-H stretch at 2999, HN-H str. at 2641 and 2583, benzenoid bands at 1611 and 1506, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR (DMSO-d6 300 MHz) (δH)
1.04 (3H,d, -CH-CH3), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.84-7.01 (3H, d, aromatic protons), 8.15 (3H, bs, HN-H)
The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6, 300 MHz) (δC)
14.75 (-CH-CH3), 52.18 (-OCH3), 55.21 (-OCH3), 55.69 (-CH-CH3), 67.32 (CH-OH), 111.38 -153.01 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (48).

Example 7
Preparation of (1R, 2R)-Methoxamine HC1 (5)
(IS, 2R)Methoxamine HC1 (120g; 0.48 mol) was dissolved in DM water (500 mL) at 30 - 35 °C and cooled to 10 - 15 °C. The clear solution was basified using 50 % sodium hydroxide solution and extracted in dichloromethane (250 mL). The organic layer was separated and concentrated under vacuum. The residue thus obtained was dissolved in toluene (200 mL) and was added slowly to acetic anhydride (120 g; 1.17mol) at 65 - 70 °C. The reaction mass was maintained under stirring and further cooled to 10 - 20 °C. Cone.Sulphuric acid (57.6g; 0.58mol) was added to the reaction mass slowly by maintaining the reaction mass at 10 - 20 °C. The reaction mass was heated to 35 - 40 °C for 3 hours and concentrated under vacuum at below 80 °C.

The reaction mass was cooled tol0-15°C and was dissolved in DM water (250 mL). The mass was maintained for 3 h at reflux temperature and again cooled to 10 - 15 °C. The pH was adjusted to 12-13 using 50% sodium hydroxide solution and extracted the (IR, 2i?)-Methoxamine base in dichloromethane (250 mL). Separated the organic layer and concentrated under vacuum. The concentrated mass was triturated with iso-Propyl alcohol (150 mL); acidified using 20% HC1 in iso-propyl alcohol Distilled the iso- propyl alcohol completely to the final traces and acetone (300 mL) was added. The material precipitated, crude (1R, 2R)-methoxamine HC1 was filtered. (90 g) White crystalline powder; Purity by HPLC: 99.1%, Chiral purity. 100%; mp: 172-175 °C;[α]D: -29.04° (c - 2% in MeOH)

Spectroscopic interpretation

The structure of the product, (1R, 2R)methoxamine HC1 was confirmed with the help of the following spectroscopic data.

a) IR (cm1) (KBr)
O-H stretch at 3356, aromatic C-H stretch at 3078, aliphatic C-H stretch at 2999, HN-H str. at 2619 and 2500, benzenoid bands at 1611 and 1508, C-N stretch at 1302, C-O stretch at 1229, C-H out of plane bending of 1,2,4-tri- substituted benzene ring at 812.

b) 1H NMR(DMSO-d6 300 MHz) (δH)
I. 04 (3H,d, -CH-CHa), 3.72 (3H, s, -OCH3), 3.75 (3H, s, -OCH3), 4.90 (1H, m, -CH- CH3),6.07 (1H, d, -CH-OH), 6.83-7.01 (3H, d, aromatic protons), 8.13 (3H, bs, HN-H) The -OH proton appears to have exchanged with the solvent.

c) 13C NMR (DMSO-d6 300 MHz) (δe)
II. 41 (-CH-CH3), 52.16 (-OCH3), 55.22 (-OCH3), 55.70 (-CH-CH3), 67.32 (CH-OH), III. 39-153.15 (aromatic carbons)

d) Mass spectrum (ESI, methanol)
[M+H]+ at m/z 212 (100), [M-H2O]+ at m/z 194 (44).

PATENT

http://www.google.com/patents/US8491931

(1,R,2S)-Methoxamine

To a stirred solution of methoxycarbonyl (MeOC) protected alcohol i.e. (1R,2S)-2-[(methoxycarbonyl)amino]-1-(2,5-dimethoxyphenyl)-1-propanol (4.0 g, 14.9 mmol) in methanol (175 cm³) was added a solution of KOH (4.06 g, 72.8 mmol in water (60 cm³). The solution was cooled and acidified with phosphoric acid (15% v/v). The solution was extracted with DCM (2×50 cm³) and the aqueous layer basified by the addition of K₂CO₃. The aqueous layer was extracted with diethyl ether (5×50 cm³) and the combined ethereal extracts dried (MgSO₄) and concentrated under reduced pressure to give the product as a clear yellow oil (1.9 g, 61%), ¹H NMR (250 MHz; C²HCl₃) 0.84 (3H, d, J 7.0, CH₃), 3.19-3.22 (1H, m, H-2), 3.71 (6H, s, 2×OCH₃), 4.67 (1H, d, J 5.0, H-1), 6.66-6.72 (2H, m, ArH), 6.92 (1H, d, J 2.5, ArH).

(1R,2S)-Methoxamine hydrochloride

To an ice cooled solution of (1R,2S)-methoxamine (1.9 g, 9.00 mmol) in anhydrous diethyl ether (30 cm³) was passed a stream of dry HCl gas for 45 mins. The resultant precipitate was filtered by suction, washed with cold diethyl ether and dried under nitrogen to yield the title compound as a white solid. (1.5 g, 68%). ¹H NMR (250 MHz; [C²H₃]₂SO) 0.89 (3H, d, J 6.8, CH₃), 3.37-3.42 (1H,M,H-2), 3.71 (3H, s, OCH₃), 3.75 (3H, s, OCH₃), 5.12 (1H, s, H-1), 5.92 (1H, d, J 4.3, OH), 6.84 (1H, dd, J 8.8, 3.0, ArH), 6.92-7.00 (2H, m, ArH); HPLC.

RACEMIC

Title: Methoxamine CAS Registry Number: 390-28-3 CAS Name: a-(1-Aminoethyl)-2,5-dimethoxybenzenemethanol Additional Names: a-(1-aminoethyl)-2,5-dimethoxybenzyl alcohol; 2-amino-1-(2,5-dimethoxyphenyl)-1-propanol; b-hydroxy-b-(2,5-dimethoxyphenyl)isopropylamine; b-(2,5-dimethoxyphenyl)-b-hydroxyisopropylamine; 2,5-dimethoxynorephedrine Molecular Formula: C11H17NO3 Molecular Weight: 211.26 Percent Composition: C 62.54%, H 8.11%, N 6.63%, O 22.72% Literature References: a1-Adrenergic agonist. Prepn: Baltzly et al., US 2359707 (1944 to Burroughs Wellcome). Metabolism: A. Klutch, M. Bordun, J. Med. Chem. 10, 860 (1967). Clinical pharmacology: N. T. Smith, C. Whitcher, Anesthesiology 28, 735 (1967); P. D. Snashall et al., Clin. Sci. Mol. Med. 54, 283 (1978). HPLC determn in plasma: I. A. Al-Meshal et al., J. Liq. Chromatogr. 12, 1589 (1989). Therapeutic use: P. M. C. Wright et al., Anesth. Analg. 75, 56 (1992); L. Cabanes et al., N. Engl. J. Med. 326, 1661 (1992). Comprehensive description: A. M. Al-Obaid, M. M. El-Domiaty, Anal. Profiles Drug Subs. 20, 399-431 (1991).   Derivative Type: Hydrochloride CAS Registry Number: 61-16-5 Trademarks: Vasoxine (Burroughs Wellcome); Vasoxyl (Burroughs Wellcome); Vasylox (Burroughs Wellcome) Molecular Formula: C11H17NO3.HCl Molecular Weight: 247.72 Percent Composition: C 53.33%, H 7.32%, N 5.65%, O 19.38%, Cl 14.31% Properties: Crystals, mp 212-216°. pKa (25°C) 9.2. Very sol in water: One gram dissolves in 2.5 ml water, in 12 ml ethanol. Practically insol in ether, benzene, chloroform. pH of a 2% aq soln between 4.5 and 5.5. Melting point: mp 212-216° pKa: pKa (25°C) 9.2   Therap-Cat: Antihypotensive. Keywords: a-Adrenergic Agonist; Antihypotensive.

//1R,2S-methoxamine

Plecanatide 普卡那肽 ليكاناتيد плеканатид

Plecanatide 普卡那肽 ليكاناتيد плеканатид

PLECANATIDE;  UNII-7IK8Z952OK;  (3-Glutamic acid(D>E))human uroguanylin (UGN); 467426-54-6;

Molecular Formula:	C65H104N18O26S4
Molecular Weight:	1681.88626 g/mol

 

IUPAC Condensed

H-Asn-Asp-Glu-Cys(1)-Glu-Leu-Cys(2)-Val-Asn-Val-Ala-Cys(1)-Thr-Gly-Cys(2)-Leu-OH

 

(2S)-2-[[(1R,4S,7S,10S,13S,16R,21R,27S,34R,37S,40S)-10-(2-amino-2-oxoethyl)-34-[[(2S)-4-carboxy-2-[[(2S)-3-carboxy-2-[[(2S)-2,4-diamino-4-oxobutanoyl]amino]propanoyl]amino]butanoyl]amino]-37-(2-carboxyethyl)-27-[(1R)-1-hydroxyethyl]-4-methyl-40-(2-methylpropyl)-3,6,9,12,15,23,26,29,35,38,41-undecaoxo-7,13-di(propan-2-yl)-18,19,31,32-tetrathia-2,5,8,11,14,22,25,28,36,39,42-undecazabicyclo[14.13.13]dotetracontane-21-carbonyl]amino]-4-methylpentanoic acid

L-Leucine, L-asparaginyl-L-alpha-aspartyl-L-alpha-glutamyl-L-cysteinyl-L-alpha-glutamyl-L-leucyl-L- cysteinyl-L-valyl-L-asparaginyl-L-valyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteinyl-, cyclic (4->12),(7->15)-bis(disulfide)

L-Asparaginyl-L-α-aspartyl-N-{(1R,4S,7S,10S,13S,16R,19S,22S,25R,32S,38R)-10-(2-amino-2-oxoethyl)-22-(2-carboxyethyl)-38-{[(1S)-1-carboxy-3-methylbutyl]carbamoyl}-32-[(1R)-1-hydroxyethyl]-19-isobut yl-7,13-diisopropyl-4-methyl-3,6,9,12,15,18,21,24,30,33,36-undecaoxo-27,28,40,41-tetrathia-2,5,8,11,14,17,20,23,31,34,37-undecaazabicyclo[14.13.13]dotetracont-25-yl}-L-α-glutamine

Plecanatide
RN: 467426-54-6

• Molecular FormulaC₆₅H₁₀₄N₁₈O₂₆S₄
• Average mass1681.886 Da
• • 105: PN: WO2012037380 SEQID: 105 claimed protein
  • 1: PN: US20100152118 SEQID: 1 claimed protein
  • 1: PN: WO2008151257 SEQID: 1 claimed protein
  • 1: PN: WO2010065751 SEQID: 1 claimed protein
  • 1: PN: WO2011069038 SEQID: 1 claimed sequence
  • 1: PN: WO2012037380 SEQID: 1 claimed protein
  • 1: PN: WO2014131024 SEQID: 1 claimed protein
  • 1: PN: WO2015054649 SEQID: 1 claimed protein
  • 20: PN: WO02078683 SEQID: 20 claimed protein
  • 78: PN: WO2010065751 SEQID: 105 claimed protein
  • Plecanatide
  • SP 304

 

 

CLIPS

Lea Eslava-Kim, PharmD

April 19, 2016

Novel Chronic Idiopathic Constipation Drug Under FDA Review

http://www.empr.com/drugs-in-the-pipeline/novel-chronic-idiopathic-constipation-drug-under-fda-review/article/490799/

Plecanatide is a once-daily, oral, uroguanylin analog

Synergy Pharmaceuticals announced the Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for plecanatide for the treatment of chronic idiopathic constipation (CIC).
The NDA submission was based on data from two double-blind, placebo-controlled Phase 3 trials and one open-label long term safety study in over 3,500 patients with CIC.
RELATED: NDA Submitted for Chronic Idiopathic Constipation Drug Plecanatide
The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of January 29, 2017 to make a decision on the NDA.
Plecanatide is a once-daily, oral, uroguanylin analog currently under development for the treatment of CIC and irritable bowel syndrome with constipation (IBS-C). It is designed to replicate the function of uroguanylin, a naturally occurring GI peptide, by working locally in the upper GI tract to stimulate digestive fluid movement and support regular bowel function.

PATENT

CN 104628827

http://www.google.com/patents/CN104628827A?cl=en

Prica exenatide Synergy Pharmaceuticals developed by the United States for the GC-C receptor in development of drugs, administered orally Limited.Currently underway include chronic idiopathic constipation (CIC) and constipation irritable bowel syndrome (IBS-C), including the phase III clinical trials. It is expected to receive US FDA clearance to market in recent years. Prica that peptides CAS: 467426-54-6 English name plecanatide, structural formula is as follows:

Preparation Prica that peptides from Shenzhen Han Yu medicine was first reported (CN103694320A), using a solid-phase synthesis of linear peptides in solution and then the two-step method to get into the ring, respectively. Since the method to form a ring carved in solution twice, the solution of complex composition, separation and purification difficult, the method should be improved.

Example 1

 Weigh the degree of substitution of 0. 51mmol / g of Fmoc-Leu- Wang resin 10g (5. Lmmol), added to the solid phase reactor, DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH 6. 34g, H0Bt 2. 07g, DIC 2. 37mL was dissolved in DMF, added to the reactor uniformly mixed, the reaction at room temperature 2h. Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

 Repeat the above steps, in accordance with the order of the sequence, followed by deprotection, coupling Fmoc-Gly-OH, Fmoc-Thr (tBu) -OH, Fmoc-Cys- (Mmt) -OH, Fmoc-Ala-OH, Fmoc- Val-OH, Fmoc-Asn (Trt) -〇H, Fmoc-Val-OH, Fmoc-Cys (Acm) -OH, Fmoc-Leu-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Cys (StBu) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Asp (OtBu) -OH, Boc-Asn (Trt) -〇H〇

 To a prepared peptide resin reactor volume percentage of 15% DMF solution of mercapto ethanol, reaction 2h; then DCM was added a solution of 20-fold amount DTNP reaction lh; was added after washing 1% TFA containing TIS 5% of DCM solution reaction 20min.

Preparation of peptide resin obtained after sufficiently washed with DMF, DMF was added 10 times the amount in the reaction solution 12 lh. Full wash sash.

After the preparation of the peptide resin was added in a volume ratio of 95/2/2/1 TFA / TIS / EDT / H lysis reagent 20 is added in an amount 20mL / g, the reaction ice bath lh, stirring was continued at room temperature 5h, then filtration.After lysis reagent suction filtrate using a rotary evaporator until no overflow TFA, precipitated reagent was added standing; Pulika centrifugation the precipitated crude peptide was peptide to give 8. 67g〇

The preparation of the crude peptide was obtained Pulika peptide using preparative HPLC system, wavelength 214nm, C18 reversed-phase column packing for the separation, the mobile phase of water and acetonitrile were used, with a gradient elution method to collect the target polypeptide The absorption peak. Using rotary evaporation at 30 ° C to remove most of the acetonitrile, were freeze-dried to obtain a purified Prica exenatide refined products.

Example 2

Weigh the degree of substitution of 0. 2mmol / g of Fmoc-Leu- Wang resin 10g (2mmol), added to the solid phase reactor. DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH1. 24g, HOBtO. 406g, DIC 0 • 465mL dissolved in DMF solution, after mixing into the reactor at room temperature the reaction 2h.Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

Repeat the above steps, in accordance with the order of the sequence, followed by deprotection, coupling Fmoc-Gly-OH, Fmoc-Thr (tBu) -OH, Fmoc-Cys- (Mmt) -OH, Fmoc-Ala-OH, Fmoc- Val-OH, Fmoc-Asn (Trt) -〇H, Fmoc-Val-OH, Fmoc-Cys (Acm) -OH, Fmoc-Leu-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Cys (StBu) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Asp (OtBu) -OH, Boc-Asn (Trt) -〇H〇

[0053] To illustrate the preparation of the present embodiment obtained peptide resin reactor volume percent of a DMF solution of 30% mercaptoethanol, reaction 4h; then 5-fold amount DTNP in DCM reaction lh; was added after washing 1% TFA containing TIS 5% in DCM reaction 20min.

 Preparation of peptide resin obtained after sufficiently washed with DMF, 20 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

Peptide Resin [0055] Preparation was added volume ratio of 82. 5/5/5/5/2. 5 TFA / thioanisole / H20 / phenol / EDT cleavage reagents, added in an amount 10mL / g, the reaction ice bath 0 After. 5h, stirring was continued at room temperature for lh, then suction filtered. After lysis reagent suction filtrate to the non-use of force blowing TFA overflow, adding precipitation reagent standing; centrifugation precipitated Prica exenatide crude peptide to give 1. 52g.

 The preparation of the crude peptide was obtained Pulika peptide using preparative HPLC system, wavelength 214nm, C18 reversed-phase column packing for the separation, the mobile phase of water and acetonitrile were used, with a gradient elution method to collect the target polypeptide The absorption peak. Using rotary evaporation at 30 ° C to remove most of the acetonitrile, were freeze-dried to obtain a purified Prica exenatide refined products.

 Example 3

 Weigh the degree of substitution of 0. 6mmol / g of Fmoc-Leu- Wang resin 10g (6mmol), added to the solid phase reactor, DMF washing 3 times, the swelling 3h. The volume ratio of 1: 4 piperidine: DMF was added to the reactor the reaction, after the reaction was washed with DCM and washed twice, DMF 4 times. Weigh Fmoc-Cys (Acm) -OH 7. 46g, H0Bt2. 44g, DIC 2. 79mL was dissolved in DMF, added to the reactor uniformly mixed, the reaction at room temperature 2h.Ninhydrin color reaction control endpoint, the resin was colorless indicates the end of the reaction, the reaction is continued if the color to colorless. After completion of the reaction, DCM was washed twice, DMF and washed 4 times.

 Repeat the above steps, in accordance with the order of the sequence, followed by deprotection, coupling Fmoc-Gly-OH, Fmoc-Thr (tBu) -OH, Fmoc-Cys- (Mmt) -OH, Fmoc-Ala-OH, Fmoc- Val-OH, Fmoc-Asn (Trt) -〇H, Fmoc-Val-OH, Fmoc-Cys (Acm) -OH, Fmoc-Leu-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Cys (StBu) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Asp (OtBu) -OH, Boc-Asn (Trt) -〇H〇

 To the prepared peptide resin reactor volume percentage of 25% DMF solution of mercapto ethanol, reaction 3h; then 10-fold amount DTNP in DCM reaction lh; was added 1% TFA washed containing TIS5% DCM solution Reaction 20min〇

 Preparation of peptide resin obtained after sufficiently washed with DMF, 15 times the amount of DMF was added in the reaction solution 12 lh. Full wash sash.

 Preparation of the peptide resin was added in a volume ratio of 90/5/3/2 TFA / thioanisole / anisole / EDT cleavage reagents, added in an amount 20mL / g, the ice bath was reacted 0.lh, stirring was continued at room temperature The reaction 10h, then filtration. After lysis reagent suction filtrate using a rotary evaporator until no overflow TFA, precipitated reagent was added standing; Pulika centrifugation the precipitated crude peptide was peptide to give 8. 46g.

 The preparation of the crude peptide was obtained Pulika peptide using preparative HPLC system, wavelength 214nm, C18 reversed-phase column packing for the separation, the mobile phase of water and acetonitrile were used, with a gradient elution method to collect the target polypeptide The absorption peak. Using rotary evaporation at 30 ° C to remove most of the acetonitrile, were freeze-dried to obtain a purified Prica exenatide refined products.

Although the above has been described with general, specific embodiments and test, the present invention has been described in detail, but on the basis of the present invention, it may make some changes or improvements, which the skilled artisan It is obvious. Thus, the present invention without departing from the spirit on the basis of these modifications or improvements made, belong to the scope of the invention as claimed.

PATENT

CN 104211777

http://www.google.com/patents/CN104211777A?cl=en

The pickup exenatide (Plecanatide) is a synthetic analogue of guanylin urine (urine guanylin is a natriuretic hormone, can regulate gastrointestinal transport of ions and liquid), pickup exenatide enter After in vivo and guanylate gastrointestinal tract endothelial cells cyclase C binding and activation, activation of the cystic fibrosis transmembrane conductance regulator (CFTR), to promote chloride and water into the intestine, thereby promoting bowel motility, improve constipation symptoms.

Synergy company announced its pick in the research of new drugs that peptide (code: SP304) on October 6, 2010 the treatment of gastrointestinal disorders II a clinical experimental results. The study, conducted in patients with chronic constipation showed that the drugs can improve bowel function in patients, promote intestinal motility and reduce abdominal discomfort shape. In the experiment, there was no diarrhea and other adverse reactions, at the doses tested did not detect the pickup system that peptides are absorbed. The drug is expected for the treatment of chronic constipation (CC), constipation-predominant irritable bowel syndrome (IBS-C) and other gastrointestinal disorders. CC and IBS-C is a common gastrointestinal disease that can cause serious impact on the work and the quality of life of patients. Synergy will continue to conduct clinical trials of other pickups that peptide.

The structure of the peptide pickup that is:

H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15)

Example 30:

 H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-C ys-Leu-〇H (4-12 disulfide, 7- 15) Preparation of

 embodiments will be prepared by the method of Example 18 H-Asn (Trt) -Asp (OtBu) -Asp (OtBu) -Cys (mmt) -Glu (Ot Bu) -Leu-Cys (StBu) -Val-Asn ( Trt) -Val-Ala-Cys (mmt) -Thr (tBu) -Gly-Cys (StBu) -Leu-CT C resin (IOOmmol, 472. 88g) disposed cracking reactor to 10ml / g resin ratio Add lysis reagent (TFA: EDT: water = 95: 2 5:.. 2 5 (V / V)), stirred at room temperature 2h. The reaction was filtered with sand core funnel, and then added a small amount of TFA The resin was washed in the funnel, collecting the filtrate, the combined filtrate was concentrated. Frozen in dry diethyl ether was added (100ml / g peptide purpose tree months) and the solution was precipitated, centrifuged to remove the precipitate was washed with diethyl ether after dry ether three times, and dried in vacuo to give a white solid powder was approximately 180g, i.e., H-Asn-Asp-Asp -Cys-Glu-Leu-Cys (StBu) -Val-Asn-Val-Ala-Cys-Thr-Gly-Cy s (StBu) -Leu-OH. The solid was dissolved with water to lmg / ml solution. Was added an aqueous solution of 1% by volume of H2O2, the reaction was stirred at room temperature 30min, to prepare H-Asn-Asp-Asp-Cys-Glu-Leu-Cys (StBu) -Val-Asn-Val-Ala-Cys-Thr-Gl y-Cys (StBu) -Leu-OH (disulfide 4-12) was treated with a rotary evaporator after drying the compound containing 500ml 20% β- mercaptoethanol and 0. IM N- methylmorpholine were dissolved in water, followed by stirring After 12h the reaction, the reaction solution was diluted with water to 3mg / ml was about 60L, dissolved in ethanol was added with IL 300mmol I2 solution, the reaction was stirred at room temperature 2h. Adding an appropriate amount Vc remove excess I2, until the color of the reaction solution was transparent, i.e., to give H-Asn-Asp-Asp-Cys-Glu-Leu-Cys-Val-As n-Val-Ala-Cys-Thr-Gly-Cys-L eu_0H (disulfide bonds 4-12, 7-15).

PATENT

WO 2014197720

CN 103694320

WO 2012118972

WO 2012037380

WO 2011069038

US 20100152118

WO 2010065751

///Plecanatide,  普卡那肽 ,  ليكاناتيد , плеканатид, 467426-54-6, Chronic Idiopathic Constipation, NDA, SP 304, SYNERGY, PEPTIDE,

C[C@H]1C(=O)N[C@H]2CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CSSC[C@H](NC(=O)CNC(=O)[C@@H](NC2=O)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N1)C(C)C)CC(=O)N)C(C)C)CC(C)C)CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(=O)N)N

OR

O=C(N[C@@H](CC(=O)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H]1CSSC[C@@H]2NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCC(=O)O)NC1=O)CC(C)C)CSSC[C@H](NC(=O)CNC(=O)[C@@H](NC2=O)[C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)C)C(C)C)[C@@H](N)CC(N)=O

ORVEPITANT

Molecular Formula:	C31H35F7N4O2
Molecular Weight:	628.624022 g/mol

CAS 579475-18-6

Orvepitant (GW823296)

(2R,4S)-4-[(8aS)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide

MALEATE

CAS [579475-24-4] MALEATE

MF C31H35F7N4O2.C4H4O4
MW 744.70

https://clinicaltrials.gov/ct2/show/NCT01000493

• Phase IICough; Pruritus
• DiscontinuedAnxiety disorders; Major depressive disorder; Post-traumatic stress disorders

Most Recent Events

• 19 Dec 2015NeRRe Therapeutics terminates a phase II trial in Pruritus in Italy and the United Kingdom (EudraCT2013-002763-25)
• 16 Dec 2013No development reported - Phase-II for Post-traumatic stress disorder in USA (PO)
• 16 Dec 2013No development reported - Phase-II for Major depressive disorder in Canada (PO)

Company	NeRRe Therapeutics Ltd.
Description	Neurokinin 1 (NK1) receptor antagonist
Molecular Target	Neurokinin 1 (NK1) substance P receptor (TACR1)
Mechanism of Action	Neurokinin-1 (NK-1) (Substance P) receptor antagonist
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase II
Standard Indication	Itch
Indication Details	Treat intense pruritus (itch) associated with epidermal growth factor receptor inhibitor (EGFRi) anticancer therapies

 

Start of Phase II study of neurokinin-1 receptor antagonist orvepitant for intense pruritus induced by epidermal growth factor receptor inhibitors

First Clinical Trial for NeRRe Therapeutics

Stevenage, UK, 23 January 2014.
NeRRe Therapeutics Ltd, which is focused on the development of neurokinin (NK) receptor antagonists for a range of indications, is pleased to announce the start of a Phase II study of the novel NK-1 receptor antagonist orvepitant. The proof-of-concept study, results of which are expected in 2015, is investigating orvepitant’s effectiveness as a treatment for the intense pruritus (itch) associated with epidermal growth factor receptor inhibitor (EGFRi) anticancer therapies. The itch intensity experienced by patients can be so severe that their EGFRi dose must be reduced or the treatment withdrawn; also pruritus along with rash has a significant effect on quality of life¹.
The RELIEVE-1 trial is a randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of two daily dose levels of oral orvepitant on EGFRi-induced intense pruritus in oncology subjects. Its primary endpoint is the difference between orvepitant and placebo in reducing the intensity of pruritus over 4 weeks, as measured on a subject-recorded numerical rating scale. RELIEVE-1 is being undertaken in 15 clinical sites in Italy, with Dr Bruno Vincenzi from Università Campus Bio-Medico di Roma as lead investigator. Dr Vincenzi and his colleagues at the centre have pioneered the use NK-1 antagonists as anti-pruritics in this setting². Chemistry, manufacturing and control support for RELIEVE-1 is being provided by Aptuit (Verona) Srl, with clinical operations assistance from the CRO Cromsource.
Dermatologic adverse events such as pruritus are a common feature of targeted anti-cancer therapies, with incidence of this symptom induced by EGFRi^a drugs in clinical trials ranging from 14.6% to 54.9% depending on the specific agent³. Open-label studies in patients suffering from refractory chronic pruritus have indicated that NK-1 receptor antagonism can provide rapid and highly effective relief as well as significantly improving quality of life.^2,4,5,6

Dr Mike Trower, Co-founder & Chief Operating Officer of NeRRe Therapeutics said: 

‘We are very pleased to announce the start of RELIEVE-1, NeRRe’s first clinical trial, in this important area of unmet medical need. There is a strong rationale and a growing body of clinical evidence supporting the potential of orvepitant as an anti-pruritic for this devastating symptom commonly associated with EGFRis. Given its known effects on mood and sleep, orvepitant may also provide additional benefits for patient well-being.’

Dr Emiliangelo Ratti, NeRRe Therapeutics Co-founder added:

‘The intense pruritus induced by EGFRis can lead to significant suffering and poor quality of life, and we believe that a treatment for this troubling side effect would be welcomed by cancer patients and supportive care doctors alike. A successful study of orvepitant in this indication would provide further evidence of the broad therapeutic potential of the NK-1 receptor antagonist mechanism which NeRRe is exploiting in its pipeline.’

–ENDS–

^a This includes monoclonal antibodies that target the extracellular domain of EFGR, small molecule tyrosine kinase (TK) inhibitors, and small molecule dual TK inhibitors.

About NeRRe Therapeutics
NeRRe Therapeutics was formed in December 2012 and is focussed on the development of a portfolio of NK receptor antagonists acquired from GlaxoSmithKline (GSK), which have therapeutic potential in a broad range of indications. NeRRe Therapeutics was co-founded by Drs Emiliangelo Ratti and Mike Trower, both of whom are both former senior leaders of neurosciences drug discovery at GSK with intimate knowledge of the transferred assets and the neurokinin receptor system field. In 2012 NeRRe Therapeutics raised £11.5 million ($18.4 million) in Series A financing from two leading European financial institutions, Novo A/S (www.novo.dk/ventures) and Advent Life Sciences (www.adventventures.com), who are represented by Dr Martin Edwards (Chairman) and Dr Kaasim Mahmood respectively on the company’s Board.
NeRRe (www.nerretherapeutics.com) is based at the state-of-the-art Stevenage Bioscience Catalyst (www.stevenagecatalyst.com), the UK’s first open innovation bioscience campus.

About Orvepitant
Orvepitant is a ‘novel generation’ brain penetrant, selective and potent, small molecule NK-1 receptor antagonist⁷ that features high receptor occupancy and full and long lasting (≥24hrs) central NK-1 receptor occupancy⁸. It has previously completed extensive safety and toxicology studies to support its clinical development; and it has already demonstrated a positive antidepressant effect in a Phase II clinical study together with beneficial effects on sleep⁸.

PATENT

http://www.google.com/patents/EP2297152A1?cl=en

NK1 antagonist compound orvepitant maleate, pharmaceutical formulations comprising this crystalline form, its use in therapy and processes for preparing the same. Background of the invention
WO03/066635 describes a number of diazabicycle derivatives having NK1 activity, including the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro- pyrrolo[1 ,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide (otherwise known as orvepitant).
The structure of the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro- pyrrolo[1 ,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide (otherwise known as orvepitant) is shown in formula (I) below:

Hereinafter any reference to orvepitant refers to the compound of formula (I).
Orvepitant may also be known as: CAS Index name
1-Piperidinecarboxamide, Λ/-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-
2-methylphenyl)-4-[(8aS)-hexahydro-6-oxopyrrolo[1 ,2-a]pyrazin-2(1 /-/)-yl]-Λ/-methyl-,
(2RAS) and IUPAC name :
(2R,4S)-Λ/-{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-
Λ/-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1 ,2-a]pyrazin-2(1 /-/)-yl]-1- piperidinecarboxamide. A preferred salt of this compound is its hydrochloride salt which is otherwise known as orvepitant hydrochloride.
A further preferred salt of this compound is its maleate salt which is otherwise known as orvepitant maleate.
Particularly Example 1 1 C of WO03/066635 describes the synthesis of orvepitant maleate using substantially the same experimental conditions described in the Example 1 in the present patent application.
We have now found that orvepitant maleate can be obtained in a new crystalline form. In particular, we have discovered a form of orvepitant maleate which is anhydrous and crystalline and which surprisingly has particularly good pharmaceutical properties. This is particularly stable and essentially non hygroscopic. It also has good storage properties and can be readily formulated into pharmaceutical compositions such as tablets and capsules.
Example 1 : preparation of orvepitant maleate (Form 2) {(1 R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethyl}methylamine - (2R)-2-hydroxybutanedioic acid (1.8 kg) was added to ethyl acetate (5.4 litres) and 15% w/w sodium carbonate solution (5.4 litres) and was stirred until all solids had dissolved. The organic phase was separated and was washed with water (5.4 litres). Fresh ethyl acetate (6.7 litres) was added and the solution was distilled to 5.4 litres under reduced pressure.
The solution was diluted with ethyl acetate (3.6 litres). The reactor was purged with carbon dioxide and a continuous steady stream of carbon dioxide was maintained. Triethylamine (810 ml) was added over 30 minutes and was rinsed in with ethyl acetate (250 ml). The reaction mixture was stirred for 30 minutes. Chlorotrimethylsilane (850 ml) was added over 30 minutes with cooling to keep the temperature between 17°C and 23°C and was rinsed in with ethyl acetate (250 ml). The reaction mixture was stirred for 30 minutes. Pyridine (720 ml) was added and was rinsed in with ethyl acetate (250 ml). Thionyl chloride (480 ml) was added over 10 minutes and then a rinse of ethyl acetate (500 ml). The reaction mixture was stirred at 20⁰C for 16 hours under a carbon dioxide atmosphere.
28% w/w Racemic malic acid solution (5.3 litres) was added and the mixture was stirred for 15 minutes. The organic phase was separated, diluted with ethyl acetate (1.5 litres) and was washed with water (2 x 2.7 litres) and 20% w/w dibasic potassium phosphate solution (5.6 litres). The solution was distilled under reduced pressure to a total volume of 2.5 litres. Ethyl acetate (5 litres) was added and the solution was redistilled to 3 litres to give a solution of {(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}methylcarbamic chloride.
(2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone - (2S)-hydroxy(phenyl)ethanoic acid (1.2 kg) was added to 15% w/w sodium carbonate solution (4.8 litres) and ethyl acetate (4.8 litres) and the mixture was stirred until solids dissolved. The organic phase was separated and was washed with 20% w/w sodium chloride solution (4 litres). Fresh ethyl acetate (4.8 litres) was added and the solution of (2R)-2-(4-fluoro- 2-methylphenyl)-4-piperidinone was distilled under reduced pressure to a volume of 3 litres. The solution of (2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone was charged to the solution of {(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}methylcarbamic chloride followed by an ethyl acetate (300 ml) rinse. Triethylamine (857 g) was added followed by ethyl acetate (300 ml) and the mixture was boiled at reflux for 18 hours. The slurry was cooled to 20⁰C and N-acetylpiperazine (240 g) was added. The reaction mixture was stirred for 30 minutes at 20⁰C and was then charged with 28% w/w racemic malic acid solution (3.6 litres). The organic phase was separated and was washed with 20% w/w sodium chloride solution (4.8 litres). Ethyl acetate (4.8 litres) was added and the solution of (2R)-N-{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1- piperidinecarboxamide was distilled under reduced pressure distillation to a total volume of 3 litres.
(8aS)-hexahydropyrrolo[1 ,2-a]pyrazin-6(2H)-one - (2S)-(acetyloxy)(phenyl)ethanoic acid (1.5 kg) was added to acetonitrile (11.4 litres) and triethylamine (450 g) was added. An acetonitrile (250 ml) rinse was added and the slurry was stirred at 20⁰C for 30 min. Sodium triacetoxyborohydride (900 g) was added and the reaction was cooled to 10⁰C. Formic acid (396 ml) was added to the mixture over 30 min, maintaining the temperature below 15°C. An acetonitrile (250 ml) rinse was added and the reaction was warmed to 20⁰C. The solution of (2R)-N-{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1- piperidinecarboxamide in ethyl acetate was added to the reaction mixture and was rinsed in with acetonitrile (1 litre). The reaction was stirred for 16 hours at 20⁰C.
The slurry was distilled to 5 litres under reduced pressure. The mixture was diluted with ethyl acetate (10 litres) and was washed with 13% w/w ammonia solution (2 x 4 litres), and 10% w/w sodium chloride solution (4 litres). The organic solution was distilled to 5 litres under reduced pressure. The solution was diluted with IPA (8 litres) and was distilled under reduced pressure to 5 litres. Further IPA (8 litres) was added and the solution was again distilled to 5 litres.
A solution of maleic acid (248.5 g) in IPA (2.5 litres) was added. The mixture was then seeded with orvepitant maleate A (1 g) and the mixture was aged for 1 hour. Iso-octane (10 litres) was added over 30 min. and the mixture further aged for 1 hour. The slurry was cooled to 7°C and was further aged for 90 minutes. The solid formed was filtered and washed with a 1 :1 mixture of IPA/iso-octane (2 x 3 litres). The resulting solid was dried at 40°C under reduced pressure to give the title compound (1.095kg, 44%). NMR (CD₃OD) δ (ppm) 1.52-1.53 (d, 3H), 1.68-1.78 (m, 1 H), 1.82-1.91 (q, 1 H), 1.95- 2.05 (m, 1 H), 2.16-2.37 (m, 3H), 2.38-2.50 (m, 2H), 2.44 (s, 3H), 2.81-2.87 (t, 1 H),
2.83 (s, 3H), 2.90-2.99 (m, 2H), 3.1 1-3.18 (dt, 1 H), 3.48-3.60 (m, 3H), 3.66-3.69 (d, 1 H), 3.89-3.96 (m, 1 H), 4.15-4.19 (dd, 1 H), 4.33-4.36 (dd , 1 H), 5.40-5.45 (q, 1 H), 6.26 (s, 2H), 6.76-6.81 (dt, 1 H), 6.85-6.88 (dd, 1 H), 7.27-7.31 (dd, 1 H), 7.70 (s, 2H), 7.88 (s, 1 H). (M+H)⁺ Calcd for C₃iH₃₅F₇N₄O 629, found 629.
References:

1. Rosen AC et al. Am J Clin Dermatol. (2013), 14(4):327-33
2. Santini D et al. Lancet Oncol. (2012), 13(10):1020-4
3. Ensslin CJ et al. J Am Acad Dermatol. (2013), 69(5):708-20
4. Duval A, Dubertret L. N Engl J Med. (2009), 1;361(14):1415-6
5. Ständer S et al. PLoS One. (2010), 5(6):e10968
6. Torres T et al. J Am Acad Dermatol. (2012), 66(1):e14-5
7. Di Fabio R et al. Bioorg Med Chem. (2013), 21(21):6264-73
8. Ratti E et al. J Psychopharmacol. (2013), 27(5):424-34

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US2015238486	2015-08-27	NOVEL USES
US2014128395	2014-05-08	Novel Method
US2011166150	2011-07-07	Anhydrous Crystal Form Of Ovrepitant Maleate
US2010317666	2010-12-16	Composition Comprising An NK-1 Receptor Antagonist And An SSRI For The Treatment Of Tinnitus And Hearing Loss
US2010152446	2010-06-17	Piperidine Derivatives
US2010105688	2010-04-29	PHARMACEUTICAL COMPOSITIONS COMPRISING 3,5-DIAMINO-6-(2,3-DICHLOPHENYL)-1,2,4-TRIAZINE OR R(-)-2,4-DIAMINO-5-(2,3-DICHLOROPHENYL)-6-FLUOROMETHYL PYRIMIDINE AND AN NK1
US7652012	2010-01-26	2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide maleate and pharmaceutical compositions thereof
US2009326032	2009-12-31	PHARMACEUTICAL COMPOSITIONS COMPRISING NK1 RECEPTOR ANTAGONISTS AND SODIUM CHANNEL BLOCKERS
US2009318530	2009-12-24	PHARMACEUTICAL COMPOSITIONS COMPRISING NK1 RECEPTOR ANTAGONISTS AND SODIUM CHANNEL BLOCKERS
US7189713	2007-03-13	Piperidine derivatives

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REFERENCES

1: Di Fabio R, Alvaro G, Braggio S, Carletti R, Gerrard PA, Griffante C, Marchioro C, Pozzan A, Melotto S, Poffe A, Piccoli L, Ratti E, Tranquillini E, Trower M, Spada S, Corsi M. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Bioorg Med Chem. 2013 Nov 1;21(21):6264-73. doi: 10.1016/j.bmc.2013.09.001. Epub 2013 Sep 11. PubMed PMID: 24075145.

2: Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013 May;27(5):424-34. doi: 10.1177/0269881113480990. Epub 2013 Mar 28. PubMed PMID: 23539641.

///////Orvepitant, GW823296, PHASE 2, Neurokinin 1 (NK1) receptor antagonist

C[C@@H](N(C)C(=O)N1CC[C@@H](C[C@@H]1c1ccc(F)cc1C)N1CCN2[C@@H](CCC2=O)C1)c1cc(cc(c1)C(F)(F)F)C(F)(F)F

CC1=C(C=CC(=C1)F)C2CC(CCN2C(=O)N(C)C(C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)N4CCN5C(C4)CCC5=O