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Eluxadoline …Diarrhea-predominant irritable bowel syndrome

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Eluxadoline

5 JAN 2014

Furiex Pharmaceuticals Inc.  more than doubled in its best day of trading after its experimental drug alleviated diarrhea and abdominal pain caused by irritable bowel syndrome in two studies.

The drug eluxadoline met targets for improvements in stool consistency and abdominal pain that were developed in conjunction with U.S. and European regulators, the company said today. Furiex will apply for approval in June, Chairman Fred Eshelman said in an investor call today. He estimated annual sales of $750 million to $1 billion.

“By our math, it looks like a pretty doggone good market,” Eshelman said on the call, noting that there is only one currently approved drug available in the U.S. for the condition.

Diarrhea-predominant irritable bowel syndrome is a chronic disorder that affects about 28 million patients in the U.S. and Europe, Furiex said in the statement.Furiex said it would apply by mid-year for U.S. approval of the drug, eluxadoline, to treat diarrhea-predominant irritable bowel syndrome (IBS-d), a debilitating bowel disorder that affects about 28 million people in the United States and major European markets.

Furiex said it expected to seek European approval in early 2015.

“We believe that there are a lot of patients out there who need this drug. There is a huge unmet need,” Furiex Chief Medical Officer June Almenoff said in a telephone interview.

Currently approved drugs for IBS address constipation associated with the disorder, but there are few options for diarrhea predominant IBS.

Furiex founder and chairman Fred Eshelman said he believes the drug has the potential for blockbuster sales, which he defined as annual sales of between $750 million and $1 billion.

Eluxadoline was tested at two doses against a placebo over the course of 12 weeks to meet requirements by the U.S. Food and Drug Administration, and for 26 weeks for European health regulators, in Phase III studies involving 2,428 patients, Furiex said.

For the combined goal of improvement in abdominal pain and stool consistency for at least half the days in the study, eluxadoline achieved a statistically significant improvement at the 100 milligram and 75 mg doses through 12 weeks in both studies.

On the 26-week measure, the higher dose succeeded in both studies but the lower dose missed statistical significance in one of the two trials, according to initial results released by the company.

The success appeared to be driven by the percentage of patients reporting improvements in diarrhea, which ranged from 30 percent to 37 percent versus 22 percent and 20.9 percent for the placebo groups.

When the composite goal was broken into its two components, researchers found a numerical improvement in pain response rates that did not achieve statistical significance.

The drug appeared to be safe and well-tolerated in both studies, Furiex said. The most commonly reported side effects were constipation and nausea.

The company plans to present a far more detailed analysis of the late stage studies at an upcoming medical meeting.

“We’re very excited about the path ahead and about how this can transform patients’ lives,” Almenoff said.

Eluxadoline 

5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

864821-90-9 CAS

JNJ-27018966

Molecular Formula: C32H35N5O5

Molecular Weight: 569.6508

Agents for Irritable Bowel Syndrome, mu-Opioid Agonists, delta-Opioid Antagonists

Mu Delta is a locally active mu opioid receptor agonist and delta opioid receptor antagonist in phase III clinical evaluation at Furiex Pharmaceuticals for the oral treatment of diarrheal predominant irritable bowel syndrome (d-IBS).

The product candidate holds an advantage over currently marketed products for this indication because it acts locally on the enteric nervous system, possibly decreasing adverse effects on the central nervous system. In 2011, fast track designation was assigned in the U.S. for the treatment of d-IBS. In 2011, Mu Delta was licensed to Furiex Pharmaceuticals by Janssen for the treatment of d-IBS, granting an option to Furiex to continue development and commercialization following phase II proof of concept studies.

The opioid receptors were identified in the mid-1970’s, and were quickly categorized into three sub-sets of receptors (mu, delta and kappa). More recently the original three types of receptors have been further divided into sub-types. Also known is that the family of opioid receptors are members of the G-protein coupled receptor (GPCR) super-family. More physiologically pertinent are the well established facts that opioid receptors are found throughout the central and peripheral nervous system of many mammalian species, including humans, and that modulation of the respective receptors can elicit numerous, albeit different, biological effects, both desirable and undesirable (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269; J. V. Aldrich, “Analgesics”, Burger’s Medicinal Chemistry and Drug Discovery, 5thEdition, Volume 3: Therapeutic Agents, John Wiley & Sons, Inc., 1996, pp. 321-441). In the most current literature, the likelihood of heterodimerization of the sub-classes of opioid receptors has been reported, with respective physiological responses yet undetermined (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development”, Drug Development 2000, pp. 203-238).

A couple biological effects identified for opioid modulators have led to many useful medicinal agents. Most significant are the many centrally acting mu opioid agonist modulators marketed as analgesic agents to attenuate pain (e.g., morphine), as well as peripherally acting mu agonists to regulate motility (e.g., loperamide). Currently, clinical studies are continuing to evaluate medicinal utility of selective delta, mu, and kappa modulators, as well as compounds possessing combined sub-type modulation. It is envisioned such explorations may lead to agents with new utilities, or agents with minimized adverse side effects relative to currently available agents (examples of side effects for morphine includes constipation, respiratory depression, and addiction potential). Some new GI areas where selective or mixed opioid modulators are currently being evaluated includes potential treatment for various diarrheic syndromes, motility disorders (post-operative ileus, constipation), and visceral pain (post operative pain, irritable bowel syndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development” Drug Development, 2000, pp. 203-238).

Around the same time the opioid receptors were identified, the enkephalins were identified as a set of endogenous opioid ligands (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncating the original pentapeptide enkephalins to simplified dipeptides yielded a series of compounds that maintained opioid activity (Schiller, P. WO 96/06855). However one potential drawback cited for such compounds is the likelihood of their inherent instability (P. W. Schiller et al., Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

More recently, a series of opioid pseudopeptides containing heteroaromatic or heteroaliphatic nuclei were disclosed, however this series is reported showing a different functional profile than that described in the Schiller works. (L. H. Lazarus et al., Peptides 2000, 21, pp. 1663-1671).

Most recently, works around morphine related structures were reported by Wentland, et al, where carboxamido morphine derivatives and it’s analogs were prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 623-626). Wentland found that substitution for the phenol moiety of the morphine related structures with a primary carboxamide led anywhere from equal activities up to 40 fold reduced activities, depending on the opioid receptor and the carboxamide. It was also revealed that any additional N-substitutions on the carboxamide significantly diminished the desired binding activity.

Compounds of the present invention have not been previously disclosed and are believed to provide advantages over related compounds by providing improved pharmacological profiles.

Opioid receptor modulators, agonists or antagonists are useful in the treatment and prevention of various mammalian disease states, for example pain and gastrointestinal disorders such as diarrheic syndromes, motility disorders including post-operative ileus and constipation, and visceral pain including post-operative pain, irritable bowel syndrome and inflammatory bowel disorders.

It is an object of the present invention to provide opioid receptor modulators. It is a further object of the invention to provide opioid receptor agonists and opioid receptor antagonists. It is an object of the present invention to provide opioid receptor ligands that are selective for each type of opioid receptor, mu, delta and kappa. It is a further object of the present invention to provide opioid receptor ligands that modulate two or three opioid receptor types, mu, delta and kappa, simultaneously.

It is an object of the invention to provide certain instant compounds that are also useful as intermediates in preparing new opioid receptor modulators. It is also an object of the invention to provide a method of treating or ameliorating a condition mediated by an opioid receptor. And, it is an object of the invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as an opioid receptor modulator.

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1 h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid is an opoid receptor modulator (mu receptor agonist and delta receptor antagonist) and may be useful for treating irritable bowel syndrome, pain or other opioid receptor disorders.

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and methods of making this molecule are disclosed in

US application 2005/02033143. Example 9 of US application 2005/02033143 makes the hydrochloride salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

Applicants have discovered a process of making the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and two novel crystals of this zwitterion. In Applicant’s hands, these novel crystals provide improved properties and can be purified at higher purity. Applicant’s new process results in improved and less costly process manufacturing conditions than the procedure disclosed in US application 2005/02033143.

………………..

FIG. 6 is the molecular structure of the zwitterion 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

US7994206

…………………..

SYNTHESIS OF 5-formyl-2- methoxy-benzoic acid methyl ester

WO2002022612A1

Example 8: 2-Methoxy-5-formylbenzoic acid

Figure imgf000023_0001

Lithium hydroxide (1.04g, 0.043mol, 3eq) in water (lOmL) was added to a stirred solution of methyl 2-methoxy-5-formylbenzoate (2.8g, 0.014mol, leq) in a mixture of tetrahydrofuran (30mL) and methanol (20mL). The solution was stirred overnight, acidified to pH 1 with 10% HCl and the organic solvents removed in vacuo. The aqueous solution was extracted with ethyl acetate (lOOmL) and the organic solution washed with brine (lOOmL), then extracted with saturated aqueous sodium bicarbonate (3 x lOOmL). The basic solution was washed with ethyl acetate (lOOmL), then acidified to pH 1 with 10% HCl and back extracted with dichloromethane (3 x lOOmL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a cream coloured powder (2.01g, 77%). 1H NMR (CDC13) δ 9.99 (s, IH, O=C- H), 4.14 (s, 3H, CH3).

………………

ANALOGOUS METHOD TO PREPARE..2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester

USE 5-formyl-2- methoxy-benzoic acid methyl ester  for 3,4- dimethoxybenzaldehyde, TO GET 2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester 

Example 4

(3,4-Dimethoxy-benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine

Figure imgf000076_0001
NOTE THIS IS NOT THE COMPD….IT IS REF FOR AN ANALOGOUS PROCEDURE

A solution of 1-(4-phenyl-1 W-imidazol-2-yl)-ethylamine (0.061 g, 0.33 mmol) of Example 3, and 0.55 g (0.33 mmol) of 3,4-dimethoxybenzaldehyde in 5 ml_ of anhydrous methanol was stirred at room temperature for 1 h and then cooled to about 0-100C in an ice bath for 1 h. The reaction was treated carefully with 0.019 g (0.49 mmol) of sodium borohydride in one portion and maintained at about 0-100C for 21 h. Cold 2M aqueous HCI was added dropwise (30 drops), the mixture was stirred for 5 min, and then partially concentrated in vacuo unheated. The residual material was taken up in EtOAc to yield a suspension that was treated with 5 ml_ of cold 3M aqueous NaOH and stirred vigorously until clear. The phases were separated and the aqueous layer was extracted three times additional with EtOAc. The combined extracts were dried over MgSO4, filtered, and concentrated to yield (3,4-dimethoxy- benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine as a light yellow oil (HPLC: 87% @ 254nm and 66% @ 214 nm).

MS (ES+) (relative intensity): 338.1 (100) (M+1)

This sample was of sufficient quality to use in the next reaction without further purification.

…………………..

SYNTHESIS

WO2006099060A2

In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (IV)

Figure imgf000016_0001

also known as, 5-({[2-amino-3-(4-carbamoyl-2,5-dimethyl-phenyl)- propionyl]-[1 -(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid

Example 1

(S)-2-ferf-Butoxycarbonylamino-3-(4-carbamoyl-2.6-dimethyl-phenyl)- propionic acid

Figure imgf000067_0001
Figure imgf000068_0001

STEP A: Trifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester

To a cooled (0°C) solution of 4-bromo-3,5-dimethylphenol (3.05 g, 15.2 mmol) in pyridine (8 ml_) was added trifluoromethanesulfonic anhydride (5.0 g, 17.7 mmol) dropwise. After completion of addition, the resulting mixture was stirred at 0°C for 15 min, and then at room temperature overnight. The reaction was quenched by addition of water, and then extracted with EtOAc. The organic extracts were washed sequentially with water, 2N HCI (2x ), brine, and then dried over MgSO4. Filtration and evaporation to dryness yielded compound 1 b as a colorless oil.

1H NMR (300 MHz, CDCI3): δ 2.45 (6H, s), 7.00 (2H, s).

Step B: 4-Bromo-3,5-dimethylbenzoic acid

Into a solution of compound 1 b (6.57 g, 19.7 mmol) in DMF (65 ml_) were added K2CO3 (13.1 g, 94.7 mmol), Pd(OAc)2 (0.44 g, 1.97 mmol) and 1 ,1′-bis(diphenylphosphino)ferrocene (2.29 g, 4.14 mmol). The resulting mixture was bubbled in gaseous CO for 10 min and was heated to 60°C for 7.5h with a CO(9) balloon. The cooled mixture was partitioned between aqueous NaHCO3 and EtOAc, and filtered. The aqueous phase was separated, acidified with aqueous 6N HCI, extracted with EtOAc, and then dried over Na2SO4. Filtration and concentration of the filtrate yielded crude compound 1c as a brown residue, which was used in the next step without further purification. STEP C: Method A: 4-Bromo-3,5-dimethyl-benzamide

Into a suspension of compound 1c in DCM (40 ml_) was added SOCI2 (3.1 rnL, 42 mmol) and the mixture was heated at reflux for 2 h. Upon removal of the solvent by evaporation, the residue was dissolved in DCM (40 ml_) and then ammonium hydroxide (28% NH3 in water, 2.8 ml_) was added. The reaction mixture was heated at 5O0C for 2 h and concentrated. The residue was diluted with H2O, extracted with EtOAc, and the organic portion was dried over Na2SO4. After filtration and evaporation, the residue was purified by flash column chramotagraphy (eluent: EtOAc) to yield compound 1 d as an off-white solid.

1H NMR (300 MHz, CD3CN): δ 2.45 (6H, s), 5.94 (1 H, br s), 6.71 (1 H, br s), 7.57 (2H, s)

MS(ES+)(relative intensity): 228.0 (100%) (M+1).

Step C: Method B: 4-Bromo-3,5-dimethyl-benzamide

A mixture of compound 1 b (3.33 g, 10 mmol), PdCI2 (0.053 g, 0.3 mmol), hexamethyldisilazane (HMDS, 8.4 ml_, 40 mmol), and DPPP (0.12 g, 0.3 mmol) was bubbled with a gaseous CO for 5 min and then stirred in a CO balloon at 80°C for 4 h. To the reaction mixture was added MeOH (5 ml_). The reaction mixture was stirred for 10 min, diluted with 2N H2SO4 (200 ml_), and then extracted with EtOAc. The EtOAc extract was washed with saturated aqueous NaHCO3, brine, and then dried over Na2SO4. Filtration and evaporation of the resultant filtrate yielded a residue, which was purified by flash column chromatography (eluent: EtOAc) to yield compound 1d as a white solid.

Step D: 2-terf-Butoxycarbonylaminoacrylic acid methyl ester

To a suspension of /V-Boc-serine methyl ester (Compound 1e, 2.19 g, 10 mmol) and EDCI (2.01 g, 10.5 mmol) in DCM (70 ml_) was added CuCI (1.04 g, 10.5 mmol). The reaction mixture was stirred at room temperature for 72 h. Upon removal of the solvent, the residue was diluted with EtOAc, washed sequentially with water and brine and then dried over MgSO4. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ~1 :4) to yield compound 1f as a colorless oil.

1H NMR (300 MHz, CDCI3): δ 1.49 (9H, s), 3.83 (3H, s), 5.73 (1 H, d, J = 1.5 Hz), 6.16 (1 H1 S), 7.02 (1 H, s).

STEP E: (2)-2-fert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)acrylic acid methyl ester

A flask charged with compound 1d (0.46 g, 2.0 mmol), compound 1f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol) and DMF (8 ml_) was purged with N2(g) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 ml_, 2.2 mol), the reaction mixture was heated at 110°C for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1 N HCI, saturated aqueous NaHCO3, brine, and dried over MgSO4. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane~1 :1 to EtOAc only) to yield compound 1g as a white solid.

1H NMR (300 MHz, CD3OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1 H, s), 7.56 (2H, s); 13C NMR (75 MHz, DMSO-d6): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4,

128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6;

MS (ES+) (relative intensity): 349.1 (38%)(M+1).

STEP F: (S)-2-ferf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid methyl ester

Into a reactor charged with a solution of compound 1g (0.56 g, 1.6 mmol) in degassed MeOH (80 mL) was added [Rh(COd)(H1R-DIPAMP)J+BF4  under a stream of argon. The reactor was sealed and flushed with H2, stirred at 6O0C under 1000 psi of H2 for 14 days. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ~1 :1) to yield compound 1 h as a white solid. ee: >99%; 1H NMR (300 MHz, CDCI3): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J = 7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1 H, m), 5.12 (1 H, d, J = 8.7 Hz), 5.65 (1 H, br s), 6.09 (1 H, br s), 7.46 (2H, s);

MS(ES+) (relative intensity): 250.9 (100) (M-BoC)+.

STEP G: (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid

Into an ice-cooled solution of compound “I h (0.22 g, 0.63 mmol) in THF (3.5 ml_) was added an aqueous LiOH solution (1 N, 3.5 ml_) and the reaction mixture stirred at 0°C. Upon completion of the reaction, the reaction mixture was concentrated and the aqueous phase was neutralized with cooled aqueous 1 N HCI at 0°C, and then extracted with EtOAc. The combined extracts were dried over Na2SO4 overnight. Filtration and evaporation of the filtrate to dryness yielded compound 1j as a white solid. 1H NMR (300 MHz, DMSO-cfe): δ 1.30 (9H, s), 2.32 (6H, s), 2.95(1 H, dd,

J= 8.8, 13.9 Hz), 3.10 (1 H, dd, J= 6.2, 14.0 Hz), 4.02-4.12 (1 H, m), 7.18-7.23 (2H, m), 7.48 (2H1 s), 7.80 (1 H, s);

MS(ES+) (relative intensity): 236.9 (6) (M-BoC)+.

Example 5

5-((r2-Amino-3-(4-carbamoyl-2.6-dimethyl-phenyl)-propionvn-n-(4-phenyl- 1 H-imidazol-2-yl)-ethvπ-aminol-methyl)-2-methoxy-benzoic acid

Figure imgf000076_0002
Figure imgf000077_0001

STEP A. 2-Methoxy-5-{[1-(4-phenyl-1 W-imidazol-2-yl)-ethylamino]-methyl}- benzoic acid methyl ester

Using the procedures described for Example 4, substituting 5-formyl-2- methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4- dimethoxybenzaldehyde, 2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester was prepared.

STEP B. 5-({[2-ferf-ButoxycarbonylmethyI-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl]-[1 -(4-phenyl-1 H-imidazoI-2-yl)-ethyl]-amino}-methyl)-2- methoxy-benzoic acid methyl ester

Using the procedure of Example 3 for the conversion of Cpd 3d to Cpd 3e, substituting 2-methoxy-5-{[1-(4-phenyl-1 /-/-imidazol-2-yl)-ethylamino]- methylj-benzoic acid methyl ester for Cpd 3d and substituting 2-tert- Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid for 2- tø/t-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, Cpd 5a was prepared.

STEP C. 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl]-[1 -(4-phenyl-1 W-imidazol-2-yl)-ethyl]-amino}-methyl)-2- methoxy-benzoic acid

5-({[2-tørf-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)- propionyl]-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid methyl ester was dissolved in an ice-chilled (0-10°C), mixed solvent system of THF (10 ml_) and MeOH (5 ml_). A LiOH H2O/water suspension (2.48 M; 3.77 ml_) was added dropwise, then the reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled in an ice bath and the basic solution was neutralized with 2N citric acid until slightly acidic. The mixture was concentrated under reduced pressure to remove the volatile materials, after which time the remaining aqueous phase was extracted with EtOAc (3 x 26 ml_). These combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to yield a pale yellowish white solid. This crude material was dissolved in a 10% MeOH/CH2CI2 solution and adsorbed onto 30 g of silica. The adsorbed material was divided and chromatographed on an ISCO normal phase column over two runs, using a 40 g Redi-Sep column for both runs. The solvent system was a gradient MeOHZCH2CI2 system as follows: Initial 100% CH2CI2, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min. The desired product eluted cleanly between 44-61 min. The desired fractions were combined and concentrated under reduced pressure to yield 5-({[2-terf- butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4- phenyl-1 /-/-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd 5b, as a white solid.

STEP D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1 – (4-phenyl-1 W-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A portion of Cpd 5b (0.27g, 0.41 mmol) was dissolved in EtOAc (39 ml_)/THF (5 ml_), filtered, and subsequently treated with gaseous HCI for 15 min. After completion of the HCI addition, the reaction was slowly warmed to room temperature and a solid precipitate formed. After 5 h the reaction appeared >97% complete by LC (@214nm; 2.56 min.). The stirring was continued over 3 d, then the solid was collected and rinsed with a small amount of EtOAc. The resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to yield Cpd 5c as a white solid di-HCI salt.

Example 2

Racemic 2-terf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethvl- phenvD-propionic acid

Figure imgf000071_0001

STEP A: Racemic 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)propionic acid methyl ester

To a reactor charged with a solution of compound 1g (0.68 g, 1.95 mmol) in MeOH (80 mL) was added 10% Pd-C (0.5 g). The reactor was connected to a hydrogenator and shaken under 51 psi of H2 overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness to yield compound 2a as a white solid.

The 1H NMR spectrum was identical to that of (S)-2-tert- butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid methyl ester, compound 1 h.

STEP B: Racemic 2-terf-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)propionic acid

Following the procedure described for Example 1 , STEP G (preparation of (S)-2-teAt-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid), compound 2b – racemic 2-te/?-butoxycarbonylamino-3- (4-carbamoyl-2,6-dimethyl-phenyl)propionic acid – was prepared.

…………….

POLYMORPHS

US8609865

Example 1 Preparation of the zwitterion of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A 1 L three-necked round-bottomed flask equipped with a mechanical stirrer, addition funnel and a thermocouple was charged without agitation. 34.2 g of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid (see Example 9 of US 2005/0203143), 340 ml of acetone, and 17 ml of 204 mmolar concentrated HCl were combined in the flask. The stirring was started and the resulting slurry formed a clear solution. This solution was heated to 45° C. under vigorous stirring and aged at this temperature for a period of two hours. After the completion, the reaction mass was cooled to ambient temperature and the supernatant was removed by suction. The vessel along with the residue was rinsed with 20 ml of acetone and then removed as previously. 170 ml of water was added and the reaction mass and was aged under stirring until a homogeneus solution resulted. This solution was then added over a period of ˜½ hr to a solution of 90 ml of 1N NaOH and water. The pH was adjusted to 6.5-7.0 accordingly. The resulting slurry was aged for about 2 hrs at ambient temperature, cooled to 10-15° C., aged at that temperature for about 1 hr, and then filtered. The solid was washed with 10 ml water, air-dried for a period of 4 to 5 hrs, and then placed in a vacuum oven at 50-55° C. until the water content was less than 3%.

Example 2 Preparation of the Form α Crystal

The Form α crystal can be prepared by storing the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid at 0-25% relative humidity for 3 days. Representative PXRD, TGA, and DSC data are shown in FIGS. 1-3 respectively.

Example 3 Preparation of the Form β crystal

The Form β crystal can be prepared by storing the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid at greater than 60% relative humidity for 3 days. Representative PXRD, TGA, and DSC data are shown in FIGS. 1, 4, and 5 respectively.

…………….

SYNTHESIS

US20050203143

Example 9 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

Figure US20050203143A1-20050915-C00035

A. 2-Methoxy-5{[1-(4-phenyl-1 H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester.

Using the procedures described for Example 3, substituting 5-formyl-2-methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4-dimethoxybenzaldehyde, 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester was prepared.

B. 5-({[2-tert-Butoxycarbonyl methyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester.

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e, substituting 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester for Cpd 1 d and substituting 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionic acid of Example 8 for 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, Cpd 9a was prepared.

C. 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[11-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

5-({[2-tert-Butoxycarbonyl methyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester was dissolved in an ice-chilled (0-10° C.), mixed solvent system of THF (10 mL) and MeOH (5 mL). A LiOH.H2O/water suspension (2.48 M; 3.77 mL) was added dropwise, then the reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled in an ice bath and the basic solution was neutralized with 2N citric acid until slightly acidic. The mixture was concentrated under reduced pressure to remove the volatile materials, after which time the remaining aqueous phase was extracted with EtOAc (3×26 mL). These combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to give 2.26 g (146% of theory) of pale yellowish white solid. This crude material was dissolved in a 10% MeOH/CH2Clsolution and adsorbed onto 30 g of silica. The adsorbed material was divided and chromatographed on an ISCO normal phase column over two runs, using a 40 g Redi-Sep column for both runs. The solvent system was a gradient MeOH/CH2Clsystem as follows: Initial 100% CH2Cl2, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min. The desired product eluted cleanly between 44-61 min. The desired fractions were combined and concentrated under reduced pressure to yield 1.74 g (113% of theory) of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd 9b, as a white solid.

D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

A portion of Cpd 9b (0.27g, 0.41 mmol) was dissolved in EtOAc (39 mL)/THF (5 mL), filtered, and subsequently treated with gaseous HCl for 15 min. After completion of the HCl addition, the reaction was slowly warmed to room temperature and a solid precipitate formed. After 5 h the reaction appeared >97% complete by LC (@214 nm; 2.56 min.). The stirring was continued over 3 d, then the solid was collected and rinsed with a small amount of EtOAc. The resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to yield 0.19 g (71%) of desired Cpd 9c as a white solid di-HCl salt.

Example 8 (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester

Figure US20050203143A1-20050915-C00034

A. (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester. Into a cool solution of Boc-L-(2,6-diMe)Tyr-OMe (7.0 g, 21.6 mmol; Sources: Chiramer or RSP AminoAcidAnalogues) and N-phenyltrifluoromethanesulfonimide (7.9 g, 22.0 mmol) in dichloromethane (60 mL) was added triethylamine (3.25 mL, 23.3 mmol). The resulting solution was stirred at 0° C. for 1 h and slowly warmed to rt. Upon completion, the reaction was quenched by addition of water. The separated organic phase was washed with 1 N NaOH aqueous solution, water and dried over Na2SOovernight. After filtration and evaporation, the residue was purified by flash column chromatography (eluent: EtOAc-hexane: 3:7) to give the desired product (9.74 g, 99%) as a clear oil; 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.39 (6H, s), 3.06 (2H, d, J=7.7 Hz), 3.64 (3H, s), 4.51-4.59 (1H, m), 5.12 (1H, d, J=8.5 Hz), 6.92 (2H, s); MS (ES+) (relative intensity): 355.8 (100) (M−Boc)+.

B. (S)4-(2-tert-Butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoic acid. To a suspension of (S)-2-tert-butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester (9.68 g, 21.3 mmol), K2CO(14.1 g, 0.102 mol), Pd(OAc)(0.48 g, 2.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.56 g, 4.47 mmol) in DMF (48 mL) was bubbled in gaseous CO for 15 min. The mixture was heated to 60° C. for 8 h with a CO balloon. The cool mixture was partitioned between NaHCOand EtOAc, and filtered. The aqueous layer was separated, acidified with 10% citric acid aqueous solution, extracted with EtOAc, and finally dried over Na2SO4. Filtration and concentration of the filtrate resulted in a residue. The residue was recrystallized from EtOAc-hexanes to afford the desired product (7.05 g, 94%); 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.42 (6H, s), 3.14 (2H, J=7.4 Hz), 3.65 (3H, s), 4.57-4.59 (1H, m), 5.14 (1H, d, J=8.6 Hz), 7.75 (2H, s); MS(ES+) (relative intensity): 251.9 (100) (M−Boc)+.

C. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid methyl ester. Into a stirring solution of (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethyl benzoic acid (3.00 g, 8.54 mmol), PyBOP (6.68 g, 12.8 mmol) and HOBt (1.74 g, 12.8 mmol) in DMF (36 mL) was added DIPEA (5.96 mL, 34.2 mmol) and NH4Cl (0.92 g, 17.1 mmol). The resulting mixture was stirred at rt for 40 min before being partitioned between aqueous NH4Cl solution and EtOAc. The separated organic phase was washed sequentially with 2N citric acid aqueous solution, saturated aqueous NaHCOsolution, and brine, then dried over Na2SOovernight. After filtration and concentration, the residue was purified by flash column chromatography (eluent: EtOAc) to give the product. (3.00 g, 100%); 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, brs), 6.09 (1H, br s), 7.46 (2H, s); MS(ES+) (relative intensity): 250.9 (100) (M−Boc)+.

D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid. Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0° C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0° C., and extracted with EtOAc, and dried over Na2SOovernight. Filtration and evaporation to dryness led to the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid (2.51 g, 87%); 1H NMR (300 MHz, DMSO-d6): δ 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M−Boc)+.

…………………..

PATENTS

1.WO 2005090315

2..WO 2006099060

3.WO 2009009480

4. WO 2010062590

5.US 2011263868 *

                   12-24-2010
                          NOVEL COMPOUNDS AS OPIOID RECEPTOR MODULATORS
                    8-32-2010
                          Compounds as opioid receptor modulators
                   6-23-2010
                          Compounds as opioid receptor modulators
                   2-12-2010
                          PROCESS FOR THE PREPARATION OF OPIOD MODULATORS
                   12-9-2009
                          Process for the preparation of opioid modulators
US7629488 * Mar 6, 2006 Dec 8, 2009 Janssen Pharmaceutica N.V. Process for the preparation of opioid modulators
US7741356 * Mar 14, 2005 Jun 22, 2010 Janssen Pharmaceutica N.V. Compounds as opioid receptor modulators
US7786158 * Oct 24, 2007 Aug 31, 2010 Janssen Pharmaceutica N.V. Compounds as opioid receptor modulators
US7994206 Jul 7, 2008 Aug 9, 2011 Janssen Pharmaceutica, N.V. Crystals and process of making 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid
CN1950342A Mar 14, 2005 Apr 18, 2007 詹森药业有限公司 Novel compounds as opioid receptor modulators

 

Update july 2015

Eluxadoline
Trade Name: Viberzi®
Research Code: JNJ-27018966, JNJ27018966, JNJ 27018966
Chemical Name: 5 – [[[(2S) -2-amino-3- [4- (aminocarbonyl) -2,6-dimethylphenyl ] -1- oxopropyl] [(1S) -1- (4-phenyl-1H-imidazol-2-yl) ethyl] amino] methyl] -2-methoxybenzoic acid
CAS No: 864821-90-9
MOA: mu opioid receptor agonist
Indication: Irritable bowel syndrome with diarrhea (IBS-D)
Approval Date: May 27, 2015 (US)
Originator: Furiex Pharmaceuticals Inc ( Furiex acquired Eluxadoline from Janssen in 2011 )
Developer: Forest Laboratories Inc. (acquired by Actavis PLC in 2014 )

Synthesis of Eluxadoline (Viberzi), Actavis' new drug for irritable bowel syndrome with diarrhea synthetic route diarrhea-predominant irritable bowel syndrome medication Eluxadoline (Viberzi) of


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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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