Conatus’s liver drug emricasan gets FDA orphan drug status

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Dec 042013

254750-02-2 cas no

emricasan

PF 03491390, IDN 6556

pfizer

Prevention of fibrosis and inflammation in chronic liver disease

The compound had been studied in phase II clinical trials for the treatment of liver transplant rejection and hepatitis B

(3S)-3-[[(2S)-2-[[2-[(2-tert-butylphenyl)amino]-2-oxoacetyl]amino]propanoyl]amino]-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid, C26 H27 F4 N3 O7, 569.5

http://www.ama-assn.org/resources/doc/usan/emricasan.pdf

Conatus’s liver drug emricasan gets FDA orphan drug status
US-based biotechnology firm Conatus Pharmaceuticals has received orphan drug designation from the US Food and Drug Administration (FDA) for its drug candidate emricasan to treat liver transplant recipients with re-established fibrosis to delay the progression to cirrhosis and end-stage liver disease.http://www.pharmaceutical-technology.com/news/newsconatuss-chronic-liver-disease-treatment-emricasan-gets-fda-orphan-drug-status-4139697?WT.mc_id=DN_News

Emricasan, also known as IDN 6556 and PF 03491390, is a first-in-class caspase inhibitor in clinical trials for the treatment of liver diseases. IDN-6556 has marked efficacy in models of liver disease after oral administration and thus, is an excellent candidate for the treatment of liver diseases characterized by excessive apoptosis. IDN-6556 appears to be a feasible therapeutic agent against ischemia-reperfusion injury in liver transplantation.

WO 2002057298

WO 2000001666

Interleukin 1 (“IL-1”) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J.H. et al.. Immunology Today, 7:45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response. Mosely, B.S. et al.. Proc. Nat. Acad. Sci.. 84:4572-4576 (1987); Lonnemann, G. et al. Eur. J. Immunol., 19:1531-1536 (1989).

IL-lβ is synthesized as a biologically inactive precursor, proIL-lβ. ProIL-lβ is cleaved by a cysteine protease called interleukin-lβ converting enzyme (“ICE”) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P.R. et al., J. Biol. Chem., 265:14526-14528 (1992); A.D. Howard et al, J. Immunol., 147:2964-2969 (1991).

ICE is a cysteine protease localized primarily in monocytes. In addition to promoting the pro -inflammatory and immunoregulatory properties of IL-lβ, ICE, and particularly its homologues, also appear to be involved in the regulation of cell death or apoptosis. Yuan, J. et al„ Cell, 75:641-652 (1993); Miura, M. et al. Cell, 75:653-660 (1993); Nett-Giordalisi, M.A. et al, J. Cell Biochem., 17B:117 (1993). In particular, ICE or ICE/ced-3 homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer’s and Parkinson’s disease. Marx, J. and M. Baringa, Science, 259:760-762 (1993); Gagliardini, N et al„ Science, 263:826-828 (1994).

Thus, disease states in which inhibitors of the ICE/ced-3 family of cysteine proteases may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, ischemic diseases such as the myocardial infarction, stroke and ischemic kidney disease; immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease. Such inhibitors are also useful for the repopulation of hematopoietic cells following chemo- and radiation therapy and for prolonging organ viability for use in transplantation.

ICE/ced-3 inhibitors represent a class of compounds useful for the control of the above-listed disease states. Peptide and peptidyl inhibitors of ICE have been described. However, such inhibitors have been typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J.J. and D.W. Norbeck, in Drug Discovery Technologies, C.R. Clark and W.H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. These undesirable properties have hampered their development into effective drugs.

Accordingly, the need exists for compounds that can effectively inhibit the action of the ICE/ced-3 family of proteases, for use as agents for preventing unwanted apoptosis, and for treating chronic and acute forms of IL-1 mediated diseases such as inflammatory, autoimmune or neurodegenerative diseases. The present invention satisfies this need and provides further related advantages.

References

1: McCall M, Toso C, Emamaullee J, Pawlick R, Edgar R, Davis J, Maciver A, Kin T, Arch R, Shapiro AM. The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice. Surgery. 2011 Jul;150(1):48-55. doi: 10.1016/j.surg.2011.02.023. Epub 2011 May 18. PubMed PMID: 21596412.

2: Pockros PJ, Schiff ER, Shiffman ML, McHutchison JG, Gish RG, Afdhal NH, Makhviladze M, Huyghe M, Hecht D, Oltersdorf T, Shapiro DA. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology. 2007 Aug;46(2):324-9. PubMed PMID: 17654603.

3: Hoglen NC, Anselmo DM, Katori M, Kaldas M, Shen XD, Valentino KL, Lassman C, Busuttil RW, Kupiec-Weglinski JW, Farmer DG. A caspase inhibitor, IDN-6556, ameliorates early hepatic injury in an ex vivo rat model of warm and cold ischemia. Liver Transpl. 2007 Mar;13(3):361-6. PubMed PMID: 17318854.

4: Baskin-Bey ES, Washburn K, Feng S, Oltersdorf T, Shapiro D, Huyghe M, Burgart L, Garrity-Park M, van Vilsteren FG, Oliver LK, Rosen CB, Gores GJ. Clinical Trial of the Pan-Caspase Inhibitor, IDN-6556, in Human Liver Preservation Injury. Am J Transplant. 2007 Jan;7(1):218-25. PubMed PMID: 17227570.

5: Poordad FF. IDN-6556 Idun Pharmaceuticals Inc. Curr Opin Investig Drugs. 2004 Nov;5(11):1198-204. Review. PubMed PMID: 15573871.

6: Hoglen NC, Chen LS, Fisher CD, Hirakawa BP, Groessl T, Contreras PC. Characterization of IDN-6556 (3-[2-(2-tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-te trafluoro-phenoxy)-pentanoic acid): a liver-targeted caspase inhibitor. J Pharmacol Exp Ther. 2004 May;309(2):634-40. Epub 2004 Jan 23. PubMed PMID: 14742742.

7: Valentino KL, Gutierrez M, Sanchez R, Winship MJ, Shapiro DA. First clinical trial of a novel caspase inhibitor: anti-apoptotic caspase inhibitor, IDN-6556, improves liver enzymes. Int J Clin Pharmacol Ther. 2003 Oct;41(10):441-9. PubMed PMID: 14703949.

8: Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther. 2004 Mar;308(3):1191-6. Epub 2003 Nov 14. PubMed PMID: 14617689.

9: Natori S, Higuchi H, Contreras P, Gores GJ. The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury. Liver Transpl. 2003 Mar;9(3):278-84. PubMed PMID: 12619025.

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WO2002057298A2

http://www.google.com/patents/WO2002057298A2

EXAMPLE 126

(3 S)-3 – [N-(N’-(2-TERT-BUTYLPHENYL)OXAMYL) ALANINYL] AMINO-5-(2′,3′,5′,6′-TETRAFLUOROPHENOXY)-4-OXOPENTANOIC ACID

Part A: [(N-Benzyloxycarbonyl Alaninyl]Aspartic Acid, β-tert-Butyl Ester

To a suspension of aspartic acid β-tert-butyl ester (3.784 g, 20 mmol) in dimethylformamide (150 mL) at room temperture under nitrogen was added bis(trimethylsilyl)-trifluoroacetamide (10.6 mL, 40 mmol). After stirring at room temperature for 30 min, the resulting clear solution was treated with (N- benzyloxycarbonyl)alanine N-hydroxysuccinimide ester (6.406 g, 20 mmol). After stirring at room temperature for an additional 48 hrs, the mixture was treated with water (20 mL), stirred for 15 min and then partitioned between EtO Ac/water. The organic phase was washed with water, 5% KHSO and saturated NaCl solutions, dried over anhydrous Na₂SO and evaporated to a dryness. The residue was dissolved in Et₂O and extracted with saturated NaHCO₃. The aqueous extract was acidified (pH 2.0) with concentrated HCl and extracted with EtOAc. The EtOAc extract was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄ and evaporated to a give the title compound (6.463 g, 82%) as a white foam. TLC(EtOAc-hexane-AcOH; 70:30:2) Rf = 0.50.

Part B: (3S,4RS -3-rAlaninynAmino-5-(2′.3′.5′.6′-TetrafluorophenoxyV4- Hydroxypentanoic Acid tert-Butyl Ester

Starting with [(N-benzyloxycarbonyl)alanmyl]aspartic acid, β-tert-butyl ester and following the methods described in Example 28, Parts B through E gave the title compound as a colorless, viscous oil. TLC(EtOAc-hexane; 1:1) Rf = 0.06.

Part C: (3 S,4RS -3-[ -(Η’-f2-tert-Butylρhenyl)Oxamyl) AlaninyllAmino-5- (2′,3′,5′,6′-Tetrafluorophenoxy)-4-Hvdroxypentanoic Acid tert-Butyl

Ester

To a solution of N-(2-tert-butylphenyl)oxamic acid (0.041 g, 0.19 mmol, prepared from 2-tert-butylaniline by the method described in Example 1, Part A) in

CH C1 (6.0 mL) at 0°C under nitrogen was added hydroxybenzofriazole hydrate (0.030 g) followed by l-ethyl-3 -(3 ‘,3 ‘-dimethyl- l’-aminopropyl)- carbodiimide hydrochloride

(0.050 g, 0.26 mmol). After stirring at 0°C for 10 min, the mixture was treated with

(3S,4RS)-3-(alaninyl)amino-5-(2′,3′,5′,6′-tetrafluorophenoxy)-4-hydroxypentanoic acid tert-butyl ester (0.079 g, 0.19 mmol) and N-methylmorpholine (22 μL, 0.20 mmol).

After stirring at room temperature for 16 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO , saturated

NaHCO₃ and saturated NaCl solutions, dried over anhydrous Na₂SO₄ and evaporated to give the crude title compound (0.090 g, 77%) as a viscous oil. TLC(EtOAc-hexane;

1:1) Rf= 0.70.

Part D: r3S -3-rN-rN’-(2-tert-Butylphenyl Oxamyl)AlaninyllAmino-5- (2′,3′,5′.6′-Tetrafluorophenoxy)-4-Oxopentanoic Acid tert-Butyl Ester

To a solution of (3S,4RS)-3-[N-(N’-(2-tert-butylphenyl)oxamyl)alaninyl] amino-5-(2′,3′,5′₃6′-tetrafluorophenoxy)-4-hydroxypentanoic acid tert-butyl ester (0.0.092 g, ca 0.15 mmol) in CH₂C1 (6.5 mL) at room temperature under nitrogen was added iodobenzene diacetate (0.188 g, 0.58 mmol) followed by a catalytic amount of 2,2,6,6-tetramethyl-l-piperidinyloxy free radical (TEMPO, 0.0046 g, 0.03 mmol). After stirring at room temperature for 16 hrs, the mixture was partitioned between EtOAc- water. The organic phase was washed with saturated NaHCO₃ and saturated NaCl solutions, dried over anhydrous Na SO₄ and evaporated to a dryness. The residue (0.096 g) was purified by preparative layer chromatography on silica gel eluting with EtOAc- hexane (3:7) to give the title compound (0.071 g, 77%) as a colorless glass. TLC(EtOAc-hexane; 2:3) Rf = 0.60.

Part E: (3S)-3-rN-(N’-r2-tert-Butylphenyl Oxamyl Alaninyl]Amino-5- (2′ ,3 ‘ , 5 ‘ ,6′ -Tetrafluorophenoxy)-4-Oxopentanoic Acid

To a solution of (3S)-3-[N-(N’-(2-tert- butylphenyl)oxamyl)alaninyl]amino-5-(2′,3′,5′,6′-tetrafluorophenoxy)-4-oxopentanoic acid, tert-butyl ester (0.071 g, 0.11 mmol) in CH₂C1₂(2.5 mL)-anisole(0.05 mL) at room temperature under nitrogen was added trifluoroacetic acid (1.5 mL). The resulting clear solution was stirred at room temperature for 1 hr, evaporated to dryness and chased with toluene-CH₂Cl₂ (1:1). The residue (0.061 g) was purified by preparative layer chromatography on silica gel eluting with MeOH-CH₂Cl₂ (1:9) to give the title compound (0.044 g, 69%) as a colorless glass. MS(ES) for C₂₆H₂₇F₄N₃O₇ (MW 569.51): positive 570(M+H); negative 568(M-H).

PRANLUKAST

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Dec 032013

PRANLUKAST

Antiasthmatic.

Launched – 1995 japan150821-03-7, C27 H23 N5 O4 . H2O, 499.5179

103177-37-3 anhydrous, 103180-28-5 (monosodium salt)

Ono-1078
Ono-RS-411
RS-411
SB-205312
Ono-1070 (monosodium salt)

N-[4-Oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-4-(4-phenylbutoxy)benzamide hemihydrate

Ono (Originator)Schering-Plough (Licensee)

……….

J Med Chem 1988, 31(1): 84,

WO 2010002075,

Synth Commun 1997, 27(6): 1065,

WO 1994012492

Leukotriene antagonist.

Prepn: M. Toda et al., EP 173516; eidem, US 4780469 (1986, 1988 both to Ono);

H. Nakai et al., J. Med. Chem. 31, 84 (1988).

Pharmacology: T. Obata et al., Adv. Prostaglandin Thromboxane Leukotriene Res. 15, 229 (1985); idem et al., ibid. 17, 540 (1987).

Clinical evaluations in asthma: Y. Taniguchi et al., J. Allergy Clin. Immunol. 92, 507 (1993); H. Yamamoto et al. Am. J. Respir. Crit. Care Med. 150, 254 (1994).

AU 8546462; EP 0173516; JP 8650977; US 4780469; US 4939141

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. It antagonizes or reduces bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.

Pranlukast is a cysteinyl leukotriene receptor-1 antagonist. This drug works similarly to Merck & Co.‘s Singulair (montelukast). It is widely used in Japan.

Medications of this class, which go under a variety of names according to whether one looks at the American, British or European system of nomenclature, have as their primary function the antagonism of bronchospasm caused, principally in asthmatics, by an allergic reaction to accidentally or inadvertently encountered allergens.

Medications of this group are normally used as an adjunct to the standard therapy of inhaled steroids with inhaled long- and/or short-acting beta-agonists. There are several similar medications in the group; all appear to be equally effective.

Nakade S, Ueda S, Ohno T, Nakayama K, Miyata Y, Yukawa E, Higuchi S (2006). “Population pharmacokinetics of pranlukast hydrate dry syrup in children with allergic rhinitis and bronchial asthma.”. Drug Metab Pharmacokinet 21 (2): 133–9. doi:10.2133/dmpk.21.133. PMID 16702733.

Toda synthetic complete with 3 – nitro-2 – hydroxyphenyl ko one for raw materials, ni ko with oxalic ester Claisen condensation occurs, and then heated to reflux for cyclization to construct benzo pyran ring; dehydrated by an amide synthesized ring cyano group, the cyano compound and then with sodium azide tetrazole synthesis. The nitro group on the compound in 5% Pd / C catalyzed hydrogenation of amino acid reacted with the compound Pranlukast held. This method directly using 4 – (4 – phenyl-butoxy)-benzoic acid reaction. Synthetic route is as follows:

[0006]

[0007]

[0008] ② Robert Graham and routes are routes to I-bromo-butane as a raw material, were used as a palladium catalyst, ligand compound formylation carbonylation reactions and condensation of potassium tert-butoxide, closed dehydration under acidic conditions benzopyran ring method. Synthetic route is as follows:

[0009] Robert routes:

[0010]

[0011] Graham route:

[0012]

[0013] The two synthetic routes are not disclosed in the I-Bromo butane feedstock pathway.

[0014] ③ Masayohi 2_ cyano synthetic route to a benzopyran derivative and hydrogen sulfide gas in the base-catalyzed addition reaction of 2 – thiocarbamoylbenzothiazol and pyran derivatives, and then were reacted with anhydrous hydrazine group hydrazone, with sodium nitrite under acidic conditions nitrosation reaction occurs tetrazole ring. Synthetic route is as follows:

[0015]

[0016] The materials used are not mentioned route synthesis method, it is only reflected in the improvement of the synthesis of the tetrazole ring.

[0017] ④ Giles, Hideki and Hayler are tetrazole substituent on the increase, making it easier condensation reaction, but the synthesis of substituted on the nitrogen with tetrazole difficult, and ultimately elimination reaction of lithium used tetrahydro aluminum and other hazardous reagents, is not easy to Eri industrialization. Reaction scheme is as follows:

[0018]

[0019] ⑤ Lee NK with 4_ (4_ Phenylbutoxy) benzonitrile and 2_ hydroxy _3_ iodobenzene ko 1H_4_ thiazolyl ketone and ester ko _5_ acid, concentrated sulfuric acid catalyzed cyclization iodide copper and potassium phosphate removal under the action of hydrogen iodide get Pranlukast held. Reaction scheme is as follows:

[0021] does not mention the route starting 4 – (4 – phenyl-butoxy)-benzonitrile synthesis method, while two – hydroxy – 3 – Synthesis of iodobenzene ko difficult one.

The synthesis method comprises the following steps: a. 4 – Synthesis of chlorobutanol THF was added concentrated hydrochloric acid, feeding the mass ratio of I: I. 389 ~ 5. 556,45-80 ° C was stirred for 5-18h, cooled, extracted with methylene chloride, removal of the solvent, distillation under reduced pressure to give 4 – chlorobutanol; b. 4 – phenyl butanol take benzene, aluminum chloride mixture ,0-25 ° C solution of 4 – chlorobutanol, reaction 5 -10h then poured into ice-water, a liquid, in addition to homogeneous solution U, distillation under reduced pressure, and the resulting colorless transparent liquid that is, 4 – phenyl butanol; c. I-bromo-4 – phenyl butane synthesis of 4 – phenyl butanol 40% hydrobromic acid mixture, feeding the mass ratio of I: 2. 857 ~ 11. 428, heat refluxing, cooling, liquid separation, the organic solvent divided by distillation under reduced pressure to give I-bromo-4 – phenyl butane; d. Synthesis of methyl p-hydroxybenzoate take-hydroxybenzoic acid and methanol, concentrated sulfuric acid and refluxed for 5-20h spin methanol, poured into cold water to precipitate a white solid which was filtered and dried to give the hydroxy benzoate; e. 4 – (4 – phenyl-butoxy)-benzoic acid methyl ester _ take I-bromo-4 – phenyl butane, DMF, toluene, methyl p-hydroxybenzoate and potassium carbonate, a reflux 5 ~ 20h, cooling water, extracted with toluene, light yellow liquid rotary evaporation, recrystallization, and the resulting white solid, that is, 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester; f. 4 – (4 – phenyl-butoxy yl) – benzoic acid taken 4 – (4 – phenyl-butoxy) – benzoic acid methyl ester, 15% NaOH solution was refluxed for I ~ 5h, cooled, acidified, filtered and dried to give 4 – (4 – phenylbutyrate oxy) – benzoic acid; g. sprinkle bromophenyl acetic acid ester molar ratio Preparation of I: I ~ I. 5: O. I ~ I of bromophenol, acetic anhydride, pyridine feeding, reflux 3 ~ 10h, distilled pyridine, acetic acid and excess acetic anhydride distilled under reduced pressure to give the acetic acid esters bromophenol; h. 5 – bromo-2 – Preparation of light taken acetophenone molar ratio of I: I ~ 5: I of acetic acid bromophenol esters, aluminum chloride, tetrachlorethylene for feeding, reflux O. 5 ~ 5. 5h, cooled, the reaction solution was poured into 5% hydrochloric acid and extracted with methylene chloride, the solvent evaporated under reduced pressure, to obtain a gray crystalline 5 – bromo-2 – Light acetophenone; i. 5 – bromo-3 – nitro-2 – Preparation of light acetophenone take 5 – bromo-2 – Light acetophenone, carbon tetrachloride, 50 ~ 90 ° C is added dropwise nitric acid, reflux I ~ 4h, cooled, filtered, and the resulting yellow solid which is 5 – bromo-3 – nitro-2 – hydroxyacetophenone; j. 3 – amino-2 – Light benzene ethanone Preparation of 5 – bromo-3 – nitro-2 – hydroxyacetophenone, 5% Pd / C, methylene chloride, methanol, concentrated hydrochloric acid, water, hydrogenation; the end of the reaction mixture was filtered, the filtrate was The solvent was removed, neutralized with sodium bicarbonate, and the resulting yellow solid ginger i.e., 3 – amino-2 – hydroxyacetophenone; k. 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 _ light base Preparation of acetophenone 4 – (4 – phenyl-butoxy)-benzoic acid, toluene, DMF, 45 ~ 105 ° C was added dropwise SOCl2, 30min the reaction liquid droplets to the 3 – amino-2 – hydroxyphenyl toluene solution of ethyl ketone, the reaction 3 ~ 10h, cooled, neutralized with dilute hydrochloric acid, extracted with toluene, rotary evaporation, and the resulting pale yellow crystals is 3 – [4 – (4_ phenylbutoxy) benzamido] 2_-hydroxyacetophenone; I. 2 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol synthetic sodium, THF, 3 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – hydroxyacetophenone, diethyl oxalate 4 ~ IOh After stirring the reaction was poured into dilute hydrochloric acid to precipitate the yellow solid which was filtered, and the resulting product, i.e. 2 – [4 – (4_ phenylbutoxy) benzamido] _6_ [1,3 – dioxo-3 – ethoxy propyl intended yl] phenyl discretion ·; m. 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran take 2 – [4 – (4 – phenyl-butoxy yl) benzoyl amino] -6 – [l, 3 – dioxo-3 – ethoxycarbonyl-propyl] phenol, THF, force mouth heat, the addition of concentrated hydrochloric acid, refluxed for 8 ~ 15h, cooled, filtered, and the resulting white solid, that is, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino]-2 – ethoxycarbonyl-4H-benzopyran; η. 4 – oxo-8 – [ 4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran synthesis take four – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – ethoxycarbonyl-4Η-benzopyran was dissolved in DMF, and leads to dry ammonia gas, the reaction solution changed from yellow to red, the reaction solution was poured into cold water, adjusted to acidic, and filtered to give the product 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoyl amino] -2 – amino-carbonyl-4Η-benzopyran; P. 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4Η-benzopyran take DMF, S0C12, 4 – oxo-8 – [4 – (4 – phenyl-butoxy)-benzoic amido] _2_ aminocarbonyl-4H-benzopyran, O ~ 15 ° C under stirring for 2 ~ IOh poured into cold water, filtered, and the resulting white solid that is, 4 – oxo-8 – [4 – (4 – phenylbutoxy) benzamido] -2 – cyano-4H-benzopyran; q. Synthesis of pranlukast take four – oxo-8 – [4 – (4 – phenyl-butoxy) benzoyl amino]-2_ cyano-4H-benzopyran, ammonium chloride, sodium azide, DMF, heating I ~ 8h then poured into ice-water, dilute hydrochloric acid, filtered, and the resulting white solid that the final product Pranlukast.

The reaction of ethyl 8-nitro-4-oxo-1-benzopyran-2-carboxylate (I) with ammonia in methanol gives the corresponding amide (II), which is dehydrated with POCl3 yielding 2-cyano-8-nitro-1-benzopyran-4-one (III). The cyclization of (III) with sodium azide by means of pyridinium chloride in hot DMF affords 8-nitro-2-(tetrazol-5-yl)-1-benzopyran-4-one (IV), which is hydrogenated with H2 over Pd/C in methanol – HCl giving 8-amino-2-(tetrazol-5-yl)-1-benzopyran-4-one (V). Finally, this compound is condensed with 4-(4-phenylbutoxy)benzoic acid (VI) by means of oxalyl chloride in dichloromethane-pyridine

GW Pharmaceuticals obtains Swiss approval for Sativex

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Dec 022013

Nabiximols


Combination of
Tetrahydrocannabinol	Cannabinoid
Cannabidiol	Cannabinoid

GW Pharmaceuticals obtains Swiss approval for Sativex
GW Pharmaceuticals has received full marketing authorisation from the Swiss authorities for its prescription medicine Sativex to treat moderate to severe spasticity in multiple sclerosis (MS) patients who have not responded to other medications.

Nabiximols (USAN,trade name Sativex) is a patented cannabinoid oromucosal mouth spray developed by the UK company GW Pharmaceuticals for multiple sclerosis (MS) patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.Nabiximols is distinct from all other pharmaceutically produced cannabinoids currently available because it is a mixture of compounds derived fromCannabis plants, rather than a mono-molecular synthetic product. The drug is a pharmaceutical product standardised in composition, formulation, and dose, although it is still effectively a tincture of the cannabis plant. Its principal active cannabinoid components are the cannabinoids: tetrahydrocannabinol (THC) and cannabidiol (CBD). The product is formulated as an oromucosal spray which is administered by spraying into the mouth. Each spray delivers a near 1:1 ratio of CBD to THC, with a fixed dose of 2.7 mg THC and 2.5 mg CBD. Nabiximols is also being developed in Phase III trials as a potential treatment to alleviate pain due to cancer. It has also been researched in various models of peripheral and central neuropathic pain.

In May 2003 GW Pharmaceuticals and Bayer entered into an exclusive marketing agreement for GW’s cannabis-based medicinal extract product, to be marketed under the brand name Sativex. “Bayer has obtained exclusive rights to market Sativex in the UK. In addition, Bayer has the option for a limited period of time to negotiate the marketing rights in other countries in European Union and selected other countries around the world.”

In April 2011, GW licensed to Novartis the rights to commercialise nabiximols in Asia (excluding China and Japan), Africa and the Middle East (excluding Israel)

Of the two preliminary Phase III studies investigating the treatment of MS patients, one showed a reduction of spasticity of 1.2 points on the 0–10 points rating scale (versus 0.6 points under placebo), the other showed a reduction of 1.0 versus 0.8 points. Only the first study reached statistical significance. The Phase III approval study consisted of a run-in phase where the response of individuals to the drug was determined. The responders (42% of patients) showed a significant effect in the second, placebo controlled, phase of the trial.^[10] A 2009 meta-analysis of six studies found large variations of effectiveness, with a trend towards a reduction of spasticity

Sativex^® is a cannabinoid medicine for the treatment of spasticity due to multiple sclerosis which is also in development in cancer pain and neuropathic pain of various origins…

Sativex^® has now been launched in 11 countries (including the UK, Spain, Italy and Germany) with approvals in an additional 11 countries

ANDARINE, Male drugs

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Nov 252013

Andarine

(SARM-4, S-4), GTx-007

Acetamidoxolutamide
Androxolutamide

401900-40-1

WO 2002016310

Selective Androgen Receptor Modulators (SARM)

Signal Transduction Modulators

Andarine (GTx-007, S-4) is an investigational selective androgen receptor modulator (SARM) developed by GTX, Inc for treatment of conditions such as muscle wasting, osteoporosis and benign prostatic hypertrophy, using the non-steroidal androgen antagonist bicalutamide as a lead compound.

Androxolutamide is a nonsteroidal selective androgen receptor modulator (SARM) which had been in early clinical trials at GTx for the treatment of cancer-related cachexia in several cancer types; however, no recent development has been reported for this indication. Preclinical studies had also been ongoing for the treatment of osteoporosis due to androgen deficiency in the aging male. The drug candidate is believed to bind to the testosterone receptor in such a way as to maximize the beneficial effects of the hormone like muscle growth, bone strengthening and enhanced libido, while minimizing the unwanted side effects, such as stimulation of prostate cancer, virilization and acne. This is accomplished by the selective modulation of the androgen receptor depending on tissue type.

The compound was originally developed at GTx. In March 2004, GTx entered into a joint collaboration and license agreement with Ortho Biotech, a wholly-owned subsidiary of Johnson & Johnson; however, in 2006 the agreement was terminated by mutual agreement of the companies.

Andarine is an orally active partial agonist for androgen receptors. It is less potent in both anabolic and androgenic effects than other SARMs. In an animal model of benign prostatic hypertrophy, andarine was shown to reduce prostate weight with similar efficacy to finasteride, but without producing any reduction in muscle mass or anti-androgenic side effects. This suggests that it is able to competitively block binding of dihydrotestosterone to its receptor targets in the prostate gland, but its partial agonist effects at androgen receptors prevent the side effects associated with the anti-androgenic drugs traditionally used for treatment of BPH

Family: Selective Androgen Receptor Modulator

Half Life: About 4 hours

Formula: C19 H18 F3 N3 O6

Chemical Structure: S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide

Anabolic Rating: Similar to Testosterone Propionate

Facts: Ostarine (*S-4) is a Selective Androgen Receptor Modulator produced by GTx Inc, which is currently in the investigational stages of development. A SARM is exactly what it sounds like: a compound (not an anabolic steroid) which has the ability to stimulate the androgen receptor (much the same way as anabolic steroids). Unfortunately, due to its status as a drug still in the developmental stage, most of the research on it has been done in rodents and trials only.

S-4 is an orally active (and highly bioavailable) selective agonist for androgen receptors which was shown to have anabolic effects in muscle and bone tissue. It has been shown to have no measurable effect on lutenizing hormone (LH) or follicle-stimulating hormone (FSH), but it has been shown to have some effect on prostate weight, with an androgenic potency around 1/3rd of its anabolic potency (1). Still, this is a good trade-off, because it’s anabolic effect has been measured to be roughly the same as testosterone. It has also been shown to produce dose-dependent increases in bone mineral density and mechanical strength in addition to being able decrease body fat and increase lean body mass (2).

Unfortunately, it has a short half-life in humans of only 4 hours (3), and thus far has only gone through phase II clinical testing in humans (4).

Practical Use: This compound has potential use for all aspects of male hormone replacement therapy, and could eventually replace testosterone for this purpose. Since there is currently no accepted test for SARMs, athletes who are subject to drug testing would find it to be a suitable replacement for anabolic steroid use. Since it doesn’t effect LH or FSH, it may also be a highly useful anabolic agent to be used while attempting post-cycle therapy.

Side Effects: Prostate enlargement (1/3rd of what is seen with testosterone) and potential acne are potential side effects, although most users don’t report either of them; much more common are vision problems (floaters, yellow-tinged vision). Water retention, gynecomastia, and most other steroid-related side effects are probably not possible. In addition, inhibition of natural hormone levels is probably minimal or nonexistent at worst.

Producing/Developing Company:

Ostarine by GTx Inc.

References:

Journal of Pharmacology And Experimental Therapeutics, Vol. 304, Issue 3, 1334-1340, March 2003
Pharmaceutical Research. 2007 Feb;24(2):328-35.
Pharmaceutical Research. 2006 Aug;23(8):1641-58.
GTx Announces That Ostarine Achieved Primary Endpoint Of Lean Body Mass And A Secondary Endpoint Of Improved Functional Performance

The androgen receptor (′AR′″) is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous androgens. Androgens are generally known as the male sex hormones. However, androgens also play a pivotal role in female physiology and reproduction. The androgenic hormones are steroids which are produced in the body by the testis and the cortex of the adrenal gland, or synthesized in the laboratory. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern (Matsumoto, Endocrinol. Met. Clin. N. Am. 23:857-75 (1994). The endogenous steroidal androgens include testosterone and dihydrotestosterone (“DHT”) Testosterone is the principal steroid secreted by the testes and is the primary circulatiag androgen found in the plasma of males. Testosterone is converted to DHT by the enzyme 5 alpha-reductase in many peripheral tissues. DHT is thus thought to serve as the intracellular mediator for most androgen actions (Zhou, et al., Molec. Endocrinol. 9:208-18 (1995)). Other steroidal androgens include esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, and decanoate esters, and other synthetic androgens such as 7-Methyl-Nortestosterone (“MENT′”) and its acetate ester (Sundaram et al., “7 Alpha-Methyl-Nortestosterone(MENT): The Optimal Androgen For Male Contraception,” Ann. Med., 25:199-205 (1993) (“Sundaram”)). Because the AR is involved in male sexual development and function, the AR is a likely target for effecting male contraception or other forms of hormone replacement therapy. The AR also regulates female sexual function (i.e., libido), bone formation, and erythropoiesis.

Worldwide population growth and social awareness of family planning have stimulated a great deal of research in contraception. Contraception is a difficult subject under any circumstances. It is fraught with cultural and social stigma, religious implications, and, most certainly, significant health concerns. This situation is only exacerbated when the subject focuses on male contraception. Despite the availability of suitable contraceptive devices, historically, society has looked to women to be responsible for contraceptive decisions and their consequences. Although health concerns over sexually transmitted diseases have made men more aware of the need to develop safe and responsible sexual habits, women still often bear the brunt of contraceptive choice. Women have a number of choices, from temporary mechanical devices such as sponges and diaphragms to temporary chemical devices such as spermicides. Women also have at their disposal more permanent options, such as physical devices like IUDs and cervical caps as well as more permanent chemical treatments, such as birth control pills and subcutaneous implants. However, to date, the only options available for men include the use of condoms or a vasectomy. Condom use, however is not favored by many men because of the reduced sexual sensitivity, the interruption in sexual spontaneity, and the significant possibility of pregnancy caused by breakage or misuse. Vasectomies are also not favored If more convenient methods of birth control were available to men, particularly long term methods that require no preparative activity immediately prior to a sexual act, such methods could significantly increase the likelihood that men would take more responsibility for contraception.

Administration of the male sex steroids (e.g., testosterone and its derivatives) has shown particular promise in this regard due to the combined gonadotropin-suppressing and androgen-substituting properties of these compounds (Steinberger et al, “Effect of Chronic Administration of Testosterone Enanthate on Sperm Production and Plasma Testosterone, Follicle Stimulating Hormones and Luteinizing Hormone Levels: A Preliminary Evaluation of a Possible Male Contraceptive”, Fertility and Sterility 28:1320-28 (1977)). Chronic administration of high doses of testosterone completely abolishes sperm production (azoospermia) or reduces it to a very low level (oligospermia). The degree of spermatogenic suppression necessary to produce infertility is not precisely known, However, a recent report by the World Health Organization showed that weekly intramuscular injections of testosterone enanthate result in azoospermia or severe oligospermia (i.e., less than 3 million sperm per ml) and infertility in 98% of men receiving therapy (World Health Organization Task Force on Methods Ar Regulation of Male Fertility, “Contraceptive Efficacy of Testosterone-Induced Azoospermia and Oligospermia in Normal Men,” Fertilily and Sterility 65:821-29 (1996)).

A variety of testosterone esters have been developed that are more slowly absorbed after intramuscular injection ancd, thus, result in greater androgenic effect. Testosterone enanthate is the most widely used of these esters. While testosterone enanthate has been valuable in terms of establishing the feasibility of hormonal agents for male contraception, it has several drawbacks, including the need for weekly injections and the presence of supraphysiologic peak levels of testosterone immediately following intramuscular injection (Wu, “Effects of Testosterone Enanthate in Normal Men: Experience From a Multicenter Contraceptive Efficacy Study,” Fertility and Sterility 65:626-36 (1996)).

“male drugs”. D. D. Miller, K. A. Veverka, and K. Chung report the large-scale synthesis of androgen-receptor modulators exemplified by 3a and 3b. These compounds have a variety of pharmaceutical applications related to male sex hormones, such as male contraceptives and drugs for treating prostate-related conditions. The inventors describe the kilogram-scale production of 3a and 3b by condensing 1 with 2a or 2b, as shown in Figure 1.

The reaction is carried out in the presence of a substantial excess of Cs2CO3 in THF. For the preparation of 3a, 6.17 mol Cs2CO3 is used with 3.37 mol 1; for 3b, 5.4 mol Cs2CO3and 2.7 mol 1 are used. (Disconcertingly, the patent shows the formula of the base as CsCO3, although the calculation of the molar amount is correct.) The preparation of 3atakes 3 h at 50 °C and is monitored by HPLC. TLC is used to monitor the synthesis of3b, which takes 8 h in refluxing THF.

To purify 3a, deionized water is added to an EtOH solution at room temperature to precipitate it; this process is repeated three times. The final yield of 3a is 83%. Purifying the product by using an alcohol and water is a key aspect of the patent and is covered in the claims. However, no analytical data are given to support the claimed purity. The workup of 3b also involves EtOH and water, but solvents EtOAc and MeO-t-Bu are also used; the product is isolated in 52% yield.

The inventors also describe the synthesis of compound 1 at kilogram scale (Figure 2). Acid chloride 5 is prepared by the reaction of carboxylic acid 4 with SOCl2. The acid chloride is not isolated, but it is treated with a solution of aniline derivative 6 and Et3N in THF over 3 h. After it is warmed to room temperature, the mixture is heated to 50 °C for 15 h. The reaction is monitored by TLC; 3.7 kg 1 is isolated by crystallization from warm toluene in 70.3% yield.

The multikilogram-scale synthesis of 4 is also described. The route, shown in Figure 3, starts with the preparation of compound 9 by simultaneously adding 4 M NaOH and a solution of acid chloride 8 in acetone to a mixture of carboxylic acid 7 and 4 M NaOH in acetone. The pH of the reaction mixture is kept at >10 by adding more 4 M NaOH as needed. Intermediate 9 is isolated by crystallization from MeO-t-Bu in 55.6% yield; it is then treated with N-bromosuccinimide (NBS) in DMF to cyclize it to 10. This is isolated in 87.7% yield by adding water to the reaction mixture. The final step is heating 10 to reflux in 24% aq HBr to produce 4, isolated as a crystalline solid from hot toluene in 81.3% yield.

The patent claims cover compounds related to 3a and 3b in which the nitro group is replaced by nitrile. Unfortunately, no examples are given describing the synthesis of these compounds. This is an efficient process for synthesizing 3a and 3b, and the inventors show that it is suitable for large-scale production. (University of Tennessee Research Foundation [Knoxville]. US Patent 7,968,721, June 28, 2011;

Novel pathway for the synthesis of arylpropionamide-derived selective androgen receptor modulator (SARM) metabolites of andarine and ostarine
TETRAHEDRON LETTERS,

Volume 54, Issue 18, Pages 2203-2282 (1 May 2013)

Pages 2239-2242
Katharina M. Schragl, Guro Forsdahl, Guenter Gmeiner, Valentin S. Enev, Peter Gaertner

DAGLUTRIL

Uncategorized Comments Off

Nov 252013

DAGLUTRIL, SLV306

phase 2

Daglutril is a novel dual-action endopeptidase inhibitor which had been in phase II clinical development by Solvay for the treatment of hypertension, congestive heart failure (CHF) and pulmonary hypertension; however, no recent development has been reported for this research.

Daglutril inhibits NEP (neutral endopeptidase) and ECE (endothelin-converting enzyme) and thereby exerts vasodilating, blood pressure-lowering and other potentially beneficial effects on the cardiovascular system.

	2-[3(S)-[1-[2(R)-(Ethoxycarbonyl)-4-phenylbutyl]cyclopentan-1-ylcarboxamido]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid
cas	182821-27-8, 182560-84-5 (undefined stereochem.)
	C31H38N2O6
mw	534.6492
	Cardiovascular Drugs, Heart Failure Therapy, Hypertension, Treatment of, Endothelin-Converting Enzyme Inhibitors, Neprilysin Inhibitors

SOLWAY

Neprilysin (Enkephalinase, Neutral Endopeptidase, NEP) Inhibitors
Endothelin-Converting Enzyme (ECE) Inhibitors

182821-27-8, 1H-1-Benzazepine-1-acetic acid, 3-(((1-(2-(ethoxycarbonyl)-4-phenylbutyl)cyclopentyl)carbonyl)amino)-2,3,4,5-tetrahydro-2-oxo-, (S-(R*,S*))-, 1H-1-Benzazepine-1-acetic acid, 3-(((1-((2R)-2-(ethoxycarbonyl)-4-phenylbutyl)cyclopentyl)carbonyl)amino)-2,3,4,5-tetrahydro-2-oxo-, (3S)-, 2-[(3S)-3-[[1-[(2R)-2-carbethoxy-4-phenyl-butyl]cyclopentanecarbonyl]amino]-2-keto-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid,

The acylation of the chiral amine (I) with the chiral cyclopentanecarboxylic aid (II) by means of N-methylmorphline (NMM), hydroxybenzotriazole (HOBT) and N-(dimethylaminopropyl)-N’-ethylcarbodiimide (EDT) in dichloromethane gives the amide (III), which is then treated with trifluoroacetic acid to elimnate the tert-butyl ester groups.


	Benzazepin-, benzoxazepin- and benzothiazepin-N-acetic acid-derivs., their preparation and their pharmaceutical compsns.
	Waldeck, H.; ET AL (Kali-Chemie AG)
	CA 2172354; EP 0733642; JP 1996269011; US 5677297

AMG 837

Phase 3 drug, Uncategorized Comments Off

Nov 172013

AMG 837

865231-46-5 (AMG-837 free acid); 865231-45-4 (AMG-837 sodium salt)

(S)-3-(4-((4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)hex-4-ynoic acid

Description of AMG-837: AMG-837 is a potent, orally bioavailable GPR40 agonist. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing ofAMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes. (PLoS One. 2011;6(11):e27270).

Current developer: Amgen Inc

Hamilton JY, Sarlah D, Carreira EM * ETH Zürich, Switzerland
Iridium-Catalyzed Enantioselective Allylic Alkynylation.Angew. Chem. Int. Ed. 2013;
52: 7532-7535

A new versatile method for the iridium-catalyzed asymmetric substitution of racemic allylic alcohols is exemplified by the depicted synthesis of AMG 837, a GPR40 receptor agonist that is of interest for the treatment of type 2 diabetes.
The allylic alkynylation (27 examples) typically provides excellent branched-to-linear regioselectivity (rr > 50:1) and high enantioselectivity (≥99%). The scope of the allylic alkynylation was explored using 12 allylic alcohols and 15 potassium alkynyltrifluoroborates.

“Enantioselective Synthesis of a GPR40 Agonist AMG 837 via Catalytic Asymmetric Conjugate Addition of Terminal Alkyne to α,β-Unsaturated Thioamide”
Yazaki, R.; Kumagai, N.; Shibasaki, M.
Org. Lett. 2011, 13, 952. 　　highlighted by Synfacts 2011, 6, 586.

PAPER

Scheme 18 Optimized preparation of biphenyl 54.

Scheme 17 Original Suzuki reaction employed for the synthesis of biphenyl 54.

Image result for AMG 837

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532014001202186

/////////

TAK 733

Phase 3 drug, Uncategorized Comments Off

Nov 172013

(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Molecular Weight:	504.23
TAK-733 Formula:	C₁₇H₁₅F₂IN₄O₄

CAS Number:	1035555-63-5

Biological Activity of TAK-733:

TAK-733 is an orally bioavailable small-molecule inhibitor of MEK1 and MEK2 (MEK1/2) with potential antineoplastic activity. MEK inhibitor TAK-733 selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. MEK1/2 (MAP2K1/K2) are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.

References:

BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors.
Dahlman et al. Cancer Discov. 2012 Jul 13. PMID: 22798288.Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer.
Dong et al. Bioorg Med Chem Lett. 2011 Mar 1;21(5):1315-9. PMID: 21310613.

Zhao Y * et al. Takeda California, San Diego, Millenium Pharmaceuticals Inc., Cambridge and IRIX Pharmaceuticals, Greenville, USA

Process Research and Kilogram Synthesis of an Investigational, Potent MEK Inhibitor.Org. Process Res. Dev. 2012;
16: 1652-1659

MEK kinases regulate the pathway that mediates proliferative and anti-apoptotic signaling factors that promote tumor growth and metastasis. TAK-733 is an MEK kinase inhibitor that entered phase I clinical trials for the treatment of cancer. A noteworthy feature of this short synthesis (25% yield overall) is the one-pot, three-step synthesis of the fluoropyridone D, in which the fluorine atom is present at the outset.
The reaction of F with the nosylate G gave a mixture of N- and O-alkylation products (8:1) from which the desired N-alkylation product was isolated by crystallization. The mixture of N-methyl pyrrolidine (NMP) and methanol used in the final deprotection step, helped to ensure formation of the desired polymorph. The nine-step discovery synthesis (3% overall yield) is also presented.

MK 6096, Filorexant in phase 2 for insomnia

phase 2, Uncategorized 1 Response »

Nov 162013

MK 6096

IUPAC Name: [(2R,5R)-5-[(5-fluoropyridin-2-yl)oxymethyl]-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone | CAS Registry Number: 1088991-73-4
Synonyms: FILOREXANT, MK6096, MK-6096, Filorexant [USAN], UNII-E6BTT8VA5Z, SureCN1716633, CHEMBL2107822, MK 6096, ((2R,5R)-5-(((5-Fluoropyridin-2-yl)oxy)methyl)-2-methylpiperidin-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone, 1088991-73-4, Methanone, ((2R,5R)-5-(((5-fluoro-2-pyridinyl)oxy)methyl)-2-methyl-1-piperidinyl)(5-methyl-2-(2-pyrimidinyl)phenyl)-

Girardin M, Ouellet SG, Gauvreau D, Moore JC, Hughes G, Devine PN, O’Shea PD, Campeau L.-C * Merck Frosst Center for Therapeutic Research, Kirkland, Canada and Merck Research Laboratories, Rahway, USA

Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist.

MK-6096 is an orexin receptor antagonist in clinical trials for the treatment of insomnia. Herein we describe its first kilogram-scale synthesis. Chirality on the α-methylpiperidine core was introduced in a biocatalytic transamination using a three-enzyme system with excellent enantioselectivity (>99% ee). Low diastereoselectivity of the lactam reduction was overcome by development of a camphor sulfonic acid salt formation and dr upgrade. A chemoselectiveO-alkylation with 5-fluoro-2-hydroxypyridine was optimized and developed. Overall, 1.2 kg of MK-6069 was prepared in nine steps and 13% overall yield.

Org. Process Res. Dev. 2013; 17: 61-68

DOI: 10.1021/op3002678

Publication Date (Web): November 30, 2012

http://pubs.acs.org/doi/abs/10.1021/op3002678?prevSearch=Convergent%2BKilogram-Scale%2BSynthesis%2Bof%2BDual%2BOrexin%2BReceptor%2BAntagonist&searchHistoryKey=

The orexins are peptides that act as neurotransmitters in the central nervous system. MK-6096 is a dual orexin receptor antagonist that is a candidate for the treatment of insomnia. A noteworthy feature of the synthesis depicted is the biocatalytic transamination reaction on prochiral substrate A using a three-enzyme cocktail that delivers piperidinone B (>99% ee) on a multikilogram scale.

kilogram-scale synthesis of an orexin receptor analyst that is in clinical trials for treating insomnia. In a key step, (6R)-methylpiperidine-3-methanol is prepared from dimethyl 2-(3-oxobutyl)malonate, which was synthesized by a Michael addition of dimethyl malonate to methyl vinyl ketone.

The synthesis of the chiral piperidine is a three-enzyme biocatalytic transamination–cyclization–reduction sequence. The authors used a transaminase enzyme as the catalyst, D-alanine as the amine donor, and pyridoxal-5’-phosphate as a cofactor to transfer the amine to the malonate substrate. The product spontaneously cyclizes to a piperidone ester.

Two additional enzymes help drive the reaction: Lactate dehydrogenase, with NADH as a cofactor, reduces the lactate byproduct; and glucose dehydrogenase recycles the NAD coproduct back to NADH. Reducing the methyl ester to a hydroxymethyl group with NaBH4 and CaCl2, followed by LiAlH4 reduction of the piperidone, completes the synthesis of the piperidine building block.

The diastereoisomeric ratio of the α-hydroxymethyl lactam (dr = 1.7:1) was improved to >40:1 by reduction of the lactam followed by salt formation using d-(+)-camphorsulfonic acid [d-(+)-CSA]. For the development of transaminase ATA-117 in the manufacture of sitagliptin, see: C. K. Savile et al. Science 2010, 329, 305.

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200025/full

MK-6096 is an orally bioavailable potent and selective reversible antagonist of Orexin 1 Receptor (OX(1)R) and Orexin 2 Receptor (OX(2)R). In radioligand binding and functional cell based assays MK-6096 demonstrated potent binding and antagonism of both human OX(1)R and OX(2)R (<3 nM in binding, 11 nM in FLIPR), with no significant off-target activities against a panel of >170 receptors and enzymes. MK-6096 occupies 90% of human OX(2)Rs expressed in transgenic rats at a plasma concentration of 142 nM, and dose-dependently reduced locomotor activity and significantly increased sleep in rats (3-30 mg/kg) and dogs (0.25 and 0.5 mg/kg). MK-6096 represents a novel and selective therapeutic for the treatment of insomnia. MK-6096 has exceptional in vivo activity in preclinical sleep models.

References:

Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties.
Coleman PJ, et al. ChemMedChem. 2012 Mar 5;7(3):415-24, 337. PMID: 22307992.Pharmacological characterization of MK-6096 – a dual orexin receptor antagonist for insomnia.
Winrow CJ, et al. Neuropharmacology. 2012 Feb;62(2):978-87. PMID: 22019562.

Zalicus starts Phase Ib clinical trial of neuropathic pain drug

phase 2, Uncategorized Comments Off

Nov 142013

Biopharmaceutical firm Zalicus has started a Phase Ib clinical trial of Z944, a novel oral T-type calcium channel blocker, for the treatment of neuropathic pain.

The company expects to release the results from the laser-evoked potentials (LEP) study in the fourth quarter of 2013.

The study is designed to offer both objective and subjective data on a drug’s ability to modulate pain signalling.

http://www.drugdevelopment-technology.com/news/newszalicus-starts-phase-ib-clinical-trial-of-neuropathic-pain-drug

Z944 is a novel, oral, T-type calcium channel modulator that we are developing for pain.

Z944, an oral T-type Calcium Channel Modulator

Z944 is a novel, oral, state-dependent, selective T-type calcium channel modulator that has demonstrated efficacy in multiple preclinical inflammatory pain models and in a Phase 1b experimental model of pain. T-type calcium channels have been recognized as key targets for therapeutic intervention in a broad range of cell functions and have been implicated in pain signaling. Zalicus is planning to advance a modified release formulation of Z944 through further clinical development.

The wide distribution of T-type calcium channels found in brain, heart, endocrine cells and other tissues provides the possibility of developing therapeutics for multiple indications, including treatment of pain. Zalicus has utilized its expertise in this field to successfully discover high affinity, selective and orally available compounds, such as Z944, that show promise for further development.

T-type Calcium Channel Modulators

T-type, or transient-type (referring to the length of time activated), calcium channel modulators target low-voltage-activated, calcium channels. These channels have been recognized as critical components in numerous cell functions and have been implicated in the frequency and intensity of pain signals. Zalicus is investigating compounds to modulate T-type calcium channel signaling in the treatment of pain. Our orally-administered T-type calcium channel blockers have shown efficacy in animal models of acute, chronic and visceral pain, as well as other indications.

patent

WO2009146540

http://www.google.com/patents/WO2009146540A1

compd may be

N-[1-(N-tert-Butylcarbamoylmethyl)piperidin-4-ylmethyl]-3-chloro-5-fluorobenzamide

Medicine Can be Sweet, Glycosylated analogues of pramlintide were synthesized

diabetes, Uncategorized Comments Off

Nov 142013

Glycosylated analogues of pramlintide were synthesized by a combination of solid-phase peptide synthesis and enzymatic glycosylation

http://www.chemistryviews.org/details/ezine/5275441/Medicine_Can_be_Sweet.html

Pramlintide (Symlin), a synthetic version of amylin, is a 37-amino acid peptide that is co-secreted with insulin by pancreatic β-cells. It was developed and approved in 2005 by the FDA for use in US patients with type I and II diabetes in conjunction with the administration of prandial insulin to improve postprandial glycemic control

Pramlintide

Pramlintide (Symlin) is a relatively new adjunct for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals (now a wholly owned subsidiary of Bristol Myers-Squibb). Pramlintide is delivered as an acetate salt.

Pramlintide is an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal.^[1] Like insulin, amylin is completely absent in individuals with Type I diabetes.^[2]

Reduction in glycated hemoglobin and weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.^[3]

By augmenting endogenous amylin, pramlintide aids in the absorption of glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors (different receptors than for GLP-1), and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin. Pramlintide also has effects in raising the acute first-phase insulin response threshold following a meal.

Pramlintide has been approved by the FDA, for use by Type 1 and Type 2 Diabetics who use insulin.^[4] Pramlintide allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating. Apart from insulin analogs, pramlintide is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s.

Design and structure

Since native human amylin is highly amyloidogenic and potentially toxic, the strategy for designing pramlintide was to substitute residues from rat amylin, which is not amyloidogenic (but would presumably retain clinical activity). Proline residues are known to be structure-breaking residues, so these were directly grafted into the human sequence.

Amino acid sequences:

Pramlintide: KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-(NH₂) Amylin: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY-(NH₂) Rat amylin: KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-(NH₂)

Pramlintide as protein is (positively charged).

Jones MC (2007). “Therapies for diabetes: pramlintide and exenatide” (pdf). American Family Physician 75 (12): 1831–5. PMID 17619527.
Edelman, Steve; Maier, Holly; Wilhelm, Ken (2008). “Pramlintide in the Treatment of Diabetes Mellitus”. BioDrugs 22 (6): 375–386. doi:10.2165/0063030-200822060-00004. ISSN 1173-8804.
Hollander, Priscilla; Maggs, David G.; Ruggles, James A.; Fineman, Mark; Shen, Larry; Kolterman, Orville G.; Weyer, Christian (2004). “Effect of Pramlintide on Weight in Overweight and Obese Insulin-Treated Type 2 Diabetes Patients” (pdf). Obesity 12 (4): 661–668. doi:10.1038/oby.2004.76. ISSN 1930-7381.
Ryan GJ, Jobe LJ, Martin R (2005). “Pramlintide in the treatment of type 1 and type 2 diabetes mellitus”. Clinical therapeutics 27 (10): 1500–12. doi:10.1016/j.clinthera.2005.10.009. PMID 16330288.