PITAVASTATIN

GENERIC, Uncategorized Comments Off

Dec 162013

PITAVASTATIN, LIVALO, Itavastatin calcium, Nisvastatin, NKS-104, NK-104,

(3R, 5S) -7 – [2-Cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 (E)-heptenoic acid calcium salt (2:1)

CAS REGISTRY NUMBER

147526-32-7 CA SALT, 147511-69-1 (free acid), 141750-63-2 (lactone), 192565-91-6 (monoK salt)

rotation is +

alpha(D20) +6.8° (c 1.74, CHCl3)

ALSO

Bioorganic and Medicinal Chemistry Letters, 1999 , VOL 9, 20 pg. 2977 – 2982…….alpha(D20) +23.1° (c 1.0, acn/water(1:))

Helvetica Chimica Acta, 2007 , vol. 90, 6 pg. 1069 – 1081…alpha(D20) +22.9° (c 1.0, acn/water)

(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxyhept-6-enoic acid

Pitavastatin a lipid-lowering agent that belongs to the statin class of medications for treatment of dyslipidemia. It is also used for primary and secondary prevention of cardiovascular disease. FDA approved in Aug 3, 2009.

2-C25-H23-FN-O4.Ca, 881.01

Nissan Chemical (Originator), Kowa (Licensee), Novartis (Licensee), Recordati (Licensee), Sankyo (Licensee)

Lipoprotein Disorders, Treatment of, METABOLIC DRUGS, APOA1 Expression Enhancers, HMG-CoA Reductase Inhibitors, SPP1 (Osteopontin) Expression Inhibitors

Launched-2003

Statin drugs are currently the most therapeutically effective drugs available for reducing the level of Low density lipoprotein (LDL) in the blood stream of a patient at risk for cardiovascular disease. A high level of LDL in the
bloodstream has been linked to the formationof coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis. It is well known that inhibitors against HMG CoA reductase which is rate limiting enzyme for cholesterol biosynthesis have been clinically proved to be potentially useful anti-hyperlipoproteinemic agents
and they are considered very effective curative and preventive for coronary artery sclerosis or atherosclerosis .
Pitavastatin calcium was discovered by Nissan Chemical Industries Limited Japan and developedfurther by Kowa Pharmaceuticals Tokyo Japan is a novel member of the medication class of statins.

LIVALO (pitavastatin) is an inhibitor of HMG-CoA reductase. It is a synthetic lipid-lowering agent for oral administration.

The chemical name for pitavastatin is (+)monocalcium bis{(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5dihydroxy-6-heptenoate}. The structural formula is:

LIVALO (pitavastatin) Structural Formula Illustration

The empirical formula for pitavastatin is C50H46CaF2N2O8 and the molecular weight is 880.98. Pitavastatin is odorless and occurs as white to pale-yellow powder. It is freely soluble in pyridine, chloroform, dilute hydrochloric acid, and tetrahydrofuran, soluble in ethylene glycol, sparingly soluble in octanol, slightly soluble in methanol, very slightly soluble in water or ethanol, and practically insoluble in acetonitrile or diethyl ether. Pitavastatin is hygroscopic and slightly unstable in light.

Each film-coated tablet of LIVALO contains 1.045 mg, 2.09 mg, or 4.18 mg of pitavastatin calcium, which is equivalent to 1 mg, 2 mg, or 4 mg, respectively of free base and the following inactive ingredients: lactose monohydrate, low substituted hydroxypropylcellulose, hypromellose, magnesium aluminometasilicate, magnesium stearate, and film coating containing the following inactive ingredients: hypromellose, titanium dioxide, triethyl citrate, and colloidal anhydrous silica.

Pitavastatin (usually as a calcium salt) is a member of the blood cholesterol loweringmedication class of statins,^[1] marketed in the United States under the trade nameLivalo. Like other statins, it is an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis. It has been available in Japan since 2003, and is being marketed under licence in South Korea and in India.^[2] It is likely that pitavastatin will be approved for use in hypercholesterolaemia (elevated levels of cholesterol in the blood) and for the prevention of cardiovascular disease outside South and Southeast Asia as well.^[3] In the US, it received FDA approval in 2009.^[4]

Pitavastatin is used to lower serum levels of total cholesterol, LDL-C, apolipoprotein B, and triglycerides, and raise levels of HDL-C for the treatment of dyslipidemia.

Like the other statins, pitavastatin is indicated for hypercholesterolaemia (elevated cholesterol) and for the prevention of cardiovascular disease. A 2009 study showed that pitavastatin increased HDL cholesterol (24.6%), especially in patients with HDL lower than 40 mg/dl, in addition to greatly reducing LDL cholesterol (–31.3%).^[5] As a consequence, pitavastatin is most likely to be appropriate for patients with metabolic syndrome with high LDL, low HDL and diabetes mellitus.

Common statin-related side effects (headaches, stomach upset, abnormal liver function tests and muscle cramps) were similar to other statins. However, pitavastatin seems to lead to fewer muscle side effects than certain statins that are lipid-soluble, as a result of the fact that pitavastatin is water-soluble (as is pravastatin, for example).^[6] One study found that coenzyme Q₁₀ was not reduced as much as with certain other statins (though this is unlikely given the inherent chemistry of the HMG-CoA reductase pathway that all statin drugs inhibit).^[3]^[7]

Hyperuricemia or increased levels of serum uric acid have been reported with pitavastatin.^[8]

Most statins are metabolised in part by one or more hepatic cytochrome P450enzymes, leading to an increased potential for drug interactions and problems with certain foods (such as grapefruit juice). Pitavastatin appears to be a substrate ofCYP2C9, and not CYP3A4 (which is a common source of interactions in other statins). As a result, pitavastatin is less likely to interact with drugs that are metabolized via CYP3A4, which might be important for elderly patients who need to take multiple medicines.^[3]

Pitavastatin (previously known as itavastatin, itabavastin, nisvastatin, NK-104 or NKS-104) was discovered in Japan by Nissan Chemical Industries and developed further byKowa Pharmaceuticals, Tokyo.^[3] Pitavastatin was approved for use in the United States by the FDA on 08/03/2009 under the trade name Livalo. Pitavastatin has been also approved by the Medicines and Healthcare products Regulatory Agency (MHRA) in UK on 17 August 2010.

Kajinami, K; Takekoshi, N; Saito, Y (2003). “Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor”.Cardiovascular drug reviews 21 (3): 199–215. PMID 12931254. edit
Zydus Cadila launches pitavastatin in India
Mukhtar, R. Y. A.; Reid, J.; Reckless, J. P. D. (2005). “Pitavastatin”. International Journal of Clinical Practice 59 (2): 239–252.doi:10.1111/j.1742-1241.2005.00461.x. PMID 15854203. edit
The Seventh Statin; Pitavastatin
http://www.ncbi.nlm.nih.gov/pubmed/19907105
ScienceDaily (11 May 2013). “Alternative Cholesterol-Lowering Drug for Patients Who Can’t Tolerate Statins”. ScienceDaily.
Clin Pharmacol Ther. 2008 May;83(5):731-9. Epub 2007 Oct 24. Comparison of effects of pitavastatin and atorvastatin on plasma coenzyme Q10 in heterozygous familial hypercholesterolemia: results from a crossover study. Kawashiri MA, Nohara A, Tada H, Mori M, Tsuchida M, Katsuda S, Inazu A, Kobayashi J, Koizumi J, Mabuchi H, Yamagishi M.
Ogata, N.; Fujimori, S.; Oka, Y.; Kaneko, K. (2010). “Effects of Three Strong Statins (Atorvastatin, Pitavastatin, and Rosuvastatin) on Serum Uric Acid Levels in Dyslipidemic Patients”. Nucleosides, Nucleotides and Nucleic Acids 29 (4–6): 321.doi:10.1080/15257771003741323. edit

FDA approval history

Country	Patent Number	Approved	Expires (estimated)
United States	7,022,713	2009-08-03	2024-02-19
United States	6,465,477	2009-08-03	2016-12-20
United States	5,856,336	2009-08-03	2016-01-05
United States	5,854,259	2009-08-03	2015-12-29
United States	5,753,675	2009-08-03	2015-05-19

JP 1993310700, JP 1994025092

Tetrahedron Lett 1993, 34, 51, 8263-6.

Bioorg Med Chem2001, 9, (10): 2727

Drugs Fut1998, 23, (8) :847-859

Bull Chem Soc Jpn1995, 68, (1) :364-72

Tetrahedron Asymmetry1993, 4, (2) :201-4

Tetrahedron Lett1993, 34, (51) :8267-70

A Endo; J. Med. Chem. 1985, 28, 401.
AM Gotta; LC Smith; IXth International Symp. Drugs Affecting Lipid Metabolism, 1986, 30- 31
Y Fujikawa, Nissan Chemical Industries Ltd, EP304063 (A3), 1989.
S Ahmed; CS Madsen; PD Stein; J. Med. Chem. 2008, 51, 2722-2733.
K Turner; Org. Process. Res. Dev, 2004, 8, 823-833.
Z Casar; M Steinbocher; J Kosmrlj; J. Org. Chem. 2010, 75(19), 6681-6684.
KL Baumann; Tetrahedron Letters, 1992, 33, 2283-2284.
N Miyachi; Y Yanagawa; H Iwasaki; Tetrahedron Lett. 1993, 34, 8267-8270.
T Minami; K Takahashi; T Hiyama; Tetrahedron Lett. 1993, 34, 3, 513-516.
DA Evans; AH Hoveyda; J. Org. Chem. 1990, 55, 5190-5192.
J Castorer; LA Sorbera; PA Leeson; Drugs Fut. 23(8), 1998, 847-859.
T Hiyama; K Takahashi; T Minami; Bull. Chem. Soc. Jpn. 1995, 68, 364-372.
MS Reddy; M Bairy; K Reddy; Oriental Journal of Chemistry. 2007, 23, 559-564.
RN Moore; G Bigam; JK Chan; AM Hogg; JC Vederas; J. Am. Chem. Soc. 1985, 107 3694-3701.
DS Johnson; JJ Li; Art of Drug Synthesis, John Wiley & Sons, New Jersey, 2007, 177-181.
MT Stone; Organic Lett. 2011, 13, 2326-2329.
SR Manne, SR Maramreddy, WO2007132482 (A2), 2007.
SD Dwivedi, DJ Patel, AP Shah, Cadila Healthcare Ltd, US0022102 (A1), 2012.

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The reaction of 1 (R) ,7,7-trimethylbicyclo [2.2.1] heptan-2-one (I) with 1 -naphthylmagnesium bromide (II) gives the tertiary alcohol (III), which by reaction with SOCl2 and then with NaHCO3 yields 2 – (1-naphthyl) -1 (R) ,7,7-trimethylbicyclo [2.2.1] heptene (IV ). Hydroboration of (IV) with BH3 followed by oxidation with H2O2 affords 4 (S) ,7,7-trimethyl-3exo-(1-naphthyl) bicyclo [2.2.1] heptan-2exo-ol (V), which is submitted to transesterification with methyl acetoacetate (VI) and dimethyl-aminopyridine (DMAP) to give the corresponding ester (VII). The condensation of (VII) with N-methoxy-N-methyl-3-[2-cyclopropyl-4-( 4-fluorophenyl) quinolin-3-yl] -2 (E)-propenamide (VIII) by means of NaH yields the corresponding chiral 3,5-dioxoheptenoic acid ester (IX), which is selectively reduced first with diisobutylaluminum hy-dride acid (DIBAL) and then with diethylmethoxyborane and sodium borohydride affording the 3 (R), 5 (S)-dihydroxyheptenoic ester (X). Finally, this compound is saponified with NaOH and treated with acetic acid / sodium acetate. The intermediate amide (VIII ) is obtained by condensation of 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-carbaldehyde (XI) with N-methoxy-N-methylacetamide (XII) by means of butyllithium to the hydroxy propionamide (XIII), which is then dehydrated with methanesulfonyl chloride and triethylamine in the usual way).

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A systematic chiral synthesis of NK-104 and its enantiomer (X) has been reported: The oxidation of the already known 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-methanol (I) with DMSO, P2O5 and triethylamine gives the corresponding aldehyde (II), which is condensed with diethyl cyanomethylphosphonate by means of NaOH in toluene yielding the propenenitrile (III). The reduction of (III) with DIBAL affords the unsaturated aldehyde (IV), which is condensed with ethyl acetoacetate by means of NaH and n-BuLi to provide the 3-oxo-5-hydroxy-6-heptenoic acid ethyl ester derivative (V). The highly syn stereoselective reduction of (V) by means of diethylmethoxyborane and NaBH4 yields the desired syn racemic mixture of erythro-beta,delta-dihydroxyesters (VII), which is submitted to optical resolution with chiral (+)-alpha-methylbenzylamine [(+)-MBA] to obtain NK-104 free acid (VIII), which is finally treated with NaOH and CaCl2. The enantiomer of NK-104 has been obtained by optical resolution of the racemic mixture (VII) with (-)-alpha-methylbenzylamine to obtain the enantiomeric free acid (IX), which is treated with NaOH and CaCl2 as before.

Fujikawa, Y.; Suzuki, M.; Iwasaki, H.; Kitahara, M.; Sakashita, M.; Sakoda, R.;. Synthesis and biological evaluations of quinolone-based HMG-CoA reductase inhibitors Bioorg Med Chem 2001, 9 , 10, 2727

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ADDITIONAL UPDATED INFO

Pitavastatin calcium is a novel member of the medication class of statins. Marketed in the United States under the trade name Livalo, it is like other statin drugs an inhibitor of HMG-CoA reductase, the enzyme that catalyses the first step of cholesterol synthesis. It is likely that pitavastatin will be approved for use in hypercholesterolaemia (elevated levels of cholesterol in the blood) and for the prevention of cardiovascular disease outside South and Southeast Asia as well.

Pitavastatin calcium is chemically known as (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid calcium salt having the formula IA is known in the literature.

Pitavastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). This enzyme catalyzes the conversions of HMG-CoA to mevalonate, inhibitors are commonly referred to as “statins”. Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Pitavastatin is used in the treatment of hyperchloesterolemia and mixed dyslipidemia.

Pitavastatin calcium has recently been developed as a new chemically synthesized and powerful statin by Kowa Company Ltd, Japan. On the basis of reported data, the potency of Pitavastatin is dose-dependent and appears to be equivalent to that of Atorvastatin. This new statin is safe and well tolerated in the treatment of patients with hypercholesterolaemia. Significant interactions with a number of other commonly used drugs can be considered to be extremely low.

Pitavastatin was disclosed for the first time in US patents US 4,761,419, US 5,01 1 ,930 and US 5,753,675. The process disclosed in these patents for the preparation of Pitavastatin is as shown below:

wherein R is hydrogen or protecting group.

US 5,284,953 discloses a process for the preparation of Pitavastatin calcium, which employs optically active a-methylbenzylamine as a resoluting agent.

The above processes are economically not viable, as resolution is carried out in final stage.

US 6,835,838 B2 discloses a process for the preparation of Pitavastatin calcium, which is as shown below:

However, it has been observed that the above process of lactonization results in ~10- 15% of unreacted Pitavastatin ethyl ester and therefore results in low yield. Further, -10% of Pitavastatin acid results during the above lactonization process and therefore does not produce a single product which is required to keep adequate control for an intermediate through specifications to have consistently better quality of the finished product.

Processes for the preparation of Pitavastatin are described in EP-A-0304063 and EP-A-1099694 and in the publications by N. Miyachi et al. in Tetrahedron Letters (1993) vol. 34, pages 8267-8270 and by K. Takahashi et al. in Bull. Chem. Soc. Japan (1995) Vol. 68, 2649-2656. These publications describe the synthesis of Pitavastatin in great detail but do not describe the hemi-calcium salt of Pitavastatin. The publications by L A. Sorbera et al. in Drugs of the Future (1998) vol. 23, pages 847-859 and by M. Suzuki at al. in Bioorganic & Medicinal Chemistry Letters (1999) vol. 9, pages 2977-2982 describe Pitavastatin calcium, however, a precise procedure for its preparation is not given. A full synthetic procedure for the preparation of Pitavastatin calcium is described in EP-A-0520406. In the process described in this patent Pitavastatin calcium is obtained by precipitation from an aqueous solution as a white crystalline material with a melting point of 190-192° C.

US20090182008 A1 discloses polymorphic form A, B, C, D, E, and F, and the amorphous form of Pitavastatin Calcium salt (2:1). In particular, crystalline Form A having water content from about. 5% to about 15% and process for its preparation are disclosed.

US20090176987 A1 also discloses polymorphic form crystal form A of Pitavastatin Calcium which contains from 5 to 15% of water and which shows, in its X-ray powder diffraction as measured by using CuKa radiation, a peak having a relative intensity of more than 25% at a diffraction angle (20) of 30.16°.

WO2007/132482 A1 discloses a novel process for the preparation of Pitavastatin Calcium by condensing bromide salt of formula-3 with aldehyde compound of formula-4 to obtain olefinic compound of formula-5 and converting olefinic compound to Pitavastatin Calcium via organic amine salt for purification.

Pitavastatin and its process were disclosed in U.S. Pat. No. 5,753,675.

Pitavastatin calcium and its process were disclosed in U.S. Pat. No. 5,856,336. PCT publication no. WO 2004/072040 (herein after referred to ‘040 patent) disclosed crystalline polymorph A, polymorph B, polymorph C, polymorph D, polymorph E, polymorph F and amorphous form of pitavastatin calcium

Synthesis of pitavastatin via cross-coupling reaction is disclosed inTetrahedron Lett. 1993, 34, 8263-8266, and in Tetrahedron Lett. 1993, 34, 8267-8270.
A method for the preparation of pitavastatin via epichlorohydrin is described in Tetrahedron: Asymmetry 1993, 4, 201-204.
Synthesis of pitavastatin heterocycle and pitavastatin molecule assembly via aldol condensation reaction is disclosed in Bioorg. Med. Chem. Lett. 1999, 9, 2977-2982, and Bioorg. Med. Chem. 2001, 9, 2727-2743:
PCT application WO 2003/064382 describes a method for preparation of pitavastatin by asymmetric aldol reaction, in which titanium complex is used as a catalyst.
HWE route to pitavastatin by utilization of 3-formyl substituted pitavastatin heterocycle is disclosed in Helv. Chim. Acta 2007, 90, 1069-1081:
Methods for preparation of pitavastatin heterocycle derivatives are described in Bull. Chem. Soc. Jpn. 1995, 68, 364-372, Heterocycles 1999, 50, 479-483, Lett. Org. Chem. 2006, 3, 289-291, and in Org. Biomol. Chem. 2006, 4, 104-110, as well as in the international patent applications WO 95/11898 and WO 2004/041787
WO 95/11898 and Bull. Chem. Soc. Jpn. 1995, 68, 364-372 disclose synthesis of PTVBR from PTVOH with PBr₃:

WO 1995/1 1898 Al discloses a process for the preparation of Pitavastatin, which is as shown below:

wherein Y represents P⁺RnRi₂Ri3Hal^“ or P(W)Ri₄R₁₅; R_9a, R_% and R_]0 are protecting groups each of Rn, Rj_2> R^_, Ri₄ and R15 which are independent of one another, is optionally substituted alkyl or optionally substituted aryl group; R14 and Rj₅ together form a 5- or 6-membered ring; Hal is chlorine, bromine or iodine; and W is O or S.

The above process results in 2-5% of Cis isomer of Pitavastatin which requires further purification and therefore results poor yield.

US 6,875,867 B2 discloses a process for the preparation of Pitavastatin arginine salt, which is as shown below:

Saponification / Base

During the above process Trifluoroacetic acid or hydrochloric acid is used to break the acetonide and the Pitavastatin ester formed is converted in situ to its corresponding alkali salt by treating with base, such as sodium hydroxide.

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nmr

http://scholarsresearchlibrary.com/dpl-vol4-iss5/DPL-2012-4-5-1553-1557.pdf

calcium bis-(E)-3,5-dihydroxy-7-[4’-(4’’-flurophenyl)-2’-
cyclopropyl-quinoline-3-yl]-hept-6-enoate , pitavastatin calcium
Melting Point: 207 degC;

IR υmax (KBr) cm-1: 3366 (OH), 2911, 1603 (C=O), 1567 (C=N), 1513 (C=C),

1488 (C-H), 1416 (C-H), 1313, 1275, 1221 (C-O-C), 1158, 1065 (C-H), 972, 843, 763.

1H-NMR (500MHz, DMSO-d6):

δ 1.01 (m, 2H), 1.09 (m, 1H), 1.19 (m, 2H), 1.41 (m, 1H),

1.98 (dd, 1H, J1 =8.5,
J2 =15.5Hz), 2.11(d, 1H, J1 =3.0, J2 =15.5Hz), 2.50 (m, 2H),

3.66 (m, 1H), 4.13 (m, 1H), 4.95 (s, 1H), 5.58 (dd, 1H,
J1 =5.5, J2 =10.5Hz), 6.49 (d, 1H, J = 16.0Hz),

7.35 (m, 6H), 7.59 (m, 1H, J = 7.0Hz), 7.83 (d, 1H, J =8.5Hz).

13CNMR & DEPT (125.76MHz, DMSO-d6):

δ 11.12(CH2, C-17), 11.23(CH2,C-18), 15.80(CH2, C-16), 44.29(CH2,
C-22), 44.61(CH2, C-24), 66.61(C-O, C-23),

69.34(C-O,C-21),115.53(C=C, C-20), 15.62(CH), 115.79(CH),
123.59(CH), 126.07(C=C, C-19),

128.79(CH),129.20(CH),130.07(CH), 32.30(CH),

132.56(CH), 133.51(C),
142.60(C), 144.09(C), 146.37(C),

161.02(C), 163.00(C), 179.13(C=O, C-25).

ESI-MS: m/z (%) 318 (100), 274 (23), 423 (13), 422 (M+, 70); EI calcd for C25H24FNO4, 421.461; found, 422.220
(M+).

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Tandospirone

Uncategorized 1 Response »

Dec 132013

Tandospirone

CAS.87760-53-0, (3aa,4b,7b,7aa)-Hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione

Additional Names: (1R*,2S*,3R*,4S*)-N-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,3-bicyclo[2.2.1]heptanedicarboximide

C21H29N5O2, m383.49

C 65.77%, H 7.62%, N 18.26%, O 8.34%

Literature References: Serotonin (5-HT1A) receptor agonist. Prepn: K. Ishizumi et al., EP 82402; eidem, US 4507303 (1983, 1985 both to Sumitomo);

US4818756, JP60087262

idem et al., Chem. Pharm. Bull. 39, 2288 (1991).

Bioorganic and Medicinal Chemistry Letters, 1997 , vol. 7, 13 pg. 1659 – 1664

Behavioral pharmacology: C. A. Sannerud et al., Drug Alcohol Depend. 32, 195 (1993). Clinical efficacy in treatment of bulimia: H. Tamai et al., Int. J. Obes. 14, 289 (1990). Clinical evaluation of potential adverse effects: M. Suzuki et al., Jpn. J. Psychopharmacol. 13, 213 (1993); of abuse liability: S. M. Evanset al., J. Pharmacol. Exp. Ther. 271, 683 (1994).

Review of pharmacology: P. A. Seymour et al., Prog. Clin. Biol. Res. 361, 453-460 (1990)

Crystals from toluene/n-hexane, mp 112-113.5°.mp 112-113.5°

Tandospirone, [112457-95-1]

US 5011841

(lR*,2S*,3R*,4S*)-N-[4-[4-(2- US 5011841 citrate Pyrimidinyl) piperazin-1-

yl] butyl ] -2 , 3-norbornane- dicarboximide citrate

Manufacturers’ Codes: SM-3997

Trademarks: Sediel (Sumitomo)

Molecular Formula: C21H29N5O2.C6H8O7

Molecular Weight: 575.61

Percent Composition: C 56.34%, H 6.48%, N 12.17%, O 25.02%

Properties: mp 169.5-170°.

Melting point: mp 169.5-170°

Tandospirone hyd, SM-3997,

Chemical Name: (3aR,4S,7R,7aS)-rel-Hexahydro-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-4,7-methano-1H-isoindole-1,3(2H)-dione hydrochloride

Molecular Formula: C21H29N5O2.HCl

Molecular Weight: 419.95

Percent Composition: C 60.06%, H 7.20%, N 16.68%, O 7.62%, Cl 8.44%

Properties: Crystals from isopropanol, mp 227-229°.

Melting point: mp 227-229°

Tandospirone (Sediel), also known as metanopirone, is an anxiolytic andantidepressant used in China and Japan, where it is marketed by Dainippon Sumitomo Pharma. It is a member of the azapirone and piperazine chemical classes and is closely related to other agents like buspirone and gepirone.

Tandospirone is most commonly used as a treatment for anxiety and depressive disorders, such as generalised anxiety disorder and dysthymia respectively.^[1] For both indications it usually takes a couple of weeks for therapeutic effects to be start being seen,^[1] although at higher doses more rapid anxiolytic responses have been seen.^[2] It has also been used successfully as a treatment for bruxism.^[3]

Tandospirone has also been tried, successfully, as an adjunctive treatment for cognitive symptoms in schizophrenic individuals.^[4]

It is not believed to be addictive but it is known to produce mild withdrawal effects (e.g. anorexia) after abrupt discontinuation.^[1]

Chemistry

Yevich, Joseph P.; New, James S.; Smith, David W.; Lobeck, Walter G.; Catt, John D.; Minielli, Joseph L.; Eison, Michael S.; Taylor, Duncan P. et al. (1986). “Synthesis and biological evaluation of 1-(1,2-benzisothiazol-3-yl)- and (1,2-benzisoxazol-3-yl)piperazine derivatives as potential antipsychotic agents”. Journal of Medicinal Chemistry 29 (3): 359–69. doi:10.1021/jm00153a010.PMID 2869146.

Tandospirone acts as a potent and selective 5-HT_1A receptor partial agonist, with a K_i affinity value of 27 ± 5 nM^[5] and approximately 55-85% intrinsic activity.^[6]^[7] It has weak and clinically negligible affinity for the 5-HT_2A (1,300 ± 200), 5-HT_2C (2,600 ± 60), α₁-adrenergic (1,600 ± 80), α₂-adrenergic (1,900 ± 400), D₁ (41,000 ± 10,000), and D₂ (1,700 ± 300) receptors, and is essentially inactive at the 5-HT_1B, 5-HT_1D, β-adrenergic, and muscarinic acetylcholine receptors, serotonin transporter (SERT), and benzodiazepine (BDZ)allosteric site of the GABA_A receptor (all of which are > 100,000).^[5] There is evidence of tandospirone having low but significantantagonistic activity at the α₂-adrenergic receptor through its active metabolite 1-(2-pyrimidinyl)piperazine (1-PP), however.^[8]^[9]

Barradell, LB; Fitton, A (February 1996). “Tandospirone” (PDF). CNS Drugs 5 (2): 147–153. doi:10.2165/00023210-199605020-00006.
Nishitsuji; To, H; Murakami, Y; Kodama, K; Kobayashi, D; Yamada, T; Kubo, C; Mine, K (2004). “Tandospirone in the treatment of generalised anxiety disorder and mixed anxiety-depression : results of a comparatively high dosage trial” (PDF). Clinical drug investigation 24 (2): 121–6. doi:10.2165/00044011-200424020-00007. PMID 17516698.
“Tandospirone”. Martindale: The Complete Drug Reference (The Royal Pharmaceutical Society of Great Britain). 23 September 2011. Retrieved 14 November 2013.
Sumiyoshi, T; Matsui, M; Nohara, S; Yamashita, I; Kurachi, M; Sumiyoshi, C; Jayathilake, K; Meltzer, HY (October 2001). “Enhancement of cognitive performance in schizophrenia by addition of tandospirone to neuroleptic treatment” (PDF). The American Journal of Psychiatry 158 (10): 1722–1725. doi:10.1176/appi.ajp.158.10.1722. PMID 11579010.
Hamik; Oksenberg, D; Fischette, C; Peroutka, SJ (1990). “Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites”. Biological Psychiatry 28 (2): 99–109. doi:10.1016/0006-3223(90)90627-E. PMID 1974152.
Tanaka; Tatsuno, T; Shimizu, H; Hirose, A; Kumasaka, Y; Nakamura, M (1995). “Effects of tandospirone on second messenger systems and neurotransmitter release in the rat brain”. General pharmacology 26 (8): 1765–72. doi:10.1016/0306-3623(95)00077-1.PMID 8745167.
Yabuuchi, Kazuki; Tagashira, Rie; Ohno, Yukihiro (2004). “Effects of tandospirone, a novel anxiolytic agent, on human 5-HT_1A receptors expressed in Chinese hamster ovary cells (CHO cells)”. Biogenic Amines 18 (3): 319. doi:10.1163/1569391041501933.
Blier; Curet, O; Chaput, Y; De Montigny, C (1991). “Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine–II. Effects of acute administration of 1-PP and long-term administration of tandospirone on noradrenergic neurotransmission”. Neuropharmacology 30 (7): 691–701. doi:10.1016/0028-3908(91)90176-C. PMID 1681447.
Miller; Thompson, ML; Byrnes, JJ; Greenblatt, DJ; Shemer, A (1992). “Kinetics, brain uptake, and receptor binding of tandospirone and its metabolite 1-(2-pyrimidinyl)-piperazine”. Journal of Clinical Psychopharmacology 12 (5): 341–5. PMID 1362206

“Azapirone” is a term that has been used to describe a structural class of psychotropic compounds that demonstrate similar pharmacology relating to interaction with monoaminergic pathways in particular brain regions.
[0002]

The azapirones amenable to the new process of this invention can be shown by some representative illustrations of certain azapirorie drug agents having structural formula (I).
[0003]

In formula I, W and Y can independently be carbonyl or sulfonyl and n is the integer 4 or 5. Z is selected inter alia from

in which R¹ and R² are selected from lower alkyl or are taken together as a butyl or pentyl bridge;
[0004]

Perhaps the best known representative of the azapirone class of psychotropic agents is buspirone (1), originally disclosed in U.S. 3,71 7,634.
[0005]
[0006]
Some other well known members are:
- gepirone, where
- (U.S. 4,423,049); ipsapirone, where
- (U.S. 4,818,756); tandospirone, where
- (U.S. 4,507,303); and WY-47,846, where
- (U.S. 4,892,943).
[0007]

The dotted and solid lines in the tandospirone-type structure can be taken as either a single or double carbon-carbon covalent bond.
[0008]

While a number of synthetic processes have been disclosed for the synthesis of these azapirones, a method of choice, currently used for large scale preparation of buspirone and gepirone, was disclosed by Sims in U.S. 4,351,939. The Sims method involves the reaction of an appropriately-substituted glutarimide (3) with a novel spiroquatemary ammonium halide (4) to yield buspirone or gepirone or

close analogs. The halide, X, is preferably bromide. The reaction is carried out in a hot inert reaction medium in the presence of an acid scavenging base. In practice, the reaction process involves a multiphasic reaction of (3) and (4) in refluxing xylene with an excess of solid potassium carbonate.
[0009]
For large-scale production, this prior art synthesis suffers from several processing disadvantages, including:
- · high temperature processing in toxic solvents, e.g., refluxing xylene;
- · a multiphasic reaction mixture requiring highly efficient stirring and as the scale increases, this factor becomes increasingly important;
- • the presence of large amounts of inorganic by-products which complicate reaction workup and product isolation;
- • long reaction time, e.g., 24 hours; and
- • lower and more erratic yields of product resulting from the generation of water as a by-product. The efficient removal of the water is a problem, particularly in these large-scale processes.
[0010]

Compounds of formula (2)

such as imidate anions of structure (2a),

wherein MIB represents an alkali or alkaline earth metal, can be reacted with a pyrimidinylpiperazinyl derivative of formula (5),

wherein Q is a nucleofuge, i.e. a leaving group of the type commonly utilized in synthetic organic chemistry; by heating in an inert solvent under standard conditions such as those described for the alkylation step of the Gabriel synthesis; cf: Gibson and Bradshaw, Angew. Chem. Int. Ed., 7/919,930, (1968).
[0011]

The reaction of certain anions, e.g., (2) with intermediates of formula (5), has been previously disclosed. This method has been reported, for example, for the preparation of buspirone (U.S. 3,717,634) and ipsapirone (U.S. 4,818,756). In general, this method has not been used on a large scale, particularly with imides, due to the additional processing requirements necessitated by the generation and handling of a reactive metal salt of the imidate component. As mentioned, the Sims process (involving the reaction of (3) and (4)-type compounds) is the current method of choice for large-scale synthesis of these azapirones.
[0012]

These prior art processes differ then from the novel improved process which utilizes a pre-formed potassium salt of the imidate-type starting material (2) which is reacted with a spiroquatemary salt (4), instead of a formula (5) compound, to provide azapirone product

Tandospirone and tandospirone salts have been described in several patents and patent applications. These describe pharmaceutical compositions of tandospironealone and in combination with other drugs for treatment of human disease and include EP 0437026 (Treatment of depression), WO 1994016699 (Compositions containing tandospirone or its analogues), EP 0082402 (Succinimide derivates and process for preparation thereof), JP 2002020291 (Therapeutic agents for cognition disorders), JP 2003335678 (Therapeutic agents for neurogenic pain), WO 2004002487 (Methods for treating attention deficit disorder), JP 2005225844 (Agents for the treatment of irritable bowel syndrome), WO 20051 17886 (Adhesive patch),WO 2008044336 (Crystal- containing adhesive preparation) and WO 2010065730 (Pharmaceutical suspension).

………………………………………

Drugs Fut 1986,11(11),949

By condensation of norbornane-2,3-di-endo-carboxylic anhydride (I) with 1-(4-aminobutyl)-4-(2 pyrimidinyl)piperazine (II) in refluxing pyridine.

……………………………………………………….

CA 1184915; EP 0082402

The cyclization of methyl 3-[4-(4-methoxybenzoylamino)-3-nitrobenzoyl]butyrate (I) with hydrazine hydrate in refluxing acetic acid gives 4,5-dihydro-6-[4-(4-methoxybenzoylamino)-3-nitrobenzoyl]-5-methylpyridazin-3(2H)-one (II), which is reduced with H2 over Pd/C in ethanol yielding the corresponding amino derivative (III). Finally, this compound is cyclized in refluxing acetic acid.

……………………………………………………..

Chem Pharm Bull 1991,39(9),2288

New syntheses of tandospirone have been described: 1) The hydrogenation of bicyclo[2.2.1]hept-5-ene-2,3-di-exo-carboxylic acid anhydride (I) with H2 over Pd/C in THF-water gives bicyclo[2.2.1]heptane-2,3-di-exo-carboxylic acid anhydride (II), which by reaction with ammonia in THF-water is converted into the imide (III). The reaction of (III) with 1,4-dibromobutane by means of K2CO3 in refluxing acetone yields N-(4-bromobutyl)bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (IV), which is finally condensed with 1-(2-pyrimidinyl)piperazine (V) by means of K2CO3 and KI in hot DMF. 2) Imide (III) is condensed with propargyl bromide (VI) by means of K2CO3 in refluxing acetone affording N-propargylbicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VII), which is allowed to react with piperazine (V) and formaldehyde by means of CuSO4 in dioxane to give N-[4-[4-(2-pyrimidinyl)piperazin-1-yl]-2-butynyl]bicyclo[2.2.1]heptane-2,3-di-exo-carboximide (VIII). Finally, this compound is reduced with H2 over Pd/C. 3) The condensation of piperazine (V) with 4-chlorobutyronitrile (IX) by means of NaOH in acetone gives 4-[4-(2-pyrimidinyl)piperazin-1-yl]butyronitrile (X), which is reduced with LiAlH4 in ether yielding 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (XI). Finally, this compound is condensed with anhydride (II) in refluxing pyridine.

………………….

CN 101362751 B

Figure CN101362751BD00063

Figure CN101362751BD00061

…………

DRUG SPOTLIGHT …TRANDOLAPRIL

Uncategorized Comments Off

Dec 072013

TRANDOLAPRIL

(2S,3aR,7aS)-1-[(2S)-2-{[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino}propanoyl]-octahydro-1H-indole-2-carboxylic acid

87679-37-6 CAS NO

C24-H34-N2-O5, 430.549

Indications. hypertention

Abbott..(opten , godrik, mavik), HOECHST MARION ROUSSEL..Odrik,

RU-44570, Preran,

Aventis Pharma (Originator), Nippon Roussel (Originator), Abbott (Licensee), Chugai (Licensee)Launched-1993

Trandolapril is a non-sulhydryl prodrug that belongs to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to its biologically active diacid form, trandolaprilat, in the liver. Trandolaprilat inhibits ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Trandolapril may be used to treat mild to moderate hypertension, to improve survival following myocardial infarction in clinically stable patients with left ventricular dysfunction, as an adjunct treatment for congestive heart failure, and to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy.

Trandolapril is an ACE inhibitor used to treat high blood pressure, it may also be used to treat other conditions. It is marketed by Abbott Laboratories with the brand name Mavik.

Tarka is the brand name of an oral antihypertensive medication that combines a slow release formulation of verapamil hydrochloride, acalcium channel blocker, and an immediate release formulation of trandolapril, an ACE inhibtor. The patent, held by Abbott Laboratories, expires on February 24, 2015.

This combination medication contains angiotensin-converting enzyme (ACE) inhibitor and calcium channel blocker, prescribed for high blood pressure.

Trandolapril is a prodrug that is deesterified to trandolaprilat. It is believed to exert its antihypertensive effect through the renin-angiotensin-aldosterone system. Trandolapril has a half life of about 6 hours, and trandolaprilat has a half life of about 10. Trandolaprilat has about 8 times the activity of its parent drug. Approximately 1/3 of Trandolapril and its metabolites are excreted in the urine, and about 2/3 of trandolapril and its metabolites are excreted in the feces. Serum protein binding of trandolapril is about 80%.

Trandolapril is a drug that is used to lower blood pressure. Blood pressure is dependent on the degree of constriction (narrowing) of the arteries and veins. The narrower the arteries and veins, the higher the blood pressure. Angiotensin Il is a chemical substance made in the body that causes the muscles in the walls of arteries and veins to contract, narrowing the arteries and veins and thereby elevating blood pressure. Angiotensin Il is formed by an enzyme called angiotensin converting enzyme (ACE). Trandolapril is an inhibitor of ACE and blocks the formation of angiotensin Il thereby lowering blood pressure. The drop in blood pressure also means that the heart does not have to work as hard because the pressure it must pump blood against is less. The efficiency of a failing heart improves, and the output of blood from the heart increases. Thus, ACE inhibitors such as trandolapril are useful in treating heart failure.

Trandolapril‘s ACE-inhibiting activity is primarily due to its diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity.

……………………

synthesis

(3aR,7aS)-octahydroindole-2(S)-carboxylic acid (I) goes through the process of esterification with benzyl alcohol (II) in the presence of SOCl₂ to produce the corresponding benzyl ester (III), and the yielding compound is then condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (IV) in the presence of 1-hydroxybenzotriazole, N-ethylmorpholine and dicyclohexylcarbodiimide (DCC) in DMF to afford the benzyl ester (V) of the desired product. Lastly, the compound is debenzylated by hydrogenation with H₂ over Pd/C in ethanol.

……………………………………………..

Trandolapril along with other related compounds was first disclosed in US4933361. The process for the synthesis of trandolapril was described in US4933361 and WO9633984.

US4933361 describes a process for the synthesis of trandolapril wherein the racemic benzyl ester of octahydro indole-2-carboxylic acid is reacted with N-[1-(S)-ethoxy carbonyl- 3- phenyl propyl]-L-alanine (ECPPA), to get racemic benzyl trandolapril, which is purified using column chromatography to get the 2S isomer of benzyl trandolapril, which is further debenzylated with Pd on carbon to get trandolapril as a foamy solid. This process has certain disadvantages, for example the product is obtained in very low yield. Purification is done using column chromatography, which is not suitable for industrial scale up.

WO9633984 discloses a process in which N-[1-(S)-ethoxy carbonyl-3- phenyl propyl]-L- alanine is activated with N-chlorosulfinyl imidazole, to get (N-[I-(S) N-[1-(S)-ethoxy carbonyl-3-phenyl propylj-L-alanyl-N-sulfonyl anhydride and which is further reacted with silyl-protected 2S,3aR,7aS octahydro indole 2-carboxyIic acid to obtain trandolapril. The main disadvantages of this process are that the silyl-protected intermediates are very sensitive to moisture, the process requires anhydrous conditions to be maintained and the solvent used has to be completely dried. It is very difficult to maintain such conditions on an industrial scale, and failing to do so leads to low yield of product.

The processes for preparing N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine N- carboxyanhydride which is used in the process of the present invention are well known and are disclosed in JP57175152A, US4496541 , EP215335, US5359086 and EP1197490B1. Trans octahydro-IH-indole-2-carboxylic acid and its esters are the key intermediates in the synthesis of trandolapril. When synthesized, trans octahydro-1 H-indole-2-carboxylic acid is a mixture of four isomers, as shown below.

From the processes known in the prior art, trans octahydro-1 H-indole-2-carboxylic acid is converted to its ester and the ester is then either reacted directly with N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine (ECPPA) and then the isomers are separated by column chromatography, or alternatively the ester is reacted with ECPPA followed by 0 deprotection. Trans octahydro-1 H-indole-2-carboxylic acid is always used in its protected form. No attempts have been made to resolve free trans octahydro-1 H-indole-2-carboxylic acid to convert it to the desired isomer (isomer D, above). Furthermore, none of the prior art processes is stereoselective, so resolution of the required isomer is required following condensation.

EP0088341 and US4490386 describe a method for the resolution of N-benzoyl (2RS,3aR,7aS) octahydro-1 H-indole-2-carboxylic acid using α-phenyl ethyl amine.

US6559318 and EP1140826 describe a process for the synthesis of (2S,3aR,7aS) 0 octahydro-1 H-indole-2-carboxylic acid using enzymatic resolution of its nitrile intermediate. Enzymatic resolution involves many steps and also requires column chromatography for purification making the process uneconomical industrially.

WO8601803 describes the preparation of (2S,3aR,7aS) octahydro-1 H-indole-2-carboxylic 5 acid ethyl ester and benzyl ester using 10-D-camphor sulphonic acid.

WO2004065368 describes the synthesis of (2S,3aR,7aS) octahydro-1 H-indole-2- carboxylic acid benzyl ester by resolution using 10-D-camphor sulphonic acid to prepare trandolapril. This process gives poor yields because the product has to be first resolved and then the ester is deprotected leading to further loss in yield, making the process low yielding and expensive.

W 02005/051909 describes a process for the preparation of trandolapril, i.e. (N-[I-(S)- carbethoxy-3-phenylpropyl}-S-alanyl-2S,3aR,7aS-octahydroindol-2-carboxyIic acid} as well as its pharmaceutical acceptable salts, using a racemic mixture of trans octahydroindole-2- carboxylic acid with the N-carboxyanhydride of {N-[1-(S)-ethoxycarbonyl-3-phenylpropyl}- S-alanyl (NCA) in a molar ratio of 1 :1 to 1.6:1 in a mixture of water and water-miscible solvent to obtain a mixture of diastereomers of trandolapril. The diastereomers are converted to salts which upon repeated crystallization from acetone and water, and reaction with a base gives pure trandolapril. Thus, the condensation reaction in the presence of water and a water-miscible solvent is not stereoselective.

The processes for preparing N-[1-(S)-ethoxy carbonyl-3- phenyl propyl]-l_-alanine N- carboxyanhydride starting from N-[1-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine (ECPPA) are well known and are disclosed in JP57175152A, US4496541 , EP215335, US5359086 and EP1197490B1

The angiotensin-converting enzyme (ACE) inhibitor trandolapril is commonly prescribed as a cardiovascular drug for the control and management of mild to severe hypertension Chigh blood pressure) and may be used alone or in combination with diuretics or other antihypertensive agents. Administration of trandolapril is typically oral at a level of around 0.5-4 mg once a 15 day and may also be used in the management of conditions such as heart failure and left ventricular dysfunction following myocardial infarction.

Trandolapril itself is a prodrug, being converted to the acid form “trandolaprilat” in vivo. It is, however, • generally desirable to prepare and administer the ester form.. The structures of trandolapril and trandolaprilat ^‘ are shown below.

Trandolapril Trandolaprilat

Various methods for the synthesis of trandolapril and related compounds have been proposed but each of these suffers from drawbacks . Frequently the syntheses require the use of dangerous reagents, which make industrial scale preparation hazardous and difficult and/or involve multiple steps resulting in a long and complex synthesis . One of the most important steps in the synthesis is the formation of the trans-fused octahydroindole ring, which is often difficult to separate from the cis-fused equivalent.

A number of the known synthetic routes to trandolapril proceed via the key intermediate (2S, 3aR,7aS) -octahydro,-lH-indole-2-carboxylic acid. This contains the key trans-fused octahydroindole ring and the correct stereochemistry for the carboxylic acid group at the 2-position. Frequently, these methods require the separation of the cis- and trans-fused rings and, in many cases, resolution of the carboxylate group at the 2 -position is necessary. Where production of the trans-fused ring junction has been possible without generating significant quantities of the cis-product, the syntheses have been long and/or required dangerous reagents such as mercury compounds.

(2S, 3aR, 7aS)-octahydro-lH-indole-2-carboxylic acid

US-A-4691022 gives a synthesis of the above intermediate compound in relatively few steps but requires the trans-octahydroindole as the starting material. The result is also a mixture of the 2-α and 2-β compounds.

EP-A-084164/US-A-4, 933,361 provides an apparently effective method for the synthesis of the cis-fused intermediate beginning with the high-pressure hydrogenation of indole at 100 atmospheres of hydrogen and a platinum catalyst. This document also provides two methods for forming the trans-fused octahydroindole ring, but neither is indicated as being efficient. The first method provides the stereochemistry for the 2 -position from substituted alanine, reacting this with activated cyclohexanone and cyclising the product to give a hexahydroindole . Unfortunately, the reduction of this hexahydroindole to the octahydro- compound produces both cis- and trans-fused product in unknown yield. The second method is to introduce the trans-ring via trans-octahydro-lH-quinolin-2 -one, but no indication of yield in the key step is given and complex series of halogenation, partial re-hydrogenation and re-arrangement are required to reach the desired intermediate .

WO 00/40555 / US 6559318 relies on enzymic resolution of a 2- (2 ‘ , 2 ‘ -methoxyethyl) cyclohexamine with Novozyme7 over 25 hours to provide the N-acetylated (1R, 2S) enantiomer which must then be separated by column chromatography from the. unreacted (IS, 2R) enantiomer. Neither the enzymic resolution nor the chromatography steps are well suited to industrial scale preparations. There are also around ten steps required to reach the desired compound.

The synthetic route to the above octahydroindole intermediate proposed by Henning et al . (Tett. Lett. 24(1983), 5343-5346) quickly and elegantly introduces a 1,2-trans configuration around a cyclohexane ring, but requires the use of mercuric nitrate. The use of mercury compounds is obviously undesirable in the preparation of pharmaceuticals. A further synthesis is provided by Brion et al . (Tett. Lett. 33 (1992) 4889-4892) but it is unclear whether they in fact prepare 5% or 95% of the desired product with 2S stereochemistry. In any case, the method requires eleven steps including an initial pig liver esterase digestion to provide the product in stereochemically pure form but in a 95:5 mixture of isomers at position 2. This method is thus complex and ill suited to industrial scale preparation.

ROUTE A – Separation of enantiomers by the formation of diastereomeric salts with a chiral resolving agent HA* (such as 0, O’ -dibenzoyl-L-tartaric acid), coupling with N- [1- (S) -ethoxycarbonyl-3-phenylpropyl] -L-alanine (ECPPA) derivative and finally deprotecting the carboxylic acid moiety R_λ (such as by hydrogenating a benzyl ester, where R_x = B_n) .

ROUTE B.- Direct reaction of 7A with ECPPA derivative that leads to the formation of diastereoisomers, deprotecting the carboxylic acid moiety and finally separation of diastereoisomers by conventional methods.

1) deprotection >■ trandolapril 2) separation of diastereoisomers

ROUTE C- Treatment of 7A in basic medium and deprotection that leads to the racemic mixture of octahydroindole acid followed by the reaction with ECPPA derivative. This will result in a diastereomeric mixture that can be separated by conventional methods.

COOEtCH,

,1 ) basic medium QC &^° ‘ – trandolapril 2) deprotection

2) separation of

racemic diastereoisomers 7A 6C

Route D. Separation of isomers of 6C by conventional methods (i.e. formation of a diastereomeric salt) and coupling with ECCPA derivative.

trandolapril

Route E

This route is an inversion of the steps of route B Firstly the isomers are separated and then the protecting group is removed. 1) separation of diastereoisomers trandolapπl

racemic 2) deprotection

Route F. – The compound 8A is treated to remove the protecting grqup and coupled with an ECPPA derivative,

1) deprotection

2) base treatment

racemic 7A 8A

X activating group

………………………………………………………………………………

US20060079698

http://www.google.com/patents/US20060079698

Figure US20060079698A1-20060413-C00013

…………..

INTERMEDIATE

(2S,3aR,7aS)-perhydroindole-2-carboxylic acid (42 g).

IR (Nujol, cm-1): 2923, 2854, 1600, 1458, 1377, 1319. 1H-NMR (D2O): δ 1.1-2.5 (m, 8H), 1.65(m,1H), 1.96-2.37 (m,2H), 2.91(td, 1H),4.46(d, 1H). Mass (m/z): 168.3(M-H).

http://www.faqs.org/patents/app/20110065930

(2S,3aR,7aS)-Octahydro-1H-indole-2-carboxylic acid hydrochloride

yield as a white solid.

¹H NMR (D₂O, 400 MHz): δ 4.42 (dd, 1H, J=11.1, 2.7 Hz), 2.93, (dt, 1H, J=11.8, 3.6 Hz), 2.36 (ddd, 1H, J=12.9, 6.7, 2.7 Hz), 2.31-2.16 (m, 1H), 2.11-2.01 (m, 2H), 1.92-1.90 (m, 1H), 1.79-1.75 (m, 1H), 1.68-1.53 (m, 2H), 1.34-1.13 (m, 3H);

LC-MS (m/z): 170.1 (M+H).sup.+. The isolated product (5) correlates to the material prepared according to U.S. Pat. No. 487,932 and Tetrahedron Lett., 1992, 33, 4889.

(2s,3aR,7aS)-octahydro-1H-indole-2-carboxylic acid HCl

CAS No: 144540-75-0

Pasted Graphic

……………………………………..

REF

Tan, X; He, W; Liu, Y (2009). “Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy”. Kidney international 76 (12): 1248–57. doi:10.1038/ki.2009.346. PMID 19759524.

Drugs Fut1989,14,(8):778

Urbach, H., Henning, R., Teetz, V., Geiger, R., Becker, R. and Gaul, H. (Hoechst A.G.) Bicyclic amino acid derivatives.DE 3151690, EP 084164, EP 170775.JP 1989301659; JP 1989301695

Mavik (PDF from manufacturer’s website)
Tarka (PDF from manufacturer’s website)
Trandolapril (patient information)
Trandolapril Information – rxlist.com (Rxlist.com, The Internet Drug Index)

……………………………………………………………………….

The ESI mass spectrum of the drug trandolapril displayed a molecular ion peak [M+H] + at 431.1 amu. The tandem mass spectra (MS2) showed the fragment ions at m/z 234.2, 170.2, 160.3, 134.2, 130.3, 117.2, 102.3 and 91

Inline image 1

The IR spectrum of new impurity showed the following absorption bands 3277cm-1 (NH stretch), 2941cm-1 (aliphatic CH stretch), 1734 and 1653cm-1 (C=O) stretch and 1192cm-1 (C-O stretch)

Inline image 2

1H NMR Inline image 3

13 C NMR

Inline image 4

TRP = TRANDOLAPRIL COMPARED WITH 2 IMPURITIES

Inline image 5

Inline image 6

………………………………………………………………………………………

TRANDOLAPRIL SPECTRAL DATA

http://www.google.com.br/patents/US20060079698

IR (KBr, cm-1): 3444, 3280, 2973, 2942, 2881, 1735, 1654, 1456, 1367, 1193, 1024, 699.

The 1H-NMR (CDCl3): δ 7.2 (s, 5H), 4.4(m,4H), 4.2 (q,2H), 3.6-1.3 (m, 18H), 1.28(d+t,6H). CI Mass (m/z): 429.6(M-H).

……………………………………

United States Patent Application 20080171885

http://www.freepatentsonline.com/y2008/0171885.html

M.P.: 122-124° C.,

IR (KBr): 3278.7, 2942.2, 1735.2, 1654.3, 1456.7, 1433.7, 1366.5, 1192.8, 1101.5, 1063.8 and 1023.8 cm⁻¹(FIG. 1).

¹H NMR (CD₃OD, δ ppm): 7.33 (s, 5H), 4.34 (m, 3H), 3.86 (q, 2H), 3.28-1.46 (m, 17H) and 1.39 (d+t, 6H),

Mass (m/z, amu): 453.5 (M+Na) and 431.7 (M+H)⁺ molecular ion.

…………………………………………………………………………….

Conatus’s liver drug emricasan gets FDA orphan drug status

Uncategorized Comments Off

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

Uncategorized Comments Off

Nov 252013

Andarine

ostarine structure

(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

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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.