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Sarpogrelate, 사르포그렐레이트염산염

January 27, 2015 5:06 am / Leave a comment

Sarpogrelate structure.png

Sarpogrelate

135159-51-2,HYROCHLORIDE

125926-17-2 (free base)

5-HT 2a receptor antagonist

Useful for treating arterial occlusive disease and ischemic heart disease.

Sarpogrelate (Anplag, MCI-9042, LS-187,118) is a drug which acts as an antagonist at the 5HT_2A^[1]^[2] and 5-HT_2B^[3] receptors. It blocks serotonin-induced platelet aggregation, and has applications in the treatment of many diseases including diabetes mellitus,^[4]^[5] Buerger’s disease,^[6] Raynaud’s disease,^[7] coronary artery disease,^[8] angina pectoris,^[9] and atherosclerosis.^[10]

사르포그렐레이트염산염

Sarpogrelate Hydrochloride

C₂₄H₃₁NO₆& : 465.97

1-[2-(Dimethylamino)-1-[[2-[2-(3-methoxyphenyl)ethyl]phenoxy]methyl]ethyl hydrogen butanedioate hydrochloride [135159-51-2]

第十六改正日本薬局方(JP16)名称データベース検索結果

詳細については第十六改正日本薬局方でご確認ください。

[検索ページへ戻る]

検索キーワード:Sarpogrelate Hydrochloride
検索件数:1

第十六改正日本薬局方　化学薬品等サルポグレラート塩酸塩
Sarpogrelate Hydrochloride
塩酸サルポグレラート

C24H31NO6.HCl : 465.97
[135159-51-2]
本品は定量するとき，換算した脱水物に対し，サルポグレラート塩酸塩(C24H31NO6・HCl)98.5～101.0％を含む

Sarpogrelate hydrochloride tablets in 1993 Japan’s first listed under the tradename Anplag, is a 5-HT2 receptor blocker, can inhibit platelet aggregation, inhibition of vascular contraction, has antithrombotic effect and microcirculation. Ulcer indications for the improvement of their chronic arterial occlusive disease caused by pain, and cold ischemic various flu symptoms. -1_ {[2- (3-methoxyphenyl) phenoxy] methyl} succinic acid ethyl ester hydrochloride, the structural formula of sarpogrelate hydrochloride chemical name 2- (dimethylamino)

As follows:

Journal of Medicinal Chemistry (J.Med.Chem, 1990,33: 1818-1823) published synthetic routes as follows:

Sarpogrelate hydrochloride drug substance used in the preparation Sarpogrelate hydrochloride tablets needed to achieve acceptable purity, single hetero content must meet the corresponding requirements. US4485258 discloses a synthesis method of the first sarpogrelate hydrochloride, and recrystallized from acetone to obtain, but the experiments show that sarpogrelate hydrochloride poor solubility in acetone, acetone, hydrochloric acid is not suitable as a recrystallization solvent sarpogrelate. CN101239920A disclosed as acetonitrile, propionitrile, 1,4_ dioxane, tetrahydrofuran, dimethyl formamide, dimethyl acetamide, sulfolane, dimethyl sulfoxide or a mixture of more than two kinds thereof with methanol, ethanol, , acetone, ethyl acetate, diethyl ether, diisopropyl ether or the like can be used as the recrystallization solvent sarpogrelate hydrochloride, the purity of the product can reach 98%. And C2-C10 alkanes, C3-C10 ketones, C2-C10 carboxylic acid esters, Cl-ClO halogenated alkanes, aromatic hydrocarbons or aromatic derivative at room temperature to the reflux temperature of the hydrochloric acid solubility is small should not alone sarpogrelate as a recrystallization solvent, sarpogrelate hydrochloride, and water as a recrystallization solvent or an organic solvent, an aqueous 5% or more can not be obtained a high purity product. Existing literature does not mention the issue of a single impurity content control.

J Med Chem1990, 33,(6): PG 1818

The reaction of 2-hydroxy-3′-methoxybibenzyl (I) with epichlorohydrin (II) by means of NaH in DMF gives 2-(2,3-epoxypropoxy)-3′-methoxybibenzyl (III), which by reaction with dimethylamine in refluxing THF yields 2-[3-(dimethylamino)-2-hydroxypropoxy]-3′-methoxybibenzyl (IV). Finally, this compound is treated with succinic anhydride (V) in refluxing THF and with HCl in acetone.

……………………………..

http://www.google.com/patents/CN103242179A?cl=en

Specific embodiments

Example 1 Preparation of crude sarpogrelate hydrochloride [0019] Example

[0020] 1_ dimethylamino _3- [2- [2- (3_-methoxyphenyl) ethyl] phenoxy] -2-propanol hydrochloride A 250ml 13.7g plus a single-neck flask, then add water 25ml, and stirred to dissolve. With 20% aqueous sodium hydroxide to adjust PH value to 9_14, and extracted with 30ml of toluene, and the organic layer was concentrated to 50 ° C under reduced pressure until no liquid slipped 0 to give a brown oil. Of tetrahydrofuran was added 30g, and stirred to dissolve, butyryl anhydride 4.5g, was heated to reflux with stirring. After the reaction was refluxed for I~4 hours, the reaction was incubated at 40 ° C and concentrated to dryness under reduced pressure; the residue was added ethyl acetate 25g, After stirring to dissolve, the dropwise addition of saturated hydrogen chloride in ethyl acetate solution to adjust PH value to I below, was stirred 50~60min. Centrifugal filtration, was Sarpogrelate hydrochloride crude wet product. 45~55 ° C under reduced pressure (-0.08~-0.1MPa) the residue was dried to less than 0.5% of ethyl acetate to give the crude sarpogrelate hydrochloride 14.7g, yield 86%, HPLC purity 98.6%, largest single heteroatom content of 1.2 %.

Purification of the crude hydrochloride Sarpogrelate Example 2 [0021] Example

[0022] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.6g, yield 92%, HPLC purity of 99.9% and a maximum content of 0.04%, a single hybrid.

Example 3 Purification of the crude hydrochloride Sarpogrelate [0023] Example

[0024] The crude product was sarpogrelate hydrochloride 5g, join butanone 30ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give 4.55 sarpogrelate hydrochloride, yield 91%, HPLC purity 99.7%, largest single matter content of 0.05%.

Example 4 Purification of the crude hydrochloride Sarpogrelate [0025] Example

[0026] The crude product was sarpogrelate hydrochloride 5g, join butanone 40ml, heated with stirring until dissolved and refluxed 20~30min, cooling to 25~35 ° C, incubated with stirring 40~60min, filtered, and the filter cake was rinsed with a small amount of methyl ethyl ketone to give a white loose solid, 55~65 ° C and dried under reduced pressure to 24h, to give sarpogrelate hydrochloride 4.5g, yield 90%, HPLC purity 99.8%, largest single matter content 0.05%.

Example 5 Purification of the crude hydrochloride Sarpogrelate [0027] Example

[0028] The crude product was sarpogrelate hydrochloride 5g, join butanone 20ml, heated with stirring until dissolved and refluxed 20~30min, cooled slowly with stirring to room temperature, at -10 ° c~o ° c stand for crystallization, filtration, The filter cake was rinsed with a small amount of methyl ethyl ketone to give a white fluffy solid, 55~65 ° C and dried under reduced pressure to 24h, to give the hydrochloride sarpogrelate 4.62g, yield 92.4%, HPLC purity 99.2%, largest single matter content of 0.09%.

………………………………..

WO-2015008973 NEW PATENT

Method for preparing crystalline form II of sarpogrelate hydrochloride is claimed. Represents first filing from Dae He Chemical on sarpogrelate, which was developed and launched by Mitsubishi Tanabe Pharma.

References

Pertz H, Elz S. In-vitro pharmacology of sarpogrelate and the enantiomers of its major metabolite: 5-HT2A receptor specificity, stereoselectivity and modulation of ritanserin-induced depression of 5-HT contractions in rat tail artery. Journal of Pharmacy and Pharmacology. 1995 Apr;47(4):310-6. PMID 7791029
Nishio H, Inoue A, Nakata Y. Binding affinity of sarpogrelate, a new antiplatelet agent, and its metabolite for serotonin receptor subtypes. Archives Internationales de Pharmacodynamie et de Therapie. 1996 Mar-Apr;331(2):189-202. PMID 8937629
Muntasir HA, Hossain M, Bhuiyan MA, Komiyama T, Nakamura T, Ozaki M, Nagatomo T. Identification of a key amino acid of the human 5-HT(2B) serotonin receptor important for sarpogrelate binding. Journal of Pharmacological Sciences. 2007 Jul;104(3):274-7. PMID 17609583
Pietraszek MH, Takada Y, Taminato A, Yoshimi T, Watanabe I, Takada A. The effect of MCI-9042 on serotonin-induced platelet aggregation in type 2 diabetes mellitus. Thrombosis Research. 1993 Apr 15;70(2):131-8. PMID 8322284
Ogawa S, Takeuchi K, Sugimura K, Sato C, Fukuda M, Lee R, Ito S, Sato T. The 5-HT2 receptor antagonist sarpogrelate reduces urinary and plasma levels of thromboxane A2 and urinary albumin excretion in non-insulin-dependent diabetes mellitus patients. Clinical and Experimental Pharmacology and Physiology. 1999 May-Jun;26(5-6):461-4. PMID 10386239
Rydzewski A, Urano T, Hachiya T, Kaneko H, Baba S, Takada Y, Takada A. The effect of a 5HT2 receptor antagonist sarpogrelate (MCI-9042) treatment on platelet function in Buerger’s disease. Thrombosis Research. 1996 Dec 15;84(6):445-52. PMID 8987165
Igarashi M, Okuda T, Oh-i T, Koga M. Changes in plasma serotonin concentration and acceleration plethysmograms in patients with Raynaud’s phenomenon after long-term treatment with a 5-HT2 receptor antagonist. Journal of Dermatology. 2000 Oct;27(10):643-50. PMID 11092268
Satomura K, Takase B, Hamabe A, Ashida K, Hosaka H, Ohsuzu F, Kurita A. Sarpogrelate, a specific 5HT2-receptor antagonist, improves the coronary microcirculation in coronary artery disease. Clinical Cardiology. 2002 Jan;25(1):28-32. PMID 11808836
Kinugawa T, Fujita M, Lee JD, Nakajima H, Hanada H, Miyamoto S. Effectiveness of a novel serotonin blocker, sarpogrelate, for patients with angina pectoris. American Heart Journal. 2002 Aug;144(2):E1. PMID 12177659
Hayashi T, Sumi D, Matsui-Hirai H, Fukatsu A, Arockia Rani P J, Kano H, Tsunekawa T, Iguchi A. Sarpogrelate HCl, a selective 5-HT2A antagonist, retards the progression of atherosclerosis through a novel mechanism. Atherosclerosis. 2003 May;168(1):23-31. PMID 12732383

Sarpogrelate
Systematic (IUPAC) name

4-[2-(dimethylamino)-1-({2-[2-(3-methoxyphenyl)ethyl]phenoxy}methyl)ethoxy]-4-oxobutanoic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	?
Identifiers
CAS number	125926-17-2
ATC code	None
PubChem	CID 5160
IUPHAR ligand	210
ChemSpider	4976
UNII	19P708E787
ChEMBL	CHEMBL52939
Synonyms	Sarpogrelate, (-)-4-[1-dimethylamino-3-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]propan-2-yl]oxy-4-oxobutanoic acid
Chemical data
Formula	C₂₄H₃₁N O₆
Molecular mass	429.506 g/mol

Lesogaberan

January 27, 2015 3:58 am / Leave a comment

Lesogaberan

AZD-3355, AZD3355, [(2R)-3-amino-2-fluoropropyl]phosphinic acid, 344413-67-8

Molecular Formula: C₃H₈FNO₂P⁺

Molecular Weight: 140.073285 g/mol

[(2R)-3-amino-2-fluoropropyl]-hydroxy-oxophosphanium

Lesogaberan (AZD-3355) was^[1] an experimental drug candidate developed by AstraZeneca for the treatment of gastroesophageal reflux disease (GERD).^[2] As a GABA_B receptor agonist,^[3] it has the same mechanism of action as baclofen, but is anticipated to have fewer of the central nervous system side effects that limit the clinical use of baclofen for the treatment of GERD.^[4]

http://pubs.acs.org/doi/abs/10.1021/jm701425k

J. Med. Chem., 2008, 51 (14), pp 4315–4320

DOI: 10.1021/jm701425k

We have previously demonstrated that the prototypical GABA_B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA_B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA_B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA_B agonists devoid of classical GABA_B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug (R)-7 (AZD3355) that is presently being evaluated in man.

(2R)-(3-Amino-2-fluoropropyl)phosphinic Acid ((R)-7)

(R)-7 as a white solid (3.12 g, 24%):

mp = 183−185 °C;

¹H NMR (300 MHz, D₂O) δ 7.90 (s, 0.5 H), 6.15 (s, 0.5 H), 5.12−5.29 (m, 0.5 H), 4.92−5.10 (m, 0.5 H), 3.12−3.42 (m, 2H), 1.74−2.26 (m, 2H);

[α]_D²⁵ −4.0° (c 1.0, H₂O);

APIMS m/z 142 [M + H]⁺. Anal. (C₃H₉FNO₂P·0.25H₂O) C, H, N.

References

AstraZeneca. “AZD3355”. Retrieved 30 December 2011.
Bredenoord, Albert J. (2009). “Lesogaberan, a GABA_B agonist for the potential treatment of gastroesophageal reflux disease”. IDrugs 12 (9): 576–584. PMID 19697277.
Alstermark, et al.; Amin, K; Dinn, SR; Elebring, T; Fjellström, O; Fitzpatrick, K; Geiss, WB; Gottfries, J et al. (2008). “Synthesis and Pharmacological Evaluation of Novel γ-Aminobutyric Acid Type B (GABAB) Receptor Agonists as Gastroesophageal Reflux Inhibitors”. Journal of Medicinal Chemistry 51 (14): 4315–4320. doi:10.1021/jm701425k. PMID 18578471.
Brian E. Lacy, Robert Chehade, and Michael D. Crowell (2010). “Lesogaberan”. Drugs of the Future 35 (12): 987–992. doi:10.1358/dof.2010.035.012.1540661.

Lesogaberan

IUPAC name [hide] ((R)-3-Amino-2-fluoropropyl)phosphinic acid
Other names[hide] AZD-3355
Identifiers
CAS number	344413-67-8=
PubChem	9833984
ChemSpider	23254384
UNII	4D6Q6HGC7Z
ChEMBL	CHEMBL448343
Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C₃H₉FNO₂P
Molar mass	141.08 g mol⁻¹

A Novel and Practical Synthesis of Ramelteon

January 26, 2015 9:59 am / 1 Comment on A Novel and Practical Synthesis of Ramelteon

RAMELTEON

An efficient and practical process for the synthesis of ramelteon 1, a sedative-hypnotic, is described. Highlights in this synthesis are the usage of acetonitrile as nucleophilic reagent to add to 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one 2 and the subsequent hydrogenation which successfully implement four processes (debromination, dehydration, olefin reduction, and cyano reduction) into one step to produce the ethylamine compound 13where dibenzoyl-l-tartaric acid is selected both as an acid to form the salt in the end of hydrogenation and as the resolution agent. Then, target compound 1 is easily obtained from13 via propionylation. The overall yield in this novel and concise process is almost twice as much as those in the known routes, calculated on compound 2.

A Novel and Practical Synthesis of Ramelteon

Sa Xiao , Chao Chen , Hongyan Li , Kuaile Lin , andWeicheng Zhou ^*

State Key Lab of New Drug & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry, Shanghai 200437,China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/op500386g

http://pubs.acs.org/doi/abs/10.1021/op500386g

Publication Date (Web): January 6, 2015

*Telephone: +86 21 55514600. E-mail: zhouweicheng58@163.com.

NMR, IR MASS………http://pubs.acs.org/doi/suppl/10.1021/op500386g/suppl_file/op500386g_si_001.pdf

Preparation of (S)-N-[2-(1,6,7,8-Tetrahydro-2H-indeno[5,4-b] furan-8-yl)ethyl]propionamide(1).

GAVE

white solid of 1(1.570 g, 85% yield, 99.8% ee). Purity by HPLC 99.6%.

Mp: 115−116 °C(113−115°C in literature 1 ).

1 H−NMR(400 MHz, CDCl3):

δ 1.39 (t, 3H); 1.63 (m, 1H); 1.83 (m, 1H); 2.02 (m, 1H); 2.16 (dd, J=8, 2H); 2.28 (m, 1H); 2.78 (m, 1H); 2.83 (m, 1H); 3.14 (m, 1H); 3.22 (m, 2H); 3.33 (m, 2H); 4.54 (m, 2H); 5.38 (br s, 1H); 6.61 (d, J=8, 1H); 6.97 (d, J=8, 1H).

13C−NMR(100 MHz, CDCl3):

δ 173.85, 159.56, 143.26, 135.92, 123.52, 122.28, 107.56, 71.26, 42.37, 38.17, 33.66, 31.88, 30.82, 29.86, 28.73, 10.01.

MS (ES+): m/z 282(M+Na) + .

[α]D −57.3(c=1.0, CHCl3, −57.8 in literature 1 ).

Anal. (C16H21NO2) Calc: C, 74.10; H, 8.16; N, 5.40; found: 74.09; H, 8.17; N, 5.47.

References

(1) Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; Kawada, M.; Matsumoto, K.; Imai, Y.; Hinuma, S.; Kato, K.; Nishikawa, H.; Hirai, K.; Miyamoto M.; Ohkawa, S. J. Med. Chem. 2002, 45, 4222-4239.

(2) Yamano, T.; Yamashita, M.; Adachi, M.; Tanaka, M.; Matsumoto, K.; Kawada, M.; Uchikawa, O.; Fukatsu, K.; Ohkawa, S. Tetrahedron: Asymmetry. 2006, 17, 184-190.

SHANGHAI

SHANGHAI CHINA

The Shanghai International Exhibition Center, an example of Soviet neoclassical architecture in Shanghai

Zibotentan

January 26, 2015 6:54 am / Leave a comment

186497-07-4, ZD4054, ZD-4054, Zd 4054, ZD4054, Zibotentan

Molecular Formula:C₁₉H₁₆N₆O₄S

Molecular Weight:424.43314 g/mol

N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide

Oncolytic Drugs, Prostate Cancer Therapy, Solid Tumors Therapy, Antimitotic Drugs, Endothelin ETA Receptor Antagonists

Zibotentan (INN) (earlier code name ZD4054) is an anti-cancer candidate.^[1] It is an endothelin receptor antagonist.^[2]

It failed a phase III clinical trial for prostate cancer^[3] but other trials are planned.^[4] Tolerability of zibotentan plus docetaxel has been evaluated.^[5]

SYN

https://www.google.com/patents/WO1996040681A1?cl=en

Bromination of 2-amino-5-methylpyrazine (I) with Br2 in CHCl3 affords the bromopyrazine (II). Subsequent bromide displacement in (II) by means of sodium methoxide gives rise to the methoxypyrazine (III). The amino group of (III) is then protected by acylation with isobutyl chloroformate, to produce carbamate (IV). Diazotization of 3-amino-2-chloropyridine (V), followed by treatment with sulfur dioxide in the presence of CuCl furnishes sulfonyl chloride (VI). Carbamate (IV) is then acylated by means of NaH and sulfonyl chloride (VI) in DMF to furnish the N-sulfonyl carbamate (VII). Esterification of 4-carboxyphenylboronic acid (VIII) with H2SO4 in MeOH gives 4-(methoxycarbonyl)phenylboronic acid (IX). Mitsunobu coupling between boronic acid (IX) and chloropyridine (VII) furnishes adduct (X). Methyl ester (X) is converted into hydrazide (XI) by treatment with hydrazine hydrate in refluxing methanol. Then, cyclization of the acyl hydrazide (XI) with boiling triethyl orthoformate gives rise to the target oxadiazole derivative.

https://www.google.com/patents/WO1996040681A1?cl=en

Example 36

Hydrazine hydrate (1.2 ml) was added to a solution of N-(isobutoxycarbonyl)-2- (4-memoxycarbonylphenyl)-N-(3-metJ oxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.54 g) in methanol (15 ml) and the mixture was heated and stiπed under reflux for 24 hours then cooled. The solid was collected and dried under reduced pressure to give the free sulphonamido-acylhydrazide (0.857 g); 1H NMR (cVDMSO): 2.2 (s, 3H), 3.7 (s, 3H), 6.7 (br s, 2H), 7.3 (s, IH), 7.5 (m, 3H), 7.8 (d, 2H), 8.4 (d, IH), 8.75 (dd, IH), 9.8 (br s, IH). A solution of this acylhydrazide (207 mg) in triethylorthoformate (5 ml) was heated under reflux for 17 hours then cooled. The resultant solid was collected and purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-10% methanol/dichloromethane to give N-(3-methoxy-5-mef ylpyrazin-2-yl)-2-(4-[l,3,4-oxadiazol-2-yl]phenyl)pyridine-3- sulphonamide (39 mg) as a solid; 1H NMR (DMSO-d_o): 2.2 (br s, 3H), 3.8 (s, 3H), 7.4 (br s, IH), 7.6-7.8 (m, 3H), 8.0 (m, 2H), 8.5 (dd, IH), 8.9 (dd, IH), 9.4 (s, IH); mass spectrum (+ve ESP): 425 (M+H)⁺.

………………………….

http://www.google.im/patents/EP1904490A1?cl=en

N-(3-methoxy-5-methylpyrazin-2-yl)-2- (4-[l,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide (hereafter “Compound (I)). More specifically the invention relates to the ethanolamine salt of Compound (I) (hereafter “Compound (I) ethanolamine salt), and to pharmaceutical compositions containing it. The invention further relates to the use of Compound (I) ethanolamine salt in the manufacture of medicament for use in treating cancer and to methods of treating cancer in a warm blooded animal such as man using this salt. The invention further relates to the use of Compound (I) ethanolamine salt in producing Compound (I) during manufacture.

Compound (I) is an endothelin antagonist. The endothelins are a family of endogenous 21 amino acid peptides comprising three isoforms, endothelin-1 (ET-I), endothelin-2 and endothelin-3. The endothelins are formed by cleavage of the Trp^2I-Val²² bond of their corresponding proendothelins by an endothelin converting enzyme. The endothelins are among the most potent vasoconstrictors known and have a characteristic long duration of action. They exhibit a wide range of other activities including cell proliferation and mitogenesis, extravasation and chemotaxis, and also interact with a number of other vasoactive agents.

The endothelins are released from a range of tissue and cell sources including vascular endothelium, vascular smooth muscle, kidney, liver, uterus, airways, intestine and leukocytes. Release can be stimulated by hypoxia, shear stress, physical injury and a wide range of hormones and cytokines. Elevated endothelin levels have been found in a number of disease states in man including cancers.

Recently, endothelin A receptor antagonists have been identified as potentially of value in the treatment of cancer (Cancer Research, 56, 663-668, February 15^th, 1996 and Nature Medicine, Volume 1, Number 9, September 1999, 944-949).

Cancer affects an estimated 10 million people worldwide. This figure includes incidence, prevalence and mortality. More than 4.4 million cancer cases are reported from Asia, including 2.5 million cases from Eastern Asia, which has the highest rate of incidence in the world. By comparison, Europe has 2.8 million cases, North America 1.4 million cases, and Africa 627,000 cases. In the UK and US, for example, more than one in three people will develop cancer at some point in their life, Cancer mortality in the U.S. is estimated to account for about 600,000 a year, about one in every four deaths, second only to heart disease in percent of all deaths, and second to accidents as a cause of death of children 1-14 years of age. The estimated cancer incidence in the U.S. is now about 1,380,000 new cases annually, exclusive of about 900,000 cases of non-melanotic (basal and squamous cell) skin cancer.

Cancer is also a major cause of morbidity in the UK with nearly 260,000 new cases (excluding non-melanoma skin cancer) registered in 1997. Cancer is a disease that affects mainly older people, with 65% of cases occurring in those over 65. Since the average life expectancy in the UK has almost doubled since the mid nineteenth century, the population at risk of cancer has grown. Death rates from other causes of death, such as heart disease, have fallen in recent years while deaths from cancer have remained relatively stable. The result is that 1 in 3 people will be diagnosed with cancer during their lifetime and 1 in 4 people will die from cancer. In people under the age of 75, deaths from cancer outnumber deaths from diseases of the circulatory system, including ischaemic heart disease and stroke. In 2000, there were 151,200 deaths from cancer. Over one fifth (22 per cent) of these were from lung cancer, and a quarter (26 per cent) from cancers of the large bowel, breast and prostate.

Worldwide, the incidence and mortality rates of certain types of cancer (of stomach, breast, prostate, skin, and so on) have wide geographical differences which are attributed to racial, cultural, and especially environmental influences. There are over 200 different types of cancer but the four major types, lung, breast, prostate and colorectal, account for over half of all cases diagnosed in the UK and US. Prostate cancer is the fourth most common malignancy among men worldwide, with an estimated 400,000 new cases diagnosed annually, accounting for 3.9 percent of all new cancer cases. Current options for treating cancers include surgical resection, external beam radiation therapy and / or systemic chemotherapy. These are partially successful in some forms of cancer, but are not successful in others. There is a clear need for new therapeutic treatments. Compound (I) is exemplified and described in WO96/40681 as Example 36. WO96/40681 claims the endothelin receptors described therein for the treatment of cardiovascular diseases. The use of Compound (I) in the treatment of cancers and pain is described in WO04/018044. Compound (I) has the following structure:

Compound (I)

In WO04/018044 an endothelin human receptor binding assay is described. The pICjo (negative log of the concentration of compound required to displace 50% of the ligand) for Compound (I) at the ET_A receptor was 8.27 [8.23 – 8.32] (n=4). Compound (I) is thus an excellent endothelin antagonist.

WO96/40681 and WO04/018044 disclose, in general terms, certain pharmaceutically acceptable salts of the compounds disclosed therein. Specifically it is stated that suitable pharmaceutically-acceptable salts include, for example, salts with alkali metal (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine. In addition, it was stated that suitable pharmaceutically-acceptable salts include, pharmaceutically-acceptable acid- addition salts with hydrogen halides, sulphuric acid, phosphoric acid and with organic acids such as citric acid, maleic acid, methanesulphonic acid and p-toluenesulphonic acid.

Example 2 Formation of Compound (I) using ethanolamine

The above organic layer from Example 1 was adjusted to 42°C and isopropyl alcohol (114 ml), water (170ml) and ethanolamine (28.2 ml) were added and stirred at 42°C for 90 mins. The reaction mixture was allowed to cool to 2O⁰C and the lower aqueous phase separated and filtered through a 1 μm filter. The aqueous phase was then charged over 40min to a stirred solution of acetic acid (141 g) and water (33.5 g) at 50⁰C and then cooled to 2O⁰C over 60 mins. The product was isolated by filtration and washed with a mixture of isopropyl alcohol (48.5 ml) and water (48.5 ml) and then isopropyl alcohol (48.5 ml). The product was dried overnight in a vacuum oven at 55°C. Weight 43.08g, Strength = 100%, 86.7%yield. ¹H NMR (400 MHz₅ DMSOd₆) 9.87 (IH, s), 9.14 (IH, s), 8.81 (lH,d), 8.52 (IH, d), 7.98 (2H, d), 7.65 (2H, d), 7.62 (IH, dd), 7.41 (IH, bs), 3.80 (3H, s), 2.23 (3H, s). Mass Spectra MH+ 425.1036 (Ci₉Hi₇N₆O₄S calculated 425.1032).

Patent	Submitted	Granted
Substituted pyrazin-2-yl-sulphonamide-(3-pyridyl) compounds and uses thereof [US6060475]	2000-05-09
COMPOSITION 064 [US8168221]	2009-04-16	2012-05-01
THERAPEUTIC TREATMENT-014 [US2009062246]	2009-03-05
Ethanolamine Salt of N- (3-Methoxy-5-Methylpyrazin-2Yl) -2- (4-[1, 3, 4-Oxadiazole-2-Yl] Phenyl) Pyridine-3-Sulphonamide [US2008221124]	2008-09-11
N-HETEROARYL-PYRIDINESULFONAMIDE DERIVATIVES AND THEIR USE AS ENDOTHELIN ANTAGONISTS [WO9640681]	1996-12-19

Zibotentan

IUPAC name [hide] N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide
Other names[hide] ZD4054
Identifiers
CAS number	186497-07-4
PubChem	9910224
ChemSpider	8085875
UNII	8054MM4902
Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C₁₉H₁₆N₆O₄S
Molar mass	424.43 g mol⁻¹

References

James and Growcott (2009). “Drugs of the Future”.
Jump up^ Tomkinson H, Kemp J, Oliver S, Swaisland H, Taboada M, Morris T (2011). “Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies”. BMC Clin Pharmacol 11: 3. doi:10.1186/1472-6904-11-3.PMC 3070638. PMID 21414193.
http://www.fiercebiotech.com/story/azs-zibotentan-flunks-late-stage-prostate-cancer-trial/2010-09-27
http://www.genengnews.com/gen-news-highlights/pfizer-astrazeneca-and-actelion-separately-report-phase-iii-trial-failures/81243985/
Jump up^ Trump DL, Payne H, Miller K, et al. (September 2011). “Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer”. Prostate 71 (12): 1264–75.doi:10.1002/pros.21342. PMID 21271613.

External links

Zibotentan

Ayurveda………..Medicinal Benefits of Liquorice (Mulethi) (मुलेठी, 甘草, شیرین بیان)

January 26, 2015 1:57 am / 6 Comments on Ayurveda………..Medicinal Benefits of Liquorice (Mulethi) (मुलेठी, 甘草, شیرین بیان)

liquorice-root

Licorice or Mulethi is a medicinal herb which is used in various Ayurvedic medicines. Its underground stems and roots are used for medicinal purpose. It has antioxidant, antimicrobial, anti-inflammatory and hepatoprotective properties.
Mulethi is useful in cough, sore throat, bronchitis, sexual weakness, skin problems, jaundice, hoarseness, vata dosha, ulcers etc. It has demulcent and expectorant properties.

read…………MY OLD ARTICLE

Liquorice, or licorice, (/ˈlɪk(ə)rɪʃ/ lik-(ə-)rish or /ˈlɪk(ə)rɪs/ lik-(ə-)ris)^[2] is the root of Glycyrrhiza glabra from which a sweet flavour can be extracted. The liquorice plant is a legume native to southern Europe, India, and parts of Asia. It is not botanically related to anise, star anise, or fennel, which are sources of similar flavouring compounds. The word liquorice / licorice is derived (via the Old French licoresse) from the Greek γλυκύρριζα (glukurrhiza), meaning “sweet root”,^[3] from γλυκύς (glukus), “sweet”^[4] + ῥίζα (rhiza), “root”,^[5]^[6] the name provided by Dioscorides.^[7] It has been traditionally known and used as medicine in Ayurveda for rejuvenation.^[8] It is called asadhimadhuram (அதிமதுரம்) in Tamil, irattimadhuram in Malayalam, yastimadhu (यस्टिमधु) in Sanskrit, mulethi (मुलेठी) in Hindi, andjethimadh (જેઠીમધ) in Gujarati language.^[9]

Licorice (Glycyrrhiza glabra), locally known as mulethi, has been revered for centuries as a medicinal herb in Ayurveda. Besides possessing numerous medicinal properties, it is also a popular flavoring herb as it is 50 times sweeter than sugar, due to the presence of a compound called glycyrrhizin.

Through research, the anti-oxidant, anti-inflammatory, anti-microbial, analgesic (pain-relieving) and expectorant properties of this is sweet, moist herb have been established worldwide. It is also diuretic, rejuvenating and mildly laxative in nature. These properties have helped Licorice find a place in both Eastern and Western medicine for treating an array of ailments, ranging from cold and cough to arthritis, respiratory, digestive and liver problems.

The Sanskrit name for licorice is Yashtimadhu, which literally means “sweet root”. It is sweet, cool and heavy to digest. The Rasa (taste) of this herb is madhura (sweet), which makes it beneficial for vata and pitta doshas, while it’s Virya (action) is sheetal (cooling), which generally increases kapha when consumed in large doses over long term.

The medicinal property of mulethi is mainly because of the presence of powerful phytochemicals namely flavonoids, chalcones, saponins and xenoestrogens. Glycyrrhizin (salts of glycyrrhizic acid) is a popular saponin found in roots of mulethi that is responsible for the characteristic sweet taste (50 times more sweet than sugar) flavor. Liquiritin, licoﬂavonol, liquiritigenin, etc are the common chalcones that provide the distinct yellowish color to mulethi; while, the aroma of its root is mainly because of anethole. Here are the ten health benefits of mulethi:

Information

Latin name: Glycyrrhiza glabra
Sanskrit: Madhuyashti
Hindi: Mulhatti, Jethimadh, Mithilakdi
English: Sweetwood, Liquorice, Licorice
Bengali: Jashtimadhu
Gujrati: Jethi Madh
Marathi: Jeshtamadhu
Kannada: Jeshthamadhu
Malayalam: Itarttimadhuram, Erattimadhuram
Tamil: Atimadhuram
Telugu: Atimadhuramu

Anti-microbial activity – Roots of mulethi are very effective in protecting against virus, bacteria and fungi due to the presence of Glycyrrhizin that blocks the microbial growth. The root extract possesses the power to control malaria (as per preliminary research), influenza and also helps in the treatment of herpes resulting in virus suppression and severity of sores.

Anti-inflammatory activity – Liquorice has powerful anti-inflammatory and anti-allergic activity and can be used to treat chronic inflammation like rheumatic problems & arthritis, skin diseases and autoimmune diseases. It is also used for preventing any inflammatory conditions related to eye and also to treat conjunctivitis with the help of glycyrrhizin activity that counteracts negative effects caused by cortisol.

Improves immunity – Root extracts of mulethi aids in increasing the production of lymphocytes and macrophage thereby improving your defense mechanism & preventing microbial attack. It also helps in minimizing immune related allergic reactions and autoimmune complications.

Memory improvement – Roots of licorice exert supportive effect on the adrenal gland and thus indirectly aid in stimulating the brain. It not only decreases the effects of amnesia & improves learning but its antioxidant property (mulethi contains flavonoids) renders a shielding effect on the brain cells.

Anti-ulcer activity – The potent antioxidant and anti-inflamatory properties of licorice makes it the best natural medicinal aid to treat ulcers of stomach, intestine and mouth. The compound carbenoxolone synthesized from glycyrrhizin plays key role in healing mouth and gastric ulcers along with reducing gastric secretions and promoting development of intestinal mucus lining.

Liver protection – Licorice is one of the most common traditional remedy used to treat jaundice. Its antioxidant property is the key for preventing your liver from the action of free radicals and toxic materials. This herb is also reported to exhibit protection against diclofenac induced toxicity and also, in inhibiting damage of liver.

Digestive aid – Roots of licorice are also used to deal with stomach and digestion problems with the help of glycyrrhizin and its compound, carbenoxolone. It is one of the ancient home remedies for relieving constipation, acidity, heartburn, stomach discomfort, inflammation of digestive system and gastro esophageal acid reflux. As a mild laxative, it plays an effective role in bowel movements and also for treatment of allergic cough in addition to maintaining normal pH levels.

Hormonal regulation – The phytoestrogenic compounds present in mulethi roots exert valuable action against women hormonal imbalance problems, menopause symptoms like hot flashes & exhaustion, mood swings, etc. It is also found to help in cortisol production and relieving premenstrual issues like nausea and menstrual cramps. Licorice powder acts as the traditional medicine for nursing mothers to regulate body hormones and aid in milk secretion.

Heart healthy effects – Research studies have proved that licorice roots help in controlling cholesterol levels by increasing the body’s flow of bile and also reducing high blood cholesterol levels. The anti-oxidant property of licorice acts in increasing the blood capillary health, reducing inflammation, prevents blood vessel damage and block development of arterial plaque.

Other effects – Licorice roots work wonders in treatment of depression, diabetes and respiratory tract infection like sore throat (hoarseness of voice), cold and cough, etc in addition to rendering effective skin benefits, oral hygiene and weight loss. It is found to act as a cancer cure remedy, a potent aphrodisiac and a powerful analgesic agent.

Description

It is a herbaceous perennial, growing to 1 m in height, with pinnate leaves about 7–15 cm (3–6 in) long, with 9–17 leaflets. The flowers are 0.8–1.2 cm (1/3 to 1/2 in) long, purple to pale whitish blue, produced in a loose inflorescence. The fruit is an oblong pod, 2–3 cm (1 in) long, containing several seeds.^[10] The roots are stoloniferous.^[11]

Chemistry

The scent of liquorice root comes from a complex and variable combination of compounds, of which anethole is up to 3% of total volatiles. Much of the sweetness in liquorice comes from glycyrrhizin, which has a sweet taste, 30–50 times the sweetness of sugar. The sweetness is very different from sugar, being less instant, tart, and lasting longer.

The isoflavene glabrene and the isoflavane glabridin, found in the roots of liquorice, are phytoestrogens.^[12]^[13]

Cultivation and uses

Liquorice, which grows best in well-drained soils in deep valleys with full sun, is harvested in the autumn two to three years after planting.^[10] Countries producing liquorice include Iran, Afghanistan, the People’s Republic of China, Pakistan, Iraq, Azerbaijan, Uzbekistan, Turkmenistan, and Turkey.^[14]

The world’s leading manufacturer of liquorice products is M&F Worldwide, which manufactures more than 70% of the worldwide liquorice flavours sold to end users.^[15]

Safe dosage

Licorice is available in various forms – root, powder and extracts. Licorice root can be chewed directly while licorice tea (prepared by boiling licorice root in water) is also extremely beneficial as a home remedy.

Daily intake of 5-6 grams of licorice powder is considered safe while 250-500 mg of concentrated extracts can be taken thrice a day. Unsupervised use in high doses is not recommended for long term. People with hypertension or heart disease, pregnant women and breastfeeding mothers should avoid using licorice without prior consulation with an Ayurveda doctor.

plant

Medicine

The compound glycyrrhizin (or glycyrrhizic acid), found in liquorice, has been proposed as being useful for liver protection in tuberculosis therapy, but evidence does not support this use, which may in fact be harmful.^[24] Glycyrrhizin has also demonstrated antiviral, antimicrobial, anti-inflammatory, hepatoprotective, and blood pressure-increasing effects in vitro and in vivo, as is supported by the finding that intravenous glycyrrhizin (as if it is given orally very little of the original drug makes it into circulation) slows the progression of viral and autoimmune hepatitis.^[25]^[26] Liquorice has also demonstrated promising activity in one clinical trial, when applied topically, against atopic dermatitis.^[27] Additionally, liquorice has also proven itself effective in treating hyperlipidaemia (a high amount of fats in the blood).^[28] Liquorice has also demonstrated efficacy in treating inflammation-induced skin hyperpigmentation.^[29]^[30] Liquorice may also be useful in preventing neurodegenerative disorders and dental caries.^[31]^[32]^[33]

The antiulcer, laxative, antidiabetic, anti-inflammatory, immunomodulatory, antitumour and expectorant properties of liquorice have been investigated.^[34]

Folk medicine

In traditional Chinese medicine, liquorice (मुलेठी, 甘草, شیرین بیان) is believed to “harmonize” the ingredients in a formula and to carry the formula to the 12 “regular meridians”.^[35]

References

“Glycyrrhiza glabra information from NPGS/GRIN”. http://www.ars-grin.gov. Retrieved 6 March 2008.
licorice. Merriam-Webster’s Medical Dictionary, © 2007 Merriam-Webster, Inc.
γλυκύρριζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
γλυκύς, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
Jump up^ ῥίζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus<
Jump up^ liquorice, on Oxford Dictionaries
Jump up^ google books Maud Grieve, Manya Marshall – A modern herbal: the medicinal, culinary, cosmetic and economic properties, cultivation and folk-lore of herbs, grasses, fungi, shrubs, & trees with all their modern scientific uses, Volume 2 Dover Publications, 1982 & Pharmacist’s Guide to Medicinal Herbs Arthur M. Presser Smart Publications, 1 Apr 2001 2012-05-19
Jump up^ Balakrishna, Acharya (2006). Ayurveda: Its Principles & Philosophies. New Delhi, India: Divya prakashan. p. 206. ISBN 8189235567.
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^ Jump up to:^a ^b Huxley, A., ed. (1992). New RHS Dictionary of Gardening. ISBN 0-333-47494-5
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Jump up^ Somjen, D.; Katzburg, S.; Vaya, J.; Kaye, A. M.; Hendel, D.; Posner, G. H.; Tamir, S. (2004). “Estrogenic activity of glabridin and glabrene from licorice roots on human osteoblasts and prepubertal rat skeletal tissues”. The Journal of Steroid Biochemistry and Molecular Biology 91 (4–5): 241–246. doi:10.1016/j.jsbmb.2004.04.008. PMID 15336701.
Jump up^ Tamir, S.; Eizenberg, M.; Somjen, D.; Izrael, S.; Vaya, J. (2001). “Estrogen-like activity of glabrene and other constituents isolated from licorice root”. The Journal of steroid biochemistry and molecular biology 78 (3): 291–298. doi:10.1016/S0960-0760(01)00093-0. PMID 11595510.
^ Jump up to:^a ^b ^c M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2010.
Jump up^ M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2001.
Jump up^ Erik Assadourian, Cigarette Production Drops, Vital Signs 2005, at 70.
Jump up^ M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2005.
^ Jump up to:^a ^b ^c Marvin K. Cook, The Use of Licorice and Other Flavoring Material in Tobacco (Apr. 10, 1975).
Jump up^ Boeken v. Phillip Morris Inc., 127 Cal. App. 4th 1640, 1673, 26 Cal. Rptr. 3d 638, 664 (2005).
Jump up^ [1] the online Dutch food composition database]
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Jump up^ “Where Liquorice Roots Go Deep”. Northern Echo. Retrieved 9 December 2008.
Jump up^ http://science.howstuffworks.com/life/botany/licorice-info.htm
Jump up^ Liu Q, Garner P, Wang Y, Huang B, Smith H (2008). “Drugs and herbs given to prevent hepatotoxicity of tuberculosis therapy: systematic review of ingredients and evaluation studies”.BMC Public Health (Systematic review) 8: 365. doi:10.1186/1471-2458-8-365. PMC 2576232. PMID 18939987.
Jump up^ Chien, CF; Wu, YT; Tsai, TH (January 2011). “Biological analysis of herbal medicines used for the treatment of liver diseases.”. Biomedical Chromatography 25 (1-2): 21–38.doi:10.1002/bmc.1568. PMID 21204110.
Jump up^ Yasui, S; Fujiwara, K; Tawada, A; Fukuda, Y; Nakano, M; Yokosuka, O (December 2011). “Efficacy of intravenous glycyrrhizin in the early stage of acute onset autoimmune hepatitis.”.Digestive Diseases and Sciences 56 (12): 3638–47. doi:10.1007/s10620-011-1789-5. PMID 21681505.
Jump up^ Reuter, J; Merfort, I; Schempp, CM (2010). “Botanicals in dermatology: an evidence-based review.”. American Journal of Clinical Dermatology 11 (4): 247–67. doi:10.2165/11533220-000000000-00000. PMID 20509719.
Jump up^ Hasani-Ranjbar, S; Nayebi, N; Moradi, L; Mehri, A; Larijani, B; Abdollahi, M (2010). “The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review.”. Current pharmaceutical design 16 (26): 2935–47. doi:10.2174/138161210793176464. PMID 20858178.
Jump up^ Callender, VD; St Surin-Lord, S; Davis, EC; Maclin, M (April 2011). “Postinflammatory hyperpigmentation: etiologic and therapeutic considerations.”. American Journal of Clinical Dermatology12 (2): 87–99. doi:10.2165/11536930-000000000-00000. PMID 21348540.
Jump up^ Leyden, JJ; Shergill, B; Micali, G; Downie, J; Wallo, W (October 2011). “Natural options for the management of hyperpigmentation.”. Journal of the European Academy of Dermatology and Venereology 25 (10): 1140–5. doi:10.1111/j.1468-3083.2011.04130.x. PMID 21623927.
Jump up^ Kannappan, R; Gupta, SC; Kim, JH; Reuter, S; Aggarwal, BB (October 2011). “Neuroprotection by spice-derived nutraceuticals: you are what you eat!” (PDF). Molecular Neurobiology 44(2): 142–59. doi:10.1007/s12035-011-8168-2. PMC 3183139. PMID 21360003.
Jump up^ Gazzani, G; Daglia, M; Papetti, A (April 2012). “Food components with anticaries activity.”. Current Opinion in Biotechnology 23 (2): 153–9. doi:10.1016/j.copbio.2011.09.003.PMID 22030309.
Jump up^ Messier, C; Epifano, F; Genovese, S; Grenier, D (January 2012). “Licorice and its potential beneficial effects in common oro-dental diseases.”. Oral Diseases 18 (1): 32–9.doi:10.1111/j.1601-0825.2011.01842.x. PMID 21851508.
Jump up^ Shibata, S (October 2000). “A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice.”. Yakugaku Zasshi 120 (10): 849–62. PMID 11082698.
Jump up^ Bensky, Dan; et al. (2004). Chinese Herbal Medicine: Materia Medica, Third Edition. Eastland Press. ISBN 0-939616-42-4.
Jump up^ Olukoga, A; Donaldson, D (June 2000). “Liquorice and its health implications.”. The Journal of the Royal Society for the Promotion of Health 120 (2): 83–9.doi:10.1177/146642400012000203. PMID 10944880.
Jump up^ Armanini, D; Fiore, C; Mattarello, MJ; Bielenberg, J; Palermo, M (September 2002). “History of the endocrine effects of licorice.”. Experimental and Clinical Endocrinology & diabetes 110 (6): 257–61. doi:10.1055/s-2002-34587. PMID 12373628.
Jump up^ Omar, Hesham R; Komarova,, Irina; El-Ghonemi,, Mohamed; Ahmed, Fathy; Rashad, Rania; Abdelmalak, Hany D; Yerramadha, Muralidhar Reddy; Ali, Yaseen; Camporesi, Enrico M. “How much is too much? in Licorice abuse: time to send a warning message from Therapeutic Advances in Endocrinology and Metabolism”. http://www.ncbi.nlm.nih.gov. SAGE Publications. Retrieved 13 January 2015.

38 Toxicology Center[2]

External links

Glycyrrhiza glabra (licorice), Kew plant profile

Labeling under flow conditions: Understanding added applications

January 24, 2015 5:40 am / Leave a comment

SynthFlow

Stepping outside traditional synthetic labs into specialty applications is not always something we are looking for in the literature, but it is an excellent way to see different techniques which might be utilized in your own labs. Neil Vasdev’s group at the Harvard Medical School specializes in labeling compounds for more advanced analysis – imaging techniques as tracers for the study of advanced disease states. His group has been using flow chemistry and flow hydrogenation for some time so I thought it be interesting for everyone to see the work.

Two recent publications illustrate their research. In the first publication Chem Commun 2013, 49, 8755 the group uses three examples where they incorporate a label for study into an advanced intermediate C11 or F18 through a microfluidic reaction, followed by a strategic deprotection of a benzyl group or CBz under flow hydrogenation. Without going into significant detail, the group absolutely needed an…

View original post 201 more words

Logistics of process R&D: transforming laboratory methods to manufacturing scale

January 24, 2015 5:31 am / 1 Comment on Logistics of process R&D: transforming laboratory methods to manufacturing scale

The manufacture of a | omeprazole (racemic product; top), and esomeprazole (the (S)-enantiomer; bottom), including b | a flow chart of the process for the …

Nature Reviews Drug Discovery 2, 654-664 (August 2003) | doi:10.1038/nrd1154

- SEARCH PUBMED FOR

- Hans-Jürgen Federsel

Logistics of process R&D: transforming laboratory methods to manufacturing scale

Hans-Jürgen Federsel

In the past, process R&D — which is responsible for producing candidate drugs in the required quantity and of the requisite quality — has had a low profile, and many people outside the field remain unaware of the challenges involved. However, in recent years, the increasing pressure to achieve shorter times to market, the demand for considerable quantities of candidate drugs early in development, and the higher structural complexity — and therefore greater cost — of the target compounds, have increased awareness of the importance of process R&D. Here, I discuss the role of process R&D, using a range of real-life examples, with the aim of facilitating integration with other parts of the drug discovery pipeline.

Federsel HJ

Process R&D, AstraZeneca, SE-151 85 Södertälje, Sweden. Hans-Jurgen.Federsel@astrazeneca.com

Novartis obtains European approval for Cosentyx to treat psoriasis

January 21, 2015 3:24 am / 4 Comments on Novartis obtains European approval for Cosentyx to treat psoriasis

Novartis obtains European approval for Cosentyx to treat psoriasis
Swiss drug-maker Novartis has received approval from the European Commission (EC) for its Cosentyx (secukinumab, formerly known as AIN457) to treat moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy.SEE

http://www.pharmaceutical-technology.com/news/newsnovartis-obtains-european-approval-for-cosentyx-to-treat-psoriasis-4492415?WT.mc_id=DN_News

PSORIAIS

secukinumab

Secukinumab is a human monoclonal antibody designed for the treatments of uveitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis. It targets member A from the cytokine family of interleukin 17.^[1]^[2] At present, Novartis Pharma AG, the drug’s developer, plans to market it under the trade name “Cosentyx.” ^[3] It is highly specific to the human immunoglobulin G1k (IgG1k) subclass.^[2]

In July 2014 secukinumab established superiority to placebo and to etanercept for the treatment of chronic plaque psoriasis in Phase III clinical trials.^[4] In October 2014, the FDA Dermatologic and Ophthalmic Drugs Advisory Committee unanimously voted to recommend the drug for FDA approval, although this vote in and of itself does not constitute an approval. However, the FDA typically follows recommendations from these committees.^[5] In October 2014, Novartis announced that the drug had achieved a primary clinical endpoint in two phase III clinical trials for ankylosing spondylitis.^[6] As of 28 October, the relevant FDA committee had not yet responded to these results. In early November 2014, Novartis also released the results of a Phase 3 study on Psoriatic Arthritis that yielded very promising results.^[7]

Although the drug was originally intended to treat rheumatoid arthritis, phase II clinical trials for this condition yielded disappointing results.^[8] Similarly, while patients in a phase II clinical trial for [psoriatic arthritis] did show improvement over placebo, the improvement did not meet adequate endpoints and Novartis is considering whether to do more research for this condition.^[9] Novartis has said that it is targeting approval and release in early 2015 for plaque psoriasis and ankyloding spondylitis indications.

It is also in a phase II clinical trial for Multiple Sclerosis ^[10] as it has exhibited efficacy in treating experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

CAS registry numbers

875356-43-7 (heavy chain)
875356-44-8 (light chain)

References

“Statement On A Nonproprietary Name Adopted By The USAN Council: Secukinumab”. American Medical Association.
Hueber, W.; Patel, D. D.; Dryja, T.; Wright, A. M.; Koroleva, I.; Bruin, G.; Antoni, C.; Draelos, Z.; Gold, M. H.; Psoriasis Study, P.; Durez, P. P.; Tak, J. J.; Gomez-Reino, C. S.; Rheumatoid Arthritis Study, R. Y.; Foster, C. M.; Kim, N. S.; Samson, D. S.; Falk, D.; Chu, Q. D.; Callanan, K.; Nguyen, A.; Uveitis Study, F.; Rose, K.; Haider, A.; Di Padova, F. (2010). “Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis”. Science Translational Medicine 2 (52): 52ra72.doi:10.1126/scitranslmed.3001107. PMID 20926833. edit
http://www.medscape.com/viewarticle/835331
Langley RG, Elewski BE, Mark Lebwohl M, et al., for the ERASURE and FIXTURE Study Groups (July 24, 2014). “Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials”. N Engl J Med 371: 326–338. doi:10.1056/NEJMoa1314258.
committees.http://www.familypracticenews.com/index.php?id=2934&type=98&tx_ttnews=306073^{[dead link]}
http://inpublic.globenewswire.com/2014/10/23/Novartis+AIN457+secukinumab+meets+primary+endpoint+in+two+Phase+III+studies+in+ankylosing+spondylitis+a+debilitating+joint+condition+of+the+spine+HUG1864939.html
http://www.medpagetoday.com/MeetingCoverage/ACR/48743
http://www.medscape.com/viewarticle/806510_6
http://www.ncbi.nlm.nih.gov/pubmed/23361084
http://clinicaltrials.gov/show/NCT01874340

Secukinumab
Monoclonal antibody
Type	Whole antibody
Source	Human
Target	IL17A
Clinical data
Legal status	Investigational
Identifiers
CAS number
ATC code	L04AC10
DrugBank	DB09029
Synonyms	AIN457
Chemical data
Formula	C₆₅₈₄H₁₀₁₃₄N₁₇₅₄O₂₀₄₂S₄₄
Molecular mass	147.94 kDa

Rupatadine

January 20, 2015 4:14 am / 1 Comment on Rupatadine

Rupatadine

CAS 158876-82-5,

8-Chloro-11-(1-((5-methylpyridin-3-yl)methyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-chloro-11-(1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin

UNII-2AE8M83G3E, UR 12592

Molecular Formula: C₂₆H₂₆ClN₃

Molecular Weight: 415.95774 g/mol

Percent Composition: C 75.07%, H 6.30%, Cl 8.52%, N 10.10%

Properties: Creamy solid, mp 58-61°.

Melting point: mp 58-61°

Platelet activating factor receptor antagonist; Histamine H1 receptor antagonist

Allergic rhinitis; Urticaria

	J. Uriach & Cia. S.A.

J. Uriach & Cia. S.A.

Uriach developed and launched rupatadine for treating of allergic rhinitis and urticaria. Family members of the product case EP577957, have SPC protection in the EU until 2016.

As of January 2015, Newport Premium™ reports that Cadila Pharmaceuticals is producing or capable of producing commercial quantities of rupatadine fumarate and holds an active USDMF since September 2012.

Rupatadine is a second generation antihistamine and PAF antagonist used to treat allergies. It was discovered and developed by J. Uriach y Cia, S. A.^[1] and is marketed under several trade names such as Rupafin, Alergoliber, Rinialer, Pafinur, Rupax and Ralif.

Therapeutic indications approved

Rupatadine fumarate has been approved for the treatment of allergic rhinitis and chronic urticaria in adults and children over 12 years. The defined daily dose (DDD) is 10 mg orally.

Derivative Type: Fumarate

CAS Registry Number: 182349-12-8

Trademarks: Rupafin (Uriach)

Molecular Formula: C26H26ClN3.C4H4O4

Molecular Weight: 532.03

Percent Composition: C 67.73%, H 5.68%, Cl 6.66%, N 7.90%, O 12.03%

Derivative Type: Trihydrochloride

CAS Registry Number: 156611-76-6

Molecular Formula: C26H26ClN3.3HCl

Molecular Weight: 525.34

Percent Composition: C 59.44%, H 5.56%, Cl 26.99%, N 8.00%

Properties: Crystals from ethyl acetate + ether, mp 213-217°.

Melting point: mp 213-217°.

Therap-Cat: Antihistaminic.

Keywords: Antihistaminic; Tricyclics; Other Tricyclics; Platelet Activating Factor Antagonist.

Available form

Rupatadine is available as round, light salmon coloured tablets containing 10 mg of rupatadine (as fumarate) to be administered orally, once a day.

Side effects

Rupatadine is a non-sedating antihistamine. However, as in other non sedating second-generation antihistamines, the most common side effects in controlled clinical studies were somnolence, headaches and fatigue.

Mechanism of action

Rupatadine is a second generation, non-sedating, long-acting histamine antagonist with selective peripheral H₁ receptor antagonist activity. It further blocks the receptors of the platelet-activating factor (PAF) according to in vitro and in vivo studies.^[2]

Rupatadine possesses anti-allergic properties such as the inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli, and inhibition of the release of cytokines, particularly of the TNF in human mast cells and monocytes.^[3]

Pharmacokinetics

Rupatadine has several active metabolites such as desloratadine, 3-hydroxydesloratadine, 6-hydroxydesloratadine and 5-hydroxydesloratadine.

History

Rupatadine discovery, pre-clinical and clinical development was performed by J. Uriach y Cia, S. A., a Spanish pharmaceutical company. It was launched in 2003 in Spain by J. Uriach y Cia, S. A., with the brand name of Rupafin. The registration of the product is approved in 23 countries from the EU, 8 Central American countries, Brazil, Argentina, Chile, Turkey and 14 African countries.

Efficacy in humans

The efficacy of rupatadine as treatment for allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) has been investigated in adults and adolescents (aged over 12 years) in several controlled studies, showing a rapid onset of action and a good safety profile even in prolonged treatment periods of a year.^[3]^[4]^[5]

Rupatadine (I) is an authorized antihistaminic agent and has IUPAC name 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, CAS number 158876-82-5 for the free base and the following chemical formula:
Rupatadine is currently marketed in 10 mg (rupatadine) tablets as rupatadine fumarate (CAS 182349-12-8 for the fumarate salt) for the treatment of allergic rhinitis and urticaria in adults and teenagers.
Rupatadine free base was first disclosed in EP0577957 .
Spanish patent application ES2087818 discloses the monofumarate salt of rupatadine (i.e. rupatadine fumarate) and aqueous liquid pharmaceutical compositions of rupatadine fumarate. In particular, this document discloses a syrup containing rupatadine fumarate at 4 g/L, sucrose, a flavouring agent, a sweetening agent and water; and a solution for injection which contains rupatadine fumarate at 20 g/L, benzyl alcohol, propyleneglycol and water.
EP0577957 discloses some liquid pharmaceutical compositions of rupatadine free base; compound 4 in EP0577957 is rupatadine free base. The formulations disclosed therein are identical to those disclosed in ES2087818 but rupatadine free base is used instead of rupatadine fumarate.
Despite the aqueous liquid pharmaceutical compositions disclosed in EP0577957 and ES2087818 , the inventors have found that the solubility in water of rupatadine fumarate is 2.9 g/L (see Reference example 1) and therefore these prior art formulations may have stability problems due to supersaturation of rupatadine free base or rupatadine fumarate and would not be suitable for use as a medicament.
CN101669901 and CN101669926 disclose liquid formulations of rupatadine free base using cyclodextrins to dissolve rupatadine.
CN101669901 is directed to liquid formulations of rupatadine free base for ophthalmic delivery comprising rupatadine, a solvent and a cyclodextrin.
CN10169926 is directed to liquid formulations of rupatadine free base for nasal delivery comprising rupatadine, a solvent and a cyclodextrin. It is stated that rupatadine has low solubility in water (1.39 mg/mL to 0.82 mg/mL at pH 3.0 to 7.0, table 9 in CN10169926 ) and the problem of its low solubility is solved using cyclodextrins (tables 10-12 of CN10169926 ) in order to obtain liquid formulations.

The reaction of 2-cyano-3-methylpyridine (I) with H2SO4 in t-BuOH gives the N-tert-butylamide (II), which is treated with two equivalents of BuLi and the corresponding dianion alkylated with 3-chlorobenzyl chloride to afford amide (III). The treatment of (III) with POCl3 gives nitrile (IV) which is cyclized to ketone (V) by subsequent treatment with CF3SO3H and aqueous HCl. Reaction of ketone (V) with the Grignard derivative prepared from chloride (VI) affords alcohol (VII) which is finally dehydrated by H2SO4 to give UR-12592 (1), as shown in Scheme 20491401a. The key intermediate (VI) is synthesized through the condensation of 5-methylnicotinic acid (VIII) with 4-hydroxypiperidine by means of DCC in DMF to give amide (IX), followed by reduction with POCl3 and NaBH4 to give the amino alcohol (X) which is treated with SOCl2. Scheme 20491402a. Description White crystals, m.p. 196-8 癈. References 1. Carceller, E., Jim閚ez, P.J., Salas, J. (J. Uriach & Cia SA). Process for the preparation of 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4 -piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. ES 9602107.

The key intermediate (VI) is synthesized through the condensation of 5-methylnicotinic acid (VIII) with 4-hydroxypiperidine by means of DCC in DMF to give amide (IX), followed by reduction with POCl3 and NaBH4 to give the amino alcohol (X), which is treated with SOCl2.

………………………….

EXAMPLE 4

http://www.google.com/patents/EP0577957A1?cl=en

8-chloro-11-(1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin

To a solution of 1.7 mL (15 mmol) of 3,5-lutidine in 100 mL of CCl₄ was added 2.6 g (15 mmol) of NBS and the mixture was stirred at reflux under an argon atmosphere for 2 h. Then, the mixture was allowed to cool, the solid obtained was filtered off and to the filtrate was added 2.4 g (7.5 mmol) of the compound obtained in preparation 1 and 20 mg of 4-(dimethylamino)pyridine. The resulting mixture was stirred at room temperature for 18 h and 1.68 mL of triethylamine was added. It was diluted with 100 mL of dichloromethane and washed with 0.5N NaHCO₃ solution and with water. The organic phase was dried over sodium sulfate and the solvent was removed, to give 5.7 g of a residue that was chromatographed on silica gel (chloroform : methanol : ammonia, 60 : 2 : 0.2). 1.3 g of the title compound of the example was obtained as a white solid (yield: 40%).
mp: 58-61°C;
IR (KBr) ν: 3419, 3014, 1635, 1576, 1472 cm⁻¹;
¹H RMN (80 MHz, CDCl₃) δ (TMS): 8.39 (m, 3H, ar), 7.48 (m, 1H, ar), 7.37 (m, 1H, ar), 7.12 (m, 4H, ar), 3.45 (s, 2H, CH₂N), 3.36 (m, 2H), 3.1-2.1 (m, 13H). ¹³C RMN (20.15 MHz, CDCl₃) δ (TMS): 157.20 (C), 148.93 (CH), 147.46 (CH), 146.48 (CH), 139.50 (C), 138.56 (C), 137.06 (CH), 133.3 (C), 132.54 (C), 130.67 (CH), 128.80 (CH), 125.85 (CH), 121.92 (CH), 59.84 (CH₂), 54.63 (CH₂), 31.70 (CH₂), 31.32 (CH₂), 30.80 (CH₂), 30.56 (CH₂), 18.14 (CH₃).

………………………….

WO2006114676

http://www.google.com/patents/WO2006114676A2?cl=en

Scheme-1

Example 1

Preparation of3-bromomethyl-5-methylpyridine hydrochloride: A mixture of carbon tetrachloride (4000ml), azobisisobutyronitrile (45.96gm, 0.279mol), 3,5-lutidine (150gm, 1.399mol) and N-bromosuccinamide (299.4gm, 1.682mol) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and solid is filtered. HCl gas is passed to the filtrate and solid obtained is separated and filtered. Yield is 196gm Yield is 67.66%. Example 2

Preparation of Rupatadine :

A mixture of desloratadine (5.0gm, 0.016mol), methylene chloride (15ml), tetrabutylammonium bromide (0.575gm, 0.0018mol) and sodium hydroxide solution (2.5gm, 0.064mol in 8ml water) is cooled to 0 to 5⁰C. 3-bromomethyl-5- methylpyridine hydrochloride (7.18gm, 0.032mol) in methylene chloride (35ml) is added to above mixture. The reaction mixture is stirred at 0 to 5⁰C for 1 hour and at room temperature for 12 hours. Layers are separated and organic layer is washed with dilute HCl solution and water. Methylene chloride is distilled. Yield = 9.5g %Yield =

67.66%.

Example 3

Preparation of ^“Rupatadine fumarate:

A solution of fumaric acid (3.3gm) in methanol (46ml) is added to solution of

Rupatadine (4.5gm) in ethyl acetate (30ml) at room temperature. The reaction mass is cooled to -5 to O⁰C for 4 hours. Rupatadine fumarate is separated filtered and Washed with ethylacetate. Yield = 5.5 gm.

…………………………..

NEW PATENT

EP-02824103…An improved process for the preparation of rupatadine fumarate, Cadila Pharmaceuticals Ltd

Process for the preparing rupatadine intermediate (particularly 5-methylpyridine-3-methanol) comprises reduction of 5-methyl nicotinic acid alkyl ester using alkali metal borohydride is claimed. For a prior filing see WO2006114676, claiming the process for preparation of rupatadine fumarate.

……………………………………

J. Med. Chem., 1994, 37 (17), pp 2697–2703

DOI: 10.1021/jm00043a009

http://pubs.acs.org/doi/abs/10.1021/jm00043a009

References

Patents: EP 577957, US 5407941, US 5476856
Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Queralt, M.; Puigdemont, A.; García-Rafanell, J.; Forn, J. (1997). “Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF)”. The Journal of Pharmacology and Experimental Therapeutics 280 (1): 114–121. PMID 8996188. edit
Picado, C. S. (2006). “Rupatadine: Pharmacological profile and its use in the treatment of allergic disorders”. Expert Opinion on Pharmacotherapy 7 (14): 1989–2001. doi:10.1517/14656566.7.14.1989. PMID 17020424. edit
Keam, S. J.; Plosker, G. L. (2007). “Rupatadine: A review of its use in the management of allergic disorders”. Drugs 67 (3): 457–474. doi:10.2165/00003495-200767030-00008. PMID 17335300. edit
Mullol, J.; Bousquet, J.; Bachert, C.; Canonica, W. G.; Gimenez-Arnau, A.; Kowalski, M. L.; Martí-Guadaño, E.; Maurer, M.; Picado, C.; Scadding, G.; Van Cauwenberge, P. (2008). “Rupatadine in allergic rhinitis and chronic urticaria”. Allergy 63: 5–28. doi:10.1111/j.1398-9995.2008.01640.x. PMID 18339040. edit

Literature References: Dual antagonist of histamine H1 and platelet-activating factor receptors. Prepn: E. Carceller et al., ES 2042421; eidem, US 5407941 (1993, 1995 both to Uriach);

eidem,J. Med. Chem. 37, 2697 (1994).

Mechanism of action: M. Merlos et al., J. Pharmacol. Exp. Ther. 280, 114 (1997).

Clinical trial in seasonal allergic rhinitis: F. Saint-Martin et al., J. Invest. Allergol. Clin. Immunol. 14, 34 (2004);

and comparison with ebastine: E. M. Guadaño et al., Allergy 59, 766 (2004).

Review of pharmacology and clinical development: N. Y. Van Den Anker-Rakhmanina, Curr. Opin. Anti-Inflam. Immunomod. Invest. Drugs 2, 127-132 (2000).

1 to 8 of 8
Patent	Submitted	Granted
8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine [US5407941]	1995-04-18
Treatment of PAF and histamine-mediated diseases with 8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine [US5476856]	1995-12-19
Process for the synthesis of n-(5-methylnicotinoyl)-4 hydroxypiperidine, a key intermediate of rupatadine [US6803468]	2004-03-04	2004-10-12
$g(b)2-ADRENERGIC RECEPTOR AGONISTS [EP1003540]	2000-05-31
$g(b)2-ADRENERGIC RECEPTOR AGONISTS $g(b)2-ADRENERGIC RECEPTOR AGONISTS [EP1019360]	2000-07-19
8-Chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. [EP0577957]	1994-01-12	1995-07-12
NOVEL CRYSTALLINE FORM OF RUPATADINE FREE BASE [US2009197907]	2009-08-06
METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS [WO9966944]	1999-12-29

Rupatadine
Systematic (IUPAC) name

8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate
Clinical data
Trade names	Rupafin, Alergoliber, Rinialer, Pafinur, Rupax, Ralif
AHFS/Drugs.com	International Drug Names
Legal status	Prescription drug
Routes	Oral
Pharmacokinetic data
Protein binding	98–99%
Metabolism	Hepatic, CYP-mediated
Half-life	5.9 hours
Excretion	34.6% urine, 60.9% faeces
Identifiers
CAS number	158876-82-5 (free base) 182349-12-8 (fumarate)
ATC code	R06AX28
PubChem	CID 133017
ChemSpider	117388
UNII	2AE8M83G3E
ChEMBL	CHEMBL91397
Chemical data
Formula	C₂₆H₂₆Cl N₃
Molecular mass	415.958 g/mol

N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide

January 19, 2015 5:55 am / Leave a comment

Abstract Image

N-[2-(7-Benzyl-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide

N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide

Acetamide, N-[2-[7-(cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl]-

339.47, C₂₂ H₂₉ N O₂

cas 1287785-08-3

Melatonin MT2 Agonists

Takeda……..innovator

Treatment of Sleep Disorders,

Melatonin (N-acetyl-5-methoxytryptamine), which is a hormone synthesized and secreted principally in the pineal gland, increases in dark circumstances and decreases in light circumstances. Melatonin exerts suppressively on pigment cells and the female gonads, and acts as a synchronous factor of biological clock while taking part in transmittance of photoperiodic code. Therefore, melatonin is expected to be used for the therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rhythm disorders, jet-lag syndrome and various disorders related to aging, etc.
Recently, it has been reported that the production of melatonin melatonin could reset the body’s aging clock (see Ann. N. Y. Acad. Sci., Vol. 719, pp. 456-460 (1994)). As previously reported, however, melatonin is easily metabolized by metabolic enzymes in vivo (see Clinical Examinations, Vol. 38, No. 11, pp. 282-284 (1994)). Therefore, it cannot be said that melatonin is suitable as a pharmaceutical substance.
Various melatonin agonists and antagonists such as those mentioned below are known.
- (1) EP-A-578620 discloses compounds of:
- - (2) EP-A-420064 discloses a compound of:
  - (3) EP-A-447285 discloses a compound of:
  - (4) EP-A-662471 discloses a compound of:
  - (5) EP-A-591057 discloses a compound of:
  - (6) EP-A-527687 discloses compounds of:
    
    X=S, 0, Y=CH
    X=0, NH, Y=N
  - (7) EP-A-506539 discloses compounds of:
- Tricyclic or more poly-cyclic compounds with a cyclic ether moiety, such as those mentioned below, are known.
  - (1) Compounds of:
    
    are disclosed in Tetrahedron Lett., Vol. 36, p. 7019 (1995).
  - (2) Compounds of:
    
    are disclosed in J. Med. Chem., Vol. 35, p. 3625 (1992).
  - (3) Compounds of:
    
    are disclosed in Tetrahedron, Vol. 48, p. 1039 (1992).
  - (4) Compounds of:
    
    are disclosed in Tetrahedron Lett., Vol. 32, p. 3345 (1991).
  - (5) A compound of:
    
    is disclosed in Bioorg. Chem., Vol. 18, p. 291 (1990).
  - (6) A compound of:
    
    is disclosed in J. Electroanal. Chem. Interfacial Electrochem., Vol. 278, p. 249 (1990).
  see

http://www.google.co.in/patents/EP0885210B1?cl=en

Highly Potent MT₂-Selective Agonists

J. Med. Chem., 2011, 54 (9), pp 3436–3444

DOI: 10.1021/jm200221q

http://pubs.acs.org/doi/full/10.1021/jm200221q

N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide (15)

By a similar procedure that described for 8, 15 (79%) was obtained as a white solid; mp 133−134 °C (EtOAc/hexane).

¹H NMR (CDCl₃) δ 0.82−1.03 (2H, m), 1.06−1.32 (3H, m), 1.42−1.78 (6H, m), 1.96 (3H, s), 2.32 (2H, d, J = 7.2 Hz), 2.74 (2H, t, J = 7.2 Hz), 3.26 (2H, s), 3.32−3.52 (4H, m), 4.59 (2H, t, J = 8.6 Hz), 5.60 (1H, s), 6.59 (1H, d, J = 7.9 Hz), 7.11 (1H, d, J= 7.9 Hz).

MS (ESI) m/z 340 (M + H)⁺. Anal. (C₂₂H₂₉NO₂) C, H, N.

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