BIMATOPROST

155206-00-1

Bimatoprost ophthalmic solution is a topical medication used for controlling the progression of glaucoma or ocular hypertension, by reducing intraocular pressure. It is a prostaglandin analogue that works by increasing the outflow of aqueous fluid from the eyes. It binds to the prostanoid FP receptor.

Allergan reported Lumigan® sales of US$625 million and Latisse® sales of US$100 million in 2013

Systematic (IUPAC) name
7-[3,5-dihydroxy-2- (3-hydroxy-5-phenyl-pent-1-enyl)- cyclopentyl]-N-ethyl-hept-5-enamide
Clinical data
Trade names	Lumigan
AHFS/Drugs.com	monograph
MedlinePlus	a602030
Licence data	US Daily Med:link
Pregnancy cat.	C (US)
Legal status	℞-only (US)
Routes	Topical (eye drops)
Identifiers
CAS number	155206-00-1
ATC code	S01EE03
PubChem	CID 5311027
IUPHAR ligand	1958
DrugBank	DB00905
ChemSpider	4470565
UNII	QXS94885MZ
Chemical data
Formula	C25H37NO4
Mol. mass	415.566 g/mol

Bimatoprost (marketed in the U.S., Canada and Europe by Allergan, under the trade name Lumigan) is a prostaglandinanalog/prodrug used topically (as eye drops) to control the progression of glaucoma and in the management of ocular hypertension. It reduces intraocular pressure (IOP) by increasing the outflow of aqueous fluid from the eyes.^[1] In December 2008, the indication to lengthen eyelashes was approved by the U.S. Food and Drug Administration (FDA); the cosmetic formulation of bimatoprost is sold as Latisse /ləˈtiːs/.^[2] In 2008-2011, at least three case series suggested that bimatoprost has the ability to reduce adipose (fat) tissue.^[3][4][5]

Cosmetic use

In patients using ophthalmic prostaglandins such as travoprost and latanoprost, it has been anecdotally noted^{[by whom?]} that there had been an increase in diameter, density and length of eyelashes. Allergan has initiatedclinical trials investigating the usage of Lumigan as a cosmetic drug.^[6] On December 5, 2008, the FDA Dermatologic and Ophthalmic Drugs Advisory Committee voted to approve bimatoprost for the cosmetic use of darkening and lengthening eyelashes.The medical term for this is treatment of hypotrichosis, however, the FDA approval is for purely cosmetic purposes.^[7]

For cosmetic purposes, it is administered once daily by applying the solution to the skin at the base of the eyelash using an applicator device “Application Guide”, where it has its effect upon the hair follicle.

Bimatoprost activates prostamide alpha F2 receptors found in the hair follicle to stimulate its growth rate. Research led by Professor Randall and the University of Bradford found that it may also offer a treatment for scalp hair regrowth in trials conducted on samples taken from men undergoing hair transplants.^[8]

According to Allergan’s package labeling, users of its Latisse cosmetic product didn’t develop darker irises in clinical studies; however, “patients should be advised about the potential for increased brown iris pigmentation which is likely to be permanent.”^[9]

Several cosmetics companies have released products based on prostaglandin analogs, as non-drug cosmetics.

• Age Intervention Eyelash by Jan Marini Skin Research
• RevitaLash by Athena Cosmetics Corp.

These companies have been sued by Allergan for patent infringement.^[6] The FDA has seized Age Intervention Eyelash as an “unapproved and misbranded drug” because Jan Marini Skin Research promoted it as something that increases eyelash growth^[10] and because it is “adulterated” with bimatoprost.^[11]

Fat-reducing properties

Reductions in orbital fat (i.e., fat around the eye) have been observed in patients using bimatoprost as glaucoma therapy.^[12] Of particular interest, the loss of orbital fat was unilateral in patients who used bimatoprost on only one eye.^[13] The effect appears reversible upon cessation of bimatoprost use. The effect is likely to explain deepening of the lid sulcus described in a series of three patients on bimatoprost.^[14] The mechanism for the apparent fat reduction remains unclear. However, bimatoprost is chemically analogous to prostaglandin F_2α (PGF_2α), a compound which is known to reduce fat by inhibition of adipocyte differentiation and survival.^[15]

Formulations

Lumigan is a 0.03% solution of bimatoprost, and contains benzalkonium chloride as a preservative. Contact lenses should therefore be removed before use, and replaced no less than 15 minutes later;^[1] other eye drops or ointments should be given no less than five minutes before or after bimatoprost.^[1]

Efficacy

Studies have shown once-daily bimatoprost 0.03% ophthalmic solution to be more effective than timolol twice daily in reduction of intraocular pressure (IOP) and as effective as or more effective than the prostaglandin analogues latanoprost and travoprost in reducing IOP.^[16]

Side effects

Possible side effects of this medication are:

• May cause blurred vision.
• May cause eyelid redness.
• May permanently darken eyelashes.
• May cause eye discomfort.
• May eventually cause permanent darkening of the iris to brown.
• May cause a temporary burning sensation during use.
• May cause thickening of the eyelashes.
• It may cause unexpected growth of hair if applied inappropriately, on the cheek, for example.
• It may cause infection if the one-time applicators which come with the genuine product are reused.
• Lashes may grow so long that they become ingrown and scratch the cornea.
• May cause darkening of the eyelid or of the area beneath the eye.^[17]

On November 19, 2007, the FDA issued a warning during the seizure of a bimatoprost-containing cosmetic.^[18] The warning stated that “the extra dose of bimatoprost may decrease the prescription drug’s effectiveness. Damage to the optic nerve may lead to decreased vision and possibly blindness.”

PATENTS

Jiang Xing Chen, “Process for the production of intermediates for making prostaglandin derivatives such as latanaprost, travaprost, and bimatoprost.” U.S. Patent US20090287003, issued November 19, 2009.

US20090287003

LUMIGAN® 0.01% and 0.03% (bimatoprost ophthalmic solution) is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and Its molecular weight is 415.58. Its molecular formula is C₂₄H₃₇NO₄. Its chemical structure is:

Bimatoprost is a powder, which is very soluble in ethyl alcohol and methyl alcohol and slightly soluble in water. LUMIGAN® 0.01% and 0.03% is a clear, isotonic, colorless, sterile ophthalmic solution with an osmolality of approximately 290 mOsmol/kg.

LUMIGAN® 0.01% contains Active: bimatoprost 0.1 mg/mL; Preservative: benzalkonium chloride 0.2 mg/mL; Inactives: sodium chloride; sodium phosphate, dibasic; citric acid; and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8.

LUMIGAN® 0.03% contains Active: bimatoprost 0.3 mg/mL; Preservative: benzalkonium chloride 0.05 mg/mL; Inactives: sodium chloride; sodium phosphate, dibasic; citric acid; and purified water. Sodium hydroxide and/or hydrochloric acid may be added to adjust pH. The pH during its shelf life ranges from 6.8-7.8.

SYNTHESIS

……………………………….

http://www.google.com/patents/EP2495235A1?cl=en

• PGF_2α prostaglandin synthetic routes so far reported may comprise the following two major steps:
• The starting compound is generally protected on the secondary hydroxyl group:

  where Y stands for p-phenylbenzoyl (PPB) (Ia) or benzoyl (Bz) (Ib) or an analogous substituted aryl group.

• For example, EP0364417B1 (Kabi Pharmacia AB) describes the following synthetic sequence:
• The product is obtained as a mixture of epimers where the 15-OH can be in α-position or β-position. The removal of unwanted β-isomer and of other impurities represents one of the main difficulties in the preparation of prostaglandins and many methods have been proposed to reduce the amount of the undesired diastereoisomers formed during the preparation.
• In EP0544899B1 (Pharmacia AB) the reduction of the α,β-unsaturated ketone is performed with lithium-tri(sec-butyl)borohydride at ―130°C.
• In this kind of processes the low selectivity in the reduction of the keto group leads to a tedious separation of the diastereomers and generally decreases the global yield of the synthesis.
• A different method of stereoselective reduction of the ketone is proposed in US7674921 B1 (Cayman Chemical Co.) where the reaction with lithium aluminium hydride in the presence of (S)-binaphtol in tetrahydrofuran at -78°C is reported.
• An alternative is presented in US6927300B2 and in US 7157590B2(Finetech Lab. Ltd.) where the critical step of the reduction of the α,β-unsaturated keto-group is performed on the compound reported below

  where R¹ is an aryl carbonyl group in the presence of (-)β-chlorodiisopinocampheylborane in tetrahydrofuran at ―25°C which allows to obtain a ratio of 95/5 of the two diastereoisomers (R)-(IV)/(S)-(IV).
• A further improvement in the preparation of PGF_2α is directed to the reduction of lactone to lactol in order to introduce the α-chain by subsequent Wittig reaction with 4-carboxybutyltriphenylphosphonium bromide.
• The reaction was usually carried out using diisobutylaluminum hydride at very low temperatures, namely between -80°C and ―40°C. Unfortunately, in these conditions the partial removal of the protecting group PPB or benzoyl (Bz) is possible.
• To avoid the inconvenient of working with mixtures of products, the p-phenylbenzoyl group or the benzoyl group R is removed by basic hydrolysis and a suitable protecting group is introduced at the two hydroxyl groups of the so obtained compound according to the following scheme:
• In this way two additional steps of protection and deprotection are introduced possibly leading to a decrease of the global yield of the process at an advanced stage of the synthesis.
• Moreover when P’ is a silylated group as reported in US7268239B2(Resolution Chemical Ltd.), a mixture of products is obtained because of the migration of the silyl group as shown in scheme 3
• The same approach of hydrolysis of the aroyl group R followed by diprotection of the two hydroxyl groups with trialkylsilyl group or triaryl silyl group or tetrahydropiranyl group is disclosed in US7642370B2(Daichii Fine Chemical Co.). The protection of the two hydroxyl groups coming before the reduction of the lactone ring to lactol is described also in US7674921B1 (Cayman Chemical Co.) and in US6689901B2(Pharmacia and Upjohn Company).
• It follows that one important issue in the synthesis of PGF_2α is the involvement of intermediates with the most appropriate hydroxyl protecting group. As a consequence the use of the starting Corey lactone carrying a protection able to survive to the conditions of the subsequent reactions allows to form intermediates easy to isolate and to purify. Moreover the protection should be selectively removed in mild conditions.
• In US5359095 (Pharmacia AB) the preparation of PGF_2α prostaglandins is described starting from the commercially available (-)-Corey lactone (Ia) which is oxidized to the corresponding aldehyde (IIa)
• The reaction is carried out in the presence of dicyclohexylcarbodiimide in dimethylsulfoxide and 1,2-dimethoxyethane; after quenching with orthophosphoric acid the aldehyde is obtained. In the same application it is reported that the crude aldehyde (II) is particularly unstable and must be used within a short period after preparation.
• In US2010/0010239A1 (Sandoz AG) compound (I) is preferably oxidized in dichloromethane with oxalyl chloride and DMSO; the aldehyde (II) is not isolated and is processed directly in the solution where it is obtained or, when necessary, stored in solution at a temperature between ―20 and 0°C.
• In US7268239B2 (Resolution Chem. Ltd.) the aldehyde (II)

  where Z is (C₆-C₁₀)-aryl optionally substituted with one to three substituents independently selected from the group consisting of halo, C₁ to C₆ alkyl and unsubstituted C₆ to C₁₀ aryl, is formed by oxidation of the alcohol with sodium hypochlorite and 2,2,6,6-tetramethtyl-1-piperidinyloxy free radical (TEMPO); in order to avoid the risk of degradation, the aldehyde is directly used in the organic solution where it is synthesized.

• According to US2009/0287003A1 (Eastar Chem. Corp.) five steps can be performed to prepare the aldehyde to be used as starting material for the synthesis of latanoprost. The five steps are reported in the scheme below:
• In WO2010/097672 (Sifavitor) the starting material is the Corey lactone where the hydroxyl group is protected astert-butyldimethyl silyl derivative and during the synthesis a second protection is introduced according the scheme reported below referred to the preparation of Bimatoprost:

  • In case Bimatoprost is the end product, compound 9 with A=benzyl (in the following scheme, compound 9a) is directly converted by Wittig reaction to the acid 10 which is then converted in one step to ethylamide affording Bimatoprost, according to the following scheme:
  • In a preferred embodiment, the conversion of compound 10a to Bimatoprost is performed by reaction with ethylamine in an organic solvent, which is chosen among amides, ethers, ketones and chlorinated solvents, more preferably N,N-dimethylformamide, at a temperature between ―35 and 25°C, more preferably between -20°C and -10°C, in the presence of triethylamine and a suitable coupling reagent, which is preferably 1-(methylsulfonyloxy)benzotriazole. The molar ratio between compound 10a and ethylamine is comprised between 1 and 5, more preferably is 3.5, while the molar ratio between compound 10a and the coupling reagent is comprised between 1 and 2.5, more preferably is 1.8.
  • When Latanoprost is the desired product the double bond on the side chain of compound 9a is hydrogenated to form compound 11, then by Wittig reaction with 4-carboxybutyltriphenylphosphonium bromide compound 11 is converted into Latanoprost acid 12. By conversion of the carboxylic acid into isopropyl ester, the final product Latanoprost is obtained:
  • In the case of Travoprost, compound 9 with A=3-(trifluoromethyl)phenoxy (in the following scheme, compound 9b) is converted into 10b, which in turn is converted into Travoprost by esterification of the carboxylic acid by reaction with 2-iodopropane, according to scheme 10:

EXAMPLE 13

(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-enyl)cyclopentyl)hept-5-enoic acid (Bimatoprost free acid)

• 4-Carboxybutyltriphenylphosphonium bromide 15 (65.4 g, 0.148 mol) was suspended in tetrahydrofuran (150.0 mL) at 0°C under nitrogen atmosphere. A solution of potassium tert-butoxide in tetrahydrofuran (296.0 mL, 0.296 mol) was added dropwise and the mixture turned into orange. After stirring for 45 minutes at 0°C the system was cooled to ―15°C. A solution of (3aR,4R,5R,6aS)-4-((S,E)-3-hydroxy-5-phenylpent-1-enyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol (10.0 g, 0.033 mol) in tetrahydrofuran (46.0 mL) was added dropwise at a temperature lower than – 10°C. After three hours at -15°C no more starting material was visible on TLC and water (200 mL) was added. The mixture was extracted with diisopropyl ether (144 mL) and the layers were separated. The aqueous phase was treated with 0.6 N HCl to pH 6.0. Two extractions with ethyl acetate (2x 250 mL) were then performed and the combined organic layers were concentrated under vacuum at 40°C. An oil (26.80 g) was obtained which was purified on silica gel (eluent: dichloromethane:methanol from 97.5:2.5 to 85:15). The fractions of interest were combined and concentrated at 35°C under reduced pressure affording a colorless oil (11.7 g, 0.030 mol, 91%).
• ¹H-NMR {400 MHz, CDCl₃, δ (ppm)}: 7.29-7.25 (m, 2H, Ph), 7.19-7.15 (m, 3H, Ph), 5.60 (dd, J=7.2, 15.2 Hz, 1H, vinyl), 5.51-5.41 (m, 2H, H vinyl), 5.38-5.31 (m, 1H, vinyl), 4.5-3.8 (m, 7H), 2.67 (m, 2H, -CH ₂-Ph), 2.37-1.43 (m, 14H).
• ¹³C-NMR {400 MHz, CDCl₃, δ (ppm)}: 177.2 (C), 141.9 (C), 134.9 (CH), 133.0 (CH), 129.6 (CH), 129.1 (CH), 128.4 (2xCH, arom.), 128.3 (2xCH arom.),125.8 (CH), 77.4 (CH), 72.3 (CH), 72.2 (CH), 55.1 (CH), 50.5 (CH), 42.7 (CH₂), 38.5 (CH₂), 32.9 (CH₂), 31.8 (CH₂), 26.3 (CH₂), 25.2 (CH₂), 24.4 (CH₂).
• HPLC-MS (ESI): [M-H₂O+1]⁺= 371; [M+Na]⁺ = 411; [2M+Na]⁺ = 799.

EXAMPLE 14

(5Z)-7-[(2R)-3,5-Dihydroxy-2-[(1E)-3-hydroxy-5-phenylpent-1-en-1-yl]cyclopentyl]-N-ethylhept-5-enamide (Bimatoprost)

• Bimatoprost acid (11.50 g, 0.030 mol) was dissolved in dimethylformamide (92.0 mL), and stirred at -15°C. Triethylamine (7.25 mL, 5.26 g, 0.052 mol) was then added over 5 minutes followed by the portionwise addition of 1-(methylsulfonyloxy)benzotriazole 16 (prepared according to Bulletin of the Chemical Society of Japan, 1978, 51(11), 3320-3329) (11.27 g, 0.053 mol). The mixture was then stirred for one hour at -15°C and an aqueous solution of ethylamine (70% weight, 8.4 mL, 0.104 mol) was added dropwise over 5 minutes. The temperature was allowed to reach 0°C and the reaction was checked by TLC. The mixture was washed with water (172.0 mL) and extracted four times with ethyl acetate (4x 230.0 mL). The combined organic layers were washed with 5% sodium bisulfate solution (100 mL, 50 mL, 50 mL). The bisulfate aqueous phases were extracted with ethyl acetate (50.0 mL). The organic layers were concentrated at 40°C under reduced pressure affording the crude product as an oil (16.98 g). Treatment with dichloromethane and diisopropylether at 0°C for one hour followed by filtration afforded a solid which was then recrystallized from ethyl acetate (6.79 g, 0.016 mol, 55%).
• ¹H-NMR {400 MHz, CDCl₃, δ (ppm)}: 7.26 (m, 2H, Ph), 7.17 (m, 3H, Ph), 6.07 (t, J=5.6Hz, 1H, -NH-), 5.57 (dd, J=7.6, 15.2 Hz, 1H, H-14), 5.45 (dd, J=8.8, 15.2 Hz, 1H, H-13), 5.35 (m, 2H, H-5+H-6), 4.32 (d, J=4.8 Hz, 1H, OH-11), 4.08 (m, 2H, H-9+H-15), 3.90 (m, 1H, H-11), 3.73 (m, 2H, OH-9+OH-15), 3.20 (m, 2H, -N-CH ₂-CH₃), 2.64 (m, 2H, -CH₂-17), 2.30 (m, 1H, H-12), 2.18 (m, 2H, H-7+H-10), 2.11 (m, 3H, CH₂-2+H-7), 2.03 (m, 2H, H-4), 1.89 (m, 1H, H-16), 1.77 (m, 2H, H-10+H-16), 1.64 (m, 2H, H-3), 1.45 (m, 1H, H-8), 1.09 (t, J=6.8Hz, 3H, -N-CH₂-CH3).
• ¹³C-NMR {400 MHz, CDCl₃, δ (ppm)}: 173.4 (C), 142.0 (C), 135.0 (CH), 133.2 (CH), 129.6 (CH), 129.1 (CH), 128.4 (2xCH arom), 128.3 (2xCH arom), 125.7 (CH arom), 77.5 (CH), 72.22 (CH), 72.20 (CH), 55.4 (CH), 50.1 (CH), 42.8 (CH₂), 38.7 (CH₂), 35.8 (CH₂), 34.3 (-N-CH₂), 31.8 (CH₂), 26.6 (CH₂), 25.6 (CH₂), 25.3 (CH₂), 14.7 (CH₃).
• HPLC-MS (ESI): [M+Na]⁺ = 438, [(M-H₂O) +H]⁺=398, [(M-2H₂O) +H]⁺=380.

………………………………..

http://www.google.com.ar/patents/US20090287003

Bimatoprost refers to (Z)-7-[(1R,2R,3R,5S)-3,5-Dihydroxy-2-[1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]-5-N-ethylheptenamide, and its molecular weight is 415.58. Its molecular formula is C₂₅H₃₇NO₄. Its chemical structure is:

References

Citations

• Chen M, Cheng C, Chen Y, Chou C, Hsu W (2006). “Effects of bimatoprost 0.03% on ocular hemodynamics in normal tension glaucoma.”. J Ocul Pharmacol Ther 22 (3): 188–93. doi:10.1089/jop.2006.22.188. PMID 16808680.
• Kruse P, Rieck P, Sherif Z, Liekfeld A (2006). “Cystoid macular edema in a pseudophakic patient after several glaucoma procedures. Is local therapy with bimatoprost the reason?”. Klinische Monatsblätter für Augenheilkunde 223 (6): 534–7. doi:10.1055/s-2005-858992. PMID 16804825.
• Steinhäuser S (2006). “Decreased high-density lipoprotein serum levels associated with topical bimatoprost therapy.”. Optometry 77 (4): 177–9.doi:10.1016/j.optm.2006.02.001. PMID 16567279.
• Park J, Cho HK, Moon JI (2011). “Changes to upper eyelid orbital fat from use of topical bimatoprost, travoprost, and latanoprost.”. Japanese Ophthalmological Society 55 (1): 22–27. doi:10.1007/s10384-010-0904-z. PMID 21331688.
• Jayaprakasam A, Ghazi-Nouri S. (2010). “Periorbital fat atrophy – an unfamiliar side effect of prostaglandin analogues.”. Orbit 29 (6): 357–359.doi:10.3109/01676830.2010.527028. PMID 21158579.
• Filippopoulos T, Paula JS, Torun N, Hatton MP, Pasquale LR, Grosskreutz CL. (2008). “Periorbital changes associated with topical bimatoprost.”. Ophthalmology Plastic and Reconstructive Surgery 24 (4): 302–307. doi:10.1097/IOP.0b013e31817d81df. PMID 18645437.

External links

• Medical News Today: FDA Seizes $2 Million Of Cosmetic Eye Product Which Contains Drug Ingredient And Makes Unapproved Drug Claims. Christian Nordqvist. 18 November 2007
• Wired Science: FDA Seizes Cosmetic That Can Blind. Brandon Keim. November 19, 2007

• Eye Drops: [The generic name of the Latisse eye drop is Bimatoprost Ophthalmic Solution 0.03%]. Crazzy Paul. Aug 01, 2013

FDA Approves Striverdi Respimat to Treat Chronic Obstructive Pulmonary Disease

See my old post cut paste here

BI launches COPD drug Striverdi, olodaterol in UK and Ireland

July 3, 2014 8:07 am /

Olodaterol

BI-1744
BI-1744-CL (hydrochloride) marketed as drug

Boehringer Ingelheim Pharma  innovator

synthesis…..http://wendang.baidu.com/view/d4f95541e518964bcf847c22.html

Olodaterol (trade name Striverdi) is a long acting beta-adrenoceptor agonist used as an inhalation for treating patients with chronic obstructive pulmonary disease (COPD), manufactured by Boehringer-Ingelheim.^[1]

see……….https://www.thieme-connect.de/DOI/DOI?10.1055/s-0029-1219649           ……… synfacts

Olodaterol is a potent agonist of the human β₂-adrenoceptor with a high β₁/β₂ selectivity. Its crystalline hydrochloride salt is suitable for inhalation and is currently undergoing clinical trials in man for the treatment of asthma. Oloda­terol has a duration of action that exceeds 24 hours in two preclinical animal models of bronchoprotection and it has a better safety margin compared with formoterol.

Olodaterol hydrochloride [USAN]

Bi 1744 cl
Bi-1744-cl
Olodaterol hydrochloride
Olodaterol hydrochloride [usan]
UNII-65R445W3V9

CAS 869477-96-3

R ENANTIOMER

2H-1,4-Benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

2H-1,4-benzoxazin-3(4H)-one, 6-hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)- 1,1-dimethylethyl)amino)ethyl)-, hydrochloride (1:1)

6-Hydroxy-8-((1R)-1-hydroxy-2-((2-(4-methoxyphenyl)-1,1-dimethylethyl)amino)ethyl)- 2H-1,4-benzoxazin-3(4H)-one hydrochloride

clinical trialshttp://clinicaltrials.gov/search/intervention=Olodaterol+OR+BI+1744

Boehringer Ingelheim has launched a new chronic obstructive pulmonary disease drug, Striverdi in the UK and Ireland.
Striverdi (olodaterol) is the second molecule to be licenced for delivery via the company’s Respimat Soft Mist inhaler, following the COPD blockbuster Spiriva (tiotropium). The drug was approved in Europe in November based on results from a Phase III programme that included more than 3,000 patients with moderate to very severe disease.http://www.pharmatimes.com/Article/14-07-01/BI_launches_COPD_drug_Striverdi_in_UK_and_Ireland.aspx

Olodaterol hydrochloride is a drug candidate originated by Boehringer Ingelheim. The product, delivered once-daily by the Respimat Soft Mist Inhaler, was first launched in Denmark and the Netherlands in March 2014 for the use as maintenance treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. In 2013, approval was obtained in Russia and Canada for the same indication, and in the U.S, the product was recommended for approval. Phase III clinical trials for the treatment of COPD are ongoing in Japan.

Systematic (IUPAC) name
6-hydroxy-8-{(1R)-1-hydroxy-2-{[1-(4-methoxyphenyl)-2-methylpropan-2-yl]amino}ethyl}-4H-1,4-benzoxazin-3-one
Clinical data
Trade names	Striverdi
AHFS/Drugs.com	UK Drug Information
Pregnancy cat.	No experience
Legal status	POM (UK)
Routes	Inhalation
Identifiers
CAS number	868049-49-4; 869477-96-3 (hydrochloride)
ATC code	R03AC19
PubChem	CID 11504295
ChemSpider	9679097
UNII	VD2YSN1AFD
ChEMBL	CHEMBL605846
Synonyms	BI 1744 CL
Chemical data
Formula	C21H26N2O5 free form C21 H26 N2 O5 . Cl H; of hcl salt
Mol. mass	386.44 g/mol free form; 422.902 as hyd salt

Medical uses

Olodaterol is a once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema, and is administered in an inhaler called Respimat Soft Mist Inhaler.^{[2][3][4][5][6][7]}

As of December 2013, olodaterol is not approved for the treatment of asthma. Olodaterol monotherapy was previously evaluated in four Phase 2 studies in asthma patients. However, currently there are no Phase 3 studies planned for olodaterol monotherapy in patients with asthma.

In late January 2013, Olodaterol CAS# 868049-49-4 was the focus of an FDA committee reviewing data for the drug’s approval as a once-daily maintenance bronchodilator to treat chronic obstructive pulmonary disease (COPD), as well as chronic bronchitis and emphysema. The FDA Pulmonary-Allergy Drugs Advisory Committee recommended that the clinical data from the Boehringer Ingelheim Phase III studies be included in their NDA.

Also known as the trade name Striverdi Respimat, Olodaterol is efficacious as a long-acting beta-agonist, which patients self-administer via an easy to use metered dose inhaler. While early statistics from clinical trials of Olodaterol were encouraging, a new set of data was released earlier this week, which only further solidified the effectual and tolerable benefits of this COPD drug.

On September 10, 2013 results from two Phase 3 studies of Olodaterol revealed additional positive results from this formidable COPD treatment. The conclusion from these two 48 week studies, which included over 3,000 patients, showed sizable and significant improvements in the lung function of patients who were dosed with Olodaterol. Patients in the aforementioned studies were administered either a once a day dosage of Olodaterol via the appropriate metered-dose inhaler or “usual care”. The “usual care” included a variety of treatment options, such as inhaled corticosteroids (not Olodaterol), short and long acting anticholinergics, xanthines and beta agonists, which were short acting. The clinical trial participants who were dosed with Olodaterol displayed a rapid onset of action from this drug, oftentimes within the first five minutes after taking this medication. Additionally, patients dispensed the Olodaterol inhaler were successfully able to maintain optimum lung function for longer than a full 24 hour period. The participants who were given Olodaterol experienced such an obvious clinical improvement in their COPD symptoms, and it quickly became apparent that the “usual care” protocol was lacking in efficacy and reliability.

A staggering 24 million patients in the United States suffer from chronic obstructive pulmonary disease, and this patient population is in need of an effectual, safe and tolerable solution. Olodaterol is shaping up to be that much needed solution. Not only have the results from studies of Olodaterol been encouraging, the studies themselves have actually been forward thinking and wellness centered. Boehringer Ingelheim is the first company to included studies to evaluate exercise tolerance in  patients with COPD, and compare the data to those patients who were dosed with Olodaterol. By including exercise tolerance as an important benchmark in pertinent data for Olodaterol, Boehringer Ingelheim has created a standard for COPD treatment expectations. The impaired lung function for patients with COPD contributes greatly to their inability to exercise and stay healthy. Patients who find treatments and management techniques to combat the lung hyperinflation that develops during exercise have a distinct advantage to attaining overall good health.

- See more at: http://www.lgmpharma.com/blog/olodaterol-offers-encouraging-results-patients-copd/#sthash.DOjcrGxc.dpuf

Data has demonstrated that Striverdi, a once-daily long-acting beta2 agonist, significantly improved lung function versus placebo and is comparable to improvements shown with the older LABA formoterol. The NHS price for the drug is £26.35 for a 30-day supply.

Boehringer cited Richard Russell at Wexham Park Hospital as saying that the licensing of Stirverdi will be welcomed by clinicians as it provides another option. He added that the trial results showing improvements in lung function “are particularly impressive considering the study design, which allowed participants to continue their usual treatment regimen. This reflects more closely the real-world patient population”.

Significantly, the company is also developing olodaterol in combination with Spiriva, a long-acting muscarinic antagonist. LAMA/LABA combinations provide the convenience of delivering the two major bronchodilator classes.

Adverse effects

Adverse effects generally were rare and mild in clinical studies. Most common, but still affecting no more than 1% of patients, were nasopharyngitis (running nose), dizziness and rash. To judge from the drug’s mechanism of action and from experiences with related drugs, hypertension (high blood pressure), tachycardia (fast heartbeat), hypokalaemia (low blood levels of potassium), shaking, etc., might occur in some patients, but these effects have rarely, if at all, been observed in studies.^[1]

Interactions

Based on theoretical considerations, co-application of other beta-adrenoceptor agonists, potassium lowering drugs (e. g. corticoids, many diuretics, and theophylline), tricyclic antidepressants, and monoamine oxidase inhibitors could increase the likelihood of adverse effects to occur. Beta blockers, a group of drugs for the treatment of hypertension (high blood pressure) and various conditions of the heart, could reduce the efficacy of olodaterol.^[1] Clinical data on the relevance of such interactions are very limited.

Pharmacology

Mechanism of action

Like all beta-adrenoceptor agonists, olodaterol mimics the effect of epinephrine at beta-2 receptors (β₂-receptors) in the lung, which causes the bronchi to relax and reduces their resistance to airflow.^[3]

Olodaterol is a nearly full β₂-agonist, having 88% intrinsic activity compared to the gold standard isoprenaline. Its half maximal effective concentration (EC₅₀) is 0.1 nM. It has a higher in vitro selectivity for β₂-receptors than the related drugs formoterol and salmeterol: 241-fold versus β₁- and 2299-fold versus β₃-receptors.^[2] The high β₂/β₁ selectivity may account for the apparent lack of tachycardia in clinical trials, which is mediated by β₁-receptors on the heart.

Pharmacokinetics

Once bound to a β₂-receptor, an olodaterol molecule stays there for hours – its dissociation half-life is 17.8 hours –, which allows for once-a-day application of the drug^[3] like with indacaterol. Other related compounds generally have a shorter duration of action and have to be applied twice daily (e.g. formoterol, salmeterol). Still others (e. g. salbutamol, fenoterol) have to be applied three or four times a day for continuous action, which can also be an advantage for patients who need to apply β₂-agonists only occasionally, for example in an asthma attack.^[8]

 

History

On 29 January 2013 the U.S. Food and Drug Administration (FDA) Pulmonary-Allergy Drugs Advisory Committee (PADAC) recommended that the clinical data included in the new drug application (NDA) for olodaterol provide substantial evidence of safety and efficacy to support the approval of olodaterol as a once-daily maintenance bronchodilator treatment for airflow obstruction in patients with COPD.^[9]

On 18 October 2013 approval of olodaterol in the first three European countries – the United Kingdom, Denmark and Iceland – was announced by the manufacturer.^[10]

 

Figure  Chemical structures of salmeterol, formoterol, inda- caterol, and emerging once-daily long-acting β2-agonists

…………………………

WO 2004045618 or

http://www.google.com/patents/EP1562603B1?cl=en

Example

a)

• To a solution of 3.6 g 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine in 100 mL of ethanol at 70 ° C. 7.5 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one )-glyoxal added and allowed to stir for 15 minutes. Then within 30 minutes at 10 to 20 ° C. 1 g of sodium borohydride added. It is stirred for one hour, with 10 mL of acetone and stirred for another 30 minutes. The reaction mixture is diluted with 150 mL ethyl acetate, washed with water, dried with sodium sulfate and concentrated. The residue is dissolved in 50 mL of methanol and 100 mL ethyl acetate and acidified with conc. Hydrochloric acid. After addition of 100 mL of diethyl ether, the product precipitates. The crystals are filtered, washed and recrystallized from 50 mL of ethanol. Yield: 7 g (68%; hydrochloride), mp = 232-234 ° C.

b)

• 6.8 g of the above obtained benzyl compound in 125 mL of methanol with the addition of 1 g of palladium on carbon (5%) was hydrogenated at room temperature and normal pressure. The catalyst is filtered and the filtrate was freed from solvent. Recrystallization of the residue in 50 mL of acetone and a little water, a solid is obtained, which is filtered and washed.
  Yield: 5.0 g (89%; hydrochloride), mp = 155-160 ° C.
• The (R) – and (S)-enantiomers of Example 3 can be obtained from the racemate, for example, by chiral HPLC (for example, column: Chirobiotic T, 250 x 1.22 mm from the company Astec). As the mobile phase, methanol with 0.05% triethylamine and 0.05% acetic acid. Silica gel with a grain size of 5 microns, to which is covalently bound the glycoprotein teicoplanin can reach as column material used. Retention time (R enantiomer) = 40.1 min, retention time (S-enantiomer) = 45.9 min. The two enantiomers can be obtained by this method in the form of free bases. According to the invention of paramount importance is the R enantiomer of Example 3

 

 

………………………………………….

WO 2005111005

http://www.google.fm/patents/WO2005111005A1?cl=en

Scheme 1.

 

 

 

Scheme 1:

Example 1 6-Hydroxy-8-{(1-hydroxy-2-r2-(4-methoxy-phenyl) – 1, 1-dimethyl-ethylamino]-ethyl)-4H-benzor 41oxazin-3-one – Hvdrochlorid

 

a) l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone

To a solution of 81.5 g (0.34 mol) l-(5-benzyloxy-2-hydroxy-phenyl)-ethanone in 700 ml of acetic acid are added dropwise under cooling with ice bath, 18 mL of fuming nitric acid, the temperature does not exceed 20 ° C. increases. The reaction mixture is stirred for two hours at room temperature, poured onto ice water and filtered. The product is recrystallized from isopropanol, filtered off and washed with isopropanol and diisopropyl ether. Yield: 69.6 g (72%), mass spectroscopy [M + H] ⁺ = 288

b) l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone

69.5 g (242 mmol) of l-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone are dissolved in 1.4 L of methanol and in the presence of 14 g of rhodium on carbon (10%) as catalyst at 3 bar room temperature and hydrogenated. Then the catalyst is filtered off and the filtrate concentrated. The residue is reacted further without additional purification. Yield: 60.0 g (96%), R _{f value} = 0.45 (silica gel, dichloromethane).

c) 8-acetyl-6-benzyloxy-4H-benzoπ .4] oxazin-3-one

To 60.0 g (233 mmol) of l-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol) of potassium carbonate while cooling with ice bath, 21.0 ml (258 mmol) of chloroacetyl chloride added dropwise. Then stirred overnight at room temperature and then for 6 hours under reflux. The hot reaction mixture is filtered and then concentrated to about 400 mL and treated with ice water. The precipitate is filtered off, dried and purified by chromatography on a short silica gel column (dichloromethane: methanol = 99:1). The product-containing fractions are concentrated, suspended in isopropanol, diisopropyl ether, and extracted with

Diisopropyl ether. Yield: 34.6 g (50%), mass spectroscopy [M + H] ⁺ = 298

d) 6-Benzyloxy-8-(2-chloro-acetyl)-4H-benzoFl, 4] oxazin-3-one 13.8 g (46.0 mmol) of 8-benzyloxy-6-Acetyl-4H-benzo [l, 4] oxazin -3-one and 35.3 g (101.5 mmol) of benzyltrimethylammonium dichloriodat are stirred in 250 mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5 hours at 65 ° C. After cooling to room temperature, treated with 5% aqueous sodium hydrogen sulfite solution and stirred for 30 minutes. The precipitated solid is filtered off, washed with water and diethyl ether and dried. Yield: 13.2 g (86%), mass spectroscopy [M + H] ⁺ = 330/32.

e) 6-Benzyloxy-8-((R-2-chloro-l-hydroxy-ethyl)-4H-benzori ,41-oxazin-3-one The procedure is analogous to a procedure described in the literature (Org. Lett ., 2002, 4, 4373-4376).

To 13:15 g (39.6 mmol) of 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo [l, 4] oxazin-3-one and 25.5 mg (0:04 mmol) Cρ * RhCl [(S, S) -TsDPEN] (Cp * = pentamethylcyclopentadienyl and TsDPEN = (lS, 2S)-Np-toluenesulfonyl-l ,2-diphenylethylenediamine) in 40 mL of dimethylformamide at -15 ° C and 8 mL of a mixture of formic acid and triethylamine (molar ratio = 5: 2) dropwise. It is allowed for 5 hours at this temperature, stirring, then 25 mg of catalyst and stirred overnight at -15 ° C. The reaction mixture is mixed with ice water and filtered. The filter residue is dissolved in dichloromethane, dried with sodium sulfate and the solvent evaporated. The residue is recrystallized gel (dichloromethane / methanol gradient) and the product in diethyl ether / diisopropyl ether. Yield: 10.08 g (76%), R _f value = 00:28 (on silica gel, dichloromethane ethanol = 50:1).

f) 6-Benzyloxy-8-(R-oxiranyl-4H-benzo ^["L4] oxazin-3-one 6.10 g (30.1 mmol) of 6-benzyloxy-8-((R)-2-chloro-l-hydroxy- ethyl)-4H-benzo [l, 4] oxazin-3-one are dissolved in 200 mL of dimethylformamide. added to the solution at 0 ° C with 40 mL of a 2 molar sodium hydroxide solution and stirred at this temperature for 4 hours. the reaction mixture is poured onto ice water, stirred for 15 minutes, and then filtered The solid is washed with water and dried to give 8.60 g (96%), mass spectroscopy [M + H] ⁺ = 298..

g) 6-Benyloxy-8-{(R-l-hydroxy-2-r2-(4-methoxy-phenyl)-dimethyl-ll-ethvIaminol-ethyl)-4H-benzo-3-Tl A1oxazin

5.25 g (17.7 mmol) of 6-benzyloxy-8-(R)-oxiranyl-4H-benzo [l, 4] oxazin-3-one and 6.30 g (35.1 mmol) of 2 – (4-methoxy-phenyl 1, 1 – dimethyl-ethyl to be with 21 mL

Of isopropanol and stirred at 135 ° C for 30 minutes under microwave irradiation in a sealed reaction vessel. The solvent is distilled off and the residue chromatographed (alumina, ethyl acetate / methanol gradient). The product thus obtained is purified by recrystallization from a mixture further Diethylether/Diisopropylether-. Yield: 5:33 g (63%), mass spectroscopy [M + H] ⁺ = 477 h) 6-Hydroxy-8-{(R)-l-hydroxy-2-[2 - (4-methoxy-phenyl)-l, l-dimethyl-ethylamino] – ethyl}-4H-benzo [1, 4, 1 oxazin-3-one hydrochloride

A suspension of 5:33 g (11.2 mmol) of 6-Benyloxy-8-{(R)-l-hydroxy-2-[2 - (4-methoxy-phenyl)-l, l-dimethyl-ethylamino]-ethyl}-4H -benzo [l, 4] oxazin-3-one in 120 mL of methanol with 0.8 g of palladium on carbon (10%), heated to 50 ° C and hydrogenated at 3 bar hydrogen pressure. Then the catalyst is filtered off and the filtrate concentrated. The residue is dissolved in 20 mL of isopropanol, and 2.5 mL of 5 molar hydrochloric acid in isopropanol. The product is precipitated with 200 mL of diethyl ether, filtered off and dried. Yield: 4.50 g (95%, hydrochloride), mass spectroscopy [M + H] ⁺ = 387

 

………………………….

WO 2007020227

http://www.google.com.ar/patents/WO2007020227A1?cl=en

 

………………………………….

WO 2008090193

or

http://www.google.com/patents/EP2125759B1?cl=en

 

………………………….

Discovery of olodaterol, a novel inhaled beta(2)-adrenoceptor agonist with a 24h bronchodilatory efficacy
Bioorg Med Chem Lett 2010, 20(4): 1410

 http://www.sciencedirect.com/science/article/pii/S0960894X09018101

The discovery of the β₂-adrenoceptor agonist (R)-4p designated olodaterol is described. The preclinical profile of the compound suggests a bronchoprotective effect over 24 h in humans.

…………..

 

Australia

http://www.tga.gov.au/pdf/auspar/auspar-olodaterol-140327-pi.pdf

 

…………………………..

DUTCH

http://mri.medagencies.org/download/NL_H_2498_001_PAR.pdf

…………..

References

1. Striverdi UK Drug Information
2. Bouyssou, T.; Casarosa, P.; Naline, E.; Pestel, S.; Konetzki, I.; Devillier, P.; Schnapp, A. (2010). “Pharmacological Characterization of Olodaterol, a Novel Inhaled  2-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models”. Journal of Pharmacology and Experimental Therapeutics 334 (1): 53–62. doi:10.1124/jpet.110.167007. PMID 20371707. edit
3. Casarosa, P.; Kollak, I.; Kiechle, T.; Ostermann, A.; Schnapp, A.; Kiesling, R.; Pieper, M.; Sieger, P.; Gantner, F. (2011). “Functional and Biochemical Rationales for the 24-Hour-Long Duration of Action of Olodaterol”. Journal of Pharmacology and Experimental Therapeutics 337 (3): 600–609. doi:10.1124/jpet.111.179259. PMID 21357659. edit
4. Bouyssou, T.; Hoenke, C.; Rudolf, K.; Lustenberger, P.; Pestel, S.; Sieger, P.; Lotz, R.; Heine, C.; Büttner, F. H.; Schnapp, A.; Konetzki, I. (2010). “Discovery of olodaterol, a novel inhaled β2-adrenoceptor agonist with a 24h bronchodilatory efficacy”. Bioorganic & Medicinal Chemistry Letters 20 (4): 1410–1414. doi:10.1016/j.bmcl.2009.12.087. PMID 20096576. edit
5. Joos G, Aumann JL, Coeck C, et al. ATS 2012 Abstract: Comparison of 24-Hour FEV1 Profile for Once-Daily versus Twice-Daily Treatment with Olodaterol, A Novel Long-Acting ß2-Agonist, in Patients with COPD^{[dead link]}
6. Van Noord, J. A.; Smeets, J. J.; Drenth, B. M.; Rascher, J.; Pivovarova, A.; Hamilton, A. L.; Cornelissen, P. J. G. (2011). “24-hour Bronchodilation following a single dose of the novel β2-agonist olodaterol in COPD”. Pulmonary Pharmacology & Therapeutics 24 (6): 666–672. doi:10.1016/j.pupt.2011.07.006. PMID 21839850. edit
7. van Noord JA, Korducki L, Hamilton AL and Koker P. Four Weeks Once Daily Treatment with BI 1744 CL, a Novel Long-Acting ß2-Agonist, is Effective in COPD Patients. Am. J. Respir. Crit. Care Med. 2009; 179: A6183^{[dead link]}
8. Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
9. Hollis A (31 January 2013). “Panel Overwhelmingly Supports Boehringer COPD Drug Striverdi”. FDA News/Drug Industry Daily.
10. “New once-daily Striverdi (olodaterol) Respimat gains approval in first EU countries”. Boehringer-Ingelheim. 18 October 2013.

External links

• Striverdi package leaflet (UK)

 

 

WO2002030928A1	28 Sep 2001	11 Apr 2003	Boehringer Ingelheim Pharma	Crystalline monohydrate, method for producing the same and the use thereof in the production of a medicament
WO2003000265A1	8 Jun 2002	3 Jan 2003	Boehringer Ingelheim Pharma	Crystalline anticholinergic, method for its production, and use thereof in the production of a drug
WO2004045618A2 *	11 Nov 2003	3 Jun 2004	Boehringer Ingelheim Pharma	Novel medicaments for the treatment of chronic obstructive pulmonary diseases
EP0073505A1 *	28 Aug 1982	9 Mar 1983	Boehringer Ingelheim Kg	Benzo-heterocycles
EP0321864A2 *	15 Dec 1988	28 Jun 1989	Boehringer Ingelheim Kg	Ammonium compounds, their preparation and use
US4460581	12 Oct 1982	17 Jul 1984	Boehringer Ingelheim Kg	Antispasmodic agents, antiallergens
US4656168 *	13 Oct 1983	7 Apr 1987	Merck & Co., Inc.	Vision defects; adrenergic blocking and hypotensive agents

 

Organic spectroscopy should be brushed up and you get confidence

read my blog

Oleanolic acid spectral data and interpretation

Oleanolic acid
(4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid

Oleanic acid, Caryophyllin, Astrantiagenin C, Giganteumgenin C, Virgaureagenin B, 3beta-Hydroxyolean-12-en-28-oic acid, OLEANOLIC_ACID

Molecular Formula: C₃₀H₄₈O₃

Molecular Weight: 456.70032

http://orgspectroscopyint.blogspot.in/2014/08/oleanolic-acid-spectral-data-and.html

Ursolic acid [(3b)-3-Hydroxyurs-12-en-28-oic acid] rarely occurs without its isomer oleanolic acid [(3b)-3-Hydroxyolean-12-en-28-oic acid] They may occur in their free acid form, as shown in Figure 1, or as aglycones for triterpenoid saponins which are comprised of a triterpenoid aglycone linked to one or more sugar moieties. Ursolic and oleanolic acids are similar in pharmacological activity

A pentacyclic triterpene that occurs widely in many PLANTS as the free acid or the aglycone for many SAPONINS. It is biosynthesized from lupane. It can rearrange to the isomer, ursolic acid, or be oxidized to taraxasterol and amyrin.

MS
EIMS m/z (rel. int.) 456 [M]+ (5), 412 (3), 248 (100), 203 (50), 167 (25), 44 (51)

IR KBR
(KBr) 3500, 2950, 2850, 1715; 1H-NMR (250 MHz, pyridine-d5) δ: 5.49 (1H, s, H-12), 3.47 (1H, t, J = 8.0 Hz, H-3), 3.30 (1H, m, H-18), 1.12 (3H, s, CH3-27), 0.96 (3H, s, CH3-30), 0.91 (3H, s, CH3-25), 0.89 (3H, s, CH3-23), 0.87 (3H, s, CH3-24), 0.75 (3H, s, CH3-26)

http://orgspectroscopyint.blogspot.in/2014/08/oleanolic-acid-spectral-data-and.html

1H NMR

(250 MHz, pyridine-d5)δ: 5.49 (1H, s, H-12), 3.47 (1H, t, J = 8.0 Hz, H-3), 3.30 (1H, m, H-18), 1.12 (3H, s, CH3-27), 0.96 (3H, s, CH3-30), 0.91 (3H, s, CH3-25), 0.89 (3H, s, CH3-23), 0.87 (3H, s, CH3-24), 0.75 (3H, s, CH3-26)

13 C NMR

(63 MHz, pyridine-d5) δ: 180.2 (C-28), 144.8 (C-13), 122.5 (C-12), 78.0 (C-3), 55.7 (C-5), 48.0 (C-9), 46.6 (C-8, 17), 42.1 (C-14), 39.7 (C-4), 39.4 (C-1), 37.3 (C-10), 33.2 (C-7), 32.9 (C-29), 32.4 (C-21), 30.9 (C-20), 28.7 (C-23), 27.2 (C-2), 26.9 (C-15), 26.1 (C-30), 23.7 (C-11), 23.6 (C-16), 18.7 (C-6), 17.4 (C-26), 16.5 (C-24), 15.5 (C-25)

http://orgspectroscopyint.blogspot.in/2014/08/oleanolic-acid-spectral-data-and.html

http://www.google.com/patents/US20120237629

FIG. 4 shows the ¹H NMR spectrum of oleanolic acid;

FIG. 5 shows the ¹³C NMR spectrum of oleanolic acid;

FIG. 6 shows the ¹³C DEPT NMR spectrum of oleanolic acid;

FIG. 7 shows the ¹H ¹³C HSQC NMR spectrum of oleanolic acid;

see below

http://orgspectroscopyint.blogspot.in/2014/08/oleanolic-acid-spectral-data-and.html

EXAMPLE 2 Extraction and Isolation of Oleanolic Acid (9) and Maslinic Acid (10) from Cloves

Syzygium aromaticum dried buds or whole cloves were obtained commercially. The cloves (1.5 kg, whole) of Syzygium aromaticum were sequentially and exhaustively extracted with hexane and ethyl acetate to give, after solvent removal in vacuo, a hexane extract (68.8 g, 4.9%) and an ethyl acetate extract (34.1 g, 2.3%). A portion of the ethyl acetate extract (10.0 g), was subjected to chromatographic separation on silica gel (60-120 mesh) column (40×5.0 cm). Elution with hexane/ethyl acetate solvent mixtures (8:2→6:4) afforded pure oleanolic acid (9) (4.7 g, 1.06%), a mixture of oleanolic acid (9) and maslinic acid (10) (0.5 g), and pure maslinic acid (10) (0.25 g). The structures of oleanolic acid (9) and maslinic acid (10) (as 2,3-diacetoxyoleanolic acid) were confirmed by spectroscopic data analysis (1D and 2D ¹H NMR and ¹³C NMR experiments) (FIGS. 4-7 and FIGS. 8-10, respectively).

http://orgspectroscopyint.blogspot.in/2014/08/oleanolic-acid-spectral-data-and.html

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST ,  INDIA
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Travoprost

cas 157283-68-6

[1R-[lα(Z),2β(lE,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1 -butenyl]cyclopentyl]-5-heptenoic acid, 1 -methylethylester

(+)-16-m-trifluoromethylphenoxy tetranor Prostaglandin F_2α isopropyl ester; (+)-Fluprostenol ispopropyl ester

(+)-(5Z,9α,1α,13E,15R)-trihydroxy-16-(3-(trifluoromethyl)phenoxy)-17,18,19,20-tetranor-prosta-5,13-dien-1-oic acid, isopropyl ester

(+) – Fluprostenol isopropyl ester,

Alcon (Originator)

Antiglaucoma Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Prostaglandins, Prostanoid FP Agonists

Ophthalmic solution used for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another intraocular pressure lowering medication.

Travoprost free acid is a selective FP prostanoid receptor agonist and is believed to reduce intraocular pressure by increasing the drainage of aqueous humor, which is done primarily through increased uveoscleral outflow and to a lesser extent, trabecular outflow facility.

Travoprost, an isopropyl ester prodrug, is a synthetic prostaglandin F2 alpha analogue that is rapidly hydrolyzed by esterases in the cornea to its biologically active free acid. The travoporst free acid is potent and highly selective for the FP prostanoid receptor.

Travoprost ophthalmic solution is a topical medication used for controlling the progression of glaucoma or ocular hypertension, by reducing intraocular pressure. It is a synthetic prostaglandin analog (or more specifically, an analog of prostaglandin F_2α)^[1][2] that works by increasing the outflow of aqueous fluid from the eyes.^[3] It is also known by the brand names of Travatan and Travatan Z, manufactured by Alcon, and Travo-Z, manufactured by Micro Labs.

Travoprost is a synthetic prostaglandin F analogue. Its chemical name is [1R-[lα(Z),2β(lE,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)phenoxy]-1 -butenyl]cyclopentyl]-5-heptenoic acid, 1 -methylethylester. It has a molecular formula of C₂₆H₃₅F₃O₆ and a molecular weight of 500.55. The chemical structure of travoprost is:

Country	Patent Number	Approved	Expires (estimated)
Canada	2181172	2003-04-29	2015-12-19
Canada	2129287	2002-05-14	2014-08-02
United States	5631287	1994-12-22	2014-12-22
United States	6503497	1995-05-06	2012-05-06

Side effects

Possible side effects of this medication are:

• May cause blurred vision
• May cause eyelid redness
• May permanently darken eyelashes
• May cause eye discomfort
• May eventually cause permanent darkening of the iris to brown (heterochromia)
• May cause a temporary burning sensation during use
• May cause thickening of the eyelashes
• May cause inflammation of the prostate gland, restricting urine flow (BPH)

Travoprost

Systematic (IUPAC) name
propan-2-yl 7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl) phenoxy]-but-1-enyl]-cyclopentyl]hept-5-enoate
Clinical data
Trade names	Travatan
AHFS/Drugs.com	monograph
MedlinePlus	a602027
Pregnancy cat.	C US
Legal status	Rx only (US)
Routes	Topical (eye drops)
Identifiers
CAS number	157283-68-6
ATC code	S01EE04
PubChem	CID 5282226
DrugBank	DB00287
ChemSpider	4445407
UNII	WJ68R08KX9
Chemical data
Formula	C26H35F3O6
Mol. mass	500.548 g/mol

The condensation of 2- [3- (trifluoromethyl) phenoxy] acetyl chloride (I) with methylphosphonic acid dimethyl ester (II) by means of BuLi in THF gives 2-oxo-3- [3- (trifluoromethyl) phenoxy] propylphosphonic acid dimethyl ester (III), which is condensed with the known bicyclic aldehyde (IV) by means of BuLi in dimethoxyethane, yielding the unsaturated ketone (V). The reduction of (V) with zinc borohydride in dimethoxyethane affords the unsaturated alcohol (VI), which is treated with K2CO3 to give a diastereomeric mixture of unsaturated diols, resolved by chromatography to yield the chiral unsaturated diol (VII). The protection of (VII) with dihydropyran and TsOH in dichloromethane provides the bis (tetrahydropyranyl) ether (VIII), which by reduction of the lactone ring with diisobutylaluminum hydride in THF gives the lactol (IX). The condensation of (IX) with the phosphonium bromide (X) by means of NaH in DMSO yields the prostenoic acid (XI), which is esterified with isopropyl iodide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) in acetone to afford the corresponding isopropyl ester (XII). Finally, this compound is deprotected with acetic acid in hot THF / water.

http://www.chemdrug.com/databases/8_0_qkvreurfepijmjcf.html

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Org Process Res Dev2002,6, (2): 138

http://pubs.acs.org/doi/abs/10.1021/op010097p

A commercial synthesis of the antiglaucoma agent, travoprost 2, is described. A total of 22 synthetic steps are required to provide the single enantiomer prostanoid, with the longest linear sequence being 16 steps from 3-hydroxybenzotrifluoride. The route is based upon a cuprate-mediated coupling of the single enantiomer vinyl iodide 13 and the tricyclic ketone 5, of high stereochemical purity, to yield the single isomer bicyclic ketone 15. A Baeyer−Villiger oxidation provides the lactone 16 as a crystalline solid, thus limiting the need for chromatographic purification. DIBAL-H reduction, Wittig reaction, esterification, and silyl group deprotection complete the synthesis of travoprost.

 (5Z,13E)-(9S,11R,15R)-9,11,15-Trihydroxy-16-(m-trifluoromethylphenoxy-17,18,19,20-tetranor-5,13-prostadienoic Acid, Isopropyl Ester (2).

The silyl-protected compound (20a+b) (202 g, 277 mmol) ………..DELETED……………………………………… All relevant fractions were combined and concentrated to give the title compound 2 (97 g, 70%) as a colourless oil, +14.6 (c 1.0, CH₂Cl₂); IR ν_max (film) 3374 and 1727 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 7.39 (1H, t, J = 8), 7.22 (1H, d, J = 8), 7.15 (1H, s), 7.08 (1H, d, J = 8), 5.70 (2H, m), 5.40 (2H, m), 4.98 (1H, heptet, J = 6.5), 4.52 (1H, m), 4.18 (1H, m), 3.97 (3H, m), 3.25 (2H, br s), 2.60 (1H, br s), 2.38 (1H, m), 2.30−1.96 (7H, m), 1.76 (1H, dd, J = 16, 4), 1.65 (2H, quintet, J = 7), 1.55 (1H, m), and 1.20 (6H, d, J = 6); ¹³C NMR (100 MHz, CDCl₃) δ 173.57, 158.67, 135.45, 131.87 (q, J = 32), 130.02, 129.85, 129.75, 128.93, 123.89 (q, J = 270), 118.06, 117.82, 111.48, 77.77, 72.70, 71.99, 70.86, 67.72, 55.82, 50.24, 42.84, 34.00, 26.60, 25.48, 24.83, and 21.81; m/z (CI) 501 (MH⁺, 21), 321 (34), 303 (44), and 249 (100).

…………………………………………

http://www.google.com/patents/EP2495235A1?cl=en

• In the case of Travoprost, compound 9 with A=3-(trifluoromethyl)phenoxy (in the following scheme, compound 9b) is converted into 10b, which in turn is converted into Travoprost by esterification of the carboxylic acid by reaction with 2-iodopropane, according to scheme 10:

……………………………

http://www.google.com/patents/EP2454227A1?cl=en

Example 2

Synthesis of Travoprost MTBE MTBE

C

7b

8b

9b-iso

Travoprost Scheme 4. Synthesis of Travoprost

References

More References:

Selective FP prostaglandin receptor agonist. Isopropyl ester of (+)-fluprostenol, q.v. General prepn (not claimed): J. W. Stjernschantz, EP 364417 (1989 to Pharmacia).

Large scale synthesis: L. T. Boulton et al., Org. Process Res. Dev. 6, 138 (2002).

Pharmacology: M. R. Hellberg et al., J. Ocul. Pharmacol. Ther. 17, 421 (2001).

LC/MS/MS determn in plasma: B. A. McCue et al., J. Pharm. Biomed. Anal. 28, 199 (2002). Ocular hypotensive effects in dogs: A. B. Carvalho et al., Vet. Ophthalmol. 9, 121 (2006).

Clinical trial in glaucoma or ocular hypertension: R. L. Fellman et al., Ophthalmology 109, 998 (2002); in combination with timolol: J. S. Schuman et al., Am. J. Ophthalmol. 140, 242-250 (2005).

• Ota T, Aihara M, Narumiya S, Araie M: The effects of prostaglandin analogues on IOP in prostanoid FP-receptor-deficient mice. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4159-63. PubMed: 16249494

• Thieme H, Schimmat C, Munzer G, Boxberger M, Fromm M, Pfeiffer N, Rosenthal R: Endothelin antagonism: effects of FP receptor agonists prostaglandin F2alpha and fluprostenol on trabecular meshwork contractility. Invest Ophthalmol Vis Sci. 2006 Mar;47(3):938-45. PubMed: 16505027

• Lim KS, Nau CB, O’Byrne MM, Hodge DO, Toris CB, McLaren JW, Johnson DH: Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects. A crossover study. Ophthalmology. 2008 May;115(5):790-795.e4. PubMed: 18452763

• Neacsu AM: [Receptors involved in the mechanism of action of topical prostaglandines] Oftalmologia. 2009;53(2):3-7. PubMed: 19697832

• Costagliola C, dell’Omo R, Romano MR, Rinaldi M, Zeppa L, Parmeggiani F: Pharmacotherapy of intraocular pressure – part II. Carbonic anhydrase inhibitors, prostaglandin analogues and prostamides. Expert Opin Pharmacother. 2009 Dec;10(17):2859-70. PubMed: 19929706

• Ferrari G, Scagliotti GV: Serum and urinary vascular endothelial growth factor levels in non-small cell lung cancer patients. Eur J Cancer. 1996 Dec;32A(13):2368-9. PubMed: 9038626

• Toris CB, Gabelt BT, Kaufman PL: Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction. Surv Ophthalmol. 2008 Nov;53 Suppl1:S107-20. PubMed: 19038618

• Arranz-Marquez E, Teus MA: Prostanoids for the management of glaucoma. Expert Opin Drug Saf. 2008 Nov;7(6):801-8. PubMed: 18983226

• Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. PubMed: 11752352

Latanoprost

isopropyl-(Z)7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate.

130209-82-4

XA41, PhXA34 [as 15 (R, S) -isomer], PhXA41, Xalatan

(Zanoni, G. et al., Tetrahedron 2010, 66, 7472)

Latanoprost (pronounced la-TA-noe-prost) ophthalmic solution is a medication administered into the eyes to control the progression of glaucoma or ocular hypertension by reducing intraocular pressure. It is a prostaglandin analogue (more specifically an analogue ofprostaglandin F_2α^[1]) that lowers the pressure by increasing the outflow of aqueous fluid from the eyes through the uvealsclearal tract.^[2] Latanoprost is an isopropyl ester prodrug, meaning it is inactive until it is hydrolyzed by esterases in the cornea to the biologically active acid.^[3]

It is also known by the brand name of Xalatan manufactured by Pfizer. Annual sales are approximately $1.6 billion. The patent for latanoprost expired in March 2011, and at least one generic version (manufactured by Mylan Inc.) is now widely available in the U.S. The Veterans Health Administration, part of the U.S. Department of Veterans Affairs, uses generic Latanoprost manufactured by Alcon Laboratories of Fort Worth, Texas distributed by Novartis generic brand Sandoz Pharmaceuticals.

Latanoprost was invented by Johan W. Stjernschantz and Bahram Resul, employees of the Pharmacia Corporation of Upsalla, Sweden.^[4]

It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.^[5]

Latanoprost

Systematic (IUPAC) name
isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2- [(3R)3-hydroxy-5-phenylpentyl]-cyclopentyl] hept-5-enoate
Clinical data
Trade names	Xalatan
AHFS/Drugs.com	monograph
MedlinePlus	a697003
Pregnancy cat.	C (US)
Legal status	℞-only (US)
Routes	Topical (eye drops)
Pharmacokinetic data
Half-life	17 minutes
Identifiers
CAS number	130209-82-4
ATC code	S01EE01
PubChem	CID 5311221
IUPHAR ligand	1961
DrugBank	DB00654
ChemSpider	4470740
UNII	6Z5B6HVF6O
KEGG	D00356
ChEBI	CHEBI:6384
ChEMBL	CHEMBL1051
Chemical data
Formula	C26H40O5
Mol. mass	432.593 g/mol

 

Medical uses

Ocular hypertension

• In well-controlled clinical trials including patients with open-angle glaucoma or ocular hypertension (IOP ≥21 mm Hg), monotherapy with latanoprost reduced IOP levels by 22 to 39% over 1 to 12 months’ treatment. Latanoprost was significantly more effective than timolol 0.5% twice daily in 3 of 4 large (n = 163 to 267) randomised, double-blind trials. Latanoprost demonstrated a stable long-term IOP-lowering effect in 1- or 2-year continuations of these trials, with no sign of diminishing effect during prolonged treatment.^[6]

• Meta analysis suggests that latanoprost is more effective than timolol in lowering IOP. However, it often causes iris pigmentation. While current evidence suggests that this pigmentation is benign, careful lifetime evaluation of patients is still justified.^[7]

Closed-angle glaucoma

• Patients who had elevated IOP despite iridotomy and/or iridectomy (including patients of Asian descent), latanoprost was significantly more effective than timolol in two double-blind, monotherapy trials (8.2 and 8.8 mm Hg vs 5.2 and 5.7 mm Hg for latanoprost vs timolol at 12 and 2 weeks, respectively).^[8]

Method of administration

One drop in the affected eye(s) once daily in the evening; do not exceed the once daily dosage because it has been shown that more frequent administration may decrease the intraocular-pressure (IOP) lowering effect^[2]

Adverse effects[

Listed from most to least common:

• >5% to 15%: Blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris causing (heterochromia), punctate epithelial keratopathy
• 4%: Cold or upper respiratory tract infections, flu-like syndrome
• 1-4%: Dry eyes, excessive tearing, eye pain, lid crusting, lid edema, lid erythema (hyperemia), lid pain, photophobia (light intolerance)
• 1 % – 2%: Chest pain, allergic skin reactions, arthralgia, back pain, myalgia, thickening of the eyelashes.(used,also bimatoprost,in cosmetic industry as eyelash growth enhancers)
• <1% (Limited to important or life-threatening): Asthma, herpes keratitis, iritis, keratitis, retinal artery embolus, retinal detachment, toxic epidermal necrolysis, uveitis, vitreous hemorrhage from diabetic retinopathy
• A single case report links latanoprost use to the progression of keratoconus.^[9]

Concerns related to adverse effects:

• Bacterial keratitis: Inadvertent contamination of multiple-dose ophthalmic solutions, has caused bacterial keratitis.
• Ocular effects: May permanently change/increase brown pigmentation of the iris, the eyelid skin, and eyelashes. In addition, may increase the length and/or number of eyelashes (may vary between eyes); changes occur slowly and may not be noticeable for months or years. Long-term consequences and potential injury to eye are not known.
• Ocular disease: Use with caution in patients with intraocular inflammation, aphakic patients, pseudophakic patients with a torn posterior lens capsule, or patients with risk factors for macular edema. Safety and efficacy have not been determined for use in patients with angle-closure-, inflammatory-, or neovascular glaucoma.

Special populations

Contact lens wearers: Contains benzalkonium chloride which may be absorbed by contact lenses; remove contacts prior to administration and wait 15 minutes before reinserting

Contraindications

Hypersensitivity to latanoprost, benzalkonium chloride, or any component of the formulation

Drug Interactions

Bimatoprost: The concomitant use of Latanoprost and Bimatoprost may result in increased intraocular pressure. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Risk C: Monitor therapy

Pregnancy

Prescription of Latanoprost is limited in human studies due to high incidence of abortion shown in animal experiments. Because of this, Latanoprost is classified as Risk factor C (Adverse events were observed in animal reproduction studies at maternally toxic doses)according to United States Food and Drug Administration’s use-in-pregnancy ratings.^[10]Lactation Excretion in breast milk unknown/use caution. Breast-Feeding Considerations It is not known if latanoprost is excreted in breast milk. The manufacturer recommends that caution be exercised when administering latanoprost to nursing women.^[2]

Storage

Latanoprost is a substance exhibiting thermal and solar instability. Concentration of latanoprost will decrease by 10% when stored at 50 and 70 degrees Celsius every 8.25 and 1.32 days respectively. Reaction with ultraviolet radiation will cause rapid degradation of Latanoprost. It is therefor important to store Latanoprost ideally in temperature below room temperature and free from sunlight in order to attain acceptable drug quality. ^[11]

Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. Its molecular formula is C₂₆H₄₀O₅and its chemical structure is:

http://www.google.com/patents/EP2495235A1?cl=en

When Latanoprost is the desired product the double bond on the side chain of compound 9a is hydrogenated to form compound 11, then by Wittig reaction with 4-carboxybutyltriphenylphosphonium bromide compound 11 is converted into Latanoprost acid 12. By conversion of the carboxylic acid into isopropyl ester, the final product Latanoprost is obtained:

……………………………….

http://www.google.com/patents/EP2454227A1?cl=en

Example 3

Synthesis of Latanoprost

ether MTBE

8c-iso

Latanoprost

Scheme 5. Synthesis of Latanoprost

Synthesis of Latanoprost from 12c:

As shown in Scheme 5 in Example 3, a 250 ml.3-necked round-bottom flask equipped with a magnetic bar, a temperature probe, rubber septa, and a nitrogen gas inlet was charged at room temperature with 7.3 g (19.6 mmol) of deprotected lactone 12c in 70 mL of 2-propanol and 1.6 g (39.2 mmol) of sodium hydride, 60%, in mineral oil. The reaction mixture was heated at 35 ⁰C for 18 h and TLC analysis indicated complete reaction. The mixture was diluted with 60 mL of water and the pH was adjusted to 6 with 1 N HCI. The layers were separated and the aqueous layer was back extracted with 40 mL of 2-propanol four times. The combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, filtered, and concentrated.

The material was dissolved in 60 mL of THF, 5.0 mL (33.3 mmol) of DBU and 3.3 mL (33.3 mmol) of iodopropane. The reaction mixture was stirred at room temperature for 18 h and TLC analysis indicated complete reaction. The mixture was diluted with 60 mL of ethyl acetate and 60 mL of water. The layers were separated and the aqueous layer was back extracted with 40 mL of ethyl acetate for two times. The combined organic layers were washed with 50 mL of brine, dried over sodium sulfate, filtered, and concentrated.

The material was purified by using reverse phase biotage, 70 : 30 ACN :

H₂O to obtain 4.1 g (49% yield) of Latanoprost, confirmed by ¹H NMR.

………………….

Wittig condensation of lactol (XIII) with (carboxybutyl) triphenylphosphonium bromide (XV) in the presence of potassium tert-butoxide produced the Z-olefin (XVI). Conversion of carboxylic acid (XVI) to the title isopropyl ester was then accomplished by alkylation with 2-iodopropane in the presence of DBU.

http://www.chemdrug.com/databases/8_0_xmmatmlqjiethrwn.html

………………………………

http://www.nature.com/nature/journal/v489/n7415/full/nature11411.html?WT.ec_id=NATURE-20120913

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http://brsmblog.com/?p=1525

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http://www.google.com/patents/WO2013186550A1?cl=en

(la) (Ic)

Example 6 – Experimental procedures for the synthesis of latanoprost

A synthesis of latanoprost is shown and described below.

latanoprost (77)

2-Phenethyloxirane, 61

m-CPBA,

A modified procedure of Woodward was used (Bernier, D. et al., The Journal of Organic Chemistry 2008, 73, 4229). A stirred solution of 4-phenyl-l-butene 62 (500 mg, 568 μΙ, 3.78 mmol) in CH₂CI₂ (20 ml) was cooled to 0 °C. m-CPBA (816 mg, 4.73 mmol) was added as a solid and the reaction mixture was stirred at 0 °C for 1.5 h, then r.t. for 24 h. The reaction mixture was poured into saturated K₂C0₃ solution (50 ml) and extracted with CH₂CI₂ (2 x 50 ml). The combined organic phases were washed with saturated K₂C0₃ solution (50 ml) before being dried (MgS0₄), filtered and concentrated to give a clear colourless liquid. This material was purified by column chromatography, eluting with petrol/EtOAc (9:1), to give the epoxide 61 (10.2 g, 91%) as a clear colourless liquid. The ¹³C, and IR data were consistent with the literature (Mitchell, J. M. et al., Journal of the American Chemical Society 2001, 123, 862; Elings, J. A. et al., European Journal of Organic Chemistry 1999, 1999, 837).

R_f = 0.42 (petrol :EtOAc, 9:1) v_max (neatycnrr¹ 3027, 2989, 2922, 2859, 1602, 1495, 1454, 1410, 835, 750, 699

*H NMR (400 MHz; CDCI₃) δ_Η = 1.83-1.99 (2 H, m, CH₂), 2.53 (1 H, dd, J = 5.0, 2.7 Hz, CHH), 2.75-2.93 (2 H, m, CH₂), 2.80 (1 H, dd, J = 5.0, 4.0 Hz, CHH), 3.01 (1 H, dddd, J = 6.5, 5.0, 4.0, 2.7 Hz, CH), 7.22-7.38 (5 H, m, Ar H’s)

1³C NMR (100 MHz; CDCI₃) 5_C = 32.2 (CH₂), 34.2 (CH₂), 47.2 (CH₂), 51.7 (CH), 126.0 (2 x ArCH), 128.3 (2 x ArCH), 128.4 (ArCH), 141.2 (ArC)

m/z (EI) 148.1 (M⁺, 10%), 130.1 (23%), 129.0 (18%), 118.1 (29%), 117.1 (83%), 115.0 (28%), 105.0 (22%), 104.0 (61%), 92.0 (22%), 91.0 (100%), 83.9 (37%), 77.0 (17%), 65.0 (31%)

(2S)-2-Phenethyloxirane, 63

A modified procedure of Jacobsen was used (Schaus, S. E. et al., Journal of the American Chemical Society 2002, 224, 1307). Racemic epoxide 61 (10.0 g, 67.5 mmol) was dissolved in THF (10 ml) and stirred at r.t.. (S^-i+J-^A/’-BisiS^-di-tert-butylsalicylidene)-!^- cyclohexanediaminocobalt(II) (204 mg, 0.34 mmol) was added and the resultant dark brown solution cooled to 0 °C. Acetic acid (77 μΙ, 1.35 mmol) and water (669 μΙ, 37.1 mmol) were added. The reaction was stirred at 0 °C for 1 h and then at r.t. for 23 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (~200 g silica), eluting with petrol/EtOAc (9:1), to give the epoxide 3 as a dark red liquid. This was re- purified by column chromatography eluting with petrol/EtOAc (9.5:0.5 to 9:1), to give the epoxide 3 (4.62 g, 46%) as an orange liquid. The analytical data matched that of the racemic material described above. The enantioselectivity of the resolution was determined after subsequent conversion to the allylic alcohol 66. The optical rotation matched closely with that reported in the literature (Martynow, J. G. et al., European Journal of Organic Chemistry 2007, 2007, 689).

[a]_D ²¹ -21.0 (c. 1.0, CHC ) (lit., [a]_D ²⁰ -22.5 (c. 1.0, CHCI₃)) 5-Phenyl-l-penten-3-ol, 64

A modified procedure of Molander was used (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297). A stirred solution of hydrocinnamaldehyde 65 (2.50 g, 2.45 ml, 18.6 mmol) in THF (25 ml) was cooled to -78 °C. Vinyl magnesium bromide solution (1 M in THF) (22.4 ml, 22.4 mmol) was added dropwise over ~ 5 min. The reaction mixture was stirred at -78 °C for 1.5 h, then 0 °C for 3 h. The reaction mixture was poured into saturated NH₄CI solution (50 ml) and extracted with Et₂0 (3 x 50 ml). The combined organic phases were washed with saturated NaCI solution (50 ml) before being dried (MgS0₄), filtered and concentrated to give a pale yellow liquid. This material was purified by column

chromatography, eluting with petrol/EtOAc (9: 1), to give the vinyl alcohol 64 (1.89 g, 63%) as a clear colourless liquid. The *H, ¹³C, and IR data were consistent with the literature (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297; Kim, J. W. et al., Chemistry – A European Journal 2008, 24, 4104). R_f = 0.40 (petrol :EtOAc, 4: 1)

max (CHC Vcnrr¹ 3335, 3026, 2923, 2859, 1496, 1454, 990, 922, 747, 698

*H NMR (400 MHz; CDCI₃) δ_Η = 1.55 (1 H, br.s, OH), 1.84-1.99 (2 H, m, CH₂), 2.70-2.89 (2 H, m, CH₂), 4.19 (1 H, app q, J = 6.0 Hz, CHO ), 5.20 (1 H, app dt, J = 10.5, 1.4 Hz, HC=C), 5.30 (1 H, app dt, J = 17.1, 1.4 Hz, HHC=C), 5.96 (1 H, ddd, J = 17.1, 10.5, 6.0 Hz, H₂C=CH), 7.20-7.40 (5 H, m, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = 31.6 (CH₂), 38.5 (CH₂), 72.4 (HCOH), 114.9 (H₂C=C), 125.8 (ArCH), 128.4 (2 x ArCH), 128.4 (2 x ArCH), 141.0 (H₂C=Q, 141.8 (ArC)

m/z (EI) 162.1 (M⁺, 30%), 144.1 (52%), 129.1 (72%), 105.1 (68%), 92.1 (71%), 91.0 (100%), 57.0 (61%) 6D. (3S)-5-Phenyl-l-penten-3-ol, 66

A modified procedure of Falck was used (Alcaraz, L. et al., Tetrahedron Letters 1994, 35, 5449). A suspension of trimethylsulfonium iodide (18.2 g, 89.1 mmol) in anhydrous THF (220 ml) was stirred and cooled to -20 °C. 1.6 M n-BuLi (55.7 ml, 89.1 mmol) was added slowly and the reaction stirred at -20 °C for 1 h. A solution of epoxide 63 (4.40 g, 29.7 mmol) in anhydrous THF (50.0 ml) was added slowly. The reaction was stirred at -20 °C for 1 h and then allowed to warm to r.t. slowly. The reaction mixture was poured into water (200 ml) and extracted with Et₂0 (1 x 200 ml, 1 x 100 ml). The combined organic phases were washed with saturated NaCI solution (100 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified by column chromatography (130 g silica), eluting with petrol/EtOAc (9:1), to give partially purified material. This was re-purified by column chromatography (50 g silica), eluting with petrol/EtOAc (9:1), to give allylic alcohol 66 (3.19 g, 66%) as a pale yellow liquid. The analytical data matched that described for the racemic material above.

[α]ο²¹ -11.0 (c. 1.0, CHCI₃) (lit – Kanbayashi, N. et al., Angewandte Chemie International Edition 2011, 50, 5197, [a]_D ²⁵ -3.6 (for 85% ee (c. 0.4, CHCI₃)))

Chiral-HPLC data: er = >99:1 (Chiralcel AD-H column, 210 nm, hexane/2-propanol: 98/2, flow rate: 0.5 mlVmin, room temperature; ¾: minor 41.0 min, major 43.7 min) 6E. tert-Butyl(dimethyl)[(lS)-l-phenethyl-2-propenyl]oxysilane, 67

67 A stirred solution of allylic alcohol 66 (3.00 g, 18.5 mmol) in CH₂CI₂ (53 ml) was cooled to 0 °C. Imidazole (2.27 g, 33.3 mmol) was added in one portion followed by t- butylchlorodimethylsilane (3.34 g, 22.2 mmol). The cooling bath was removed and the reaction mixture stirred at r.t. for 16 h before being poured into 10% aq. HCI (100 ml). The mixture was extracted with 40/60 petroleum ether (2 x 100 ml). The combined organics were washed with saturated NaCI solution (100 ml), dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified by column chromatography, eluting with 40/60 petroleum ether, to give the protected alcohol 67 (4.68 g, 92%) as a colourless liquid. The *H NMR data and optical rotation matched that reported in the literature (Uenishi, J. i. et al., Organic Letters 2011, 13, 2350).

R_f = 0.25 (40/60 petroleum ether)

v_max (film)/cm-¹3064, 3027, 2952, 2929, 2886, 2856, 1497, 1472, 1462, 1455, 1361, 1251, 1122, 1083, 1030, 990, 921, 834, 774, 697

*H NMR (400 MHz; CDCI₃) δ_Η = 0.05 (3 H, s, SiCH₃), 0.08 (3 H, s, SiCH₃), 0.93 (9 H, s, C(CH₃)₃), 1.82 (2 H, m, CH₂), 2.66 (2 H, m, CH₂), 4.17 (1 H, m, OCH), 5.08 (1 H, ddd, J = 10.4, 1.5, 1.3 Hz, HA =CH), 5.19 (1 H, app dt, J = 17.2, 1.5 Hz, HHC=CH), 5.86 (1 H, ddd, J = 17.2, 10.4, 6.0 Hz, H₂C=CH), 7.18 (3 H, m, ArH’s), 7.28 (2 H, m, ArH’s)

1³C NMR (100 MHz; CDCI₃) 5_C = -4.8 (SiCH₃), -4.3 (SiCH₃), 18.3 (C(CH₃)₃), 25.9 (C(CH₃)₃), 31.5 (CH₂), 39.8 (CH₂), 73.3 (CHOSi), 114.0 (H₂C=C), 125.7 (ArCH), 128.3 (2 x ArCH), 128.4 (2 x ArCH), 141.4 (H₂C=Q, 142.5 (ArC).

[a]_D” 12.0 (c. 1.0, CHCI₃) (lit., [a]_D ²⁰ 14.5 (c. 1.0, CHCI₃)) 6F. (3S)-3-[l-(tert-Butyl)-l,l-dimethylsilyl]oxy-5-phenylpentan-l-ol, 68

67

A modified procedure of Denmark was used (Denmark, S. E. et al., Organic Letters 2005, 7, 5617). Compound 67 (2.00 g, 7.23 mmol) was added to a flame dried schlenk flask under N₂. 9-BBN (0.5 M in THF) (15.9 ml, 7.96 mmol) was added via syringe and the resulting solution stirred at r.t. for 1 h. A further 1.1 eq. (15.9 ml, 7.96 mmol) of 9-BBN was added and the reaction stirred at r.t. for 2 h. Water (16.0 ml) and NaB0₃.4H₂0 (5.56 g, 36.2 mmol) were added and the reaction stirred at r.t. for 2 h. The reaction mixture was poured into saturated NH₄CI solution (60 ml) and extracted with Et₂0 (3 x 100 ml). The combined organic phases were washed with sat. NaCI solution (100 ml), dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified 3 times by column chromatography (twice eluting with petrol/EtOAc (6:1) and once with petrol/ EtOAc/Eti⁾ (9:0.5:0.5)) to give the alcohol 68 (672 mg, 32%) as a clear colourless oil.

R_f = 0.18 (petrol :EtOAc, 9:1)

v_max (film)/cm-¹3351 (broad), 3063, 2950, 2928, 2885, 2856, 1496, 1471, 1462, 1454, 1360, 1253, 1092, 1057, 1028, 1005, 834, 773, 746, 698

*H NMR (400 MHz; CDCI₃) δ_Η = 0.09 (3 H, s, SiCH₃), 0.10 (3 H, s, SiCH₃), 0.92 (9 H, s, C(CH₃)₃), 1.75 (1 H, m, CHH), 1.83-1.94 (3 H, m, CH₂, CHH), 2.32 (1 H, app t, J = 5.2 Hz, OH), 2.64 (2 H, m, CH₂), 3.75 (1 H, app dq, J = 10.8, 5.5 Hz, OCHH), 3.87 (1 H, app ddt, J = 10.8, 8.1, 4.8 Hz, OCHtf), 3.99 (1 H, app qd, J = 6.1, 4.4 Hz, HCOTBDMS), 7.16-7.23 (3 H, m, ArCH’s), 7.27-7.33 (2 H, m, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = -4.7 (SiCH₃), -4.4 (SiCH₃), 18.0 (C(CH₃)₃), 25.8 (C(CH₃)₃), 31.7 (CH₂), 37.8 (CH₂), 38.7 (CH₂), 60.1 (CH₂), 71.2 (SiOCH), 125.8 (ArCH), 128.2 (2 x ArCH), 128.4 (2 x ArCH), 142.1 (ArC)

HRMS (ESI) calcd for Ci₇H₃₀O₂SiNa [MNa⁺] 317.1907, found 317.1906

[a]_D ²³ 23.0 (c. 1.0, CHCI₃) 6G. tert-Butyl[(lS)-3-iodo-l-phenethylpropyl]oxydimethylsilane, 69

68 A modified procedure of Rychnovsky was used (Dalgard, J. E. et al., Organic Letters 2004, 6, 2713). Alcohol 68 (600 mg, 2.04 mmol) was added to a flame dried schlenk flask under N₂. CH₂CI₂ (10 ml) was added via syringe and the resulting solution stirred at r.t..

Triphenylphosphine (695 mg, 2.65 mmol) and imidazole (222 mg, 3.26 mmol) were added as solids in one portion. Iodine (672 mg, 2.65 mmol) was added to the resulting solution. A slight exotherm was noted and the solution changed from a light yellow colour to a brown colour with the formation of a precipitate. The reaction was stirred at r.t. for 1 h. The reaction mixture was dry loaded onto silica (2 g) and purified by column chromatography (14 g silica), eluting with petrol to petrol/EtOAc (9: 1). This gave the iodide 69 (725 mg, 88%) as a clear, colourless oil.

R_f = 0.20 (40/60 petroleum ether)

ifiln /cnr^OeS, 3026, 2951, 2928, 2886, 2856, 1495, 1471, 1461, 1360, 1253, 1187, 1165, 1140, 1092, 1063, 1005, 975, 931, 833, 773, 697

*H NMR (400 MHz; CDCI₃) δ_Η = 0.09 (3 H, s, SiCH₃), 0.10 (3 H, s, SiCH₃), 0.92 (9 H, s, (C(CH₃)₃), 1.79 (2 H, m, CH₂), 2.05 (2 H, m, CH₂), 2.64 (2 H, m, CH₂), 3.24 (2 H, m, CH₂), 3.82 (1 H, quin., J = 5.7 Hz, OCH), 7.16-7.23 (3 H, m, ArCH’s), 7.27-7.33 (2 H, m, ArCH’s) ¹³C NMR (100 MHz; CDCI₃) 5_C = -4.3 (SiCH₃), -4.3 (SiCH₃), 3.0 (CH₂), 18.1 (C(CH₃)₃), 25.9 (C(CH₃)₃), 31.3 (CH₂), 38.7 (CH₂), 40.8 (CH₂), 71.7 (OCH), 125.8 (ArCH), 128.3 (2 x ArCH), 128.4 (2 x ArCH), 142.1 (ArC)

HRMS (ESI) calcd for Ci₇H₃₀OSiI [MH⁺] 405.1108, found 405.1105

[a]_D ²³ 26.0 (c. 1.0, CHCI₃)

6H. [(lR)-3-((3aR,4R,6aS)-2-Methoxy-5-(£)-l-[(l,l,l- trimethylsilyl)oxy]methylideneperhydrocyclopenta[d]furan-4-yl)-l- phenethylpropyl]oxy(tert-butyl)dimethylsilane, 70

70 Iodide 69 (1.32 g, 3.27 mmol, 1.1 eq.) was added via syringe to a flame dried schlenk flask (evacuated and purged with nitrogen several times and allowed to cool). Anhydrous Et₂0 (13.3 ml) was added via syringe and the resulting solution cooled to -78 °C. 1.63 M t-BuLi (4.01 ml, 6.54 mmol, 2.2 eq.) was added dropwise and the reaction mixture stirred at -78 °C for 2 h and -40 °C for 2 h before being cooled back to -78 °C. Meanwhile, thiophene (275 mg, 262 μΙ, 3.27 mmol, 1.1 eq.) was added via syringe to a flame dried schlenk flask (evacuated and purged with nitrogen several times and allowed to cool). Anhydrous THF (13.3 ml) was added via syringe and the resulting solution cooled to -30 °C. 1.63 M n-BuLi (2.01 ml, 3.27 mmol, 1.1 eq.) was added dropwise and the solution stirred at -30 °C for 30 min. CuCN (293 mg, 3.27 mmol, 1.1 eq.) was added as a solid, in one portion. The cooling bath was removed and the suspension allowed to warm to r.t. The resulting tan/brown solution of cuprate was added dropwise via syringe to the schlenk flask containing the alkyl lithium and anhydrous THF (13.3 ml) added. The mixture was stirred at -20 °C for 1 h to allow formation of mixed cuprate 71. This was cooled to -78 °C and a solution of enal 24 (500 mg, 2.97 mmol, 1.0 eq.) in anhydrous THF (13.3 ml) was added dropwise. The mixture was stirred at -78 °C for 1 h and then allowed to warm slowly to -20 °C. TMSCI (1.61 g, 1.89 ml, 14.9 mmol, 5.0 eq.) was added via syringe followed by NEt₃ (1.80 g, 2.49 ml, 17.8 mmol, 6 eq.). The reaction was quenched by the addition of saturated NH₄CI solution (50 ml) and extracted with Et₂0 (3 x 50 ml). The combined organic phases were washed with saturated NH₄CI solution (50 ml) and saturated NaCI solution (50 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude material as a yellow oil. This was used directly in the next step.

61. (3aR 4R,5R,6aS)-4-((3R)-3-[l-(tert-Butyl)-l,l-dimethylsilyl]oxy-5- phenylpentyl)-2-methoxyperhydrocyclopenta[d]furan-5-ol, 73

70 73 The crude material from the conjugate addition / trapping experiment, containing 70, was dissolved in CH₂Cl2/MeOH (3: 1) (30 ml) and cooled to -78 °C. A stream of ozone was passed through the stirred solution. The reaction was monitored periodically by TLC in order to judge completion of the ozonolysis (judged by consumption of silyl enol ether). The reaction mixture was flushed with a stream of N₂, for 15 min, to remove excess 0₃. NaBH₄ (202 mg, 5.35 mmol) was added in one portion. The reaction mixture was stirred at -78 °C for 2 h before the cooling bath was removed and the reaction allowed to warm to r.t.. The reaction was stirred at r.t. for 1 h. NaBH₄ (67.4 mg, 1.78 mmol) was added and the reaction stirred at r.t. for a further 15 min. The reaction mixture was poured into saturated NaCI solution (25 ml) and extracted with EtOAc (3 x 25 ml). The combined organic phases were dried (MgS0₄), filtered, and concentrated to give the crude product as a pale yellow oil. This was purified by column chromatography on silica, eluting with petrol/EtOAc (4: 1), giving the alcohol 73 (as an approximately 2:1 mixture of diastereoisomers) as a clear, colourless oil (800 mg, 62% (2 steps from enal 24)).

R_f = 0.23 (petrol :EtOAc, 4:1)

v_max (neatycnrr¹ 3434 (broad), 3026, 2928, 2856, 1496, 1471, 1454, 1360, 1343, 1254, 1098, 1053, 1004, 937, 833, 773, 698

¹H NMR (400 MHz; CDCI₃) 5H = (mixture of 2 diastereoisomers, signals of minor diastereoisomer indicated by *) 0.05 (3 H, s, CH₃), 0.06* (3 H, s, CH₃), 0.07 (3 H, s, CH₃), 0.07* (3 H, s, CH₃), 0.91 (9 H, s, C(CH₃)₃), 0.92* (9 H, s, C(CH₃)₃), 1.12-1.80 (7 H, m), 1.12- 1.80* (7 H, m), 1.90-2.38 (5 H, m), 1.90-2.38* (5 H, m), 2.53-2.75 (2 H, m, CH₂), 2.53-2.75* (2 H, m, CH₂), 3.32 (3 H, s, OCH₃), 3.39* (3 H, s, OCH₃), 3.72 (1 H, m, CHOTBDMS), 3.72* (1 H, m, CHOTBDMS), 3.79* (1 H, m, CHOH), 3.89 (1 H, m, CHOH), 4.55 (1 H, app td, J = 6.3, 2.5 Hz, CH), 4.64* (1 H, app td, J = 6.8, 2.7 Hz, CH), 5.06* (1 H, d, J = 5.5 Hz, OCHO), 5.11 (1 H, d, J = 4.9 Hz, OCHO), 7.19 (3 H, m, ArCH’s), 7.19* (3 H, m, ArCH’s), 7.29 (2 H, m, ArCH’s), 7.29* (2 H, m, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = (observed signals, mixture of 2 diastereoisomers) -4.42 (SiCH₃), -4.41 (SiCH₃), -4.33 (SiCH₃), 18.1 (2 x C(CH₃)₃), 25.9 (2 x C(CH₃)₃), 29.3 (CH₂), 30.3 (CH₂), 31.7 (CH₂), 35.1 (CH₂), 38.8 (CH₂), 39.9 (CH₂), 40.0 (CH₂), 41.1 (CH₂), 42.7 (CH₂),

46.5, 47.2, 54.4, 55.1, 55.3, 55.7, 71.8, 71.8, 79.3, 79.7, 82.5, 85.8, 106.5 (OCHOCH₃), 108.0 (OCHOCH₃), 125.7 (ArCH), 125.7 (ArCH), 128.3 (4 x ArCH), 128.3 (4 x ArCH), 142.6 (ArC), 142.6 (ArC). One SiCH₃ and three CH₂‘s could not be assigned due to overlapping signals. 6J. (3aR,4R,5R,6aS)-4-[(3R)-3-Hydroxy-5- phenylpentyl]perhydrocyclopenta[b]furan-2,5-diol, 74

Alcohol 73 (400 mg, 0.920 mmol) was stirred with 1.5% aqueous HQ / THF (3:2) (18 ml) at r.t. for 16 h. The mixture was neutralised with 1 M NaOH and extracted with CH₂CI₂ (5 x 30 ml). The combined organic phases were dried (MgS0₄), filtered, and concentrated to give the triol 74 and silanol by-product as a clear, colourless oil (~400 mg). This material was taken forward for the subsequent transformation without purification.

(4-Carboxybutyl)(triphenyl)phosphonium bromide 29 (2.45 g, 5.52 mmol) was added to a flame dried schlenk flask, under N₂, and anhydrous THF (20.0 ml) added. The resulting suspension was cooled to 0 °C. KOt-Bu (1.24 g, 11.0 mmol) was added in one portion and the resulting orange mixture stirred at 0 °C for 40 min. A solution of crude triol 74 (282 mg, 0.920 mmol) in anhydrous THF (5.0 ml) was added dropwise via syringe. After complete addition the cooling bath was removed and the mixture was stirred at r.t. for 1.5 h. The reaction was quenched with H₂0 (30 ml) and washed with Et₂0 (2 x 30 ml) to remove triphenylphosphine oxide. The aqueous phase was made acidic with 1 M HQ (~10 ml) and extracted with CH₂CI₂ (5 x 25 ml). The combined organic phases were dried (MgS0₄), filtered, and concentrated to give the crude material as solids. These were placed on a sinter funnel and washed with petrol/EtOAc (1: 1) (4 x 20 ml) and then EtOAc (2 x 40 ml). The filtrate was concentrated under vacuum and purified by column chromatography on silica, eluting with CH₂Cl2/MeOH (9.5:0.5 to 9:1) to give acid 75 (163 mg, 45% over 2 steps from alcohol 73) as a clear, colourless oil. The *Η data and optical rotation were consistent with the literature (Martynow, J. G. et al., European Journal of Organic Chemistry 2007, 2007, 689).

R_f = 0.27 (CH₂CI₂:MeOH, 9:1)

v_max (neatycnrr¹ 3338 (broad), 2930, 2857, 1704, 1452, 1407, 1254, 1028, 747, 699, 636 *H NMR (400 MHz; CDCI₃) δ_Η = 1.39 (2 H, m, CH₂), 1.47-1.97 (10 H, m, 4 x CH₂, 2 x CH), 2.07-2.48 (6 H, m, 3 x CH₂), 2.67 (1 H, m, CH ), 2.80 (1 H, m, CH/-/), 3.60-4.85 (6 H, broad signal, 2 x OCH, 3 x OH, COOH), 3.72 (1 H, m, OCH), 5.40 (1 H, m, =CH), 5.49 (1 H, m, =CH), 7.15-7.24 (3 H, m, ArCH’s), 7.25-7.32 (2 H, m, ArCH’s)

[a]_D ²⁴ 29.0 (c. 1.0, MeOH) (lit, [a]_D ²⁰ 29.7 (c. 1.0, MeOH)) 6L. Isopropyl (Z)-7-(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5- phenylpentyl]cyclopentyl-5-heptenoate, latanoprost, 77

A modified procedure of Zanoni and Vidari was used (Zanoni, G. et al., Tetrahedron 2010, 66, 7472). Carboxylic acid 75 (100 mg, 0.256 mmol) was dissolved in DMF (2.0 ml) and stirred at r.t.. Cs₂C0₃ (125 mg, 0.384 mmol) was added in one portion followed by 2- iodopropane (51 μΙ, 0.512 mmol). The reaction was stirred at r.t. for 18 h. The reaction mixture was poured into 3% citric acid solution (10 ml) and extracted with TBME (4 x 10 ml). The combined organic phases were washed with 10% NaHC0₃ solution (10 ml) and saturated NaCI (2 x 10 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude product as a clear, colourless oil (95 mg). This was purified by column chromatography (3 g silica), eluting with petrol/EtOAc (2: 1 to 1:2), to give latanoprost 77 (71 mg, 64 %) as a clear colourless oil. The IR, ¹³C, and optical rotation data were consistent with the literature (Zanoni, G. et al., Tetrahedron 2010, 66, 7472). R_f = 0.44 (EtOAc)

v_max (neatVcm^“1 3360 (broad), 2980, 2931, 2857, 1712, 1495, 1454, 1374, 1311, 1247, 1180, 1106, 1030, 966, 910, 820, 731, 699

*H NMR (400 MHz; CDCI₃) δ_Η = 1.23 (6 H, d, J = 6.4 Hz, 2 x CH₃), 1.30-1.90, (14 H, m, 5 x CH₂, 2 x CH, 2 x OH), 2.07-2.39 (6 H, m, 3 x CH₂), 2.45 (1 H, d, J = 5.5 Hz, OH), 2.63- 2.86 (2 H, m, CH₂), 3.68 (1 H, br.s, CHO ), 3.95 (1 H, br.s, CHOH), 4.18 (1 H, br.s, CHO ), 5.01 (1 H, sept., J = 6.4 Hz, OCH(CH₃)₂), 5.35-5.52 (2 H, m, 2 x =CH), 7.16-7.24 (3 H, m, ArH’s), 7.25-7.32 (2 H, m, ArH’s)

¹³C NMR (125 MHz; CDCI₃) 5_C = 21.9 (2 x CH₃), 24.9 (CH₂), 26.6 (CH₂), 26.8 (CH₂), 29.6 (CH₂), 32.1 (CH₂), 34.0 (CH₂), 35.7 (CH₂), 39.0 (CH₂), 42.5 (CH₂), 51.8 (CH), 52.7 (CH), 67.6 (OCH), 71.2 (OCH), 74.5 (OCH), 78.6 (OCH), 125.7 (CH), 128.3 (2 x ArCH), 128.3 (2 x ArCH), 129.3 (CH), 129.5 (CH), 141.1 (ArC), 173.5 (C=0)

[a]_D ²³ 33.0 (c. 1.0, MeCN) (lit, [a]_D ²⁰ 32.7 (c. 1.0, MeCN))

References

External links

• LATANOPROST solution [Greenstone LLC] (Nov 2011), Daily Med, U.S. National Library of Medicine, National Institutes of Health

Gemeprost, SC-37681, Ono-802, Cergem, Preglandin, Cervagem,

(E) -7 – [(1R, 2R, 3R-3-Hydroxy-2 – [(E) - (3R) -3-hydroxy-4,4-dimethyl-1-octenyl] -5-oxocyclopentyl] -2 -heptenoic acid methyl ester;

16,16-Dimethyl-DELTA2-trans-PGE1 methyl ester;

9-Oxo-11alpha, 15alpha-dihydroxy-16,16-dimethyl-2-trans, 13-trans-prostadiene-1-oic acid

Gemeprost (16, 16-dimethyl-trans-delta2 PGE₁ methyl ester) is an analogue of prostaglandin E₁.

Clinical use

It is used as a treatment for obstetric bleeding.

It is used with mifepristone to terminate pregnancy up to 24 weeks gestation. ^[1]

Side effects

Vaginal bleeding, cramps, nausea, vomiting, loose stools or diarrhea, headache, muscle weakness; dizziness; flushing; chills; backache; dyspnoea; chest pain; palpitations and mild pyrexia. Rare: Uterine rupture, severe hypotension, coronary spasms with subsequent myocardial infarctions

Gemeprost

Systematic (IUPAC) name
methyl (2E,11α,13E,15R)-11,15-dihydroxy-16,16-dimethyl-9-oxoprosta-2,13-dien-1-oate
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	?
Routes	Pessary
Identifiers
CAS number	64318-79-2
ATC code	G02AD03
PubChem	CID 5282237
ChemSpider	4445416
UNII	45KZB1FOLS
KEGG	D02073
Synonyms	methyl (E)-7-[(1R,2S,3R)-3-hydroxy-2-[(E,3R)-3-hydroxy-4,4-dimethyl-oct-1-enyl]-5-oxo-cyclopentyl]hept-2-enoate
Chemical data
Formula	C23H38O5
Mol. mass	394.545 g/mol

………………………………

http://www.chemdrug.com/databases/8_0_oqxuqtwlqgeukaaa.html

The reaction of 3-bromopropionic acid (I) with triphenylphosphine (II) in refluxing acetonitrile gives (2-carboxyethyl) -triphenylphosphonium bromide (III), which by a Wittig reaction with 2-oxa-3-hydroxy-6-syn- ( 3alpha-tetrahydropyranyloxy-4,4-dimethyl-1-trans-octen-1-yl) -7-anti-tetrahydropyranyloxybicyclo- [3.3.0] cis-octane (IV) (prepared according to reference 2) by means of sodium dimethylsulfinate in DMSO yields 9alpha-hydroxy-11alpha, 15alpha-bis (tetrahydropyranyloxy) -16,16-dimethyl-alpha-dinorprosta-5-cis-13-trans-dienoic acid (V). The reduction of (V) with H2 over Pd / C in methanol affords the 13-trans-prostenoic acid (VI), which is methylated with CH2N2 in ether yielding the methyl ester (VII). The reduction of (VII) with diisobutyl aluminum hydride in toluene affords the corresponding aldehyde (VIII) , which by a Wittig reaction with triethyl phosphonoacetate (IX) by means of NaH in THF is converted into 9alpha-hydroxy-11alpha, 15alpha-bis (tetrahydropyranyloxy) -16,16-dimethylprosta-2-trans-dienoic acid ethyl ester (X .) The hydrolysis of the ester (X) with KOH in ethanol-water gives the corresponding acid (XI), which is oxidized with CrO3, MnSO4 and H2SO4 in ether – water yielding the protected ketoacid (XII) The hydrolysis of (XII. ) with acetic acid-water at 80 C gives 9-oxo-11alpha, 15alpha-dihydroxy-16,16-dimethyl-prosta-2-trans-13-trans-dienoic acid (16,16-dimethyl-DELTA2-trans-PGE1 ) (XIII), which is finally methylated with CH2N2 in ether

References

1.  Bartley J, Brown A, Elton R, Baird DT (October 2001). “Double-blind randomized trial of mifepristone in combination with vaginal gemeprost or misoprostol for induction of abortion up to 63 days gestation”. Human reproduction (Oxford, England) 16 (10): 2098–102.doi:10.1093/humrep/16.10.2098. PMID 11574498. Retrieved 2008-10-29.

: Gemeprost CAS  64318-79-2 CAS Name: (2E,11a,13E,15R)-11,15-Dihydroxy-16,16-dimethyl-9-oxoprosta-2,13-dien-1-oic acid methyl ester Additional Names: 16,16-dimethyl-trans-D2-PGE1 methyl ester Manufacturers’ Codes: ONO-802 Trademarks: Cergem (Searle); Cervagem(e) (M & B); Preglandin (Ono) Molecular Formula: C23H38O5 Molecular Weight: 394.54 Percent Composition: C 70.02%, H 9.71%, O 20.28% Literature References: Analog of prostaglandin E1, q.v. Prepn: M. Hayashi et al., DE 2700021; eidem, US 4052512 (both 1977 to Ono); H. Suga et al., Prostaglandins 15, 907 (1978). Effects on uterine contractility and steroid hormone plasma levels: K. Oshimaet al., J. Reprod. Fertil. 55, 353 (1979). Effects on reproductive function: K. Matsumoto et al., Nippon Yakurigaku Zasshi 79, 15 (1982), C.A. 96, 98392 (1982). Use in termination of first trimester pregnancy: O. Reiertsen et al., Prostaglandins Leukotrienes Med. 8, 31 (1982). Therap-Cat: Abortifacient; oxytocic. Keywords: Abortifacient/Interceptive; Oxytocic; Prostaglandin/Prostaglandin Analog

NS 398

N-[2-(Cyclohexyloxy)-4-nitrophenyl]methanesulfonamide

Taisho (Originator)

Taisho Pharmaceutical Co. Ltd

N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.

123653-11-2, 123653-43-0 (Ca salt), 123653-44-1 (Na salt)

Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Cyclooxygenase-2 Inhibitors

NS-398 is a COX-2 inhibitor used in the study of the function of cyclooxygenases.^[2]

Selective cyclooxygenase-2 inhibitor (IC₅₀ values are 3.8 and > 100 μM for COX-2 and COX-1 respectively). Orally active. Anti-inflammatory, anti-pyretic, analgesic and non-ulcerogenic in vivo. Induces apoptosis and cell cycle arrest

Cyclooxygenase (COX-2) has been recently suggested to play a role in hepatocarcinogenesis. However, the exact pathway by which COX-2 affects the growth of hepatocellular carcinoma (HCC) is not clear. This study investigated the effects of a specific COX-2 inhibitor, NS-398, on the cell proliferation and apoptosis of COX-2-expressing and non-expressing HCC cell lines.

In addition, the modulatory effect of NS-398 on apoptosis-regulating gene expression was examined. Semi-quantitative/quantitative reverse transcription-polymerase chain reaction and Western blot showed that Hep3B and HKCI-4 cells expressed COX-2 mRNA and protein, but HepG2 cells did not. NS-398 suppressed cell proliferation and induced apoptosis in the two COX-2-expressing cell lines in a dose-dependent manner, but not in HepG2 cells.

Fas ligand mRNA and protein expression were increased by the treatment with NS-398 (10 micro M) in COX-2-expressing cell lines. The expressions of Fas and Bcl-2 family genes (Bax, Bcl-2, Bcl-xL, Bcl-xS) were not affected by NS-398 treatment in all three cell lines. In conclusion, specific COX-2 inhibitor suppresses cell proliferation and induces apoptosis in HCC cell lines that express COX-2. Our finding suggests that COX-2 inhibition may offer a new approach for HCC chemoprevention.

IUPAC name N-[2-(Cyclohexyloxy)-4-nitrophenyl]methanesulfonamide
Identifiers
CAS number	123653-11-2
PubChem	4553
Jmol-3D images	Image 1
SMILES [show]
Properties
Molecular formula	C13H18N2O5S
Molar mass	314.36 g mol−1
Appearance	Off-white solid
Solubility in water	Insoluble
Solubility in DMSO	5 mg/mL
Hazards
S-phrases	S22 S24/25

The condensation of 2-fluoronitrobenzene (I) with cyclohexanol (II) by means of NaH gives 2-(cyclohexyloxy)nitrobenzene (III), which is reduced with H2 over Pd/C in methanol yielding 2-(cyclohexyloxy)aniline (IV). The acylation of (IV) with methanesulfonyl chloride (V) in pyridine affords N-(2-cyclohexyloxy phenyl)methanesulfonamide (VI), which is finally nitrated with concentrated HNO3 in hot acetic acid.

EP 0317332

http://www.google.com/patents/EP0317332A2?cl=en

Example 1
• [0045]
  (1) To 40 ml of a dioxane suspension containing 0.92 g of 60% sodium hydride was added 2.5 ml of cyclo­hexanol at room temperature over a 15-minute period, and the mixture was stirred at the same temperature for 1 hour and then at 50°C for 3.5 hours. The temperature of the reaction solution was returned to room temperature, 10 ml of a dioxane containing 3.2 g of 2-fluoro­nitrobenzene was added dropwise, and the mixture was stirred at room temperature overnight. The dioxane was evaporated, the residue was extracted with chloroform, and the chloroform layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was evaporated to give an oil, which was then distilled under reduced pressure to give 3.8 g of 2-cyclohexyloxy­nitrobenzene.
  b.p. 130 – 134°C/0.5 – 0.7 mmHg
• [0046]
  (2) Fifty ml of a methanol solution containing 3.7 g of 2-cyclohexyloxynitrobenzene and 0.2 g of 5% palladium on carbon was stirred at room temperature under a hydrogen atmosphere for catalytic reduction. The catalyst was removed by filtration, and the filtrate was evaporated off to give 2.9 g of 2-cyclo­hexyloxyaniline as pale brown crystals.
  m.p. 55 – 56°C
• [0047]
  (3) To 20 ml of a pyridine solution containing 2.7 g of 2-cyclohexyloxyaniline was added dropwise 1.8 g of methanesulfonyl chloride under ice cooling with stir­ring. After completion of the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and made acidic with dilute hydrochloric acid. The crystals which formed were collected by filtration, washed with water and dried to give 3.8 g of the crude crystals, which were then recrystallized from ethanol-n hexane to give 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide.
  m.p. 113 – 115°C
• [0048]
  (4) To 20 ml of an acetic acid solution containing 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide was added dropwise 1.5 g of 61% nitric acid on heating at 110°C over a 30-minute period, and then the mixture was stirred for 1 hour. The reaction solution was poured into ice water and neutralized with a dilute aqueous sodium hydroxide solution. The crystals which formed were collected by filtration, washed with water and dried to give 4.5 g of the crude crystals, which were then recrystallized from ethanol-n-hexane to give 3.3 g of N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide.
  m.p. 136 – 137°C

The cortical collecting duct (CCD) is a major site of intrarenal prostaglandin E₂ (PGE₂) synthesis. This study examines the expression and regulation of the prostaglandin synthesizing enzymes cyclooxygenase-1 (COX-1) and -2 in the CCD. By indirect immunofluorescence using isoform-specific antibodies, COX-1 and -2 immunoreactivity was localized to all cell types of the murine M-1 CCD cell line. By immunohistochemistry, both COX-1 and COX-2 were localized to intercalated cells of the CCD on paraffin-embedded mouse kidney sections. When COX enzyme activity was measured in the M-1 cells, both indomethacin (COX-1 and -2 inhibitor) and the specific COX-2 inhibitor NS-398 effectively blocked PGE₂ synthesis. These results demonstrate that COX-2 is the major contributor to the pool of PGE₂synthesized by the CCD. By Western blot analysis, COX-2 expression was significantly upregulated by incubation with either indomethacin or NS-398. These drugs did not affect COX-1 protein expression. Evaluation of COX-2 mRNA expression by Northern blot analysis after NS-398 treatment demonstrated that the COX-2 protein upregulation occurred independently of any change in COX-2 mRNA expression. These studies have for the first time localized COX-2 to the CCD and provided evidence that the intercalated cells of the CCD express both COX-1 and COX-2. The results also demonstrate that constitutively expressed COX-2 is the major COX isoform contributing to PGE₂synthesis by the M-1 CCD cell line. Inhibition of COX-2 activity in the M-1 cell line results in an upregulation of COX-2 protein expression.

http://jasn.asnjournals.org/content/10/11/2261.abstract
…………………………………………….

NS398 inhibits the growth of OSCC cells by mechanisms that are dependent and independent of suppression of PGE₂ synthesis. Molecular targeting of COX-2, PGE₂ synthase, or PGE₂ receptors may be useful as a chemopreventive or therapeutic strategy for oral cancer.

http://clincancerres.aacrjournals.org/content/9/5/1885.full

…………………………………

References

Empagliflozin

For synthesis see http://newdrugapprovals.org/2013/12/19/empagliflozin/

August 1, 2014

The U.S. Food and Drug Administration today approved Jardiance (empagliflozin) tablets as an addition to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Type 2 diabetes affects approximately 26 million people and accounts for more than 90 percent of diabetes cases diagnosed in the United States. Over time, high blood sugar levels can increase the risk for serious complications, including heart disease, blindness, and nerve and kidney damage.

“Jardiance provides an additional treatment option for the care of patients with type 2 diabetes,” said Curtis J. Rosebraugh, M.D., M.P.H., director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “It can be used alone or added to existing treatment regimens to control blood sugar levels in the overall management of diabetes.”

Jardiance is a sodium glucose co-transporter 2 (SGLT2) inhibitor. It works by blocking the reabsorption of glucose (blood sugar) by the kidney, increasing glucose excretion, and lowering blood glucose levels in diabetics who have elevated blood glucose levels. The drug’s safety and effectiveness were evaluated in seven clinical trials with 4,480 patients with type 2 diabetes receiving Jardiance. The pivotal trials showed that Jardiance improved hemoglobin A1c levels (a measure of blood sugar control) compared to placebo.

Jardiance has been studied as a stand-alone therapy and in combination with other type 2 diabetes therapies including metformin, sulfonylureas, pioglitazone, and insulin. Jardiance should not be used: to treat people with type 1 diabetes; in those who have increased ketones in their blood or urine (diabetic ketoacidosis); and in those with severe renal impairment, end stage renal disease, or in patients on dialysis.

The FDA is requiring four postmarketing studies for Jardiance:

• Completion of an ongoing cardiovascular outcomes trial.
• A pediatric pharmacokinetic/pharmacodynamic study.
• A pediatric safety and efficacy study. As part of the safety and efficacy study, the effect on bone health and development will be evaluated.
• A nonclinical (animal) juvenile toxicity study with a particular focus on renal development, bone development, and growth.

Jardiance can cause dehydration, leading to a drop in blood pressure (hypotension) that can result in dizziness and/or fainting and a decline in renal function. The elderly, patients with impaired renal function, and patients on diuretics to treat other conditions appeared to be more susceptible to this risk.

The most common side effects of Jardiance are urinary tract infections and female genital infections.

Jardiance is distributed by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

synthesis see http://newdrugapprovals.org/2013/12/19/empagliflozin/

Human glucosidase, prepro-α-[199-arginine,223-histidine] ^[1]

Alglucosidase alfa

C₄₄₃₅H₆₇₃₉N₁₁₇₅O₁₂₇₉S₃₂

105270.8020

August 1, 2014

The U.S. Food and Drug Administration today announced the approval of Lumizyme (alglucosidase alfa) for treatment of patients with infantile-onset Pompe disease, including patients who are less than 8 years of age. In addition, the Risk Evaluation and Mitigation Strategy (REMS) known as the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program is being eliminated.

Pompe disease is a rare genetic disorder and occurs in an estimated 1 in every 40,000 to 300,000 births. Its primary symptom is heart and skeletal muscle weakness, progressing to respiratory weakness and death from respiratory failure.

The disease causes gene mutations to prevent the body from making enough of the functional form of an enzyme called acid alpha-glucosidase (GAA). This enzyme is necessary for proper muscle functioning. GAA is used by the heart and muscle cells to convert a form of sugar called glycogen into energy. Without the enzyme action, glycogen builds up in the cells and, ultimately, weakens the heart and muscles. Lumizyme is believed to work by replacing the deficient GAA, thereby reducing the accumulated glycogen in heart and skeletal muscle cells.

Lumizyme, a lysosomal glycogen-specific enzyme, was approved by the FDA in 2010 with a REMS to restrict its use to treatment of patients with late (non-infantile) onset Pompe disease who are 8 years of age and older. The REMS was required to mitigate the potential risk of rapid disease progression in the infantile-onset Pompe disease patients and patients with late  onset disease less than 8 years of age, and to communicate the risks of anaphylaxis, severe allergic reactions and severe skin and systemic immune mediated reactions to prescribers and patients.

At the time of Lumizyme’s approval, there were insufficient data to support the safety and efficacy of Lumizyme in the infantile-onset Pompe population, so Lumizyme was approved for use only in late onset Pompe disease patients who are at least 8 years of age. Pompe patients with infantile-onset disease and patients younger than 8 years of age continued treatment with Myozyme, which was already approved. Myozyme and Lumizyme, both manufactured by Genzyme Corporation, are produced from the same cell line at different production scales.

This approval provides access to Lumizyme for all Pompe disease patients, regardless of their age.

The FDA reviewed newly available information and determined that Lumizyme and Myozyme are chemically and biochemically comparable. Consequently, the safety and effectiveness of Lumizyme and Myozyme are expected to be comparable. In addition, a single-center clinical study of 18 infantile-onset Pompe disease patients, aged 0.2 to 5.8 months at the time of first infusion, provides further support that infantile-onset patients treated with Lumizyme will have a similar improvement in ventilator-free survival as those treated with Myozyme.

Because data were submitted supporting approval of Lumizyme for all Pompe patients, a REMS restricting its use to a specific age group is no longer necessary. While the risk of anaphylaxis, severe allergic reactions, and severe cutaneous and immune mediated reactions for Lumizyme still exist, these risks are comparable to Myozyme and are communicated in labeling through the Warnings and Precautions, and a Boxed Warning.

“REMS continue to be vital tools for the agency to employ as we work with companies to address the serious risks associated with drugs and monitor their appropriate and safe use in various health care settings,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “The agency remains committed to exercising a flexible and responsible regulatory approach that ensures REMS programs are being effectively and efficiently used and not resulting in an unnecessary burden on health care professionals and patients.”

Health care professionals and patients should also be aware:

• The Warnings and Precautions section of the Lumizyme product label and the Clinical Studies section of the Lumizyme label have been updated to include the safety information of the drug in infantile-onset Pompe disease patients. This includes information from the currently approved Myozyme label and information from a new, uncontrolled study in which patients with infantile onset disease were treated with Lumizyme.
• Lumizyme is approved with a Boxed Warning because of the risk of anaphylaxis, severe allergic reactions, immune-mediated reactions and cardiorespiratory failure.
• Health care professionals should continue to refer to the drug prescribing information for the latest recommendations on prescribing Lumizyme and report adverse events to the FDA’s MedWatch program (http://www.fda.gov/Safety/MedWatch/default.htm).
• Distribution of Lumizyme will no longer be restricted. Health care professionals, healthcare facilities, and patients will no longer be required to enroll in the Lumizyme REMS program (Lumizyme ACE Program) to be able to prescribe, dispense, or receive Lumizyme.

The most commonly reported side effects for Lumizyme were infusion-related reactions and included severe allergic reactions, hives, diarrhea, vomiting, shortness of breath, itchy skin, skin rash, neck pain, partial hearing loss, flushing, pain in extremities, and chest discomfort.

Myozyme and Lumizyme are marketed by Cambridge, Massachusetts-based Genzyme.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

>Alglucosidase alfa
AHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGAQMGQPWCFF
PPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLHFTIKDPANR
RYEVPLETPHVHSRAPSPLYSVEFSEEPFGVIVRRQLDGRVLLNTTVAPLFFADQFLQLS
TSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLALEDGGSAHG
VFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYWGL
GFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAMVQ
ELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKVWPGSTAFPD
FTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELENPPYVPGVVG
GTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPFVISRSTFAGHGRY
AGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVRWTQLGAFYP
FMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVARPLFL
EFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPVEALGSLPPP
PAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAVALTK
GGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKVTVLGV
ATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC

Systematic (IUPAC) name
Human glucosidase, prepro-α-[199-arginine,223-histidine] [1]
Clinical data
AHFS/Drugs.com	monograph
Legal status	FDA approved for children[2]
Routes	Intravenous[2]
Identifiers
CAS number	420794-05-0
ATC code	A16AB07
DrugBank	DB01272
UNII	DTI67O9503
KEGG	D03207
Chemical data
Formula	C4758H7262N1274O1369S35[1]
Mol. mass	105338 [1]

Alglucosidase alfa (Lumizyme, Myozyme, Genzyme) is an enzyme replacement therapy (ERT) orphan drug for treatment of Pompe disease (Glycogen storage disease type II), a rare lysosomal storage disorder (LSD).^[3] Chemically speaking, the drug is ananalog of the enzyme that is deficient in patients affected by Pompe disease, alpha-glucosidase. It is the first drug available to treat this disease.^[2]

Status

Orphan drug pharmaceutical company, Genzyme, markets alglucosidase alfa as “Myozyme”. In 2006, the U.S. Food and Drug Administration (FDA) approved Myozyme as a suitable ERT treatment for children.^[2] Some health plans have refused to subsidize Myozyme for adult patients because it lacks approval for treatment in adults, as well as its high cost (US$300,000/yr for life).^[4]

On August 1, 2014 the U.S. Food and Drug Administration announced the approval of Lumizyme (alglucosidase alfa) for treatment of patients with infantile-onset Pompe disease, including patients who are less than 8 years of age. In addition, the Risk Evaluation and Mitigation Strategy (REMS) known as the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program is being eliminated. ^[5]

Side effects

Common observed adverse reactions to alglucosidase alfa treatment are pneumonia, respiratory complications, infections and fever. More serious reactions reported includeheart and lung failure and allergic shock. Myozyme boxes carry warnings regarding the possibility of life-threatening allergic response.^[2]

References

External links

• Myozyme (alglucosidase alfa), Genzyme official website
• MTAP (Myozyme Temporary Access Program), Genzyme official website

MYOZYME (alglucosidase alfa), a lysosomal glycogen-specific enzyme, consists of the human enzyme acid α-glucosidase (GAA), encoded by the most predominant of nine observed haplotypes of this gene. MYOZYME is produced by recombinant DNA technology in a Chinese hamster ovary cell line. The MYOZYME manufacturing process differs from that for LUMIZYME®, resulting in differences in some product attributes. Alglucosidase alfa degrades glycogen by catalyzing the hydrolysis of α-1,4- and α-1,6- glycosidic linkages of lysosomal glycogen.

Alglucosidase alfa is a glycoprotein with a calculated mass of 99,377 daltons for the polypeptide chain, and a total mass of approximately 110 kilo Daltons, including carbohydrates. Alglucosidase alfa has a specific activity of 3 to 5 U/mg (one unit is defined as that amount of activity that results in the hydrolysis of 1 μmole of synthetic substrate per minute under the specified assay conditions). MYOZYME is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, white to off-white, lyophilized cake or powder for reconstitution with 10.3 mL

Sterile Water for Injection, USP. Each 50 mg vial contains 52.5 mg alglucosidase alfa, 210 mg mannitol, 0.5 mg polysorbate 80, 9.9 mg sodium phosphate dibasic heptahydrate, 31.2 mg sodium phosphate monobasic monohydrate. Following reconstitution as directed, each vial contains 10.5 mL reconstituted solution and a total extractable volume of 10 mL at 5.0 mg/mL alglucosidase alfa. MYOZYME does not contain preservatives; each vial is for single use only.

Lenvatinib

For the treatment of patients with progressive radioiodine-refractory, differentiated thyroid cancer (RR-DTC).

European regulators have agreed to undertake an accelerated assessment of Eisai’s lenvatinib as a treatment for progressive radioiodine-refractory, differentiated thyroid cancer.

The drug, which carries Orphan Status in the EU, is to be filed “imminently” and could become the first in a new class of tyrosine kinase inhibitors, the drugmaker said.

Read more at: http://www.pharmatimes.com/Article/14-07-31/Eisai_s_lenvatinib_to_get_speedy_review_in_Europe.aspx#ixzz39OGhRHas

Lenvatinib was granted Orphan Drug Designation for thyroid cancer by the health authorities in Japan in 2012, and in Europe and the U.S in 2013. The first application for marketing authorization of lenvatinib in the world was submitted in Japan on June 2014. Eisai is planning to submit applications for marketing authorization in Europe and the U.S. in the second quarter of fiscal 2014.

Lenvatinib is an oral multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor receptors (VEGFR), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor receptors (FGFR), the platelet-derived growth factor (PDGF) receptor PDGFRalpha, KIT and RET that are involved in tumor proliferation. This potentially makes lenvatinib a first-in-class treatment, especially given that it simultaneously inhibits the kinase activities of FGFR as well as VEGFR.

Systematic (IUPAC) name
4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carboxamide
Clinical data
Legal status	℞ Prescription only
Identifiers
CAS number
ATC code	None
PubChem	CID 9823820
ChemSpider	7999567
UNII	EE083865G2
Chemical data
Formula	C21H19ClN4O4
Mol. mass	426.853 g/mol

Lenvatinib (E7080) is a multi-kinase inhibitor that is being investigated for the treatment of various types of cancer by Eisai Co. It inhibits both VEGFR2 and VEGFR3 kinases.^[1]

The substence was granted orphan drug status for the treatment of various types of thyroid cancer that do not respond toradioiodine; in the US and Japan in 2012 and in Europe in 2013^[2] and is now approved for this use.

Clinical trials

Lenvatinib has had promising results from a phase I clinical trial in 2006^[3] and is being tested in several phase II trials as of October 2011, for example against hepatocellular carcinoma.^[4] After a phase II trial testing the treatment of thyroid cancer has been completed with modestly encouraging results,^[5] the manufacturer launched a phase III trial in March 2011.^[6]

Chemical Structure of Lenvatinib Mesilate

Molecular formula: C21H19ClN4O4,CH4O3S =523.0.

CAS: 857890-39-2. UNII code: 3J78384F61.

About the Lenvatinib (E7080) Phase II Study
The open-label, global, single-arm Phase II study of multi-targeted kinase inhibitor lenvatinib (E7080) in advanced radioiodine (RAI)-refractory differentiated thyroid cancer involved 58 patients with advanced RAI refractory DTC (papillary, follicular or Hurthle Cell) whose disease had progressed during the prior 12 months. (Disease progression was measured using Response Evaluation Criteria in Solid Tumors (RECIST).) The starting dose of lenvatinib was 24 mg once daily in repeated 28 day cycles until disease progression or development of unmanageable toxicities.

2.   About Thyroid Cancer
Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat or near the trachea. It affects more women than men and usually occurs between the ages of 25 and 65.
The most common types of thyroid cancer, papillary and follicular (including Hurthle Cell), are classified as differentiated thyroid cancer and account for 95 percent of all cases. While most of these are curable with surgery and radioactive iodine treatment, a small percentage of patients do not respond to therapy.

3.   About Lenvatinib (E7080)
Lenvatinib is multi-targeted kinase inhibitor with a unique receptor tyrosine kinase inhibitory profile that was discovered and developed by the Discovery Research team of Eisai’s Oncology Unit using medicinal chemistry technology. As an anti-angiogenic agent, it inhibits tyrosine kinase of the VEGF (Vascular Endothelial Growth Factor) receptor, VEGFR2, and a number of other types of kinase involved in angiogenesis and tumor proliferation in balanced manner. It is a small molecular targeting drug that is currently being studied in a wide array of cancer types.

4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (additional name: 4-[3-chloro-4-(N′-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide) is known to exhibit an excellent angiogenesis inhibition as a free-form product, as described in Example 368 of Patent Document 1. 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide is also known to exhibit a strong inhibitory action for c-Kit kinase (Non-Patent Document 1, Patent Document 2).

However, there has been a long-felt need for the provision of a c-Kit kinase inhibitor or angiogenesis inhibitor that has high usability as a medicament and superior characteristics in terms of physical properties and pharmacokinetics in comparison with the free-form product of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide.

[Patent Document 1] WO 02/32872

[Patent Document 2] WO 2004/080462

[Non-Patent Document 1] 95th Annual Meeting Proceedings, AACR (American Association for Cancer Research), Volume 45, Page 1070-1071, 2004

………………………..

http://www.google.co.in/patents/US8058474

EXAMPLES

Examples will now be described to facilitate understanding of the invention, but the invention is not limited to these examples.

Example 1Phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

After suspending 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) and adding pyridine (23.4 mL) while cooling on ice, phenyl chloroformate (23.2 ml) was added dropwise below 20° C. Stirring was performed at room temperature for 30 minutes, and then water (400 mL), ethyl acetate (300 mL) and 6N HCl (48 mL) were added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. The solvent was removed to give 46 g of the title compound as a solid.

¹H-NMR (CDCl₃): 5.12 (1h, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s)

Example 21-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

After dissolving phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL), cyclopropylamine (22.7 mL) was added while cooling on ice and the mixture was stirred overnight at room temperature. Water (400 mL), ethyl acetate (300 mL) and 6N HCl (55 mL) were then added, the mixture was stirred and the organic layer was separated. The organic layer was washed twice with 10% brine (200 mL), and dried over magnesium sulfate. Prism crystals obtained by concentrating the solvent were filtered and washed with heptane to give 22.8 g of the title compound (77% yield from 4-amino-3-chlorophenol).

¹H-NMR (CDCl₃): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8H)

Example 34-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethylsulfoxide (20 mL) were added 7-methoxy-4-chloro-quinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), followed by heating and stirring at 70° C. for 23 hours. After the reaction mixture was allowed to cool down to room temperature, water (50 mL) was added, and the produced crystals were collected by filtration to give 1.56 g of the title compound (88% yield).

¹H-NMR (d₆-DMSO): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz)

Example 44-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

In a reaction vessel were placed 7-methoxy-4-chloro-quinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethylsulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) in that order, under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes, the temperature was raised to 65° C. over a period of 2.5 hours. After stirring at the same temperature for 19 hours, 33% (v/v) acetone water (5.0 L) and water (10.0 L) were added dropwise over a period of 3.5 hours. Upon completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours, and 33% (v/v) acetone water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or higher over a period of 1 hour. After then stirring at 40° C. for 16 hours, the precipitated crystals were collected by filtration using a nitrogen pressure filter, and the crystals were washed with 33% (v/v) acetone water (33.3 L), water (66.7 L) and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum drier to give 7.78 kg of the title compound (96.3% yield).

…………………………

 …………………..

http://www.google.co.in/patents/US7253286

EX 368

Example 368

4-(3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

The title compound (22.4 mg, 0.052 mmol, 34.8%) was obtained as white crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (70 mg, 0.15 mmol) and cyclopropylamine, by the same procedure as in Example 11.

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.41 (2H, m), 0.66 (2H, m), 2.56 (1H, m), 4.01 (3H, s), 6.51 (1H, d, J=5.6 Hz), 7.18 (1H, d, J=2.8 Hz), 7.23 (1H, dd, J=2.8, 8.8 Hz), 7.48 (1H, d, J=2.8 Hz), 7.50 (1H, s), 7.72 (1H, s), 7.84 (1H, s), 7.97 (1H, s), 8.25 (1H, d, J=8.8 Hz), 8.64 (1H, s), 8.65 (1H, d, J=5.6 Hz).

The starting material was synthesized in the following manner.

Production Example 368-1Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate

The title compound (708 mg, 1.526 mmol, 87.4%) was obtained as light brown crystals from 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.745 mmol), by the same procedure as in Production Example 17.

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.14 (3H, s), 5.89 (1H, br), 6.50 (1H, d, J=5.6 Hz), 7.16 (2H, dd, J=2.4, 8.8 Hz), 7.22–7.30 (4H, m), 7.44 (2H, m), 7.55 (1H, s), 7.81 (1H, br), 8.31 (1H, d, J=8.8 Hz), 8.68 (1H, d, J=5.6 Hz), 9.27 (1H, s).

……………………

CRYSTALLINE FORM

http://www.google.co.in/patents/US7612208

Preparation Example 1

Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (1)

Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (17.5 g, 37.7 mmol) disclosed in WO 02/32872 was dissolved in N,N-dimethylformamide (350 mL), and then cyclopropylamine (6.53 mL, 94.25 mmol) was added to the reaction mixture under a nitrogen atmosphere, followed by stirring overnight at room temperature. To the mixture was added water (1.75 L), and the mixture was stirred. Precipitated crude crystals were filtered off, washed with water, and dried at 70° C. for 50 min. To the obtained crude crystals was added ethanol (300 mL), and then the mixture was heated under reflux for 30 min to dissolve, followed by stirring overnight to cool slowly down to room temperature. Precipitated crystals was filtered off and dried under vacuum, and then further dried at 70° C. for 8 hours to give the titled crystals (12.91 g; 80.2%).

Preparation Example 2Preparation of 4-(3-cloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (2)

(1) Preparation of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate

To a suspension of 4-amino-3-chlorophenol (23.7 g) in N,N-dimethylformamide (100 mL) was added pyridine (23.4 mL) while cooling in an ice bath, and phenyl chloroformate (23.2 mL) was added dropwise below 20° C. After stirring at room temperature for 30 min, water (400 mL), ethyl acetate (300 mL), and 6N-HCl (48 mL) were added and stirred. The organic layer was separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give 46 g of the titled compound as a solid.

• ¹H-NMR Spectrum (CDCl₃) δ(ppm): 5.12 (1H, br s), 6.75 (1H, dd, J=9.2, 2.8 Hz), 6.92 (1H, d, J=2.8 Hz), 7.18-7.28 (4H, m), 7.37-7.43 (2H, m), 7.94 (1H, br s).
  (2) Preparation of 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

To a solution of phenyl N-(2-chloro-4-hydroxyphenyl)carbamate in N,N-dimethylformamide (100 mL) was added cyclopropylamine (22.7 mL) while cooling in an ice bath, and the stirring was continued at room temperature overnight. Water (400 mL), ethyl acetate (300 mL), and 6N-HCl (55 mL) were added thereto, and the mixture was stirred. The organic layer was then separated off, washed twice with a 10% aqueous sodium chloride solution (200 mL), and dried over magnesium sulfate. The solvent was evaporated to give prism crystals, which were filtered off and washed with heptane to give 22.8 g of the titled compound (yield from 4-amino-3-chlorophenol: 77%).

• ¹H-NMR Spectrum (CDCl₃) δ(ppm): 0.72-0.77 (2H, m), 0.87-0.95 (2H, m), 2.60-2.65 (1H, m), 4.89 (1H, br s), 5.60 (1H, br s), 6.71 (1H, dd, J=8.8, 2.8 Hz), 6.88 (1H, d, J=2.8 Hz), 7.24-7.30 (1H, br s), 7.90 (1H, d, J=8.8 Hz)
  (3) Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide

To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).

Preparation Example 3Preparation of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (3)

7-Methoxy-4-chloroquinoline-6-carboxamide (5.00 kg, 21.13 mol), dimethyl sulfoxide (55.05 kg), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea 5.75 kg, 25.35 mol) and potassium t-butoxide (2.85 kg, 25.35 mol) were introduced in this order into a reaction vessel under a nitrogen atmosphere. The mixture was stirred for 30 min at 20° C., and the temperature was raised to 65° C. over 2.5 hours. The mixture was stirred at the same temperature for 19 hours. 33% (v/v) acetone-water (5.0 L) and water (10.0 L) were added dropwise over 3.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 2 hours. 33% (v/v) acetone-water (20.0 L) and water (40.0 L) were added dropwise at 55° C. or more over 1 hour. After stirring at 40° C. for 16 hours, precipitated crystals were filtered off using a nitrogen pressure filter, and was washed with 33% (v/v) acetone-water (33.3 L), water (66.7 L), and acetone (50.0 L) in that order. The obtained crystals were dried at 60° C. for 22 hours using a conical vacuum dryer to give 7.78 kg of the titled compound (yield: 96.3%).

¹H-NMR chemical, shift values for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamides obtained in Preparation Examples 1 to 3 corresponded to those for 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide disclosed in WO 02/32872.

Example 5A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A)

(Preparation Method 1)

In a mixed solution of methanol (14 mL) and methanesulfonic acid (143 μL, 1.97 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (700 mg, 1.64 mmol) at 70° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, the reaction mixture was cooled to room temperature over 5.5 hours, further stirred at room temperature for 18.5 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (647 mg).

(Preparation Method 2)

In a mixed solution of acetic acid (6 mL) and methanesulfonic acid (200 μL, 3.08 mmol) was dissolved 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (600 mg, 1.41 mmol) at 50° C. After confirming the dissolution of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, ethanol (7.2 mL) and seed crystals of a crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) (12 mg) were added in this order to the reaction mixture, and ethanol (4.8 mL) was further added dropwise over 2 hours. After the addition was completed, the reaction mixture was stirred at 40° C. for 1 hour then at room temperature for 9 hours, and crystals were filtered off. The resultant crystals were dried at 60° C. to give the titled crystals (545 mg).

Example 6A Crystalline Form of the Methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form B)

A crystalline form of the acetic acid solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form I) (250 mg) obtained in Example 10 was dried under aeration at 30° C. for 3 hours and at 40° C. for 16 hours to give the titled crystals (240 mg)…………MORE IN PATENT

 KEEP WATCHING WILL BE UPDATED

References

Carfilzomib

Amgen’s Multiple Myeloma Drug Shows Promise in Phase 3 Trial

https://finance.yahoo.com/video/amgens-multiple-myeloma-drug-shows-195603222.html

Carfilzomib (marketed under the trade name Kyprolis, Onyx Pharmaceuticals, Inc.) is an anti-cancer drug acting as a selectiveproteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin.^[1]

The U.S. Food and Drug Administration (FDA) approved it on 20 July 2012 for use in patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib and an immunomodulatory therapy and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.^[2]

The abbreviation CFZ is common for referring to carfilzomib, but abbreviating drug names is not best practice in medicine.

Discovery, early development and regulatory approval

Carfilzomib is derived from epoxomicin, a natural product that was shown by the laboratory of Craig Crews at Yale University to inhibit the proteasome.^[3] The Crews laboratory subsequently invented a more specific derivative of epoxomicin named YU101,^[4] which was licensed to Proteolix, Inc. Craig Crews, Raymond Deshaies from Caltech, Phil Whitcome, the former CEO of Neurogen and Larry Lasky, a venture capitalist, founded Proteolix, and along with other researchers and scientists, advanced YU101. The scientists at Proteolix invented a new, distinct compound that had potential use as a drug in humans, known as carfilzomib. Proteolix advanced carfilzomib to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval.^[5]Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009.^[5]

In January 2011, the FDA granted carfilzomib fast-track status, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib.^[6] In December 2011, the FDA granted Onyx standard review designation,^[7][8] for its new drug application submission based on the 003-A1 study, an open-label, single-arm Phase 2b trial. The trial evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide.^[9] It costs approximately $10,000 per 28-day cycle, making it the most expensive FDA-approved drug for multiple myeloma.^[10]

Mechanism

Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth.^[1]

Clinical trials

Completed

A single-arm, Phase II trial (003-A1) of carfilzomib in patients with relapsed and refractory multiple myeloma showed that single-agent carfilzomib demonstrated a clinical benefit rate of 36 percent in the 266 patients evaluated and had an overall response rate of 22.9 percent and median duration of response of 7.8 months. The FDA approval of carfilzomib was based on results of the 003-A1 trial.^[11]

In a Phase II trial (004), carfilzomib had a 53 percent overall response rate among patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib. This study also included a bortezomib-treated cohort. Results were reported separately.^[12] This study also found prolonged carfilzomib treatment was tolerable, with approximately 22 percent of patients continuing treatment beyond one year. The 004 trial was a smaller study originally designed to investigate the impact of carfilzomib treatment in relationship to bortezomib treatment in less heavily pretreated (1-3 prior regimens) patients.^[13]

A Phase II trial (005), which assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, in patients with multiple myeloma and varyi ng degrees of renal impairment, where nearly 50 percent of patients were refractory to both bortezomib and lenalidomide, demonstrated that pharmacokinetics and safety were not influenced by the degree of baseline renal impairment. Carfilzomib was tolerable and demonstrated efficacy.^[14]

In another Phase II trial (006) of patients with relapsed and/or refractory multiple myeloma, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 69 percent.^[15]

A Phase II trial (007) for multiple myeloma and solid tumors showed promising results.^[16][17]

In Phase II trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were thrombocytopenia, anemia, lymphoenia, neutropenia, pneumonia, fatigue and hyponatremia.^[18]

In a frontline Phase I/II study, the combination of carfilzomib, lenalidomide, and low-dose dexamethasone was highly active and well tolerated, permitting the use of full doses for an extended time in newly-diagnosed multiple myeloma patients, with limited need for dose modification. Responses were rapid and improved over time, reaching 100 percent very good partial response.^[19]

Ongoing

A phase III confirmatory clinical trial, known as the ASPIRE trial, comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.^[20] It is no longer recruiting and should report in 2014.

http://www.info-farmacia.com/medico-farmaceuticos/informes-tecnicos/carfilzomib-new-drug-for-multiple-myeloma

http://pubs.rsc.org/en/content/articlelanding/2013/np/c3np20126k/unauth#!divAbstract

The initial enthusiasm following the discovery of a pharmacologically active natural product is often fleeting due to the poor prospects for its ultimate clinical application. Despite this, the ever-changing landscape of modern biology has a constant need for molecular probes that can aid in our understanding of biological processes. After its initial discovery by Bristol-Myers Squibb as a microbial anti-tumor natural product, epoxomicin was deemed unfit for development due to its peptide structure and potentially labile epoxyketone pharmacophore. Despite its drawbacks, epoxomicin’s pharmacophore was found to provide unprecedented selectivity for the proteasome. Epoxomicin also served as a scaffold for the generation of a synthetic tetrapeptide epoxyketone with improved activity, YU-101, which became the parent lead compound of carfilzomib (Kyprolis™), the recently approved therapeutic agent for multiple myeloma. In this era of rational drug design and high-throughput screening, the prospects for turning an active natural product into an approved therapy are often slim. However, by understanding the journey that began with the discovery of epoxomicin and ended with the successful use of carfilzomib in the clinic, we may find new insights into the keys for success in natural product-based drug discovery.

References

External links

• “Carfilzomib Prescribing Information”. NCI Drug Dictionary.

http://www.hnkeyuan.com/

Shanghai Natural Bio-engineering Profile

Japanese knotweed extract (Polygonum cuspidatum) Resveratrol 98%

link is

https://www.linkedin.com/today/post/article/20140805055958-283555965-japanese-knotweed-extract-polygonum-cuspidatum-resveratrol-98?trk=hb_ntf_MEGAPHONE_ARTICLE_POST

posted by

Stanford Lee

Sales Manager at Shanghai Natural Bio-engineering Co., Ltd

Songjiang District, Shanghai, China

Pharmaceuticals

 

synonyms	Japanese knotweed extract, Polygonum cuspidatum, red wine extract, trans-3,5,4′-trihydroxystilbene, trans-Resveratrol, cis-resveratrol
CAS number	501-36-0
Latin Name	Polygonum cuspidatum
Botanical source	1.Japanese knotweed plant Polygonum cuspidatum 2. red wine 3. red grape extracts
Molecular Formula	C14H12O3
Molecular weight	228.24
Appearance	white powder with slight yellow
Solubility in water	0.03 g/L
Dosage	500mg
Key benefits	Anti-aging, Anti-Cancer, cardiovascular support, regulate estrogen level, weight loss
Applied industry	Sports nutrition, nutraceuticals, cosmetics

What is resveratrol?

When talk about resveratrol, we have to mention red wine since resveratrol is first popularly known in red wine. In fact, resveratrol was actually first isolated in 1940 from white hellebore roots by the Japanese scientist Michio Takaoka. Red wine, in moderation, has long been thought of as heart healthy. However, the most popular source of resveratrol is from Japanese knotweed extract (Latin name:Polygonum cuspidatum)

Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.

Resveratrol exists as two geometric isomers: “cis-” (“Z”) and “trans-” (“E”). The ”trans-” form can undergo isomerisation to the “cis-” form when exposed to ultraviolet irradiation. Trans-resveratrol in the powder form was found to be stable under “accelerated stability” conditions of 75% humidity and 40 degrees C in the presence of air. Resveratrol content also stayed stable in the skins of grapes and pomace taken after fermentation and stored for a long period.

Sources of resveratrol

The resveratrol in red wine comes from the skin of grapes used to make wine. Because red wine is fermented with grape skins longer than is white wine, red wine contains more resveratrol. Simply eating grapes, or drinking grape juice, has been suggested as one way to get resveratrol without drinking alcohol. Red and purple grape juices may have some of the same heart-healthy benefits of red wine.

Other foods that contain some resveratrol include peanuts, blueberries and cranberries. It’s not yet known how beneficial eating grapes or other foods might be compared with drinking red wine when it comes to promoting heart health. The amount of resveratrol in food and red wine can vary widely.

Benefits of taking reveratrol supplements

Numerous studies have been conducted regarding various purported resveratrol benefits. Studies have primarily been conducted on laboratory animals, and while human search is very promising, is still in its earliest stages. Current research into resveratrol benefits points to resveratrol having amazing anti-aging properties, hence dubbed “The Fountain of Youth.” Many other key benefits such as cardiovascular effects, anti-cancer, estrogen regulating effects are mentioned here.

1.Resveratrol and its anti-aging benefits

The study by Harvard Medical School researchers shows that resveratrol stimulates production of SIRT1, a serum that blocks diseases by speeding up the cell’s energy production centers known as mitochondria.

Resveratrol affects the activity of enzymes called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process. Resveratrol is only one of many natural and synthetic sirtuin-activating compounds (STACs) now known. Certain metabolic diseases, including type 2 diabetes and heart disease, tend to strike as we age. In animal studies, severely restricting calories can help prevent some of these diseases. Over a decade ago, researchers found that resveratrol can mimic calorie restriction in some ways and extend the lifespans of yeast, worms, flies and fish.

2.Resveratrol and cardiovascular benefits

Resveratrol is famous for its Cardioprotective effects.According to Wikipedia, moderate drinking of red wine has long been known to reduce the risk of heart disease. This is best known as “the French paradox”.

Studies suggest resveratrol in red wine may play an important role in this phenomenon. It achieves the effects by the following functions: (1) inhibition of vascular cell adhesion molecule expression;(2) inhibition of vascular smooth muscle cell proliferation;(3) stimulation of endolethelial nitric oxide synthase (eNOS) activity;(4) inhibition of platelet aggregation;and (5) inhibition of LDL peroxidation.

The cardioprotective effects of resveratrol also are theorized to be a form of preconditioning—the best method of cardioprotection, rather than direct therapy.Study into the cardioprotective effects of resveratrol is based on the research of Dipak K. Das, however, who has been found guilty of scientific fraud and many of his publications related to resveratrol have been retracted. A 2011 study concludes, “Our data demonstrate that both melatonin and resveratrol, as found in red wine, protect the heart in an experimental model of myocardial infarction via theSAFE pathway.”

Resveratrol, a polyphenol in red wine, induces nitric oxide (NO) synthase, the enzyme responsible for the biosynthesis of NO, in cultured pulmonary artery endothelial cells, suggesting that Resveratrol could afford cardioprotection by affecting the expression of nitric oxide synthase.

3.Reveratrol and anti-cancer benefits

Experts already claim it can help you beat cancer – from brain tumours to breast, colon, prostate cancers and many more. Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation and as an anti-mutagen in rat models. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation, inhibited enzymes that promote tumor growth, and exerted antitumor effects in neuroblastomas. Noting that in animal studies, resveratrol was effective against tumors of the skin, breast, gastrointestinal tract, lung, and prostate gland. Memorial Sloan-Kettering, the American pillar of cancer treatment, conducted research on theinflammatory effects on cells leading to cancer. It is widely known that an enzyme, COX-2, lies behind the stimulation of localised hormones (eicosanoids) causing inflammation, the precursor to cancer. In the research Resveratrol completely turned off the COX-2 driver. MD Anderson´s studies have shown this same anti-inflammatory benefit too. Plus, after conversion in the liver to a sulphated form the compound can attack several of the steps in the cancer process even killing cancer cells.

4. The Benefits of Resveratrol Weight Loss

Resveratrol is actually a very popular nutrient that has been shown on Dr. Oz, Oprah, Barbara Walters, and a number of other national television shows. It is quickly becoming one of the country’s best natural supplements.

How does Resveratrol help you lose weight? Resveratrol on its own will not be effective at helping you to lose weight, but you have to use it in conjunction with exercise and a proper diet if you really want to obtain the maximum benefits from the supplement.

However, the vitamin, when in concentrated form, has been proven to help speed up the metabolism. This speeding up of the metabolism causes the body to metabolize and process to food consumed faster, which causes the calories in the food to be used more effectively. When the body metabolizes food faster, there is less risk of excess calories being stored in the body in the form of fat.

However, in order to ensure that Resveratrol actually works, you need to take sufficient amounts of the vitamin. The supplement is effective because it is a concentrated form of the helpful vitamin, and taking the supplement is the best way to ensure that Resveratrol works effectively in helping you shed those excess pounds.

Another way Resveratrol helps you to lose weight is through reducing the amounts of estrogen that your body produces. Estrogen increases body fat and decreases muscle mass, so reducing the amounts of estrogen produced by your body will help you lose weight and build muscle. Taking Resveratrol can be a good way to ensure that your body doesn’t produce the amounts of estrogen that will keep it from building muscle.

Side Effects of taking resveratrol supplements

Because there have been very few studies conducted on resveratrol in humans, doctors still can’t confirm what adverse effects these supplements might have on people over the long term. So far, studies have not discovered any severe side effects, even when resveratrol is taken in large doses. However, resveratrol supplements might interact with blood thinners such as warfarin (Coumadin), and nonsteroidal anti-inflammatory medications such as aspirin and ibuprofen, increasing the risk for bleeding.

Like other supplements, resveratrol isn’t regulated by the FDA, so it’s difficult for consumers to know exactly what they’re getting when they buy a bottle, or whether the product is actually effective.

Dosage of resveratrol supplements

There also isn’t any specific dosage recommendation, and dosages can vary from supplement to supplement. The dosages in most resveratrol supplements are typically far lower than the amounts that have been shown beneficial in research studies. Most supplements contain 250 to 500 milligrams of resveratrol. To get the equivalent dose used in some animal studies, people would have to consume 2 grams of resveratrol (2,000 milligrams) or more a day.

Fallopia japonica, commonly known as Japanese knotweed, is a large, herbaceous perennial plant of the family Polygonaceae, native toEastern Asia in Japan, China and Korea. In North America and Europe the species is very successful and has been classified as aninvasive species in several countries. Japanese knotweed has hollow stems with distinct raised nodes that give it the appearance ofbamboo, though it is not closely related. While stems may reach a maximum height of 3–4 m each growing season, it is typical to see much smaller plants in places where they sprout through cracks in the pavement or are repeatedly cut down. The leaves are broad oval with a truncated base, 7–14 cm long and 5–12 cm broad,^[1] with an entire margin. The flowers are small, cream or white, produced in erectracemes 6–15 cm long in late summer and early autumn.

Closely related species include giant knotweed (Fallopia sachalinensis, syn. Polygonum sachalinense) and Russian vine (Fallopia baldschuanica, syn. Polygonum aubertii, Polygonum baldschuanicum).

Other English names for Japanese knotweed include fleeceflower, Himalayan fleece vine, monkeyweed, monkey fungus, Hancock’s curse, elephant ears, pea shooters, donkey rhubarb (although it is not a rhubarb), sally rhubarb, Japanese bamboo, American bamboo, and Mexican bamboo (though it is not a bamboo). In Chinese medicine, it is known as Huzhang (Chinese: 虎杖; pinyin: Hǔzhàng), which translates to “tiger stick.” There are also regional names, and it is sometimes confused with sorrel. In Japanese, the name is itadori (虎杖, イタドリ^?).^[2]

Old stems remain in place as new growth appears

A hedgerow made up of roses and Japanese knotweed in Caersws, Wales in 2010

Erect inflorescence

Invasive species

It is listed by the World Conservation Union as one of the world’s worst invasive species.^[3]

The invasive root system and strong growth can damage concrete foundations, buildings, flood defences, roads, paving, retaining walls and architectural sites. It can also reduce the capacity of channels in flood defences to carry water.^[4]

It is a frequent colonizer of temperate riparian ecosystems, roadsides and waste places. It forms thick, dense colonies that completely crowd out any other herbaceous species and is now considered one of the worst invasive exotics in parts of the eastern United States. The success of the species has been partially attributed to its tolerance of a very wide range of soil types, pH and salinity. Its rhizomes can survive temperatures of −35 °C (−31 °F) and can extend 7 metres (23 ft) horizontally and 3 metres (9.8 ft) deep, making removal by excavation extremely difficult.

The plant is also resilient to cutting, vigorously resprouting from the roots. The most effective method of control is by herbicideapplication close to the flowering stage in late summer or autumn. In some cases it is possible to eradicate Japanese knotweed in one growing season using only herbicides. Trials in the Queen Charlotte Islands (Haida Gwaii) of British Columbia using sea water sprayed on the foliage have demonstrated promising results, which may prove to be a viable option for eradication where concerns over herbicide application are too great.^{[citation needed]}

Two biological pest control agents that show promise in the control of the plant are the psyllid Aphalara itadori^[5] and a leaf spotfungus from genus Mycosphaerella.^[6]

New Zealand

It is classed as an unwanted organism in New Zealand and is established in some parts of the country.^[7]

United Kingdom

In the UK, Japanese Knotweed is established in the wild in many parts of the country and creates problems due to the impact on biodiversity, flooding management and damage to property. It is an offence under section 14(2) of the Wildlife and Countryside Act 1981 to “plant or otherwise cause to grow in the wild” any plant listed in Schedule nine, Part II to the Act, which includes Japanese knotweed. It is also classed as “controlled waste” in Britain under part 2 of the Environmental Protection Act 1990. This requires disposal at licensed landfill sites. The species is expensive to remove; Defra‘s Review of Non-native Species Policy states that a national eradication programme would be prohibitively expensive at £1.56 billion.^[8]

The decision was taken on 9 March 2010 in the UK to release into the wild a Japanese psyllid insect, Aphalara itadori.^[9] Its diet is highly specific to Japanese knotweed and shows good potential for its control.^[10][11]

In Scotland, the Wildlife and Natural Environment (Scotland) Act 2011 came into force in July 2012 that superseded the Wildlife and Countryside Act 1981. This act states that is an offence to spread intentionally or unintentionally Japanese knotweed (or other non-native invasive species).

North America

The weed can be found in 39 of the 50 United States^[12] and in six provinces in Canada. It is listed as an invasive weed in Maine,Ohio, Vermont, Virginia, West Virginia, New York, Alaska, Pennsylvania, Michigan, Oregon and Washington state.^[13]

Uses

A variegated variety of Japanese Knotweed, used as a landscape plant

Japanese knotweed flowers are valued by some beekeepers as an important source of nectar for honeybees, at a time of year when little else is flowering. Japanese knotweed yields a monofloral honey, usually called bamboo honey by northeastern U.S. beekeepers, like a mild-flavored version of buckwheat honey (a related plant also in the Polygonaceae).

The young stems are edible as a spring vegetable, with a flavor similar to extremely sour rhubarb. In some locations, semi-cultivating Japanese knotweed for food has been used as a means of controlling knotweed populations that invade sensitive wetland areas and drive out the native vegetation.^[14] It is eaten in Japan as sansai or wild foraged vegetable.

Similarly to rhubarb, knotweed contains oxalic acid, which when eaten may aggravate conditions such as rheumatism, arthritis, gout, kidney stones or hyperacidity.^[15]

Both Japanese knotweed and giant knotweed are important concentrated sources of resveratrol and its glucoside piceid,^[16] replacing grape byproducts. Many large supplement sources of resveratrol now use Japanese knotweed and use its scientific name in the supplement labels. The plant is useful because of its year-round growth and robustness in different climates.^[17]

This antique locomotive at Beekbergen,Netherlands is overgrown by knotweed. A few years before, it was free of knotweed

Control

Japanese knotweed has a large underground network of roots (rhizomes). To eradicate the plant the roots need to be killed. All above-ground portions of the plant need to be controlled repeatedly for several years in order to weaken and kill the entire patch. Picking the right herbicide is essential, as it must travel through the plant and into the root system below. Glyphosate is the best active ingredient in herbicide for use on Japanese knotweed as it is ’systemic’; it penetrates through the whole plant and travels to the roots.

Digging up the rhizomes is a common solution where the land is to be developed, as this is quicker than the use of herbicides, but safe disposal of the plant material without spreading it is difficult; knotweed is classed as controlled waste in the UK, and disposal is regulated by law.Digging up the roots is also very labor-intensive and not always efficient. The roots can go to up to 10 feet (3 meters) deep, and leaving only a few inches of root behind will result in the plant quickly growing back.

Covering the affected patch of ground with a non-translucent material can be an effective follow-up strategy. However, the trimmed stems of the plant can be razor sharp and are able to pierce through most materials. Covering with non-flexible materials such as concrete slabs has to be done meticulously and without leaving even the smallest splits. The slightest opening can be enough for the plant to grow back.

More ecologically-friendly means are being tested as an alternative to chemical treatments. Soil steam sterilization ^[18] involves injecting steam into contaminated soil in order to kill subterranean plant parts. Research has also been carried out on Mycosphaerella leafspot fungus, which devastates knotweed in its native Japan. This research has been relatively slow due to the complex life cycle of the fungus.^[19]

Research has been carried out by not-for-profit inter-governmental organisation CABI in the UK. Following earlier studies imported Japanese knotweed psyllid insects (Aphalara itadori), whose only food source is Japanese knotweed, were released at a number of sites in Britain in a study running from 1 April 2010 to 31 March 2014. In 2012, results suggested that establishment and population growth were likely, after the insects overwintered successfully.^[20][21]

Detail of the stalk

Controversy

In the United Kingdom, Japanese Knotweed has received a lot of attention in the press as a result of very restrictive lending policies by banks and other mortgage companies. Several lenders have refused mortgage applications on the basis of the plant being discovered in the garden or neighbouring garden.^[22] The Royal Institution of Chartered Surveyors published a report in 2012 in response to lenders refusing to lend “despite [knotweed] being treatable and rarely causing severe damage to the property.” ^[23]

There is a real lack of information and understanding of what Japanese Knotweed is and the actual damage it can cause. Without actual advice and guidance, surveyors have been unsure of how to assess the risk of Japanese Knotweed, which can result in inconsistent reporting of the plant in mortgage valuations. RICS hopes that this advice will provide the industry with the tools it needs to measure the risk effectively, and provide banks with the information they require to identify who and how much to lend to at a time when it is essential to keep the housing market moving.

—Philip Santo, RICS Residential Professional Group^[23]

In response to this guidance, several lenders have relaxed their criteria in relation to discovery of the plant. As recently as 2012, the policy at the Woolwich (part of Barclays plc) was “if Japanese Knotweed is found on or near the property then a case will be declined due to the invasive nature of the plant.”^[24][25] Their criteria have since been relaxed to a category-based system depending on whether the plant is discovered on a neighbouring property (categories 1 and 2) or the property itself (categories 3 and 4) incorporating proximity to the property curtilage and the main buildings. Even in a worst-case scenario (category 4), where the plant is “within 7 metres of the main building, habitable spaces, conservatory and/or garage and any permanent outbuilding, either within the curtilage of the property or on neighbouring land; and/or is causing serious damage to permanent outbuildings, associated structures, drains, paths, boundary walls and fences” Woolwich lending criteria now specify that this property may be acceptable if “remedial treatment by a Property Care Association (PCA) registered firm has been satisfactorily completed. Treatment must be covered by a minimum 10-year insurance-backed guarantee, which is property specific and transferable to subsequent owners and any mortgagee in possession.” ^[26] Santander have relaxed their attitude in a similar fashion (citation needed).

Property Care Association chief executive Steve Hodgson, whose trade body has set up a task force to deal with the issue, said: “japanese knotweed is not “house cancer” and could be dealt with in the same way qualified contractors dealt with faulty wiring or damp.”^[27]

Japan

The plant is known as itadori (イタドリ, 虎杖^?). The kanji expression is from the Chinese meaning “tiger staff”, but as to the Japanese appellation, one straightforward interpretation is that it comes from “remove pain” (alluding to its painkilling use),^[28][29] though there are other etymological explanations offered.

It grows widely throughout Japan and is foraged as a wild edible vegetable (sansai), though not in sufficient quantities to be included in statistics.^[30] They are called by such regional names as: tonkiba (Yamagata),^[30] itazuiko (Nagano, Mie),^[30] itazura (Gifu, Toyama, Nara, Wakayama, Kagawa),^[30] gonpachi (Shizuoka, Nara, Mie, Wakayama),^[30]sashi (Akita, Yamagata),^[30] jajappo (Shimane, Tottori, Okayama),^[30] sukanpo (many areas).

Young leaves and shoots, which look like asparagus, are used. They are extremely sour; the fibrous outer skin must be peeled, soaked in water for half a day raw or after parboiling, before being cooked.

Places in Shikoku such as central parts of Kagawa Prefecture ^[31] pickle the peeled young shoots by weighting them down in salt mixed with 10% nigari (magnesium chloride).Kochi also rub these cleaned shoots with coarse salt-nigari blend. It is said (though no authority is cited) that the magnesium of the nigari binds with the oxalic acid thus mitigating its hazard.^[32]

A novel use for a related species known as oh-itadori (Polygonum sachalinense) in Hokkaido is feeding it to larvae of sea urchins in aquaculture.^[33]

See also

• Persicaria capitata for another plant species called Japanese knotweed.

References

1. Jump up^ RHS. “RHS on Japanese Knotweed”. RHS. Retrieved 6 June 2014.
2. Jump up^ “itadori”. Denshi Jisho — Online Japanese dictionary. Retrieved 9 March 2010.
3. Jump up^ Synergy International Limited <http://www.synergy.co.nz> (2004-01-30). “IUCN Global Invasive Species Database”. Issg.org. Retrieved 2014-06-30.
4. Jump up^ “Article on the costs of Japanese Knotweed”. Gardenroots.co.uk. Retrieved 2014-06-30.
5. Jump up^ Matthew Chatfield (2010-03-14). “”Tell me, sweet little lice” Naturenet article on psyllid control of knotweed”. Naturenet.net. Retrieved 2014-06-30.
6. Jump up^ Morelle, R. Alien invaders hit the UK. BBC News October 13, 2008.
7. Jump up^ “Asiatic knotweed”. Biosecurity New Zealand. 14 January 2010. Retrieved 29 December 2012.
8. Jump up^ “Review of non-native species policy”. Defra. Retrieved 14 July 2013.
9. Jump up^ Morelle, Rebecca (2010-03-09). “BBC News”. BBC News. Retrieved 2014-06-30.
10. Jump up^ Richard H. Shaw, Sarah Bryner and Rob Tanner. “The life history and host range of the Japanese knotweed psyllid, Aphalara itadori Shinji: Potentially the first classical biological weed control agent for the European Union”. UK Biological Control. Volume 49, Issue 2, May 2009, Pages 105-113.
11. Jump up^ “CABI Natural control of Japanese knotweed”. Cabi.org. Retrieved 2014-06-30.
12. Jump up^ PUSDA
13. Jump up^ National Invasive Species Information Center. “USDA weed profile for Japanese knotweed”. Invasivespeciesinfo.gov. Retrieved 2014-06-30.
14. Jump up^ “Pilot project of Bionic Knotweed Control in Wiesbaden, Germany”. Newtritionink.de. Retrieved 2014-06-30.
15. Jump up^ “Japanese Knotweed”. Edible Plants. Retrieved 2014-06-30.
16. Jump up^ Wang, H.; Liu, L.; Guo, Y. -X.; Dong, Y. -S.; Zhang, D. -J.; Xiu, Z. -L. (2007). “Biotransformation of piceid in Polygonum cuspidatum to resveratrol by Aspergillus oryzae”. Applied Microbiology and Biotechnology 75 (4): 763–768. doi:10.1007/s00253-007-0874-3. PMID 17333175. edit
17. Jump up^ Pest Diagnostic Unit, University of Guelph^{[dead link]}
18. Jump up^ Soil-Steaming-Report, 03. Okt. 2009
19. Jump up^ “Notes on Biological control and Japanese knotweed”. Gardenroots.co.uk. Retrieved 2014-06-30.
20. Jump up^ “Testing the psyllid: first field studies for biological control of knotweed United Kingdom”. CABI. Retrieved 2014-06-30.
21. Jump up^ “On CABI Web site, Japanese Knotweed Alliance: Japanese knotweed is one of the most high profile and damaging invasive weeds in Europe and North America”. Cabi.org. Retrieved 2014-06-30.
22. Jump up^ Leah Milner Last updated at 11:30AM, July 8, 2013 (2013-07-08). “Japanese knotweed uproots home sales”. The Times. Retrieved 2014-06-30.
23. ^ Jump up to:^{a b} 05 Jul 2013 (2013-07-05). “RICS targets the root of Japanese Knotweed risk to property”. Rics.org. Retrieved 2014-06-30.
24. Jump up^ “Woolwich Lending Criteria – Property Types”.
25. Jump up^ “Japanese knotweed, the scourge that could sink your house sale”. The Guardian. 2014-09-08.
26. Jump up^ “Residential Lending Criteria”. Woolwich. July 2014.
27. Jump up^ “Brokers demand action on Japanese knotweed”. Mortgagesolutions.co.uk. 2013-08-14. Retrieved 2014-06-30.
28. Jump up^ 日本國語大辞典 (Nihon kokugo daijiten) dictionary (1976)
29. Jump up^ Daigenkai (大言海) dictionary, citing Wakunsai(『和訓菜』)
30. ^ Jump up to:^{a b c d e f g} MAFF 2004 山菜関係資料(Sansai-related material) (webpage pdf). Excerpted from “山菜文化産業懇話会報告書”
31. Jump up^ “イタドリ”. 讃岐の食(Sanuki eating). 2001. Retrieved Apr 2012.
32. Jump up^ Given in Japanese wiki article ja:イタドリ, traced to contribution 2006.2.17 (Fri) 16:23 by ウミユスリカ
33. Jump up^ “北海道食材ものがたり２１　ウニ”. 道新ＴＯＤＡＹ. Sept-1999 1999. Retrieved Apr 2012.

External links

• 
  Species Profile- Japanese Knotweed (Fallopia japonica), National Invasive Species Information Center, United States National Agricultural Library. Lists general information and resources for Japanese Knotweed.
• Best management practice A variety of ways to control knotweed (under “knotweed”)(USA)
• Strategies for the eradication of Japanese knotweed
• American Journal of Botany – Sexual Reproduction in the Invasive Species Fallopia japonica
• Knotweed page on KnottyBits.com
• Japanese Knotweed Alliance (UK)
• Recipes from “Wildman” Steve Brill
• Time lapse video of knotweed growth BBC
• Insect that fights Japanese knotweed to be released BBC News 2010-03-0
  9

Japanese Knotweed
Scientific classification
Kingdom:	Plantae
(unranked):	Angiosperms
(unranked):	Eudicots
(unranked):	Core eudicots
Order:	Caryophyllales
Family:	Polygonaceae
Genus:	Fallopia
Species:	F. japonica
Binomial name
Fallopia japonica (Houtt.) Ronse Decr.
Synonyms
Polygonum cuspidatum Siebold & Zucc. Reynoutria japonica Houtt.

Identifying target product profile (TPP). TPP has been defined as a “prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and thus the safety and efficacy, of a drug product is realized”. This includes dosage form and route of administration, dosage form strength(s), therapeutic moiety release or delivery and pharmacokinetic characteristics (e.g., dissolution and aerodynamic performance) appropriate to the drug product dosage form being developed and drug product-quality criteria (e.g., sterility and purity) appropriate for the intended marketed product. The concept of TPP in this form and its application is novel in the QbD paradigm.

Identifying CQAs. Once TPP has been identified, the next step is to identify the relevant CQAs. A CQA has been defined as “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality”¹⁰. Identification of CQAs is done through risk assessment as per the ICH guidance Q9 . Prior product knowledge, such as the accumulated laboratory, nonclinical and clinical experience with a specific product-quality attribute, is key in making these risk assessments. Such knowledge may also include relevant data from similar molecules and data from literature references. Taken together, this information provides a rationale for relating the CQA to product safety and efficacy. The outcome of the risk assessment would be a list of CQAs ranked in order of importance. Use of robust risk assessment methods for identification of CQAs is novel to the QbD paradigm.

Defining product design space. After CQAs for a product have been identified, the next step is to define the product design space (that is, specifications for in-process, drug substance and drug product attributes). These specifications are established based on several sources of information that link the attributes to the safety and efficacy of the product, including, but not limited to, the following:

• Clinical design space
• Nonclinical studies with the product, such as binding assays, in vivo assays and in vitro cell-based assays
• Clinical and nonclinical studies with similar platform products
• Published literature on other similar products
• Process capability with respect to the variability observed in the manufactured lots

The difference between the actual experience in the clinic and the specifications set for the product would depend on our level of understanding of the impact that the CQA under consideration can have on the safety and efficacy of the product. For example, taking host cell proteins as a CQA, it is common to propose a specification that is considerably broader than the clinical experience. This is possible because of a greater ability to use data from other platform molecules to justify the broader specifications. On the other hand, in the case of an impurity that is unique to the product, the specifications would rely solely on clinical and nonclinical studies.

In QbD, an improved understanding of the linkages between the CQA and safety and efficacy of the product is required. QbD has brought a realization of the importance of the analytical, nonclinical and animal studies in establishing these linkages and has led to the creation of novel approaches.

Defining process design space. The overall approach toward process characterization involves three key steps. First, risk analysis is performed to identify parameters for process characterization. Second, studies are designed using design of experiments (DOE), such that the data are amenable for use in understanding and defining the design space. And third, the studies are executed and the results analyzed to determine the importance of the parameters as well as their role in establishing design space.

Failure mode and effects analysis (FMEA) is commonly used to assess the potential degree of risk for every operating parameter in a systematic manner and to prioritize the activities, such as experiments, necessary to understand the impact of these parameters on overall process performance. A team consisting of representatives from process development, manufacturing and other relevant disciplines performs an assessment to determine severity, occurrence and detection. The severity score measures the seriousness of a particular failure and is based on an estimate of the severity of the potential failure effect at a local or process level and the potential failure effect at end product use or patient level. Occurrence and detection scores are based on an excursion (manufacturing deviation) outside the operating range that results in the identified failure. Although the occurrence score measures how frequently the failure might occur, the detection score indicates the probability of timely detection and correction of the excursion or the probability of detection before end product use. All three scores are multiplied to provide a risk priority number (RPN) and the RPN scores are then ranked to identify the parameters with a high enough risk to merit process characterization.  FMEA outcome for a process chromatography step in a biotech process. RPN scores are calculated and operating parameters with an RPN score >50 are characterized using a qualified scaled-down model. For the case study presented here, these include gradient slope, temperature, flow rate, product loading, end of pool collection, buffer A pH, start of pool collection, volume of wash 1, buffer B pH, buffer C pH and bed height. Process characterization focused on parameters such as temperature, that have a high impact on the process (severity = 6), occur frequently in the manufacturing plant (occurrence = 6) and are difficult to quickly correct if detected (detection = 7). In contrast, parameters such as equilibration volume, with a low impact on the process (severity = 3), low occurrence (occurrence = 2) and a limited ability to detect and correct (detection = 5), were not examined in process characterization.

I liked this pic

SEE AT

http://www.tevapharm.com/Media/EventsUpdates/Pages/Quality-by-Design.aspx

// // //

Anna Popova, Head of the Federal Service for Supervision of Consumer Protection and Welfare (Rospotrebnadzor)

Russian Ebola Vaccine in Preclinical Trials

RIA Novosti

As of today, it is in a stage of preclinical drug trials. The works are intensified now,” Popova said. She added that there are currently no licensed drugs …

see link

http://en.ria.ru/russia/20140805/191739156/Russian-Ebola-Vaccine-in-Preclinical-Trials.html