Home » Uncategorized (Page 114)

Category Archives: Uncategorized

Bimatoprost

July 31, 2014 2:37 pm / 1 Comment on Bimatoprost

BIMATOPROST

155206-00-1

Lumigan, Latisse, AGN 192024, bimatoprostum, UNII-QXS94885MZ, Lumigan (TN), CHEBI:51230, AC1NSJUW, AGN-192024

Molecular Formula: C₂₅H₃₇NO₄

Molecular Weight: 415.56558

(Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010); Gutman, A. et al., US 20090163596 (2009)).

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	C₂₅H₃₇N O₄
Mol. mass	415.566 g/mol

Chemical structure for bimatoprost

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]

Allergen originally developed Bimatoprost and marketed it as Lumigan® for the treatment of elevated intraocular pressure (IOP), with open-angle glaucoma or ocular hypertension. Bimatoprost was later reformulated as a topical formulation and marketed as Latisse® for use in the treatment of hypotrichosis of the eyelashes.

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

Country	Patent Number	Approved	Expires (estimated)
Canada	2585691	2009-05-19	2026-03-14
Canada	2144967	2003-11-11	2013-09-09
United States	7351404	2004-05-25	2024-05-25
United States	6403649	1992-09-21	2012-09-21

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:

LUMIGAN® (bimatoprost) Structural Formula Illustration

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:

……………………………

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

Example 1

Synthesis of Bimatoprost

9a-iso

Bimatoprost

Scheme 3. Synthesis of Bimatoprost.

An exemplary synthesis of bimatoprost, a prostaglandin analog, is shown in Scheme 3. The synthesis is scalable, highly convergent and includes a conjugate addition between two chiral synthons, cyclopentenone derivative 6 and vinyl iodide 7a to form ketone 8a. 7a and similar vinyl halides can be prepared in a manner analogous to that shown for the corresponding THP- protected vinyl iodide in U.S. Patent No. 7,109,371 to Clissold et al., or by other methods known in the art. Ketone 8a is reduced to the corresponding isomeric alcohols 9a and 9a-iso, followed by esterification with 5-hexenoic acid to produce ester intermediate 10a. A single isomer of the alcohol can be produced, if desired, by using a stereoselective reducing agent, such as a SELECTRIDE™ (Sigma-Aldrich, St. Louis, Missouri, United States of America) reducing agent. Ring-closure metathesis (RCM) of 10a produced 10- membered ring lactone 11a, which was subsequently deprotected to form lactone 12a. Ring-opening of lactone 12a with ethylamine produced Bimatoprost. The overall yield of Bimatoprost starting from 6 and 7a was good, with each step having a yield of about 60% or greater.

Individual steps in the synthesis of Bimatoprost are described further hereinbelow in Examples 5-10. An alternative step for the synthesis of ketone 8a, using an alkyne reagent, is also shown hereinbelow in Example 13. Ring- opening of 11a prior to deprotection to form a hydroxy-protected Bimatoprost and its subsequent deprotection are described in Examples 11 and 12. As shown below in Schemes 4-6 of Examples 2-4, other exemplary prostanoids were prepared via analogous routes as that shown in Scheme 3. Details regarding individual steps in these syntheses are also shown hereinbelow in Examples 5-10.

Synthesis of Bimatoprost from 12a:

As shown in Scheme 3 in Example 1 , 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 4.1 g (11.1 mmol) of deprotected lactone 12a in 20 ml_ of THF, 22.2 mi_( 44.3 mmol) of 2 M trimethylaluminum in THF, and 67 ml_ (133 mmol) of 2 M ethylamine in THF. The reaction mixture was heated at 40 °C for 18 h and TLC analysis indicated complete reaction. The mixture was diluted with 50 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 20 mL of ethyl acetate for two times. The combined organic layers were washed with 40 mL of brine, dried over sodium sulfate, filtered, and concentrated.

The crude product was triturated with 20 mL of MTBE at 35 ⁰C for 3 h, cooled to room temperature, and filtered to obtain 3.1 g (67.3% yield) of Bimatoprost, confirmed by ¹H NMR.

Example 11

Synthesis of Protected Bimatoprost

Protected Bimatoprost

Scheme 7. Synthesis of Protected Bimatoprost.

As shown in Scheme 7 above, a 250 mL 3-necked round-bottom flask, equipped with a magnetic stirring bar, a temperature probe, rubber septa, and nitrogen inlet, was charged at room temperature, under nitrogen, with 3.0 g (5.01 mmol) of compound 11a in 3O mL of THF, and 15mL ethylamine, 2.0 M in THF. The mixture heated at 40 °C for 24 h and then reflux for another 3 h. TLC analysis (hexanes/ethyl acetate, 10:1) indicated complete reaction. The mixture was cooled to room temperature and diluted with 30 mL of MTBE and 25 mL of water. The layers were separated and the aqueous layer was washed with 15 mL of MTBE. The combined organic extracts were washed with 25 mL of brine, dried over sodium sulfate, filtered, concentrated, and chromatographically purified to afford 2.90 g (90.0% yield) of bis-silylated bimatoprost, confirmed by ¹H NMR.

Example 12

Deprotection of Protected Bimatoprost

(8)

Protected Bimatoprost

Bimatoprost Scheme 8. Deprotection of Protected Bimatoprost.

As shown in Scheme 8 above, a 250 ml_ 3-necked round-bottom flask, equipped with a magnetic stirring bar, a temperature probe, rubber septa, and nitrogen inlet, was charged at room temperature, under nitrogen, with 3.Og (3.11 mmol) of protected bimatoprost from Example 12, 30 ml. of THF₁ and 0.9 g (90.8 mmol) of ammonium hydrogen difluoride. The reaction mixture was heated at 40 ⁰C for 24 h and TLC analysis (hexanes/ethyl acetate, 1 :1) indicated complete reaction. The mixture was then diluted with 30 ml. of MTBE and 25 ml_ of water followed by layer separation. The aqueous layer was back extracted with 15 ml_ of MTBE. The combined organic extracts were washed with 25 mL of brine, dried over sodium sulfate, filtered, concentrated, and chromatographically purified to afford 1.02 g (80.0% yield) of bimatoprost confirmed by ¹H NMR.

………………………………

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

Figure imgf000033_0001

Example 7 – Experimental procedures for the synthesis of bimatoprost

A synthesis of bimatoprost is shown and described below.

bimatoprost (97) 7A. (±)-5-Phenyl-l-(trimethylsilyl)pent-l-yn-3-ol, 81

Following a modified procedure of Matsuda (Matsuda, F. Et al., C em. Eur. J. 5, 3252-3259 (1999)); n-butyllithium (1.6 M in hexanes, 8.8 ml, 14.1 mmol, 1.0 eq.) was added dropwise to a solution of ethynyltrimethylsilane (2.0 ml, 14.1 mmol, 1.0 eq.) in THF (6 ml) at -78 °C. After addition, the mixture was allowed to warm slowly to 0 °C and stirred for 1 h. The mixture was cooled to -78 °C and a solution of hydrocinnamaldehyde (2.2 ml, 17.0 mmol, 1.2 eq.) in THF (3 ml) was added dropwise. The mixture was then allowed to slowly warm to -10 °C and stirred for 1 h before being quenched by the addition of saturated NH₄CI solution (10 ml) followed by EtOAc (10 ml). The aqueous layer was extracted with EtOAc (3 x 10 ml), the combined organic phases were washed with brine (15 ml) before being dried (MgS0₄), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/EtOAc (100:5), giving the title product 81 as a clear, colourless oil (3.1 g, 94 %). Analytical data consistent with the literature (Matsuda, F. Et al., Chem. Eur. J. 5, 3252-3259 (1999)). max (filmVcm-¹ 3326 (broad), 2951, 2172, 1604, 1496, 1454, 1249, 1045, 838

*H NMR (400 MHz; CDCI₃) δ_Η = 0.23 (s, 9H, 3 x CH₃), 2.07 (m, 3H, CH₂, OH), 2.84 (t, J = 7.8 Hz, 2H, CH₂), 4.40 (t, J = 6.6 Hz, 1H, CHO ), 7.25 (m, 3H, ArCH’s), 7.33 (app t, J = 7.3 Hz, 2H, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = 0.0 (3 x CH₃), 31.6 (CH₂), 39.3 (CH₂), 62.3 (CH), 90.0 (C), 106.7 (C), 126.1 (ArCH), 128.6 (2 x ArCH), 128.7 (2 x ArCH), 141.4 (ArC)

m/z (ESI⁺) 255.1 [MNa]⁺, 215.1

7B. Methyl 3-phenylpropanoate, 82

82 Hydrocinnamic acid (10.0 g, 66.6 mmol, 1 eq.) was dissolved in methanol (90 ml), cone. H₂S0₄ (1 ml) added dropwise with stirring and the reaction mixture was stirred under reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (100 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phases were washed with 10 % NaHC0₃ aq. (2 x 50 ml), brine (50 ml) before being dried (MgS0₄), filtered and concentrated to give the title compound 82 (10.8 g, 99 %) as a clear, colourless oil. Analytical data consistent with the literature (Black, P. J. et al., Eur. J. Org. Chem. 4367-4378 (2006)). v_max (filmVcm-¹ 3028, 2952, 1734, 1436, 1194, 1160, 749, 697

*H NMR (400 MHz; CDCI₃) δ_Η = 2.68 (t, J = 7.8 Hz, 2H, CH₂), 3.00 (t, J = 7.8 Hz, 2H,

CH₂), 3.71 (s, 3H, CH₃), 7.25 (m, 3H, ArCH’s), 7.33 (m, 2H, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = 31.1 (CH₂), 35.8 (CH₂), 51.7 (CH₃), 126.4 (2 x ArCH),

128.4 (ArCH), 128.6 (2 x ArCH), 140.6 (ArC), 173.5 (C=0)

m/z (CI⁺) 165.1 [MH]⁺ (20%), 133.1 (100%), 105.1 (55%), 93.1 (51%), 85.0 (57%)

7C. /V-Methoxy-/V-methyl-3-phenylpropanamide, 83

Following a procedure of Trost (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754

(2006)); to a slurry of Λ/,Ο-dimethylhydroxylamine hydrochloride (4.91 g, 50.4 mmol, 2.1 eq.) in toluene (50 ml) at -10 °C was added AIMe₃ (2 M in hexanes, 25.2 ml, 50.4 mmol, 2.1 eq.) dropwise. After addition, the mixture was allowed to warm to r.t. and stirred for 1 h. The mixture was cooled to -5 °C and a solution of methyl 3-phenylpropanoate 82 (3.94 g, 24.0 mmol, 1 eq.) in toluene (40 ml) was added dropwise. The reaction mixture was then allowed to warm slowly to r.t. and stirred for 3 h. The solution was cooled to 0 °C and quenched carefully by dropwise addition of HCI and the reaction mixture was extracted with EtOAc (4 x 70 ml). The combined organic phases were washed with brine (50 ml) before being dried (MgS0₄), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/EtOAc (80:20 to 75:25), giving the Weinreb amide 83 as a clear, colourless oil (4.45 g, 97 %). Analytical data consistent with the literature (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006); Murphy, J. A. et al., Org. Lett. 7, 1427-1429 (2005)). max (film cm-¹ 3017, 2937, 1659, 1453, 1414, 1383, 1176, 988, 750

*H NMR (400 MHz; CDCI₃) δ_Η = 2.74 (t, J = 7.8 Hz, 2H, CH₂), 2.97 (t, J = 7.8 Hz, 2H, CH₂), 3.18 (s, 3H, CH₃), 3.60 (s, 3H, CH₃0), 7.25 (m, 5H, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = 30.7 (CH₃), 32.2 (CH₂), 33.8 (CH₂), 61.2 (CH₃0), 126.1

(ArCH), 128.4 (4 x ArCH), 141.3 (ArC), 173.7 (C=0)

m/z (CI⁺) 194.1 [MH]⁺ (100%), 164.1 (20%), 133.1 (12%)

7D. 5-Phenyl-l-(tri/sopropylsilyl)pent-l-yn-3-one, 84

Following a procedure of Trost (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754

(2006)); /7-Butyllithium (2.5 M in hexanes, 10.4 ml, 26 mmol, 1.7 eq.) was added dropwise to a solution of tri/sopropylsilyl acetylene (5.8 ml, 26 mmol, 1.7 eq.) in THF (53 ml) at -78 °C. After addition, the mixture was allowed to warm slowly to 0 °C and stirred for 1 h. The mixture was cooled to -78 °C and a solution of 83 (3.0 g, 15.3 mmol, 1 eq.) in THF (20 ml) was added dropwise. The mixture was then allowed to slowly warm to -10 °C and stirred for 1 h before being quenched by the addition of saturated aq. NH₄CI (50 ml). The mixture was extracted with EtOAc (3 x 30 ml) and the combined organic phases were washed with brine (50 ml) before being dried (MgS0₄), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et₂0 (100:0 to 98:2), giving the title product 84 as a clear, colourless oil (4.61 g, 96 %). max (filmycnr¹ 2944, 2866, 1675, 1462, 1445, 1103, 881, 696

*H NMR (400 MHz; CDCI₃) δ_Η = 1.12 (m, 21 H, 6 x CH₃, 3 x CH), 2.92 (m, 2H, CH₂), 3.03 (m, 2H, CH₂), 7.22 (m, 3H, ArCH’s), 7.31 (m, 2H, ArCH’s)

1³C NMR (100 MHz; CDCI₃) 5_C = 11.1 (3 x CH), 18.6 (6 x CH₃), 30.2 (CH₂), 47.4 (CH₂), 96.2 (C), 104.2 (C), 126.4 (ArCH), 128.4 (2 x ArCH), 128.7 (2 x ArCH), 140.4 (ArC), 186.7 (C=0) m/z (CI⁺) 315.3 [MH]⁺ (100%), 271.2 52%), 157.2 (27%)

HRMS (CI⁺) calcd for C₂₀H₃iOSi [MH]⁺ 315.2144, found 315.2139

7E. (S)-5-Phenyl-l-(tri/sopropylsilyl)pent-l-yn-3-ol, 85

Following a modified procedure of Trost (Trost, B. M. et al., J. Am. C em. Soc. 128, 6745- 6754 (2006)); Potassium hydroxide (8.5 mg, 0.15 mmol, 1.2 mol%) and RuCI(p- cymene)[(S,S)-Ts-DPEN] (80.7 mg, 0.127 mmol, 1 mol%) were added to /PrOH (110 ml) and the resultant mixture was stirred for 2 min at r.t.. 5-Phenyl-l-(tri/sopropylsilyl)pent-l-yn-3-one 84 (4.0 g, 12.7 mmol, 1 eq.) was added via syringe and the mixture was stirred at r.t. for 45 min. The mixture was concentrated in vacuo to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et₂0 (20:1 to 10:1), giving the title product 85 as a clear, colourless oil (4.0 g, 99 %). The enantiomeric excess was determined to be 99 % via HPLC analysis of its derivative 87. Analytical data consistent with the literature (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)). max (filmVcm-¹ 3322 (broad), 2942, 2864, 1462, 1045, 1011, 996, 882, 697, 675

*H NMR (300 MHz; CDCI₃) δ_Η = 1.07-1.11 (m, 21 H, 6 x CH₃, 3 x CH), 1.83 (d, J = 5.5 Hz, 1H, OH), 2,03 (m, 2H, CH₂), 2.82 (t, J = 7.9 Hz, 2H, CH₂), 4.40 (dd, J = 6.4, 5.5 Hz, 1H, CHOH), 7.17-7.32 (m, 5H, ArCH’s)

¹³C NMR (75 MHz; CDCfe) 5_C = 11.2 (3 x CH), 18.7 (6 x CH₃), 31.6 (CH₂), 39.7 (CH₂), 62.4 (CH), 86.1 (C), 108.5 (C), 126.1 (ArCH), 128.6 (4 x ArCH), 141.5 (ArC)

m/z (ESI⁺) 339.2 [MNa]⁺, 299.2., 225.0

HRMS (ESI⁺) calcd for C₂₀H₃₂OSiNa [MNa]⁺ 339.2114, found 339.2127

[a]_D ²² + 28.5 (c. 2.0, CHCI₃) (lit., +27.17 (c. 2.14, CH₂CI₂)) 7F. (S)-5-Phenylpent-l-yn-3-ol, 86

Following a modified procedure of Trost (Trost, B. M. et al., J. Am. C em. Soc. 128, 6745- 6754 (2006)); Tetrabutylammonium fluoride (1.0 M in THF, 25 ml, 25 mmol, 2.5 eq.) was added to a solution of (S)-5-phenyl-l-(tri/sopropylsilyl)pent-l-yn-3-ol 85 (3.165 g, 10 mmol, 1 eq.) in THF (95 ml). The reaction mixture was stirred for 1 h at r.t. and then quenched by addition of saturated aq. NH₄CI (50 ml). The mixture was extracted with Et₂0 (3 x 40 ml), the combined organic phases were washed with brine (50 ml) before being dried (MgS0₄), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et₂0 (10: 1 to 9:1), giving the title product 86 as a clear, colourless oil (1.6 g, 99 %). max (filmVcm-¹ 3289 (broad), 1603, 1496, 1454, 1300 (broad), 1040, 1010, 744

*H NMR (400 MHz; CDCI₃) δ_Η = 2.10 (m, 3H, CH₂, OH), 2.55 (d, J = 2.2 Hz, 1H, C≡CH), 2.85 (t, J = 7.8 Hz, 2H, CH₂), 4.40 (m, 1H, CHOH), 7.25 (m, 3H, ArCH’s), 7.33 (m, 2H, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = 31.4 (CH₂), 39.2 (CH₂), 61.7 (CHOH), 73.5 (C≡CH), 84.8 (C≡CH), 126.2 (2 x ArCH), 128.6 (3 x ArCH), 141.2 (ArC)

m/z (CI⁺) 161.1 [MH]⁺ (15%), 155.1 (37%), 143.1 (88%), 119.1 (42%), 91.1 (100%) HRMS (CI⁺) calcd for CnH₁₃0 [MH]⁺161.0966, found 161.0972

[a]_D ²² + 20.0 (c. 2.0, CHC )

7G. (S)-5-Phenyl-l-(trimethylsilyl)pent-l-yn-3-ol, 87

1) nBuLi, THF

-78 °C to 0 °C

OH 2) Me₃SiCI OH

3) Citric acid

86 87 Following a procedure of Trost (Trost, B. M. et al., J. Am. C em. Soc. 128, 6745-6754 (2006)); /7-butyllithium (2.5 M in hexanes, 474 pL, 1.18 mmol, 3 eq.) was added dropwise to a solution of (S)-5-phenylpent-l-yn-3-ol 86 (63.3 mg, 0.39 mmol, 1 eq.) in THF (1 ml) at -78 °C. The mixture was allowed to warm to 0 °C and stirred 30 min before being cooled to -78 °C. TMSCI (148.2 pL, 1.18 mmol, 3 eq.) was added dropwise and the mixture was allowed to warm to r.t. and stirred for 2 h. Citric acid (65 mg) in methanol (0.7 ml) was added and the mixture stirred for 1 h. The mixture was poured into a mixture of brine (3 ml) and Et₂0 (5 ml). The aqueous layer was extracted with Et₂0 (3 x 10 ml) and the combined organic phases were washed with brine (10 ml) before being dried (MgS0₄), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et₂0 (9:1), giving the title product 87 as a clear, colourless oil (18.5 mg, 15.5 %). Analytical data consistent with the literature (Trost, B. M. et al., J. Am. Chem. Soc. 128, 6745-6754 (2006)). v_max(filmVcm-¹ 3344 (broad), 2956, 2172, 1496, 1454, 1249, 1046, 838

*H NMR (400 MHz; CDCI₃) δ_Η = 0.19 (s, 9H, 3 x CH₃), 1.80 (d, J = 5.6 Hz, 1H, OH), 2.02 (m, 2H, CH₂), 2.80 (t, J = 7.8 Hz, 2H, CH₂), 4.36 (dd, J = 6.3, 5.6 Hz, 1H, CHOH), 7.20 (m, 3H, ArCH’s), 7.29 (m, 2H, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = -0.1 (3 x CH₃), 31.4 (CH₂), 39.2 (CH₂), 62.2 (CHOH), 89.9 (C), 106.4 (C), 125.9 (ArCH), 128.4 (2 x ArCH), 128.5 (2 x ArCH), 141.3 (ArC)

m/z (ESI⁺) 255.1 [MNa]⁺

HRMS (ESI⁺) calcd for Ci₄H₂₀OSiNa [MNa]⁺ 255.1175, found 255.1185

[a]_D ²² + 28.6 (c. 0.735, CHCI₃) (lit., +32.91 (c. 2.37, CH₂CI₂))

Chiral-HPLC data: ee = >99 % (Chiralcel OD column, 210 nm, hexane/2-propanol: 90/10, flow rate: 0.7 mlVmin, room temperature; ¾: minor 15.5 min, major 10.7 min)

7H. (S)-tert-Butyldimethyl(5-phenylpent-l-yn-3-yloxy)silane, 88

Following a procedure of Noyori (Suzuki, M. et al., J. Med. Chem. 41, 3084-3090 (1998)); Imidazole (919.1 mg, 13.5 mmol, 1.8 eq.) and t-butylchlorodimethylsilane (1.35 g, 9.0 mmol) were added to a solution of (S)-5-phenylpent-l-yn-3-ol 86 (1.2 g, 7.5 mmol, 1 eq.) in CH₂CI₂ (18 ml), cooled to 0 °C. The reaction mixture was then stirred at room temperature for 14 h before being poured into 1 M HCI (50 ml). The mixture was extracted with 40/60 petroleum ether (3 x 50 ml). The combined organic phases were washed with brine (50 ml) before being dried (MgS0₄), filtered and concentrated to give the crude product. This was purified by column chromatography on silica, eluting with petrol/Et₂0 (99:1), giving the title product 88 as a clear, colourless oil (1.77 g, 86 %). Analytical data consistent with the literature (Kiyotsuka, Y. et al., Org. Lett. 10, 1719-1722 (2008).; Sato, F. et al., EP 1211241 Al, Taisho Pharmaceutical co., LTD (2002)). max (filmVcm-¹ 3309, 2954, 2929, 2886, 2857, 1251, 1091, 834, 776

*H NMR (400 MHz; CDCI₃) δ_Η = 0.15 (s, 3H, CH₃), 0.17 (s, 3H, CH₃), 0.95 (s, 9H, 3 x CH₃), 2.04 (m, 2H, CH₂), 2.46 (d, J = 2.1 Hz, C≡CH), 2.81 (m, 2H, CH₂), 4.41 (dt, J = 6.3, 2.1 Hz, CHOTBDMS), 7.24 (m, 3H, ArCH’s), 7.32 (m, 2H, ArCH’s)

1³C NMR (100 MHz; CDCI₃) 5_C = -4.9 (CH₃), -4.4 (CH₃), 18.3 (C), 25.9 (3 x CH₃), 31.4

(CH₂), 40.3 (CH₂), 62.2 (CHOTBDMS), 72.5 (C≡CH), 85.4 (C≡CH), 125.9 (ArCH), 128.5 (2 x ArCH), 128.6 (2 x ArCH), 141.7 (ArC)

m/z (CI⁺) 275.2 [MH]⁺ (12%), 259.1 (37%), 217.1 (50%), 189.1 (38%), 143.1 (100%) HRMS (CI⁺) calcd for Ci₇H₂₇OSi [MH]⁺275.1831, found 275.1825

[a]_D ²² -17.0 (c. 2.0, CHCI₃)

71. (S,£)-teif-Butyl(l-iodo-5-phenylpent-l-en-3-yloxy)dimethylsila

A flame dried Schlenk flask, evacuated and purged with nitrogen, was charged with alkyne 88 (1.50 g, 5.46 mmol, 1 eq.). Anhydrous CH₂CI₂ (35 ml) was added and the reaction stirred at r.t. Zr(Cp)₂HCI (2.82 g, 10.9 mmol, 2 eq.) was added as a solid, in portions. The yellow suspension was stirred at r.t. for 1 h. The resulting yellow solution was cooled to 0 °C and iodine (1.52 g, 6.01 mmol, 1.1 eq.) added as a solid, in one portion. The cooling bath was removed and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was poured into water (100 ml) and extracted with 40/60 petroleum ether (4 x 50 ml). The combined organic phases were washed with water (100 ml), saturated Na₂S₂0₃ solution (2 x 100 ml) and brine (100 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with 40/60 petroleum ether. The fractions containing product were combined and washed with saturated Na₂S₂0₃ solution (20 ml), dried (MgS0₄), filtered, and concentrated to give the title compound 89 (1.98 g, 90%) as a clear, colourless oil. Analytical data consistent with the literature (Sato, F. et al., EP 1211241 Al, Taisho Pharmaceutical co., LTD (2002)). max (filmVcm-¹ 2952, 2928, 2856, 1604, 1360, 1251, 1086, 942, 833, 774

*H NMR (400 MHz; CDCI₃) δ_Η = 0.04 (s, 3H, CH₃), 0.06 (s, 3H, CH₃), 0.92 (s, 9H, 3 x CH₃), 1.82 (m, 2H, CH₂), 2.65 (m, 2H, CH₂), 4.15 (dq, J = 6.0, 1.2 Hz, 1H, C /-/OTBDMS), 6.25 (dd, J = 14.3, 1.2 Hz, 1H, CH=CHI), 6.57 (dd, J = 14.3, 6.0 Hz, 1H, CH=CHI), 7.18 (m, 3H, ArCH’s), 7.29 (m, 2H, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = -4.9 (CH₃), -4.5 (CH₃), 18.2 (C), 25.8 (3 x CH₃), 31.0 (CH₂), 39.1 (CH₂), 74.6 (CHOTBDMS), 76.1 (CH=CHI), 125.8 (ArCH), 128.3 (2 x ArCH), 128.4 (2 x ArCH), 141.8 (ArC), 148.8 (CH=CHI)

m/z (ESI⁺) 425.1 [MNa]⁺

HRMS (ESI⁺) calcd for Ci₇H₂₇IOSiNa [MNa]⁺ 425.0768, found 425.0754

[a]_D ²² -4.5 (c. 2.0, CHCI₃)

73. tert-Butyl((S,l£)-l-((3aR,4R,6aS)-2-methoxy-5- ((trimethylsilyloxy)methylene)hexahydro-2H-cyclopenta[d]furan-4-yl)-5- phenylpent-l-en-3-yloxy)dimethylsilane, 92

90 92 Vinyl iodide 89 (1.45 g, 3.6 mmol, 1.2 eq.) was added via syringe to a flame dried Schlenk flask (evacuated and purged with nitrogen several times and allowed to cool). Anhydrous Et₂0 (14.5 ml) was added via syringe and the resulting solution cooled to -78 °C. t-BuLi (1.6 M, 4.5 ml, 7.2 mmol, 2.4 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 (303 mg, 288 μΙ, 3.6 mmol, 1.2 eq.) was added via syringe to a flame dried Schlenk flask (evacuated and purged with nitrogen several times and allowed to cool). Anhydrous THF (14.5 ml) was added via syringe and the resulting solution cooled to -30 °C. n-BuLi (1.6 M, 2.25 ml, 3.6 mmol, 1.2 eq.) was added dropwise and the solution stirred at -30 °C for 30 min. The solution was then cooled to -78 °C and CuCN (322.4 mg, 3.6 mmol, 1.2 eq.) 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 vinyl lithium and anhydrous THF (14.5 ml) added. The mixture was stirred at -20 °C for 1 h to allow formation of mixed cuprate 90. This was cooled to -78 °C and a solution of enal 24 (504.6 mg, 3.0 mmol, 1.0 eq.) in anhydrous THF (14.5 ml) was added dropwise. The mixture was stirred at -78 °C for 1 h and then allowed to warm slowly to -20 °C. TMSCI (2.2 ml) was added via syringe followed by NEt₃ (2.8 ml). The reaction was quenched by the addition of saturated NH₄CI solution (80 ml) and extracted with Et₂0 (3 x 80 ml). The combined organic phases were washed with saturated NH₄CI solution (40 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.

7K. (3aR 4R,5R,6aS)-4-((S,£)-3-(tert-Butyldimethylsilyloxy)-5-phenylpent-l- enyl)-2-methoxyhexahydro-2H-cyclopenta[d]furan-5-ol, 93

92 93

The crude material from the conjugate addition / trapping experiment, containing 92, was dissolved in C^Cb/MeOH (3:1) (32 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). At this point, the flask was purged with a stream of nitrogen during 10 min and NaBH₄ (204 mg, 5.4 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. The reaction mixture was poured into saturated NaCI solution (20 ml) and extracted with EtOAc (3 x 40 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 (9:1 to 8:2), giving the alcohol 93 (as a mixture of diastereoisomers) as a clear, colourless oil (731.0 mg, 56.0% (2 steps from enal 24)). max (filmVcm-¹ 3434 (broad), 2928, 1496, 1471, 1454, 1360, 1250, 1098, 1044, 1003, 970, 834, 774

*H NMR (400 MHz; CDCI₃)

δ_Η = (mixture of 2 diastereoisomers, signals of minor diastereoisomer indicated by *) 0.05 (s, 3H, CH₃), 0.06* (s, 3H, CH₃), 0.07 (s, 3H, CH₃), 0.08* (s, 3H, CH₃), 0.93 (s, 9H, 3 x CH₃), 0.94* (s, 9H, 3 x CH₃), 1.74-2.52* (m, 8H, 3 x CH₂, 2 x CH), 1.74-2.52 (m, 7H, 3 x CH₂, CH), 2.56-2.76* (m, 2H, CH₂), 2.56-2.76 (m, 3H, CH₂, CH), 3.35 (s, 3H, OCH₃), 3.39* (s, 3H, OCH₃), 3.81* (m, 1H, CHOH), 3.94 (m, 1H, CHOH), 4.15* (m, 1H, C/-OTBDMS), 4.15 (m, 1H, CHOTBDMS), 4.53 (app td, J = 6.6, 3.2 Hz, 1H, CH), 4.63* (app td, J = 7.5, 4.6 Hz, 1H, CH), 5.09* (app d, J = 5.6 Hz, 1H, CH), 5.14 (app d, J = 4.4 Hz, 1H, CH), 5.48* (m, 1H, =CH), 5.48 (m, 1H, =CH), 5.60* (m, 1H, =CH), 5.60 (m, 1H, =CH), 7.20* (m, 3H, ArCH’s), 7.20 (m, 3H ArCH’s), 7.30* (m, 2H, ArCH’s), 7.30 (m, 2H, ArCH’s)

¹³C NMR (100 MHz; CDCI₃) 5_C = (mixture of 2 diastereoisomers, signals of minor diastereoisomer indicated by *) -4.6 (CH₃), -4.6* (CH₃), -4.0* (CH₃), -3.9 (CH₃), 18.4 (C), 18.4* (C), 26.0 (3 x CH₃), 26.0* (3 x CH₃), 31.8 (CH₂), 31.9 (CH₂), 38.0 (CH₂), 39.3 (CH₂), 39.7 (CH₂), 40.2 (CH₂), 40.3 (CH₂), 42.5 (CH₂), 45.8 (CH), 46.1* (CH), 54.6* (CH₃0), 55.0 (CH₃0), 56.7* (CH), 57.6 (CH), 72.8 (CHOTBDMS), 72.9* (CHOTBDMS), 77.9* (CHOH), 78.9 (CHOH), 81.2 (CH), 83.3* (CH), 106.6 (CH), 107.7* (CH), 125.7 (ArCH), 125.8 (ArCH), 126.0 (ArCH), 128.4 (ArCH), 128.5 (ArCH), 128.6 (ArCH), 130.3* (=CH), 131.1 (=CH), 135.1* (=CH), 135.2 (=CH), 142.2* (ArC), 142.5 (ArC)

m/z (ESI⁺) 455.1 [MNa]⁺

HRMS (ESI⁺) calcd for C₂₅H4o0₄SiNa [MNa]⁺ 455.2588, found 455.2587 7L. (3a ?,4 ?,5 ?,6aS)-4-((S,E)-3-Hydroxy-5-phenylpent-l-enyl)hexahyd cyclopenta[b]furan-2,5-diol, 94

93 94

Alcohol 93 (210 mg, 0.485 mmol) was stirred with 1.5% aqueous HCI / THF (3:2) (10 ml) at r.t. for 16 h. The mixture was extracted with CH₂CI₂ (5 x 15 ml) and the combined organic phases were dried (MgS0₄), filtered, and concentrated to give the triol 94 and silanol byproduct as a clear, colourless oil. This material was taken forward for the subsequent transformation without purification.

7M. 5-Bromo-/V-ethylpentanamide, 95

1) SOCI₂, DMF cat.

Toluene, 55 °C

Dimethylformamide (116 μΙ_, 1.5 mmol, 0.1 eq.) and thionyl chloride (1.63 ml, 22.5 mmol, 1.5 eq.) were added to a solution of 5-bromovaleric acid (2.71 g, 15 mmol, 1 eq.) in toluene (20 ml) and the reaction mixture was stirred at 50 °C for 4 h. The volatiles were removed under high vacuum, THF (130 ml) was added and the mixture was cooled to 0 °C. N,N- Diisopropylethylamine (4.2 ml, 24 mmol, 1.6 eq.) and ethylamine (2 M solution in THF, 9.0 ml, 18 mmol, 1.2 eq.) were added dropwise. The reaction mixture was stirred for 1 h at 0 °C before being quenched by the addition of saturated aq. NH₄CI (100 ml). The reaction mixture was extracted with Et₂0 (4 x 75 ml) and the combined organic phases were washed with brine (100 ml) before being dried (MgS0₄), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with petrol/EtOAc (4:6), giving the title product 95 as a clear, colourless oil (2.75 g, 88 %). Analytical data consistent with the literature (Halazy, S. et al., WO 9612713, Pierre Fabre Medicament (1996)). max (filmVcm-¹ 3275 (broad), 2970, 2933, 1640, 1543, 1439, 1276, 1150, 643

*H NMR (400 MHz; CDCI₃) δ_Η = 1.13 (t, J = 7.2 Hz, 3H, CH₃), 1.78 (m, 2H, CH₂), 1.89 (m, 2H, CH₂), 2.19 (t, J = 7.3 Hz, CH₂CO), 3.27 (dt, J = 7.2, 5.5 Hz, 2H, NHCH₂), 3.41 (t, J = 6.5 Hz, 2H, BrCH₂), 5.79 (broad s, 1H, NH)

1³C NMR (100 MHz; CDCI₃) 5_C = 15.0 (CH₃), 24.4 (CH₂), 32.2 (CH₂Br), 33.4 (CH₂), 34.4 (NHCH₂), 35.7 (CH₂C=0), 172.3 (C=0)

m/z (CI⁺) 210.0 [M⁸¹BrH]⁺ (80%), 208.0 [M⁷⁹BrH]⁺ (80%), 128.1 (100%), 107.1 (60%) HRMS (CI⁺) calcd for C₇Hi₅ ⁸¹BrNO [M⁸¹BrH]⁺ 210.0317, found 210.0320; calcd for

C₇H₁₅ ⁷⁹BrNO [M⁷⁹BrH]⁺ 208.0337, found 208.0341

(5-(Ethylamino)-5-oxopentyl)triphenylphosphonium bromide, 96

Triphenylphosphine (2.88 g, 11 mmol, 1.1 eq.) was added to a solution of 5-bromo-A/- ethylpentanamide 95 (2.08 g, 10 mmol, 1 eq.) in MeCN (5 ml) and the mixture was stirred for 14 h at 80 °C. The mixture was allowed to cool to r.t. and concentrated under vacuum. The residue was added dropwise into Et₂0 (100 ml) and stirred vigourously for 10 min. The resulting solid was filtered, washed with Et₂0 (2 x 10 ml) and dissolved in CH₂CI₂ (15 ml). This solution was then added dropwise into Et₂0 (200 ml) and stirred for 10 min. Solids were filtered, washed with Et₂0 (2 x 10 ml) and dried under high vacuum to give the title product 96 as a white powder (3.87 g, 82 %).

Mp 177-179 °C

max (filmVcm^“1 3275 (broad), 2970, 2933, 1640, 1543, 1439, 1276, 1150, 643

*H NMR (400 MHz; CDCI₃) δ_Η = 1.06 (t, J = 7.3 Hz, 3H, CH₃), 1.63 (m, 2H, CH₂), 1.91 (quin., J = 6.5 Hz, CH₂), 2.57 (t, J = 6.5 Hz, 2H, CH₂C=0), 3.15 (q, J = 7.3, 5.6 Hz, 2H, NHCH₂), 3.66 (m, 2H, CH₂P⁺), 7.66 (m, 6H, ArCH’s), 7.75-7.82 (m, 9H, ArCH’s), 8.26 (t, J = 5.6 Hz, 1H, NH)

¹³C NMR (100 MHz; CDCI₃) 5_C = 14.8 (s, CH₃), 21.1 (d, J = 4.6 Hz, CH₂), 22.4 (d, J = 49.9 Hz, CH₂P⁺), 26.1 (d, J = 17.7 Hz, CH₂), 34.1 (s, CH₂), 34.2 (s, CH₂NH), 118.2 (d, J = 86.1 Hz, 3 x ArC), 130.6 (d, J = 12.3 Hz, 6 x ArCH), 133.8 (d, J = 10.0 Hz, 6 x ArCH), 135.1 (d, J = 3.1 Hz, 3 x ArCH), 172.7 (C=0) m/z (ESI⁺) 390.2 [M-Br]⁺

HRMS (ESI⁺) calcd for C25H29NOP [M-Br]⁺ 390.1981, found 390.1971

70. (Z)-7-((lR,2R,3R,5S)-3,5-Dihydroxy-2-((S,£)-3-hydroxy-5-phenylpent-l- enyl)cyclopentyl)-/V-ethylhept-5-enamide, bimatoprost, 97

(5-(Ethylamino)-5-oxopentyl)triphenylphosphonium bromide 96 (1.37 g, 2.91 mmol, 6 eq.) was added to a flame dried Schlenk flask, under N₂, and anhydrous THF (10 ml) added. The resulting suspension was cooled to 0 °C. KOt-Bu (653.0 mg, 5.82 mmol, 12 eq.) was added in one portion and the resulting orange mixture stirred at 0 °C for 40 min. A solution of crude triol 94 (0.485 mmol, 1 eq.) in anhydrous THF (2.5 ml) was added dropwise via syringe. After complete addition the mixture was stirred at r.t. for 1 h. The reaction was quenched with saturated aq. NH₄CI (10 ml) and extracted with EtOAc (5 x 10 ml). The combined organic phases were dried (MgS0₄), filtered, and concentrated to give the crude material as solids. These were triturated with EtOAc (10 ml) and the solids filtered and washed with EtOAc (4 x 10 ml). The filtrate was concentrated under vacuum and purified by column chromatography on silica, eluting with EtOAc/MeOH (97.5:2.5 to 95:5) to give 97 (99.2 mg) as a yellowish oil which was further purified by preparative TLC (EtOAc/MeOH 5%) to give BIMATOPROST97 (82.6 mg, 41% over 2 steps) as a clear, colourless oil. Analytical data consistent with the literature (Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010); Gutman, A. et al., US 20090163596 (2009)).

max (filmVcm-¹ 3300 (broad), 2930, 1643, 1550, 1453, 1332, 1293, 1048, 1029, 968, 729, 698

*H NMR (400 MHz; CDCI₃) δ_Η = 1.09 (t, J = 7.1 Hz, 3H, CH₃), 1.42-2.40 (m, 14H, 6 x CH₂, 2 x CH), 2.67 (m, 2H, CH₂), 3.22 (dq, J = 7.1, 6.3 Hz, 2H, CH₂NH), 3.41 (broad s, 3H, 3 x OH), 3.80-4.30 (broad m, 3H, 3 x CHOH), 5.37 (m, 2H, 2 x =CH), 5.47 (dd, J = 15.2, 7.9 Hz, 1H, =CH), 5.59 (dd, J = 15.2, 7.9 Hz, 1H, =CH), 5.90 (broad s, 1H, NH), 7.17 (m, 3H, ArCH’s), 7.26 (m, 2H, ArCH’s)

¹³C NMR ( 100 MHz; CDCI₃) 5_C = 14.8 (CH₃), 25.4 (CH₂), 25.6 (CH₂), 26.7 (CH₂), 31.9 (CH₂), 34.4 (CH₂NH), 35.8 (CH₂C=0), 38.8 (CH₂), 42.9 (CH₂), 50.2 (CH), 55.5 (CH), 72.3 (CHOH), 72.4 (CHOH), 77.7 (CHOH), 125.8 (ArCH), 128.4 (2 x ArCH), 128.5 (2 x ArCH), 129.1 (=CH), 129.7 (=CH), 133.7 (=CH), 135.1 (=CH), 142.0 (ArC), 173.4 (C=0)

m/z (ESI⁺) 438.2 [MNa]⁺

HRMS (ESI⁺) calcd for Q^IV^Na [MNa]⁺ 438.2614, found 438.2615

[a]_D ²² +41.1 (c. 0.35, CH₂CI₂) (lit. – Zanoni, G. et al., Tetrahedron 66, 7472-7478 (2010), +32.7 (c. 0.33, CH₂CI₂)) (lit. – Gutman, A. et al., US 20090163596 (2009), +36 (c. 1, MeOH))

References

“Bimatoprost Ophthalmic”. MedlinePlus. January 1, 2003. Archived from the original on 2007-10-05. Retrieved 2007-11-19.
“Allergan gets FDA approval for eyelash treatment”. BusinessWeek. Associated Press. December 26, 2008. Retrieved December 26, 2008.
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.
Rundle, Rhonda L. (2007-11-19). “Drug That Lengthens Eyelashes Sets Off Flutter”. The Wall Street Journal. Retrieved 2007-11-19.
The Pink Sheet: [1] Lauren Smith December 15, 2008; Volume 70, Number 050,Page^{[verification needed]}
Federation of American Societies for Experimental Biology Journal “The prostamide-related glaucoma therapy, bimatoprost, offers a novel approach for treating scalp alopecias” Randall et all. October 26, 2012.
Latisse prescribing information: “Important Safety Information”
MSNBC: FDA Seizes $2 Million Of Potentially Harmful SJ Eye Product KNTV-TV November 17, 2007^{[dead link]}
Reuters: “U.S. seizes discontinued eyelash product”. Jim Wolf. November 16, 2007.
Tappeiner C, Perren B, Iliev ME, Frueh BE, Goldblum D (May 2008). “Orbitale Fettgewebsatrophie bei lokaler Bimatoprost-Therapie – Kann Bimatoprost einen Enophthalmus verursachen?” [Orbital fat atrophy in glaucoma patients treated with topical bimatoprost–can bimatoprost cause enophthalmos?]. Klinische Monatsblätter für Augenheilkunde (in German)225 (5): 443–5. doi:10.1055/s-2008-1027362. PMID 18454393.
Filippopoulos T, Paula JS, Torun N, Hatton MP, Pasquale LR, Grosskreutz CL (2008). “Periorbital changes associated with topical bimatoprost”. Ophthalmic Plastic and Reconstructive Surgery 24 (4): 302–7. doi:10.1097/IOP.0b013e31817d81df. PMID 18645437.
Peplinski LS, Albiani Smith K (August 2004). “Deepening of lid sulcus from topical bimatoprost therapy”. Optometry and Vision Science 81 (8): 574–7.doi:10.1097/01.opx.0000141791.16683.4a. PMID 15300114.
Serrero G, Lepak NM (April 1997). “Prostaglandin F2alpha receptor (FP receptor) agonists are potent adipose differentiation inhibitors for primary culture of adipocyte precursors in defined medium”. Biochemical and Biophysical Research Communications 233 (1): 200–2. doi:10.1006/bbrc.1997.6433. PMID 9144422.
Curran MP (2009). “Bimatoprost: a review of its use in open-angle glaucoma and ocular hypertension”. Drugs Aging 26 (12): 1049–71. doi:10.2165/11203210-000000000-00000.PMID 19929032.
“Long Lashes Without Prescription, but With Risks”. Catherine Saint Louis. The New York Times. May 1, 2010
“Potentially Harmful “Cosmetic” Eye Product Seized” (Press release). U.S. Food and Drug Administration (FDA). November 19, 2007. Retrieved 2007-12-05.

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

US8101161	1-25-2012	Method of enhancing hair growth
US8101658	1-25-2012	NITRIC OXIDE DONATING PROSTAMIDES
US2011288179	11-25-2011	BIMATOPROST CRYSTALLINE FORM I
US8038988	10-19-2011	Method of Enhancing Hair Growth
US2011178340	7-22-2011	IMPROVED PROCESS FOR THE PRODUCTION OF BIMATOPROST
US2011130577	6-3-2011	Process for the Preparation of Prostaglandin Analogues and Intermediates Thereof
US2011124736	5-27-2011	COMPOSITIONS AND METHODS FOR STIMULATING HAIR GROWTH
US2011124737	5-27-2011	ENHANCED BIMATOPROST OPHTHALMIC SOLUTION
US7947740	5-25-2011	Bimatoprost crystalline form I
US2011112198	5-13-2011	COMPOSITIONS FOR ENHANCING HAIR GROWTH

US7897795	3-2-2011	Process for the Preparation of Prostaglandin Analogues and Intermediates Thereof
US2010324313	12-24-2010	METHOD FOR THE PURIFICATION OF PROSTAGLANDINS
US7851504	12-15-2010	Enhanced bimatoprost ophthalmic solution
US2010234466	9-17-2010	Compositions and Methods for Reducing Body Fat
US2010130444	5-28-2010	COMPLEXES OF PROSTAGLANDIN DERIVATIVES AND MONOSUBSTITUTED, CHARGED BETA-CYCLODEXTRINS
US2010105771	4-30-2010	AMINO ACID SALTS OF PROSTAGLANDINS
US2010105775	4-30-2010	AMINO ACID SALTS OF PROSTAGLANDINS
US7666912	2-24-2010	Compositions and methods for reducing body fat
US7652063	1-27-2010	10-HYDROXY-11-DIHYDROPROSTAGLANDIN ANALOGS AS SELECTIVE EP4 AGONISTS
US2010010239	1-15-2010	Process for the Production of Prostaglandins and Prostaglandin Analogs

US2009287003	11-20-2009	Process for the production of intermediates for making prostaglandin derivatives such as latanaprost, travaprost, and bimatoprost
US7611886	11-4-2009	Enzymatic transformation of a prostaglandin (bimatoprost) intermediate
US2009259066	10-16-2009	Method for preparing prostaglandin F analogue
US2009203659	8-14-2009	METHOD OF ENHANCING HAIR GROWTH
US2009149546	6-12-2009	Enhanced Bimatoprost Ophthalmic Solution
US2009088473	4-3-2009	METHOD FOR SCREENING OF PROSTAGLANDIN COMPOUNDS COMPRISING AN OPTIMAL FORMULATION FOR THE ENHANCEMENT OF HAIR GROWTH AND THE STIMULATION OF FOLLICULAR ANAGEN AND FORMULATIONS RESULTING THEREFROM
US7435746	10-15-2008	5-Thiopiperdinyl prostaglandin e analogs
US7332526	2-20-2008	COMPOSITIONS AND METHODS COMPRISING PROSTAGLANDIN-RELATED COMPOUNDS AND TREFOIL FACTOR FAMILY PEPTIDES FOR THE TREATMENT OF GLAUCOMA WITH REDUCED HYPEREMIA
US2008039507	2-15-2008	Novel Prostamides For The Treatment Of Glaucoma And Related Diseases
US2007270346	11-23-2007	COMPOSITIONS AND METHODS COMPRISING PROSTAGLANDIN-RELATED COMPOUNDS AND TREFOIL FACTOR FAMILY PEPTIDES FOR THE TREATMENT OF GLAUCOMA WITH REDUCED HYPEREMIA

US7244768	7-18-2007	Compositions and methods comprising prostaglandin related compounds and trefoil factor family peptides for the treatment of glaucoma with reduced hyperemia
US2007112058	5-18-2007	NOVEL PROSTAMIDES FOR THE TREATMENT OF GLAUCOMA AND RELATED DISEASES
US2007093507	4-27-2007	Compositions comprising benzo (g) quinoline derivatives and prostaglandin derivatives
US7186744	3-7-2007	Prostamides for the treatment of glaucoma and related diseases
US7169807	1-31-2007	10-Hydroxy-11-dihydroprostaglandin analogs as selective EP4 agonists
US7166730	1-24-2007	Process for the preparation of prostaglandin derivatives
US7161042	1-10-2007	Protected diols for prostaglandin synthesis
US7157590	1-3-2007	Process for the preparation of 17-phenyl-18,19,20-thinor-pgf 2a and its derivatives
US7141706	11-29-2006	Protected and unprotected triols for prostaglandin synthesis
US7109371	9-20-2006	Prostaglandin synthesis


US7101904	9-6-2006	Cyclopentane heptan(ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US7070768	7-5-2006	Method for imparting artificial tan to human skin
US6933289	8-24-2005	Inhibition of irritating side effects associated with use of a topical ophthalmic medication
US2005058614	3-18-2005	Methods for the treatment of gray hair using cyclopentane(ene) heptan(en)oic acid amides
US6864282	3-9-2005	9,11-cycloendoperoxide pro-drugs of prostaglandin analogues for treatment of ocular hypertension and glaucoma
US2005031697	2-11-2005	Compositions for delivery of therapeutics into the eyes and methods for making and using same
US6395787	5-29-2002	Ocular hypotensive lipids

EP0364417A1	Sep 6, 1989	Apr 18, 1990	Pharmacia AB	Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
EP0364417B1	Sep 6, 1989	Feb 9, 1994	Pharmacia AB	Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
EP0544899B1	Jun 19, 1992	Sep 6, 1995	CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT.	Prostaglandins
US5359095	Feb 8, 1994	Oct 25, 1994	Pharmacia Ab	Hydrogenation of doulbe bond in intermediate compound without deoxygenatio of allytic alcohol
US6689901	Jun 25, 2002	Feb 10, 2004	Pharmacia & Upjohn Company	Process and intermediates to prepare latanoprost
US6927300	Jan 26, 2001	Aug 9, 2005	Finetech Laboratories Ltd	Process for the preparation of Latanoprost
US7157590	May 3, 2002	Jan 2, 2007	Finetech Laboratories Ltd.	Chemical intermediate for vision defect drug
US7268239	Jul 27, 2005	Sep 11, 2007	Resolution Chemicals Limited	Process for the preparation of prostaglandins and analogues thereof
US7642370	Mar 20, 2007	Jan 5, 2010	Daiichi Fine Chemical Co., Ltd.	Method for preparing prostaglandin derivative
US7674921	Feb 25, 2008	Mar 9, 2010	Cayman Chemical Company, Inc.	cloprostenol or latanoprost; topical use; highly crystalline structures that are easy to formulate into ophthalmic solutions; hydrolysis of these analogs releases only the active PGF2 alpha analog free acid, without the production of toxic and irritant small aliphatic alcohol coproducts
US20090259066 *	Jul 3, 2008	Oct 15, 2009	Everlight Usa, Inc.	Method for preparing prostaglandin F analogue
US20090287003	Sep 29, 2006	Nov 19, 2009	Jiang Xing Chen	Process for the production of intermediates for making prostaglandin derivatives such as latanaprost, travaprost, and bimatoprost
US20100010239	Jul 10, 2009	Jan 14, 2010	Sandoz Ag	Process for the Production of Prostaglandins and Prostaglandin Analogs
WO2010097672A1	Feb 18, 2010	Sep 2, 2010	Sifavitor S.R.L.	Process for the preparation of prostaglandin derivatives

Organic spectroscopy should be brushed up and you get confidence

read my blog

ORGANIC SPECTROSCOPY INTERNATIONAL is the blog

Organic chemists from Industry and academics to interact on Spectroscopy techniques for Organic compounds ie NMR, MASS, IR, UV Etc. email me ……….. amcrasto@gmail.com

http://orgspectroscopyint.blogspot.in/ is the link

feder-0005.gif from 123gifs.eu amcrasto@gmail.com

Lumiracoxib…Selective cyclooxygenase-2-(COX-2) inhibitor. Anti-inflammatory.

July 31, 2014 7:21 am / Leave a comment

Lumiracoxib

2-[(2-Chloro-6-fluorophenyl)amino]-5-methylbenzeneacetic Acid;

2-[2-(2-Chloro-6-fluorophenylamino)-5-methylphenyl]acetic Acid;

CGS 35189; COX 189; Prexige;

Applications: Selective cyclooxygenase-2-(COX-2) inhibitor. Anti-inflammatory.

Lumiracoxib
Systematic (IUPAC) name

{2-[(2-chloro-6-fluorophenyl)amino]-5-methylphenyl} acetic acid
Clinical data
Trade names	Prexige
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	C (AU)
Legal status	℞-only Withdrawn (Australia, New Zealand, Canada, UK, Germany,Austria, Belgium, Cyprus, Brazil)
Routes	Oral
Pharmacokinetic data
Bioavailability	74-90%^[1]
Protein binding	>98%^[1]
Metabolism	Predominantly in the liver viaoxidation and hydroxylation(CYP2C9)^[1]
Half-life	5-8 hours^[1]
Excretion	Urine (54%) and faeces (43%)^[1]
Identifiers
CAS number	220991-20-8
ATC code	M01AH06
PubChem	CID 151166
DrugBank	DB01283
ChemSpider	133236
UNII

PDB ligand ID	LUR (PDBe, RCSB PDB)
Chemical data
Formula	C₁₅H₁₃Cl F N O₂
Mol. mass	293.72 g/mol

Lumiracoxib (rINN) is a carboxylic acid COX-2 selective inhibitor non-steroidal anti-inflammatory drug, manufactured by Novartis and still sold in few countries, including Mexico, Ecuador and the Dominican Republic, under the trade name Prexige (sometimes misquoted as “Prestige” by the media).^[1]

Lumiracoxib has several distinctive features. Its structure is different from that of other COX-2 inhibitors, such as celecoxib: lumiracoxib is an analogue of diclofenac (one chlorine substituted by fluorine, the phenylacetic acid has another methyl group in meta position), making it a member of the arylalkanoic acid class of NSAIDs; it binds to a different site on the COX-2 enzyme than do other COX-2 inhibitors; it is the only acidic coxib and has the highest COX-2 selectivity of any NSAID.^[2]

Since its original approval, lumiracoxib has been withdrawn from the market in several countries, mostly due to its potential for causing liver failure (sometimes requiring liver transplantation). It has never been approved for use in the United States.^[1]

History

The TARGET study (Therapeutic Arthritis Research and Gastrointestinal Event Trial) was conducted with more than 18,000 patients to test its gastrointestinal and cardiovascular safety against naproxen and ibuprofen and also study its efficacy against these two NSAIDs.

In November 2006, Prexige received marketing approval for all European Union countries through a common procedure called MRP. However, in August 2007, Prexige was withdrawn from the market in Australia following 8 serious liver adverse events, including 2 deaths and 2 liver transplants.^[3] On September 27, 2007, the US Food and Drug Administration issued a not approvable letter for lumiracoxib, requiring additional safety data.^[4] Canada withdrew Prexige (approved at 100 mg dose only) in October 2007.^[5] Several European Union countries followed suit in November 2007.^[6]

The FDA rejected Prexige as a trade name for lumiracoxib in 2003. Prexede was suggested as an alternative, but the FDA Division of Medication Errors and Technical Support (DMETS) subsequently recommended against it as well.^[7]

Withdrawal from market

On August 11, 2007, Australia’s Therapeutic Goods Administration (TGA, the national agency responsible for regulation of pharmaceuticals) cancelled the registration of lumiracoxib in Australia due to concerns that it may cause liver failure.^[8]

According to the TGA’s Principal Medical Adviser, Dr Rohan Hammett, as of 10 August 2007 the TGA had received 8 reports of serious adverse liver reactions to the drug, including two deaths and two liver transplants.

“The TGA and its expert advisory committee, the Adverse Drug Reactions Advisory Committee (ADRAC), have urgently investigated these reports. ADRAC has today recommended the cancellation of the registration of Lumiracoxib due to the severity of the reported side effects associated with this drug,” Dr Hammett said.

“The TGA has taken this advice to cancel the registration of Lumiracoxib in order to prevent further cases of severe liver damage.

“It seems that the longer people are on the medicine, the greater the chance of liver injury. The TGA is, therefore, advising people to stop taking the Lumiracoxib immediately and to discuss alternative treatments with their doctor,” Dr Hammett said.^[9]

New Zealand has followed suit with Australia in recalling Prexige.^[10]

On October 3, 2007, Health Canada requested sales of Prexige to stop. Novartis has agreed to the request and has taken steps to do so.^[11] On December 13, 2007, the European Medicines Agency recommended the withdrawal for Prexige from all EU markets.^[12]

On January 17, 2008, the Philippines Department of Health ordered Novartis Healthcare Phils. Inc. (Novartis) to remove (recall) all lumiracoxib from local drug stores in 2 weeks due to the harmful effects of the drug (potential serious liver-related side effects, hepatotoxicity or malfunction of the lungs).^[13]

On July 22, 2008, The Brazilian National Health Surveillance Agency ordered the withdrawal of 100 mg formulations of lumiracoxib and suspended marketing of the 400 mg formulation for 90 days,^[14] after a three-year safety review found a marked increase in adverse event reports; 35% of lumiracoxib-associated adverse events reported worldwide between July 2005 and April 2008 were found to have occurred in Brazil.^[15] Lumiracoxib was definitively withdrawn from the Brazilian market on October 3, 2008.^[16]

On November 12, 2008, INVIMA, the Colombian National Institute for Food and Drug Surveillance ordered the withdrawal of all presentations of lumiracoxib (Prexige), due to the international reports on hepatotoxicity.

MECHANISM

Synthesis

The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia / THF / ethanol gives the enol ether (II), which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene / THF to yield the imine (IV), which, without isolation, is aromatized with I2 in AcOH / THF to provide N- (2-chloro-6-fluorophenyl) -N- (4-methylphenyl) amine (V). The acylation of ( V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII), which is cyclized by means of AlCl3 by heating at 160? C to afford 1- (2-chloro-6-fluorophenyl) -5 -methylindolin-2-one (VIII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol / water and acidified with 1N HCl. Alternatively, the intermediate N- (2-chloro-6-fluorophenyl) -N- (4- methylphenyl) amine (V) can also be obtained by condensation of 2-chloro-N- (4-methylphenyl) acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2- ( 2-chloro-6-fluorophenoxy) -N- (4-methylphenyl) acetamide (XI), which is treated with MeONa in methanol to obtain the target secondary amine (V).

WO 0123346

The reduction of 2-iodo-5-methylbenzoic acid (I) with BH3/THF in THF gives 2-iodo-5-methylbenzyl alcohol (II), which is treated with refluxing 48% HBr to yield the benzyl bromide (III). Reaction of (III) with NaCN in ethanol/water afford the phenylacetonitrile (IV), which is hydrolyzed with NaOH in refluxing EtOH/water to provide the phenylacetic acid (V). Reaction of (V) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VI), which is treated with dimethylamine in diethyl ether/THF to yield 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide (VII). Condensation of (VII) with 2-chloro-6-fluoroaniline (VIII) by means of Cu powder, Cu2I2 and K2CO3 in refluxing xylene affords 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]-N,N-dimethylacetamide (IX), which is finally hydrolyzed with NaOH in refluxing butanol/water.

JP 2001514244; US 6291523; WO 9911605

References

Shi, S; Klotz, U (March 2008). “Clinical use and pharmacological properties of selective COX-2 inhibitors.”. European Journal of Clinical Pharmacology 64 (3): 233–52.doi:10.1007/s00228-007-0400-7. PMID 17999057.
Tacconelli S, Capone ML, Patrignani P (2004). “Clinical pharmacology of novel selective COX-2 inhibitors”. Curr Pharm Des 10 (6): 589–601. doi:10.2174/1381612043453108.PMID 14965322.
Urgent medicine recall – Lumiracoxib (PREXIGE)
http://hugin.info/134323/R/1156327/223186.pdf
Withdrawal of Market Authorization for Prexige
Media releases
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090B1_33_GG-FDA-Tab-U.pdf
Medicines Regulator cancels registration of anti inflammatory drug, Lumiracoxib, Therapeutic Goods Administration, 11 August 2007. Retrieved on 2007-08-11
http://www.tga.gov.au/media/2007/070811-lumiracoxib.htm
“NZ regulators ban arthritis drug”. The New Zealand Herald. 21 August 2007. Retrieved 12 September 2011.
http://www.novartis.ca/downloads/en/letters/prexige_fact_20071003_e.pdf
Press release: European Medicines Agency recommends withdrawal of the marketing authorisations for lumiracoxib-containing medicines, 13 December 2007
Abs-Cbn Interactive, DOH recalls lumiracoxib, sets two-week deadline
“Anvisa cancela registro do Prexige; consumidor deve substituir medicamento”. Folha de S. Paulo (in Portuguese). July 22, 2008. Retrieved 2008-07-22.
“Anvisa cancela registro do antiinflamatório Prexige” (Press release) (in Portuguese). Anvisa. July 22, 2008. Retrieved 2008-07-22.
“Anvisa suspende venda e uso de 2 antiinflamatórios” (in Portuguese). Terra. October 3, 2008. Retrieved 2008-10-03.

External links

ROFECOXIB

July 31, 2014 3:48 am / 2 Comments on ROFECOXIB

ROFECOXIB

MK-966, MK-0966, Vioxx

162011-90-7

C17-H14-O4-S

314.3596

Rofecoxib /ˌ r ɒ f ɨ ˈ k ɒ k s ɪ b / is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was approved by the Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx.

Rofecoxib
Systematic (IUPAC) name


4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one
Clinical data
Pregnancy cat.	C (AU)
Legal status	Prescription Only (S4) (AU)withdrawn
Routes	oral
Pharmacokinetic data
Bioavailability	93%
Protein binding	87%
Metabolism	hepatic
Half-life	17 hours
Excretion	biliary/renal
Identifiers
CAS number	162011-90-7
ATC code	M01 AH02
PubChem	CID 5090
DrugBank	DB00533
ChemSpider	4911
UNII	0QTW8Z7MCR

Chemical data
Formula	C₁₇H₁₄O₄S
Mol. mass	314.357 g/mol

Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.^[1]

On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib’s risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.^[2] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.^[3] Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens.

Rofecoxib was available on prescription in both tablet-form and as an oral suspension. It was available by injection for hospital use.

Mode of action

Pharmacokinetics

The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%.^[5]^[6]^[7] Rofecoxib crossed the placenta and blood–brain barrier,^[5]^[6]^[8]and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) of approximately 17 hours.^[5]^[7]^[9] The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib^[5]^[9] which are primarily excreted through urine.

Fabricated efficacy studies

On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated in order to augment the analgesic effects of the drugs. There is no evidence that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company Pfizer (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union’s regulatory agencies prior to the drug’s approval. Drug manufacturer Merckhad no comment on the disclosure.^[10]

Adverse drug reactions

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs.

Prostaglandin is a large family of lipids. Prostaglandin I2/PGI2/prostacyclin is just one member of it. Prostaglandins other than PGI2 (such as PGE2) also play important roles in vascular tone regulation. Prostacyclin/thromboxane are produced by both COX-1 and COX-2, and rofecoxib suppresses just COX-2 enzyme, so there is no reason to believe that prostacyclin levels are significantly reduced by the drug. And there is no reason to believe that only the balance between quantities of prostacyclin and thromboxane is the determinant factor for vascular tone.^[11] Indeed Merck has stated that there was no effect on prostacyclin production in blood vessels in animal testing.^[12] Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionized under physiological conditions. (Reddy & Corey, 2005)

Adverse cardiovascular events

VIGOR study and publishing controversy

The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary artery bypass).

Merck’s scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks “is primarily due to” this protective effect (Targum, 2001). Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference (Michaels 2005), and some outside scientists warned Merck that this claim was implausible before VIGOR was published.^[13] No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin.^[14]^[15] Though Dr. Topol’s 2004 paper criticized Merck’s naproxen hypothesis, he himself co-authored a 2001 JAMA article stating “because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib.” (Mukherjee, Nissen and Topol, 2001.)

The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, “Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen).”^[16] This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA were not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data.^[17] They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.^[18]

The editors charged that “more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article.” These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the “aspirin not indicated” group) and the editors noted that the omission “resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups.” The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication.^[19]

The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the “omitted” table were printed in the text of the article. The authors stood by the original article.^[20]

NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks).^[19]

Some scientists have accused the NEJM editorial board of making unfounded accusations.^[21]^[22] Others have applauded the editorial. Renowned research cardiologist Eric Topol,^[23] a prominent Merck critic, accused Merck of “manipulation of data” and said “I think now the scientific misconduct trial is really fully backed up”.^[24] Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying “this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies”.^[25]

On May 15, 2006, the Wall Street Journal reported that a late night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that “the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine‘s own role in aiding Vioxx sales.”^[26]

“Internal emails show the New England Journal’s expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal’s handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article.” The Journal stated that NEJM‘s “ambiguous” language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; “the New England Journal says it didn’t attempt to have these mistakes corrected.”^[26]

Alzheimer’s studies

In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer’s disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to rofecoxib.^[27] Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib’s safety.

APPROVe study

In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for theprophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (includingheart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations.^[28]

In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Other studies

Pre-approval Phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that “study 090,” a pre-approval trial, showed a 3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another [NSAID]), and an 8-fold increase in heart attacks and strokes combined compared to both control groups.^[29]^[30] Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib’s cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes.

Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005).

Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.^[31]

Other COX-2 inhibitors

Any increased risk of renal and arrhythmia pathologies associated with the class of COX-2 inhibitors, e.g. celecoxib (Celebrex), valdecoxib (Bextra), parecoxib (Dynastat),lumiracoxib, and etoricoxib is not evident,^[31] although smaller studies^[32]^[33] had demonstrated such effects earlier with the use of celecoxib, valdecoxib and parecoxib.

Nevertheless, it is likely that trials of newer drugs in the category will be extended in order to supply additional evidence of cardiovascular safety. Examples are some more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), which are currently (circa 2005) undergoing Phase III/IV clinical trials.

Besides, regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:^[34]

Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease
Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking
Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment

Other NSAIDs

Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older “trusted” NSAIDs such as ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties.

Withdrawal

Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.^[35]

In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.^[36]

On November 5, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004).

In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib’s benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen—though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.^[37]

In 2005, Merck retained Debevoise & Plimpton LLP to investigate Vioxx study results and communications conducted by Merck. Through the report, it was found that Merck’s senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team’s overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and showed that Merck intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results and withholding of information was the result of oversight, not malicious behavior. The Martin Report did conclude that the Merck’s marketing team exaggerated the safety of Vioxx and replaced truthful information with sales tactics.^{[citation needed]} The report was published in February 2006, and Merck was satisfied with the findings of the report and promised to consider the recommendations contained in the Martin Report. Advisers to the US Food and Drug Administration (FDA) have voted, by a narrow margin, that it should not ban Vioxx — the painkiller withdrawn by drug-maker Merck.

They also said that Pfizer’s Celebrex and Bextra, two other members of the family of painkillers known as COX-2 inhibitors, should remain available, despite the fact that they too boost patients’ risk of heart attack and stroke. url = http://www.nature.com/drugdisc/news/articles/433790b.html The recommendations of the arthritis and drug safety advisory panel offer some measure of relief to the pharmaceutical industry, which has faced a barrage of criticism for its promotion of the painkillers. But the advice of the panel, which met near Washington DC over 16–18 February, comes with several strings attached.

For example, most panel members said that manufacturers should be required to add a prominent warning about the drugs’ risks to their labels; to stop direct-to-consumer advertising of the drugs; and to include detailed, written risk information with each prescription. The panel also unanimously stated that all three painkillers “significantly increase the risk of cardiovascular events”.

The panel voted 17 to 15 against banning Vioxx (rofecoxib) entirely; the vote on Bextra (valdecoxib) was 17 to 13 with 2 abstentions; Celebrex (celecoxib) was endorsed 31 to 1. Shares of Merck, based in Whitehouse Station, New Jersey, and New York-based Pfizer closed up 13% and 7% respectively on 18 February, 2013, the day of the votes.

The FDA is expected to act on the recommendations within weeks. Although the agency usually follows the recommendations of its outside advisers, it is not bound to do so. A top official said that, in light of the closeness of some of the votes, the agency will examine the panel members’ comments in detail before deciding what to do.

An official from Merck said during the meeting that it would consider reintroducing Vioxx, which it withdrew in September 2004. On April 7, 2005, Pfizer withdrew Bextra from the U.S. market on recommendation by the FDA. Pfizer’s other painkiller, Celebrex, is still on the market.

Litigation

As of March 2006, there had been over 10,000 cases and 190 class actions filed against Merck^{[citation needed]} over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck’s warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.[1]

On August 19, 2005, a jury in Texas voted 10-2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack. The plaintiffs’ lead attorney was Mark Lanier. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award will almost certainly be capped at no more than US$26.1 million because of punitive damages limits under Texas law.[2] As of March 2006, the plaintiff had yet to ask the court to enter a judgment on the verdict; Merck has stated that it will appeal.

On November 3, 2005, Merck won the second case Humeston v. Merck, a personal injury case, in Atlantic City, New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston’s injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug’s risk.[3]

The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005 in Houston. The trial ended in a hung jury and a mistrial was declared on December 12, 2005. According to the Wall Street Journal, the jury hung by an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, where the Vioxx multidistrict litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study.

On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding.

In January 2006, Garza v. Merck began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The Texas state court of appeals in San Antonio later rules Garza’s fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award.[4]

On April 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr McDarby $4.5 million in compensatory damages based on Merck’s failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial, but was liable for fraud in the sale of the drug to Cona.

Merck has reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens. Patients who claim to have suffered as a result of taking Vioxx in countries outside the US are campaigning for this to be extended.

In March 2010, an Australian class-action lawsuit against Merck ruled that Vioxx doubled the risk of heart attacks, and that Merck had breached the Trade Practices Act by selling a drug which was unfit for sale.^[38]

In November 2011, Merck announced a civil settlement with the US Attorney’s Office for the District of Massachusetts, and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx.[5] Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability. Litigation with seven additional states remains outstanding. Under separate criminal proceedings, Merck plead guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.[6]

Other effects

Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.^[39]

Synthesis

Rofecoxib synthesis.^[40]

,,,,,,,,,,,,,,,,,

The oxidation of 4- (methylsulfanyl) acetophenone (X) with monoperoxyphthalic acid (MMPP) in dichloro-methane / methanol gives the corresponding sulfone (XI), which is brominated with Br2 / AlCl3 in chloroform, yielding the expected phenacyl bromide ( XII). Finally, this compound is cyclocondensed with phenylacetic acid (I) by means of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and triethylamine in acetonitrile. 5) Reaction of [4- (methylsulfonyl ) phenyl] phenylacetyl-ene (XIII) with CO catalyzed by Rh4 (CO) 12 in THF at 100 C in a stainless steel autoclave at 100 Atm pressure, followed by a chromatographic separation in a silicagel column to eliminate the undesired regioisomer.

……………….

The synthesis of rofecoxib can be performed by several different ways: 1) The condensation of phenylacetic acid (I) with ethyl bromoacetate (II) by means of triethylamine in THF yields 2- (phenylacetoxy) acetic acid ethyl ester (III), which is cyclized to the hydroxyfuranone (IV) by means of potassium tert-butoxide in tert-butanol. The reaction of (IV) with triflic anhydride and diisopropylethylamine in dichloro-methane affords the corresponding triflate (V), which by reaction with LiBr in hot acetone yields the bromofuranone (VI) The condensation of (VI) with 4- (methylsulfanyl) phenylboronic acid (VII) by means of Na2CO3 and Pd (Ph3P) 4 in hot toluene gives 4- [4- (methylsulfanyl) -phenyl]. – 3-phenylfuran-2 (5H) -one (VIII), which is finally oxidized with 2KHSO5.KHSO4.K2SO4 (oxone). 2) The intermediate (VIII) can also be obtained by condensation of triflate (V) with boronic acid ( VII) by means of Na2CO3 and Pd (Ph3P) 4 in hot toluene. 3) The intermediate (VIII) can also be synthesized by the reaction of triflate (V) with tetramethylammonium chloride, giving the chlorofuranone (IX), which is then condensed with boronic acid (VII) as before.

Footnotes

Jump up^ http://www.npr.org/templates/story/story.php?storyId=4054991
Jump up^ “Up to 140,000 heart attacks linked to Vioxx.”. New Scientist. 2005-01-25. p. 1.
Jump up^ “Merck Sees Slightly Higher 2007 Earnings”. New York Times. Reuters. 2006-12-07. p. A1.
Jump up^ Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M. B.; Hawkey, C. J.; Hochberg, M. C.; Kvien, T. K.; Schnitzer, T. J.; Vigor Study, G. (2000). “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis”. New England Journal of Medicine 343 (21): 1520–1528, 2 1528 following 1528. doi:10.1056/NEJM200011233432103. PMID 11087881. edit
^ Jump up to:^a ^b ^c ^d Merck & Co. VIOXX (rofecoxib tablets and oral suspension). Accessed at: http://www.merck.com/product/usa/pi_circulars/v/vioxx/vioxx_pi.pdf 01 Feb 2010
^ Jump up to:^a ^b Gold Standard Inc. Rofecoxib Vioxx Accessed at: http://www.mdconsult.com/das/pharm/body/181267313-3/946823742/full/2399 01 Feb 2010
^ Jump up to:^a ^b Davies, N. M.; Teng, X. W.; Skjodt, N. M. (2003). “Pharmacokinetics of rofecoxib: a specific cyclo-oxygenase-2 inhibitor”. Clinical pharmacokinetics 42 (6): 545–556.PMID 12793839. edit
Jump up^ Padi, S.; Kulkarni, S. (2004). “Differential effects of naproxen and rofecoxib on the development of hypersensitivity following nerve injury in rats”. Pharmacology, Biochemistry, and Behavior 79 (2): 349–358. doi:10.1016/j.pbb.2004.08.005. PMID 15501312. edit
^ Jump up to:^a ^b Scott, L. J.; Lamb, H. M. (1999). “Rofecoxib”. Drugs 58 (3): 499–505; discussion 506–7. doi:10.2165/00003495-199958030-00016. PMID 10493277. edit
Jump up^ Winstein, Keith J. (March 11, 2009). “Top Pain Scientist Fabricated Data in Studies, Hospital Says”. The Wall Street Journal.
Jump up^ Vane, J.; Bakhle, Y.; Botting, R. (1998). “Cyclooxygenases 1 and 2”. Annual review of pharmacology and toxicology 38: 97–120. doi:10.1146/annurev.pharmtox.38.1.97.PMID 9597150. edit
Jump up^ sfgate.com
Jump up^ www.saferdrugsnow.org
Jump up^ Karha, J.; Topol, E. J. (2004). “The sad story of Vioxx, and what we should learn from it”. Cleveland Clinic journal of medicine 71 (12): 933–934, 936, 934–9.doi:10.3949/ccjm.71.12.933. PMID 15641522. edit
Jump up^ Solomon, D. H.; Glynn, R. J.; Levin, R.; Avorn, J. (2002). “Nonsteroidal anti-inflammatory drug use and acute myocardial infarction”. Archives of Internal Medicine 162 (10): 1099–1104.doi:10.1001/archinte.162.10.1099. PMID 12020178. edit
Jump up^http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM166383.pdf
Jump up^ Curfman, G.; Morrissey, S.; Drazen, J. (2005). “Expression of concern: Bombardier et al., “Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis,” N Engl J Med 2000;343:1520-8″. The New England Journal of Medicine 353 (26): 2813–2814. doi:10.1056/NEJMe058314. PMID 16339408. edit
Jump up^ http://www.forbes.com/work/feeds/ap/2006/02/13/ap2523250.html. Missing or empty |title= (help)^{[dead link]}
^ Jump up to:^a ^b Curfman, G.; Morrissey, S.; Drazen, J. (2006). “Expression of concern reaffirmed”. The New England Journal of Medicine 354 (11): 1193. doi:10.1056/NEJMe068054.PMID 16495386. edit
Jump up^ Bombardier, C.; Laine, L.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M.; Hawkey, C.; Hochberg, M.; Kvien, T.; Schnitzer, T. J.; Weaver, A. (2006). “Response to expression of concern regarding VIGOR study”. The New England Journal of Medicine 354 (11): 1196–1199. doi:10.1056/NEJMc066096. PMID 16495387. edit
Jump up^ http://pipeline.corante.com/archives/2006/02/22/nejm_vs_its_contributors_round_two.php
Jump up^ http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=3293
Jump up^ http://genetics.case.edu/faculty2.php?fac=ejt9
Jump up^ http://www.medicinenet.com/script/main/art.asp?articlekey=56384&page=2
Jump up^ http://www.beasleyallen.com/news/vioxx-plaintiffs-seek-mistrial-after-allegation-on-merck-study/
^ Jump up to:^a ^b David Armstrong (2006-05-15). “How the New England Journal Missed Warning Signs on Vioxx”. Wall Street Journal. p. A1.
Jump up^ Konstam, M. A.; Weir, M. R.; Reicin, A.; Shapiro, D.; Sperling, R. S.; Barr, E.; Gertz, B. J. (2001). “Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib”. Circulation104 (19): 2280–2288. doi:10.1161/hc4401.100078. PMID 11696466. edit
Jump up^ Bresalier, R.; Sandler, R.; Quan, H.; Bolognese, J.; Oxenius, B.; Horgan, K.; Lines, C.; Riddell, R.; Morton, D.; Lanas, A.; Konstam, M. A.; Baron, J. A.; Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators (2005). “Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial”. The New England Journal of Medicine 352(11): 1092–1102. doi:10.1056/NEJMoa050493. PMID 15713943. edit
Jump up^ http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf
Jump up^ Wolfe, M. M. (2004). “Rofecoxib, Merck, and the FDA”. The New England Journal of Medicine 351 (27): 2875–2878; author 2878 2875–2878. doi:10.1056/NEJM200412303512719.PMID 15625749. edit
^ Jump up to:^a ^b Zhang, J.; Ding, E.; Song, Y. (2006). “Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials”. Journal of the American Medical Association 296 (13): 1619–1632. doi:10.1001/jama.296.13.jrv60015. PMID 16968832. edit
Jump up^ Solomon, S.; McMurray, J.; Pfeffer, M.; Wittes, J.; Fowler, R.; Finn, P.; Anderson, W.; Zauber, A.; Hawk, E.; Bertagnolli, M.; Adenoma Prevention with Celecoxib (APC) Study Investigators (2005). “Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention”. The New England Journal of Medicine 352 (11): 1071–1080.doi:10.1056/NEJMoa050405. PMID 15713944. edit
Jump up^ Nussmeier, N.; Whelton, A.; Brown, M.; Langford, R.; Hoeft, A.; Parlow, J.; Boyce, S.; Verburg, K. (2005). “Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery”. The New England Journal of Medicine 352 (11): 1081–1091. doi:10.1056/NEJMoa050330. PMID 15713945. edit
Jump up^ “European Medicines Agency concludes action on COX-2 inhibitors” (pdf). European Medicines Agency. Retrieved 2008-04-16.
Jump up^ “Merck Announces Voluntary Worldwide Withdrawal of VIOXX” (pdf). Retrieved 2008-04-16.
Jump up^ “Congress Questions Vioxx, FDA”. PBS NewsHour. 2004-11-18. Retrieved 2013-06-03.
Jump up^ “SUMMARY: Report of the Expert Advisory Panel on the Safety of Cox-2 Selective Non-steroidal Anti-Inflammatory Drugs (NSAIDs)”. Health Canada. 2005-07-06. Retrieved 2011-06-04.
Jump up^ Drug unfit for sale, says judge in compo case The Age, March 6, 2010
Jump up^ http://bioline.utsc.utoronto.ca/archive/00002693/01/dv04120.pdf#search=%22acne%20rofecoxib%22
Jump up^ http://vioxxlawyer.org/rofecoxib-synthesis/

References

FDA (2005). “Summary minutes for the February 16, 17 and 18, 2005, Joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee.” Published on the internet, March 2005. Link
Fitzgerald GA, Coxibs and Cardiovascular Disease, N Engl J Med 2004;351(17): 1709–1711. PMID 15470192.
Grassley CE (15 Oct 2004). Grassley questions Merck about communication with the FDA on Vioxx. Press Release.
Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M (2004). Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet (published online; see also Merck response below)
Karha J and Topol EJ. The sad story of Vioxx, and what we should learn from it Cleve Clin J Med 2004; 71(12):933-939. PMID 15641522
Michaels, D. (June 2005) DOUBT Is Their Product, Scientific American, 292 (6).
Merck & Co., (5 Nov 2004). Response to Article by Juni et al. Published in The Lancet on Nov. 5. Press Release.
Merck & Co (30 Sep 2004) Merck Announces Voluntary Worldwide Withdrawal of VIOXX. Press release [7].
D. M. Mukherjee, S. E. Nissen, and E. J. Topol, “Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors,” Journal of the American Medical Association 186 (2001): 954–959.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352(11):1081-91. PMID 15713945
Okie, S (2005) “Raising the safety bar–the FDA’s coxib meeting.” N Engl J Med. 2005 Mar 31;352(13):1283-5. PMID 15800221.
Leleti Rajender Reddy, Corey EJ. Facile air oxidation of the conjugate base of rofecoxib (Vioxx), a possible contributor to chronic human toxicity Tetrahedron Lett 2005, 46: 927. doi:10.1016/j.tetlet.2004.12.055
Swan SK et al., Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet. Annals of Int Med 2000; 133:1–9
Targum, SL. (1 Feb. 2001) Review of cardiovascular safety database. FDA memorandum. [8]
Wolfe, MM et al., Gastrointestinal Toxicity of Nonsteroidal Anti-anflamattory Drugs, New England Journal of Medicine. 1999; 340; 1888-98.

External links

National Public Radio 2004 Q&A on the case, following withdrawal announcement
Court TV’s full coverage of the Vioxx civil trials
Merck website on Vioxx litigation
FDA Public Health Advisory on Vioxx
David Michaels. Doubt is Their Product Scientific American, June 2004, p. 96-101
JURIST, Much Pain, Much Gain: Skeptical Ruminations on the Vioxx Litigation
Ted Frank, American Enterprise Institute, The Vioxx Litigation, Part I and Part II, December 2005
briandeer.com – Vioxx: the UK connection
Campaign for compensation for Vioxx victims outside the US

Cimicoxib

July 30, 2014 9:06 am / Leave a comment

Cimicoxib

UR-8880,

CAS 265114-23-6,

Molecular Formula: C₁₆H₁₃ClFN₃O₃S

Molecular Weight: 381.809123

Uriach (Originator)

4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)-1H-imidazol-1-yl]benzenesulfonamide

IN PHASE 2

Cimicoxib (trade name Cimalgex) is a non-steroidal anti-inflammatory drug (NSAID) used in veterinary medicine to treat dogs for pain and inflammation associated with osteoarthritis and for the management of pain and inflammation associated with surgery.^[1] It acts as a COX-2 inhibitor.

Cimicoxib is a selective COX-2 inhibitor being developed by Affectis as a treatment for depression and schizophrenia. If approved, Cimicoxib would be the first drug in decades to treat depression by a new mechanism of action

Cimicoxib, an imidazole derivative, is a selective cyclooxygenase-2 (COX-2) inhibitor. The product was in phase II development at Affectis Pharmaceuticals for the oral treatment of major depression, however, no recent development have been reported. Originally developed by Uriach, the compound was acquired by Palau Pharma, a spin-off created by Uriach in November 2006.

In 2007, Palau Pharma licensed global rights to cimicoxib to Affectis Pharmaceuticals for all CNS indications. Palau had been clinically evaluating the compound for the treatment of osteoarthritis, pain and rheumatoid arthritis, however, no recent development has been reported for these indications. The compound holds potential for the treatment of schizophrenia.

Chemical structure for CID 213053

Treatment of 4-(acetylamino)phenylsulfonyl chloride (I) with tert-butylamine yields sulfonamide (II), which on deprotection with potassium hydroxide gives amine (III). Reaction of compound (III) with 4-methoxy-3-fluorobenz-aldehyde gives imine (IV), which is cyclized with tosylmethyl isocyanide to afford imidazole (V). Regioselective chlorination of compound (V) with N-chlorosuccinimide (NCS) to afford the chloroimidazole (VI) and then deprotection of the sulfonamide group of (VI) yields cimicoxib in 40% overall yield.

EP 1122243; JP 2002527508; WO 0023426, ES 2184633; WO 0316285

……………………………….

http://www.google.com/patents/EP1424329A1?cl=en

EXAMPLE 1

4-Amino-N- tert -butylbenzenesulfonamide Method A:

[0031]

a) N-tert-Butyl-4-nitrobenzenesulfonamide

[0032]

To a solution of tert-butylamine (0.47 L, 6.4 mol) in THF (0.55 L) is slowly added, at 0 °C, a solution of 4-nitrobenzenesulfonyl chloride (50 g, 0.23 mol) in THF (0.55 L) and the resulting mixture is stirred for 24 h at room temperature. The solvent is removed and the residue is taken up in a CHCl₃/0.5 N HCl mixture, the layers are separated and the aqueous phase is extracted with CHCl₃. The combined organic extracts are washed with H₂O and brine and dried over MgSO₄. The solvent is removed, yielding 56.3 g of a yellowish solid which is directly used in the next reaction (yield: 97%).
Mp: 105-109°C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.29 (s, 9 H), 5.07 (s, 1 H), 8.13 (d, J = 9 Hz, 2 H), 8.39 (d, J = 9 Hz, 2 H).

b) Title compound

[0033]

A solution of N-tert-butyl-4-nitrobenzenesulfonamide (10.0 g, 39 mmol) in EtOH (100 mL) is stirred for 48 h under a H₂ atmosphere in the presence of 10% Pd/C (1.50 g). The resulting mixture is filtered and concentrated to give the desired product as a slightly-coloured solid (8.7 g, yield: 98%).
Mp: 127 °C; ¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 1.19 (s, 9 H), 3.74 (s, CD₃OD + 1 H), 6.93 (d, J = 9 Hz, 2 H), 7.66 (d, J = 9 Hz, 2 H).

Method B:

[0034]

a) 4-Acetylamino-N-tert-butylbenzenesulfonamide

[0035]

To a suspension of 4-acetylaminobenzenesulfonyl chloride (10 g, 43 mmol) in DME (103 mL) is added, at 0 °C, tert-butylamine (9 mL, 86 mmol) in DME (103 mL). Next, the reaction mixture is stirred for 4 h at reflux. The solvent is removed and CHCl₃ is added. The resulting suspension is filtered and the solid is washed with CHCl₃, H₂O and Et₂O. The solid obtained is dried in vacuo to give 8.0 g of the product as a white solid (yield: 68%).
Mp: 200-201 °C; ¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 1.15 (s, 9 H), 2.12 (s, 3 H), 4.21 (s, 2H + CD₃OD), 7.66 (d, J = 9 Hz, 2 H), 7.75 (d, J = 9 Hz, 2 H).

b) Title compound

[0036]

A solution of 4-acetylamino-N-tert-butylbenzenesulfonamide (8.0 g, 29.6 mmol), KOH (8.30 g, 148 mmol), H₂O (6 mL) and MeOH (24 mL) is heated at 100°C for 2 h. H₂O (24 mL) is added and the mixture is heated for two more hours. It is allowed to cool, H₂O is added and it is brought to pH 8 with 1N HCl. It is then extracted with EtOAc, dried over Na₂SO₄ and the solvent is removed, to give 6.0 g of the product as a white solid (yield: 89%).

EXAMPLE 2 N- tert -Butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide

[0037]
[0038]

A mixture of 4-amino-N-tert-butylbenzenesulfonamide (52.3 g, 0.23 mol, obtained in example 1), 3-fluoro-4-methoxybenzaldehyde (35.3 g, 0.23 mol) and toluene (2.5 L) is heated at reflux in a Dean-Stark for 24 h. The solvent is removed, yielding 83.5 g of the title compound (yield: quantitative).
Mp: 129-131 °C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.23 (s, 9 H), 3.98 (s, 3 H), 4.65 (s, 1 H), 7.04 (t, J = 8.1 Hz, 1 H), 7.21 (d, J = 6.7 Hz, 2 H), 7.58 (m, 1 H), 7.73 (dd, J_H-F = 11.8 Hz, J = 2 Hz, 1 H), 7.90 (d, J = 6.7 Hz, 2 H), 8.33 (s, 1 H).

EXAMPLE 3 N-tert-Butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

[0039]
[0040]

A mixture of N-tert-butyl-4-[(3-fluoro-4-methoxybenzylidene)amino]benzenesulfonamide (41.5 g, 114 mmol, obtained in example 2), tosylmethylisocyanide (33.22 g, 171 mmol), K₂CO₃ (31.1 g, 228 mmol), DME (340 mL) and MeOH (778 mL) is heated at reflux for 3 h. The solvent is removed and the residue is taken up in a CHCl₃/H₂O mixture and the layers are separated. The aqueous phase is extracted with CHCl₃ and the combined organic extracts are dried over MgSO₄ and concentrated. A crude product is obtained, which is washed with Et₂O several times to give 41.40 g of a creamy solid that is directly used in the next reaction (yield: 90%).
Mp: 229-232°C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (s, 1 H), 7.29 (d, J = 8.7 Hz, 2 H), 7.73 (s, 1 H), 7.94 (d, J = 8.7 Hz, 2 H).

EXAMPLE 4 N-tert-Butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

[0041]
[0042]

A mixture of N-tert-butyl-4-[5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (41.40 g, 103 mmol, obtained in example 3) and acetonitrile (840 mL) is heated at reflux and acetonitrile is added until complete dissolution (200 mL more). Next, N-chlorosuccinimide (15.0 g, 113 mmol) is added and the mixture is refluxed for 24 h. The solvent is removed and the residue is suspended in EtOAc and 1N HCl and is stirred for 10 min. The solid obtained is filtered and washed directly in the filter with 1N HCl, 1N NaOH, saturated NH₄Cl solution, H₂O and Et₂O. A solid is obtained, which is dried in vacuo to give 37.0 g of the product as a creamy solid (yield: 82%).
Mp: 208-210 °C; ¹H-NMR (300 MHz, CDCl₃) δ (TMS): 1.24 (s, 9 H), 3.89 (s, 3 H), 4.51 (s, 1 H), 6.90 (m, 3 H), 7.23 (d, J = 8.7 Hz, 2 H), 7.63 (s, 1 H), 7.92 (d, J = 8.7 Hz, 2 H).

EXAMPLE 5 4-[4-Chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide

[0043]
[0044]

A mixture of N-tert-butyl-4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (37.0 g, 85 mmol, obtained in example 4), concentrated HCl (200 mL) and H₂O (200 mL) is heated at reflux for 3 h. The mixture is allowed to cool and is brought to pH 6 with 6N NaOH. A white precipitate appears, which is collected by filtration and washed with plenty of H₂O and then with CHCl₃. 31 g of the title compound of the example is obtained (yield: 97%), which are recrystallized from acetonitrile.
Mp: 211-212 °C;
¹H-NMR (300 MHz, CDCl₃ + CD₃OD) δ (TMS): 3.90 (s, 3 H), 4.16 (s, CD₃OD + 2 H), 6.93 (m, 3 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.73 (s, 1 H), 7.95 (d, J = 8.7 Hz, 2 H).

References

“European Public Assessment Report: Cimalgex (cimicoxib)”. European Medicines Agency.

23685411	9-1-2013	Detection and quantification of cimicoxib, a novel COX-2 inhibitor, in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology.	Journal of pharmaceutical and biomedical analysis
23710692	6-1-2013	Efficacy and safety of cimicoxib in the control of perioperative pain in dogs.	The Journal of small animal practice
17335184	4-5-2007	NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties.	Journal of medicinal chemistry
15481993	10-21-2004	New water-soluble sulfonylphosphoramidic acid derivatives of the COX-2 selective inhibitor cimicoxib. A novel approach to sulfonamide prodrugs.	Journal of medicinal chemistry
12877584	7-31-2003	Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.	Journal of medicinal chemistry

US2005080084	4-15-2005	Compositions of a cyclooxygenase-2 selective inhibitor and a serotonin-modulating agent for the treatment of central nervous system damage
US2005075341	4-8-2005	Compositions of a cyclooxygenase-2 selective inhibitor and an IKK inhibitor for the treatment of ischemic mediated central nervous system disorders or injury

US2009012307	1-9-2009	Process for the Preparation of 4-(imidazol-1-yl)benzenesulfonamide Derivatives
US2008213376	9-5-2008	Medicament that is Intended for Oral Administration, Comprising a Cyclooxygenase-2 Inhibitor, and Preparation Method Thereof
US7351836	4-2-2008	Method of preparing 4-(imidazol-1-yl)benzenesulphonamide derivatives
US2007149591	6-29-2007	Compositions of a cyclooxygenase-2 selective inhibitor administered under hypothermic conditions for the treatment of ischemic mediated central nervous system disorders or injury
US2005148589	7-8-2005	Compositions of a cyclooxygenase-2 selective inhibitor and a neurotrophic factor-modulating agent for the treatment of central nervous system mediated disorders
US2005113434	5-27-2005	Compositions of a cyclooxygenase-2 selective inhibitor administered under hypothermic conditions for the treatment of ischemic mediated central nervous system disorders or injury
US2005101597	5-13-2005	Compositions of a cyclooxygenase-2 selective inhibitior and a non-NMDA glutamate modulator for the treatment of central nervous system damage
US2005085478	4-22-2005	Compositions of a cyclooxygenase-2 selective inhibitor and a low-molecular-weight heparin for the treatment of central nervous system damage
US2005085479	4-22-2005	Mediated central nervous system compositions of a cyclooxygenase-2 selective inhibitor and a corticotropin releasing factor antagonist for the treatment of ischemic disorders or injury

Tilmacoxib

July 30, 2014 8:13 am / Leave a comment

Tilmacoxib

JTE-522, JTP-19605, RWJ-57504,

CAS 180200-68-4,

4-(4-Cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide

4-(4-cyclohexyl-2-methyl-1,3-oxazol-5-yl)-2-fluorobenzenesulfonamide

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo(4,5)imidazo(1,2a)pyridine-4-N–(2-fluorophenyl)carboxamide

4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide

Molecular Formula: C₁₆H₁₉FN₂O₃S

Molecular Weight: 338.397063

Japan Tobacco (JT) (Originator)

Tilmacoxib or JTE-522 is a COX-2 inhibitor and is an effective chemopreventive agent against rat experimental liver fibrosis.^[1]

A member of the class of 1,3-oxazoles that is that is 1,3-oxazole which is substituted at positions 2, 4 and 5 by methyl, cyclohexyl, and 3-fluoro-4-sulfamoylphenyl groups, respectively.

………..

4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: Enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522
J Med Chem 2002, 45(7): 1511

http://pubs.acs.org/doi/abs/10.1021/jm010484p

A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities. In contrast, introduction of a fluorine atom preserved COX-2 potency and notably increased COX1/COX-2 selectivity. This work led to the identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522 [9d, 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide], which is currently in phase II clinical trials for the treatment of rheumatoid arthritis, osteoarthritis, and acute pain.

9d as a white solid: mp 166−167 °C; ¹H NMR (CDCl₃) δ 1.3−1.5 (m, 3H), 1.6−1.9 (m, 7H), 2.51 (s, 3H), 2.79 (tt, J = 3.7, 11.3 Hz, 1H), 5.11 (s, 2H), 7.36−44 (m, 2H), 7.94 (t, J = 7.9 Hz, 1H). Anal. (C₁₆H₁₉FN₂O₃S) C, H, N.

………………

WO 1996019463 OR http://www.google.com/patents/EP0745596A1?cl=en

Example 2

[0080]

Synthesis of 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)
Step 10) Cyclohexyl 3-fluorobenzyl ketone (formula (IV’); R’=cyclohexyl, R₁‘=3-fluorophenyl)
[0081]

To a solution of tetrakis(triphenylphosphine)palladium (2.00 g) and zinc powder (17.98 g) in 1,2-dimethoxyethane (50 ml) was added a solution of cyclohexanecarbonyl chloride (20.00 g) in 1,2-dimethoxyethane (50 ml) at room temperature under a nitrogen atmosphere. A solution of 3-fluorobenzyl bromide (26.00 g) in 1,2-dimethoxyethane (100 ml) was gradually added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, and at room temperature for 2 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. Then, ethyl acetate (200 ml) was added to the residue, and the mixture was washed with 1N hydrochloric acid, and then with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 29.20 g of an oily crude product.
Step 16) 2-Cyclohexyl-1-(3-fluorophenyl)-2-oxoethyl acetate (formula (V”); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂‘=methyl, Z=oxygen atom)
[0082]

Lead tetraacetate (75.00 g) was added to a solution of the compound (29.20 g) obtained in the above Step 10) in acetic acid (300 ml). The mixture was refluxed under heating for 1.5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give 18.30 g of the title compound as an oil (yield 50%).
Step 17) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂=methyl, Z=oxygen atom)
[0083]

A solution of the compound (18.00 g) obtained in the above Step 16) and ammonium acetate (15.00 g) in acetic acid (100 ml) was refluxed under heating for 5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 17.20 g of an oily crude product. Step 15) 5-(4-Aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom)
[0084]

To a solution of the compound (17.00 g) obtained in the above Step 17) in chloroform (80 ml) was added dropwise chlorosulfonic acid (27 ml) with stirring under ice-cooling, and the mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature, and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
[0085]

Aqueous ammonia (28%) was added to a solution of the obtained compound (10.00 g) in tetrahydrofuran (40 ml) with stirring at room temperature, and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent; dichloromethane:ethyl acetate=6:1) to give 5.74 g of the title compound (yield 61%).

Example 2′

[0086]

The compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom) was synthesized according to another synthetic method.
Step 11) Cyclohexyl 3-fluorobenzyl ketone oxime (formula (XI); R’= cyclohexyl, R₁‘=3-fluorophenyl)
[0087]

To a solution of the compound (353 g) obtained according to a method similar to that of the above Example 2, Step 10) in ethanol (1300 ml) were added hydroxylamine hydrochloride (123 g) and sodium acetate (158 g). The mixture was refluxed under heating for 2 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was recrystallized from n-heptane to give 160 g of the title compound (yield 42%).
Step 14) 4-Cyclohexyl-5-(3-fluorophenyl)-2-methyloxazole (formula (XIII); R’=cyclohexyl, R₁‘=3-fluorophenyl, R₂=methyl, Z=oxygen atom)
[0088]

Acetic anhydride (95 ml) was dropwise added to a solution of the compound (158 g) obtained in the above Step 11) in acetic acid (900 ml) with stirring at room temperature, and the mixture was refluxed under heating for 7 hours. The solvent was evaporated under reduced pressure and n-heptane was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution, saturated brine and acetonitrile. The solvent was evaporated under reduced pressure to give 119 g of the title compound as an oil.
[0089]

Then, the obtained compound (119 g) was reacted in the same manner as in the above Example 2, Step 15) to give a compound of Example 2 (formula (I); R=cyclohexyl, R₁=4-aminosulfonyl-3-fluorophenyl, R₂=methyl, Z=oxygen atom).

Example 3

[0090]

Synthesis of 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)
Step 15) 4-Cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (formula (I); R=cyclohexyl, R₁=3-fluoro-4-methylsulfonylphenyl, R₂=methyl, Z=oxygen atom)
[0091]

To a solution of the compound (17.00 g) obtained in the above Example 2, Step 17) in chloroform (80 ml) was dropwise added chlorosulfonic acid (27 ml) with stirring under ice-cooling. The mixture was heated at 100°C for 3 hours. The reaction mixture was cooled to room temperature and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
[0092]

Water (25 ml) was added to the obtained compound (3.66 g). To the mixture were added sodium sulfite (1.42 g) and sodium hydrogencarbonate (1.89 g) successively with stirring at room temperature. The mixture was heated at 70°C for 2 hours. Ethanol (25 ml) and methyl iodide (2.20 g) were added to the mixture, and the mixture was heated at 100°C for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate.
[0093]

The solvent was evaporated under reduced pressure, and the residue was saparated and purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to give 0.82 g of the title compound (yield 24%).

References

Yamamoto, H., Kondo, M., Nakamori, S., Nagano, H., Wakasa, K., Sugita, Y., Chang-De, J., Kobayashi, S., Damdinsuren, B., Dono, K., Umeshita, K., Sekimoto, M., Sakon, M., Matsuura, N., Monden, M. (2003). “JTE-522, a cyclooxygenase-2 inhibitor, is an effective chemopreventive agent against rat experimental liver fibrosis1”. Gastroenterology 125 (2): 556–571. doi:10.1016/s0016-5085(03)00904-1. PMID 12891558.

11906292

3-28-2002

4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522(1).

Journal of medicinal chemistry

10406640

7-5-1999

The discovery of rofecoxib, [MK 966, Vioxx, 4-(4′-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxygenase-2-inhibitor.

Bioorganic & medicinal chemistry letters

Apricoxib, A COX-2 inhibitor.

July 29, 2014 3:52 am / 1 Comment on Apricoxib, A COX-2 inhibitor.

APRICOXIB

A COX-2 inhibitor.

MF; C19H20N2O3S

Mol wt: 356.439

CAS: 197904-84-0

CS-701; TG01, R-109339, TG-01 ,TP-1001
TP-2001, Capoxigem, Kymena, UNII-5X5HB3VZ3Z,

Benzenesulfonamide, 4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]-;

4-[2-(4-Ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide

4-[2-(4-ethoxyphenyl)-4-methyl-1H-pyrrol-1-yl]benzenesulfonamide .

PHASE 2 http://clinicaltrials.gov/search/intervention=Apricoxib

Daiichi Sankyo (innovator)Daiichi Sankyo Co Ltd,

Current developer: Tragara Pharmaceuticals, Inc.

Apricoxib is an orally bioavailable nonsteroidal anti-inflammatory agent (NSAID) with potential antiangiogenic and antineoplastic activities. Apricoxib binds to and inhibits the enzyme cyclooxygenase-2 (COX-2), thereby inhibiting the conversion of arachidonic acid into prostaglandins. Apricoxib-mediated inhibition of COX-2 may induce tumor cell apoptosis and inhibit tumor cell proliferation and tumor angiogenesis. COX-related metabolic pathways may represent crucial regulators of cellular proliferation and angiogenesis.

Chemical structure for apricoxib

R-109339 is a cyclooxygenase-2 (COX-2) inhibitor currently in phase II clinical development at Tragara Pharmaceuticals for the oral treatment of non-small cell lung cancer (NSCLC) and for the treatment of inflammation. Additional phase II clinical trials are ongoing in combination with gemcitabine and erlotinib for the treatment of pancreas cancer. The company had been evaluating R-109339 for the treatment of colorectal cancer, but development for this indication was discontinued for undisclosed reasons. Daiichi Sankyo and Tragara Pharmaceuticals had been conducting phase II clinical trials with the drug candidate for the oral treatment of arthritis and for the treatment of breast cancer, respectively; however, no recent development for this indication has been reported.

COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid, which is derived from the cellular phospholipid bilayer by phospholipase A2. In addition to several other functions, prostaglandins act as messenger molecules in the process of inflammation. The compound is also designed to act against a well-defined cancer pathway that affects several routes of cancer pathogenesis. In preclinical cancer models, R-109339 demonstrated superiority to compounds with similar mechanisms of action and potential for use in combination with cisplatin. Furthermore, the compound demonstrated the ability to inhibit the cachexia and weight loss seen in mouse tumor models.

Apricoxib, (CS-706, 1) 2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, a small-molecule, orally active, selective COX-2 inhibitor was discovered by investigators at Daiichi Sankyo in 1996. Clinical studies demonstrated potent analgesic activity and preclinical studies demonstrated good pharmacokinetics, pharmacodynamics and gastrointestinal tolerability. As an anticancer agent, preclinical studies demonstrated efficacy in biliary tract cancer models and colorectal carcinoma, and Recamp et al.

The original synthetic route is outlined below. Though the initial two steps were accomplished with decent yields, the final step of pyrrolidine formation followed by dehydration and dehydrocyanation produced only 3% of 1 as a brown powder. The yield in the last step of the synthesis of the 2-(4-methoxyphenyl) analog, 2-(4-methoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-pyrrole, was 6%, indicating that this synthesis route is problematic.

14 Kimura T, Noguchi Y, Nakao A, Suzuki K, Ushiyama S, Kawara A, Miyamoto M. 799823. EP. 1997:A1.

An external file that holds a picture, illustration, etc. 
Object name is nihms324531f1.jpg

……………………….

Synthesis

Bioorg Med Chem Lett. Oct 15, 2011; 21(20): 6071–6073.

Published online Aug 19, 2011. doi: 10.1016/j.bmcl.2011.08.050

SEE AT

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310163/

An efficient synthesis of apricoxib (CS-706), a selective cyclooxygenase inhibitor, was developed using copper catalysed homoallylic ketone formation from methyl 4-ethoxybenzoate followed by ozonolysis to an aldehyde, and condensation with sulphanilamide. This method provided multi-gram access of aprocoxib in good yield. Apricoxib exhibited potency equal to celecoxib at inhibition of prostaglandin E₂ synthesis in two inflammatory breast cancer cell lines.

We envisioned that 7 could be prepared by ozonolysis of homoallylic ketone (8) (Route B). A recent development in the synthesis of homoallylic ketones by Dorr et al. via copper-catalyzed cascade addition of alkenylmagnesium bromide to an ester a²⁴ was examined. Treatment of commercially available methyl 4-ethoxybenzoate with 1-propenylmagnesium bromide (4.0 equiv) in presence of CuCN (0.6 equiv) resulted in 95% yield of desired ketone8 after silica gel chromatography, along with a minor amount of unreacted ester).b²⁵

An external file that holds a picture, illustration, etc.<br /><br /><br /><br /><br /><br /><br /><br /><br /><br /><br />
Object name is nihms324531f3.jpg

Efficient synthesis of apricoxib (1):

The product was a mixture of cis/trans R/S stereoisomers, as detected in the ¹H NMR spectrum, and was used directly in the next step without separation. Ozone was bubbled through a solution of 8 in MeOH/CH₂Cl₂ at −78°C, until all starting materials were consumed. The ozonide was then reduced to aldehyde 7 by treatment with Me₂S overnight. Removal of volatiles and subsequent addition and evaporation of toluene gave the crude 1,4-dicarbonyl compound 7 which was sufficiently pure for the following condensation step. The ¹H NMR signal at 9.78 ppm of the crude product confirmed the formation of the aldehyde. No attempt was made to characterize the enantiomeric ratio of 7 since the dehydration/aromatization reaction of the next step removes the chirality of the product. Treatment of 7 with sulfanilamide in 40% acetic acid-acetonitrile at 70°C for three hours resulted in a brown product. Purification by silica gel flash chromatography yielded 71% of pure 1 as a white solid.c²⁶

a24. Dorr AA, Lubell WD. Can J Chem. 2007;85:1006.

b25. Synthesis of 1-(4-ethoxy-phenyl)-3-methyl-hex-4-en-1-one (8): To a stirred suspension of CuCN (1.8 g, 20.0 mmol) in 50 mL of dry THF at −78°C under argon, a solution of 1-propenylmagnesium bromide (133.2 mmol, 265 mL of 0.5 M solution in THF) was added dropwise. The slurry was stirred for an additional 30 min and then a solution of methyl 4-ethoxybenzoate (6.0 g, 33.3 mmol) in 60 mL of dry THF was added slowly. The stirred reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with ice cold saturated aqueous NaH₂PO₄ (100mL) and the mixture was extracted with ether (4 × 100 mL). The combined ether extracts were washed with brine (2 × 100mL), dried (MgSO₄), filtered, and evaporated to dryness. The crude homoallylic ketone was purified by silica gel flash chromatography using a gradient of ethyl acetate in hexane as the eluent to give 8 (7.4 g, 95%) as a colorless oil. ¹H NMR (CDCl₃, 300.0 MHz) δ 1.04–1.07 (m, 3H), 1.44 (t, J = 6.9 Hz, 3H), 1.6–1.64 (m, 3H), 2.8–2.96 (m, 2.5H), 3.2 (m, 0.5H), 4.1 (q, J = 6.9 Hz, 2H), 5.25 (m, 0.5 H), 5.34–5.46 (m, 1.5H), 6.92 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H). ¹³C NMR (CDCl₃, 75.0 MHz) δ 12.9, 14.6, 17.9, 20.4, 21.0, 28.4, 33.0, 45.4, 45.5, 63.7, 114.1, 123.1, 123.4, 130.2, 130.3, 135.5, 136.0, 141.9, 162.7, 198.1. M+H Calcd: 233.1542; Found, 233.2482.

c26. Synthesis of Apricoxib (1): Homoallylic ketone (8) (5.0 g, 21.53 mmol) in 180 mL of CH₂Cl₂/MeOH (1:5) was treated with ozone bubbles at −78°C until a blue coloration persisted. The solution was purged with argon, 8.0 mL of dimethylsulphide (21.5 mmol) was added, and the reaction mixture then warmed slowly to rt overnight. The solvent was evaporated under vacuum to give 7 which was then diluted with 100 mL of 40 % acetic acid in acetonitrile, (v/v) and sulphanilamide (4.0 g, 23.2 mmol) was added. The mixture was refluxed until complete consumption of 1,4-dicarbonyl compound was detected by TLC (ca 3 h). After cooling to room temperature, the product was concentrated under vacuum and diluted with 250 mL of ethyl acetate. The organic layer then washed with saturated Na₂CO₃ solution (3 × 50 mL) followed by brine (1 × 50 mL), dried (MgSO₄), and evaporated to dryness. The crude brown material was purified by silica gel flash chromatography using a gradient of EtOAc in hexane to give apricoxib as white solid (5.5 g, 15.43 mmol, 71%).

m.p. 161–163°C (lit. 135–139°C¹⁴).

¹H NMR (CDCl₃, 300.0 MHz) δ 1.32 (t, J = 6.9 Hz, 3H), 2.1 (s, 3H), 3.92 (q, J = 6.9 Hz, 2H), 4.95 (s, 2H), 6.14 (m, 1H), 6.63 (m, 1H), 6.69 (d, J = 6.6 Hz, 2H), 6.94 (d, J = 6.6 Hz, 2H), 7.13 (d, J = 6.6 Hz, 2H), 7.74 (d, J= 6.6 Hz, 2H).

¹³C NMR (CDCl₃, 75.0 MHz) δ 11.7, 14.8, 63.4, 82.4, 113.2, 114.4, 121.0, 121.1, 124.9, 125.2, 127.4, 129.7, 133.6, 138.7, 144.2, 158.0

M+H Calcd: 357.1273; Found, 357.1252.

01

Click here to view.^{(2.1M, pdf) DOWNLOAD TO GET NMR , 13C, COSY}

Supplementary Material

¹H, ¹³C, and COSY NMR spectra of compounds 1 and 8.

……………

SYNTHESIS

synthesis

In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,Ndiisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib

Intermediate (V) can also be prepared by reaction of 1-(4- ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitroderivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).In an alternativestrategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishesN-(4-ethoxybenzylidene)-

4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α- amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib

reference for above

Drugs of the Future 2011, 36(7): 503-509
Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617.
Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078
Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives,their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858.

References

1. Bierbach, Ulrich. Platinum acridine anti-cancer compounds and methods thereof. PCT Int. Appl. (2010), 54pp. CODEN: PIXXD2 WO 2010048499 A1 20100429 CAN 152:517954 AN 2010:529827

2. Zaknoen, Sara L.; Lawhon, Tracy. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders. PCT Int. Appl. (2009), 119 pp. CODEN: PIXXD2 WO 2009070546 A1 20090604 CAN 151:24882 AN 2009:676598

3. Zaknoen, Sara L.; Lawhon, Tracy. Cancer treatment using a 1,2-diphenylpyrrole derivative cyclooxygenase 2 (COX-2) inhibitor and antimetabolite combinations. PCT Int. Appl. (2009), 107pp. CODEN: PIXXD2 WO 2009070547 A1 20090604 CAN 151:24877 AN 2009:672256

4. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Therapies for treating cancer using combinations of COX-2 inhibitors and anti-HER2(ErbB2) antibodies or combinations of COX-2 inhibitors and HER2(ErbB2) receptor tyrosine kinase inhibitors. PCT Int. Appl. (2009), 121pp. CODEN: PIXXD2 WO 2009042618 A1 20090402 CAN 150:390188 AN 2009:386123

5. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Therapies for treating cancer using combinations of COX-2 inhibitors and aromatase inhibitors or combinations of COX-2 inhibitors and estrogen receptor antagonists. PCT Int. Appl. (2009), 88pp. CODEN: PIXXD2 WO 2009042612 A1 20090402 CAN 150:390184 AN 2009:385226

6. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Combination therapy for the treatment of cancer using COX-2 inhibitors and dual inhibitors of EGFR (ErbB1) and HER-2 (ErbB2). PCT Int. Appl. (2009), 87pp. CODEN: PIXXD2 WO 2009042613 A1 20090402 CAN 150:390183 AN 2009:385196

7. Lawhon, Tracy; Zaknoen, Sara; Estok, Thomas; Green, Mark. Patient selection and therapeutic methods using markers of prostaglandin metabolism. PCT Int. Appl. (2009), 121pp. CODEN: PIXXD2 WO 2009009776 A2 20090115 CAN 150:136599 AN 2009:55595

8. Estok, Thomas M.; Zaknoen, Sara L.; Mansfield, Robert K.; Lawhon, Tracy. Methods and compositions for the treatment of cancer, tumors, and tumor-related disorders using combination of a 1,2-diphenylpyrrole derivative and an EGFR inhibitor. PCT Int. Appl. (2009), 104 pp. CODEN: PIXXD2 WO 2009009778 A1 20090115 CAN 150:136628 AN 2009:54177

9. Rohatagi, Shashank; Kastrissios, Helen; Sasahara, Kunihiro; Truitt, Kenneth; Moberly, James B.; Wada, Russell; Salazar, Daniel E. Pain relief model for a COX-2 inhibitor in patients with postoperative dental pain. British Journal of Clinical Pharmacology (2008), 66(1), 60-70.
10. Senzaki, Michiyo; Ishida, Saori; Yada, Ayumi; Hanai, Masaharu; Fujiwara, Kosaku; Inoue, Shin-Ichi; Kimura, Tomio; Kurakata, Shinichi. CS-706, a novel cyclooxygenase-2 selective inhibitor, prolonged the survival of tumor-bearing mice when treated alone or in combination with anti-tumor chemotherapeutic agents. International Journal of Cancer (2008), 122(6), 1384-1390. CODEN: IJCNAW ISSN:0020-7136. CAN 148:440459 AN 2008:228248

11. Kojima, Shunshi; Ooyama, Jo. Process for production of brominated acetophenone as drug intermediate. PCT Int. Appl. (2008), 37pp. CODEN: PIXXD2 WO 2008020617 A1 20080221 CAN 148:262335 AN 2008:220659

12. Ushiyama, Shigeru; Yamada, Tomoko; Murakami, Yukiko; Kumakura, Sei-ichiro; Inoue, Shin-ichi; Suzuki, Keisuke; Nakao, Akira; Kawara, Akihiro; Kimura, Tomio. Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects. European Journal of Pharmacology (2008), 578(1), 76-86.

13. Oitate, Masataka; Hirota, Takashi; Murai, Takahiro; Miura, Shin-ichi; Ikeda, Toshihiko. Covalent binding of rofecoxib, but not other cyclooxygenase-2 inhibitors, to allysine aldehyde in elastin of human aorta. Drug Metabolism and Disposition (2007), 35(10), 1846-1852. CODEN: DMDSAI ISSN:0090-9556. CAN 147:439860 AN 2007:1124386

14. Kiguchi, Kaoru; Ruffino, Lynnsie; Kawamoto, Toru; Franco, Eugenia; Kurakata, Shin-ichi; Fujiwara, Kosaku; Hanai, Masaharu; Rumi, Mohammad; DiGiovanni, John. Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice. Molecular Cancer Therapeutics (2007), 6(6), 1709-1717.

15. Moberly, James B.; Xu, Jianbo; Desjardins, Paul J.; Daniels, Stephen E.; Bandy, Donald P.; Lawson, Janet E.; Link, Allison J.; Truitt, Kenneth E. A randomized, double-blind, celecoxib- and placebo-controlled study of the effectiveness of CS-706 in acute postoperative dental pain. Clinical Therapeutics (2007), 29(3), 399-412.
16. Rohatagi, S.; Kastrissios, H.; Gao, Y.; Zhang, N.; Xu, J.; Moberly, J.; Wada, R.; Yoshihara, K.; Takahashi, M.; Truitt, K.; Salazar, D. Predictive population pharmacokinetic/pharmacodynamic model for a novel COX-2 inhibitor. Journal of Clinical Pharmacology (2007), 47(3), 358-370.

17. Moberly, James B.; Harris, Stuart I.; Riff, Dennis S.; Dale, James Craig; Breese, Tara; McLaughlin, Patrick; Lawson, Janet; Wan, Yaping; Xu, Jianbo; Truitt, Kenneth E. A Randomized, Double-Blind, One-Week Study Comparing Effects of a Novel COX-2 Inhibitor and Naproxen on the Gastric Mucosa. Digestive Diseases and Sciences (2007), 52(2), 442-450.

18. Oitate, Masataka; Hirota, Takashi; Koyama, Kumiko; Inoue, Shin-ichi; Kawai, Kenji; Ikeda, Toshihiko. Covalent binding of radioactivity from [14C] rofecoxib, but not [14C] celecoxib or [14C] CS-706, to the arterial elastin of rats. Drug Metabolism and Disposition (2006), 34(8), 1417-1422.

19. Kastrissios, H.; Rohatagi, S.; Moberly, J.; Truitt, K.; Gao, Y.; Wada, R.; Takahashi, M.; Kawabata, K.; Salazar, D. Development of a predictive pharmacokinetics model for a novel cyclooxygenase-2 inhibitor. Journal of Clinical Pharmacology (2006), 46(5), 537-548. CODEN: JCPCBR ISSN:0091-2700. CAN 145:327959 AN 2006:479516

20. Denis, Louis J.; Compton, Linda D. Method using camptothecin compounds, pyrimidine derivatives, and antitumor agents for treating abnormal cell growth. U.S. Pat. Appl. Publ. (2005), 32 pp. CODEN: USXXCO US 2005272755 A1 20051208 CAN 144:17160 AN 2005:1294044

21. Wajszczuk, Charles Paul; Gans, Hendrik J. Dekoning; Di Salle, Enrico; Piscitelli, Gabriella; Massimini, Giorgio; Purandare, Dinesh. Methods using exemestane, alone or with other therapeutic agents, for treating estrogen-dependent disorders. U.S. Pat. Appl. Publ. (2004), 21 pp., Cont.-in-part of WO 2002 72,106. CODEN: USXXCO US 2004082557 A1 20040429 CAN 140:368700 AN 2004:353144

22. Di Salle, Enrico; Piscitelli, Gabriella; Massimini, Giorgio; Purandare, Dinesh; Dekoning, Gans Hendrik. Combined method for treating hormone-dependent disorders with aromatase inactivator exemestane and other therapeutic agents. PCT Int. Appl. (2002), 49 pp. CODEN: PIXXD2 WO 2002072106 A2 20020919 CAN 137:226651 AN 2002:716096

23. McKearn, John P.; Gordon, Gary; Cunningham, James J.; Gately, Stephen T.; Koki, Alane T.; Masferrer, Jaime L. Method of using a cyclooxygenase-2 inhibitor and an integrin antagonist as a combination therapy in the treatment of neoplasia. PCT Int. Appl. (2000), 348 pp. CODEN: PIXXD2 WO 2000038786 A2 20000706 CAN 133:84244 AN 2000:456950

24. McKearn, John P.; Gordon, Gary; Cunningham, James J.; Gately, Stephen T.; Koki, Alane T.; Masferrer, Jaime L. Method of using a cyclooxygenase-2 inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia. PCT Int. Appl. (2000), 236 pp. CODEN: PIXXD2 WO 2000038730 A2 20000706 CAN 133:84243 AN 2000:456927

25. McKearn, John P.; Masferrer, Jaime L.; Milas, Luka. Combination therapy of radiation and a cyclooxygenase 2 (COX-2) inhibitor for the treatment of neoplasia. PCT Int. Appl. (2000), 96 pp. CODEN: PIXXD2 WO 2000038716 A1 20000706 CAN 133:84241 AN 2000:456913

26. McKearn, John P.; Gordon, Gary; Cunningham, James J.; Gately, Stephen T.; Koki, Alane T.; Masferrer, Jaime L. Method of using a cyclooxygenase-2 inhibitor and a matrix metalloproteinase inhibitor as a combination therapy in the treatment of neoplasia. PCT Int. Appl. (2000), 437 pp. CODEN: PIXXD2 WO 2000037107 A2 20000629 CAN 133:68922 AN 2000:441655

27. Noguchi, Yasuo; Saito, Toshinori; Fujimoto, Katsuhiko; Takebayashi, Toyonori. Preparation of 4-methyl-1,2-diarylpyrroles and and their intermediates. Jpn. Kokai Tokkyo Koho (2000), 14 pp. CODEN: JKXXAF JP 2000080078 A 20000321 CAN 132:207760 AN 2000:181022

28. Kurakata, Shinichi; Hanai, Masaharu; Kanai, Saori; Kimura, Tomio. Use of cyclooxygenase-2 inhibitors for the treatment and prevention of tumors, tumor-related disorders and cachexia. Eur. Pat. Appl. (1999), 49 pp. CODEN: EPXXDW EP 927555 A1 19990707 CAN 131:82985 AN 1999:440003

29. Kimura, Fumio; Noguchi, Yasuo; Nakao, Akira; Suzuki, Keisuke; Ushiyama, Shigeru; Kawahara, Akihiro; Miyamoto, Masaaki. Diphenylpyrrole derivatives as cyclooxygenase-2 inhibitors. Jpn. Kokai Tokkyo Koho (1999), 69 pp.

30. Kimura, Tomio; Noguchi, Yasuo; Nakao, Akira; Suzuki, Keisuke; Ushiyama, Shigeru; Kawara, Akihiro; Miyamoto, Masaaki. Preparation of 1,2-diphenylpyrroles as cyclooxygenase-2 inhibitors. Eur. Pat. Appl. (1997), 140 pp. CODEN: EPXXDW EP 799823 A1 19971008 CAN 127:331392 AN 1997:678926

31. Rao P N Praveen; Grover Rajesh K Apricoxib, a COX-2 inhibitor for the potential treatment of pain and cancer. IDrugs : the investigational drugs journal (2009), 12(11), 711-22.

US2002128267	9-13-2002	Method of using COX-2 inhibitors in the treatment and prevention of ocular COX-2 mediated disorders
US5908858	6-2-1999	1,2-diphenylpyrrole derivatives, their preparation and their therapeutic uses

US2006154990	7-14-2006	Use of MEK inhibitors in treating abnormal cell growth
US2006074073	4-7-2006	Therapeutic combinations comprising poly (ADP-ribose) polymerases inhibitor
US2005272755	12-9-2005	Method for treating abnormal cell growth
US2005143360	6-31-2005	Method of using a cyclooxygenase-2 inhibitor and sex steroids as a combination therapy for the treatment and prevention of dismenorrhea
US6887893	5-4-2005	Methods and compositions for treatment and prevention of tumors, tumor-related disorders and cachexia
US2004082543	4-30-2004	Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
US2004082557	4-30-2004	Methods for treating estrogen-dependent disorders
US2004072889	4-16-2004	Method of using a COX-2 inhibitor and an alkylating-type antineoplastic agent as a combination therapy in the treatment of neoplasia
US2004058926	3-26-2004	Method of using cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
US2004053900	3-19-2004	Method of using a COX-2 inhibitor and an aromatase inhibitor as a combination therapy

US8247423	8-22-2012	Methods and Compositions for the Treatment of Cancer, Tumors, and Tumor-Related Disorders
US8080646	12-21-2011	HUMAN MONOCLONAL ANTIBODIES TO ACTIVIN RECEPTOR-LIKE KINASE-1
EP0927555	10-6-2011	Use of cyclooxygenase-2 inhibitors for the treatment and prevention of tumours, tumour-related disorders and cachexia
US7745481	6-30-2010	Methods and compositions for the treatment and prevention of tumors, tumor-related disorders and cachexia
US2009281073	11-13-2009	HETEROAROMATIC DERIVATIVES USEFUL AS ANTICANCER AGENTS
US7537762	5-27-2009	Human monoclonal antibodies to activin receptor-like kinase-1
US2009111805	4-31-2009	BICYCLIC HETEROAROMATIC DERIVATIVES USEFUL AS ANTICANCER AGENTS
US2008274192	11-7-2008	Pharmaceutical Compositions Comprising an Amorphous Form of a Vegf-R-Inhibitor
US2008260817	10-24-2008	Compositions for the Treatment of Inflammation and Pain Using a Combination of a Cox-2 Selective Inhibitor and a Ltb4 Receptor Antagonist
EP0799823	10-32-2007	1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses

Golden Root (Rhodiola rosea)…….a queen of adaptogenic herbs

July 28, 2014 11:27 am / Leave a comment

Golden Root (Rhodiola rosea) – Also called Arctic Root or Roseroot, golden root is considered a queen of adaptogenic herbs. As one blogger puts it, “[Golden root] allows us to regulate our immune, physiological and neurological responses to stress, allowing us to survive not only rough environmental/weather challenges, but also to adapt and adjust our often neurotic mental habits and crazy social/political climates as well.

”The Russians use it to improve physical stamina and adapt to environmental stress. In Siberia, people still say, “Those who drink Rhodiola tea will live more than 100 years old.” The extract possesses positive mood enhancing and anti-stress properties with no detectable levels of toxicity. Golden root works by enhancing the body’s ability to make serotonin, dopamine, and other neurotransmitters that aid in happiness and stress-reduction.

Rhodiola rosea (commonly golden root, rose root, roseroot, Aaron’s rod, arctic root, king’s crown, lignum rhodium, orpin rose) is a perennial flowering plant in the family Crassulaceae. It grows in cold regions of the world, including much of the Arctic, the mountains ofCentral Asia, scattered in eastern North America from Baffin Island to the mountains of North Carolina, and mountainous parts of Europe, such as the Alps, Pyrenees, and Carpathian Mountains, Scandinavia, Iceland, Great Britain and Ireland. It grows on sea cliffs and on mountains^[2] at altitudes up to 2280 meters.^[where?]^{[citation needed]} Several shoots grow from the same thick root. Shoots may reach 5 to 35 cm in height. R. rosea is dioecious – having separate female and male plants.

History

The first time that R. rosea is described was from Dioscorides in De Materia Medica.

Uses

Plant

Some studies have found support for it having antidepressant effects.^[3]^[4] It is not approved by the U.S. Food and Drug Administration (FDA) to cure, treat, or prevent any disease. In fact, the FDA has forcibly removed some products containing R. rosea from the market due to disputed claims that it treats cancer, anxiety, influenza, the common cold, bacterial infections, and migraines.^[5]

R. rosea may be effective for improving mood and alleviating depression. Pilot studies on human subjects^[6]^[7]^[8] showed it improves physical and mental performance, and may reduce fatigue.

In Russia and Scandinavia, R. rosea has been used for centuries to cope with the cold Siberianclimate and stressful life.^{[citation needed]}^[9]^[10] Such effects were provided with evidence in laboratory models of stress using the nematode C. elegans,^[11] and in rats in which Rhodiola effectively prevented stress-induced changes in appetite, physical activity, weight gain and the estrus cycle.^[12]

The plant has been used in traditional Chinese medicine, where it is called hóng jǐng tiān (红景天). The medicine can be used to prevent altitude sickness.^{[citation needed]}

The aerial portion is consumed as food in some parts of the world, sometimes added to salads.^[13]

Phytochemicals and potential health effects

Withering flower

Scientists have identified about 140 chemical compounds in the subterranean portions of R. rosea.^[14] Rhodiola roots contain phenols,rosavin, rosin, rosarin, organic acids, terpenoids, phenolcarbonic acids and their derivatives, flavonoids, anthraquinones, and alkaloids.

The chemical composition of the essential oil from R. rosea root growing in different countries varies. For example, rosavin, rosarin and rosin at their highest concentration according to many tests can be found only in R. rosea of Russian origin; the main component of the essential oil from Rhodiola growing in Bulgaria are geraniol and myrtenol; in China the main components are geraniol and 1-octanol; and in India the main component is phenylethilic alcohol. Cinnamic alcohol was discovered only in the sample from Bulgaria.^[15]

R. rosea contains a variety of compounds that may contribute to its effects,^[16] including the class of rosavins that includes rosavin, rosarin, and rosin. Several studies have suggested that the most active components are likely to be rhodioloside and tyrosol,^[17] with other components being inactive when administered alone, but showing synergistic effects when a fixed combination of rhodioloside, rosavin, rosarin and rosin was used.^[18] Authentication, as well as potency, of R. rosea crude material and standardized extracts thereof are carried out with validated high-performance liquid chromatography analyses to verify the content of the marker constituents salidroside, rosarin, rosavin, rosin and rosiridin.^[19]

Although rosavin, rosarin, rosin and salidroside (and sometimes p-tyrosol, rhodioniside, rhodiolin and rosiridin) are among suspected active ingredients of R. rosea, these compounds are mostly polyphenols. There is no evidence that these chemicals have any physiological effect in humans that could prevent or reduce risk of disease.^[20]

Although these phytochemicals are typically mentioned as specific to Rhodiola extracts, there are many other constituent phenolic antioxidants, including proanthocyanidins,quercetin, gallic acid, chlorogenic acid and kaempferol.^[21]^[22]

Dried R. rosea root

Animal tests have suggested a variety of beneficial effects for R. rosea extracts,^[23] and there is some scientific evidence for its efficacy as a treatment for depression and fatigue ^[6]^[7]^[24]^[25] in humans.

Scientific evidence

R. rosea extract exerts an antifatigue effect that increases mental performance, particularly the ability to concentrate in healthy subjects^[6]^[7]^[24] and burnout patients with fatigue syndrome.^[25] Rhodiola significantly reduced symptoms of fatigue and improved attention after four weeks of repeated administration.^[25] A 2007 clinical trial from Armenia showed significant effect for a Rhodiola extract in doses of 340–680 mg per day in male and female patients from 18 to 70 years old with mild to moderate depression. No side effects were demonstrated at these doses.^[3] One study found inhibition of MAO-A and MAO-B.^[26] Studies on whether Rhodiola improves physical performance have been inconclusive, with some studies showing some benefit,^[27] while others show no significant difference.^[28]

Two systematic reviews on R. rosea extracts concluded that the research evidence is contradictory, and definite conclusions over its efficacy to relieve mental and physical fatigue are hampered by the lack of rigorously-designed, well-controlled randomized control trials ^[29]

In clinical medical trials on people R. rosea extract has a positive effect on sensitive and fading skin improving overall skin condition.^[30]^{[full citation needed]}

R. rosea promotes the release of norepinephrine from rat pineal corpus cavernosum smooth muscle cell and artery endothelium cell, which was correlated with its effect of resisting senility.^[31] R. rosea extract has been found to increase the life span of fruit fly (Drosophila) by 24% independently of dietary restriction.^[32]

R. rosea may enhance the detoxification of many toxic heavy metals.^[33]

References

Jump up^ “Rhodiola rosea – Plants For A Future database report”. http://www.pfaf.org. Retrieved 2008-02-23.
Jump up^ Stace, C.A. (2010). New flora of the British isles (Third ed.). Cambridge, U.K.: Cambridge University Press. p. 138. ISBN 9780521707725.
^ Jump up to:^a ^b Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A (2007). “Clinical trial of Rhodiola rosea L. extract in the treatment of mild to moderate depression”. Nord J Psychiatry 61 (5): 343–8. doi:10.1080/08039480701643290.PMID 17990195.
Jump up^ Dwyer AV, Whitten DL, Hawrelak JA (March 2011). “Herbal medicines, other than St. John’s Wort, in the treatment of depression: a systematic review” (PDF). Altern Med Rev 16 (1): 40–9. PMID 21438645.
Jump up^ See for example, Letter, dated April 21, 2005, Food and Drug Administration
^ Jump up to:^a ^b ^c Shevtsov VA, Zholus BI, Shervarly VI, et al. (Mar 2003). “A randomized trial of two different doses of Rhodiola rosea extract versus placebo and control of capacity for mental work”. Phytomedicine 10 (2–3): 95–105. doi:10.1078/094471103321659780.PMID 12725561.
^ Jump up to:^a ^b ^c Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G, Wagner H (Oct 2000). “Rhodiola rosea in stress induced fatigue—a double blind cross-over study of a standardized extract with a repeated low-dose regimen on the mental performance of healthy physicians during night duty”. Phytomedicine 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
Jump up^ Ha Z, Zhu Y, Zhang X, et al. (Sep 2002). “[The effect of rhodiola and acetazolamide on the sleep architecture and blood oxygen saturation in men living at high altitude]”.Zhonghua Jie He He Hu Xi Za Zhi (in Chinese) 25 (9): 527–30. PMID 12423559.
Jump up^ Azizov, AP; Seĭfulla, RD (May–Jun 1998). “[The effect of elton, leveton, fitoton and adapton on the work capacity of experimental animals].”. Eksperimental’naia i klinicheskaia farmakologiia 61 (3): 61–3. PMID 9690082.
Jump up^ Darbinyan, V; Kteyan, A; Panossian, A; Gabrielian, E; Wikman, G; Wagner, H (Oct 2000). “Rhodiola rosea in stress induced fatigue–a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty.”. Phytomedicine : international journal of phytotherapy and phytopharmacology 7 (5): 365–71. doi:10.1016/S0944-7113(00)80055-0. PMID 11081987.
Jump up^ Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman G, Post JA (Jun 2008). “Plant adaptogens increase lifespan and stress resistance in C. elegans”.Biogerontology 10 (1): 27–42. doi:10.1007/s10522-008-9151-9. PMID 18536978.
Jump up^ Mattioli L, Funari C, Perfumi M (May 2008). “Effects of Rhodiola rosea L. extract on behavioural and physiological alterations induced by chronic mild stress in female rats”.Journal of Psychopharmacology (Oxford) 23 (2): 130–42.doi:10.1177/0269881108089872. PMID 18515456.
Jump up^ Saratikov A.S. (1974). Golden Root (Rhodiola Rosea) (2nd ed.). Publishing House of Tomsk University. p. 158.
Jump up^ Panossian, A., Wikman, G. (2010). “Rosenroot (Roseroot): Traditional Use, Chemical Composition, Pharmacology, and Clinical Efficacy”. Phytomedicine 17 (5-6): 481–493.doi:10.1016/j.phymed.2010.02.002.
Jump up^ Evstavieva L., Todorova M., Antonova D., Staneva J. (2010). “Chemical composition of the essential oils of Rhodiola rosea L. of three different origins”. Pharmacogn Mag. 6 (24): 256–258.
Jump up^ Kucinskaite A, Briedis V, Savickas A (2004). “[Experimental analysis of therapeutic properties of Rhodiola rosea L. and its possible application in medicine]”. Medicina (Kaunas) (in Lithuanian) 40 (7): 614–9. PMID 15252224.
Jump up^ Mao Y, Li Y, Yao N (Nov 2007). “Simultaneous determination of salidroside and tyrosol in extracts of Rhodiola L. by microwave assisted extraction and high-performance liquid chromatography”. J Pharm Biomed Anal 45 (3): 510–5. doi:10.1016/j.jpba.2007.05.031.PMID 17628386.
Jump up^ Panossian A, Nikoyan N, Ohanyan N, et al. (Jan 2008). “Comparative study of Rhodiola preparations on behavioral despair of rats”. Phytomedicine 15 (1–2): 84–91.doi:10.1016/j.phymed.2007.10.003. PMID 18054474.
Jump up^ Ganzera M, Yayla Y, Khan IA (April 2001). “Analysis of the marker compounds of Rhodiola rosea L. (golden root) by reversed phase high performance liquid chromatography”. Chem. Pharm. Bull. 49 (4): 465–7. doi:10.1248/cpb.49.465.PMID 11310675.
Jump up^ Boudet AM (2007). “Evolution and current status of research in phenolic compounds”.Phytochemistry 68 (22–24): 2722–35. doi:10.1016/j.phytochem.2007.06.012.PMID 17643453.
Jump up^ Yousef GG, Grace MH, Cheng DM, Belolipov IV, Raskin I, Lila MA (Nov 2006). “Comparative phytochemical characterization of three Rhodiola species”. Phytochemistry67 (21): 2380–91. doi:10.1016/j.phytochem.2006.07.026. PMID 16956631.
Jump up^ Liu Q, Liu ZL, Tian X (Feb 2008). “[Phenolic components from Rhodiola dumulosa]”.Zhongguo Zhong Yao Za Zhi (in Chinese) 33 (4): 411–3. PMID 18533499.
Jump up^ Perfumi M, Mattioli L (Jan 2007). “Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice”.Phytother Res 21 (1): 37–43. doi:10.1002/ptr.2013. PMID 17072830.
^ Jump up to:^a ^b Spasov. A.A., Mandrikov, V.B., Mitonova, I.A., 2000b. The effect of Dhodaxonon psycho-physiologic and physical adaptation of students to the academic load. Experimental and Clinical Pharmacology 63 (1), 76-78.
^ Jump up to:^a ^b ^c Olsson E.M.G., von Schéele B., Panossian A.G. (2009). “A randomized double-blind placebo controlled parallel group study of an extract of Rhodiola rosea roots as treatment for patients with stress related fatigue”. Planta medica 75 (2): 105–112.doi:10.1055/s-0028-1088346. PMID 19016404.
Jump up^ van Diermen, D.; Marston, A.; Bravo, J.; Reist, M.; Carrupt, PA.; Hostettmann, K. (Mar 2009). “Monoamine oxidase inhibition by Rhodiola rosea L. roots.”. J Ethnopharmacol122 (2): 397–401. doi:10.1016/j.jep.2009.01.007. PMID 19168123.
Jump up^ De Bock K, Eijnde BO, Ramaekers M, Hespel P (Jun 2004). “Acute Rhodiola rosea intake can improve endurance exercise performance”. Int J Sport Nutr Exerc Metab 14(3): 298–307. PMID 15256690.
Jump up^ Walker TB, Altobelli SA, Caprihan A, Robergs RA (Aug 2007). “Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men”. Metab Clin Exp. 56(8): 1111–7. doi:10.1016/j.metabol.2007.04.004. PMID 17618958.
Jump up^ Ishaque, Sana; Shamseer, Larrisa; Bukutu, Cecilia; Vohra, Sunita. “Rhodiola rosea for physical and mental fatigue: a systematic review”. BMC Complementary and Alternative Medicine 12 (1): 70. doi:10.1186/1472-6882-12-70. PMID 3541197.
Jump up^ Diemant et al., 2008
Jump up^ Effect of Rodiola on level of NO and NOS in cultured rats penile corpus cavernosum smooth muscle cell and artery endothelium cell Kong X., Shi F., Chen Y., Lu H., Yao M., Hu M. Chinese Journal of Andrology 2007 21:10 (6-11)
Jump up^ Schriner, Samuel E.; Lee, Kevin; Truong, Stephanie; Salvadora, Kathyrn T.; Maler, Steven; Nam, Alexander; Lee, Thomas; Jafari, Mahtab; Englert, Christoph (21 May 2013). “Extension of Drosophila Lifespan by Rhodiola rosea through a Mechanism Independent from Dietary Restriction”. PLoS ONE 8 (5): e63886. doi:10.1371/journal.pone.0063886.
Jump up^ Boon-Niermeijer, E.K.; van den Berg, A.; Wikman, G.; Wiegant, F.A.C. “Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis”. Phytomedicine 7 (5): 389–399. doi:10.1016/S0944-7113(00)80060-4.

External links

Media related to Rhodiola rosea at Wikimedia Commons
Whole Health MD, Reference Library
Plants For A Future, Rhodiola rosea Rose Root PFAF
Wilderness Medical Society, Lack of Effect of Rhodiola on Hypoxemia and Oxidative Stress

Tiny amounts of BPA can alter mammary gland development

July 28, 2014 2:09 am / Leave a comment

CLINICALNEWS.ORG

Researchers see BPA effects in monkey mammary glands

Study adds to growing health concerns about common plastic additive

PULLMAN, Wash.—A new study finds that fetal exposure to the plastic additive bisphenol A, or BPA, alters mammary gland development in primates. The finding adds to the evidence that the chemical can be causing health problems in humans and bolsters concerns about it contributing to breast cancer.

“Previous studies in mice have demonstrated that low doses of BPA alter the developing mammary gland and that these subtle changes increase the risk of cancer in the adult,” says Patricia Hunt, a geneticist in Washington State University’s School of Molecular Biosciences. “Some have questioned the relevance of these findings in mice to humans. But finding the same thing in a primate model really hits uncomfortably close to home.”

View original post 288 more words

Mom will teach you NMR

July 26, 2014 11:38 am / Leave a comment

Dedicated to all moms in the world

ETHYL PROPIONATE NMR, carbonyl is dad and oxygen mom, a methyl gets more attention

ORIGINALLY IN http://orgspectroscopyint.blogspot.in/2014/07/ethyl-propionate-nmr-carbonyl-is-dad.html

C=O group is dad

O atom is mom

Carbonyl is dad and oxygen mom hence c labelled methyl has higher chemical shift and gets a little more attention

SEE BELOW

NMR IS EASY

A chemical has Formula: C₅H₁₀O₂

C₅H₁₀O₂
Rule 2, omit O, gives C₅H₁₀
5 – 10/2 + 1 = 1 degree of unsaturation.
Look for 1 pi bond or aliphatic ring.

The band at 1740 indicates a carbonyl, probably a saturated aliphatic ester. The bands at 3000-2850 indicate C-H alkane stretches. The bands in the region 1320-1000 could be due to C-O stretch, consistent with an ester.

Structure answer

This is the structure. See if you can assign the peaks on your own.

NMR answer

C has a higher chemical shift than D because it’s closer to a more electron-withdrawing functional group.

Carbonyl is dad and oxygen mom, hence c has higher chemical shift and gets a little more attention in proton nmr

13 C NMR

Mass spectrum

RAMAN

WHAT HAPPENS WHEN A CHLORO IS INTRODUCED

THE INTERPRETATION IS BELOW

remember “a” labelled CH3 appears as a doublet

WHEN THERE IS ONE METHYL

WHEN THERE ONE CH2 SHORT

WHEN MOM HAS ONE MORE CH2

PROPYL PROPIONATE, try this on your own

1H NMR

see interpretation

BIGGER ONE THAN OBOVE

13C NMR

APT

COSY

WILL PASTE INTERPRETATION AFTER ONE WEEK……………….

Natural products from plants protect skin during cancer radiotherapy

July 26, 2014 3:15 am / Leave a comment

CLINICALNEWS.ORG

PUBLIC RELEASE DATE:

24-Jul-2014
Radiotherapy for cancer involves exposing the patient or their tumor more directly to ionizing radiation, such as gamma rays or X-rays. The radiation damages the cancer cells irreparably. Unfortunately, such radiation is also harmful to healthy tissue, particularly the skin over the site of the tumor, which is then at risk of hair loss, dermatological problems and even skin cancer. As such finding ways to protect the overlying skin are keenly sought.

Writing in the International Journal of Low Radiation, Faruck Lukmanul Hakkim of the University of Nizwa, Oman and Nagasaki University, Nagasaki, Japan, and colleagues there and at Macquarie University, New South Wales, Australia, Bharathiar University, India and Konkuk University, South Korea, explain how three ubiquitous and well-studied natural products derived from plants can protect the skin against gamma radiation during radiotherapy.

View original post 295 more words

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Category Archives: Uncategorized

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Cosmetic use

Fat-reducing properties

Formulations

Efficacy

Side effects

References

Citations

External links

Organic spectroscopy should be brushed up and you get confidence

read my blog

ORGANIC SPECTROSCOPY INTERNATIONAL is the blog

Share this:

History

Withdrawal from market

References

External links

Share this:

Mode of action

Pharmacokinetics

Fabricated efficacy studies

Adverse drug reactions

Adverse cardiovascular events

VIGOR study and publishing controversy

Alzheimer’s studies

APPROVe study

Other studies

Other COX-2 inhibitors

Other NSAIDs

Withdrawal

Litigation

Other effects

Synthesis

Footnotes

References

External links

Share this:

References

Share this:

References

Share this:

01

Share this:

History

Uses

Phytochemicals and potential health effects

Scientific evidence

References

External links

Share this:

Share this:

Share this:

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email