WORLD RECORD VIEWS holder on THIS BLOG, ………live, by DR ANTHONY MELVIN CRASTO, Worldpeaceambassador, Worlddrugtracker, Helping millions, 100 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 45 lakh plus VIEWS on this blog in 227 countries, 7 CONTINENTS ……A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, [THIS BLOG HOLDS WORLD RECORD VIEWS ]
Home » Posts tagged 'drugs' (Page 5)
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
.....FOR BLOG HOME CLICK HERE
Subscribe in a reader
Enter your email address:
Delivered by FeedBurner
Subscribe to New Drug Approvals by Email
 | 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 |
(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Eisai Expands Marketing and Supply Agreement for Anti-obesity Agent Lorcaserin to Include Most Countries Worldwide
HATFIELD, England, November 8, 2013 /PRNewswire/ —
Eisai announces today that it has expanded the marketing and supply agreement between its U.S. subsidiary Eisai Inc. and U.S-based Arena Pharmaceuticals Inc.’s Swiss subsidiary, Arena Pharmaceuticals GmbH, for the anti-obesity agent lorcaserin hydrochloride (lorcaserin) (U.S. brand name: BELVIQ®). Whilst the existing agreement granted Eisai Inc. exclusive rights to market and distribute lorcaserin in 21 countries throughout the Americas, the expanded agreement now includes most countries and territories worldwide, most notably, the member states of the European Union, Japan and China (but excludes South Korea, Taiwan, Australia, New Zealand and Israel).http://www.pharmalive.com/eisai-expands-lorcaserin-marketing-and-supply-agreement
Lorcaserin (previously APD-356), a highly selective 5HT2C receptor agonist, is used for the treatment of obesity. It has been shown to reduce body weight and food intake in animal models of obesity, and it is thought that targeting the 5HT2C receptor may alter body weight by regulating satiety. Lorcaserin is marketed as a salt form called Belviq, which is lorcaserin hydrochloride.
Lorcaserin (APD-356, trade name upon approval Belviq, expected trade name during development, Lorqess) is aweight-loss drug developed by Arena Pharmaceuticals. It has serotonergic properties and acts as an anorectic. On 22 December 2009 a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States. On 16 September 2010, an FDA advisory panel voted to recommend against approval of the drug based on concerns over both safety and efficacy. In October 2010, the FDA stated that it could not approve the application for lorcaserin in its present form.anti-obesity drug that Arena Pharmaceuticals is creation, Eisai Co., Ltd. has the right to sell “BELVIQ ®” (generic name lorcaserin hydrochloride) was to get the FDA approval on June 27, 2012
On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity like high blood pressure or type 2 diabetes.
On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol”.
On 7 May 2013, the US Drug Enforcement Administration has classified lorcaserin as a Schedule IV drug under the Controlled Substances Act.
Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer and gallbladder disease.
Obesity is now a major healthcare issue in the Western World and increasingly in some third world countries. The increase in numbers of obese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people’s lives. Currently about 30% of the population of the USA is now considered obese.
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m2 and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m2, and obesity as a BMI greater than 30 kg/m2 (see table below).
Classification Of Weight By Body Mass Index (BMI)
As the BMI increases there is an increased risk of death from a variety of causes that are independent of other risk factors. The most common diseases associated with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. The strength of the link between obesity and specific conditions varies. One of the strongest is the link with type 2 diabetes. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women (Seidell, Semin Vase Med, 5:3-14 (2005)). Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.
This compound is useful in the treatment of 5-HT2c receptor associated disorders, such as, obesity, and is disclosed in PCT patent publication, WO2003/086303.
Various synthetic routes to (R)-8-chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in WO 2005/019179 WO2003/086303, WO 2006/069363, WO 2007/120517, WO 2008/07011 1 , WO 2009/111004, and WO 2010/148207 each of which is incorporated herein by reference in its entirety. Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety.
Lorcaserin is a selective 5-HT2C receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT2Cover other related targets.[14][15][16] 5-HT2C receptors are located almost exclusively in the brain, and can be found in the choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus. The activation of 5-HT2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss throughsatiety.[17] This hypothesis is supported by clinical trials and other studies. While it is generally thought that 5-HT2C receptors help to regulate appetite as well as mood, and endocrine secretion, the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100x selectivity for 5-HT2C versus the closely related 5-HT2B receptor, and 17x selectivity over the 5-HT2A receptor.
BELVIQ (lorcaserin hydrochloride) is a serotonin 2C receptor agonist for oral administration used for chronic weight management. Its chemical name is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate. The empirical formula is C11H15Cl2N•0.5H2O, and the molecular weight of the hemihydrate form is 241.16 g/mol.
The structural formula is:
 |
Lorcaserin hydrochloride hemihydrate is a white to off-white powder with solubility in water greater than 400 mg/mL. Each BELVIQ tablet contains 10.4 mg of crystalline lorcaserin hydrochloride hemihydrate, equivalent to 10.0 mg anhydrous lorcaserin hydrochloride, and the following inactive ingredients: silicified microcrystalline cellulose; hydroxypropyl cellulose NF; croscarmellose sodium NF; colloidal silicon dioxide NF, polyvinyl alcohol USP, polyethylene glycol NF, titanium dioxide USP, talc USP, FD&C Blue #2 aluminum lake, and magnesium stearate NF. NDA 022529 APPR2012-06-27 TO EISAI FOR BELVIQ 10 MG ORAL TAB
METHOD FOR CHRONIC WEIGHT MANAGEMENT BY DECREASING FOOD INTAKE U1252
| Patent No US | PatentExpiry Date | patent use code |
|---|---|---|
| 7514422 | Apr 10, 2023 | U-1252 |
| 7977329 | Apr 10, 2023 | U-1252 |
| 8168624 | Apr 18, 2029 | |
| 8207158 | Apr 10, 2023 | U-1252 |
| 8273734 | Apr 10, 2023 | U-1254 |
| Exclusivity Code | Exclusivity_Date |
|---|---|
| NCE | Jun 27, 2017 |
Compound 1 is disclosed in PCT patent publication WO2003/086303, which is incorporated herein by reference in its entirety.
1
Various synthetic routes to (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in PCT publications, WO 2005/019179, WO 2006/069363, WO 2007/120517, WO 2008/070111 , WO 2009/111004, and in United States provisional application 61/396,752 each of which is incorporated herein by reference in its entirety.
Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety
The following United States provisional applications are related to (R)-8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-3-benzazepine: 61/402,578; 61/403,143; 61/402,580; 61/402,628; 61/403,149; 61/402,589; 61/402,611 ; 61/402,565; 61/403, 185; each of which is incorporated herein by reference in its entirety.
| Date | Supplement No. | Action | Documents |
|---|---|---|---|
| 2012-06-27 | 000 | Approval | |
| 2013-01-04 | 001 | Manufacturing Change or Addition | |
| 2013-11-01 | 002 | Manufacturing Change or Addition |
This compound is useful in the treatment of 5-HT2c receptor associated disorders, such as, obesity, and is disclosed in PCT patent publication, WO2003/086303.
Various synthetic routes to (R)-8-chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in WO 2005/019179, WO 2006/069363, WO 2007/120517, WO 2008/07011 1 , WO 2009/111004, and WO 2010/148207 each of which is incorporated herein by reference in its entirety. Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety.
3-Benzazepines have been found to be agonists of the 5HT2C receptor and show effectiveness at reducing obesity in animal models (see, e.g., U.S. Ser. No. 60/479,280 and U.S. Ser. No. 10/410,991, each of which is incorporated herein by reference in its entirety). Numerous synthetic routes to 3-benzazepines have been reported and typically involve a phenyl-containing starting material upon which is built an amine- or amide-containing chain that is capable of cyclizing to form the fused 7-member ring of the benzazepine core. Syntheses of 3-benzazepines and intermediates thereof are reported in U.S. Ser. No. 60/479,280 and U.S. Ser. No. 10/410,991 as well as Nair et al., Indian J. Chem., 1967, 5, 169; Orito et al., Tetrahedron, 1980, 36, 1017; Wu et al., Organic Process Research and Development,1997, 1, 359; Draper et al., Organic Process Research and Development, 1998, 2, 175; Draper et al., Organic Process Research and Development, 1998, 2, 186; Kuenburg et al., Organic Process Research and Development, 1999, 3, 425; Baindur et al., J. Med. Chem.,1992, 35(1), 67; Neumeyer et al., J. Med. Chem., 1990, 33, 521; Clark et al., J. Med. Chem.,1990, 33, 633; Pfeiffer et al., J. Med. Chem., 1982, 25, 352; Weinstock et al., J. Med. Chem., 1980, 23(9), 973; Weinstock et al., J. Med. Chem., 1980, 23(9), 975; Chumpradit et al., J. Med. Chem., 1989, 32, 1431; Heys et al., J. Org. Chem., 1989, 54, 4702; Bremner et al., Progress in Heterocyclic Chemistry, 2001, 13, 340; Hasan et al., Indian J. Chem., 1971, 9(9), 1022; Nagle et al., Tetrahedron Letters, 2000, 41, 3011; Robert, et al., J. Org. Chem., 1987, 52, 5594); and Deady et al., J. Chem. Soc., Perkin Trans. I, 1973, 782.
Other routes to 3-benzazepines and related compounds are reported in Ladd et al., J. Med. Chem., 1986, 29, 1904; EP 204349; EP 285 919; CH 500194; Tetrahedron Letters, 1986, 27, 2023; Ger. Offen., 3418270, 21 Nov. 1985; J. Org. Chem.,1985, 50, 743; U.S. Pat. Nos. 4,957,914 and 5,015,639; Synthetic Commun., 1988, 18, 671; Tetrahedron, 1985, 41, 2557;Hokkaido Daigaku Kogakubu Kenhyu Hokoku, 1979, 96, 414; Chemical & Pharmaceutical Bulletin, 1975, 23, 2584; J. Am. Chem. Soc., 1970, 92, 5686; J. Am. Chem. Soc., 1968, 90, 6522; J Am. Chem. Soc., 1968, 90, 776; J. Am. Chem. Soc.,1967, 89, 1039; and Chang et al., Bioorg. Med. Chem. Letters, 1992, 2, 399
Its synthesis starting from compound 1 and, via SN2 coupling to form 3, thionyl chloride, to form 4, aluminum chloride catalyzed Friedel-Crafts alkylation ring closure to give the racemic product 5, through L- tartaric acid separation, obtained chiral
Smith, J.; Smith, B. 5HT2C receptor modulators. U.S. Patent 2003225057, 2003.
http://www.google.com/patents/US8367657
Example 6 Preparation of 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride
To a dry 100-milliliter, round bottom flask under nitrogen with stirring was added 2-(4-chlorophenyl)ethyl-N-2-chloropropionylamide (8.8 g, 35.8 mmol) followed by borane in THF (1.8 M, 70 mL, 140 mmol) over 10 minutes (gas evolution and solid becomes solubilized). After the addition was complete, boron trifluoride in tert-butyl methyl ether (8 mL, 70.8 mmol) was added over 10 minutes with more gas evolution. After 4 hours, LC/MS showed complete reaction. The reaction mixture was quenched with 20 mL of conc. HCL (37%) with additional of gas evolution. The reaction mixture was stirred at 40° C. for 2 hours, cooled to room temperature and evaporated. Then, the white slurry was taken up in 40 mL ethyl acetate and 20 mL of 2.5 M NaOH to make a yellow solution over a white slurry. The yellow organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give 12.2 grams of white to yellow solid. This solid was recrystallized from ethyl acetate/hexane in two crops to give 6.7 grams of white solid product (80% yield).
1H NMR (DMSO-d6): 9.0 (br s, 2 H, NH, HCl), 7.2 (d, 2H, J=8 Hz), 7.05 (d, 2H, J=8 Hz), 4.5 (m, 1H), 3.2 (m, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 1.5 (d, 3H, J=7 Hz).
LC/MS: 1.71 minute, 232.1 M+H+ and 139 major fragment. Minor impurity observed at 2.46 min with 321 and 139 peaks.
Example 1 Preparation of 2-(4-chlorophenyl)ethyl-N-2-chloropropionamide
To a 1-liter, 3-necked round bottom flask under argon balloon equipped with reflux condenser and addition funnel, were added sequentially 2-(4-chlorophenyl) ethylamine (30 g, 193 mmol), 400 mL acetonitrile, triethylamine (19.5 g, 193 mmol) and 80 mL acetonitrile. The clear colorless solution was stirred and cooled to 0° C. 2-Chloropropionyl chloride (24.5 g, 193 mmol, distilled) in 5 mL acetonitrile was slowly added over 20 minutes to evolution of white gas, formation of white precipitate, and color change of reaction mixture to slight yellow. An additional 10 mL of acetonitrile was used to rinse the addition funnel. The mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred vigorously for an additional one hour. The yellow reaction mixture was concentrated on the rotary evaporator to a solid containing triethylamine hydrochloride (76.36 grams). This material was taken up in 100 mL ethylacetate and 200 mL water, and stirred vigorously. The layers were separated and the aqueous layer was extracted with an additional 100 mL ethylacetate. The combined organic layers were washed twice with 25 mL of saturated brine, dried over magnesium sulfate, filtered, and concentrated to a light tan solid (41.6 grams, 88%). TLC in ethylacetate-hexane, 8:2 showed a major spot two-thirds of the way up the plate and a small spot at the baseline. Baseline spot was removed as follows: This material was taken up in 40 mL of ethylacetate and hexane was added until the solution became cloudy. Cooling to 0° C. produced a white crystalline solid (40.2 grams, 85% yield). The product is a known compound (Hasan et al., Indian J. Chem., 1971, 9(9), 1022) with CAS Registry No. 34164-14-2.
LC/MS gave product 2.45 minute; 246.1 M++H+.
1H NMR (CDCl3): δ 7.2 (dd, 4H, Ar), 6.7 (br S, 1H, NM, 4.38 (q, 1H, CHCH3), 3.5 (q, 2H, ArCH2CH2NH), 2.8 (t, 2H, ArCH2), 1.7 (d, 3H, CH3).
13C NMR (CDCl3): 169 (1C, C═O), 136 (1C, Ar—Cl), 132 (1C, Ar), 130 (2C, Ar), 128 (2C, Ar), 56 (1C, CHCl), 40 (1C, CHN), 34 (1C, CHAr), 22 (1C, CH3).
Example 2 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) of Example 1 and aluminum chloride (16 g, 119.9 mmol) were added to a clean dry 100 mL round bottom flask equipped with an argon balloon, stirring apparatus, and heating apparatus. The white solid melted to a tan oil with bubbling at 91° C. (Note: if impure starting materials are used, a black tar can result but clean product can still be isolated). The mixture was heated and stirred at 150° C. for 12 hours. (Note: The time is dependent on the reaction scale and can easily be followed by LC/MS; higher temperatures can be used for shorter time periods. E.g., a 1 gram sample was complete in 5 hours.) The reaction can be followed by LC/MS with the starting material at 2.45 minutes (246.1 M++H+), the product at 2.24 minutes (209.6 M++H+) on a 5 minute reaction time from 5-95% w/0.01% TFA in water/MeCN (50:50).
After cooling to room temperature, the reaction mixture was quenched with slow addition of 10 mL of MeOH followed by 5 mL of 5% HCl in water and 5 mL of ethyl acetate. After separation of the resulting layers, the aqueous layer was extracted a second time with 10 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to a tan solid (6.78 grams, 80% yield). LC/MS showed one peak, at 2.2 min and 209.6 MI. This material was taken up in ethyl acetate, filtered through celite and Kieselgel 60 (0.5 inch plug on a 60 mL Buchner funnel) and the filtrate was recrystallized from hexane/ethyl acetate to give final product (4.61 grams, 54% yield).
1H NMR (CDCl3): 7.3-7.1 (m, 3H, Ar), 5.6 (br S, 1H, NH), 4.23 (q, 1H, CHCH3), 3.8 (m, 1H, ArCH2CH 2NH), 3.49 (m, 1H, ArCH2CH 2NH), 3.48 (m, 1H, ArCH 2CH2NH), 3.05 (m, 1H, ArCH 2CH2NH), 1.6 (d, 3H, CH2).
13C NMR (CDCl3): 178 (1C, C═O), 139 (1C, Ar), 135 (1C, Ar), 130, 129 (2C, Ar), 126 (2C, Ar), 42 (1C, C), 40 (1C, CHN), 33 (1C, CHAr), 14 (1C, CH3).
Example 3 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Procedure A
HPLC purified 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (150 mg, 0.716 mmol) of Example 2 was added to a 50 mL round bottom flask with 2M borane-tetrahydrofuran solution (2 mL, 2.15 mmol). The mixture was stirred 10 hours at room temperature under an argon balloon. LC/MS showed the desired product as the major peak with approximately 5% of starting material still present. The reaction mixture was quenched with 5 mL methanol and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours in vacuo to give the product as a white solid (117 mg, 70% yield).
NMR, LC/MS and other analytical data are provided below.
Procedure B
Recrystallized 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (137 mg, 0.653 mmol) was added to a 50 mL round bottom flask with stirring under nitrogen gas. To the flask was slowly added borane-tetrahydrofuran solution (1M, 10 mL) followed by boron trifluoride TBME solution (1 mL, 8.85 mmol) with vigorous gas evolution. The mixture was stirred 6 hours at room temperature under nitrogen gas. LC/MS showed the desired product. The reaction mixture was quenched with 5 mL methanol and 3 mL conc. HCl and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol and HCl addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours on the pump to dryness to give 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine hydrochloride (106 mg, 70% yield).
1H NMR (CDCl3): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).
LC/MS: 1.41 minute, 196.1 M+H+and 139 major fragment. No impurities were observed.
Example 4 Preparation of L-(+)-tartaric acid salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
To a clean, dry 50 mL round bottom flask were added 11.5 g (0.06 mol) of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine from Example 3 to 2.23 g (0.015 mol) of L-(+)-tartaric acid. The suspension was diluted with 56 g of tert-butanol and 6.5 mL of H2O. The mixture was heated to reflux (75-78° C.) and stirred for 10 min to obtain a colorless solution. The solution was slowly cooled down to room temperature (during 1 h) and stirred for 3 h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60° C. to yield 6.3 g of the tartrate salt (ee=80). This tartrate salt was added to 56 g of tert-butanol and 6.5 mL of H2O. The resulting suspension was heated to reflux and 1 to 2 g of H2O was added to obtain a colorless solution. The solution was slowly cooled down to room temperature (over the course of 1 h) and stirred for 3 h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60° C. to produce 4.9 g (48% yield) of product (ee>98.9).
If the ee value of the product obtained is not satisfactory, an additional recrystallization can be carried out as described. Either enantiomer can be synthesized in high ee utilizing this method.
Example 5 Conversion of Salt Form to Free Amine
The L-tartaric acid salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (300 mg, 0.87 mmol) from Example 4 was added to a 25 mL round bottom flask with 50% sodium hydroxide solution (114 μL, 2.17 mmol) with an added 2 mL of water. The mixture was stirred 3 minutes at room temperature. The solution was extracted with methylene chloride (5 mL) twice. The combined organic extracts were washed with water (5 mL) and evaporated to dryness on the pump to get free amine (220 mg crude weight). LC/MS 196 (M+H).
Example 14 Preparation of Hydrochloric Acid Salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
To a clean, dry 25 mL round bottom flask were added (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free amine (220 mg), 3 ML methylene chloride, and 1.74 mL of 1M HCl in ether. The mixture was stirred for 5 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid, the HCl salt. The salt was re-dissolved in methylene chloride (3 mL) and an additional 1.74 mL of 1 M HCl was added and the solution was again stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to give the desired HCl salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine (190 mg crude weight, 95% yield). NMR data was consistent with the desired product.
1H NMR (CDCl3): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H, 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).
A novel synthesis of antiobesity drug lorcaserin hydrochloride was accomplished in six steps.N-protection of 2-(4-chlorophenyl)ethanamine with di-tert-butyl dicarbonate, N-alkylation with allyl bromide, deprotection, intramolecular Friedel–Crafts alkylation, chiral resolution with l-(+)-tartaric acid, and the final salification led to the target molecule lorcaserin hydrochloride in 23.1% overall yield with 99.9% purity and excellent enantioselectivity (>99.8% ee). This convenient and economical procedure is remarkably applicable for scale-up production.
(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride (1)
| WO2010148207A2 | 17 Jun 2010 | 23 Dec 2010 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-ht2c receptor agonists |
| WO2011153206A1 | 1 Jun 2011 | 8 Dec 2011 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-ht2c receptor agonists |
| WO2012030927A2 | 31 Aug 2011 | 8 Mar 2012 | Arena Pharmaceuticals, Inc. | Modified-release dosage forms of 5-ht2c agonists useful for weight management |
| WO2012030938A1 | 31 Aug 2011 | 8 Mar 2012 | Arena Pharmaceuticals, Inc. | Salts of lorcaserin with optically active acids |
| WO2012030939A1 | 31 Aug 2011 | 8 Mar 2012 | Arena Pharmaceuticals, Inc. | Administration of lorcaserin to individuals with renal impairment |
| WO2012030951A1 | 31 Aug 2011 | 8 Mar 2012 | Arena Pharmaceuticals, Inc. | Fast-dissolve dosage forms of 5-ht2c agonists |
| WO2012030953A1 | 31 Aug 2011 | 8 Mar 2012 | Arena Pharmaceuticals, Inc. | 5-ht2c receptor agonists in the treatment of disorders ameliorated by reduction of norepinephrine level |
| WO2012030957A2 | 31 Aug 2011 | 8 Mar 2012 | Arena Pharmaceuticals, Inc. | Non-hygroscopic salts of 5-ht2c agonists |
| EP2443080A2 * | 17 Jun 2010 | 25 Apr 2012 | Arena Pharmaceuticals, Inc. | Process for the preparation of 5-ht2c receptor agonists |
| WO2007120517A2 * | 2 Apr 2007 | 25 Oct 2007 | Arena Pharm Inc | Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto |
back to home for more updates
DR ANTHONY MELVIN CRASTO Ph.D
PARIS, France, November 8, 2013 /PRNewswire/ —
Yervoy, an innovative immuno-oncology therapy that has demonstrated durable long-term survival in some patients, [1] , [2] is now approved for use in previously-untreated patients
Bristol-Myers Squibb today announced that the European Commission (EC) has approved YERVOY® (ipilimumab) for the first-line treatment of adult patients with advanced (unresectable or metastatic) melanoma.[3] When initially approved in Europe in July 2011 for the treatment of adult patients with previously-treated advanced melanoma, ipilimumab represented the first major treatment advance in this disease in more than 30 years, providing the first overall survival benefit ever seen in the treatment of metastatic melanoma in a phase III study.[ 1 ]
http://www.pharmalive.com/ec-approves-yervoy
Ipilimumab
In early 2011, the Food and Drug Administration approved Bristol-Myers Squibb‘s drug Yervoy as a treatment for skin cancer melanoma. The drug marked the first approved treatment proven to extend the life of a person diagnosed with the disease. It marked a big leap forward in medicine as an early leader in immunotherapy, or the unleashing of the body’s immune system on cancer.
read all at
http://www.dailyfinance.com/2013/09/28/yervoy-battles-melanoma-but-can-it-become-a-blockb/
Ipilimumab’s molecular target is CTLA-4 (Uniprot: P16410; canSAR ; PFAM: P16410), a negative regulator of T-cell activation. Ipilimumab augments T-cell activation and proliferation by binding to CTLA-4 and preventing its interaction with its ligands (CD80 and CD86). CTLA-4 is a membrane-bound, 223 amino acid long, T-cell protein. It contains an immunoglobulin V-type domain (PFAM:PF07686). The structure of CTLA-4 is determined (see e.g. PDBe:3osk)
Ipilimumab (i pi lim′ ue mab; also known as MDX-010 and MDX-101), marketed asYervoy, is a drug used for the treatment of melanoma, a type of skin cancer. It is a U.S. Food and Drug Administration (FDA) approved human monoclonal antibody developed byBristol-Myers Squibb, and works by activating the immune system by targeting CTLA-4.
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy cancer cells.
In addition to melanoma, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC) and metastatic hormone-refractory prostate cancer.
Yervoy is a monoclonal antibody drug indicated for treating metastatic melanoma. The drug was developed by Bristol-Myers Squibb.
In March 2011, The US Food and Drug Administration (FDA) approved Yervoy to treat patients with newly diagnosed or previously-treated unresectable or metastatic melanoma. Yervoy is the first drug approved vor the treatment of metastatic melanoma in the US.
Bristol-Myers Squibb submitted a marketing authorisation application to the European Medicines Agency in May 2010. The drug received approval from the European Commission in July 2011.
Approval from Australia’s Therapeutic Goods Association was received in July 2011. The drug is currently being reviewed by Health Canada.
Metastatic melanoma
Melanoma responsible for majority of skin cancer deaths in the US. In metastatic melanoma the cancer spreads to other parts of the body from its starting point. It becomes difficult to treat the disease once it spreads beyond the skin to other parts of the body. The disease is also known as stage IV melanoma.
If the melanoma spreads to the lungs then the patient faces breathing problems. The patients with metastatic melanoma may feel symptoms of fatigue, loss of weight, and appetite and bowel problems.
The incidence of the disease has increased steadily in the US after 1970s. The American Cancer Society (ACS) estimated that more than 68,000 new cases of melanoma were registered in the US in 2009. The ACS estimated that the number of deaths occurred due to melanoma in 2010 was more than 8,700.
Yervoy mechanism
Yervoy treats metastatic melanoma by activating the immune system. The drug works by binding or inhibiting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule that plays vital role in relating natural immune responses. The presence or absence of CTLA-4 can curb or increase the immune system’s T-cell response in fighting disease.
The drug also works by blocking a complex set of interactions in the immune system. It is designed to inhibit the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells.
Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. On February 1, 2012, Health Canada approved ipilimumab for “treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease.” Additionally Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma, November 2012
US-based clinical-stage biotechnology firm Advaxis has received orphan drug designation from the US Food and Drug Administration (FDA) for its lead drug candidate ADXS-HPV to treat human papillomavirus (HPV) associated head and neck cancer patients.
Advaxis’s cancer vaccine gets FDA orphan status for treatment of HPV-associated head and neck cancer
PRINCETON, N.J., Nov 05, 2013 (BUSINESS WIRE) — Advaxis, Inc., /quotes/zigman/23528806/delayed/quotes/nls/adxs ADXS +2.61% , a leader in developing the next generation of cancer immunotherapies, announced that it has been granted Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) for ADXS-HPV, its lead drug candidate, for the treatment of human papillomavirus (HPV)-associated head and neck cancer.
Orphan Drug Designation is granted to drug therapies intended to treat diseases or conditions that affect fewer than 200,000 people in the United States. Orphan Drug Designation entitles the sponsor to clinical protocol assistance with the FDA, as well as federal grants, tax credits, and potentially a seven year market exclusivity period.
“We are very pleased to have been granted an orphan drug designation for ADXS-HPV in this unmet medical need,” commented Dr. Robert Petit, Chief Scientific Officer of Advaxis. “Patients with head and neck cancer have limited treatment options and we hope to improve their survival by developing ADXS-HPV for this indication. We plan to initiate an additional Phase 1/2 study in early stage head and neck cancer for ADXS-HPV with a nationally recognized center of excellence, and we will continue the ongoing Phase 1 study being sponsored by the University of Liverpool and Aintree University Hospitals NHS Foundation Trust that is evaluating the safety and efficacy of ADXS-HPV when combined with standard chemotherapy and radiation treatment in patients with head and neck cancer.”
“Receiving orphan drug designation for ADXS-HPV in head and neck cancer is excellent news for a technology that may offer the potential to treat an indication with few therapy options, and, importantly, it helps define a clear path forward to registration,” commented Daniel J. O’Connor, President and Chief Executive Officer of Advaxis.
About Orphan Drug Designation
Under the Orphan Drug Act (ODA), the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug or biological product available in the United States for this type of disease or condition will be recovered from sales of the product. The benefits of orphan drug designation can be substantial and include federal grants, tax credits, and potentially a seven year market exclusivity period once the product is approved, provided that the product is first to market.
In order for a sponsor to obtain orphan designation for a drug or biological product, an application must be submitted to OOPD, and the designation approved. The approval of an application for orphan designation is based upon the information submitted by the sponsor. A drug that has obtained orphan designation is said to have “orphan status.” Each designation request must stand on its own merit. Sponsors requesting designation of the same drug for the same indication as a previously designated product must submit their own data in support of their designation request. The approval of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval. Safety and efficacy of a compound must be established through adequate and well-controlled studies.
About ADXS-HPV
ADXS-HPV is an immunotherapy that is designed to target cells expressing the HPV gene E7. Expression of the E7 gene from high-risk HPV variants is responsible for the transformation of infected cells into dysplastic and malignant tissues. Eliminating these cells can eliminate the dysplasia or malignancy. ADXS-HPV is designed to infect antigen-presenting cells and direct them to generate a powerful, cellular immune response to HPV E7. The resulting cytotoxic Tcells infiltrate and attack the tumors while specifically inhibiting tumor Tregs and MDSCs in the tumors that are protecting it.
About Head and Neck Cancer
Cancer of the head and neck includes cancers arising from mucosa lining the oral cavity, oropharynx, hypopharynx, larynx, sinonasal tract, and nasopharynx. The most common histologic type observed is squamous cell carcinoma; therefore, the term “head and neck squamous cell carcinoma” (HNSCC) is frequently used to imply squamous cell carcinomas involving these anatomical sites. Excessive tobacco and alcohol are important risk factors for HNSCCs overall, but human papillomavirus (HPV) is now recognized as the causative agent in a subset of HNSCCs.
While the incidence of head and neck cancers that are linked to alcohol and tobacco use as the primary risk factor has fallen in the past three decades, a trend attributed to decreasing tobacco use in the United States, the incidence of HPV-associated head and neck cancer has been increasing. The increase was observed particularly among young individuals (<60 years of age), men, and Caucasians. Studies have shown that oral HPV infection is likely to be sexually acquired, as the increase in the incidence of HPV-associated head and neck cancers may be attributed to changing sexual practices. According to the World Health Organization’s Human Papillomavirus and Related Cancers in the World Summary Report 2010, HPV is associated with 20-50% of oral squamous cell carcinomas. HPV-associated head and neck cancer is growing at an epidemic rate in western countries; and occurs more frequently (3:1) in men than women. In the United States, the number of HPV-positive head and neck cancer cases has already equaled the number of cervical cancer cases.
About Advaxis, Inc.
Advaxis is a clinical-stage biotechnology company developing the next generation of immunotherapies for cancer and infectious diseases. Advaxis immunotherapies are based on a novel platform technology using live, attenuated bacteria that are bio-engineered to secrete an antigen/adjuvant fusion protein(s) that is designed to redirect the powerful immune response all human beings have to the bacterium to the cancer itself.
ADXS-HPV is currently being evaluated in four clinical trials for human papillomavirus (HPV)-associated cancers: recurrent/refractory cervical cancer (India), locally advanced cervical cancer (GOG/NCI U.S. study, Clinical Trials.gov Identifier NCT01266460), head & neck cancer (CRUK study, Clinical Trials.gov Identifier NCT01598792), and anal cancer (BrUOG study, Clinical Trials.gov Identifier NCT01671488). Advaxis has over 15 distinct immunotherapies in various stages of development, developed directly by Advaxis and through strategic collaborations with recognized centers of excellence such as: the University of Pennsylvania, the Georgia Regents University Cancer Center, Brown University Oncology Group, and others.
ADXS-HPV is currently in Phase 1/2 clinical development for recurrent/refractory and advanced cervical cancer, HPV caused head and neck cancers, and anal cancer.
Links to ADXS-HPV trials:
ADXS-HPV is an immunotherapy that is designed to target cells expressing the HPV gene E7. Expression of the E7 gene from high-risk HPV variants is responsible for the transformation of infected cells into dysplastic and malignant tissues. Eliminating these cells can eliminate the dysplasia or malignancy. ADXS-HPV is designed to infect antigen-presenting cells and direct them to generate a powerful, cellular immune response to HPV E7. The resulting cytotoxic Tcells infiltrate and attack the tumors while specifically inhibiting tumor Tregs and MDSCs in the tumors that are protecting it.
The American Cancer Society estimates that there will be about 12,340 newly diagnosed cervical cancer cases and 7,060 newly diagnosed cases of anal cancer in the U.S. in 2013.
In 2009, the CDC reported that about 45% of women aged 20 to 24 had HPV. HPV causes a number of different types of cancer. The same types of genital HPV that cause cervical cancer (HPV-16, HPV-18) cause about 8 out of 10 squamous cell anal cancers. In addition, nearly half of cancers of the vulva and about 7 out of 10 vaginal cancers are HPV-related. Some other genital cancers (cancers of the penis and urethra) and some head and neck cancers (mostly the throat, tongue, and tonsils) are also related to high-risk types of HPV. For additional information about HPV, please visit: http://www.cancer.org/.
back to home for more updates
DR ANTHONY MELVIN CRASTO Ph.D
1 st oct 2013, US5560903, CAS 122795-43-1
| GADODIAMIDE | INJECTABLE; INJECTION | 287MG/ML | RX | NDA 020123 |
Gadodiamide is a gadolinium-based MRI contrast agent, used in MR imaging procedures to assist in the visualization of blood vessels. It is commonly marketed under the trade name Omniscan.
For intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues.
Gadodiamide is a contrast medium for cranial and spinal magnetic resonance imaging (MRI) and for general MRI of the body after intravenous administration. The product provides contrast enhancement and facilitates visualisation of abnormal structures or lesions in various parts of the body including the central nervous system (CNS). It does not cross an intactblood brain barrier but might give enhancement in pathological conditions.
Based on the behavior of protons when placed in a strong magnetic field, which is interpreted and transformed into images by magnetic resonance (MR) instruments. Paramagnetic agents have unpaired electrons that generate a magnetic field about 700 times larger than the proton’s field, thus disturbing the proton’s local magnetic field. When the local magnetic field around a proton is disturbed, its relaxation process is altered. MR images are based on proton density and proton relaxation dynamics. MR instruments can record 2 different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and the T2 (spin-spin or transverse relaxation time). In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in the T2. When placed in a magnetic field, gadodiamide shortens both the T1 and the T2 relaxation times in tissues where it accumulates. At clinical doses, gadodiamide primarily affects the T1 relaxation time, thus producing an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier; therefore, it does not accumulate in normal brain tissue or in central nervous system (CNS) lesions that have not caused an abnormal blood-brain barrier (e.g., cysts, mature post-operative scars). Abnormal vascularity or disruption of the blood-brain barrier allows accumulation of gadodiamide in lesions such as neoplasms, abscesses, and subacute infarcts.
1.Schenker MP, Solomon JA, Roberts DA. (2001). Gadolinium Arteriography Complicated by Acute Pancreatitis and Acute Renal Failure, Journal of vascular and interventional radiology 12(3):393.[1]
2 Unal O, Arslan H. (1999). Cardiac arrest caused by IV gadopentetate dimeglumine. AJR Am J Roentgenol 172:1141.[2]
3 Cacheris WP, Quay SC, Rocklage SM. (1990). The relationship between thermodynamics and the toxicity of gadolinium complexes, Magn Reson Imaging 8(6):467-81. doi:10.1016/0730-725X(90)90055-7
4 Canavese, C; Mereu, MC; Aime, S; Lazzarich, E; Fenoglio, R; Quaglia, M; Stratta, P (2008). “Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists’ awareness”. Journal of nephrology 21 (3): 324–36. PMID 18587720.
COUNTRY PATENT APPROVED, EXPIRY
| United States | 5560903 | 1993-10-01 | 2013-10-01 |
| Canada | 1335819 | 1995-06-06 | 2012-06-06 |
| United States | 5362475 | 1994-11-08 | 2011-11-08 |
| Canada | 1335819 | 1995-06-06 | 2012-06-06 |
| United States | 5560903 | 1993-10-01 | 2013-10-01 |
Gadolinium contrast agents are used as contrast media to enhance magnetic resonance imaging as they are paramagnetic. This compound has a low incidence of adverse side effects, although there is a rare association with nephrogenic systemic fibrosis (NSF) when given to people with severe renal impairment (ie, GFRglomerular filtration rate <30mL/min/1·73m2).It seems to be related to the liberation of free gadolinium ions, and UK CHM advice is against using the least stable of the agents – Omniscan (gadodiamide) – in patients with severe renal impairment, and carefully considering whether to use others where renal function is impaired.
OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection.
The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl)11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9•xH2O, and the following structural formula:
 |
Pertinent physicochemical data for OMNISCAN are noted below:
PARAMETER
| Osmolality (mOsmol/kg water) | @ 37°C | 789 |
| Viscosity (cP) | @ 20°C | 2 |
| @ 37°C | 1.4 | |
| Density (g/mL) | @ 25°C | 1.14 |
| Specific gravity | @ 25°C | 1.15 |
OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use.
gadodiamide, chemical name: [5,8 _ bis (carboxymethyl) -11 – [2_ (methylamino)-2_ ethyl] -3 – O 2 ,5,8, 11 – tetraazacyclododecane-decane -13 – oxo-(3 -)] gadolinium trihydrate. Its structure is shown in formula one.
[0003] Structural Formula:
[0004]
[0005] Magnetic resonance contrast agent gadodiamide resonance than ionic contrast agents safer generation of products, it is non-ionic structure significantly reduces the number of particles in solution, osmotic balance of body fluids is very small.Meanwhile, gadodiamide relatively low viscosity to bring the convenience of nursing staff, making it easier to bolus. In addition, gadodiamide pioneered the use of amide-substituted carboxyl part, not only reduces the toxicity of carboxyl groups and ensure the non-ionic nature of the product solution.
[0006] reported in the literature and their intermediates gadodiamide synthetic route is as follows:
[0007] 1. Compound III synthetic routes for its preparation in U.S. Patent No. US5508388 described as: In the synthesis process, the inventors using acetonitrile as solvent, acetic anhydride as dehydrating agent, pyridine as acid-binding agent, at 55 ~ 60 ° C, the reaction 18h. Anti-
See the reaction should be a process. The disadvantage of this synthesis are acetonitrile toxicity, not widely used.
[0008]
[0009] Reaction a
[0010] (2) Synthesis of Compound III in many articles are reported in the patent and its implementation method similar to the patent US5508388.
[0011] In US3660388, the diethylenetriamine pentaacetic acid (Compound II), pyridine, acetic anhydride, the mixture was reacted at 65 ° C or 20h at 125 ° C the reaction 5min, to give compound III.
[0012] In US4822594, the compounds II, pyridine, acetic anhydride mixture was reacted at 65 ° C 20h, to give compound III.
[0013] In US4698263, the compounds II, pyridine, acetic anhydride heated in a nitrogen or argon atmosphere under reflux for 18h, to give compound III. [0014] In the EPO183760B1, the compounds II, pyridine, acetic anhydride mixture was reacted at 55 ° C 24h, to give compound III.
[0015] In CN1894223A, the compounds II, pyridine, acetic anhydride, the mixture above 65 ° C the reaction mixture, and the pyridine of DTPA feed ratio is: 1: (0.5 to 3).
[0016] The above patents do not provide for the compound III is post-processing method.
[0017] 3 Synthesis of Compound IV.
[0018] In U.S. Patent US4859451, the diethylenetriamine pentaacetic acid dianhydride (compound III) and ammonia, methanol and the reaction of compounds IV, see Reaction Scheme II.
[0019]
[0020] Reaction two
[0021] In the patent US5087439, the compound III with methylamine in aqueous solution for several hours, or overnight reactions, see reaction formula III.
[0022]
[0023] Reactive three
[0024] These two patents using ammonia and methylamine, which can form explosive mixtures with air, in case of fire or high pressure can cause an explosion in the production process of great insecurity. Although raw material prices are lower, but higher production conditions (such as requiring sealed, low temperature, etc.). Compared to this synthesis process,
[0025] 4, gadodiamide (Compound I) synthesis.
[0026] In the patent US4859451, the use of gadolinium chloride with the compound IV is carried out under acidic conditions, complexing. Finally, tune
Section PH neutral, see reaction IV.
[0027]
[0028] Reaction formula tetrakis [0029] in the patent US5087439, the chlorides are used as reactants, and details of the post-processing method of Compound I.
[0030] In the patent US5508388, the use of gadolinium oxide with compound IV in acetonitrile, water with stirring, the resulting compound I.
[0032] The synthetic route is as follows:
[0033]
[0034] 1) Compound II (diethylenetriamine pentaacetic acid) in pyridine, acetic anhydride in the presence of a dehydration reaction into the acid anhydride, and the product was stirred with cold DMF, leaving the solid filtered, washed with ether reagents, drying , to obtain a white powdery solid compound III (diethylenetriamine pentaacetic acid anhydride);
[0035] 2) Compound III in DMF with methylamine hydrochloride, the reaction of the compound IV (5,8 _ bis carboxymethyl methyl-11 – [2 – (dimethylamino) -2 – oxoethyl] – 3 – oxo -2,5,8,11 – tetraazacyclododecane _13_ tridecyl acid); and the control compound III: MeNH2 · HCl molar ratio = 1: (1 to 4), control the temperature between 20 ~ 80 ° C, the reaction time is 4 ~ 6h, after the treatment, the method of distillation under reduced pressure to remove DMF, the product is dissolved in a polar solvent, methanol, and then adding a solvent polarity modulation, so that the target Compound IV from system completely precipitated;
[0036] 3) Compound IV with gadolinium oxide formed in the presence of hydrochloric acid of the complex, after the reaction, filtration and drying, to obtain a white powdery compound I, i.e. gadodiamide.
[0037] Existing gadodiamide Synthesis basically from the synthesis of Compound IV as a starting material, the present invention is first introduced to the compound II as a starting material to synthesize gadodiamide. Synthesis of the conventional method of gadodiamide, the present invention has the advantage of inexpensive starting materials, convenient and easy to get. In addition, the synthetic pathway intermediates are involved in the post-processing is simple, enabling continuous reaction, saving time and cost savings, the reaction becomes controlled step by step, and try to avoid the use of toxic reagents, reducing the possibility of operator injury , while also greatly reducing damage to the environment.
PRONUNCIATION nye vol’ ue mab
THERAPEUTIC CLAIM Treatment of cancer
CHEMICAL DESCRIPTION
A fully human IgG4 antibody blocking the programmed cell death-1 receptor (Medarex/Ono Pharmaceuticals/Bristol-Myers Squibb)
MOLECULAR FORMULA C6362H9862N1712O1995S42
MOLECULAR WEIGHT 143.6 kDa
SPONSOR Bristol-Myers Squibb
CODE DESIGNATION MDX-1106, BMS-936558
CAS REGISTRY NUMBER 946414-94-4
Bristol-Myers Squibb announced promising results from an expanded phase 1 dose-ranging study of its lung cancer drug nivolumab
Nivolumab (nye vol’ ue mab) is a fully human IgG4 monoclonal antibody designed for the treatment of cancer. Nivolumab was developed by Bristol-Myers Squibb and is also known as BMS-936558 and MDX1106.[1] Nivolumab acts as an immunomodulator by blocking ligand activation of the Programmed cell death 1 receptor.
A Phase 1 clinical trial [2] tested nivolumab at doses ranging from 0.1 to 10.0 mg per kilogram of body weight, every 2 weeks. Response was assessed after each 8-week treatment cycle, and were evaluable for 236 of 296 patients. Study authors concluded that:”Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.”[3]
Phase III clinical trials of nivolumab are recruiting in the US and EU.[4]
The PD-1 blocking antibody nivolumab continues to demonstrate sustained clinical activity in previously treated patients with advanced non-small cell lung cancer (NSCLC), according to updated long-term survival data from a phase I trial.
Survival rates at one year with nivolumab were 42% and reached 24% at two years, according to the median 20.3-month follow up. Additionally, the objective response rate (ORR) with nivolumab, defined as complete or partial responses by standard RECIST criteria, was 17% for patients with NSCLC. Results from the updated analysis will be presented during the 2013 World Conference on Lung Cancer on October 29.
“Lung cancer is very difficult to treat and there continues to be a high unmet medical need for these patients, especially those who have received multiple treatments,” David R. Spigel, MD, the program director of Lung Cancer Research at the Sarah Cannon Research Institute and one of the authors of the updated analysis, said in a statement.
“With nivolumab, we are investigating an approach to treating lung cancer that is designed to work with the body’s own immune system, and these are encouraging phase I results that support further investigation in larger scale trials.”
In the phase I trial, 306 patients received intravenous nivolumab at 0.1–10 mg/kg every-other-week for ≤12 cycles (4 doses/8 week cycle). In all, the trial enrolled patients with NSCLC, melanoma, renal cell carcinoma, colorectal cancer, and prostate cancer.
The long-term follow up focused specifically on the 129 patients with NSCLC. In this subgroup, patients treated with nivolumab showed encouraging clinical activity. The participants had a median age of 65 years and good performance status scores, and more than half had received three or more prior therapies. Across all doses of nivolumab, the median overall survival was 9.9 months, based on Kaplan-Meier estimates.
In a previous update of the full trial results presented at the 2013 ASCO Annual Meeting, drug-related adverse events of all grades occurred in 72% of patients and grade 3/4 events occurred in 15%. Grade 3/4 pneumonitis related to treatment with nivolumab emerged early in the trial, resulting in 3 deaths. As a result, a treatment algorithm for early detection and management was developed to prevent this serious side effect.
Nivolumab is a fully human monoclonal antibody that blocks the PD-1 receptor from binding to both of its known ligands, PD-L1 and PD-L2. This mechanism, along with early data, suggested an associated between PD-L1 expression and response to treatment.
In separate analysis presented at the 2013 World Conference on Lung Cancer, the association of tumor PD-L1 expression and clinical activity in patients with NSCLC treated with nivolumab was further explored. Of the 129 patients with NSCLC treated with nivolumab in the phase I trial, 63 with NSCLC were tested for PD-L1 expression by immunohistochemistry (29 squamous; 34 non-squamous).
http://www.ibef.org/download/Biosimilars-in-India-30312.pdf
patented/registered biotech products, but are manufactured by new companies after the patent expiry of the originator product. The global. Biosimilars market is …
cyclic pyranopterin monophosphate (cPMP, ALXN1101)
Alexion Pharma International Sàrl has received a breakthrough therapy designation from the US Food and Drug Administration (FDA) for its cyclic pyranopterin monophosphate (cPMP, ALXN1101), an enzyme co-factor replacement therapy to treat patients with molybdenum cofactor deficiency (MoCD) type A.
Alexion obtains FDA breakthrough therapy status for cPMP to treat MoCD type A disorder
read all at
Cyclic pyranopterin monophosphate (cPMP) is an experimental treatment formolybdenum cofactor deficiency type A, which was developed by José Santamaría-Araujo and Schwarz at the German universities TU Braunschweig and the University of Cologne.[1][2]
cPMP is a precursor to molybdenum cofactor, which is required for the enyzme activity ofsulfite oxidase, xanthine dehydrogenase/oxidase and aldehyde oxidase.[3]
Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder. Moco consists of molybdenum covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by a biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclicpyranopterin monophosphate; cPMP), MPT, and adenylated MPT. Mutations in the Moco biosynthetase genes result in the loss of production of the molybdenum dependent enzymes sulfite-oxidase, xanthine oxidoreductase, and aldehyde oxidase. Whereas the activities of all three of these cofactor-containing enzymes are impaired by cofactor deficiency, the devastating consequences of the disease can be traced to the loss of sulfite oxidase activity. Human Moco deficiency is a rare but severe disorder accompanied by serious neurological symptoms including attenuated growth of the brain, unbeatable seizures, dislocated ocular lenses, and mental retardation. Until recently, no effective therapy was available and afflicted patients suffering from Moco deficiency died in early infancy.
It has been found that administration of the molybdopterin derivative precursor Z, a relatively stable intermediate in the Moco biosynthetic pathway, is an effective means of therapy for human Moco deficiency and associated diseases related to altered Moco synthesis {see U.S. Patent No. 7,504,095). As with most replacement therapies for illnesses, however, the treatment is limited by the availability of the therapeutic active agent.
WO 2012112922 A1
In this synthesis, the deprotection may involve, for example, either sequential or one-pot deprotection of certain amino and hydroxyl protecting groups on a compound of formula (VII) to furnish the compound of formula (I). Suitable reagents and conditions for the deprotection of a compound of formula (VII) can be readily determined by those of ordinary skill in the art. For example, compound (I) may be formed upon treatment of a compound of formula (VII) under conditions so that hydroxyl protecting groups, such as acetate, isopropylidine, and benzylidine protecting groups, are removed from the formula (VII) structure. The acetate group can be cleaved, for example, under Zemplen conditions using catalytic NaOMe as a base in methanol. The benzylidene and isopropylidene groups can be cleaved by hydrogenation or using acidic hydrolysis as reported by R.M. Harm et ah, J. Am. Chem. Soc, 72, 561 (1950). In yet another example, the deprotection can be performed so that amino protecting groups, such as 9- fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (Boc), and carboxybenzyl carbamate (cbz) protecting groups are cleaved from the compound of formula (VII). 9-fluorenylmethyl carbamate (Fmoc) can be removed under mild conditions with an amine base (e.g. , piperidine) to afford the free amine and dibenzofulvene, as described by E. Atherton et al, “The
Fluorenylmethoxycarbonyl Amino Protecting Group,” in The Peptides, S. Udenfriend and J. Meienhofer, Academic Press, New York, 1987, p. 1. t-butyl carbamate (Boc) can be removed, as reported by G.L. Stahl et al., J. Org. Chem., 43, 2285 (1978), under acidic conditions (e.g., 3 M HC1 in EtOAc). Hydrogenation can be used to cleave the carboxybenzyl carbamate (cbz) protecting group as described by J. Meienhofer et al., Tetrahedron Lett., 29, 2983 (1988).
To prevent oxidation of formula (I) during the reaction, the deprotection may be performed under anaerobic conditions. The deprotection may also be performed at ambient temperature or at temperatures of from about 20 – 60 °C (e.g. , 25, 30, 35, 40, 45, 50, or 55 °C).
The compound of formula (I) may be isolated in the form of a pharmaceutically acceptable salt. For example, the compound of formula (I) may be crystallized in the presence of HC1 to form the HC1 salt form of the compound. In some embodiments, the compound of formula (I) may be crystallized as the HBr salt form of the compound. The compound of formula (I) may also be isolated, e.g., by precipitation as a sodium salt by treating with NaOH. The compound of formula (I) is labile under certain reaction and storage conditions. In some embodiments, the final solution comprising the compound of formula (I) may be acidified by methods known in the art. For example, the compound of formula (I), if stored in solution, can be stored in an acidic solution.
In some embodiments, the compound of formula (I) may be prepared, for example, by: reacting a compound of formula (II- A):
with a compound of formula (III- A):
in the presence of a hydrazine to produce a compound of formula (IV- A):
selectively protecting the compound of formula (IV-A) to prepare a compound of formula (V-A):
wherein:
Rj is a protecting group, as defined above;
phosphorylating the compound of formula (V-A) to prepare a compound of formula (VI- A):
oxidizing the compound of formula (VI-A) to prepare a compound of formula (VII- A):
; and deprotecting the compound of formula (VII-A) to prepare the compound of formula (I). For example, a compound of formula (I) can be prepared as shown in Scheme 3.
Scheme 3.
5 R = Fraoc
In another embodiment, the compound of formula (I) is prepared by:
reacting a compound of formula (II- A):
with a compound of formula (III- A):
in the presence of a hydrazine to produce a compound of formula (IV-A):
selectively protecting the compound of formula (IV-A) to prepare a compound of formula (V-B):
wherein:
each Ri is independently a protecting group, as defined above;
phosphorylating the compound of formula (V-B) to prepare a compound of formula (VI-B):
oxidizing the compound of formula (VI-B) to prepare a compound of formula (VII-B):
; and deprotecting the compound of formula (VII-B) to prepare the compound of formula (I), example, a compound of formula (I) can be prepared as shown in Scheme 4.
Scheme 4.
Alternatively, a compound of formula (I) can be formed as shown in Scheme 5. A diaminopyrimidinone compound of formula (II) can be coupled with a phosphorylated hexose sugar of formula (VIII), to give a compound of formula (IX). The piperizine ring nitrogen atoms can be protected to give a compound of formula (X) which can be oxidized to give a diol of formula (XI). The diol of formula (XI) can then be deprotected using appropriate conditions and converted to the compound of formula (I).
Scheme 5
In this embodiment, the phosphate may be introduced at the beginning of the synthesis to avoid undesirable equilibrium between the pyrano and furano isomers during subsequent steps of the synthesis. For example, a compound of formula (I) can be prepared as shown in Scheme 6.
Scheme 6.
ridine
A compound of formula (I) can also be formed as shown in Scheme 7. A diaminopyrimidinone compound of formula (II) can be coupled to a compound of formula (III) to afford the piperizine derivative of formula (IV). The piperizine ring nitrogen atoms of the compound of formula (IV) can be protected under standard conditions to give a derivative of formula (V). The formula (V) structure can be oxidized to afford compounds of formula (XII). Phosphorylation of a compound of formula (XII) gives a compound of formula (VII). Global deprotection of the compound of formula (VII) can afford the compound of formula (I).
Scheme 7
Piperizine ring protection
sphorylation
(VII)
For example, a compound of formula (I) can be prepared as shown in Scheme 8.
Scheme 8.
With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.
By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),
which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.
Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.
Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”
Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials
http://www.uni-giessen.de/cms/fbz/fb11/forschung/graduierte/mbml/faculty
Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million
BAYER PIPELINE AS ON OCT 25 2013
phase 1
| Project | Indication |
|---|---|
| CDK-Inhibitor (BAY 1000394) | Cancer |
| Mesothelin-ADC (BAY 94-9343) | Cancer |
| PSMA Bi TE Antibody (BAY 2010112) | Cancer |
| PI3K-Inhibitor (BAY 1082439) | Cancer |
| FGFR2 Antibody (BAY 1179470) | Cancer |
| HIF-PH (BAY 85-3934) | Anemia |
| Partial Adenosine A1 Agonist(BAY 1067197) | Heart Failure |
| Vasopressin Receptor Antagonist(BAY 86-8050) | Heart Failure |
| sGC Stimulator (BAY 1021189) | Heart Failure |
| S-PRAnt (BAY 1002670) | Symptomatic uterine fibroids |
| BAY 1026153 | Endometriosis |
phase2
| Project | Indication |
|---|---|
| PI3K-Inhibitor (BAY 80-6946) | Cancer |
| Regorafenib | Cancer |
| Refametinib (MEK-Inhibitor) | Cancer |
| Radium-223-Dichloride | Cancer |
| Sorafenib | Additional Indications |
| MR-Antagonist (BAY 94-8862) | Congestive Heart Failure (CHF) |
| MR-Antagonist (BAY 94-8862) | Diabetic Nephopathy |
| Riociguat (sGC Stimulator) | Pulmonary Hypertension |
| Neutrophil Elastase Inhibitor(BAY 85-8501) | Bronchiectasis |
phase 3
| Project | Indication |
|---|---|
| Sorafenib | Breast Cancer |
| Sorafenib | Adjuvant HCC |
| Sorafenib | Adjuvant RCC |
| Regorafenib | HCC 2nd line |
| Rivaroxaban | Major Adverse Cardiac Events |
| Rivaroxaban | CHF and CAD |
| peg rFVIII(BAY 94-9027) | Hemophilia |
| Aflibercept | Myopic choroidal neovascularization (mCNV) |
| Aflibercept | Diabetic Macular Edema (DME) |
| LCS 16 | Contraception |
| Vaginorm | Vulvovaginal atrophy (VVA) |
| Sodium Deoxycholate | Submental fat removal |
| Cipro DPI | Lung infection |
| Tedizolid | Skin and Lung Infections |
| Amikacin Inhale | Gram-negative pneumonia |
Sorafenib tosylate
https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/
TEDIZOLID PHOSPHATE
Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.
“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”
Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”
Cl 223Ra Cl
Xofigo
https://newdrugapprovals.wordpress.com/2013/09/21/xofigo-injection-recommended-for-approval-in-eu/
The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.
Finerenone (BAY 94-8862)
The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.
For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.
Molidustat (BAY 85-3934)
In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.
Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.
Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.
Regorafenib, stivarga
Bayer’s Eylea (aflibercept),
https://newdrugapprovals.wordpress.com/2013/06/01/lucentis-rival-one-step-away-from-nhs-approval/
Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.
In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.
Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.
In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.
In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.
ALCAFTADINE
Alcaftadine is used to prevent eye irritation brought on by allergic conjunctivitis. It is a H1histamine receptor antagonist.
It was approved by the U.S. Food and Drug Administration in 2010 under the trade name Lastacaft.
| Active Ingredient | Form | Dosage | Drug Type | Application | Product | |
|---|---|---|---|---|---|---|
| ALCAFTADINE | SOLUTION/DROPS; OPHTHALMIC | 0.25% | RX | 022134 | 001 |
There are 1 patent(s) protecting ALLERGAN’s LASTACAFT.
The last patent expires on 2013-11-21.
| Patent | Expiration | |
|---|---|---|
| US5468743 | Imidazo[2,1-b]benzazepine derivatives, compositions and method of use
The present invention is concerned with novel imidazo[2, 1-b][3]benzazepines of formula ##STR1## the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein each of the dotted lines independently represents an optional bond; R.sup.1 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy; R.sup.2 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy; R.sup.3 represents hydrogen, C.sub.1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, hydroxyC.sub.1-4 alkyl, formyl or hydroxycarbonyl; R.sup.4 represents hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, phenyl or halo; R.sup.5 represents hydrogen, C.sub.1-4 alkyl or halo; L represents hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with one substituent selected from the group consisting of hydroxy, halo, C.sub.1-4 alkyloxy, hydroxycarbonyl, C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyloxycarbonyl-C.sub.1-4 alkyloxy, hydroxycarbonylC.sub.1-4 alkyloxy, C.sub.1-4 alkyloxycarbonylamino, C.sub.1-4 alkylaminocarbonyl, C.sub.1-4 alkylaminocarbonylamino, C.sub.1-4 alkylaminothiocarbonylamino, aryl, aryloxy and arylcarbonyl; C.sub.1-6 alkyl substituted with both hydroxy and aryloxy; C.sub.3-6 alkenyl; C.sub.3-6 alkenyl substituted with aryl; or, L represents a radical of formula –Alk–Y–Het.sup.1 (a-1),–Alk–NH–CO–Het.sup.2 (a-2)or –Alk–Het.sup.3 (a-3); provided that 6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine is ecxluded, which are useful antiallergic compounds.Compositions comprising said compounds, methods of using and processes for preparing the same.
|
2013-11-21 |
Exclusivity is marketing rights granted by the FDA to the ALLERGAN.
Exclusivity ends on 2015-07-28.
| Date | Supplement No. | Action | Documents |
|---|---|---|---|
| 2010-07-28 | 000 | Approval |
New Drug Approvals 