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Poziotinib for the treatment of Adenocarcinoma of Lung Stage IIIB or Adenocarcinoma of Lung Stage IV

August 7, 2014 4:16 am / Leave a comment

Chemical structure for Poziotinib

Poziotinib

l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazol in-6- yloxy)piperidin-l-yl)prop-2-en-l-one

: 1 – [4 – [[4 – [(3, 4 – dichloro – 2 – phenyl) amino] – 7 – methoxy – 6 – base] quinazoline oxygen radicals] – 1 – piperidine base] – 2 – acrylic – 1 – ketone

UNII-OEI6OOU6IK;

cas 1092364-38-9

HM781-36B

NOV120101

Erbb2 tyrosine kinase receptor inhibitor; EGFR family tyrosine kinase receptor inhibitor

Non-small-cell lung cancer; Stomach tumor

for the treatment of Adenocarcinoma of Lung Stage IIIB or Adenocarcinoma of Lung Stage IV

http://www.centerwatch.com/clinical-trials/listings/external-studydetails.aspx?StudyID=NCT01819428

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation…….http://clinicaltrials.gov/show/NCT01819428

KR 1013319

………………………………………………………….

WO2013051883

http://www.google.com/patents/WO2013051883A2?cl=en

1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidin-l-yl)-prop-2-en-l-one hydrochloride of formula (I) below is an important drug having antiproliferative activities such as anti-tumor activity, which can be used for selectively and effectively treating drug resistance caused by tyrosine kinase mutation. Its free base form, i.e., l-(4-(4-(3,4-dichloro-2- fluoropheny lamino)-7-methoxyquinazolin-6-y loxy)piperidin- 1 -y l)-prop-2-en- 1 – one having formula (II) below is identified as CAS Registry Number 1092364-38-

The compound of formula (II) may be prepared by, e.g., the method disclosed in Korean Patent No. 1013319, the reaction mechanism thereof being shown in Reaction Scheme 1 below. The compound of formula (II) prepared according to Reaction Scheme 1 may then be reacted with hydrochloric acid to produce the compound of formula (I).

wherein R is halogen.

Figure imgf000008_0003

formula (I):

In accordance with another aspect of the present invention, there are provided N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride of formula (III), tert-butyl 4-(4-(3,4- dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l- carboxylate of formula (IV) and 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol of formula (V), which can be used as intermediates for preparing the compound of formula (I).

Example 1: Preparation of 4-(3,4-dichloro-2-fluorophenyIamino)-7- methoxyquinazolin-6-yl acetate the compound of formula (VI))

7-methoxy-4-oxo-3,4-dihydroquinazolin-yl acetate (100 g) was added to toluene (850 ml) and NN-diisopropylethylamine (82.5 ml). Phosphorusoxy chloride (100 ml) was added thereto over 20 minutes at 75°C, followed by stirring for 3 hours. Toluene (450 ml) and 3,4-dichloro-2-fluoroaniline (84.6 g) were added to the resulting mixture, followed by stirring for 2 hours. Upon completion of the reaction, the resulting mixture was cooled to 25°C. The solid thus obtained was filtered under a reduced pressure and washed with toluene (400 ml). Isopropanol (1,000 ml) was added to the solid, which was then stirred for 2 hours. The resulting solid was filtered and washed with isopropanol (400 ml). The solid was dried at 40°C in an oven to produce the compound of formula (VI) (143 g, yield: 83%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) δ 8.92 (s, 1H), 8.76 (s, 1H), 7.69- 7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

Example 2: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol (the com ound of formula (V))

4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate (100 g) was admixed with methanol (1,000 ml). The mixture was cooled to 10 to 15°C, added with an ammonia solution (460 g), and stirred for 3 hours at 25°C. The solid thus obtained was filtered and washed with a mixed solvent of methanol (200 ml) and water (200 ml). The resulting solid was dried at 40°C in an oven to produce the compound of formula (V) (74 g, yield: 83%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 6 9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s, 1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

Example 3: Preparation of /er/-but l-4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l-carboxylate (the compound of formu

4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (60 g) was admixed with N-dimethylformamide (360 ml) under stirring, followed by addition of tert-butyl 4-(tosyloxy)piperidin-l-carboxylate (120 g) and potassium carbonate (72 g) to the mixture. The reaction temperature was raised to 70°C, and the mixture was stirred for 14 hours. The temperature of the resulting solution was cooled to 25°C, and water (480 ml) was slowly added thereto. The solid thus obtained was filtered and dried. The solid was dissolved in a mixed solvent (600 ml) of dichloromethane and methanol. Active carbon (6 g) was then added thereto, followed by stirring for 30 minutes. The resulting mixture was filtered through a Celite pad, distilled under a reduced pressure, added with acetone (300 ml), and stirred for 2 hours. The resulting solid was filtered and washed with acetone (100 ml). The solid was dried at 40°C in an oven to produce the compound of formula (IV) (75 g, yield: 83%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 6 8.69 (s, 1H), 8.47 (t, 1H), 7.34- 7.29 (m, 2H), 7.20 (s, 1H), 4.63-4.60 (m, 1H), 3.82 (s, 3H), 3.83-3.76 (m, 2H), 3.37-3.29 (m, 2H), 1.99-1.96 (m, 2H), 1.90-1.84 (m, 2H), 1.48 (s, 9H).

Example 4: Preparation of N-(3,4-dichIoro-2-fluorophenyi)-7- methoxy-6-(piperidin-4-yloxy)quinazoIin-4-amine dihydrochloride (the compound of formula (III))

Acetone (740 ml) was added to ter/-butyl 4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-l-carboxylate (75 g), which was then stirred. The mixture was added with hydrochloric acid (145 ml) for 10 minutes and stirred for 5 hours. Upon completion of the reaction, the resulting mixture was filtered, and the solid thus obtained was washed with acetone (73 ml). The solid was dried at 30°C in an oven to produce the compound of formula (III) (71 g, yield: 99%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 512.95 (bs, 1H), 9.42 (bs, 1H), 9.18 (bs, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 7.69-7.56 (m, 2H), 7.45 (s, 1H), 5.11- 5.08 (m, 1H), 4.03 (s, 3H), 3.29-3.20 (m, 4H), 2.33-2.30 (m, 2H), 1.96-1.93 (m, 2H).

Example 5: Preparation of l-(4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazoIin-6-yloxy)piperidin-l-yl)prop-2-en- 1-one (the compound of formula II))

N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4- yloxy)quinazolin-4-amine dihydrochloride (100 g) and sodium hydrogen carbonate (66 g) were added to a mixed solvent of tetrahydrofuran (630 ml) and water (1 L), and the temperature of the reaction mixture was cooled to 0°C with iced water. Acryloyol chloride (24 ml) diluted with tetrahydrofuran (370 ml) was slowly added to the reaction mixture over 30 minutes, followed by stirring at 0°C for 30 minutes. Upon completion of the reaction, aqueous acetone (2.0 L) was added to the resulting mixture, which was stirred for 12 hours and filtered to produce 1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidin-l-yl)prop-2-en-l-one (72 g, yield: 75%). The solid thus obtained was dissolved in a mixed solvent of dichloromethane (200 ml) and methanol (100 ml), added with ethyl acetate (1.2 L), and stirred for 12 hours. The resulting solid was filtered and washed with ethyl acetate (100 ml). The solid was dried at 40°C in an oven to produce the compound of formula (II) (55 g, yield: 76%, total yield = 57%).

Ή-NMR (CDC1₃, 300 MHz, ppm) 68.68(s, 1H), 8.39(t, 3H), 7.3 l(m, 3H), 6.61(m, 1H), 6.29(m, 1H), 5.72(m, 1H), 4.75(m, 1H), 4.02(s, 3H), 3.89(m, 2H), 3.60(m, 2H), 1.86(m, 4H). Example 6: Preparation of l-(4-(4-(3,4-dichloro-2- fluorophenylamino)-7-methoxyquinazolin-6-yIoxy)piperidin-l-yl)prop-2-en- 1-one hydrochloride (the com ound of formula (I))

1 -(4-(4-(3 ,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6- yloxy)piperidine-l-yl)prop-2-en-l-one (150 g) was added to methanol (700 ml). Hydrochloric acid (38.2 ml) diluted with methanol (300 ml) was added thereto, followed by stirring for 24 hours. The solid thus obtained was filtered and washed with acetone (100 ml). The resulting solid was dried at 40°C in an oven for 24 hours to produce the compound of formula (I) (131 g, yield: 81%).

1H-NMR (DMSO-d₆, 300 MHz, ppm) 512.31 (bs, 1H), 8.83 (s, 1H), 8.67 (s, 1H), 7.64-7.55 (m, 2H), 7.39 (s, 1H), 6.87-6.78 (m, 1H), 6.12-6.06 (m, 1H), 5.68-5.64 (m, IH), 5.07-5.01 (m, IH), 4.06-3.88 (m, 5H), 3.51 (t, IH), 3.32 (t, IH), 2.10 (t, IH), 1.60 (t, IH).

…………………………………………………………..

WO-2014116070

http://www.sumobrain.com/patents/wipo/Method-preparing-1-4-34/WO2014116070.html

Process for preparing poziotinib – comprising the reaction of a 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol compound with an N-acyl piperidine derivative.

A process for preparing poziotinib comprising the reaction of a 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol compound with an N-acyl piperidine derivative in the presence of an inert polar protic solvent (eg N,N-dimethylformamide), and a base (eg sodium bicarbonate) is claimed. Also claimed are processes for preparing intermediates of poziotinib. Poziotinib is known to be an inhibitor of EGFR family, and Erbb2 tyrosine kinase receptors, useful for the treatment of stomach tumor and non-small-cell lung cancer. Novel method for preparing poziotinib. Follows on from WO2013051883 claiming method for preparing poziotinib and its intermediates. Hanmi, in collaboration with National Oncoventure, is developing poziotinib for the oral treatment of non small cell lung cancer and gastric cancer. As of August 2014, the drug is in phase 2 trials for both indications.

Compound of formula (II) is (I) and compound of formula (I) (poziotinib) is (II) (claim 1, page 13).The synthesis of (II) via intermediate (I) is described (example 1, pages 8-11).

Preparation Example 1: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)- 7-methoxyquinazolin-6-ol, the compound of formula (II)

Step (i): Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-yl acetate, the compound of formula (V)

7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate (100 g) was added to toluene (850 mL) and NN-diisopropylethylamine (82.5 mL). Phosphorus oxychloride (100 mL) was added thereto over 20 minutes at 75°C, followed by stirring for 3 hours. Toluene (450 mL) and 3,4-dichloro-2-fluoroaniline (84.6 g) were added to the resulting mixture, followed by stirring for 2 hours. Upon completion of the reaction, the resulting mixture was cooled to 25°C, and the solid thus obtained was filtered under a reduced pressure and washed with toluene (400 mL). Isopropanol (1,000 mL) was added to the solid, and the resulting mixture was stirred for 2 hours. The solid thus obtained was filtered and washed with isopropanol (400 mL), and then was dried at 40°C in an oven to obtain the target compound (143 g, yield: 83%).

1H-NMR (DMSO-d ₆, 300 MHz, ppm) δ 8.92 (s, 1H), 8.76 (s, 1H), 7.69- 7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

Step (ii): Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-ol, the compound of formula (II)

4-(3,4-dichloro-2-fluorophenyIamino)-7-methoxyquinazolin-6-y l acetate (100 g) prepared in step (i) was admixed with methanol (1,000 mL). The mixture was cooled to 10 to 1 °C, added with an ammonia solution (460 g), and stirred for 3 hours at 25°C. The solid thus obtained was filtered and washed with a mixed solvent of methanol (200 mL) and water (200 mL). The resulting solid was dried at 40°C in an oven to obtain the target compound (74 g, yield: 83%). 1H-NMR (DMSO-d ₆, 300 MHz, ppm) 5 9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s,

1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

Example 1: Preparation of l-(4-(4-(3,4-dichIoro-2-fluorophenylamino)-7- methoxyquinazolin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I) Step (1-1 : Preparation of l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate. the compound of formula (HI)

Piperidin-4-yl 4-methylbenzenesulfonate hydrochloride (200 g, 685 mmol), tetrahydrofuran (THF, 1.6 L) and NaHCO ₃ (172 g, 2047 mmol) were added to water (2 L), and the mixture was cooled to 0°C. A solution prepared by adding acryloyl chloride (56 mL, 519 mmol) to THF (0.4 L) was added thereto over 30 minutes, followed by stirring for 1 hour. Upon completion of the reaction, MeOH (0.4 L) was added thereto for quenching. The solution was extracted with ethyl ester (2 L), and washed with water (2 L). The organic layer was separated, distilled under a reduced pressure, and the residue thus obtained was recrystallized from dichloromethane-hexane to obtain the target compound (174 g, yield: 82%). 1H-NMR (300 MHz, DMSO-d ₆) δ 7.82 (d, 2H), 7.48 (d, 2H), 6.80-6.71 (m,

1H), 6.10-6.03 (m, 1H), 5.67-5.62 (m, 1H), 4.76-4.71 (m, 1H), 3.70-3.68 (m, 2H), 3.43-3.31 (m, 2H), 2.42 (s, 3H), 1.73 (m, 2H), 1.52 (m, 2H).

Step (1-2): Preparation of l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazolin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I)

4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-o l (12 g, 34 mmol) prepared in Preparation Example 1, l-acryloylpiperidin-4-yl 4- methylbenzenesulfonate (16 g, 51 mmol) prepared in step (1-1), K ₂CO ₃ (9.4 g, 68 mmol) and dimethylacetamide (DMAc, 300 mL) were admixed. The reaction temperature was raised to 70°C, and the mixture was stirred for 24 hours. Upon completion of the reaction, the mixture was cooled down to room temperature, extracted with ethyl ester (300 mL), and then washed with water (300 mL). The organic layer was separated, and distilled under a reduced pressure. The residue thus obtained was solidified by adding ethyl ester, filtered, and dried to obtain the target compound (12.8 g, yield: 77%). 1H-NMR (300 MHz, DMSO-d ₆) δ 9.65 (bs, 1H), 8.40 (s, 1H), 7.88 (s, 1H),

7.64-7.56 (m, 2H), 7.24 (s, 1H), 6.89-6.80 (m, 1H), 6.15-6.08 (m, 1H), 5.70-5.66 (m, 1H), 4.78 (m, 1H), 3.94 (s, 3H), 3.87 (m, 2H), 3.48 (m, 2H), 2.03 (m, 2H), 1.70 (m, 1H). Example 2: Preparation of l-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7- methoxyquinazoIin-6-yloxy)piperidin-l-yl)prop-2-en-l-one, the compound of formula (I)

SEE

http://www.yuaigongwu.com/thread-8891-1-1.html

WO2005030765A1 *	Sep 22, 2004	Apr 7, 2005	Astrazeneca Ab	Quinazoline derivatives as antiproliferative agents
WO2008150118A2 *	Jun 5, 2008	Dec 11, 2008	Hanmi Pharm Ind Co Ltd	Novel amide derivative for inhibiting the growth of cancer cells
WO2010122340A2 *	Apr 22, 2010	Oct 28, 2010	Astrazeneca Ab	Process 738
US20070135463 *	Dec 6, 2006	Jun 14, 2007	Frank Himmelsbach	Bicyclic heterocycles, drugs containing said compounds, the use thereof and method for preparing same

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
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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.

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……………………….

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

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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.

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Sage Therapeutics receives fast track designation for status epilepticus therapy

July 24, 2014 7:34 am / 1 Comment on Sage Therapeutics receives fast track designation for status epilepticus therapy

SAGE-547

ALLOPREGNANOLONE

Sage Therapeutics (Originator)

Sage Therapeutics

For Epilepsy, status epilepticus

SGE-102; SAGE-547; allopregnanolone; allosteric GABA A receptor modulators (CNS disorders),

Sage Therapeutics receives fast track designation for status epilepticus therapy
Ligand Pharmaceuticals announced that its partner Sage Therapeutics has received fast track designation from the US Food and Drug Administration (FDA) for the Captisol-enabled SAGE-547 to treat status epilepticus.

read at

http://www.pharmaceutical-technology.com/news/newssage-therapeutics-receives-fast-track-designation-for-status-epilepticus-therapy-4324543?WT.mc_id=DN_News

Chemical Name: (3α)-Allopregnanolone

Synonyms: (+)-3α-Hydroxy-5α-pregnan-20-one; (3α,5α)-3-Hydroxypregnan-20-one; 3α,5α-THP; 3α,5α-Tetrahydroprogesterone; 3α-Hydroxy-5α-dihydroprogesterone; 3α-Hydroxy-5α-pregnan-20-one; 3α-Hydroxy-5α-pregnane-20-one; 5α-Pregnan-3α-ol-20-one; 5α-Pregnane-3α-ol-20-one; Allopregnan-3α-ol-20-one; Allopregnanolone; Allotetrahydroprogesterone;

CAS Number: 516-54-1

Applications: (3α)-Allopregnanolone acts as a GABAA receptor positive allosteric modulator. (3α)-Allopregnanolone is a metabolite of Progesterone (P755900). (3α)-Allopregnanolone is a neuroactive steroid present in the blood and also the brain.

References: Puja, G. et al.: Neuron, 4, 759 (1990); Belelli, D. et ael. Neurosteroid, 6, 565 (2006); Viapiano, M. et al.: Neurochem. Res., 23, 155 (1998);

Mol. Formula: C21H34O2

Appearance: White Solid

Melting Point: 174-176°C

Mol. Weight: 318.49

SAGE-547 is a GABA(A) receptor modulator in phase I/II clinical trials at Sage Therapeutics as adjunctive therapy for the treatment of adults with super-refractory status epilepticus (SRSE).

In 2014, orphan drug designation was assigned in the U.S for the treatment of status epilepticus. In July 2014, fast track designation was received in the U.S. for the treatment of adults with super-refractory status epilepticus (SRSE).

July 22, 2014

SAGE Therapeutics, a biopharmaceutical company developing novel medicines to treat life-threatening, rare central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has granted fast track designation to the SAGE-547 development program. SAGE-547 is an allosteric modulator of GABAA receptors in development for the treatment of adult patients with refractory status epilepticus who have not responded to standard regimens (super-refractory status epilepticus, or SRSE). SAGE is currently evaluating SAGE-547 in a Phase 1/2 clinical trial for the treatment of SRSE. Preliminary data indicate that the first four patients enrolled in the clinical trial met the key efficacy endpoint, in that each was successfully weaned off his or her anesthetic agent while SAGE-547 was being administered. There have also been no reported drug-related serious adverse events in these four patients to date.

“The fast track designation for SAGE-547 recognizes the significant unmet need that exists in the treatment of super-refractory status epilepticus,” said Jeff Jonas, MD, chief executive officer of SAGE Therapeutics. “The receipt of orphan drug designation earlier this year for status epilepticus and the fast track designation are both significant regulatory milestones for SAGE-547, and we will continue to work closely with the FDA to advance our lead compound and the additional programs in our pipeline for the treatment of life-threatening CNS disorders.”

Fast track designation is granted by the FDA to facilitate the development and expedite the review of drug candidates that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

About SAGE-547

SAGE-547 is an allosteric modulator of both synaptic and extra-synaptic GABAA receptors. GABAA receptors are widely regarded as validated drug targets for a variety of CNS disorders, with decades of research and multiple approved drugs targeting these receptor systems. SAGE-547 is an intravenous agent in Phase 1/2 clinical development as an adjunctive therapy, a therapy combined with current therapeutic approaches, for the treatment of SRSE.

About Status Epilepticus (SE)

SE is a life-threatening seizure condition that occurs in approximately 150,000 people each year in the U.S., of which 30,000 SE patients die.1 We estimate that there are 35,000 patients with SE in the U.S. that are hospitalized in the intensive care unit (ICU) each year. An SE patient is first treated with benzodiazepines, and if no response, is then treated with other, second-line, anti-seizure drugs. If the seizure persists after the second-line therapy, the patient is diagnosed as having refractory SE (RSE), admitted to the ICU and placed into a medically induced coma. Currently, there are no therapies that have been specifically approved for RSE; however, physicians typically use anesthetic agents to induce the coma and stop the seizure immediately. After a period of 24 hours, an attempt is made to wean the patient from the anesthetic agents to evaluate whether or not the seizure condition has resolved. Unfortunately, not all patients respond to weaning attempts, in which case the patient must be maintained in the medically induced coma. At this point, the patient is diagnosed as having SRSE. Currently, there are no therapies specifically approved for SRSE.

About SAGE Therapeutics

SAGE Therapeutics (NASDAQ: SAGE) is a biopharmaceutical company committed to developing and commercializing novel medicines to treat life-threatening, rare CNS disorders. SAGE’s lead program, SAGE-547, is in clinical development for super-refractory status epilepticus and is the first of several compounds the company is developing in its portfolio of potential seizure medicines. SAGE’s proprietary chemistry platform has generated multiple new compounds that target GABAA and NMDA receptors, which are broadly accepted as impacting many psychiatric and neurological disorders. SAGE Therapeutics is a public company launched in 2010 by an experienced team of R&D leaders, CNS experts and investors. For more information, please visitwww.sagerx.com.

Allopregnanolone

IUPAC name 1-(3-hydroxy-10,13-dimethyl- 2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro- 1H-cyclopenta[a] phenanthren-17-yl)ethanone
Other names 3α,5α-Tetrahydroprogesterone
Identifiers

PubChem	262961
ChemSpider	17216124
ChEMBL	CHEMBL38856
Jmol-3D images	Image 1

Properties
Molecular formula	C₂₁H₃₄O₂
Molar mass	318.49 g/mol

Allopregnanolone (3α-hydroxy-5α-pregnan-20-one or 3α,5α-tetrahydroprogesterone), generally abbreviated as ALLO or as 3α,5α-THP, is an endogenous inhibitory pregnane neurosteroid.^[1] It is synthesized from progesterone, and is a potent positive allosteric modulator of the GABA_A receptor.^[1] Allopregnanolone has effects similar to those of other potentiators of the GABA_A receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.^[1]

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions.^[1]

Biosynthesis

The biosynthesis of allopregnanolone starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.^[1]

Depression, anxiety, and sexual dysfunction are frequently-seen side effects of 5α-reductase inhibitors such as finasteride, and are thought to be caused, in part, by interfering with the normal production of allopregnanolone.^[2]

Mechanism

Allopregnanolone acts as a potent positive allosteric modulator of the GABA_A receptor.^[1] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABA_A receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.^[1] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABA_A-ρ receptor, though the implications of this action are unclear.^[3]^[4] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,^[5] and also appears to act as a negative allosteric modulator of the 5-HT₃ receptor.^[6] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.^[7]

Unlike progesterone, allopregnanolone is inactive at the nuclear progesterone receptor (nPR).^[7] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which is an agonist of the nPR, and thus/in accordance, allopregnanolone does appear to have indirect nPR-mediated progestogenic effects.^[8] In addition, allopregnanolone has recently been found to be an agonist of the newly-discovered membrane progesterone receptors (mPR), including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABA_A receptor.^[9]^[10] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.^[9]^[11] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.^[7]^[12]

Similarly to many other GABA_A receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),^[13] including α₁ subtypes Ca_v1.2 and Ca_v1.3.^[14] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.^[14] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.^[14] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).^[15] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.^[15]

Function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,^[16] prosocial,^[17] antiaggressive,^[18] prosexual,^[17] sedative, pro-sleep,^[19] cognitive and memory-impairing, analgesic,^[20] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.^[1]

Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.^[21]^[22]^[23]

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.^[24]^[25]^[26] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABA_A receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.^[24]^[25] This seems to be a common effect of many GABA_A receptor positive allosteric modulators.^[26]^[21] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels), have been found to have negative effects on mood, while higher doses have a neutral effect.^[27]

Therapeutic applications

Allopregnanolone and the other endogenous inhibitory neurosteroids have very short half-lives, and for this reason, have not been pursued for clinical use themselves. Instead, synthetic analogs with improved pharmacokinetic profiles, such as ganaxolone, have been synthesized and are being investigated. However, exogenous progesterone, such as oral micronized progesterone (OMP), reliably elevates allopregnanolone levels in the body with good dose-to-serum level correlations.^[28] Due to this, it has been suggested that OMP could be described as a prodrug of sorts for allopregnanolone.^[28] As a result, there has been some interest in using OMP to treat catamenial epilepsy,^[29] as well as other menstrual cycle-related and neurosteroid-associated conditions.

……………………………………….

http://www.google.com/patents/WO2006037016A2?cl=en

Materials and Methods

[0181] The materials and methods used for the follwing experiments have been described in Griffin L.D., et al, Nature Medicine 10: 704-711 (2004). This reference is hereby incorporated by reference in its entirety.

Example 1: Allopregnanolone Treatment of Niemann Pick type-C Mice Substantially Reduces Accumulation of the Gangliosides GMl, GM2, and GM3 in the Brain [0182] Mice were given a single injection of allopregnanolone, prepared in 20% βcyclodextrin in phosphate buffered saline, at a concentration of 25 mg/kg. The injection was on day 7 of life (P7, postnatal day 7). Concentrations of gangliosides GMl, GM2, GM3, were measured as well as other lipids such as ceramides and cerebrosides.

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WO-2014031792 OR EQ

http://www.google.com/patents/US20140057885?cl=en

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WO-2013112605

http://www.google.com/patents/WO2013112605A2?cl=en

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Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV (July 2002). “The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens”. Eur. J. Neurosci. 16 (1): 169–73. PMID 12153544.
Frye CA (December 2009). “Neurosteroids’ effects and mechanisms for social, cognitive, emotional, and physical functions”. Psychoneuroendocrinology. 34 Suppl 1: S143–61. doi:10.1016/j.psyneuen.2009.07.005. PMC 2898141. PMID 19656632.
Pinna G, Costa E, Guidotti A (February 2005). “Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior”. Proc. Natl. Acad. Sci. U.S.A. 102 (6): 2135–40. doi:10.1073/pnas.0409643102. PMC 548579. PMID 15677716.
Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). “Steroid hormones and sleep regulation”. Mini Rev Med Chem 12 (11): 1040–8. PMID 23092405.
Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). “Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain”. Prog. Neurobiol. 113: 70–8. doi:10.1016/j.pneurobio.2013.07.004. PMID 23948490.
Bäckström T, Andersson A, Andreé L, et al. (December 2003). “Pathogenesis in menstrual cycle-linked CNS disorders”. Ann. N. Y. Acad. Sci. 1007: 42–53. PMID 14993039.
Guille C, Spencer S, Cavus I, Epperson CN (July 2008). “The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment”. Epilepsy Behav 13 (1): 12–24. doi:10.1016/j.yebeh.2008.02.004. PMID 18346939.
Finocchi C, Ferrari M (May 2011). “Female reproductive steroids and neuronal excitability”. Neurol. Sci. 32 Suppl 1: S31–5. doi:10.1007/s10072-011-0532-5. PMID 21533709.
Bäckström T, Haage D, Löfgren M, et al. (September 2011). “Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons”. Neuroscience 191: 46–54. doi:10.1016/j.neuroscience.2011.03.061. PMID 21600269.
Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (September 2009). “Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators”. Psychoneuroendocrinology 34 (8): 1121–32. doi:10.1016/j.psyneuen.2009.02.003. PMID 19272715.
Bäckström T, Bixo M, Johansson M, et al. (February 2014). “Allopregnanolone and mood disorders”. Prog. Neurobiol. 113: 88–94. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486.
Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (August 2006). “Allopregnanolone concentration and mood–a bimodal association in postmenopausal women treated with oral progesterone”. Psychopharmacology (Berl.) 187 (2): 209–21. doi:10.1007/s00213-006-0417-0. PMID 16724185.
Andréen L, Spigset O, Andersson A, Nyberg S, Bäckström T (June 2006). “Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone”. Maturitas 54 (3): 238–44. doi:10.1016/j.maturitas.2005.11.005. PMID 16406399.
Orrin Devinsky; Steven Schachter; Steven Pacia (1 January 2005). Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. pp. 378–. ISBN 978-1-934559-08-6.

Additional reading

Herd, MB; Belelli, D; Lambert, JJ (2007). Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. Pharmacol. Ther. 116(1):20-34. doi:10.1016/j.pharmthera.2007.03.007.

Ario Kicks Off Efficacy Trial of Chronic Idiopathic Cough Drug

July 11, 2014 3:52 am / Leave a comment

http://www.google.nl/patents/US8173841

XEN-D0501

Xention (Originator)

XEN-D0501, a novel TRPV1 antagonist, is being developed to treat overactive bladder.

in phase 2 Chronic obstructive pulmonary disease (COPD)

Ario Kicks Off Efficacy Trial of Chronic Idiopathic Cough Drug
Ario Pharma Ltd, the biopharmaceutical company developing innovative new treatments for respiratory disease, announced that it has commenced a Phase 2a study of its oral TRPV1 antagonist, XEN-D0501, for the treatment and prevention of cough in patients with chronic idiopathic cough (CIC).http://www.dddmag.com/news/2014/07/ario-kicks-efficacy-trial-chronic-idiopathic-cough-drug?et_cid=4039308&et_rid=523035093&type=cta

BMS-582949 in phase 2 for Treatment of Antipsoriatics , Rheumatoid arthritis

July 8, 2014 5:09 am / Leave a comment

BMS 582949, PS-540446

UNII-CR743OME9E

CAS 623152-17-0

4-[5-(N-Cyclopropylcarbamoyl)-2-methylphenylamino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide

4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide

Bristol-Myers Squibb Company
M.Wt: 406.48
Cas : 623152-17-0 Formula: C22H26N6O2

BMS-582949 had been in phase II clinical trials at Bristol-Myers Squibb for the oral treatment of moderate to severe psoriasis and for the treatment of rheumatoid arthritis (RA) in combination with methotrexate and for the treatment of inflammation in atherosclerotic plaque. However, no recent development has been reported for this research.

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http://www.google.com/patents/WO2012031057A1?cl=en

The present invention generally relates to a method of treating resistant rheumatic disease, such as refractory rheumatoid arthritis, with a therapeutically effective amount of a dual action p38 inhibitor that is safe and well-tolerated. A dual action p38 kinase inhibitor is a compound that inhibits both activation of p38 kinase and p38 kinase activity in cells.

A large number of cytokines participate in the inflammatory response, including IL- 1 , IL-6, IL-8 and TNF-a. Overproduction of cytokines such as IL-1 and TNF-a are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer’s disease, and congestive heart failure, among others. See e.g., Henry et al., Drugs Fut. , 24: 1345- 1354 ( 1999); Salituro et al., Curr. Med. Ckem., 6:807-823 (1999)]. Important mediators of proinflammatory cytokines such as TNFct and IL-1 β,. as well as cellular responses to such cytokines production, are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. See e.g., Schieven, G.L., “The biology of p38 kinase: a central role in inflammation”, Current Topics in Medicinal Chemistry, 5 :921 – 928 (2005). Accordingly, modulation of p38 kinase may be useful in the treatment of inflammatory disease including rheumatic diseases such as rheumatoid arthritis (RA).

Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-a for use in treating inflammatory diseases are disclosed in U.S. Patent Nos.

6,277,989 and 6, 130,235 to Scios, Inc; U.S. Patent. Nos. 6, 147,080 and 5,945,41 8 to Vertex Pharmaceuticals Inc; U.S. Patent Nos. 6,251 ,914, 5,977, 103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Patent Nos. 5,932,576 and 6,087,496 to G.D. Searle & Co.; WO 00/56738 and WO 01 /27089 to Astra Zeneca; WO 01/34605 to Johnson & Johnson; WO 00/12497 (quinazoHne derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors). Other compounds that inhibit p38 kinase are pyrrolotriazine aniline compounds, information on these compounds is disclosed in U.S. Patent Nos. 6,670,357; 6,867,300; 7,034, 151 ; 7, 160,883; 7,21 1,666; 7,253, 167; and U.S. Publication Nos. 2003/023283 1 (published Dec. 18, 2003); 2004/0229877 (published Nov. 1 8, 2004); 2005/0043306 (published Feb. 24, 2005; 2006/0003967 (published Jan. 5, 2006); 2006/0030708 (published Feb. 9, 2006); 2006/0041 124 (published Feb. 23, 2006); 2006/0229449 (published Oct. 12, 2006); 2006/0235020 (published Oct. 19, 2006); and 2007/0213300 (published Sept 13, 2007).

In particular, WO 2003/090912 (U.S. Patent Nos. 7, 160,883, 7,388,009, p38 inhibitor, BMS-582949 (Example 7,

including processes of making and uses thereof.

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http://www.google.com/patents/WO2003090912A9?cl=en

Examples 4-22

Compounds having the formula (Id), above, wherein R₄ has the values listed in the following Table, were prepared following the same procedure described for Example 3, using the appropriate amine in place of ra-butylamine.

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WO 2006020904

http://www.google.com.br/patents/WO2006020904A1?cl=en

EXAMPLE IA St

Part a.

A solution of Example 1 (0.86 g, 2.20 mmol, 1.0 eq.) in THF (4.0 mL) and 1 N aqueous NaOH (9.0 mL, 4.1 eq.) was stirred at 6O⁰C overnight. After cooling to RT, the reaction mixture was concentrated in vacuo but not to dryness. To the solution at O⁰C was added 1 N aqueous hydrochloric acid until it was acidic and the precipitate was collected and dried to afford crude Example IA acid (0.51 g, 64.0 % yield). HPLC Ret. t. = 2.400 min.; LC/MS (M+H) ⁺ = 366.06⁺. The filtrate was then extracted with EtOAc (3x) and the organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give Example IA acid (0.035 g, 4.4 % yield). Part b.

A solution of Part a. acid (0.026 g, 0.071 mmol, 1.0 eq.), EDC (0.021 g, 0.11 mmol, 1.5 eq.), HOBt (0.015 g, 0.11 mmol, 1.5 eq), ^-propylamine (0.015 mL, 0.15 mmol, 2.1 eq.) and DIPEA (0.040 mL, 0.23 mmol, 3.2 eq.) in DMF (0.20 mL) was shaken at RT overnight. Water (1 mL) was added and the precipitate collected by filtration, washed with water, and dried to give Example IA amide (0.021 g, 70% yield); HPLC Ret. t. = 2.883 min.; LC/MS (M+H)⁺ = 421.18 ⁺.

EJiAMPLE 2 Direct Aminolysis Procedure

n-Buli/THF

Ester Compound I or Hexyllithium/THF

,NH₉

1. Aminolysis with hexyllithium

To a dried 100 ml flask was added THF (10 ml) under nitrogen, which was then cooled to -10⁰C. Hexyllithium (2.3 M in hexane, 6.5 ml, 15.0 mmol) was added slowly (exothermic, temperature was up to 5°C), followed by dropwise addition of propylamine (1.01 g, 1.4 ml, 17.1 mmol) at such a rate to maintain the temperature below 5°C. The resulting mixture was stirred at O⁰C for 20 minutes. A suspension of ester compound I (1.0 g, 2.5 mmol) in THF (12 ml) was added over a 10 minute period (exothermic, T<5°C). After being stirred at 0⁰C for 20 minutes, the mixture was allowed to warm to room temperature and stirred for 5 hours. Ester compound I was <0.1 AP at this point by HPLC analysis. The mixture was cooled to -5⁰C. Acetic acid (2 ml) was added slowly to maintain the temperature <10°C. The resulting thick slurry was stirred at room temperature for 20 minutes, and then solvents were exchanged with DMF (15 ml) on a rotavapor. To the resulting yellow slurry, water (15 ml) was added slowly to keep T<25°C. During the addition of water, the slurry became a clear solution, and a new slurry was formed. The slurry was stirred at room temperature for overnight. In the morning the slurry was filtered and the solid was washed with DMF/water (1:1, 5 ml), water (5 ml) and acetone (5 ml). The cake was dried under vacuum at 55°C for 24 hours to afford 0.90 g of amide product II (yield: 87.2%) as a white solid. HPLC: 99.70 AP.

2. Aminolysis with n-butyllithium

To a dried 100 ml of flask was added THF (10 ml) under nitrogen and then cooled to -10⁰C. n-Butyllithium (2.5 M in hexane, 6.0 ml, 15.0 mmol) was added slowly, followed by dropwise addition of propylamine (0.98 g, 16.5 mmol) at such a rate to keep the temperature below 0⁰C. The resulting mixture was stirred at O⁰C for 20 minutes. A suspension of ester compound I (1.0 g, 2.5 mmol) in THF (12 ml) was added over a 10 minute period (T<5°C). After being stirred at O⁰C for 30 minutes, the mixture was allowed to warm to room temperature and stirred for overnight (~22h, Note 1). Compound I was not detected at this point by HPLC analysis. The mixture was cooled to -7°C. Acetic acid (2 ml) was added dropwise to maintain the temperature <10°C. The resulting thick slurry was stirred at 5⁰C for 2 hours and at room temperature for 20 minutes, followed by evaporation on a rotavapor to give a wet yellow solid. To this solid was added acetone (10 ml) and water (20 ml). The slurry was stirred at room temperature for one and half hours. Filtration gave a white solid. This solid was washed with 35% acetone in water (10 ml), water (5 ml) and acetone (5 ml). The cake was dried under vacuum at 55°C for the weekend to afford 0.94g of amide product II (yield: 91.0%) as a white solid. HPLC: 99.76 AP. Note 1: Compound I was -0.056 AP at 2.5 hours.

……………………

WO 2003090912

http://www.google.com/patents/WO2003090912A1?cl=en

……………………..

Discovery of 4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38a MAP kinase inhibitor for the treatment of inflammatory diseases
J Med Chem 2010, 53(18): 6629

http://pubs.acs.org/doi/abs/10.1021/jm100540x

The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp² character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.

Abstract Image

4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (7k)

A mixture of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carboxylic acid (6b) (2.16 g, 5.91 mmol), n-propylamine (1.0 mL, 12.2 mmol), BOP (3.40 g, 7.69 mmol), and N-methylmorpholine (2.5 mL, 22.7 mmol) in DMF (10 mL) was stirred at 50 °C for 3 h. The mixture was poured into a mixture prepared from saturated NaHCO₃ solution (60 mL) and water (60 mL). The precipitating product was collected by suction filtration was washed with water. This crude product was suspended into ethyl acetate (100 mL) and stirred at 70 °C for 1 h. Upon cooling to rt, the title compound (2.07 g, 86% yield) was collected as a white solid by suction filtration; 98% purity by HPLC. LCMS (EI)

m/z Calcd for C₂₂H₂₆N₆O₂ (M + H)⁺ = 407.21. Found: 407.22.

¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J = 3.6 Hz, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 3.20 (m, 2H), 2.87 (m, 1H), 2.82 (s, 3H), 2.25 (s, 3H), 1.54 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H), 0.68 (m, 2H), 0.59 (m, 2H).

¹³C NMR (125 MHz, DMSO-d₆) δ 167.3, 164.45, 155.3, 148.7, 138.8, 137.1, 133.0, 130.6, 127.2, 125.8, 119.6, 118.8, 114.4, 113.3, 41.0, 23.6, 23.1, 18.5, 12.1, 12.0, 6.2.

EXAMPLE 3

Direct Aminolysis

Ester Compound I

Amide Product II

Method A:

A solution of n-propylamine (6.5 eq) in THF (20 ml/g of ester compound I) was cooled to — 5°C and was slowly treated with 2.5 M solution of n-butyllithium (6.1 eq). The mixture was stirred for 10 minutes. At the end of the period, a slurry of ester compound I (1 eq) in THF (14 ml/g of ester compound I) was cannulated into the performed Li-NHPr solution. The reaction mixture was warmed to 25°C and stirred till all of ester compound I was consumed (~ 3 hours). After the reaction was judged to be completed by HPLC, the reaction mixture was cooled to ~0°C and was slowly treated with acetic acid (5 ml/g of ester compound I). The slurry was then warmed to -2O⁰C and was stirred for 1 hour. At the end of the period, the solvent was distilled under vacuum to the minimum volume and the concentrated slurry was diluted with a solution of acetone (10 ml/g of ester compound I) and water (20 ml/g of ester compound I). The slurry was stirred for 1 hour and was cooled to ~5°C. The slurry was filtered and the cake was washed with acetone (5 ml/g of ester compound I). The cake was dried to give the amide product II (typically in 85% yield and 99 AP).

Method B:

A solution of n-propylamine (20 eq) in 2,2,2-trifmoroethanol (10 ml/g of ester compound I) was slowly treated with 2.5 M solution of n-butyllithium (1.5 eq). The mixture was stirred for 5 minutes. At the end of the period, the starting material, ester compound I, was added and the reaction mixture was warmed to 90⁰C. The reaction mixture was held at 90⁰C for 24 hours and was allowed to cool to ~20°C. The reaction mixture was then analyzed by HPLC. Typically, analysis indicated there was only 1.57 AP of starting material left.

Method C:

A solution of n-propylamine (2 eq) in methylene chloride (10 ml/g of ester compound I) at 20⁰C was slowly treated with 2.0 M solution of trimethylaluminum (4 eq) in hexanes. The mixture was stirred for 15 minutes. At the end of the period, the starting material, ester compound 1 (1 eq), was added and the reaction mixture was warmed to 60⁰C. The reaction mixture was held at 60⁰C for 24 hours and was allowed to cool to ~20°C. The reaction mixture was then slowly quenched with aqueous HCl solution and analyzed by HPLC. Typically, analysis indicated there was 96.8AP of amide compound II product with 0.03 AP of the dipropylamide impurity.

…………………………………….

WO2003090912A1 *	15 abr. 2003	6 nov. 2003	Squibb Bristol Myers Co	Pyrrolo-triazine aniline compounds useful as kinase inhibitors

Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor.

Liu C, Lin J, Everlof G, Gesenberg C, Zhang H, Marathe PH, Malley M, Galella MA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheris K.

Bioorg Med Chem Lett. 2013 May 15;23(10):3028-33. doi: 10.1016/j.bmcl.2013.03.022. Epub 2013 Mar 15.

Methods: implementation of in vitro and ex vivo phagocytosis and respiratory burst function assessments in safety testing.

Freebern WJ, Bigwarfe TJ, Price KD, Haggerty HG.

J Immunotoxicol. 2013 Jan-Mar;10(1):106-17. doi: 10.3109/1547691X.2012.736427. Epub 2012 Nov 23.

Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases.

Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, Dyckman AJ, Li T, Wityak J, Gillooly KM, Pitt S, Shen DR, Zhang RF, McIntyre KW, Salter-Cid L, Shuster DJ, Zhang H, Marathe PH, Doweyko AM, Sack JS, Kiefer SE, Kish KF, Newitt JA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheris K.

J Med Chem. 2010 Sep 23;53(18):6629-39. doi: 10.1021/jm100540x.

BMS-582949: crystalline form of a p38alpha inhibitor? WO2008079857.

Norman P.

Expert Opin Ther Pat. 2009 Aug;19(8):1165-8. doi: 10.1517/13543770902816160.

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Japan First to Approve Alectinib アレクチニブ塩酸塩 (AF 802) for ALK+ NSCLC

July 8, 2014 4:08 am / 3 Comments on Japan First to Approve Alectinib アレクチニブ塩酸塩 (AF 802) for ALK+ NSCLC

Alectinib (AF802, CH5424802, RG7853, RO5424802)

CAS 1256580-46-7 FREE

1256589-74-8 (Alectinib Hydrochloride)

9-Ethyl-6,11-dihydro-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile

Formula:	C₃₀H₃₄N₄O₂
M.Wt:	482.62

Mechanism of Action:ALK inhibitor
Indication:Non-small cell lung cancer (NSCLC)
Current Status:Phase II (US,EU,UK), NDA(Japan)
Company:中外製薬株式会社 (Chugai), Roche

Japan First to Approve Alectinib for ALK+ NSCLC

http://www.dddmag.com/news/2014/07/japan-first-approve-alectinib-alk-nsclc?et_cid=4034150&et_rid=523035093&type=headline

Roche announced that the Japanese Ministry of Health, Labor and Welfare (MHLW) has approved alectinib for the treatment of people living with non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase fusion gene-positive (ALK+). The approval was based on results from a Japanese Phase 1/2 clinical study (AF-001JP) for people whose tumors were advanced, recurrent or could not be removed completely through surgery (unresectable).

Company	Chugai Pharmaceutical Co. Ltd.
Description	Anaplastic lymphoma kinase (ALK) inhibitor
Molecular Target	Anaplastic lymphoma kinase (ALK)
Mechanism of Action	Anaplastic lymphoma kinase (Ki-1) (ALK) inhibitor
Therapeutic Modality	Small molecule

Latest Stage of Development	Registration
Standard Indication	Non-small cell lung cancer (NSCLC)
Indication Details	Treat advanced ALK-positive non-small cell lung cancer (NSCLC); Treat non-small cell lung cancer (NSCLC); Treat unresectable progressive or recurrent ALK-positive non-small cell lung cancer (NSCLC)
Regulatory Designation	U.S. – Breakthrough Therapy (Treat advanced ALK-positive non-small cell lung cancer (NSCLC)); Japan – Orphan Drug (Treat advanced ALK-positive non-small cell lung cancer (NSCLC)); Japan – Orphan Drug (Treat unresectable progressive or recurrent ALK-positive non-small cell lung cancer (NSCLC)); Japan – Standard Review (Treat advanced ALK-positive non-small cell lung cancer (NSCLC))
Partner	Roche

Alectinib (also known as CH5424802,RO5424802), a second generation oral inhibitor of anaplastic lymphoma kinase (ALK), is being developed by Chugai and Roche for the treatment of patients with ALK-positive non-small cell lung cancer (NSCLC) that has progressed on Xalkori (Crizotinib).

Alectinib was discovered by Chugai Pharmaceutical Co. Ltd. Chugai became a subsidiary of Roche in 2002 and the Swiss group currently owns 59.9 percent of the company.

On October 8, 2013, Chugai Pharmaceutical announced that it has filed a new drug application to Japan’s Ministry of Health, Labour and Welfare (MHLW) for alectinib hydrochloride for the treatment of ALK fusion gene positive non-small cell lung cancer (NSCLC).

IT is a potent and selective ALK inhibitor with IC50 of 1.9 nM.Alterations in the anaplastic lymphoma kinase (ALK) gene have been implicated in human cancers. Among these findings, the fusion gene comprising EML4 and ALK has been identified in non-small cell lung cancer (NSCLC) and fusion of ALK to NPM1 has been observed in anaplastic large cell lymphoma (ALCL). The possibility of targeting ALK in human cancer was advanced with the launch of crizotinib for NSCLC in the U.S. in 2011. The development of resistance to crizotinib in tumors, however, has led to the need for second-generation ALK inhibitors. One of these, alectinib hydrochloride, has been found to be an orally active, potent and highly selective ALK inhibitor with activity in ALK-driven tumor models. Alectinib has shown preclinical activity against cancers with ALK gene alterations, including NSCLC cells expressing the EML4-ALK fusion and ALCL cells expressing the NPM-ALK fusion. Alectinib was well tolerated and active in a phase I/II study conducted in Japan in patients with ALK-rearranged advanced NSCLC and in patients with ALK-positive NSCLC who had progressed on crizotinib. Alectinib has been submitted for approval in Japan for the treatment of ALK fusion gene-positive NSCLC and is in phase I/II development for ALK-rearranged NSCLC in the U.S.

……………..

………………….

WO2012023597

http://www.google.fm/patents/WO2012023597A1?cl=en

(Preparation 30)
Compound F6-20
9 – ethyl-6, 6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3 – carbonitrile

Under the same conditions as the synthesis of the compound B3-13-1, and the title compound was synthesized from compound F5-49.
¹ H-NMR (400MHz, DMSO-D ₆₎ ^δ: 12.70 (1H, s), 8.32 (1H, d, J = 7.9 Hz), 8.04 (1H, s), 8.00 (1H, s), 7.61 (1H , d, J = 8.5 Hz), 7.34 (1H, s), 3.64-3.57 (4H, m), 3.27-3.18 (2H, m), 2.82-2.66 (4H, m), 2.39-2.28 (1H, m ), 1.96-1.87 (2H, m), 1.76 (6H, s), 1.69-1.53 (2H, m), 1.29 (3H, t, J = 7.3 Hz)
LCMS: m / z 483 [M ⁺ H] +
HPLC retention time: 1.98 minutes (analysis conditions U)

Hydrochloride 9 of compound F6-20 – ethyl-6, 6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b I was dissolved at 60 ℃ in a mixture of 10 volumes of methyl ethyl ketone, 3 volumes of water and acetic acid volume 4-carbonitrile -] carbazol-3. I was dropped hydrochloric acid (2N) 1 volume of solution. After stirring for 30 minutes at 60 ℃, and the precipitated solid was filtered and added dropwise to 25 volume ethanol, 9 – Dry ethyl -6,6 – dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) I got a one-carbonitrile hydrochloride – 11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3. Ethyl-6, 6 – 9 – obtained dimethyl-8 – (4 – morpholin-4 – yl – piperidin-1 – yl) -11 – oxo-6 ,11 – dihydro-5H-benzo [b] carbazol-3 – I was pulverized with a jet mill carbonitrile monohydrochloride.
¹ H-NMR (400MHz, DMSO-D ₆₎ ^δ: 12.78 (1H, s), 10.57 (1H, br.s), 8.30 (1H, J = 8.4 Hz), 8.05 (1H, s), 7.99 (1H , s), 7.59 (1H, d, J = 7.9 Hz), 7.36 (1H, s) ,4.02-3 .99 (2H, m) ,3.84-3 .78 (2H, m) ,3.51-3 .48 (2H, m), 3.15-3.13 (1H, s) ,2.83-2 .73 (2H, s) ,2.71-2 .67 (2H, s) ,2.23-2 .20 (2H, m) ,1.94-1 .83 (2H, m), 1.75 (6H, s ), 1.27 (3H, t, J = 7.5 Hz)
FABMS: m / z 483 [M ⁺ H] +

I was dissolved at 90 ℃ to 33 volume dimethylacetamide F6-20 F6-20 mesylate. Was added to 168 volumes mesylate solution (2 N) 1.2 volume, ethyl acetate solution was stirred for 4 hours. The filtered crystals were precipitated, and dried to obtain a F6-20 one mesylate. I was milled in a jet mill F6-20 one mesylate salt was obtained.

……………………

Journal of Medicinal Chemistry, 54(18), 6286-6294; 2011

http://pubs.acs.org/doi/abs/10.1021/jm200652u

WO2002043704A1 *	30 Nov 2001	6 Jun 2002	Yasuki Kato	Composition improved in solubility or oral absorbability
WO2008051547A1 *	23 Oct 2007	2 May 2008	Cephalon Inc	Fused bicyclic derivatives of 2,4-diaminopyrimidine as alk and c-met inhibitors
WO2009073620A2 *	1 Dec 2008	11 Jun 2009	Newlink Genetics	Ido inhibitors
WO2010143664A1 *	9 Jun 2010	16 Dec 2010	Chugai Seiyaku Kabushiki Kaisha	Tetracyclic compound
JP2008280352A				Title not available
JP2009100783A				Title not available
JPH0892090A *				Title not available

References

1: Ignatius Ou SH, Azada M, Hsiang DJ, Herman JM, Kain TS, Siwak-Tapp C, Casey C, He J, Ali SM, Klempner SJ, Miller VA. Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol. 2014 Apr;9(4):549-53. doi: 10.1097/JTO.0000000000000094. PubMed PMID: 24736079.

2: Gouji T, Takashi S, Mitsuhiro T, Yukito I. Crizotinib can overcome acquired resistance to CH5424802: is amplification of the MET gene a key factor? J Thorac Oncol. 2014 Mar;9(3):e27-8. doi: 10.1097/JTO.0000000000000113. PubMed PMID: 24518097.

3: Latif M, Saeed A, Kim SH. Journey of the ALK-inhibitor CH5424802 to phase II clinical trial. Arch Pharm Res. 2013 Sep;36(9):1051-4. doi: 10.1007/s12272-013-0157-8. Epub 2013 May 23. Review. PubMed PMID: 23700294.

4: Seto T, Kiura K, Nishio M, Nakagawa K, Maemondo M, Inoue A, Hida T, Yamamoto N, Yoshioka H, Harada M, Ohe Y, Nogami N, Takeuchi K, Shimada T, Tanaka T, Tamura T. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol. 2013 Jun;14(7):590-8. doi: 10.1016/S1470-2045(13)70142-6. Epub 2013 Apr 30. PubMed PMID: 23639470.

5: Kinoshita K, Asoh K, Furuichi N, Ito T, Kawada H, Hara S, Ohwada J, Miyagi T, Kobayashi T, Takanashi K, Tsukaguchi T, Sakamoto H, Tsukuda T, Oikawa N. Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802). Bioorg Med Chem. 2012 Feb 1;20(3):1271-80. doi: 10.1016/j.bmc.2011.12.021. Epub 2011 Dec 22. PubMed PMID: 22225917.

6: Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90. doi: 10.1016/j.ccr.2011.04.004. PubMed PMID: 21575866.

Gadgeel S, Ou SH, Chiappori A, et al: A phase I dose escalation study of a new ALK inhibitor, CH542480202, in ALK+ non-small cell lung cancer patients who have failed crizotinib. Abstract O16.06. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.

Ou SH, Gadgeel S, Chiappori AA, et al: Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer patients in an ongoing phase I/II study. Abstract O16.07. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.

Kinoshita, Kazuhiro et al,Preparation of tetracyclic compounds such as 11-oxo-5,6-dihydrobenzo[b]carbazole-3-carbonitrile derivatives as anaplastic lymphoma kinase (ALK) inhibitors,Jpn. Kokai Tokkyo Koho, 2012126711, 05 Jul 2012

Furumoto, Kentaro et al, Composition containing tetracyclic compound and dissolution aid (４環性化合物を含む組成物), PCT Int. Appl., WO2012023597, 23 Feb 2012, Also published as CA2808210A1, CN103052386A, EP2606886A1, EP2606886A4, US20130143877

Kinoshita, Kazutomo et al,Design and synthesis of a highly selective, orally active and potent anaplastic lymphoma kinase inhibitor (CH5424802), Bioorganic & Medicinal Chemistry, 20(3), 1271-1280; 2012

Kinoshita, Kazutomo et al,9-Substituted 6,6-Dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as Highly Selective and Potent Anaplastic Lymphoma Kinase Inhibitors, Journal of Medicinal Chemistry, 54(18), 6286-6294; 2011

Kinoshita, Kazuhiro et al, Preparation of tetracyclic compounds such as 11-oxo-5,6-dihydrobenzo[b]carbazole-3-carbonitrile derivatives as anaplastic lymphoma kinase (ALK) inhibitors,Jpn. Tokkyo Koho, 4588121, 24 Nov 2010

Cebranopadol GRT 6005 セブラノパドール a Potent Analgesic NOP and Opioid Receptor Agonist

July 4, 2014 6:14 am / 1 Comment on Cebranopadol GRT 6005 セブラノパドール a Potent Analgesic NOP and Opioid Receptor Agonist

Cebranopadol

(GRT-6005; GRT 6005; GRT6005)

CAS: 863513-91-1

(1r,4r)-6′-Fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine

Spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-

C₂₄H₂₇FN₂O
Average mass: 378.482391 Da

Grünenthal GmbH innovator

Cebranopadol(GRT-6005) is a novel first in class compounds with potent agonist activity on ORL-1 (opioid receptor like -1) and the well established mu opioid receptor.

Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several experimental model models of acute and chronic pain (tail–flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED50 values of 0.5–5.6 μg/kg after intravenous and 25.1 μg/kg after oral administration. Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side–effect profile.

GRT-6005 is a centrally active analgesic in phase II clinical development for the oral treatment of neuropathic pain in patients with painful diabetic polyneuropathy and for the treatment of pain due to osteoarthritis of the knee. It is being developed by Grüenenthal and Forest. No recent development has been reported for research into the treatment of moderate to severe pain following bunionectomy. In 2010, GRT-6005 was licensed to Forest and Grünenthal in Canada and the U.S. for the treatment of moderate to severe chronic pain.

ChemSpider 2D Image | Cebranopadol | C24H27FN2O

Description: IC50 Value: N/A Cebranopadol and GRT 6006 are novel first-in-class compounds with unique pharmacological and pharmacokinetic profiles that may enhance their effect in certain pain conditions. The unique mode of action of these compounds builds on the ORL-1 receptor and, supported by the established mu opioid receptor, is particularly suitable for the treatment of moderate to severe chronic pain [1]. in vitro: N/A in vivo: N/A Clinical trial: Cebranopadol has successfully completed initial proof-of-concept studies in nociceptive and neuropathic pain with further Phase II studies planned prior to initiation of Phase III studies.

A Randomized 4 Week Phase IIa Trial Evaluating the Efficacy, Safety, and Tolerability of GRT6005, a New Centrally Acting Analgesic, in Subjects With Moderate to Severe Pain Due to Osteoarthritis (OA) of the Knee

Neuropathic pain

Neuropathic pain is caused when peripheral nerves are damaged by mechanical, metabolic or inflammatory way. The pain occurring images are mainly due to the occurrence of spontaneous pain, hyperalgesia and allodynia (pain is already triggered by non-noxious stimuli) in. As a result, the lesions to increased expression of Na + channels and thus to spontaneous activity in the damaged axons and their Nachbaraxonen (England et al., Neurology, 1996, 47, 272-276).The excitability of the neurons is increased and they react to incoming stimuli with an increased discharge frequency. This results in an increased sensitivity to pain, which contributes to the development of hyperalgesia and spontaneous pain (Baron, Clin J Pain 2000;. 16 (2 Suppl), 12-20). The causes and manifestations, and therefore the treatment needs of neuropathischerm pain are varied. They arise as a result of injury or disease of the brain, spinal cord or peripheral nerves.Causes may be operations, such as phantom pain after amputation, stroke, multiple sclerosis, spinal cord injury, alcohol or drug abuse or other toxins, cancers but also

Metabolic diseases such as diabetes, gout, kidney failure or liver cirrhosis, or infectious diseases such as mononucleosis, ehrlichiosis, typhoid, diphtheria, HIV, syphilis or Lyme disease. The pain experience is very different signs and symptoms that can change over time in number and intensity. Paradoxically, patients with neuropathic pain outline a slowdown or failure of acute pain perception and the simultaneous increase of neuropathic pain. The typical symptoms of neuropathic pain as tingling, burning, shooting or described, or radiating electrifying. Pharmacological basis for treatment of neuropathic pain include tricyclic antidepressants and anticonvulsants, which are used as monotherapy or in combination with opioids. These drugs usually provide only a certain pain relief during a pain-free but is often not achieved. The often-adjusting side effects are dose increases while the drug to achieve adequate pain relief often in the way. In fact, a higher dosage of a μ-opioid is often required as the treatment of acute pain, thereby reducing the side effects get even more important for satisfactory treatment of neuropathic pain. By the occurrence of typical μ-opioid tolerance development and the concomitant need for dose escalation of this problem is exacerbated. In summary it can be stated that neuropathic pain is difficult to treat and today is alleviated by high doses of μ-opioids only partially (Saudi Pharm J. 2002, 10 (3), 73-85). There is therefore an urgent need for medicines for the treatment of chronic pain, the dose should not be increased until the occurrence of intolerable side effects to ensure a satisfactory pain treatment.

……………

http://www.google.com/patents/US7547707

Example 24 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 537 mg, 3 mmoles) were initially introduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added very rapidly. The mixture was stirred at RT for 20 h. For working up, 1 M NaOH (30 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×60 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The solid contained in the suspension was filtered off with suction and dried. 955 mg of the more non-polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole were obtained (m.p. 284-292° C.). 850 mg of this were dissolved in hot ethanol (900 ml), and a similarly hot solution of citric acid (1 g, 5.2 mmoles) in ethanol (20 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 h. The solid formed was filtered off with suction. 640 mg of the hemicitrate were obtained as a white solid (m.p. 258-282° C.).

Example 25 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 179 mg, 1 mmole) were dissolved in conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowly added dropwise to this mixture. The mixture was stirred at RT for 16 h. For working up, the mixture was diluted with water (20 ml), brought to pH 11 with 5 M NaOH and extracted with MC (3×20 ml). The combined organic phases were dried with sodium sulfate and evaporated. The residue (364 mg of white solid) was suspended in hot ethanol (20 ml), and a similarly hot solution of citric acid (185 mg, 0.96 mmole) in ethanol (5 ml) was added. The residue thereby dissolved completely and no longer precipitated out even on cooling to approx. 5° C. Ethanol was removed on a rotary evaporator and the hemicitrate of the more polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained in this way in a yield of 548 mg as a white solid (m.p. 148-155° C.).

24	hemicitrate	more non-polar diastereomer

25	hemicitrate	more polar diastereomer

………………..

WO 2013113690

(1 r,4r)-6′-fluoro-N,N- dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1 ,1 ‘-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):

http://www.google.com/patents/WO2013113690A1?cl=en

…………………

http://www.google.com/patents/WO2008040481A1?cl=en

see A4

…………………………

http://www.google.com/patents/US20130231381

One particular drug that is of great interest for use in treating cancer pain (and other acute, visceral, neuropathic and chronic pain pain disorders) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine. This drug is depicted below as the compound of formula (I).

The solid forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine that are known so far are not satisfactory in every respect and there is a demand for advantageous solid forms

A) Synthesis of Crystalline Form A100 mg (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by FT Raman, TG-FTIR and PXRD.

……………………

In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

http://pubs.acs.org/doi/full/10.1021/ml500117c

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/ml500117c

synthesis…………http://pubs.acs.org/doi/suppl/10.1021/ml500117c/suppl_file/ml500117c_si_001.pdf

6′-Fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-
b]indol]-4-amine, trans-, 2-hydroxy-1,2,3-propanetricarboxylate (2:1)

hemicitrate were obtained as a white solid (mp 258-282 °C).1H-NMR (300 MHz; DMSO-d6): 1.75-1.87 (m, 4 H); 2.14 (s, 6 H); 2.27 (t, 2 H); 2.61-
2.76 (m,6 H); 3.88 (t, 2 H); 6.86 (dt, 1 H); 7.10 (dd, 1 H); 7.30-7.43 (m, 6 H); 10.91 (br
s, 1 H).

13C-NMR (75.47 MHz; DMSO-d6): 22.1; 27.6; 30.2 (2 C); 38.0 (2 C); 43.1; 58.8 (2 C,
overlap); 71.5; 72.2; 102.3 (2JC,F = 23 Hz); 105.6 (3JC,F = 4 Hz); 108.3 (2JC,F = 26 Hz);

112.0 (3JC,F = 10 Hz); 126.5; 126.6; 126.7 (2 C); 127.4 (2 C); 132.4; 138.7; 141.5;
156,7 (1JC,F = 231 Hz); 171.3 (2 C), 175.3.HPLC-MS: m/z 378.9 [M + H]+

…………………………..

US20120034297 *	Aug 4, 2011	Feb 9, 2012	Gruenenthal Gmbh	Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 *	Jul 6, 2012	Jan 10, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

WO2004043967A1	Nov 5, 2003	May 27, 2004	Otto Aulenbacher	Spirocyclic cyclohexane derivatives
WO2008040481A1	Sep 26, 2007	Apr 10, 2008	Gruenenthal Gmbh	MIXED ORL 1/μ AGONISTS FOR TREATING PAIN

CORAL – Cebranopadol Versus Morphine Prolonged-release in Patients With Chronic Moderate to Severe Pain Related to Cancer

Efficacy, Safety, and Tolerability of Oral Cebranopadol Versus Morphine Sulfate PR in Subjects With Chronic Moderate to Severe Pain Related to Cancer.Average amount of daily rescue medication at the end of the maintenance period.

UK Clinical Trials Gateway, 07 October 2013
+

CORAL XT – Open-label Extension Trial of the CORAL Trial

An Open-label, Multi-site Trial to Describe the Safety and Tolerability of Oral Cebranopadol Administered for 26 Weeks in Subjects With Cancer-related Pain Who Have Completed Treatment in the KF6005/07 Trial.Absolute…

UK Clinical Trials Gateway, 12 December 2013

WO2004043967A1 *	Nov 5, 2003	May 27, 2004	Otto Aulenbacher	Spirocyclic cyclohexane derivatives
WO2005066183A1 *	Dec 21, 2004	Jul 21, 2005	Gruenenthal Gmbh	Spirocyclic cyclohexane derivatives with affinity for the orl1-receptor
US20050153998 *	Aug 19, 2004	Jul 14, 2005	Fumitaka Ito	Tetrahydroisoquinoline or isochroman compounds

Citing Patent	Filing date	Publication date	Applicant	Title
US7799931 *	Feb 17, 2009	Sep 21, 2010	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US7951948 *	Apr 19, 2010	May 31, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US7960404	Aug 21, 2009	Jun 14, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US8034936	Nov 4, 2010	Oct 11, 2011	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds useful to treat substance dependency
US8053576	Feb 17, 2009	Nov 8, 2011	Gruenenthal Gmbh	Treating conditions associated with the nociceptin/ORL1 receptor system, e.g. pain, drug withdrawal, anxiety, muscle relaxants, anxiolytic agents; e.g. 1,1-[3-dimethylamino-3-(pyridin-2-yl)pentamethylene]-3,4-dihydro-1H-2,9-diazafluorene
US8288406	Sep 22, 2010	Oct 16, 2012	Gruenenthal Gmbh	Hydroxymethylcyclohexylamines
US8288430	Mar 25, 2009	Oct 16, 2012	Grunenthal Gmbh	Spiro(5.5)undecane derivatives
US8293758 *	Mar 25, 2009	Oct 23, 2012	Grunenthal Gmbh	Substituted spirocyclic cyclohexane derivatives
US8357705	Mar 25, 2009	Jan 22, 2013	Gruenenthal Gmbh	Substituted cyclohexyldiamines
US8404740	Aug 21, 2009	Mar 26, 2013	Gruenenthal Gmbh	Spirocyclic cyclohexane compounds
US8614245 *	Jan 8, 2013	Dec 24, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US8618156 *	Jul 6, 2012	Dec 31, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 *	Jul 6, 2012	Jan 10, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

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

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , INDIA
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RedHill Biopharma Ltd. Acquires Phase 2 Oncology Drug Upamostat MESUPRON From Wilex AG

July 1, 2014 4:00 am / Leave a comment

Upamostat

CAS: 590368-25-5

Chemical Formula: C32H47N5O6S

Exact Mass: 629.32470

Synonym: WX 671; WX-671; WX671. Upamostat; Brand name: Mesupron.

IUPAC/Chemical name:

(S)-ethyl 4-(3-(3-(N-hydroxycarbamimidoyl)phenyl)-2-(2,4,6-triisopropylphenylsulfonamido)propanoyl)piperazine-1-carboxylate

RedHill Biopharma Ltd. , an Israeli biopharmaceutical company focused on late clinical-stage drugs for inflammatory and gastrointestinal diseases, including cancer, and WILEX AG , a biopharmaceutical company focused on oncology, based in Munich, Germany, today announced that they have signed an exclusive license agreement for the oncology drug … (more)

http://www.topix.com/de/munich/2014/06/redhill-biopharma-ltd-acquires-phase-2-oncology-drug-mesupron-from-wilex-ag

Upamostat, also known as Mesupron, WX-671, is an orally bioavailable, 3-amidinophenylalanine-derived, second generation serine protease inhibitor prodrug targeting the human urokinase plasminogen activator (uPA) system with potential antineoplastic and antimetastatic activities. After oral administration, serine protease inhibitor WX-671 is converted to the active Nα-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenyla lanine-4-ethoxycarbonylpiperazide (WX-UK1), which inhibits several serine proteases, particularly uPA; inhibition of uPA may result in the inhibition of tumor growth and metastasis. uPA is a serine protease involved in degradation of the extracellular matrix and tumor cell migration and proliferation.

Information about this agent

WX-671 (Mesupron) is an orally available prodrug of WX-UK1, a serine protease inhibitor that inhibits uPA as well as other serine proteases. WX-UK1 (Setyono-Han et al., Thromb Haemost 2005) and WX-671 have shown to efficiently reduce primary tumor growth and metastasis formation in a variety of animal models. The proteolytic factor uPA and its inhibitor PAI-1 belong to those biological factors which have provided the highest level of evidence (LOE1) in terms of their prognostic and predictive significance. WX-671 is currently the only drug in Phase II aiming at this target.Results: All 95 patients were accrued between Jun 2007 and Aug 2008. Efficacy is assessed by a central reader at regular intervals based on digital CT images. By end of 2009, 2 patients were still on treatment without signs of progression, 64 patients had died. Preliminary analysis of overall survival showed an increase in overall survival from 10.2 mo (gemcitabine alone) to 13.5 mo for the combination of gemcitabine and WX-671. 1-year survival increased from 37% with gemcitabine to 53% when combined with 400 mg WX- 671. Conclusions: The combination of daily oral WX-671 in combination with weekly i.v. gemcitabine was well tolerated. see asco.com’s website.

References

1. Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes) By Kotthaus, Joscha; Steinmetzer, Torsten; van de Locht, Andreas; Clement, Bernd From Journal of Enzyme Inhibition and Medicinal Chemistry (2011), 26(1), 115-122.

2. Combined treatment of cancer by urokinase inhibition and a cytostatic anti-cancer agent for enhancing the anti-metastatic effect By Schmalix, Wolfgang; Schneider, Anneliese; Setyono-Han, Buddy; Foekens, Johannes From U.S. Pat. Appl. Publ. (2008), US 20080226624 A1 20080918.

3. Peptides and small molecules targeting the plasminogen activation system: towards prophylactic anti-metastasis drugs for breast cancer By Tyndall, Joel D. A.; Kelso, Michael J.; Clingan, Phillip; Ranson, Marie From Recent Patents on Anti-Cancer Drug Discovery (2008), 3(1), 1-13.

4. Synthesis of hydroxyamidine and hydroxyguanidine amino acid or oligopeptide derivatives for use as urokinase plasminogen activator inhibitors for the treatment of cancer and its metastasis By Sperl, Stefan; Buergle, Markus; Schmalix, Wolfgang; Wosikowski, Katja; Clement, Bernd From U.S. Pat. Appl. Publ. (2006), US 20060142305 A1 20060629.

5. Crystalline modifications of N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamidino-(l)-phenylalanine-4-ethoxycarbonylpiperazide and/or its salts By Grunenberg, Alfons; Lenz, Jana From PCT Int. Appl. (2006), WO 2006056448 A1 20060601.

6. Synthesis of hydroxyamidine and hydroxyguanidine amino acid or oligopeptide derivatives for use as urokinase plasminogen activator inhibitors for the treatment of cancer and its metastasis By Sperl, Stefan; Burgle, Markus; Schmalix, Wolfgang; Wosikowski, Katja; Clement, Bernd From PCT Int. Appl. (2004), WO 2004103984 A1 20041202.

7. Preparation of 3-amidinophenylalanine derivatives from 3-cyanophenylalanines via reduction and hydrogenation under mild conditions By Ziegler, Hugo; Wikstroem, Peter From PCT Int. Appl. (2003), WO 2003072559 A1 20030904.

1. Buddy et al, Suppression of Rat Brest Cancer Metastasis and Reduction of Primary Tumor Growth by the Small Synthetic Urokinase Inhibitor WX-UK1. Thromb Haemost. 2005, 93:779-786.

2. Ertongur S, Lang S, Mack B, Wosikowski K, Muehlenweg B, Gires O. Inhibition of the invasion capacity of carcinoma cells by WX-UK1, a novel synthetic inhibitor of the urokinase-type plasminogen activator system. Int J Cancer. 2004, 110(6):815-24.

3. Setyono-Han B, Stürzebecher J, Schmalix WA, Muehlenweg B, Sieuwerts AM, Timmermans M, Magdolen V, Schmitt M, Klijn JG, Foekens JA. Suppression of rat breast cancer metastasis and reduction of primary tumour growth by the small synthetic urokinase inhibitor WX-UK1. Thromb Haemost. 2005, 93(4):779-86.

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