| Patent ID | Date | Patent Title |
|---|---|---|
| US2015182533 | 2015-07-02 | 5-HT3 RECEPTOR ANTAGONISTS |
| US2014024644 | 2014-01-23 | 5-HT3 RECEPTOR ANTAGONISTS |
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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai)
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TAK-058 (ENV-8058)
TAK-058 , ENV-8058
5-HT 3 receptor antagonist
1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide
l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5 .7S)-9-methyl-3-oxa-9-azabicyclo[3.3.11nonan-7-yl)-lH-indole-3-carboxamide
1-(1-methyl-1H- pyrazol-4-yl)-N- ((1R,5S,7S)- 9-methyl-3- oxa-9-azabicyclo [3.3.1]nonan-7- yl)-1H-indole-3- carboxamide, 2,2,2- trifluoroacetic acid salt
N-(9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1-methylpyrazol-4-yl)indole-3-carboxamide
| Molecular Formula: | C21H25N5O2 |
|---|---|
| Molecular Weight: | 379.4555 g/mol |
https://clinicaltrials.gov/ct2/show/NCT02153099
Phase I Schizophrenia
| Latest Stage of Development | Phase I |
| Standard Indication | Schizophrenia |
| Indication Details | Treat schizophrenia |
- 01 Dec 2015 Phase-I clinical trials in Schizophrenia (Combination therapy) in USA (PO)
- 01 Dec 2015 Takeda completes a phase I trial in Healthy volunteers in USA (NCT02389881)
- 28 Nov 2015 Takeda plans a phase I trial in Schizophrenia (Combination therapy) in USA (NCT02614586)
1 -( 1 -methyl- 1 H-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, free base, which is an antagonist of the 5-HT3 receptor. 1 -(1 -Methyl- 1 H-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-lH-indole-3-carboxamide, 2,2,2-trifluoroacetic acid salt, is disclosed in PCT Publication No. WO
2014/014951, published January 23, 2014.
1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide a 5-HT3 receptor antagonist, useful for treating anxiety, depression, eating disorder, schizophrenia, cognitive dysfunction, Parkinson’s disease, Huntington’s Chorea, presenile dementia, Alzheimer’s disease and atherosclerosis.
This compound was originally claimed in WO2014014951, Takeda, following its acquisition of Envoy Therapeutics, is developing TAK-058 (ENV-8058), a 5-HT3 receptor antagonist, as an oral solution for treating schizophrenia, especially cognitive impairment associated with schizophrenia.
In July 2015, the drug was listed as being in phase I development. TAK-058 may have emerged from a schizophrenia therapy program which used Envoy’s bacTRAP translational profiling technology to identify a protein target in the brain.
PATENT
Example 5
Synthesis of l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5 .7S)-9-methyl-3-oxa-9-azabicyclo[3.3.11nonan-7-yl)-lH-indole-3-carboxamide. 2.2.2-trifluoroacetic acid salt
Step 1 : methyl 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indole-3-carboxylate. TFA
To a sealed tube was added copper(I) iodide (65.2 mg, 0.342 mmol), methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) and potassium phosphate (509 mg, 2.397 mmol), then the reaction vessel was evacuated and purged with nitrogen (3x). Next, 4-bromo-l-methyl-lH-pyrazole (184 mg, 1.142 mmol) and (lR,2R)- ,N2-dimethylcyclohexane-l,2-diamine (109 μΐ, 0.685 mmol) were added, followed by toluene (1 142 μΐ). The reaction tube was evacuated and purged with nitrogen, then sealed and heated at 1 10 °C for 24 h. HPLC purification provided the title compound as a colorless oil.
Step 2: 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indole-3-carboxylic acid hydrochloride
To a solution of methyl 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indole-3-carboxylate, TFA
(3.5 mg, 9.48 μιηοΐ) in MeOH (95 μΐ) was added a solution of aq. KOH (33.2 μΐ, 0.066 mmol, 2 M). The reaction mixture was stirred at RT overnight, then acidified with IN HC1.
The solvent was evaporated under reduced pressure and the residue was dried under vacuum overnight. The title compound was used without further purification.
Step 3 : l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5 .7S)-9-methyl-3-oxa-9-azabicyclor3.3.11nonan-7-yl)-lH-indole-3-carboxamide, 2,2,2-trifluoroacetic acid salt
To a mixture of 1-(1 -methyl- lH-pyrazol-4-yl)-lH-indole-3-carboxylic acid hydrochloride (2.6 mg, 9.36 μιηοΐ) in DMF (187 μΐ) was added HATU (4.27 mg, 0.01 1 mmol) and DIPEA (8.18 μΐ, 0.047 mmol). After the reaction mixture was stirred at RT for 15 min, (lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine, TFA (3.04 mg, 0.01 1 mmol) was added and stirring was continued for 2 h. HPLC purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 380.30 (M+l).
PATENT
EXAMPLE 1 : l-(l-methyl-lH-pyrazol-4-yl)-N-((lR,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1 ]nonan-7-yl)- lH-indole-3-carboxamide
l-(l-Methyl-lH-pyrazol-4-yl)-lH-indole-3-carboxylic acid (128.7 g, 0.53 mol,) and anhydrous THF (645 mL) was heated to about 43°C. Oxalyl chloride (137.7 g, 92 mL, 1.08 mol) was added dropwise between 40 and 50°C. Gas evolution ceased in approximately 30 minutes. The resulting suspension was stirred for 2 hours at 50°C, allowed to cool to room temperature, and then stirred overnight. The suspension was diluted with heptane (1.5 L), stirred for 10 minutes, and allowed to settle. The supernatant was removed. The addition of heptane (1.5 L), followed by stirring, settling, and decanting was repeated two more times.
The resulting suspension was diluted with anhydrous THF (645 mL) and the ratio between THF and heptane was determined by NMR to be 3:2. The reaction mixture was cooled to 5°C and to the mixture was added DIPEA base (138 g, 1.07 mol) at such a rate that the temperature did not exceed 20°C. Next (li?,55*,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine (101.4 g, 0.63 mol) in 500 mL of anhydrous THF was added. The reaction mixture was warmed to ambient temperature and stirred at 20 to 23°C overnight to give a suspension.
The suspension was filtered and the cake was dissolved in IN HC1 (2.6 L). The aqueous layer was washed with EtOAc (3 x 2.6 L). The aqueous layer was cooled to 5°C and was basified to pH 12 with aqueous potassium hydroxide (230 g) solution in water (500 mL). The mixture was stirred at 5 to 10°C overnight to give a solid. The product was filtered, washed with water (2 x 1.2 L), followed by MTBE (2 x 1.2 L), and then dried to give 128 g (64%) of the (crude) title compound.
Patent
https://www.google.co.in/patents/US20140024644
1-(1-methyl-1H- pyrazol-4-yl)-N- ((1R,5S,7S)- 9-methyl-3- oxa-9-azabicyclo [3.3.1]nonan-7- yl)-1H-indole-3- carboxamide, 2,2,2- trifluoroacetic acid salt
Synthetic Procedures Reference 1 Synthesis of (1R,5S,7S)-tert-butyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate
-
-
Sodium borohydride (259 mg, 6.84 mmol) was added portion-wise to a solution of (1R,5S)-tert-butyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (550 mg, 2.279 mmol) in MeOH (4559 μl) at 0° C. After 5 min, the reaction mixture was allowed to warm to RT then stirred for 30 min. The mixture was concentrated under reduced pressure, dissolved in EtOAc and washed with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound as a white solid, which was used without further purification.
Example 4 Synthesis of N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1-(1H-pyrazol-4-yl)-1H-indole-3-carboxamide, 2,2,2-trifluoroacetic acid salt
-
-
A mixture of 1-((1-benzyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide 2,2,2-trifluoroacetate (85 mg, 0.149 mmol) and 10% Pd—C (120 mg) in MeOH (1.0 ml) was stirred at RT under H2 for 2 days. Filtration and concentration afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 366.20 (M+1).
Example 5 Synthesis of 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide, 2,2,2-trifluoroacetic acid salt
Step 1: methyl 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylate, TFA
-
To a sealed tube was added copper(I) iodide (65.2 mg, 0.342 mmol), methyl 1H-indole-3-carboxylate (200 mg, 1.142 mmol) and potassium phosphate (509 mg, 2.397 mmol), then the reaction vessel was evacuated and purged with nitrogen (3×). Next, 4-bromo-1-methyl-1H-pyrazole (184 mg, 1.142 mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (109 μl, 0.685 mmol) were added, followed by toluene (1142 μl). The reaction tube was evacuated and purged with nitrogen, then sealed and heated at 110° C. for 24 h. HPLC purification provided the title compound as a colorless oil.
Step 2: 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylic acid hydrochloride
-
To a solution of methyl 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylate, TFA (3.5 mg, 9.48 μmol) in MeOH (95 μl) was added a solution of aq. KOH (33.2 μl, 0.066 mmol, 2 M). The reaction mixture was stirred at RT overnight, then acidified with 1N HCl. The solvent was evaporated under reduced pressure and the residue was dried under vacuum overnight. The title compound was used without further purification.
Step 3: 1-(1-methyl-1H-pyrazol-4-yl)-N-((1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-1H-indole-3-carboxamide, 2,2,2-trifluoroacetic acid salt
-
To a mixture of 1-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carboxylic acid hydrochloride (2.6 mg, 9.36 μmol) in DMF (187 μl) was added HATU (4.27 mg, 0.011 mmol) and DIPEA (8.18 μl, 0.047 mmol). After the reaction mixture was stirred at RT for 15 min, (1R,5S,7S)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-amine, TFA (3.04 mg, 0.011 mmol) was added and stirring was continued for 2 h. HPLC purification afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 380.30 (M+1).
| 15 |
 |
 |
TFA |
| 379.456 MW | 380.30 MS +1
|
/////////TAK-058 , ENV-8058, phase I, takeda, 5-HT 3 receptor antagonist, Envoy Therapeutics, Inc., Phase I, Schizophrenia
C12CC(CC(N1C)COC2)NC(c4c3ccccc3n(c4)c5cnn(c5)C)=O
CN1C=C(C=N1)N2C=C(C3=CC=CC=C32)C(=O)NC4CC5COCC(C4)N5C
GSK-525762A
GSK 525762A; 1260907-17-2; I-BET-762; GSK525762A; UNII-5QIO6SRZ2R; 5QIO6SRZ2R;
CAS1260907-17-2
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide
| Molecular Formula: | C22H22ClN5O2 |
|---|---|
| Molecular Weight: | 423.89538 g/mol |
| Solubility: | Soluble in DMSO (84 mg/ml at 25 °C), ethanol (42 mg/ml at 25 °C, warmed), DMF (~30 mg/ml), ethanol:PBS (pH 7.2, 1:1) (~0.5 mg/ml), and water (<1 mg/ml at 25 °C). |
| Storage: | Store at -20° C |
| Density: | ~1.4 g/cm3 (Predicted) |
| Refractive Index: | n20D 1.67 (Predicted) |
| Optical Activity: | α20D 85º±5º, c = 0.3 in methanol |
| IC50: | BRD2: IC50 = 32.5 nM (human); BRD4: IC50 = 36.1 nM (human); BRD3: IC50 = 42.4 nM (human); PBMC: IC50 = 316.23 nM (human); HepG2: EC5050 = 700 nM (human) |
| pK Values: | pKb: 2.43 (Predicted) |
In April 2016, GSK-525762 was reported to be in phase 2 clinical development. GSK-525762 was originally disclosed in WO2011054553, claiming benzodiazepine derivatives as bromodomain inhibitors, useful for treating cancer. See WO2014028547, claiming use of GSK-525762 for treating small cell lung cancer.
GSK 525762A, is a BET Bromodomain Inhibitor, which is now in clinical development. BET bromodomains have emerged as promising drug targets for treatment of cancers, inflammatory diseases, and other medical conditions.
Patent
Patent applications WO201 1/054553 and WO201 1/054845 (both in the name of GlaxoSmithKline LLC) disclose the compound 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4/-/-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide as a BET family bromodomain inhibitor and describes therapeutic uses thereof. The chemical structure of this compound is represented by formula (I):
(I)
Scheme 1
Example 1
Preparation of an acetonitrile solvate of 2-[(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-yV-ethylacetamide
Amorphous 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide (prepared for instance as described in WO201 1/054553, 1 wt) was dissolved in acetonitrile (20 vol) upon heating (up to reflux). The solution was then distilled to 10 vol keeping the temp 50 °C – 60 °C by adjusting the vacuum. Nucleation occurred during the final stage of the distillation. The slurry was then held at 60 °C before being cooled to 20 °C and filtered. The cake was then washed with
acetonitrile (2 vol). The cake was dried under vacuum with a nitrogen bleed at approximately 60 °C to provide the titled product.
1H-NMR (500 MHz, DMSO-d6, referenced to TMS = 0.00 ppm, T = 25 C) δ ppm 8.22 (1 H, t, J = 5 Hz), 7.79 (1 H, d, J = 9 Hz), 7.53 (2H, d, J = 9 Hz), 7.49 (2H, d, J = 9 Hz), 7.38 (1 H, dd, J = 3 Hz, 9 Hz), 6.87 (1 H, d, J = 3 Hz), 4.49 (1 H, m), 3.79 (3H, s), 3.25 (1 H, m), 3.20-3.06 (3H, several m), 2.54 (3H, s), 2.08 (3H, s), 1 .07 (3H, t, J = 7 Hz).
Example 2
Preparation of a benzene sulphonic acid salt of 2-[(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-A/-ethylacetamide in crystalline solid state form
Preparation 1
The acetonitrile solvate of 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4/-/-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide (for a preparation see Example 1 , 2.58 g) was slurried in acetonitrile (7 mL) and 2-methyltetrahydrofuran (7 mL). Benzenesulfonic acid (1.17 g) was dissolved in acetonitrile (7 mL). The resulting solution was charged to the slurry of 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4/-/-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide acetonitrile solvate in acetonitrile and 2-methyltetrahydrofuran. An additional rinse of acetonitrile (1.4 mL) and 2-methyltetrahydrufran (0.7 mL) was added to the slurry. The slurry was then warmed to 60 °C to dissolve. 2-methyltetrahydrofuran (50 mL) was then added over 30 minutes. Crystals formed during this addition. The resulting suspension was then cooled to 5 °C at a controlled, linear rate of 0.5 °C/minute. The slurry was aged for 1 hour. The crystalline product was then isolated by filtration and rinsed with a 5 to 1 mixture of 2-methyltetrahydrofuran and acetonitrile (15 mL). The product was then dried in a vacuum oven at 55 °C overnight.
Preparation 2
The acetonitrile solvate of 2-[(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4/-/-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide (prepared for example in a process such as Example 1 above, 1 wt) was dissolved in 9 vol 2-methyltetrahydrofuran at 65 °C. Once cooled to 20°C the solution was filtered into the crystallization vessel. The dissolution vessel and inline filter were rinsed with 1 vol 2-methyltetrahydrofuran. The solution was then heated to 45 °C.
1 .05 eq of benzene sulphonic acid was dissolved in 1 volume of filtered acetonitrile. 10% of this solution was added to a reactor to which 0.05 wt% of a benzene sulphonic acid
salt of 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide micronized seed (prepared for example as in Preparation 1 above) slurry was charged. The remaining benzene sulphonic acid solution was charged at a steady rate over 2 hours, maintaining the reactor at 45 °C.
The slurry was cooled to 0 °C at no greater than 0.2 °C/minute. The slurry was filtered.
The crystallizer was charged with the first wash, 3 vol of filtered 2-methyltetrahydrofuran, which was cooled to <10 °C while stirring in the crystallizer, before being used to wash the cake. The crystallizer was charged with the second wash, 3 vol of filtered 2-methyltetrahydrofuran, which was cooled to <10 °C while stirring in the crystallizer, before being used to wash the cake. The crystallizer was charged with the third wash, 4 vol of filtered 2-MeTHF, which was cooled to <10 °C while stirring in the crystallizer, before being used to wash the cake. The cake was blown-down until the solvent being removed was reduced to a trickle. The title compound was then dried in a vacuum oven at 50 °C until the loss on drying (LOD) indicates <0.2% wt. loss (LOD method: 10 min at 120 °C). The product was then delumped using a comil.
Example 3
Characterisation of a benzene sulphonic acid salt of 2-[(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-yV-ethyl acetamide in crystalline solid state form
XRPD
The X-ray powder diffraction (XRPD) data were acquired on a PANalytical X’Pert Pro powder diffractometer, model PW3050/60, using an X’Celerator detector. The acquisition conditions were: radiation: Cu Ka, generator tension: 45 kV, generator current: 40 mA, step size: 0.017 °2Θ, time per step: 500 seconds, divergence slit type: fixed, divergence slit size: 0.4354 °, measurement temperature: 20-25 °C, goniometer radius: 240 mm. The sample was prepared by packing sample in a 0.9 mm capillary. Peak positions were obtained using PANalytical X’Pert Highscore Plus software. The margin of error is approximately ± 0.1° 2Θ for each of the peak assignments.
The X-ray powder diffraction (XRPD) pattern is shown in Figure 1 and shows characteristic peaks, expressed in degrees 2Θ, at 5.5, 7.4, 9.1 , 10.0, 10.4, 13.3, 13.6, 14.9, 18.7, 20.4, 20.9, 22.8 and 23.1 ° ( ± 0.1 °).
13C Solid State NMR (SSNMR)
A 13C SSNMR spectrum was obtained at 273K on a spectrometer operating at a frequency of 100.56 MHz for 13C observation using a cross-polarization pulse sequence with a Bruker 4-mm triple resonance magic-angle spinning probe at a rotor frequency of 8 kHz. The margin of error is ± 0.2 ppm for each of the peak assignments.
The 13C SSNMR spectrum is shown in Figure 2 and comprises chemical shifts (ppm) at 169.6, 167.5 165.6, 160.1 , 159.4, 157.1 , 155.9, 154.3, 152.4, 146.9, 145.8, 140.0, 137.9, 135.9, 133,4, 132.0, 130.6, 129.9, 128.3, 127.1 , 125.6, 123.5, 120.6, 1 19.1 , 1 14.1 , 1 13.7, 58.0, 53.6, 53.1 , 40.7, 37.0, 34.9, 15.8, 14.7, and 12.0 ( ±0.2 ppm).
PATENT
WO2011054553
http://www.google.com/patents/WO2011054553A1?cl=en
formula (I) which is 2-[(4S)-6-(4- Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V- ethylacetamide
(I)
or a salt thereof.
It will be appreciated that the present invention covers compounds of formula (I) as the free base and as salts thereof, for example as a pharmaceutically acceptable salt thereof.
In one embodiment there is provided a compound which is 2-[(4S)-6-(4-Chlorophenyl)-1- methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide.
Because of their potential use in medicine, salts of the compounds of formula (I) are desirably pharmaceutically acceptable. In another embodiment there is provided a compound which is 2-[(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]-/V-ethylacetamide or a pharmaceutically acceptable salt thereof.
The compound of formula (I) may be prepared according to reaction scheme 1 by reaction of a compound of formula (II) with EtNH2 in the presence of HATU or HBTU and DIEA at room temperature. Alternatively compounds of formula (I) may be prepared by reacting the compound of formula (II) with oxalyl chloride followed by addition of EtNH2 in the presence of triethylamine.
Scheme 1
The compound of formula (II) may be prepared according to reaction Scheme 2. Suitable reaction conditions comprise reacting a compound of formula (III) with alkaline hydroxide preferably sodium hydroxide or lithium hydroxide.
Scheme 2
wherein R represents C-|.galkyl such as methyl.
Compounds of formula (III), may be prepared according to reaction scheme 3 by reacting compounds of formula (IV) with AcOH. Scheme 3
Compounds of formula (IV) may be prepared according to reaction scheme 4 by reacting compounds of formula (VI) with hydrazine below 15 °C followed by reaction of the resulting hydrazone (V) with MeCOCI at 0°C. Generally hydrazone (V) is used without further purification and is reacted with MeCOCI at , for example 0 °C.
Scheme 4
(IV) Compounds of formula (VI) in which R is Ci-6alkyl (such as methyl) may be prepared according to reaction scheme 5 from compounds of formula (VII) by treatment with Lawesson’s reagent or P4Si0. Suitable reaction conditions comprise reacting compounds of formula (VIII) with P4Si0 in 1 ,2-dichloroethane at, for example 70 °C.
Scheme 5
Compounds of formula (VII) may be prepared according to reaction scheme 6, by reacting compounds of formula (IX) with an organic base such as triethylamine followed by reaction of the resulting amine (VIII) with acetic acid. Generally, amine (VIII) is used without further purification and is reacted with AcOH at, for example 60 °C.
Scheme 6
Compounds of formula (IX) may be prepared according to reaction scheme 7, by reacting compounds of formula (XI) with the acylchloride (X) derived from protected aspartic acid. Scheme 7
Compounds of formula (XI) may be prepared according to procedures described in Synthesis 1980, 677-688. Acyl chlorides of formula (X) may be prepared according to procedures described in J. Org. Chem., 1990, 55, 3068-3074 and J. Chem. Soc. Perkin Trans. 1 , 2001 , 1673-1695.
Alternatively the compound of formula (I) may be prepared according to reaction scheme 8.
wherein R represents C-|_4alkyl such as methyl.
The compound of formula (IIIA) may be prepared according to reaction scheme 9 by reacting compounds of formula (IVA) with EtNH2 in the presence of HATU and DIEA at, for example room temperature.
Scheme 9
The compound of formula (IVA) may be prepared according to reaction scheme 10. Suitable reaction conditions comprise reacting compounds of formula (VI) with alkaline hydroxide such as sodium hydroxide. Scheme 10
Example 1 : 2-[(4S)-6-(4-Chlorophenyl)-1 -methyl-8-(methyloxy)-4H-[1 ,2,4]triazolo[4,3-
To a solution of [(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1 !2!4]triazolo[4,3- a][1 ,4]benzodiazepin-4-yl]acetic acid (for a preparation see Intermediate 1 )(16.0 g, 40 mmol) in THF at RT was added DIEA (14 mL, 80 mmol) followed by HATU (30.4 g, 80 mmol). The reaction mixture was stirred for 3h at this temperature and ethylamine (40 mL, 2M in THF, 80 mmol) was added. The mixture was stirred for 48h before being concentrated under reduced pressure. The crude material was suspended in water and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude solid was purified by chromatography on Si02 (DCM/MeOH 95/5) and the resulting solid recrystallised in MeCN. The solid was then dissolved in DCM and precipited with /‘-Pr20 to give the title compound (8 g, 47% yield) as a white solid.
Rf = 0.48 (DCM/MeOH : 90/10). Mp >140 °C (becomes gummy). 1H NMR (300 MHz, CDCI3) 7.53-7.47 (m, 2H), 7.39 (d, J = 8.9 Hz, 1 H), 7.37-7.31 (m, 2H), 7.20 (dd, J = 2.9 and 8.9 Hz, 1 H), 6.86 (d, J = 2.9 Hz, 1 H), 6.40 (m, 1 H), 4.62 (m, 1 H), 3.80 (s, 3H), 3.51 (dd, J = 7.3 and 14.1 Hz, 1 H), 3.46-3.21 (m, 3H), 2.62 (s, 3H), 1.19 (t, J = 7.3 Hz, 3H). LC/MS : m/z 424 [M(35CI)+H]+, Rt 2.33 min.
Intermediate 1 : [(4S)-6-(4-Chlorophenyl)-1 -methyl-8-(methyloxy)-4H-
[1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]acetic acid
To a solution of methyl [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]acetate (for a preparation see Intermediate 2)(28 g, 68 mmol) in THF (450 mL) at RT was added 1 N NaOH (136 mL, 136 mmol). The reaction mixture was stirred at this temperature for 5h before being cooled down and quenched with 1 N HCI (136 mL). THF was removed under reduced pressure and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The crude solid was recrystallised in CH3CN to give the title compound (23.9 g, 89% yield) as a pale yellow powder. 1H NMR (300 MHz, CDCI3) δ 7.55-7.48 (m, 2H), 7.41 (d, J = 8.9 Hz, 1 H), 7.38- 7.31 (m, 2H), 7.22 (dd, J = 2.9 and 8.9 Hz, 1 H), 6.90 (d, J = 2.9 Hz, 1 H), 4.59 (dd, J = 6.9 and 6.9 Hz, 1 H), 3.81 (s, 3H), 3.70 (dd, J = 6.9 and 25.7 Hz, 1 H), 3.61 (dd, J = 6.9 and 25.7 Hz, 1 H), 2.63 (s, 3H). LC/MS: m/z 397 [M(35CI)+H]+, Rt 2.1 1 min.
Intermediate 2: Methyl [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]benz
To crude methyl [(3S)-2-[(1 Z)-2-acetylhydrazino]-5-(4-chlorophenyl)-7-(methyloxy)-3H- 1 ,4-benzodiazepin-3-yl]acetate (for a preparation see Intermediate 3) (34 g, 79 mmol) was suspended in THF (200 mL) and AcOH (200 mL) was added at RT. The reaction mixture was stirred at this temperature overnight before being concentrated to dryness. The residue was suspended in saturated NaHC03 and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude solid was purified by chromatography on Si02 (DCM/MeOH : 90/10) to give the title compound (28 g, 86% yield) as a yellow powder.
1H NMR (300 MHz, CDCI3) δ 7.54-7.47 (m, 2H), 7.40 (d, J = 8.8 Hz, 1 H), 7.37-7.31 (m, 2H), 7.22 (dd, J = 2.8 and 8.8 Hz, 1 H), 6.89 (d, J = 2.8 Hz, 1 H), 4.61 (dd, J = 6.4 and 7.8 Hz, 1 H), 3.82 (s, 3H), 3.78 (s, 3H), 3.66 (dd, J = 7.8 and 16.9 Hz, 1 H), 3.60 (dd, J = 6.4 and 16.9 Hz, 1 H), 2.62 (s, 3H). LC/MS m/z 41 1 [M(35CI)+H]+, Rt 2.88 min. Intermediate 3: Methyl [(3S)-2-[2-acetylhydrazino]-5-(4-chlorophenyl)-7-(methyloxy)- 3H-1 ,4-benzodiazepin-3-yl]acetate
To a suspension of methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-thioxo-2,3-dihydro- 1 H-1 ,4-benzodiazepin-3-yl]acetate (for a preparation see Intermediate 4)(30.2 g, 77.7 mmol) in THF (800 mL) at 0°C was added hydrazine monohydrate (1 1 .3 ml_, 233 mmol) dropwise. The reaction mixture was stirred for 4h between 0°C and 15°C before being cooled at 0°C. Et3N (32.4 mL, 230 mmol) was then added slowly and AcCI (16.3 mL, 230 mmol) was added dropwise. The mixture was allowed to warm to RT and stir for 1 h then quenched with water and concentrated under reduced pressure. The resulting aqueous layer was then extracted with DCM and the organic layer was dried over Na2S04, filtered and concentrated in vacuo to give the crude title compound (34 g, 100% yield) which was used without further purification. LC/MS: m/z 429 [M(35CI)+H]+, Rt 2.83 min. Intermediate 4: Methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-thioxo-2,3-dihydro- 1H-1 ,4-benzodiazepin-3-yl]acetate
A suspension of P4Si0 (85.8 g, 190 mmol) and Na2C03 (20.5 g, 190 mmol) in 1 ,2-DCE (1.5 L) at RT was stirred for 1 h before methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2- oxo-2,3-dihydro-1 H-1 ,4-benzodiazepin-3-yl]acetate (for a preparation see Intermediate 5) (40 g, 107 mmol) was added. The resulting mixture was stirred at 65°C for 4 h before being cooled and filtered. The solid was washed with DCM and the filtrate washed with sat. NaHC03. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The title compound was precipitated from a DCM//‘-Pr20 mixture and filtered. The filtrate was then concentrated and purified by flash chromatography (DCM/MeOH : 98/2) to afford another batch of product. The title compound was obtained combining the two fractions (30.2 g, 73%) as a yellow powder. LC/MS: m/z 389
[M(35CI)+H]+, Rt 3.29 min.
Intermediate 5: Methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-oxo-2,3-dihydro-1H- 1 ,4-benzodiazepin-3-yl]acetat
To a solution of the crude methyl /V1-[2-[(4-chlorophenyl)carbonyl]-4-(methyloxy)phenyl]- /V2-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-a-asparaginate (for a preparation see Intermediate 6) (assumed 0.2 mol) in DCM (500 mL) was added Et3N (500 mL, 3.65 mol) and the resulting mixture was refluxed for 24h before being concentrated. The resulting crude amine was dissolved in 1 ,2-DCE (1.5 L) and AcOH (104 mL, 1.8 mol) was added carefully. The reaction mixture was then stirred at 60°C for 2h before being concentrated in vacuo and dissolved in DCM. The organic layer was washed with 1 N HCI and the aqueous layer was extracted with DCM (x3). The combined organic layers were washed twice with water, and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude solid was recrystallised in MeCN leading to the title compound (51 g) as a pale yellow solid. The filtrate could be concentrated and recrystallised in MeCN to give another 10 g of Intermediate 9 (total: 61 g, 69% yield based on recovered
Intermediate 12). Rf = 0.34 (DCM/MeOH : 95/5). LC/MS m/z 373 [M(35CI)+H]+, Rt 2.76 min.
Intermediate 6: Methyl W^2-[(4 :hlorophenyl)carbonyl]-4-(methyloxy)phenyl] V2– {[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-a-asparaginate
A mixture of Methyl /V-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-a-aspartyl chloride (prepared from J. Org. C em. 1990, 55, 3068-3074 and J. C em. Soc. Perkin Trans. 1 2001 , 1673-1695) (221 g, 0.57 mol) and [2-amino-5-(methyloxy)phenyl](4- chlorophenyl)methanone (for a preparation see Intermediate 7) (133 g, 0.5 mol) in CHCI3 (410 mL) was stirred at 60°C for 1.5h before being cooled and concentrated under reduced pressure and used without further purification. LC/MS: m/z 613 [M(35CI)+H]+, Rt = 3.89 min. Intermediate 7: [2-amino-5-(methyloxy)phenyl](4-chlorophenyl)methanone
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Intermediate 8)(40.0 g, 0.21 mol) in a toluene (560 ml_)/ether (200 mL) mixture at 0°C was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 mL, 1 M in Et20, 0.17 mol). The reaction mixture was allowed to warm to RT and stirred for 1 h before being quenched with 1 N HCI. The aqueous layer was extracted with EtOAc (3 x) and the combined organics were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude compound was then dissolved in EtOH (400 mL) and 6N HCI (160 mL) was added. The reaction mixture was refluxed for 2 h before being concentrated under reduced pressure. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1 N NaOH. The aqueous layer was extracted with EtOAc (3 x) and the combined organics were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88 % yield) which was used without further purification. Intermediate 8 : 2-methyl-6-(methyloxy)-4H-3,1 -benzoxazin-4-one
A solution of 5-methoxyanthranilic acid (7.8 g, 46.5 mmol) was refluxed in acetic anhydride (60 mL) for 2h15 before being cooled and concentrated under reduced pressure. The crude residue was then concentrated twice in the presence of toluene before being filtered and washed with ether to yield to the title compound (6.8 g, 77% yield) as a beige solid; LC/MS: m/z 192 [M+H]+, Rt 1.69 min.
Preparation of reference compound for use in biological assays
Experimental details of LC-MS methods A and B as referred to herein are as follows:
LC/MS (Method A) was conducted on a Supelcosil LCABZ+PLUS column (3μηΊ, 3.3cm x 4.6mm ID) eluting with 0.1 % HCO2H and 0.01 M ammonium acetate in water (solvent A), and 95% acetonitrile and 0.05% HCO2H in water (solvent B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0→100%B, 4.2-5.3 minutes 100%B, 5.3-5.5 minutes 100→0%B at a flow rate of 3 mL/minute. The mass spectra (MS) were recorded on a Fisons VG Platform mass spectrometer using electrospray positive ionisation [(ES+ve to give [M+H]+ and [M+NH4]+ molecular ions] or electrospray negative ionisation
[(ES-ve to give [M-H]- molecular ion] modes. Analytical data from this apparatus are given with the following format : [M+H]+ or [M-H]-.
LC/MS (Method B) was conducted on an Sunfire C18 column (30mm x 4.6mm i.d. 3.5μηι packing diameter) at 30 degrees centigrade, eluting with 0.1 % v/v solution of Trifluoroacetic Acid in Water (Solvent A) and 0.1 % v/v solution of Trifluoroacetic Acid in Acetonitrile (Solvent B) using the following elution gradient 0-0.1 min 3%B, 0.1- 4.2min 3 – 100% B, 4.2-4.8min 100% B, 4.8-4.9min 100-3%B, 4.9 – 5.0min 3% B at a flow rate of 3ml/min. The UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using positive electrospray ionization. Ionisation data was rounded to the nearest integer. LC/HRMS: Analytical HPLC was conducted on a Uptisphere-hsc column (3μηι 33 x 3 mm id) eluting with 0.01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B), using the following elution gradient 0-0.5 minutes 5% B, 0.5-3.75 minutes 5→100% B, 3.75-4.5 100% B, 4.5-5 100→5% B, 5-5.5 5% B at a flow rate of 1 .3 mL/minute. The mass spectra (MS) were recorded on a micromass LCT mass spectrometer using electrospray positive ionisation [ES+ve to give MH+ molecular ions] or electrospray negative ionisation [ES-ve to give (M-H)- molecular ions] modes.
TLC (thin layer chromatography) refers to the use of TLC plates sold by Merck coated with silica gel 60 F254.
Silica chromatography techniques include either automated (Flashmaster or Biotage SP4) techniques or manual chromatography on pre-packed cartridges (SPE) or manually- packed flash columns.
Reference compound A : 2-meth -6-(methyloxy)-4H-3,1 -benzoxazin-4-one
A solution of 5-methoxyanthranilic acid (Lancaster) (41.8 g, 0.25 mol) was refluxed in acetic anhydride (230 mL) for 3.5 h before being concentrated under reduced pressure. The crude compound was then concentrated twice in the presence of toluene before being filtered and washed twice with ether to yield to the title compound (33.7 g, 71 % yield) as a brown solid; LC/MS (Method A): m/z 192 [M+H]+, Rt 1.69 min.
Reference compound B: [2-amino- -(methyloxy)phenyl](4-chlorophenyl)methanone
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Reference compound A) (40.0 g, 0.21 mol) in a toluene/ether (2/1 ) mixture (760 mL) at 0°C was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 mL, 1 M in Et20, 0.17 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being quenched with 1 N HCI (200 mL). The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organics were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The crude compound was then dissolved in EtOH (400 mL) and 6N HCI (160 mL) was added. The reaction mixture was refluxed for 2 h before being concentrated to one-third in volume. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1 N NaOH. The aqueous layer was extracted with EtOAc (3 x 150 mL) and the combined organics were washed with brine (150 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88 % yield); LC/MS (Method A): m/z 262 [M+H]+, Rt 2.57 min.
Reference Compound C: Methyl /^-^-[(^chlorophenyljcarbonyl]^- (methyloxy)phenyl]-yV2-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-a-asparaginate
Methyl /V-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-a-aspartyl chloride {Int. J. Peptide Protein Res. 1992, 40, 13-18) (93 g, 0.24 mol) was dissolved in CHCI3 (270 mL) and [2- amino-5-(methyloxy)phenyl](4-chlorophenyl)methanone (for a preparation see Reference compound B) (53 g, 0.2 mol) was added. The resulting mixture was stirred at 60°C for 1 h before being cooled and concentrated at 60% in volume. Ether was added at 0°C and the resulting precipitate was filtered and discarded. The filtrate was concentrated under reduced pressure and used without further purification.
Reference compound D: Methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-oxo-2,3- dihydro-1H-1 ,4-benzodiazepin-3-yl]acetate
To a solution of Methyl N1-[2-[(4-chlorophenyl)carbonyl]-4-(methyloxy)phenyl]-N2-{[(9H- fluoren-9-ylmethyl)oxy]carbonyl}-L-a-asparaginate (for a preparation see Reference compound C) (assumed 0.2 mol) in DCM (500 mL) was added Et3N (500 mL, 3.65 mol) and the resulting mixture was refluxed for 24h before being concentrated. The resulting crude amine was dissolved in 1 ,2-DCE (1.5 L) and AcOH (104 mL, 1.8 mol) was added carefully. The reaction mixture was then stirred at 60°C for 2h before being concentrated in vacuo and dissolved in DCM. The organic layer was washed with 1 N HCI and the aqueous layer was extracted with DCM (x3). The combined organic layers were washed twice with water, and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude solid was recrystallised in MeCN leading to the title compound (51 g) as a pale yellow solid. The filtrate could be concentrated and recrystallised in MeCN to give to another 10 g of the desired product Rf = 0.34 (DCM/MeOH : 95/5).
HRMS (M+H)+ calculated for C19H18 35CIN204 373.0955; found 373.0957.
Reference compound E: Methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-thioxo-2,3- dihydro-1 H-1 ,4-benzodiazepi -3-yl]acetate
A suspension of P4Si0 (36.1 g, 81.1 mmol) and Na2C03 (8.6 g, 81.1 mmol) in 1 ,2-DCE (700 mL) at room temperature was stirred for 2 h before Methyl [(3S)-5-(4-chlorophenyl)- 7-(methyloxy)-2-oxo-2,3-dihydro-1 H-1 ,4-benzodiazepin-3-yl]acetate (for a preparation see Reference compound D) (16.8 g, 45.1 mmol) was added. The resulting mixture was stirred at 70°C for 2 h before being cooled and filtered. The solid was washed twice with DCM and the filtrate washed with sat. NaHC03 and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by flash-chromatography on silica gel (DCM/MeOH : 99/1 ) to afford the title compound (17.2 g, 98% yield) as a yellowish solid. LC/MS (Method A): m/z 389 [M(35CI)+H]+, Rt 2.64 min
HRMS (M+H)+ calculated for C19H18 35CIN203S 389.0727; found 389.0714. Reference compound F: Methyl [(3S)-2-[2-acetylhydrazino]-5-(4-chlorophenyl)-7- (methyloxy)-3H-1 ,4-benzodiazepin-3- l]acetate
To a suspension of Methyl [(3S)-5-(4-chlorophenyl)-7-(methyloxy)-2-thioxo-2,3-dihydro- 1 H-1 ,4-benzodiazepin-3-yl]acetate (for a preparation see Reference compound E (9.0 g, 23.2 mmol) in THF (300 mL) at 0°C was added hydrazine monohydrate (3.4 mL, 69.6 mmol) dropwise. The reaction mixture was stirred for 5h between 5°C and 15°C before being cooled at 0°C. Et3N (9.7 mL, 69.6 mmol) was then added slowly and acetyl chloride (7.95 mL, 69.6 mmol) was added dropwise. The mixture was then allowed to warm to room temperature for 16h before being concentrated under reduced pressure. The crude product was dissolved in DCM and washed with water. The organic layer was dried over Na2S04, filtered and concentrated in vacuo to give the crude title compound (9.7 g, 98% yield) which was used without further purification. Rf = 0.49 (DCM/MeOH : 90/10).
Reference compound G: Methyl [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]benz
The crude Methyl [(3S)-2-[(1 Z)-2-acetylhydrazino]-5-(4-chlorophenyl)-7-(methyloxy)-3H- 1 ,4-benzodiazepin-3-yl]acetate (for a preparation see Reference compound F) (assumed 9.7 g) was suspended in THF (100 ml) and AcOH (60 mL) was added at room temperature. The reaction mixture was stirred at this temperature for 2 days before being concentrated under reduced pressure. The crude solid was triturated in /‘-Pr20 and filtered to give the title compound (8.7 g, 91 % over 3 steps) as an off-white solid.
HRMS (M+H)+ calculated for C21 H20CIN4O3 41 1.1229; found 41 1.1245.
Reference compound H: [(4S)-6-(4-Chlorophenyl)-1 -methyl-8-(methyloxy)-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]acetic acid
To a solution of Methyl [(4S)-6-(4-chlorophenyl)-1 -methyl-8-(methyloxy)-4H- [1 ,2,4]triazolo[4,3-a][1 ,4]benzodiazepin-4-yl]acetate (for a preparation see Reference compound G)(7.4 g, 18.1 mmol) in THF (130 mL) at room temperature was added 1 N NaOH (36.2 mL, 36.2 mmol). The reaction mixture was stirred at this temperature for 5h before being quenched with 1 N HCI (36.2 mL) and concentrated in vacuo. Water is then added and the aqueous layer was extracted with DCM (x3) and the combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound (7 g, 98% yield) as a pale yellow solid.
PATENT
WO2014028547
http://www.nature.com/nature/journal/v468/n7327/fig_tab/nature09589_F1.html
http://www.google.com/patents/WO2014028547A1?cl=en
Zhao, Y., et al.: J. Med. Chem., 56, 7498 (2013); Mirguet, O., et al.: J. Med. Chem., 56, 7501 (2013);
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/////GSK-525762A, GSK-525762, GSK 525762A, GSK 525762, 1260907-17-2, phase 2,
CCNC(=O)CC1C2=NN=C(N2C3=C(C=C(C=C3)OC)C(=N1)C4=CC=C(C=C4)Cl)C
Asvasiran sodium (ALN-RSV01)
RNA, (C-U-U-G-A-C-U-U-U-G-C-U-A-A-G-A-G-C-C-DT-DT), COMPLEX WITH RNA (G-G-C-U-C-U-U-A-G-C-A-A-A-G-U-C-A-A-G-DT-DT)
Duplex of guanylyl-(3′->5′)-guanylyl-(3′->5′)-cytidylyl-(3′->5′)-uridylyl-(3′->5′)-cytidylyl-(3′->5′)-uridylyl-(3′->5′)-uridylyl-(3′->5′)-adenylyl-(3′->5′)-guanylyl-(3′->5′)-cytidylyl-(3′->5′)-adenylyl-(3′->5′)-adenylyl-(3′->5′)-adenylyl-(3′->5′)-guanylyl-(3′->5′)-uridylyl-(3′->5′)-cytidylyl-(3′->5′)-adenylyl-(3′->5′)-adenylyl-(3′->5′)-guanylyl-(3′->5′)-thymidylyl-(3′->5′)-thymidine and thymidylyl-(5′->3′)-thymidylyl-(5′->3′)-cytidylyl-(5′->3′)-cytidylyl-(5′->3′)-guanylyl-(5′->3′)-adenylyl-(5′->3′)-guanylyl-(5′->3′)-adenylyl-(5′->3′)-adenylyl-(5′->3′)-uridylyl-(5′->3′)-cytidylyl-(5′->3′)-guanylyl-(5′->3′)-uridylyl-(5′->3′)-uridylyl-(5′->3′)-uridylyl-(5′->3′)-cytidylyl-(5′->3′)-adenylyl-(5′->3′)-guanylyl-(5′->3′)-uridylyl-(5′->3′)-uridylyl-(5′->3′)-cytidine
Asvasiran sodium (ALN-RSV01),
C401H500N150O290P40,
CAS 1386946-83-3, 870094-26-1
Alnylam Pharmaceuticals
- Originator Alnylam Pharmaceuticals
- Class Antivirals; Small interfering RNA
- Mechanism of Action Nucleocapsid protein modulators; RNA interference
Treatment of Human Respiratory Syncytial Virus (RSV) Infection
Nucleocapsid protein modulators, RNA interference
- 05 Nov 2014 Alnylam receives patent allowance for RNAi technology in USA
- 20 Feb 2014 Suspended – Phase-II for Respiratory syncytial virus infections in USA (Intranasal) (Alnylam Form 10-K filed in February 2014)
- 20 Feb 2014 Suspended – Phase-I for Respiratory syncytial virus infections in Europe (Intranasal) (Alnylam Form 10-K filed in February 2014)
Aerosolised ALN-RSV01 – Alnylam; ALN RSV01; Intranasal ALN-RSV01 – Alnylam
Alnylam, under license from the University of South Alabama, and with Asian licensee Kyowa Hakko Kirin (formerly Kyowa Hakko Kogyo), is developing a nasally administered formulation of asvasiran sodium (ALN-RSV01), an siRNA that targets the respiratory syncytial virus (RSV) N gene and inhibits viral replication, for the potential treatment or prevention of RSV infection.
.In June 2007, a phase II trial was initiated; in January 2008, top-line data were reported . In March 2013, development was ongoing . In August 2008, Kyowa planned to file the drug for marketing approval in 2014. In March 2013, Alnylam was planning on seeking to outlicense the program to continue to advance the program in other regions .
Alnylam is also developing second-generation agents.
Ex-Asian licensee, Cubist Pharmaceuticals, in collaboration with Alnylam, was previously developing the program for the potential treatment or prevention of RSV infection . However, in February 2013, the deal was terminated . Alnylam was also developing an inhaled formulation of asvasiran sodium; however, in February 2014, the drug was no longer listed on the company’s development pipeline.
| WO-2006074346 | |
| WO-2009076679 | |
| WO-2006062596 | |
| WO-2010048590 |
WO 2016022464
WO 2015173701
WO 2015026792
WO 2014209983
WO 2014031784
US 20130273037
Nucleic Acids Research (2012), 40(21), 10585-10595
WO 2011163518
Drugs of the Future (2009), 34(10), 781-783
Current Opinion in Infectious Diseases (2008), 21(6), 639-643
Antiviral Research (2008), 77(3), 225-231
John Maraganore, president and chief executive officer of Alnylam Pharmaceuticals,
Delivering Value with Integrated Communications led by Cynthia Clayton, Vice President, Investor Relations and Corporate Communications at Alnylam Pharmaceuticals
From the left, Alnylam COO Barry Greene, Adrian Dede, Lauren Virnoche, CEO
Dr. Rachel Meyers, Senior Vice President, Research at Alnylam Pharmaceuticals
Dr. Dinah Sah, Vice President of Research and the head of the Alnylam HD team
//////Asvasiran sodium, ALN-RSV01, PHASE 2, Alnylam
SOME OTHER CHEMISTRY
Figure 6: GalNAc–siRNA conjugates.
From Delivery materials for siRNA therapeutics
- Nature Materials12,967–977(2013)doi:10.1038/nmat3765
- 23 October 2013
Structure of the triantennary GalNAc–siRNA conjugate used in several drug candidates from Alnylam Pharmaceuticals.
http://www.nature.com/nmat/journal/v12/n11/fig_tab/nmat3765_F6.html
\
http://www.google.com/patents/EP2836595A2?cl=en
PF-05387552
PF-05387552
IRAK4
CAS 1604034-71-0
C25 H27 N5 O2
11H-Indolo[3,2-c]quinoline-9-carbonitrile, 2-methoxy-3-[3-(4-methyl-1-piperazinyl)propoxy]-
2-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]-11H-indolo[3,2-c]quinoline-9-carbonitrile
- Molecular Weight429.51
| Molecular Formula: | C25H27N5O2 |
|---|---|
| Molecular Weight: | 429.51418 g/mol |
Synthesis
PAPER
Bioorganic & Medicinal Chemistry Letters (2014), 24(9), 2066-2072
Volume 24, Issue 9, 1 May 2014, Pages 2066–2072
Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4
- L. Nathan Tumeya, , ,
- Diane H. Boschellia,
- Niala Bhagiratha,
- Jaechul Shima,
- Elizabeth A. Murphyb,
- Deborah Goodwinb,
- Eric M. Bennettc,
- Mengmeng Wangd,
- Lih-Ling Linb,
- Barry Pressa,
- Marina Shenb,
- Richard K. Frisbiea,
- Paul Morganb,
- Shashi Mohanb,
- Julia Shinb,
- Vikram R. Raob
a Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA
- b Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA
- c Pfizer Global R&D, 87 Cambridgepark Dr., Cambridge, MA 02140, USA
- d Pfizer Global R&D, 1 Burtt Rd., Andover, MA 01810, USA
http://www.sciencedirect.com/science/article/pii/S0960894X14002832?np=y
IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis.
Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPS- and R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway.
A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and c log P. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNFα in an in vivo murine model.
To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice.
L. Nathan Tumey, Ph.D., Principal Research Scientist, Pfizer Global R&D
REFERENCES
///////////TLR signaling, Indoloquinoline, IRAK4, Kinase inhibitor, Inflammation, PF-05387552, PF 05387552, 1604034-71-0
N#Cc3ccc4c5cnc2cc(OCCCN1CCN(C)CC1)c(OC)cc2c5nc4c3
ETAMICASTAT
Etamicastat HCl salt
CAS: 677773-32-9 (HCl salt)
CAS 760173-05-5 (free base).
Chemical Formula: C14H16ClF2N3OS
Molecular Weight: 347.8088
Synonym: BIA 5-453; BIA5-453; BIA-5-453; Etamicastat
IUPAC/Chemical Name: (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydro-2H-imidazole-2-thione hydrochloride
5-(2-Aminoethyl)-1-((3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl)-1,3-dihydro-2h-imidazole-2-thione
R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride,
PHASE 2, Treatment of Heart Failure Therapy, Hypertension
Bial-Portela and Ca, S.A
is a novel peripherally selective dopamine β-hydroxylase (DBH) inhibitor being developed by Bial-Portela and Ca, S.A. for treatment of hypertension and congestive heart failure.(1) The compound was shown to be well tolerated in healthy volunteers.
Etamicastat, also known as BIA 5-453, is a potent, reversible, peripherally selective dopamine β-hydroxylase inhibitor (DBH inhibitor). Chronic dopamine ß-hydroxylase inhibition with etamicastat effectively decreases blood pressure, although does not prevent the development of hypertension in the spontaneously hypertensive rat.
aReagents and conditions: a) Boc2O, EtOH, rt, 2 h; b) TBDMS-Cl, Et3N, DMAP, DCM, rt, 18 h; c) Dess–Martin periodinane, DCM, rt, 1 h; d) 2, KSCN, AcOH, EtOAc, reflux, 7 h; e) 2 N HCl, EtOAc, rt, 2 h.
Paper
Development of the Asymmetric Hydrogenation Step for Multikilogram Production of Etamicastat
Laboratory of Chemistry, Department of Research & Development, BIAL, 4745-457 S. Mamede do Coronado, Portugal
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00041
Publication Date (Web): March 21, 2016
Copyright © 2016 American Chemical Society
The asymmetric hydrogenation of methyl (6,8-difluoro-2H-chromen-3-yl)carbamate is a key step in the manufacturing route to etamicastat. A development of this step including the ruthenium or rhodium catalyst screening and the influence of the catalyst preparation (isolated, preformed in solution or in situ), solvent, temperature, pressure, additive, and concentration on the performance of the given ligand was discussed. Scale-up experiments for the best catalysts under optimized conditions were described.
PAPER
Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethione-based inhibitors of dopamine beta-hydroxylase
J Med Chem 2006, 49(3): 1191
J Med Chem 2006, 49(3): 1191
PATENT
in the processes .
(J?) -5- (2-Aminoethyl) -1- (6, 8-difluorochroman-3-yl) -1, 3-dihydroimidazole-2 -thione hydrochloride (the compound of formula 1, below) is a potent, non-toxic and peripherally selective inhibitor of ϋβΗ, which can be used for treatment of certain cardiovascular disorders. Compound 1 is disclosed in WO2004/033447 , along with processes for its preparation.
1
The process disclosed in WO2004/033447 involves the reaction of ( R) – 6 , 8 -difluorochroman-3 -ylamine hydrochloride (the structure of ( R) -6, 8-difluorochroman-3 -ylamine is shown below as compound QA) , [4 – ( tert-butyldimethylsilanyloxy) -3 -oxobutyl] carbamic acid tert-butyl ester and potassium thiocyanate .
QA
(R) -6 , 8-difluorochroman- 3 -ylamine (compound QA) is a key intermediate in the synthesis of compound 1. The stereochemistry at the carbon atom to which the amine is attached gives rise to the stereochemistry of compound 1, so it is advantageous that compound QA is present in as pure enantiomeric form as possible. In other words, the (R) -enantiomer of compound QA should be in predominance, with little or no (S) enantiomer present. Thus, the process for preparing compound QA will advantageously produce compound QA with as high enantiomeric excess (ee) as possible.
Advantageous processes for preparing, for example, the compound of formula QA have now been found. In one aspect, the processes involve a biotransformation step. In another aspect, the processes involve chemical transformation. The processes may also be employed in the preparation of similar precursors useful in the production of other peripherally-selective inhibitors of dopamine -β -hydroxylase .
WO2008/136695 discloses a compound of formula YA, its (R) or (S) enantiomer, a mixture of its (R) and (S) enantiomers, or pharmaceutically acceptable salts thereof.
YA
The (R) -enantiomer of the compound of formula YA has been found to be a potent dopamines-hydroxylase inhibitor having high potency and significantly reduced brain access.
As disclosed in WO2008/136695 , the compound of formula YA may be prepared by reacting the compound of formula 1 with benzaldehyde under reductive alkylation conditions. In particular, (R) -5- (2 -aminoethyl ) -1- (6 , 8-difluorochroman-3 -yl) – 1 , 3 -dihydroimidazole-2 -thione and benzaldehyde may be reacted in the presence of a solvent or mixture of solvents, and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride .
The compound of formula W may be prepared using a process as disclosed herein from the nitro chromene compound M.
The compound of formula WA may also be prepared using a process comprising bromination of 2 , 4 -difluorophenol to give bromophenol, alkylation of bromophenol with 4 -chloro-3 -oxo butanoate to give ketone followed by cyclization and decarboxylation to produce compound WA.
WA
According to an aspect of the present invention, there is provided the following 2 -part synthetic route from the starting material 2 , 4 -difluorophenol to (R) -5- (2 -aminoethyl ) -1- (6 , 8-difluorochroman-3 -yl) -1 , 3 -dihydroimidazole-2 – thione
hydrochloride :
Part (1)
Preferred reagents and conditions:
a) HMTA, CF3COOH, 115°C, 18 hours
b) CH2CHCN, DABCO, DMF, water, 70°C, 16 hours
c) H2S04, AcOH, 100°C, 1 hour
d) NaClO, NaOH, MeOH, 25°C, 24 hours
e) (R) -C3 -TunePhosRu (acac) 2 S/C 3000, 30 bar H2, MeOH, 80°C, 20 hours
f) Water, 2-propanol, reflux to 20°C
g) 40% KOH, MeOH, reflux, 24 hours
h) L-tartaric acid, ethanol, water, RT, 1 hour
Part (2)
Preferred reagents and conditions
a’) methyl vinyl ketone, t-BuONa, EtOAc, EtOH, 40-50°C, 2-3 hours
Br2, MeOH, 20-25°C, 5 hours
water, reflux, 1 hour
KOH, AcOH, reflux, 1 hour
HCl, water, 2-propanol, 75 °C, 4 hours
KSCN, AcOH, 100°C, 2-4 hours
NaHC03, water, EtOH
NaBH4, 2-propanol, THF, water, 20-25°C, 16 hours
HCl, 2-propanol, water, reflux, 1-2 hours
The ( R ) -5- (2-Aminoethyl) -1- (6, 8-difluorochroman-3 -yl) -1,3-dihydroimidazole-2 – thione hydrochloride
EXAMPLES
Example 1
Nitro chromene synthesis
To 3 , 5-difluoro-2-hydroxybenzaldehyde (lOg, 63mmol, leq) , di-n-butylamine (4.1g, 32mmol, 0.5eq) , phtalic anhydride (18.7g, 126mmol, 2eq) in toluene (500mL) was added nitroethanol (5.75g, 63mmol, leq) . The round bottomed flask fitted with a dean stark apparatus was refluxed for 18h. The mixture was cooled and nitroethanol (5.75g, 63mmol, leq) was added. The resulting reaction mixture was then reflux for 12h. After cooling, the solution was evaporated down to approximately 150mL and purified over silica gel (eluent ethyl acetate : hexane 1:1) this gave several fractions that contained only the product by TLC, these was evaporated under reduced pressure to yield 1.8g which was 100% pure by HPLC aera. Several more fractions were collected containing a mixture of product and starting material. These were combined and washed with 2% NaOH solution (2x50mL) to remove starting material. The organic layer was washed with water (50mL) , dried over sodium sulfate and evaporated under reduced pressure to give 2.49g of brown solid ( 100% pure by HPLC aera) . More fractions were collected. These were combined, washed with 2% NaOH solution (3xl00mL) , water (lOOmL) and dried over sodium sulfate. This was then filtered and evaporated down in vacuum to yield 6.14g of a brown solid which was 91.3% pure by HPLC aera. 6 , 8 -difluoro-3 -nitro-2H-chromene (9.90g, 73.4%) was obtained as a brown solid.
Example 2
Nitro chromene synthesis with column purification
To a solution of isobenzofuran-1 , 3 -dione (4,68 g, 31,6 mmol) , 3 , 5-difluoro-2 -hydroxybenzaldehyde (2,5 g, 15,81 mmol) in Toluene (25 ml) was added 2 -nitroethanol (2,88 g, 31,6 mmol). The resulting mixture was heated to reflux overnight (Dean stark) .
The reaction conversion was checked by TLC (eluent PE/EtOAc 9:1) . A yellow spot was observed and corresponds to the expected product .
Reaction was cooled to room temperature and a plug of silica gel was performed. A pale brown solid (3.9g) was obtained. “””H-NMR showed presence of product and starting material. The solid was dissolved in diethylether and the organic layer was washed with aqueous sodium carbonate, dried over Na2S04, filtered and concentrated under reduced pressure. A pale brown solid (1.7g,) was obtained. The 1H-NMR was indicated no starting material but still polymer from nitroethanol and residue of phtalic anhydride. A second silica plug (eluent: PE/EtOAc 95:5) was done. A pale yellow solid (1.5g) was obtained. 1H-NMR of solid showed only product and polymer. The solid was recrystallized from methanol/water . A pale yellow solid (1.05g, 31.2%) was obtained.
Example 3
Nitro chromene synthesis without column purification
To a solution of isobenzofuran- 1 , 3 -dione (18,74 g, 127 mmol) , 3 , 5-difluoro-2 -hydroxybenzaldehyde (10 g, 63,3 mmol) in Toluene (100 ml) was added 2 -nitroethanol (6,86 ml, 95 mmol) . The resulting mixture was heated to reflux for 24h (Dean stark) .
The reaction conversion was checked by HPLC and by 1H-NMR. Only 50% conversion was obtained.
The reaction mixture was cooled to room temperature and diluted with DCM (lOOmL) and 1M NaOH solution (200mL) .
The biphasic system was stirred for 30 minutes and then separated (very difficult to see phase separation) . The aqueous layer was washed with DCM (50mL) and the combined organic layers were washed twice with water (2x50ml) , dried over sodium sulfate. The filtered organic layer was concentrated under reduced pressure. To the residue was added methanol (50mL) . The methanol was then removed by distillation under reduced pressure. A brown solution precipitated when most of the methanol was removed. More methanol was added and more solid crushed out then few drops of water was added to increase the product precipitation. The brown slurry was stirred for 30 minutes and filtered. The brown solid was washed with methanol/water (1:9, 5mL) and dried in a vacuum oven at 40°C for 12h.6, 8-difluoro-3 -nitro-2H-chroraene (4,9 g, 22,99 mmol,) was obtained as brown solid in 36.3% yield.
HPLC showed a purity of 98% and 1H-NMR confirmed the structure and purity around 95%
Example 4
Reduction of nitro chromene to nitro-alkane (racemic mixture)
To a suspension of 6 , 8 -difluoro-3 -nitro-2H-chromene (213mg, 0,999 mmol) and silica (0,8 g, 0,999 mmol) in a mixture of CHC13 (10 ml) and IPA (3,4 ml) at 0°C was added portion wise sodium borohydride (95 mg, 2,498 mmol). The resulting mixture was stirred at 0°C for 45 minutes. Reaction conversion was checked by HPLC. 1 mL of acetic acid was added at 0°C and the resulting mixture was stirred for 30 minutes at room temperature. The slurry was filtered and the silica was washed with DCM. The filtrate was diluted with ethyl acetate and water and the biphasic system was separated. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure.
6 , 8-difluoro-3 -nitrochroman (196mg, 0,911 mmol, 91 % yield) was obtained as a pale yellow oil.
Example 5
Preparation of 6 , 8 -difluorochroman-3 -one from nitro chromene
A solution of 6, 8-difluoro-3 -nitro-2H-chromene (lOOmg, 0,469 mmol) in acetic acid (0.5 ml) is added slowly to a stirred slurry of iron (262 mg, 4,69 mmol) in acetic acid (1 ml) at 60.deg. C. The reaction mixture is stirred at 60. °C for 2 hour then allowed to cool to room temperature and stirred overnight. The reaction mixture is poured onto ice-water (30 ml) and filtered through Celite. The solid was wash with dichloromethane (DCM) (50 ml) . The organic portion is separated and washed with water (2 x 30 ml) and brine (30 ml) , dried over MgS04, filtered and concentrated in vacuo to give a brown oil. 6,8-difluorochroman-3 -one (75 mg, 0,407 mmol, 87 % yield) was obtained as a brown oil.
Example 6
Preparation of 6 , 8-difluorochroman-3 -one from methyl 6,8-difluoro-2H-chromen-3 -yl-carbamate
Methanol (1000m ml) was added to a slurry of methyl fluoro-2H-chromen-3 -yl -carbamate (250 g, 1.037 mol) hydrogen chloride 6N (2000 ml, 12 mol) at room temperature. The resulting mixture was reflux and stirred for 2 hours. Reaction monitored by HPLC.
Reaction was not complete but was stopped in order to avoid degradation of the product. The yellow solution was cooled to room temperature. A slurry (two type of solid) was observed and diluted with diethyl ether (300mL) . The resulting slurry was stirred at 5°C for 1 hour then filtered. The yellow solid was washed with water. The resulting wet yellow solid was suspended in diethylether (400mL) and petroleum ether (PE) (400mL) was added. Slight yellow solid was stirred at room temperature overnight, filtered and washed with PE (300mL) , dried in a vacuum oven at 30 °C for 4h. The wet sample was checked by NMR. No starting material was detected. A pale yellow solid (72.5g, solid 1) was obtained. The mother liquors were concentrated to dryness. A yellow solid was obtained, suspended in diethyl ether and PE. The slurry was then stirred for 4 hours, filtered, washed with PE . A dark yellow solid (4.5g, solid 2) was obtained. Solid 1 (2g) was diluted in DCM and washed with water (pH =6). The organic layer was then dried over Na2S04, filtered, concentrated to dryness. A crystalline pale yellow solid (1.9g, solid 3) was obtained. NMR showed the same purity for solid 3 as for solid 1. The remaining part of solid 1 was then diluted in DCM. The resulting organic layer was washed with water, dried over Na2S04, filtered and then concentrated to dryness. Slight yellow crystalline solid (68.5g, solid 4) was obtained. NMR confirmed high quality material.
Loss on Drying (LOD) : 1.03% .
Example 7
Biotransformation: Transaminases
Codexis transaminases ATA-025, ATA-251 and ATA-P2-A07 recognized 6 , 8 -difluorochroman-3 -one as the substrate and produced the corresponding 6 , 8 -difluorochroman-3 -amine .
PATENT
WO 2004033447
WO 2008094056
WO 2008143540
WO 2009064210
References
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16: Beliaev A, Learmonth DA, Soares-da-Silva P. Synthesis and biological evaluation of novel, peripherally selective chromanyl imidazolethione-based inhibitors of dopamine beta-hydroxylase. J Med Chem. 2006 Feb 9;49(3):1191-7. PubMed PMID: 16451083.
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| 4 | * | COMOY, C. ET AL.: “3-Amino-3,4-dihydro-2H-1-benzopyran Derivatives as 5-HT1A Receptor Ligandsand Potential Anxiolytic Agents. 2. Synthesis and QuantitativeStructure-Activity Relationship Studies of Spiro[pyrrolidine- andpiperidine-2,3′(2’H)-benzopyrans]“, JOURNAL OF MEDICINAL CHEMISTRY., vol. 39, no. 21, 1996, AMERICAN CHEMICAL SOCIETY. WASHINGTON; US, pages 4285 – 4298, XP002731797, ISSN: 0022-2623, DOI: 10.1021/JM950861W |
| 5 | * | SHIN, C. ET AL.: “Total Synthesis of Bistratamide G, a Metabolite of the PhilippinesAscidian Lissoclinum bistratum, from Dehydrotripeptides“, CHEMISTRY LETTERS, vol. 33, no. 6, 2004, Chemical Society of Japan, Tokyo; JP, pages 664 – 665, XP002731799, ISSN: 0366-7022, DOI: 10.1246/cl.2004.664 |
| 6 | * | VASSE, J. L. ET AL.: “New efficient conditions for the reduction with NADH models“, SYNLETT, October 1998 (1998-10-01), THIEME INTERNATIONAL, STUTTGART; DE, pages 1144 – 1146, XP002731796, ISSN: 0936-5214, DOI: 10.1055/s-1998-1876 |
| 7 | * | XIAO, G.-Q. ET AL.: “3-Nitro-2H-chromenes as a New Class of Inhibitors against Thioredoxin Reductase and Proliferation of Cancer Cells“, ARCHIV DER PHARMAZIE, no. 345, 2012, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM; DE, pages 767 – 770, XP002731794, ISSN: 0365-6233, DOI: 10.1002/ardp.201200121 |
////////Etamicastat, BIA-5-453 , PHASE 2, Treatment, Heart Failure Therapy, Hypertension, Bial-Portela and Ca, S.A
SMILES Code: FC1=CC(F)=C(OC[C@H](N2C(CCN)=CNC2=S)C3)C3=C1.[H]Cl
c1c(cc(c2c1C[C@H](CO2)n3c(c[nH]c3=S)CCN)F)F
Zamicastat
CAS 1080028-80-3 BASE
1383828-47-4 OF HCL SALT
C21 H21 F2 N3 O S BASE
2H-Imidazole-2-thione, 1-[(3R)-6,8-difluoro-3,4-dihydro-2H– 1-benzopyran-3-yl]-1,3-dihydro-5-[2-[(phenylmethyl)amino] ethyl] -(R)-5-(2-(Benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione
(R)-5-(2-(Benzylamino)ethyl)-1-(6,8-difluorochroman-3-yl)-1H-imidazole-2(3H)-thione
Molecular Weight, 401.47 BASE
- BIAL – PORTELA & CA., S.A. [PT/PT]; À Avenida da Siderurgia Nacional P-4745-457 S. Mamede do Coronado (PT)
- Zamicastat is a dopamine beta-monooxygenase inhibitor in phase I clinical studies at BIAL for the treatment of hypertension and heart failure.
- Zamicastat is a potent and selective dopamine β-mono-oxygenase inhibitor. Zamicastat Prevents the Deterioration of Cardiometabolic and Inflammatory Biomarkers in a Genetic Model of Salt-sensitive Hypertension. Chronic high salt intake deteriorates several cardiometabolic and inflammatory biomarkers in Dahl/SS rats, which can be prevented by dopamine β-hydroxylase inhibition with zamicastat.
- crystalline forms of l-[(3R)-6,8-difluoro- 3,4-dihydro-2H-l-benzopyran-3-yl]-l,3-dihydro-5-[2-[(phenylmethyl)amino]ethyl]-2H- imidazole-2-thione, i.e. the Renantiomer of
and processes for preparing the same. Background and prior art:Interest in the development of inhibitors of dopamines-hydroxylase (ϋβΗ) has centred on the hypothesis that inhibition of this enzyme may provide significant clinical improvements in patients suffering from cardiovascular disorders such as hypertension or chronic heart failure. The rationale for the use of ϋβΗ inhibitors is based on their capacity to inhibit the biosynthesis of noradrenaline, which is achieved via enzymatic hydroxylation of dopamine. Activation of neurohumoral systems, chiefly the sympathetic nervous system, is the principal clinical manifestation of congestive heart failure (Parmley, W.W., Clinical Cardiology, 18: 440-445, 1995). Congestive heart failure patients have elevated concentrations of plasma noradrenaline (Levine, T.B. et al., Am. J. Cardiol., 49: 1659-1666, 1982), increased central sympathetic outflow (Leimbach, W.N. et al., Circulation, 73: 913- 919, 1986) and augmented cardiorenal noradrenaline spillover (Hasking, G.J. et al., Circulation, 73:615-621, 1966). Prolonged and excessive exposure of the myocardium to noradrenaline may lead to down-regulation of cardiac β] -adrenoceptors, remodelling of the left ventricle, arrhythmias and necrosis, all of which can diminish the functional integrity of the heart. Congestive heart failure patients who have high plasma concentrations of noradrenaline also have the most unfavourable long-term prognosis (Cohn, J.N. et al., N. Engl. J. Med., 311 :819-823, 1984). Of greater significance is the observation that plasma noradrenaline concentrations are already elevated in asymptomatic patients with no overt heart failure and can predict ensuing mortality and morbidity (Benedict, C.R. et al., Circulation, 94:690-697, 1996). An activated sympathetic drive is not therefore merely a clinical marker of congestive heart failure, but may contribute to progressive worsening of the disease.
Potent dopamines-hydroxylase inhibitors having high potency and significantly reduced brain access are disclosed in WO 2008/136695. WO 2008/136695 describes compounds of formula I:
I where Rls R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R4 signifies -alkylaryl or – alkylheteroaryl; X signifies CH2, oxygen atom or sulphur atom; n is 2 or 3; including the individual (R)- and (S)-enantiomers or mixtures of enantiomers thereof; and including pharmaceutically acceptable salts and esters thereof, wherein the term alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means a phenyl or naphthyl group, optionally substituted by alkyl, alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine; the term heteroaryl means heteroaromatic group. In particular, WO 2008/136695 describes l-[(3R)-6,8-difluoro-3,4-dihydro-2H-l-benzopyran-3-yl]-l,3-dihydro-5-[2- [(phenylmethyl)amino]ethyl]-2H-Imidazole-2-thione.
Processes for the preparation of compounds of formula I, and in particular l-[(3R)-6,8- difluoro-3,4-dihydro-2H-l-benzopyran-3-yl]-l,3-dihydro-5-[2-[(phenylmethyl)amino] ethyl] -2H-Imidazole-2-thione, are described in WO 2008/136695 and are incorporated by reference herein. It is known that polymorphic forms of the same drug may have substantially different pharmaceutically important properties such as dissolution characteristics and bioavailability as well as stability of the drug. Furthermore, different forms may have different particle size, hardness and glass transition temperature. Thus, one form may provide significant advantages over other forms of the same drug in solid dosage form manufacture processes, such as accurate measurement of the active ingredients, easier filtration, or improved stability during granulation or storage. Furthermore, a particular process suitable for one form may also provide drug manufacturers several advantages such as economically or environmentally suitable solvents or processes, or higher purity or yield of the desired product.
PATENT
http://www.google.com/patents/WO2012087174A2?cl=en
Preparation of compound 2
[0090] Six lots of compound 2 (designated as lots 1, 2, 3, 4, 5 and 6) were prepared. The starting materials were prepared according to the following experimental protocols.
Lot 1 (Form A)
To a suspension of (R)-5-(2-aminoethyl)-l-(6,8-difluorochroman-3-yl)-lH- imidazole-2(3H)-thione (6.23 g, 20 mmol) in a mixture of Dichloromethane (DCM – 40 ml) and Methanol (40.0 ml) was added BENZALDEHYDE (2.230 ml, 22.00 mmol). To the resulting clear solution SODIUM CYANOBOROHYDRIDE (1.9 g, 28.7 mmol) was added in portions at 20-25°C to avoid intensive foaming and the solution was stirred at 20- 25°C for 40 h. The solution was quenched at 20-25°C with IN HC1 (35 ml), neutralised with 3N NaOH (35 ml), the mixture was extracted with DCM (200 ml). The organic phase was washed with brine, dried (MgS04), evaporated to dryness. The oily residue crystallised from 2-propanol (40 ml) at 20-25°C over a week-end. The crystals were collected, washed with 2-propanol, dried to give 5.2 g of the crude product. Re- crystallisation from 2-propanol-DCM hasn’t removed all impurities. Everything collected, evaporated with silica, applied on a column, eluted with Ethyl Acetate (EA)->EA-MeOH 9:1->4: 1, fractions 8-25 collected to give 3.8 g. Re-crystallised from 2-propanol (45 ml) and DCM (120 ml, removed on a rotavap) to give 2.77 g => initial lot (a) (HPLC 98.3% area) and 0.3 g of undissolved filtered off, by TLC right product. Initial lot (a) re- crystallised from 2-propanol (35 ml) and DCM (95 ml, removed on a rotavap) to give 2.51 g => initial lot (b) (HPLC 98.3% area). Combined with the above undissolved, re- crystallised from acetonitrile (200 ml, reflux to ice bath) to give 2.57 g => initial lot (c) (HPLC 98.8% area). Re-crystallised from acetonitrile (180 ml, reflux to 15°C) to give 2.25 g => Lot 1 (HPLC 99.2% area), mp 190-92°C. Lot 2 (Form A)
[0092] (R)-5-(2-(benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-lH-imidazole- 2(3H)-thione (12 g, 29.9 mmol) was dissolved with heating to reflux in Tetrahydrofuran (300 ml), the solution was cooled to 5-10°C, Water (510 ml) was added slowly (approx 10 min) with stirring. The mixture was stirred for 1 h, solid was collected, washed with water, dried to give 11.73 g of product, by HPLC 1% of (R)-5-(2-Aminoethyl)-l-(6,8- difluorochroman-3-yl)-l,3-dihydroimidazole-2-thione hydrochloride and 1% of less polar impurity. The product was dissolved in Tetrahydrofuran (300 ml) with heating to reflux, 2- Propanol (150 ml) was added, the solution was concentrated to approx 100 ml (crystallisation occured), stirred in ice for 1.5 h. Solid was collected, washed with 2- propanol, dried to give 11.2 g of product, by HPLC 0.8% of (R)-5-(2-aminoethyl)-l-(6,8- difluorochroman-3-yl)-lH-imidazole-2(3H)-thione hydrochloride and 0.5% of less polar impurity. The product was dissolved in Tetrahydrofuran (300 ml) with heating to reflux, 2- Propanol (150 ml) was added, the solution was concentrated to approx 100 ml (crystallisation occured), stirred at 20-25°C for 1 h. Solid was collected, washed with 2- propanol, dried to give (R)-5-(2-(benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-lH- imidazole-2(3H)-thione (10.22 g, 25.5 mmol, 85 % yield).,
Lot 3 (form B)
To (R)-5-(2-aminoethyl)-l-(6,8-difluorochroman-3-yl)-lH-imidazole-2(3H)- thione (2.36 g, 7.58 mmol) in a mixture of Methanol (15.00 ml) and Dichloromethane (15 ml) was added BENZALDEHYDE (0.845 ml, 8.34 mmol). To the resulting clear solution SODIUM CYANOBOROHYDRIDE (0.702 g, 10.61 mmol) was added in portions at 20- 25°C to avoid intensive foaming and the solution was stirred at 20-25°C for 40 h. The solution was quenched at 20-25°C with IN HC1 (12 ml), neutralised with 3N NaOH (12 ml), the mixture was extracted with DCM (100 ml). The organic phase was washed with brine, dried (MgS04), evaporated to dryness. The residue was purified on a column with EA-MeOH 9: 1 as eluent, fractions collected, concentrated to approx 20 ml, cooled in ice. The precipitate collected, washed with Ethyl Acetate-Petroleum Ether 1 : 1, dried on air to give (R)-5-(2-(benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-lH-imidazole-2(3H)- thione (1.55 g, 3.86 mmol, 50.9 % yield). Lot 4 (Form A)
To a 500 mL flask set up for atmospheric distillation was added (R)-5-(2- (benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-lH-imidazole-2(3H)-thione (20 g, 49,8 mmol) and Tetrahydrofuran (400 ml) to afford a suspension. The suspension was heated until full dissolution was achieved (61°C) whereupon it was filtered. The resulting solution was then heated to 66°C in order to commence the distillation. A mixture of Water (125 ml) & 2-Propanol (125 ml) was added at the same rate as the distillate was collected. The distillation was continued until 400 mL of distillate was collected. Crystallisation commenced after ~320 mL of distillate was collected. The suspension was cooled to 20°C and aged for 45 min. before filtering and washing with additional 2- propanol (80 mL) and then dried under vacuum at 50°C overnight to give (R)-5-(2- (benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-lH-imidazole-2(3H)-thione (18.79 g, 94%). Lot 5 (Form A)
To a mixture of Methanol (66 L) and Water (10 L) at 20°C was added purified (R)-5-(2-(benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-lH-imidazole-2(3H)-thione hydrochloride (4.37 kg, 9.98 mol) to afford a suspension. The reaction mixture was then heated to 67°C to affect complete dissolution, whereupon IN Sodium hydroxide (10.48 Ls 10.48 mol, 1.05 eq) was added in a single portion. The reaction mixture was adjusted back to 67°C and held at 67°C for 30 min. The reaction mixture was then cooled to 20°C and aged at 20°C for at least 30 min. The reaction was then filtered and the filter cake washed with aqueous Methanol (1 : 1 v/v, 20 L), sucked down for 15 min. and then dried at 45°C under vacuum, to afford (R)-5-(2-(benzylamino)ethyl)-l-(6,8-difluorochroman-3-yl)-lH- imidazole-2(3H)-thione (3.855 kg, 96%) as a pale tan crystalline solid.
PATENT
WO 2015038022
http://www.google.com/patents/WO2015038022A1?cl=en
processes .
(J?) -5- (2-Aminoethyl) -1- (6, 8-difluorochroman-3-yl) -1, 3-dihydroimidazole-2 -thione hydrochloride (the compound of formula 1, below) is a potent, non-toxic and peripherally selective inhibitor of ϋβΗ, which can be used for treatment of certain cardiovascular disorders. Compound 1 is disclosed in WO2004/033447 , along with processes for its preparation.
1
The process disclosed in WO2004/033447 involves the reaction of ( R) – 6 , 8 -difluorochroman-3 -ylamine hydrochloride (the structure of ( R) -6, 8-difluorochroman-3 -ylamine is shown below as compound QA) , [4 – ( tert-butyldimethylsilanyloxy) -3 -oxobutyl] carbamic acid tert-butyl ester and potassium thiocyanate .
QA
(R) -6 , 8-difluorochroman- 3 -ylamine (compound QA) is a key intermediate in the synthesis of compound 1. The stereochemistry at the carbon atom to which the amine is attached gives rise to the stereochemistry of compound 1, so it is advantageous that compound QA is present in as pure enantiomeric form as possible. In other words, the (R) -enantiomer of compound QA should be in predominance, with little or no (S) enantiomer present. Thus, the process for preparing compound QA will advantageously produce compound QA with as high enantiomeric excess (ee) as possible.
Advantageous processes for preparing, for example, the compound of formula QA have now been found. In one aspect, the processes involve a biotransformation step. In another aspect, the processes involve chemical transformation. The processes may also be employed in the preparation of similar precursors useful in the production of other peripherally-selective inhibitors of dopamine -β -hydroxylase .
WO2008/136695 discloses a compound of formula YA, its (R) or (S) enantiomer, a mixture of its (R) and (S) enantiomers, or pharmaceutically acceptable salts thereof.
YA
The (R) -enantiomer of the compound of formula YA has been found to be a potent dopamines-hydroxylase inhibitor having high potency and significantly reduced brain access.
As disclosed in WO2008/136695 , the compound of formula YA may be prepared by reacting the compound of formula 1 with benzaldehyde under reductive alkylation conditions. In particular, (R) -5- (2 -aminoethyl ) -1- (6 , 8-difluorochroman-3 -yl) – 1 , 3 -dihydroimidazole-2 -thione and benzaldehyde may be reacted in the presence of a solvent or mixture of solvents, and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride .
process comprises the following steps:
The route from 2 , 4-difluorophenol may be as described 9/064210.
Preferably, the reagents and conditions are:
(i) H2S04, acetic acid
(ii) NaOCl, MeOH/water
(iii) Ru-based catalyst, H2, 30 bars, MeOH
(iv) aqueous KOH, MeOH, L-tartaric acid
(v) KSCN, AcOH/lPA
(vi) NaBH4, BF3.THF complex, THF then IPA
n one aspect, the process comprises the following steps
i. KOH, Thioglycolic acid or cysteine
ii. MEK
According to an aspect of the present invention, there is provided the following 2 -part synthetic route from the starting material 2 , 4 -difluorophenol to (R) -5- (2 -aminoethyl ) -1- (6 , 8-difluorochroman-3 -yl) -1 , 3 -dihydroimidazole-2 – thione
hydrochloride :
Part (1)
Preferred reagents and conditions:
a) HMTA, CF3COOH, 115°C, 18 hours
b) CH2CHCN, DABCO, DMF, water, 70°C, 16 hours
c) H2S04, AcOH, 100°C, 1 hour
d) NaClO, NaOH, MeOH, 25°C, 24 hours
e) (R) -C3 -TunePhosRu (acac) 2 S/C 3000, 30 bar H2, MeOH, 80°C, 20 hours
f) Water, 2-propanol, reflux to 20°C
g) 40% KOH, MeOH, reflux, 24 hours
h) L-tartaric acid, ethanol, water, RT, 1 hour
Part (2)
Preferred reagents and conditions
a’) methyl vinyl ketone, t-BuONa, EtOAc, EtOH, 40-50°C, 2-3 hours
Br2, MeOH, 20-25°C, 5 hours
water, reflux, 1 hour
KOH, AcOH, reflux, 1 hour
HCl, water, 2-propanol, 75 °C, 4 hours
KSCN, AcOH, 100°C, 2-4 hours
NaHC03, water, EtOH
NaBH4, 2-propanol, THF, water, 20-25°C, 16 hours
HCl, 2-propanol, water, reflux, 1-2 hours
The ( R ) -5- (2-Aminoethyl) -1- (6, 8-difluorochroman-3 -yl) -1,3-dihydroimidazole-2 – thione hydrochloride may then be used to
prepare (R) -5- (2- (benzylamino) ethyl) -1- (6, 8-difluorochroman-3 -yl) -lH-imidazole-2 (3H) -thione as follows.
Preferred reaction conditions/reagents:
q) NaBH(OAc)3, PhCHO, IPA;
t) NaOH, MeOH , H20
Either r) and s) :
r) HCI aq;
s) MeOH/Toluene;
Or n) , o) and p) :
n) HCI aq;
o) MeOH, toluene;
p) IPA.
EXAMPLES
Example 1
Nitro chromene synthesis
To 3 , 5-difluoro-2-hydroxybenzaldehyde (lOg, 63mmol, leq) , di-n-butylamine (4.1g, 32mmol, 0.5eq) , phtalic anhydride (18.7g, 126mmol, 2eq) in toluene (500mL) was added nitroethanol (5.75g, 63mmol, leq) . The round bottomed flask fitted with a dean stark apparatus was refluxed for 18h. The mixture was cooled and nitroethanol (5.75g, 63mmol, leq) was added. The resulting reaction mixture was then reflux for 12h. After cooling, the solution was evaporated down to approximately 150mL and purified over silica gel (eluent ethyl acetate : hexane 1:1) this gave several fractions that contained only the product by TLC, these was evaporated under reduced pressure to yield 1.8g which was 100% pure by HPLC aera. Several more fractions were collected containing a mixture of product and starting material. These were combined and washed with 2% NaOH solution (2x50mL) to remove starting material. The organic layer was washed with water (50mL) , dried over sodium sulfate and evaporated under reduced pressure to give 2.49g of brown solid ( 100% pure by HPLC aera) . More fractions were collected. These were combined, washed with 2% NaOH solution (3xl00mL) , water (lOOmL) and dried over sodium sulfate. This was then filtered and evaporated down in vacuum to yield 6.14g of a brown solid which was 91.3% pure by HPLC aera. 6 , 8 -difluoro-3 -nitro-2H-chromene (9.90g, 73.4%) was obtained as a brown solid.
Example 2
Nitro chromene synthesis with column purification
To a solution of isobenzofuran-1 , 3 -dione (4,68 g, 31,6 mmol) , 3 , 5-difluoro-2 -hydroxybenzaldehyde (2,5 g, 15,81 mmol) in Toluene (25 ml) was added 2 -nitroethanol (2,88 g, 31,6 mmol). The resulting mixture was heated to reflux overnight (Dean stark) .
The reaction conversion was checked by TLC (eluent PE/EtOAc 9:1) . A yellow spot was observed and corresponds to the expected product .
Reaction was cooled to room temperature and a plug of silica gel was performed. A pale brown solid (3.9g) was obtained. “””H-NMR showed presence of product and starting material. The solid was dissolved in diethylether and the organic layer was washed with aqueous sodium carbonate, dried over Na2S04, filtered and concentrated under reduced pressure. A pale brown solid (1.7g,) was obtained. The 1H-NMR was indicated no starting material but still polymer from nitroethanol and residue of phtalic anhydride. A second silica plug (eluent: PE/EtOAc 95:5) was done. A pale yellow solid (1.5g) was obtained. 1H-NMR of solid showed only product and polymer. The solid was recrystallized from methanol/water . A pale yellow solid (1.05g, 31.2%) was obtained.
Example 3
Nitro chromene synthesis without column purification
To a solution of isobenzofuran- 1 , 3 -dione (18,74 g, 127 mmol) , 3 , 5-difluoro-2 -hydroxybenzaldehyde (10 g, 63,3 mmol) in Toluene (100 ml) was added 2 -nitroethanol (6,86 ml, 95 mmol) . The resulting mixture was heated to reflux for 24h (Dean stark) .
The reaction conversion was checked by HPLC and by 1H-NMR. Only 50% conversion was obtained.
The reaction mixture was cooled to room temperature and diluted with DCM (lOOmL) and 1M NaOH solution (200mL) .
The biphasic system was stirred for 30 minutes and then separated (very difficult to see phase separation) . The aqueous layer was washed with DCM (50mL) and the combined organic layers were washed twice with water (2x50ml) , dried over sodium sulfate. The filtered organic layer was concentrated under reduced pressure. To the residue was added methanol (50mL) . The methanol was then removed by distillation under reduced pressure. A brown solution precipitated when most of the methanol was removed. More methanol was added and more solid crushed out then few drops of water was added to increase the product precipitation. The brown slurry was stirred for 30 minutes and filtered. The brown solid was washed with methanol/water (1:9, 5mL) and dried in a vacuum oven at 40°C for 12h.6, 8-difluoro-3 -nitro-2H-chroraene (4,9 g, 22,99 mmol,) was obtained as brown solid in 36.3% yield.
HPLC showed a purity of 98% and 1H-NMR confirmed the structure and purity around 95%
Example 4
Reduction of nitro chromene to nitro-alkane (racemic mixture)
To a suspension of 6 , 8 -difluoro-3 -nitro-2H-chromene (213mg, 0,999 mmol) and silica (0,8 g, 0,999 mmol) in a mixture of CHC13 (10 ml) and IPA (3,4 ml) at 0°C was added portion wise sodium borohydride (95 mg, 2,498 mmol). The resulting mixture was stirred at 0°C for 45 minutes. Reaction conversion was checked by HPLC. 1 mL of acetic acid was added at 0°C and the resulting mixture was stirred for 30 minutes at room temperature. The slurry was filtered and the silica was washed with DCM. The filtrate was diluted with ethyl acetate and water and the biphasic system was separated. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure.
6 , 8-difluoro-3 -nitrochroman (196mg, 0,911 mmol, 91 % yield) was obtained as a pale yellow oil.
Example 5
Preparation of 6 , 8 -difluorochroman-3 -one from nitro chromene
A solution of 6, 8-difluoro-3 -nitro-2H-chromene (lOOmg, 0,469 mmol) in acetic acid (0.5 ml) is added slowly to a stirred slurry of iron (262 mg, 4,69 mmol) in acetic acid (1 ml) at 60.deg. C. The reaction mixture is stirred at 60. °C for 2 hour then allowed to cool to room temperature and stirred overnight. The reaction mixture is poured onto ice-water (30 ml) and filtered through Celite. The solid was wash with dichloromethane (DCM) (50 ml) . The organic portion is separated and washed with water (2 x 30 ml) and brine (30 ml) , dried over MgS04, filtered and concentrated in vacuo to give a brown oil. 6,8-difluorochroman-3 -one (75 mg, 0,407 mmol, 87 % yield) was obtained as a brown oil.
Example 6
Preparation of 6 , 8-difluorochroman-3 -one from methyl 6,8-difluoro-2H-chromen-3 -yl-carbamate
Methanol (1000m ml) was added to a slurry of methyl fluoro-2H-chromen-3 -yl -carbamate (250 g, 1.037 mol) hydrogen chloride 6N (2000 ml, 12 mol) at room temperature. The resulting mixture was reflux and stirred for 2 hours. Reaction monitored by HPLC.
Reaction was not complete but was stopped in order to avoid degradation of the product. The yellow solution was cooled to room temperature. A slurry (two type of solid) was observed and diluted with diethyl ether (300mL) . The resulting slurry was stirred at 5°C for 1 hour then filtered. The yellow solid was washed with water. The resulting wet yellow solid was suspended in diethylether (400mL) and petroleum ether (PE) (400mL) was added. Slight yellow solid was stirred at room temperature overnight, filtered and washed with PE (300mL) , dried in a vacuum oven at 30 °C for 4h. The wet sample was checked by NMR. No starting material was detected. A pale yellow solid (72.5g, solid 1) was obtained. The mother liquors were concentrated to dryness. A yellow solid was obtained, suspended in diethyl ether and PE. The slurry was then stirred for 4 hours, filtered, washed with PE . A dark yellow solid (4.5g, solid 2) was obtained. Solid 1 (2g) was diluted in DCM and washed with water (pH =6). The organic layer was then dried over Na2S04, filtered, concentrated to dryness. A crystalline pale yellow solid (1.9g, solid 3) was obtained. NMR showed the same purity for solid 3 as for solid 1. The remaining part of solid 1 was then diluted in DCM. The resulting organic layer was washed with water, dried over Na2S04, filtered and then concentrated to dryness. Slight yellow crystalline solid (68.5g, solid 4) was obtained. NMR confirmed high quality material.
Loss on Drying (LOD) : 1.03% .
Example 7
Biotransformation: Transaminases
Codexis transaminases ATA-025, ATA-251 and ATA-P2-A07 recognized 6 , 8 -difluorochroman-3 -one as the substrate and produced the corresponding 6 , 8 -difluorochroman-3 -amine .
PATENT
WO 2014077715
WO 2013002660
WO 2008136695
REFERNCES
International Journal of Pharmaceutics (Amsterdam, Netherlands) (2016), 501(1-2), 102-111.
| WO2012087174A2 | Dec 21, 2011 | Jun 28, 2012 | BIAL – PORTELA & Cª., S.A. | Crystalline forms and processes for their preparation |
| WO2012087174A3 * | Dec 21, 2011 | May 10, 2013 | BIAL – PORTELA & Cª., S.A. | Crystalline forms and processes for their preparation |
| WO2013002660A2 | Jun 29, 2012 | Jan 3, 2013 | BIAL – PORTELA & Cª, S.A. | Process |
| WO2014077715A1 * | Nov 14, 2013 | May 22, 2014 | BIAL – PORTELA & Cª, S.A. | 1,3-dihydroimidazole-2-thione derivatives for use in the treatment of pulmonary arterial hypertension and lung injury |
| US8481582 | May 6, 2008 | Jul 9, 2013 | Bial-Portela & Ca, S.A. | 1,3-dihydroimidazole-2-thione derivatives as inhibitors of dopamine-beta-hydroxylase |
| US8865913 | Jun 19, 2013 | Oct 21, 2014 | Bial-Portela & Ca, S.A. | Crystalline forms and processes for their preparation |
| WO1995007284A1 * | Aug 29, 1994 | Mar 16, 1995 | Smithkline Beecham Plc | Phosphinic acid derivatives with anti-hyper glycemic and/or anti-obesity activity |
| WO2006044293A2 * | Oct 11, 2005 | Apr 27, 2006 | Pharmacopeia Drug Discovery, Inc. | Bicyclic compounds as selective melanin concentrating hormone receptor antagonists for the treatment of obesity and related disorders |
| WO2012007548A1 * | Jul 14, 2011 | Jan 19, 2012 | Dsm Ip Assets B.V. | (r)-selective amination |
| WO2013002660A2 * | Jun 29, 2012 | Jan 3, 2013 | BIAL – PORTELA & Cª, S.A. | Process |
| GR1005093B * | Title not available |
///////Zamicastat, BIA-5-1058, dopamine beta-monooxygenase inhibitor, phase I, clinical studies, BIAL, treatment of hypertension , heart failure.
S=C4NC=C(CCNCc1ccccc1)N4[C@@H]2Cc3cc(F)cc(F)c3OC2
FDA approves new drug Venclexta (venetoclax) for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality
Venclexta (venetoclax)
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04/11/2016 12:12 PM EDT
The U.S. Food and Drug Administration today approved Venclexta (venetoclax) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with a least one prior therapy. Venclexta is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with CLL.
April 11, 2016
Release
The U.S. Food and Drug Administration today approved Venclexta (venetoclax) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. Venclexta is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with CLL.
According to the National Cancer Institute, CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed each year. CLL is characterized by the progressive accumulation of abnormal lymphocytes, a type of white blood cell. Patients with CLL who have a 17p deletion lack a portion of the chromosome that acts to suppress cancer growth. This chromosomal abnormality occurs in approximately 10 percent of patients with untreated CLL and in approximately 20 percent of patients with relapsed CLL.
“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumor cells alive,” said Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For certain patients with CLL who have not had favorable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”
The efficacy of Venclexta was tested in a single-arm clinical trial of 106 patients with CLL who have a 17p deletion and who had received at least one prior therapy. Trial participants took Venclexta orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg. Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer.
Venclexta is indicated for daily use after detection of 17p deletion is confirmed through the use of the FDA-approved companion diagnostic Vysis CLL FISH probe kit.
The most common side effects of Venclexta include low white blood cell count (neutropenia), diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count (thrombocytopenia) and fatigue. Serious complications can include pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia and metabolic abnormalities known as tumor lysis syndrome. Live attenuated vaccines should not be given to patients taking Venclexta.
The FDA granted the Venclexta application breakthrough therapy designation, priority review status, and accelerated approval for this indication. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions. Venclexta also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.
Venclexta is manufactured by AbbVie Inc. of North Chicago, Illinois, and marketed by AbbVie and Genentech USA Inc. of South San Francisco, California. The Vysis CLL FISH probe kit is manufactured by Abbott Molecular of Des Plaines, Illinois.
///FDA, approves, new drug, chronic lymphocytic leukemia, specific chromosomal abnormality, Venclexta, venetoclax, fda 2016
Curis and Aurigene’s CA 4948, AU 4948
Example 13 WO2015104688
6-(6-aminopyridin-3-yl)-N-(2-morpholin-4-yl-1,3-benzothiazol-6-yl)pyridine-2-carboxamide
| Molecular Formula: | C22H20N6O2S |
|---|---|
| Molecular Weight: | 432.4982 g/mol |
1428335-77-6
[2,3′-Bipyridine]-6-carboxamide, 6′-amino-N-[2-(4-morpholinyl)-6-benzothiazolyl]-
PROBABLE STRUCTURE
Example 1 ……..6′-amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamideWO2015104688
Compound-6: 6′-amino-N-(5-(cyclopropyIamino)-2-morpholinobenzo [d]oxazoI-6-yl)-[2,3′-bipyridine]-6-carboxamide.WO2013042137
PROBABLE CA 4948, AU 4948,AU-4948, CA-4948
STRUCTURE AND SYNTHESIS COMING……..
| Latest Stage of Development | Preclinical |
| Standard Indication | B cell lymphoma |
| Indication Details | Treat diffuse large B cell lymphoma (DLBCL) |
| Regulatory Designation | |
| Partner | Curis Inc. |
Interleukin-1 Receptor Associated Kinase-4 (IRAK-4) is a serine/threonine protein kinase belonging to tyrosine like kinase (TLK) family. IRAK-4 is one of the important signalling components downstream of IL-1/Toll family of receptors (IL-1R, IL-18R, IL-33R, Toll-like receptors). Recent studies have reported occurrence of oncogenic mutations in MYD88 in 30% of ABC diffuse large B cell lymphomas (ABC DLBCL) and 90% of Waldenstrom’s macroglobulinemia (WM). Most of ABC DLBCLs have a single amino acid substitution of proline for the leucine at position 265 (L265P) in the TIR domain of MYD88 protein resulting in constitutive activation of IRAK-4. Thus, IRAK4 is an attractive therapeutic target for the treatment of B-cell lymphomas with activating MYD88 L265P mutation. We have designed, synthesized and tested small molecule IRAK-4 inhibitors based on hits originating from Aurigene’ s compound library. These novel compounds were profiled for IRAK4 kinase inhibition, anti-proliferative activity, kinase selectivity, and drug-like properties. Furthermore, selected compounds were tested in a proliferation assay and pIRAK1 mechanistic assay using ABC-DLBCL cell lines with activating MYD88 L265P mutation, OCI-lLy10 and OCI-lLy3. We have identified a series of novel bicyclic heterocycles as potent inhibitors of IRAK-4. Aurigene Lead compound exhibited potent inhibitory activity for IRAK-4 with an IC50 of 3nM in biochemical assay. Aurigene Lead compound inhibited pIRAK1 levels, and proliferation of OCI-Ly3 and OCI-Ly10 cells with an IC501of 132nM and 52nM respectively. To the best of our knowledge, Aurigene Lead compound represents the most potent IRAK4 inhibitor reported for target modulation and anti-proliferative activity in DLBCL cell lines with activating MYD88 L265P mutation. Aurigene Lead compound has good oral pharmacokinetic profile in mice and has demonstrated excellent pharmacodynamic effect in an in vivo LPS induced TNF-α model with an ED50 of 3.8 mg/Kg in mice. Preliminary in vitro tox studies indicated clean safety profile. Demonstration of efficacy in OCI-lLy10 mouse tumor model is ongoing. In summary, a series of potent IRAK-4 inhibitors belonging to 3 different chemical series have been discovered and are being evaluated for treatment of B-cell lymphomas.
Curis with the option to exclusively license Aurigene’s orally-available small molecule inhibitor of Interleukin-1 receptor-associated kinase 4 (IRAK4) in the precision oncology field. Curis expects to exercise its option to obtain exclusive licenses to both programs and file IND applications for a development candidate from each in 2015.
Recent studies have also shown that alterations of the MYD88 gene lead to dysregulation of its downstream target IRAK4 in a number of hematologic malignancies, including Waldenström’s Macroglobulinemia and a subset of diffuse large B-cell lymphomas, making IRAK4 an attractive target for the treatment of these cancers.
Jan 21, 2015
Curis and Aurigene Announce Collaboration, License and Option Agreement to Discover, Develop and Commercialize Small Molecule Antagonists for Immuno-Oncology and Precision Oncology Targets
— Agreement Provides Curis with Option to Exclusively License Aurigene’s Antagonists for Immuno-Oncology, Including an Antagonist of PD-L1 and Selected Precision Oncology Targets, Including an IRAK4 Kinase Inhibitor —
— Investigational New Drug (IND) Application Filings for Both Initial Collaboration Programs Expected this Year —
— Curis to issue 17.1M shares of its Common Stock as Up-front Consideration —
— Management to Host Conference Call Today at 8:00 a.m. EST —
LEXINGTON, Mass. and BANGALORE, India, Jan. 21, 2015 (GLOBE NEWSWIRE) — Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, and Aurigene Discovery Technologies Limited, a specialized, discovery stage biotechnology company developing novel therapies to treat cancer and inflammatory diseases, today announced that they have entered into an exclusive collaboration agreement focused on immuno-oncology and selected precision oncology targets. The collaboration provides for inclusion of multiple programs, with Curis having the option to exclusively license compounds once a development candidate is nominated within each respective program. The partnership draws from each company’s respective areas of expertise, with Aurigene having the responsibility for conducting all discovery and preclinical activities, including IND-enabling studies and providing Phase 1 clinical trial supply, and Curis having responsibility for all clinical development, regulatory and commercialization efforts worldwide, excluding India and Russia, for each program for which it exercises an option to obtain a license.
The first two programs under the collaboration are an orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field and an orally-available small molecule inhibitor of Interleukin-1 receptor-associated kinase 4 (IRAK4) in the precision oncology field. Curis expects to exercise its option to obtain exclusive licenses to both programs and file IND applications for a development candidate from each in 2015.
“We are thrilled to partner with Aurigene in seeking to discover, develop and commercialize small molecule drug candidates generated from Aurigene’s novel technology and we believe that this collaboration represents a true transformation for Curis that positions the company for continued growth in the development and eventual commercialization of cancer drugs,” said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. “The multi-year nature of our collaboration means that the parties have the potential to generate a steady pipeline of novel drug candidates in the coming years. Addressing immune checkpoint pathways is now a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients. Recent studies have also shown that alterations of the MYD88 gene lead to dysregulation of its downstream target IRAK4 in a number of hematologic malignancies, including Waldenström’s Macroglobulinemia and a subset of diffuse large B-cell lymphomas, making IRAK4 an attractive target for the treatment of these cancers. We look forward to advancing these programs into clinical development later this year.”
Dr. Fattaey continued, “Aurigene has a long and well-established track record of generating targeted small molecule drug candidates with bio-pharmaceutical collaborators and we have significantly expanded our drug development capabilities as we advance our proprietary drug candidates in currently ongoing clinical studies. We believe that we are well-positioned to advance compounds from this collaboration into clinical development.”
CSN Murthy, Chief Executive Officer of Aurigene, said, “We are excited to enter into this exclusive collaboration with Curis under which we intend to discover and develop a number of drug candidates from our chemistry innovations in the most exciting fields of cancer therapy. This unique collaboration is an opportunity for Aurigene to participate in advancing our discoveries into clinical development and beyond, and mutually align interests as provided for in our agreement. Our scientists at Aurigene have established a novel strategy to address immune checkpoint targets using small molecule chemical approaches, and have discovered a number of candidates that modulate these checkpoint pathways, including PD-1/PD-L1. We have established a large panel of preclinical tumor models in immunocompetent mice and can show significant in vivo anti-tumor activity using our small molecule PD-L1 antagonists. We are also in the late stages of selecting a candidate that is a potent and selective inhibitor of the IRAK4 kinase, demonstrating excellent in vivo activity in preclinical tumor models.”
In connection with the transaction, Curis has issued to Aurigene approximately 17.1 million shares of its common stock, or 19.9% of its outstanding common stock immediately prior to the transaction, in partial consideration for the rights granted to Curis under the collaboration agreement. The shares issued to Aurigene are subject to a lock-up agreement until January 18, 2017, with a portion of the shares being released from the lock-up in four equal bi-annual installments between now and that date.
The agreement provides that the parties will collaborate exclusively in immuno-oncology for an initial period of approximately two years, with the option for Curis to extend the broad immuno-oncology exclusivity.
In addition Curis has agreed to make payments to Aurigene as follows:
- for the first two programs: up to $52.5 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any;
- for the third and fourth programs: up to $50 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any; and
- for any program thereafter: up to $140.5 million per program, including $87.5 million per program in approval and commercial milestones, plus specified approval milestone payments for additional indications, if any.
Curis has agreed to pay Aurigene royalties on any net sales ranging from high single digits to 10% in territories where it successfully commercializes products and will also share in amounts that it receives from sublicensees depending upon the stage of development of the respective molecule.
About IRAK4:
Interleukin-1 receptor-associated kinase 4, or IRAK4 is a signaling kinase that becomes inappropriately activated in certain cancers including activated B cell-diffuse large B cell lymphoma (ABC-DLBCL), an aggressive form of lymphoma with poor prognosis. There appears to be a mechanistic link with IRAK4 in ABC-DLBCL where these tumors from approximately 35% of patients harbor oncogenic mutations in the MYD88 gene, which encodes an adaptor protein that interacts directly with IRAK4. MYD88 mutations appear to constitutively activate the IRAK4 kinase complex, driving pro-survival pathways in ABC-DLBCL disease. Oncogenic MYD88 mutations have also been identified in other cancers, including in over 90% of patients with Waldenström’s Macroglobulinemia as well as in a subset of patients with chronic lymphocytic leukemia (CLL).
About Curis, Inc.
Curis is a biotechnology company focused on the development and commercialization of novel drug candidates for the treatment of human cancers. Curis’ pipeline of drug candidates includes CUDC-907, a dual HDAC and PI3K inhibitor, CUDC-427, a small molecule antagonist of IAP proteins, and Debio 0932, an oral HSP90 inhibitor. Curis is also engaged in a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are developing and commercializing Erivedge®, the first and only FDA-approved medicine for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at www.curis.com.
About Aurigene
Aurigene is a specialized, discovery stage biotechnology company, developing novel and best-in-class therapies to treat cancer and inflammatory diseases. Aurigene’s Programmed Death pathway program is the first of several immune checkpoint programs that are at different stages of discovery and preclinical development. Aurigene has partnered with several large- and mid-pharma companies in the United States and Europe and has delivered multiple clinical compounds through these partnerships. With over 500 scientists, Aurigene has collaborated with 6 of the top 10 pharma companies. Aurigene is an independent, wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (NYSE:RDY). For more information, please visit Aurigene’s website at http://aurigene.com/.
Small Molecule IRAK4 Kinase Inhibitor)
Innate immune responses mediated through Toll-like receptors or certain interleukin receptors are important mediators of the body’s initial defense against foreign antigens, while their dysregulation is associated with certain inflammatory conditions. Toll-like receptor and interleukin receptor signaling through the adaptor protein MYD88, results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NFκB. More recently, components of this pathway are recognized to be genetically altered and have important roles in specific human cancers. Toll-like receptor and interleukin receptor signaling through the adaptor protein MYD88, results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the transcription factor NFκB. MYD88 gene mutations are shown to occur in approximately 30% of Activated B-Cell (ABC) subtype of diffuse large B-cell lymphomas (DLBCL)1,2 and in over 90% of the B-cell malignancy Waldenstrom’s macroglobulinemia.3 Due to IRAK4’s central role in these signaling pathways, it is considered an attractive target for generation of therapeutics to treat these B-cell malignancies as well as certain inflammatory diseases.
As part of the collaboration with Aurigene, in October 2015 we exercised our option to exclusively license a program of orally-available, small molecule inhibitors of IRAK4 kinase, including the development candidate, CA-4948. Curis expects to file an IND and initiate clinical testing of CA-4948 in patients with advanced hematologic cancers during the second half of 2016.
1Nature. 2011; 470(7332):115–1192Immunology and Cell Biology. 2011; 89(6):659–6603N Engl J Med. 30, 2012; 367(9):826–833
CLIP
In November 2015, preclinical data were presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA
Aurigene Collaboration (IRAK4 Inhibitor):
In October 2015, Curis exercised its option to exclusively license a program of orally available small molecule inhibitors of IRAK4 kinase, a serine/threonine kinase involved in innate immune responses as well as in certain hematologic cancers. The Company has since designated the development candidate as CA-4948 and expects to file an IND application for this molecule during 2016.
In November 2015, Curis’ collaborator Aurigene presented preclinical data from the IRAK4 program at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA. This presentation included data from chemically distinct series of small molecule compounds with potent IRAK4 inhibitory activity in biochemical assays as well as in in vivo preclinical models, including MYD88 mutant DLBCL xenograft tumor models as well as a model of inflammatory disease.
CLIP
In April 2014, preclinical data presented at the CHI’s Ninth Drug Discovery Chemistry Conference in San Diego, CA, showed the compounds in vivo to have activity down to 10 mg/kg .
CLIP
10:50 Novel IRAK4 Inhibitors for Oncology and Inflammation
Susanta Samajdar, Ph.D., Research Director, Medicinal Chemistry, Aurigene Discovery Technologies LimitedThis presentation will discuss the discovery and optimization of hit series, some preliminary in vivo data, combination therapy strategy, present focus and further advancements.
CLIP
April 24-25 2014
Drug Discovery Chemistry – CHI’s Ninth Annual Conference: Fifth Annual Kinase inhibitor Chemistry, San Diego, CA, USA
Novel IRAK4 inhibitors
Susanta Samajdar from Aurigene Discovery Technologies presented the discovery of new IRAK4 (IL-1 receptor-associated kinase 4) inhibitors. Research began with a HTS campaign using two types of libraries: rationally designed novel scaffolds by hopping and morphing of known IRAK4 inhibitors and novel scaffolds identified by virtual screening of drug-like commercial library. A benzoxazol series was identified and crystallography was used to help their design. Lead optimization culminated in the identification of very potent compounds (AU-2807 and AU-2202) in cell assay (inflammation pathway and oncology pathway, respectively). The compounds were also active against Flt3 and KDR. Some PD in vivo data using LPS and TNFalpha release were presented in which the compound showed activity down to 10 mg/kg: no other in vivo model data were disclosed, but it was mentioned that studies in the CIA (collagen induced arthritis) model was ongoing. Dr Samajdar answered to three questions, one related to IRAK1 selectivity (the answer was that the compound is fully selective against IRAK1 and IRAK2). It was also mentioned that the compounds have a PBB higher than 98%. And the last question was related to the synergetic effect with BTK inhibitor in activated B-cell like diffuse large B-cell lymphoma, and this effect was observed with these compounds.
Research Director at Aurigene Discovery Technologies
PATENT
http://www.google.com/patents/WO2013042137A1?cl=en
Compound-6: Synthesis of 6′-amino-N-(5-(cyclopropyIamino)-2-morpholinobenzo [d]oxazoI-6-yl)-[2,3′-bipyridine]-6-carboxamide.
Step_l^N-cyclopropyl-2-morpholino-6-nitrobenzo[d]oxazol-5-amine.
N-cyclopropyl-2-moφholino-6-nitrobenzo[d]oxazol-5-amine(0.7g,70%) was prepared from 5-fluoro-2-mo holino-6-nitrobenzo[d]oxazole(lg,Intermediate-2) by treating with cyciopropanamine in sealed tube at 100°C for 8-14h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15ml) and dichioromethane (2x 15ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude. MS (ES) m/e 305(M+1, 50%).
Steg2:6-bromo-N-(5-(cyclopropylamino)-2-morpholinobenzo[d]oxazol-6-yl)
picolinamide.
Step Π and ii):The process of these steps are adopted from step 2 and step 3 of compound- 1.
Step3:6′-amino-N-(5-(cvclopropvlamino)-2-morpholinobenzord]oxazol-6-yl)-r2,3′- bipyridine]-6-carboxamide.
(i) N-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyridin
Na2C03, Pd(dppf)Cl2, ACN, H20, 80-100°C, 8-14h; TFA, 60-70°C, 8-14h.
6′-amino-N-(5-(cyclopropylamino)-2-mo holinobenzo[d]oxazol-6-yl)-[2,3′-bipyridine]-6- carboxamide (0.03g,61%) was prepared from 6-bromo-N-(5-(cyclopropyIamino)-2- moφholinobenzo[d]o azoI-6-yl)picolinamide(0.07g, step-3) by following the same process used in step-1 and 2 of compound-3.
Ή NMR (400 MHz, DMSO-< ):6 1 1.63 (s, IH), 8.90 (s, IH), 8.61 (s, IH), 8.55 (s, IH), 8.37- 8.03 (m, 2H), 7.39 (s, IH), 6.80-6.62 (s, IH), 3.80-3.59 (m, 15H), 2.88-2.64 (m, 2H). MS (ESI): 472 (M+l , 60%).
PATENT
Example 13
6′-amino-N-(2-morphol ne]-6-carboxamide
Step-1: Synthesis of 6-chloro thiazolo[4,5-c]pyridine-2(3H)-thione
Using the same reaction conditions as described in step 1 of example 1, 4,6-dichloropyridin-3-amine (1.3 g, 7 mmol) was cyclised using potassium ethyl xanthate (2.55 g, 15 mmol) in DMF (25mL) at 150°C for 8h to afford the title compound (1.3 g, 86.6 %) as a light brown solid.
1HNMR (400 MHz, DMSO-d6): δ 14.2-14.0 (b, 1H), 8.274 (s, 1H), 7.931 (s, 1H); LCMS: 100%, m/z = 201.3 (M+l)+.
Step-2: Synthesis of 4-(6-chloro thiazolo[4,5-c]pyridin-2-yl) morpholine
To a suspension of 6-chlorothiazolo[4,5-c]pyridine-2(3H)-thione (0.3 g, 1.16 mmol) in
DCM (4 mL), oxalyl chloride (0.2 mL, 2.38 mmol) and DMF (1.5 mL) were added at 0°C. The resulting mixture was slowly allowed to warm to room temperature and stirred there for 1 h. The reaction mixture was again cooled to 0°C and triethyl amine (0.66 mL, 4.76 mmol) and morpholine (0.13 mL, 1.75 mmol) were added. The reaction mixture was stirred at RT for 1 h and quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by column chromatography (EtOAc/n-hexanes 3:7) to afford the title compound (0.14 g, 39.6 %) as a light brown solid.
1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 8.04 (s, 1H), 3.74-3.72 (m, 4H), 3.61-3.59 (m, 4H); LCMS: m/z = 256.1 (M+l)+.
Step-3: Synthesis of 6′-amino-/V-(2-morpholino thiazolo [4,5-c]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide
Using the same reaction conditions as described in step 4 of example 12, 4-(6-chlorothiazolo[4,5-c] pyridin-2-yl) morpholine (0.081 g, 0.32 mmol), was coupled with tert-butyl (6-carbamoyl-[2,3′-bipyridin]-6′-yl)carbamate (intermediate 2) (0.1 g, 0.32 mmol) using cesium carbonate (0.21 g, 0.64 mmol), XantPhos (0.028g, 0.047mmol) and Pd2(dba)3 (0.015 mg, 0.015 mmol) in toluene : dioxane (2:2mL) to get the crude product. The resultant crude was purified by 60-120 silica gel column chromatography using 2% methanol in DCM as eluent. Further the resultant crude was purified by prep HPLC to afford title compound (0.01 g, 6 %) as an off-white solid.
1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.88 (d, 1H), 8.85 (dd, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.22-8.13 (m, 4 H), 7.09 (d, 1H), 3.73 (t, 4H), 3.58 (t, 4H). LCMS: 100%, m/z = 434.2 (M+l)+.
Example 11
(S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide
Step l:Preparation of (S)-tert-butyl 3-((2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine- 1 -carboxylate
A solution of 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (300mg, 1.0563 mmol) (S)-tert-butyl 3 -aminopyrrolidine- 1 -carboxylate (237mg, 1.267 mmol) and potassium carbonate (292mg, 2.112 mmol) in DMF (2mL) was heated at 100°C for 2h. Reaction was quenched with ice water and filtered the solid. The resultant crude was purified by 60-120 silica gel column chromatography using 1 % methanol in DCM as eluent to obtain the title compound (350mg, 76.25%). LCMS: m/z: 435.4 (M+l)+.
Step 2:Preparation of (S)-tert-butyl 3-((6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine- 1 -carboxylate
Using the same reaction conditions as described in step 5 of example 1, (S)-tert-butyl 3- ((2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-l -carboxylate (350mg, 0.806 mmol) was reduced with zinc dust (422mg, 6.451 mmol) and ammonium chloride (691mg, 12.903 mmol) in THF/methanol/H20 (10mL/2mL/lmL) to get the title compound (240mg, 71.8%). LCMS: m/z: 405.2 (M+l)+.
Step 3:Preparation of (S)-tert-butyl 3-((6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-l-carboxylate
Using the same reaction conditions as described in step 6 of example 1, (S)-tert-butyl 3-((6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-l -carboxylate (115mg, 0.284 mmol), was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (70mg, 0.341 mmol) using EDCI.HCl (82mg, 0.426 mmol), HOBt (58mg, 0.426 mmol), DIPEA (0.199mL, 1.138 mmol) in DMF (2mL) to afford the title compound (lOOmg, 59.52%). LCMS: m/z: 591.4 (M+l)+.
Step 4: Preparation of (S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide
Using the same reaction conditions as described in step 8 of example 1, (S)-tert-butyl 3- ((6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-l -carboxylate (lOOmg, 0.169 mmol) was deprotected using methanolic HC1 (5mL) to get the crude product. This was then purified by prep HPLC to get the title compound (9mg, 10.84%).
1HNMR (CDCI3, 400MHz): δ 9.91 (s, 1H), 8.78 (s, 1H), 8.74-8.73 (d, 1H), 8.45 (s, 1H), 7.82 (s, 1H), 7.76-7.74 (d, 1H), 4.50 (s, 1H), 4.04-4.03 (d, 4H), 3.30-3.00 (m, 7H), 2.70 (s, 3H), 2.40-1.80 (m, 4H), 1.00-0.08 (m, 1H). LCMS: 100%, m/z = 491.3 (M+l)+.
REFERENCES
http://www.curis.com/images/stories/pdfs/posters/Aurigene_IRAK4_AACR-NCI-EORTC_2015.pdf
http://www.curis.com/images/stories/pdfs/posters/Aurigene_IRAK4_AACR_20150421.pdf
1Nature. 2011; 470(7332):115–119
2Immunology and Cell Biology. 2011; 89(6):659–660
3N Engl J Med. 30, 2012; 367(9):826–833
April 2014, preclinical data presented at the CHI’s Ninth Drug Discovery Chemistry Conference in San Diego, CA
November 2015, preclinical data were presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA
http://pubs.acs.org/doi/abs/10.1021/jm5016044
http://cancerres.aacrjournals.org/content/75/15_Supplement/3646
2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3646. doi:10.1158/1538-7445.AM2015-3646
////////IRAK4 Kinase Inhibitor, Curis, Aurigene, CA 4948, AU 4948, CA-4948, AU-4948, 1428335-77-6
c21ccc(cc1sc(n2)N3CCOCC3)NC(c4nc(ccc4)c5ccc(nc5)N)=O
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Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 
Curis and Aurigene’s AUPM 170, CA 170
1,2,4-oxadiazole and 1 ,2,4-thiadiazole compounds of formula (I):
ONE EXAMPLE
EXAMPLES
PREDICTED AUPM 170, CA 170, AUPM-170, CA-170
Synthesis coming………….
WATCH THIS SPACE
Aurigene Discovery Technologies Limited INNOVATOR
Curis with the option to exclusively license Aurigene’s orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field
Addressing immune checkpoint pathways is a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients.
Through its collaboration with Aurigene, Curis is now engaged in the discovery and development of the first ever orally bioavailable, small molecule antagonists that target immune checkpoint receptor-ligand interactions, including PD-1/PD-L1 interactions. In the first half of 2016, Curis expects to file an IND application with the U.S. FDA to initiate clinical testing of CA-170, the first small molecule immune checkpoint antagonist targeting PD-L1 and VISTA. The multi-year collaboration with Aurigene is focused on generation of small molecule antagonists targeting additional checkpoint receptor-ligand interactions and Curis expects to advance additional drug candidates for clinical testing in the coming years. The next immuno-oncology program in the collaboration is currently targeting the immune checkpoints PD-L1 and TIM3.
In November 2015, preclinical data were reported. Data demonstrated tha the drug rescued and sustained activation of T cells functions in culture. CA-170 resulted in anti-tumor activity in multiple syngeneic tumor models including melanoma and colon cancer. Similar data were presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA
By August 2015, preclinical data had been reported. Preliminary data demonstrated that in in vitro studies, small molecule PD-L1 antagonists induced effective T cell proliferation and IFN-gamma production by T cells that were specifically suppressed by PD-L1 in culture. The compounds were found to have effects similar to anti-PD1 antibodies in in vivo tumor models
(Oral Small Molecule PD-L1/VISTAAntagonist)
Certain human cancers express a ligand on their cell surface referred to as Programmed-death Ligand 1, or PD-L1, which binds to its cognate receptor, Programmed-death 1, or PD-1, present on the surface of the immune system’s T cells. Cell surface interactions between tumor cells and T cells through PD-L1/PD-1 molecules result in T cell inactivation and hence the inability of the body to mount an effective immune response against the tumor. It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PD1 antibodies or anti-PD-L1 antibodies can lead to activation of T cells that result in the observed anti-tumor effects in the tumor tissues. Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the U.S. FDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.
In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint molecules that are involved in the modulation of immune responses to tumor cells1. One such regulator is V-domain Ig suppressor of T-cell activation or VISTA that shares structural homology with PD-L1 and is also a potent suppressor of T cell functions. However, the expression of VISTA is different from that of PD-L1, and appears to be limited to the hematopoietic compartment in tissues such as spleen, lymph nodes and blood as well as in myeloid hematopoietic cells within the tumor microenvironment. Recent animal studies have demonstrated that combined targeting/ blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors2.
As part of the collaboration with Aurigene, in October 2015 Curis licensed a first-in-class oral, small molecule antagonist designated as CA-170 that selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation. CA-170 was selected from the broad PD-1 pathway antagonist program that the companies have been engaged in since the collaboration was established in January 2015. Preclinical data demonstrate that CA-170 can induce effective proliferation and IFN-γ (Interferon-gamma) production (a cytokine that is produced by activated T cells and is a marker of T cell activation) by T cells that are specifically suppressed by PD-L1 or VISTA in culture. In addition, CA-170 also appears to have anti-tumor effects similar to anti-PD-1 or anti-VISTA antibodies in multiple in vivo tumor models and appears to have a good in vivo safety profile. Curis expects to file an IND and initiate clinical testing of CA-170 in patients with advanced tumors during the first half of 2016.
Jan 21, 2015
Curis and Aurigene Announce Collaboration, License and Option Agreement to Discover, Develop and Commercialize Small Molecule Antagonists for Immuno-Oncology and Precision Oncology Targets
— Agreement Provides Curis with Option to Exclusively License Aurigene’s Antagonists for Immuno-Oncology, Including an Antagonist of PD-L1 and Selected Precision Oncology Targets, Including an IRAK4 Kinase Inhibitor —
— Investigational New Drug (IND) Application Filings for Both Initial Collaboration Programs Expected this Year —
— Curis to issue 17.1M shares of its Common Stock as Up-front Consideration —
— Management to Host Conference Call Today at 8:00 a.m. EST —
LEXINGTON, Mass. and BANGALORE, India, Jan. 21, 2015 (GLOBE NEWSWIRE) — Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, and Aurigene Discovery Technologies Limited, a specialized, discovery stage biotechnology company developing novel therapies to treat cancer and inflammatory diseases, today announced that they have entered into an exclusive collaboration agreement focused on immuno-oncology and selected precision oncology targets. The collaboration provides for inclusion of multiple programs, with Curis having the option to exclusively license compounds once a development candidate is nominated within each respective program. The partnership draws from each company’s respective areas of expertise, with Aurigene having the responsibility for conducting all discovery and preclinical activities, including IND-enabling studies and providing Phase 1 clinical trial supply, and Curis having responsibility for all clinical development, regulatory and commercialization efforts worldwide, excluding India and Russia, for each program for which it exercises an option to obtain a license.
The first two programs under the collaboration are an orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field and an orally-available small molecule inhibitor of Interleukin-1 receptor-associated kinase 4 (IRAK4) in the precision oncology field. Curis expects to exercise its option to obtain exclusive licenses to both programs and file IND applications for a development candidate from each in 2015.
“We are thrilled to partner with Aurigene in seeking to discover, develop and commercialize small molecule drug candidates generated from Aurigene’s novel technology and we believe that this collaboration represents a true transformation for Curis that positions the company for continued growth in the development and eventual commercialization of cancer drugs,” said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. “The multi-year nature of our collaboration means that the parties have the potential to generate a steady pipeline of novel drug candidates in the coming years. Addressing immune checkpoint pathways is now a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients. Recent studies have also shown that alterations of the MYD88 gene lead to dysregulation of its downstream target IRAK4 in a number of hematologic malignancies, including Waldenström’s Macroglobulinemia and a subset of diffuse large B-cell lymphomas, making IRAK4 an attractive target for the treatment of these cancers. We look forward to advancing these programs into clinical development later this year.”
Dr. Fattaey continued, “Aurigene has a long and well-established track record of generating targeted small molecule drug candidates with bio-pharmaceutical collaborators and we have significantly expanded our drug development capabilities as we advance our proprietary drug candidates in currently ongoing clinical studies. We believe that we are well-positioned to advance compounds from this collaboration into clinical development.”
CSN Murthy, Chief Executive Officer of Aurigene, said, “We are excited to enter into this exclusive collaboration with Curis under which we intend to discover and develop a number of drug candidates from our chemistry innovations in the most exciting fields of cancer therapy. This unique collaboration is an opportunity for Aurigene to participate in advancing our discoveries into clinical development and beyond, and mutually align interests as provided for in our agreement. Our scientists at Aurigene have established a novel strategy to address immune checkpoint targets using small molecule chemical approaches, and have discovered a number of candidates that modulate these checkpoint pathways, including PD-1/PD-L1. We have established a large panel of preclinical tumor models in immunocompetent mice and can show significant in vivo anti-tumor activity using our small molecule PD-L1 antagonists. We are also in the late stages of selecting a candidate that is a potent and selective inhibitor of the IRAK4 kinase, demonstrating excellent in vivo activity in preclinical tumor models.”
In connection with the transaction, Curis has issued to Aurigene approximately 17.1 million shares of its common stock, or 19.9% of its outstanding common stock immediately prior to the transaction, in partial consideration for the rights granted to Curis under the collaboration agreement. The shares issued to Aurigene are subject to a lock-up agreement until January 18, 2017, with a portion of the shares being released from the lock-up in four equal bi-annual installments between now and that date.
The agreement provides that the parties will collaborate exclusively in immuno-oncology for an initial period of approximately two years, with the option for Curis to extend the broad immuno-oncology exclusivity.
In addition Curis has agreed to make payments to Aurigene as follows:
- for the first two programs: up to $52.5 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any;
- for the third and fourth programs: up to $50 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any; and
- for any program thereafter: up to $140.5 million per program, including $87.5 million per program in approval and commercial milestones, plus specified approval milestone payments for additional indications, if any.
Curis has agreed to pay Aurigene royalties on any net sales ranging from high single digits to 10% in territories where it successfully commercializes products and will also share in amounts that it receives from sublicensees depending upon the stage of development of the respective molecule.
About Immune Checkpoint Modulation and Programmed Death 1 Pathway
Modulation of immune checkpoint pathways has emerged as a highly promising therapeutic approach in a wide range of human cancers. Immune checkpoints are critical for the maintenance of self-tolerance as well as for the protection of tissues from excessive immune response generated during infections. However, cancer cells have the ability to modulate certain immune checkpoint pathways as a mechanism to evade the immune system. Certain immune checkpoint receptors or ligands are expressed by various cancer cells, targeting of which may be an effective strategy for generating anti-tumor activity. Some immune-checkpoint modulators, such as programmed death 1 (PD-1) protein, specifically regulate immune cell effector functions within tissues. One of the mechanisms by which tumor cells block anti-tumor immune responses in the tumor microenvironment is by upregulating ligands for PD-1, such as PD-L1. Hence, targeting of PD-1 and/or PD-L1 has been shown to lead to the generation of effective anti-tumor responses.
About Curis, Inc.
Curis is a biotechnology company focused on the development and commercialization of novel drug candidates for the treatment of human cancers. Curis’ pipeline of drug candidates includes CUDC-907, a dual HDAC and PI3K inhibitor, CUDC-427, a small molecule antagonist of IAP proteins, and Debio 0932, an oral HSP90 inhibitor. Curis is also engaged in a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are developing and commercializing Erivedge®, the first and only FDA-approved medicine for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at www.curis.com.
About Aurigene
Aurigene is a specialized, discovery stage biotechnology company, developing novel and best-in-class therapies to treat cancer and inflammatory diseases. Aurigene’s Programmed Death pathway program is the first of several immune checkpoint programs that are at different stages of discovery and preclinical development. Aurigene has partnered with several large- and mid-pharma companies in the United States and Europe and has delivered multiple clinical compounds through these partnerships. With over 500 scientists, Aurigene has collaborated with 6 of the top 10 pharma companies. Aurigene is an independent, wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (NYSE:RDY). For more information, please visit Aurigene’s website at http://aurigene.com/.
POSTER
WO2011161699, WO2012/168944, WO2013144704 and WO2013132317 report peptides or peptidomimetic compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.
PATENT
Example 5: Synthesis of
The compound was synthesised using similar procedure as depicted in Example 4 (compound 4) using D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH, Fmoc-D-Asn(trt)-OH in place of Fmoc-Asn(trt)-OH and H-D-Ser(‘Bu)-0’Bu was used in place of H-Thr^Bu^O’Bu to yield 0.3 g crude material of the title compound. The cmde solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.3 (M+H)+. HPLC: tR = 13.58 min.
Example 8: Synthesis of
The compound was synthesised using similar procedure as depicted in Example 2 (compound 2) using Fmoc-Glu(0’Bu)-OH instead of Fmoc-Asn(Trt)-OH to get 0.4 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 362.1 (M+H)+. HPLC: tR = 13.27 min.
PATENT
Example 3: Synthesis of compound 3
Step 3a:
3a
Lawesson’s reagent (2.85 g, 7.03 mmol) was added to a solution of compound 2e (4 g, 4.68 mmol) in THF (40 mL) and stirred at 75°C for 4 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced
pressure and the obtained residue was partitioned between ice water and ethyl acetate. The organic layer was washed with NaHCC>3 solution followed brine solution. The organic layer was dried over Na2S04, filtered and evaporated under reduced pressure to get residue which was further purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in hexane) to afford 2.7 g of compound 3a (Yield: 67.66%). LCMS: 852.3 (M+H)+,
Step 3
3a 3b
Fmoc group on compound 3a was deprotected by adding diethylamine (3.8 mL) to the solution of compound 3a (1 g, 1.17 mmol) in CH2CI2 (3.8 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting solution was concentrated in vacuum to get a thick gummy residue. The crude compound was purified by neutral alumina column chromatography (eluent: 0-50% ethyl acetate in hexane then 0-5% methanol in chloroform) to attain 0.62 g of compound 3b. LCMS: 630.5 (M+H)+.
Step 3c
To a solution of compound 3b (0.6 g) in CH2CI2 (7.5 mL), trifluoroacetic acid (2.5 mL) and catalytic amount of triisopropylsilane were added and stirred at room temperature for 3 h. The resulting solution was concentrated in vacuum to get 0.13 g of compound 3 which was purified by preparative HPLC method described under experimental conditions. LCMS: 232.3 (M+H)+.
Example 1: Synthesis of compound 1
Step la:
Potassium carbonate (7.9 g, 57.39 mmol) and Methyl iodide (1.3 mL, 21.04 mmol) were added to a solution of compound la (5.0 g, 19.13 mmol) in DMF (35 mL) and stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2S04 and evaporated under reduced pressure to get 5.0 g of compound lb (Yield: 96.1%). LCMS: 176.1 (M-Boc)+.
Step lb:
Hydrazine hydrate (7.2 mL) was added to a solution of compound lb (5.0 g, 18.16 mmol) in methanol (30 mL) and stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure, the residue obtained was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2S04 and evaporated under reduced pressure to get 4.0 g of compound lc (Yield: 80.0%). LCMS: 276.3 (M+H)+. Step lc:
NMM (0.67 ml, 6.52 mmol) was slowly added to a stirred solution of lc (1.2 g, 4.35 mmol), Id (1.43 g, 4.35 mmol), HOBt (0.7 g, 5.22 mmol) and EDC.HC1 (0.99 g, 5.22 mmol) in DMF (15 mL) at 0°C. The reaction mixture was stirred at room temperature for 12 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice and the solid precipitated was filtered and dried under vacuum to obtain 2.0 g of pure product le (Yield: 83.3%). LCMS: 591.5 (M+Na)+.
St
1 e
1f
To a stirred solution of le (1.5 g, 2.63 mmol) in dry THF (15.0 mL) and DMF (5.0 mL) triphenylphosphine (1.38 g, 5.27 mmol) and iodine (1.33 g, 5.27 mmol) were added at 0°C. After the iodine was completely dissolved, Et3N (1.52 mL, 10.54 mmol) was added to this reaction mixture at ice cold temperature. Reaction mixture was allowed to attain room temperature and stirred for 4 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice water and extracted with ethyl acetate. Organic layer was washed with saturated sodium thiosulphate and brine solution.
The separated Organic layer was dried over Na2SC>4 and evaporated under reduced pressure to get residue, which was further purified by silica gel column chromatography (eluent: 30% ethyl acetate in hexane) to afford 0.8 g of compound If (Yield: 55%). LCMS: 551.3 (M+H)+.
Step le:
1f i g
Fmoc group was deprotected by the addition of diethylamine (20.0 mL) to a solution of compound If (0.8 g, 1.45 mmol) in CH2CI2 (20.0 mL) at 0°C. The reaction was stirred at room temperature for 2 h. The resulting solution was concentrated in vacuum to get a thick gummy residue. The crude compound was purified by neutral alumina column chromatography (eluent: 2% methanol in chloroform) to afford 0.38 g of compound lg (Yield: 80.0%): LCMS: 329.4 (M+H)+.
Step If:
ig 1 i
Compound lg (0.38 g, 1.16 mmol), TEA (0.33 mL, 2.32 mmol) dissolved in DMF (10 mL) were added drop wise to a solution of lh (0.55 g, 1.39 mmol) at 0°C for urea bond formation and the mixture was stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice water, the solid precipitated was filtered and dried under vacuum to get crude compound, which was further purified by silica gel column chromatography (eluent: 0-35% ethyl acetate in hexane) to get 0.4 g of product li (Yield: 59.7%). LCMS: 586.4 (M+H)+.
Step lg:
BocHN’ IJ, H LT Y~™
1
To a solution of compound li (0.4 g, 0.68 mmol) in CH2CI2 (5 m L), trifluoro acetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred at room temperature for 3 h to remove the acid sensitive protecting groups. The resulting solution was concentrated under nitrogen and the solid material was purified by preparative HPLC method as described under experimental conditions (Yield: 0.05 g). LCMS: 318.0 (M+H)+; HPLC: tR= 10.96 min.
Synthesis of compound lh (N02-C6H4-OCO-Thr(tBu)- 0¾u):
To a solution of 4-nitrophenylchloroformate (4.79 g, 23.77 mmol) in DCM (25.0 mL) was added a solution of H-Thr(tBu)-OtBu (5.0 g, 21.61 mmol) TEA (6.2 mL, 43.22 mmol) in CH2CI2 (25 mL) slowly at 0°C and allowed to stir for 30 min. The completion of the reaction was confirmed by TLC analysis. After completion of reaction it was diluted with DCM and washed with 1.0 M of citric acid followed by 1.0 M sodium carbonate solution. The organic layer was dried over Na2S04 and evaporated under reduced pressure to afford crude compound 1 h, which was further purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in hexane) to get 3.0 g of product lh. jH NMR (CDCI3, 400 MHz): £1.17 (s, 9H), 1 .28 (d, 3H), .50 (s, 9H), 4.11 (m, 1 H), 4.28 (m, 1H , 5.89 (d, 1H), 7.37 (d, 2H), 8.26 (d, 2H).
Brahma Reddy V, Thomas Antony, Murali Ramachandra, Venkateshwar Rao G, Wesley Roy Balasubramanian, Kishore Narayanan, Samiulla DS, Aravind AB, and Shekar Chelur.
REFERENCES
US20150073024
| WO2011161699A2 | 27 Jun 2011 | 29 Dec 2011 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
| WO2012168944A1 | 21 Dec 2011 | 13 Dec 2012 | Aurigene Discovery Technologies Limited | Therapeutic compounds for immunomodulation |
| WO2013132317A1 | 4 Mar 2013 | 12 Sep 2013 | Aurigene Discovery Technologies Limited | Peptidomimetic compounds as immunomodulators |
| WO2013144704A1 | 28 Mar 2013 | 3 Oct 2013 | Aurigene Discovery Technologies Limited | Immunomodulating cyclic compounds from the bc loop of human pd1 |
http://www.curis.com/images/stories/pdfs/posters/Aurigene_PD-L1_VISTA_AACR-NCI-EORTC_2015.pdf
////////Curis and Aurigene, AUPM 170, CA 170, AUPM-170, CA-170, PD-L1, VISTA antagonist
ND 2158
(2S)-2-hydroxy-3-[(3R)-12-{[(1r,4r)-4-(morpholin-4-yl)cyclohexyl]oxy}-7-thia-9,11-diazatricyclo[6.4.0.0²,⁶]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanamide
S)-2-hydroxy-3-((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5-yl)propanamide
CAS 1388896-07-8
C22 H30 N4 O4 S
5H-Cyclopenta[4,5]thieno[2,3-d]pyrimidine-5-propanamide, 6,7-dihydro-α-hydroxy-4-[[trans-4-(4-morpholinyl)cyclohexyl]oxy]-, (αS,5R)-
- Molecular Weight446.56
ND 2158
IRAK4, 446.2
ND-2158 is a potent and selective experimental inhibitor of IRAK4 described in patent WO2013106535 [2] and in a poster presented at the American College of Rheumatology meeting in 2012 (Abstract #1062 in Supplement: Abstracts of the American College of Rheumatology & Association of Rheumatology Health Professionals, Annual Scientific Meeting, November 9-4, 2012 Washington DC, Volume 64, Issue S10, Page S1-S1216).
PATENT
http://www.google.com/patents/WO2013106535A1?cl=en
Scheme II
Example 88: (S)-l-((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7-dihydro- 5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)butan-2-ol (1-64) and Example 89: (R)-l- ((R)-4-(((lr,4R)-4-morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-
Synthesis of compound 88.1. Note: For the preparation of the starting material compound 29.2, please see Example 29. A solution of
yl)cyclohexyl]oxy]-7-thia-9,l l-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,l l-tetraen-3- yl]ethan-l-ol (190 mg, 0.47 mmol, 1.00 equiv) in 10 mL of dichloromethane was added Dess- Martin periodinane at 0 °C in a water/ice bath under nitrogen. The resulting mixture was stirred for 2 h at room temperature. After completion of the reaction, the mixture was then diluted with saturated aqueous sodium bicarbonate and extracted with 3 x 30 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :5 to 1 : 1) to afford 2-[(3Λ)-12-[[4-^ο 1ιο1ϊη-4-γ1)ογο1ο1ιβχγ1]οχγ]-7-ωΕ-9,11- diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,l l-tetraen-3-yl]acetaldehyde (130 mg, 69%) as a colorless oil. MS (ES): m/z 402 [M+H]+.
Synthesis of Compound 1-64 and Compound 1-65. A solution of [(3i?)-12-[[4- (moφholin-4-yl)cyclohexyl]oxy]-7-thia-9,l l-diazatricyclo[6.4.0.0[2,6]]dodeca-l(8),2(6),9,l l- tetraen-3-yl]acetaldehyde (130 mg, 0.32 mmol, 1.00 equiv) in 5 mL of anhydrous THF was added bromo(ethyl)magnesium (1 M in THF, 0.62 mL, 2.0 equiv) dropwise at 0 °C under nitrogen. The resulting solution was stirred for 4 h at room temperature and then quenched by the addition of saturated aqueous NH4CI and extracted with 3 x 50 mL of DCM/i-PrOH (3:1). The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (150 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5um; mobile phase: water with 0.05% NH4CO3 and CH3CN (6.0% CH3CN up to 54.0% in 25 min); UV detection at 254/220 nm to afford (S)-l-((R)-4-(((lr,4R)-4-moφholinocyclohexyl)oxy)-6,7-dihydro-5H- cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)butan-2-ol (11.8 mg) and (R)-l-((R)-4-(((lr,4R)-4- mo holinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-5-yl)butan- 2-ol (23.9 mg) as white solids.
Example 88 (1-64): MS: 432 (M+H)+. ¾ NMR (300 MHz, CDC13) S 8.47 (s, 2H), 5.24-5.20 (m, 1H), 3.75-3.58 (m, 5H), 3.06-2.93 (m, 2H), 2.70-2.61 (m, 4H), 2.28-1.98 (m, 3H), 1.59-1.41 (m, 10H), 1.28-1.23 (m, 2H),0.95-0.85 (m, 3H).
Example 89 (1-65): MS: 432 (M+H)+. ¾ NMR (300 MHz, CDC13) S 8.47 (s, 2H), 5.25 (m, 1H), 3.71-3.39 (m, 6H), 3.04-2.90 (m, 2H), 2.67-2.55 (m, 5H), 2.34-2.22 (m, 4H), 2.01- 1.81 (m, 3H), 1.64-1.39 (m, 7H), 0.94-0.92 (m, 3H).
WATCH OUT SYNTHESIS COMING…………
PATENT
WO 2014011906
https://www.google.co.in/patents/WO2014011906A2?cl=en
PATENT
WO-2014194242
https://www.google.com/patents/WO2014194242A2?cl=en
Example 49: Synthesis of Intermediate 49.1.
step 1 step 2
35.1 49.1 49.2
step 3 49 3
] Intermediate 49.3 was prepared from 35.1 in a manner analogous to the synthesis of 36.3. Isolated 150 mg of a white solid in 57% overall yield. MS (ES): m/z 402 [M+H]+.
Example 50: Synthesis of Intermediate 50.4.
49.3 50.1 50.2
50.3 50.4
Intermediate 50.4 was prepared from 49.3 in a manner analogous to the synthesis of 1-25, except that HCl/MeOH rather than TBAF/THF was used in the second step. Isolated 124 mg of a white solid in 48% overall yield. MS (ES): m/z 447 [M+H]+. 1H NMR (400 MHz, CDCls): δ 8.46 (s, 1H), 5.28-5.25 (m, 1H), 4.17-4.06 (m, 51H), 3.74-3.72 (m, 5H), 3.37-2.98 (m, 2H), 2.72-2.28 (m, 10H), 2.11-2.08 (m, 2H), 1.79-1.46 (m, 5H).
Example 51: Synthesis of (S)-2-hydroxy-3-((R)-4-(((lr,4R)-4- morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5- yl)propanamide (1-34) and Example 52: Synthesis of (R)-2-hydroxy-3-((R)-4-(((lr,4R)-4- morpholinocyclohexyl)oxy)-6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidin-5- yl)propanamide (1-44)
The racemic 50.4 (1.6 g, 96.5% purity) was separated by Chiral-HPLC with the following conditions (Gilson G x 281): column: Chiralpak AD-H, 2*25 cm Chiral-P(AD-H); mobile phase: phase A: hex (O. P/oDEA) (HPLC grade), phase B: IPA (HPLC grade), gradient: 30% B in 9 min; flow rate: 20 mL/min; UV detection at 220/254 nm. The former fractions (tR = 4.75 min) were collected and evaporated under reduced pressure and lyophilized overnight to afford 1-44 (520 mg) with 100% ee as a white solid. And the latter fractions (tR = 5.82 min) were handled as the former fractions to give the desired 1-34 (510 mg) with 99.6%> ee as a white solid. The ee values of the two isomers were determined by the chiral-HPLC with the following conditions (SHIMADZU-SPD-20A): column: Chiralpak AD-H, 0.46*25 cm, 5um (DAICEL); mobile phase: hex (0.1% TEA): IPA = 85:15; UV detection at 254 nm. Flow rate: 1.0 mL/min. tR (1-44) = 7.939 min and tR (1-34) = 11.918 min.
[00431] Analytical data for 1-44: MS: (ES, m/z) 447 [M+H]+. 1H NMR (400 MHz, CD3OD+CDCI3): δ 8.47 (s, 1H), 5.32-5.22 (m, 1H), 4.08 (dd, 1H), 4.89-4.62 (m, 5H), 3.20-3.10 (m, 1H), 3.05-2.95 (m, 1H), 2.75-2.55 (m, 5H), 2.44-2.38 (m, 2H), 2.34-2.28 (m, 3H), 2.10 (d, 2H), 1.82-1.62 (m, 3H), 1.58-1.40 (m, 2H).
Analytical data for 1-34: MS: (ES, m/z) 447 [M+H]+. 1H NMR (400 MHz, CDC13): δ 8.46 (s, 1H), 5.32-5.22 (m, 1H), 4.15 (t, 1H), 3.73 (t, 4H), 3.59 (td, 1H), 3.19-3.08 (m, 1H), 3.02- 2.92 (m, 1H), 2.78-2.70 (m, 1H), 2.69-2.60 (m, 4H), 2.58-2.20 (m, 5H), 2.10 (d, 2H), 1.75-1.63 (m, 3H), 1.53-1.40 (m, 2H).
Paper
http://pubs.acs.org/doi/abs/10.1021/jm5016044
Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders
Miniperspective
†Nimbus Discovery, 25 First Street, Suite 404, Cambridge, Massachusetts 02141, United States
‡Schrödinger Inc., 120 West Forty-Fifth Street, New York, New York 10036, United States
J. Med. Chem., 2015, 58 (1), pp 96–110
DOI: 10.1021/jm5016044
IRAK4, a serine/threonine kinase, plays a key role in both inflammation and oncology diseases. Herein, we summarize the compelling biology surrounding the IRAK4 signaling node in disease, review key structural features of IRAK4 including selectivity challenges, and describe efforts to discover clinically viable IRAK4 inhibitors. Finally, a view of knowledge gained and remaining challenges is provided.
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78 Romero, D. L.; Robinson, S.; Wessel, M. D.; Greenwood, J. R. IRAK Inhibitors and Uses Thereof. WO201401902, January 16, 2014.
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Harriman, G. C.; Romero, D. L.; Masse, C. E.; Robinson, S.; Wessel, M. D.; Greenwood, J. R. IRAK Inhibitors and Uses Thereof. WO2014011911A2, January 16, 2014.
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Harriman, G. C.; Wester, R. T.; Romero, D. L.; Masse, C. E.; Robinson, R.; Greenwood, J. R. IRAK Inhibitors and Uses Thereof. WO2014011906A2, January 16, 2014
| Patent ID | Date | Patent Title |
|---|---|---|
| US2013231328 | 2013-09-05 | IRAK INHIBITORS AND USES THEREOF |
PATENT
WO 2014194242
WO 2013106535
WO 2012097013
| US20070155777 * | Feb 21, 2007 | Jul 5, 2007 | Amgen, Inc. | Antiinflammation agents |
| US20100041676 * | Feb 18, 2010 | Hirst Gavin C | Kinase inhibitors | |
| US20100143341 * | Jun 21, 2006 | Jun 10, 2010 | Develogen Aktiengesellschaft | Thienopyrimidines for pharmaceutical compositions |
| US20120015962 * | Jan 19, 2012 | Nidhi Arora | PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS | |
| US20120283238 * | Nov 8, 2012 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
| References |
| 1. Chaudhary D, Robinson S, Romero DL. (2015) Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders. J. Med. Chem., 58 (1): 96-110. [PMID:25479567] |
| 2. Harriman GC, Wester RT, Romero DL, Robinson S, Shelley M, Wessel MD, Greenwood JR, Masse CE, Kapeller-Libermann R. (2013) Irak inhibitors and uses thereof. Patent number: WO2013106535. Assignee: Nimbus Iris, Inc.. Priority date: 18/07/2013. Publication date: 10/01/2012. |
http://nimbustx.com/sites/default/files/uploads/posters/irak4_nimbus_acr_poster_2012_small.pdf
///////ND 2158, IRAK4, ND-2158, NIMBUS, 1388896-07-8
NC(=O)C(CC1CCc2c1c1c(ncnc1s2)OC1CCC(CC1)N1CCOCC1)O
C1CC(CCC1N2CCOCC2)OC3=C4C5=C(CCC5CC(C(=O)N)O)SC4=NC=N3
DR ANTHONY MELVIN CRASTO
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