MALONITRILE DERIVATIVES
20230242520 · 2023-08-03
Assignee
Inventors
- Guillaume DÉCORET (Eschentzwiller, FR)
- Guido GALLEY (Rheinfelden, DE)
- Katrin GROEBKE ZBINDEN (Liestal, CH)
- Wolfgang GUBA (Müllheim, DE)
- Daniel HUNZIKER (Möhlin, CH)
Cpc classification
C07D217/22
CHEMISTRY; METALLURGY
A61K31/519
HUMAN NECESSITIES
A61P31/00
HUMAN NECESSITIES
C07D233/64
CHEMISTRY; METALLURGY
A61K31/501
HUMAN NECESSITIES
C07D263/32
CHEMISTRY; METALLURGY
A61K31/422
HUMAN NECESSITIES
A61K31/4439
HUMAN NECESSITIES
C07D261/08
CHEMISTRY; METALLURGY
A61K31/517
HUMAN NECESSITIES
C07D417/12
CHEMISTRY; METALLURGY
C07D401/12
CHEMISTRY; METALLURGY
C07D249/04
CHEMISTRY; METALLURGY
International classification
C07D413/12
CHEMISTRY; METALLURGY
C07D233/64
CHEMISTRY; METALLURGY
C07D261/08
CHEMISTRY; METALLURGY
C07D249/04
CHEMISTRY; METALLURGY
C07D263/32
CHEMISTRY; METALLURGY
Abstract
The invention relates to a compound of formula (I) wherein R.sup.1-R.sup.2 are as defined in the description and in the claims The compound of formula (I) can be used as a medicament.
##STR00001##
Claims
1. A compound of formula (I) ##STR00032## wherein R.sup.1 is alkylisoxazolyl, alkyltriazolyl, alkylimidazolyl, alkylisothiazolyl or oxazolyl; and R.sup.2 is alkyl-dioxido-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidinyl, alkoxy-5,6,7,8-tetrahydroquinazolinyl, phenyl-5,6,7,8-tetrahydroquinazolinyl, (alkoxyphenyl)-1-oxo-1,2-dihydroisoquinolinyl, dialkylphenylaminocarbonylpyridyl, alkoxypyrazinyl, pyridyl, naphtalenyl, alkoxypyridyl, alkoxypyridazinyl, oxo-pyridyl, (N-alkyl)oxo-pyridyl, oxo-indanyl, haloalkylphenyl, alkoxycarbonylphenyl, (alkoxycarbonyl)alkylthiophenyl or (alkoxycarbonyl)thiophenyl; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
2. A compound according to claim 1, wherein R.sup.1 is alkylisoxazolyl.
3. A compound according to claim 1 or 2, wherein R.sup.1 is methylisoxazolyl.
4. A compound according to any one of claims 1 to 3, wherein R.sup.2 is methyl-dioxido-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidinyl, methoxy-5,6,7,8-tetrahydroquinazolinyl, phenyl-5,6,7,8-tetrahydroquinazolinyl, (methoxyphenyl)-1-oxo-1,2-dihydroisoquinolinyl, dimethylphenylaminocarbonylpyridyl, methoxypyrazinyl, pyridyl, naphtalenyl, methoxypyridyl, methoxypyridazinyl, oxo-pyridyl, (N-methyl)oxo-pyridyl, oxo-indanyl, trifluoromethylphenyl, methyloxycarbonylphenyl, (ethoxycarbonyl)methylthiophenyl or (methoxycarbonyl)thiophenyl.
5. A compound according to any one of claims 1 to 4, wherein R.sup.2 is oxo-pyridyl, (N-methyl)oxo-pyridyl or oxoindanyl.
6. A compound according to any one of claims 1 to 5 selected from (Z)-2-cyano-3-hydroxy-N-(4-methyl-6,6-dioxido-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-yl)-3-(5-methylisoxazol-4-yl)acrylamide; (Z)-2-cyano-3-hydroxy-N-(4-methoxy-5,6,7,8 -tetrahydroquinazolin-2-yl)-3-(5-methylisoxazol-4-yl)acrylamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(4-phenyl-5,6,7,8-tetrahydroquinazolin-2-yl)acrylamide; (Z)-2-cyano-3-hydroxy-N-(3-(3-methoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-3-(5-methylisoxazol-4-yl)acrylamide; (Z)-5-(2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)acrylamido)-N-(2,6-dimethylphenyl)picolinamide; (Z)-2-cyano-3-hydroxy-N-(5-methoxypyrazin-2-yl)-3-(5-methylisoxazol-4-yl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(4-pyridyl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(naphthalen-2-yl)acrylamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(naphthalen-1-yl)acrylamide; (Z)-2-cyano-3-hydroxy-N-(6-methoxy-3-pyridyl)-3-(5-methylisoxazol-4-yl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-N-(6-methoxypyridazin-3-yl)-3-(5-methylisoxazol-4-yl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(2-oxo-1H-pyridin-4-yl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol -4-yl)-N-(1-methyl-2-oxo-4-pyridyl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(1-methyl-1H-1,2,3-triazol-5-yl)-N-(4-(trifluoromethyl)phenyl)acrylamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(1-oxoindan-5-yl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-N-(4-(trifluoromethyl)phenyl)acrylamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(3-pyridyl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisothiazol-4-yl)-N-(4-(trifluoromethyl)phenyl)acrylamide; (Z)-2-cyano-3-hydroxy-3-(4-methylisoxazol-5-yl)-N-(4-(trifluoromethyl)phenyl)acrylamide; (Z)-2-cyano-3-hydroxy-3-(oxazol-5 -yl)-N-(4-(trifluoromethyl)phenyl)acrylamide; methyl (Z)-4-(2-cyano-3-hydroxy-3-(3-methylisoxazol-4-yl)acrylamido)benzoate; (Z)-2-cyano-3-hydroxy-3-(3-methylisoxazol-4-yl)-N-(4-(trifluoromethyl)phenyl)acrylamide; ethyl (Z)-2-(2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)acrylamido)-4-methylthiophene-3-carboxylate; and methyl (Z)-3-(2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)acrylamido)thiophene-2-carboxylate; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
7. A compound according to any one of claims 1 to 6 selected from (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(2-oxo-1H-pyridin-4-yl)prop-2-enamide; (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(1-methyl-2-oxo-4-pyridyl)prop-2-enamide; and (Z)-2-cyano-3-hydroxy-3-(5-methylisoxazol-4-yl)-N-(1-oxoindan-5-yl)prop-2-enamide; or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
8. A process for the preparation of a compound according to any one of claims 1 to 7, comprising the coupling of a compound of formula (A1) ##STR00033## with a compound of formula (A2) ##STR00034## in the presence of a base; wherein R.sup.1 and R.sup.2 are as defined in any one of claims 1 to 7 and X is a leaving group, such as a halogen, mesylate or tosylate.
9. A compound according to any one of claims 1 to 7, when manufactured according to a process of claim 8.
10. A compound according to any one of claims 1 to 7, for use as therapeutically active substance.
11. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 7 and a therapeutically inert carrier.
12. The use of a compound according to any one of claims 1 to 7 for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).
13. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).
14. A compound according to any one of claims 1 to 7 for use in the treatment or prophylaxis of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS).
15. A method for the treatment of systemic lupus erythrematosus (SLE), cutaneous skin diseases like dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutieres syndrome (AGS), which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 7 to a patient in need thereof.
16. The invention as hereinbefore described. ***
Description
EXAMPLES
Abbreviations
[0097] ATP=adenosine triphosphate; BSA=bovine serum albumine; DCC=dicyclohexylurea;
DIPEA=diisopropylamine; DMF=dimethylformamide; DMSO=dimethyl sulfoxide;
DNA=deoxyribonucleic acid; EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;
ESI=electrospray ionization; EtOAc=ethyl acetate; GTP=guanosine triphosphate;
HATU=hexafluorophosphate azabenzotriazole tetramethyl uronium; MeOH=methanol;
MS=mass spectrometry; RT=room temperature; SD=standard deviation; THF=tetrahydrofuran; TRIS=tris(hydroxymethyl)aminomethane.
Example 1
(Z)-2-Cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-N-(4-(trifluoromethyl)phenyl)acrylamide
[0098] ##STR00008##
Step 1: 1-Methyl-1H-imidazole-5-carbonyl chloride
[0099] To a stirred suspension of 1-methyl-1H-imidazole-5-carboxylic acid (500 mg, 3.96 mmol) at room temperature (RT) in THF (8 mL) under an argon atmosphere were added 2 drops of DMF followed by oxalyl chloride (554 mg, 369 μl, 4.36 mmol). The mixture immediately turned dark. Stirring at RT was continued for 3 h 30. The reaction mixture was concentrated to dryness to leave the crude product as a brown solid (568 mg).
Step 2: 2-Cyano-N-(4-(trifluoromethyl)phenyl)acetamide
[0100] To a stirred solution of 2-cyanoacetic acid (4.17 g, 49 mmol) at RT in ethyl acetate (85 mL) under an argon atmosphere was added 4-(trifluoromethyl)aniline (5 g, 3.9 mL, 31 mmol) in one portion. To the resulting clear, light yellow solution was added dropwise a solution of DCC (7.05 g, 34.2 mmol) in ethylacetate (45 mL) for 20 min. When the addition was complete (a white solid soon precipitated out: urea from DCC), stirring at RT was continued overnight. The insoluble urea was filtered off and the cake (white powder) was washed with EtOAc. The filtrate was washed with saturated aq. NaHCO.sub.3, then with 1 N HCl, and then with brine. The organic phase was dried (MgSO.sub.4), filtered and concentrated to leave the crude product as a light yellow solid. The crude product was taken up in isopropanol (85 mL) and the suspension was heated to 80° C. (oil bath temperature) under stirring until a clear light yellow solution was obtained. The mixture was allowed to cool to RT, a solid precipitated out. The suspension was stirred at RT for another 1 h. The product was collected by filtration, washed with 2-propanol and dried to provide the title compound as a white solid. The filtrate still contains some product. It was concentrated to leave a light yellow sticky solid. This was triturated in 10 mL of MeOH. The suspension was stirred at RT for 1 h. The solid was collected by filtration, washed with MeOH and dried. Another 1.03 g of the title compound was isolated as a white solid. Total yield: 5.58 g, 77%. MS: 227.1 [M-H]-ESI neg.
Step 3: (Z)-2-Cyano-3-hydroxy-3-(1-methyl-1H-imidazol-5-yl)-N-(4-(trifluoromethyl)-phenyl)acrylamide
[0101] To a stirred solution of 2-cyano-N-(4-(trifluoromethyl)phenyl)acetamide (200 mg, 877 μmol) at RT in THF (5 mL) under an argon atmosphere was added sodium hydride 60% dispersion in mineral oil (80.6 mg, 2.02 mmol). After stirring for 10 mins, a solution of 1-methyl-1H-imidazole-5-carbonyl chloride (158 mg, 877 μmol) in CH.sub.2Cl.sub.2 (0.5 ml) was added in one portion. Stirring at RT was continued for 17 hrs. The mixture was carefully treated with 0.5 M HCl (3 mL), diluted with CH.sub.2Cl.sub.2. A precipitate formed. The solid was collected by filtration and washed with CH.sub.2Cl.sub.2. This brown solid was then triturated in ˜5 mL of MeOH. The suspension was stirred at RT for 17 hrs. The product was collected by filtration, washed with MeOH and dried to provide the title compound (159 mg, 51%) as light brown solid. MS: 337.1 [M+H]+ ESI pos.
[0102] In analogy to the procedures described in example 1, examples 2-24 (Table 1) where prepared using a suitable acid in the first step and a suitable amine in the second step.
TABLE-US-00001 TABLE 1 Ex. Systematic name Structure MS 2 (Z)-2-cyano-3-hydroxy-3- (5-methylisoxazol-4-yl)- N-(3-pyridyl)prop-2-
Example 25
cGAS Activity Assay—Malachite Green
[0103] Compounds were tested for cGAS inhibition in a coupled enzymatic assay based on Phosphate detection by Malachite Green. Final assay conditions were 20 mM TRIS pH 7.5 (Applichem), 5 mM MgCl.sub.2 (Sigma) and 0.01% BSA (Sigma) supplemented with 80 μM ATP (Sigma), 80 μM GTP (Sigma) and 100 nM Interferon Stimulating DNA (ISD) (Microsynth). Recombinantly expressed purified human cGAS (residues 161-522) was used at 25 nM.
[0104] All compounds were prepared as 10 mM stock solutions in DMSO and a 16 pt dilution series in DMSO with a dilution factor of 2.5 was prepared. 1 μL of DMSO dilution series was transferred to 32.3 μL reaction buffer, mixed by pipetting up/down, spun for 1 minute at 3000 rpm and was visually inspected for precipitation. 5 μL of 3-fold enzyme stock solution were transferred to an empty 384-well Black/Clear Flat Bottom Polystyrene NBS (Corning) rows 3-24. Rows 1-2 were filled with assay buffer. Plates were spun 10 seconds at 1000 rpm (164×g). 5 μL of compound intermediate dilution was added and mixed by pipetting up/down to rows 3-24. Rows 1-2 were filled with 3.1% DMSO assay buffer. Plates were spun 10 seconds at 1000 rpm (164×g). 5 μL 3-fold Nucleotide/DNA mix was added to all wells to start the reaction. Plates were spun 10 seconds at 1000 rpm (164×g) and incubated for 4 hour at room temperature (RT) in the dark. 5 μL 4 U/mL PPase (Sigma) were added to all wells. Plates spun 10 seconds at 1000 rpm (164×g). 10 μL BioMol green Solution (Enzo Life Sciences) was added to all wells. Plates spun 10 seconds at 1000 rpm (164×g) and incubated 30 minutes at RT in the dark. Absorbance data was collected 620 nm on an EnVision Multilable Reader (Perkin Elmer) and the following measurement settings were used: excitation filter photometric was 620 nm; excitation from the top; measurement height was 1 mm; number of flashes was 30; number of flashes integrated was 1.
[0105] All plates are checked for abnormalities and outliers in the Blank Control (no protein, row 1) and the Neutral Control (no compound, row 2) are excluded using the 3*SD rule. Data was normalized to 0 and 100% by Blank and Neutral Control and each curve was fitted and judged using the 4 parameter logistic equation to determine the IC50 for cGAS inhibition.
[0106] The results of this assay are provided in Table 2. Table 2 provides IC50 values (μM ) for cGAS inhibition obtained for particular examples of the present invention as measured by the above-described assay.
TABLE-US-00002 TABLE 2 Example IC50 cGAS (μM) 1 1.85 2 1.57 3 0.22 4 6.31 5 0.17 6 0.18 7 1.02 8 1.34 9 1.27 10 0.82 11 3.99 12 1.13 13 7.19 14 8.48 15 4.76 16 1.79 17 1.11 18 0.62 19 0.84 20 0.50 21 1.06 22 0.97 23 5.21 24 0.45
Example A
[0107] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
TABLE-US-00003 Ingredients Per tablet Kernel: Compound of formula (1) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg
[0108] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution/suspension of the above mentioned film coat.
Example B
[0109] Capsules containing the following ingredients can be manufactured in a conventional manner:
TABLE-US-00004 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
[0110] Injection solutions can have the following composition:
TABLE-US-00005 Compound of formula (1) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml
[0111] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.