Sulfamoylamide Derivatives

Abstract

The invention relates to a compound of formula (I) wherein R1-R3 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) ##STR00013## wherein one of R.sup.1 and R.sup.2 is hydrogen and the other one is hydrogen, alkyl, morpholinylalkyl, pyridinylalkyl or phenylalkyl; and R.sup.3 is halogen; or a pharmaceutically acceptable salt or thereof.

2. A compound according to claim 1, wherein one of R.sup.1 and R.sup.2 is hydrogen and the other one is hydrogen or morpholinylalkyl.

3. A compound according to claim 1 or 2, wherein one of R.sup.1 and R.sup.2 is hydrogen and the other one is hydrogen or morpholinylethyl.

4. A compound according to any one of claims 1 to 3, wherein R.sup.3 is chlorine.

5. A compound according to any one of claims 1 to 4 selected from 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; 6-(2-chloro-4-methylphenyl)-1-(2-morpholinoethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; 6-(2-chloro-4-methylphenyl)-1-(pyridin-4-ylmethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; 6-(2-chloro-4-methylphenyl)-1-phenethyl-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; 6-(2-chloro-4-methylphenyl)-3-(2-morpholinoethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; 1-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 6 selected from 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; 6-(2-chloro-4-methylphenyl)-1-(2-morpholinoethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide; or a pharmaceutically acceptable salt thereof.

7. A process for the preparation of a compound according to any one of claims 1 to 6, comprising one of the following steps: (a) the reaction of a compound of formula (A) ##STR00014## with H.sub.2NSO.sub.2Cl in a solvent and in the presence of an aqueous base; or (b) the reaction of a compound of formula (B) ##STR00015## with R—X, optionally with a base, wherein R is R.sup.1 or R.sup.2 are as defined in any one of claims 1-6 and X is a leaving group.

8. A compound according to any one of claims 1 to 6, when manufactured according to a process of claim 7.

9. A compound according to any one of claims 1 to 6, for use as therapeutically active sub stance.

10. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 6 and a therapeutically inert carrier.

11. The use of a compound according to any one of claims 1 to 6 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).

12. The use of a compound according to any one of claims 1 to 6 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).

13. A compound according to any one of claims 1 to 6 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).

14. 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 6 to a patient in need thereof.

15. The invention as hereinbefore described.

Description

EXAMPLES

Abbreviations

[0072] DMF=dimethylformamide; DMSO=dimethyl sulfoxide; ESI=electrospray ionization; EtOAc=ethyl acetate; HPLC=high performance liquid chromatography; MS=mass spectrometry; RT=room temperature.

Example 1

6-(2-Chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide

[0073] ##STR00007##

a) 4-Amino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate

[0074] Methyl 2-amino-5-bromobenzoate (5 g, 21.7 mmol, Eq: 1), (2-chloro-4-methylphenyl)boronic acid (3.7 g, 21.7 mmol, Eq: 1) and potassium phosphate (9.23 g, 43.5 mmol, Eq: 2) were combined with dioxane (80 ml) and water (20 ml). The vial was degassed with argon before X-phos (518 mg, 1.09 mmol, Eq: 0.05) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (562 mg, 543 μmol, Eq: 0.025) were added. The vial was closed and the reaction mixture was heated to 110° C. and stirred for 2 h. The reaction mixture was poured into 50 ml of water and extracted with EtOAc (3×50 ml). The organic layers were combined, dried over Na.sub.2SO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 40% EtOAc in heptane). The fractions were combined, concentrated and dried in vacuo to afford the title compound methyl 4-amino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (5.08 g, 15.7 mmol, 72.3% yield) as brown solid. MS (ESI): 276.17 [M+H]+.

b) 6-(2-Chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide

[0075] To a solution of methyl 4-amino-2′-chloro-4′-methyl-[1,1′-biphenyl]-3-carboxylate (450 mg, 1.63 mmol, Eq: 1) in THF (12 ml) under argon was added sulfamoyl chloride (283 mg, 2.45 mmol, Eq: 1.5) at 10° C. The mixture was stirred for 5 h at room temp. At 0° C. aqueous NaOH solution (4.08 ml, 2M, 8.16 mmol, Eq: 5) was added. The reaction was diluted with 10 ml of water and extracted with EtOAc (3×20 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The reaction was diluted in diethylether, filtered through sartorius to obtain the title compound 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (403.5 mg, 1.23 mmol, 75.2% yield), MS (ESI): 323.08 [M+H]+.

Example 2

6-(2-Chloro-4-methylphenyl)-1-(2-morpholinoethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide

[0076] ##STR00008##

[0077] In a 10 ml round-bottomed flask, 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (40 mg, 124 μmol, Eq: 1) was combined with aqueous NaHCO.sub.3 (2.5 ml). 4-(2-bromoethyl)morpholine (36.1 mg, 186 μmol, Eq: 1.5) was added and the reaction was stirred for 4 days at reflux. Every day another amount of 4-(2-bromoethyl)morpholine (36.1 mg, 186 μmol, Eq: 1.5) was added. The reaction mixture was diluted with 15 ml NaHCO.sub.3 and extracted with EtOAc (3×20 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. The crude material was purified by preparative HPLC to obtain 6-(2-chloro-4-methylphenyl)-1-(2-morpholinoethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (4.3 mg, 7.95 μmol, 6.4% yield). MS (ESI): 436.3 [M+H]+.

Example 3

6-(2-Chloro-4-methylphenyl)-1-(pyridin-4-ylmethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide

[0078] ##STR00009##

[0079] In a 10 ml round-bottomed flask, 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (40 mg, 124 μmol, Eq: 1) was combined with aqueous NaHCO.sub.3 (2.5 ml). 4-(chloromethyl)pyridine hydrochloride (30.5 mg, 186 Eq: 1.5) was added and the reaction was stirred for 2 h at reflux. The reaction mixture was diluted with 15 ml NaHCO.sub.3 solution and extracted with EtOAc (3×20 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo to afford the title compound 6-(2-chloro-4-methylphenyl)-1-(pyridin-4-ylmethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (13.6 mg, 30.9 μmol, 24.9% yield) as a white solid. MS (ESI): 412.0509 [M−H]−.

Example 4

6-(2-Chloro-4-methylphenyl)-1-phenethyl-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide

[0080] ##STR00010##

[0081] In a 10 ml round-bottomed flask, 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (40 mg, 124 μmol, Eq: 1) was combined with aqueous NaHCO.sub.3 solution (2.5 ml). (2-Bromoethyl)benzene (34.4 mg, 25.4 μl, 186 Eq: 1.5) was added and the reaction was stirred over night at reflux. The reaction mixture was diluted with 15 ml NaHCO.sub.3 solution and extracted with EtOAc (3×20 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo to afford the title compound 6-(2-chloro-4-methylphenyl)-1-phenethyl-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (10.2 mg, 23.4 μmol, 18.9% yield) as a white solid. MS (ESI): 425.0716 [M−H]−.

Example 5

6-(2-Chloro-4-methylphenyl)-3-(2-morpholinoethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide

[0082] ##STR00011##

[0083] In a 10 ml round-bottomed flask, 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (40 mg, 124 μmol, Eq: 1) was combined with DMF (1 ml). 4-(2-Bromoethyl)morpholine (36.1 mg, 186 μmol, Eq: 1.5) was added and the reaction was stirred for 2 h at reflux. The reaction mixture was diluted with 15 ml NaHCO.sub.3 solution and extracted with EtOAc. The organic layer was discarded. 2M HCl was added to the aqueous phase till the pH was acidic. Then it was extracted with EtOAc (3×20 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo. 27 mg of the dried material were further purified by preparative HPLC to afford the title compound 6-(2-chloro-4-methylphenyl) (2-morpholinoethyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (7 mg, 16.1 μmol, 13% yield) as a white solid. MS (ESI): 435.1022 [M−H]−.

Example 6

1-Benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide

[0084] ##STR00012##

[0085] In a 10 ml round-bottomed flask, 6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (15 mg, 46.5 μmol, Eq: 1) was combined with aqueous NaHCO.sub.3 (1 ml). Benzylbromide (11.9 mg, 8.28 μl, 69.7 μmol, Eq: 1.5) was added and the reaction was stirred for 2 h at reflux. The reaction mixture was diluted with 15 ml NaHCO.sub.3 solution and extracted with EtOAc (3×20 ml). The organic layers were combined, dried over MgSO.sub.4, filtered through sintered glass, concentrated and dried in vacuo to afford the title compound 1-benzyl-6-(2-chloro-4-methylphenyl)-1H-benzo[c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (14 mg, 32.9 μmol, 70.8% yield) as a white solid. MS (ESI): 413.09 [M+H]+.

Example 7

[0086] Malachite Green Assay to Measure cGAS Activity

[0087] 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.

[0088] 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.

[0089] 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.

[0090] The results of this assay are provided in Table 1. Table 1 provides IC50 values (04) for cGAS inhibition obtained for particular examples of the present invention as measured by the above-described assay.

TABLE-US-00001 Example IC50 cGAS (μM) 1 2.94 2 9.6 3 14.23 4 17.21 5 17.58 6 20.1

Example A

[0091] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00002 Ingredients Per tablet Kernel: Compound of formula (I)  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

[0092] 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

[0093] Capsules containing the following ingredients can be manufactured in a conventional manner:

TABLE-US-00003 Ingredients Per capsule Compound of formula (I)  25.0 mg Lactose 150.0 mg Maize starch  20.0 mg Talc  5.0 mg

[0094] The components are sieved and mixed and filled into capsules of size 2.

Example C

[0095] Injection solutions can have the following composition:

TABLE-US-00004 Compound of formula (I)  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

[0096] 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.