Novel compounds
AssigneeBoehringer Ingelheim International GmbH
InventorsKathrin Pachur, Uwe Joerg Ries, Ulrike Werthmann, Sonja Sproll
Life of this patent
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Abstract
The invention relates to the novel salts AB of the base A with a physiologically acceptable acid B which is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid and silcylic acid and the polymorphic compounds, the corresponding solvates and hydrates thereof.
Claims15
A salt AB of the base A
- with a physiologically acceptable acid B which is hydrochloric acid, hydrobromic acid, sulphuric acid, fumaric acid or salicylic acid.
(canceled)
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate hydrochloride (1a;
- polymorph 1), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=10.74 Å, 7.76 Å, 5.28 Å, 4.69 Å, 4.60 Å, 4.44 Å and 4.10 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate hydrochloride (1b;
- polymorph 2), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=19.60 Å, 7.84 Å, 6.20 Å, 4.46 Å, 4.33 Å, 4.20 Å and 4.03 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate hydrochloride (1c;
- polymorph 3), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=6.37 Å, 5.20 Å, 5.01 Å, 4.98 Å, 4.73 Å, 4.55 Å, 4.41 Å and 4.26 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate hydrobromide (2), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=11.02 Å, 4.74 Å, 4.64 Å, 4.55 Å, 4.43 Å and 4.03 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate difumarate (3), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=20.53 Å, 8.97 Å, 6.04 Å, 5.76 Å, 5.27 Å, 5.19 Å, 5.02 Å, 4.82 Å, 4.74 Å, 4.32 Å, 3.80 Å, 3.74 Å and 3.70 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate sulphate (4), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=17.04 Å, 7.91 Å, 7.36 Å, 4.72 Å, 4.33 Å, 3.95 Å and 3.91 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate salicylate (5a, polymorph 1), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=21.28 Å, 7.07 Å, 4.71 Å, 4.61 Å, 4.35 Å and 4.19 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate salicylate (5b, polymorph 2), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=19.92 Å, 13.93 Å, 5.09 Å, 4.78 Å, 4.70 Å, 4.58 Å, 4.31 Å, 4.23 Å, 4.12 Å, 3.95 Å and 3.89 Å.
Crystalline ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate salicylate (5c, polymorph 3), characterised in that in the X-ray powder diagram it has, inter alia, the characteristic values d=5.32 Å, 5.27 Å, 5.09 Å, 4.68 Å, 4.25 Å and 4.21 Å.
14-18. (canceled)
A process for preparing the crystalline salt ethyl 4-[4-[(2R)-3-[4-amino-3-chloro-5-(trifluoromethyl)phenyl]-1-oxo-2-[[[4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-piperidinyl]carbonyl]oxy]propyl]-1-piperazinyl]-piperidine-1-acetate difumarate (3), comprising the steps of:
- (a) mixing the base 2-oxoethyl (1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-[[4-amino-3-chloro-5-trifluoro-phenyl]methyl]-2-[4-(1-piperazinyl)-ethyl 1-piperidinoacetate]-1-piperidinecarboxyate with a polar solvent at ambient temperature and subsequently heating the reaction mixture;
- (b) adding a mixture of fumaric acid in a polar solvent to the reaction mixture obtained under (a);
- (c) slowly cooling the reaction mixture obtained under (b), isolating and drying the salt formed and
- (d) optionally recrystallising the salt (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl]-2-[4-(1-ethoxycarbonylmethyl-piperidin-4-yl)-piperazin-1-yl]-2-oxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate difumarate, obtained under (c), from a suitable solvent.
Dependencies are inferred from the claim text.