Magnesium complexes of S-omeprazole
The invention provides magnesium S-omeprazolato coordination compounds according to formula (I): [Mg(solv a ) x (solv b ) y ][Mg(S-omeprazolato) 3 ] 2 .(solv c ) z (I), pharmaceutical compositions and processes of making the same. In formula (I), solv a , solv b , and solv c represent solvent molecules where x and y are independently selected from integers 0 to 6, the sum of which is 4 or 6, while z is a positive rational number from 0 to 6. The compounds are useful for the treatment of gastric acid related conditions and the inhibition of gastric acid secretion.
1 . A magnesium S-omeprazolato coordination compound in the solid state according to formula (I):
[Mg(solv a ) x (solv b ) y ][Mg(S-omeprazolato) 3 ] 2 .(solv c ) z (I),
wherein
solv a is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv b is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv c represents at least one solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N, wherein each solv c can be the same as or different from another solv c ;
wherein R, at each occurrence, is independently hydrogen or a C 1-6 -alkyl group;
x and y, independently of each other, are selected from the integers 0-6 inclusive such that (x+y) is not more than 8;
z is a positive rational number from 0 to 6, inclusive; and
each S-omeprazolato ligand, independently of the others, is an anionic ligand of 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole.
2 . The compound according to claim 1 wherein at least one S-omeprazolato ligand bears a 6-methoxy group.
3 . The compound according to claim 2 wherein at least three S-omeprazolato ligands bear 6-methoxy groups.
4 . The compound according to claim 3 wherein at least four S-omeprazolato ligands bear 6-methoxy groups.
5 . The compound according to claim 4 wherein at least five S-omeprazolato ligands bear 6-methoxy groups.
6 . The compound according to claim 5 wherein each S-omeprazolato ligand bears a 6-methoxy group.
7 . The compound according to claim 1 wherein solv a , solv b and solv c are independently selected from the group consisting of H 2 O, DMSO, DMF, acetone, and a C 1-6 -alkyl alcohol.
8 . The compound according to claim 7 wherein the C 1-6 -alkyl-alcohol is methanol or ethanol.
9 . The compound according to claim 7 wherein solv a , solv b and solv c are independently selected from DMF and H 2 O.
10 . The compound according to claim 9 wherein solv a is H 2 O and solv b and solv c each are DMF.
11 . The compound according to claim 7 wherein solv a , solv b and solv c are independently selected from DMSO and H 2 O.
12 . The compound according to claim 7 wherein at least one of solv 8 , solv b and solv c is H 2 O.
13 . The compound according to claim 7 wherein at least one of solv a , solv b and solv c is DMSO.
14 . The compound according to claim 7 wherein at least one of solv a , solv b and solv c is DMF.
15 . The compound according to claim 7 wherein at least one Of solv a , solv b and solv c is acetone.
16 . The compound according to claim 7 wherein at least one of solv a , solv b and solv c is methanol
17 . The compound according to claim 7 wherein at least one of solv a , solv b and solv c is ethanol.
18 . The compound according to claim 10 wherein x is 5 and y and z are each 1.
19 . The compound according to claim 7 wherein solv a is H 2 O and solv b is DMSO.
20 . The compound according to claim 19 wherein x and y are each 3 and z is 0.
21 . The compound according to claim 1 that is:
Δ,Δ-[Mg(H 2 O) 5 DMF][Mg(6-methoxy-5-omeprazolato) 3 ][Mg(6-methoxy-S-omeprazolato) 2 (5-methoxy-5-omeprazolato)].DMF;
Δ,Δ-[Mg(H 2 O) 5 DMF][Mg(6-methoxy-5-omeprazolato) 3 ][Mg(6-methoxy-S-omeprazolato) 2 (5-methoxy-5-omeprazolato)].H 2 O;
Δ,Δ-[Mg(H 2 O) 5 DMF][Mg(6-methoxy-5-omeprazolato) 3 ][Mg(6-methoxy-S-omeprazolato) 2 (5-methoxy-5-omeprazolato)].(H 2 O) z (DMF) z ; or
mer-[Mg(H 2 O) 3 (DMSO) 3 ]-Δ,Δ-[Mg(5(6)-methoxy-5-omeprazolato) 3 ] 2 .(H 2 O) 3 ,
wherein S designates the absolute stereochemistry about each sulfur atom.
22 . The compound according to claim 1 , wherein at least one of solv a , solv b , and solv c represents H 2 O and wherein x, y, and z are selected such that the ratio of total H 2 O represented by at least one of solv a , solv b , and solv c to Mg ions in formula I ranges from about 1.5 to about 2.4.
23 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
15.3
vs
10.5
s
8.2
s
5.0
s
4.8
vs
4.0
s
3.7
s
2.9
s
24 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
15.5
vs
10.6
m
8.4
s
5.1
vs
4.8
vs
3.4
s
2.9
s
25 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
14.8
vs
12.2
w
10.8
w
8.4
w
7.6
m
6.7
w
5.5
w
5.1
s
4.8
s
4.3
m
4.1
m
3.8
w
3.5
w
2.9
m
26 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
15.1
vs
12.5
m
10.8
m
10.0
m
8.5
m
7.8
m
5.1
vs
4.8
vs
4.3
m
4.1
m
3.8
m
3.4
m
2.9
m
27 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
15.1
vs
12.4
m
10.9
m
8.5
w
7.8
m
6.9
m
5.5
m
5.1
s
5.0
s
4.8
s
4.8
w
4.3
m
4.1
m
3.9
w
3.7
w
3.5
w
3.5
m
3.4
m
2.9
m
2.5
w
28 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
15.1
vs
12.3
m
10.9
m
8.5
m
7.8
m
6.9
m
5.5
m
5.1
s
5.0
s
4.9
vs
4.7
m
4.3
m
4.1
m
3.9
m
3.7
m
3.5
m
3.4
m
3.4
m
2.9
m
2.5
w
29 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
14.9
vs
12.2
m
10.8
m
8.4
m
7.7
m
6.8
m
5.5
m
5.1
s
5.0
s
4.8
vs
4.6
m
4.4
m
4.3
m
4.1
s
4.0
m
3.9
m
3.8
w
3.7
m
3.5
m
3.4
m
2.9
m
2.5
m
30 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
14.9
vs
12.2
m
10.8
m
8.4
m
7.7
m
6.8
m
5.5
s
5.1
s
5.0
s
4.8
vs
4.6
m
4.4
w
4.2
m
4.1
s
3.9
m
3.8
w
3.7
m
3.5
m
3.4
s
2.9
m
2.5
w
31 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
19.0
vs
12.0
m
10.6
vs
9.2
m
7.3
vs
6.0
m
5.8
m
4.8
vs
4.4
s
4.1
s
3.5
m
3.3
m
2.9
m
2.8
m
32 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
18.6
vs
12.0
s
10.5
vs
7.8
vs
4.8
vs
4.8
vs
4.3
s
3.5
s
33 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
14.8
vs
12.1
s
10.7
m
8.4
s
7.8
m
6.7
m
5.7
m
5.4
s
5.0
vs
4.8
vs
4.7
vs
4.6
s
4.4
m
4.3
s
4.1
s
4.0
w
3.8
w
3.6
m
3.4
m
2.9
m
2.9
m
2.5
w
34 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
14.8
vs
12.2
s
10.7
m
8.4
s
7.7
m
7.3
m
6.7
m
5.7
m
5.5
s
5.3
m
5.0
vs
4.8
vs
4.7
s
4.6
s
4.4
m
4.3
s
4.1
s
4.0
m
3.8
w
3.7
m
3.4
m
2.9
m
2.9
m
2.5
w
35 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
17.3
vs
11.7
m
10.3
s
7.2
vs
6.3
s
4.8
vs
4.2
s
3.5
s
3.1
m
36 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
15.0
vs
12.2
m
7.7
w
7.1
w
6.5
vs
6.1
vs
5.8
s
5.2
vs
5.2
s
4.7
vs
4.5
s
4.3
m
4.2
vs
4.0
s
3.8
m
3.5
m
3.4
m
3.3
m
3.2
s
3.0
s
2.9
m
2.7
w
2.6
m
2.5
w
2.4
m
2.3
m
37 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
14.7
vs
12.2
s
10.6
s
8.5
s
7.8
s
7.3
m
6.7
m
5.7
m
5.4
m
5.3
m
5.1
vs
4.8
vs
4.7
s
4.6
s
4.4
m
4.3
s
4.1
s
4.0
m
3.8
s
3.7
m
3.4
m
2.9
m
2.9
m
2.5
m
38 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
15.0
vs
12.3
s
10.9
s
8.4
s
7.8
m
5.4
s
5.0
vs
4.8
vs
4.7
vs
4.1
s
3.4
s
2.9
s
39 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
17.0
vs
11.9
m
10.2
s
7.2
m
6.3
m
5.3
s
4.8
vs
4.2
m
4.0
s
3.5
m
3.2
m
2.7
m
40 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
19.4
vs
12.1
m
10.7
vs
9.2
s
7.3
vs
6.1
s
5.8
s
5.4
s
5.0
vs
4.8
vs
4.7
s
4.5
s
4.1
s
3.9
s
3.5
s
3.3
s
3.2
m
3.1
m
2.7
m
41 . A compound according to claim 1 , characterized in that it exhibits the following major peaks in its powder X-ray diffractogram:
d-value/Å
Relative Intensity
13.7
vs
9.4
s
8.7
s
8.0
s
7.2
s
6.2
s
5.8
vs
5.2
vs
5.0
vs
5.0
vs
4.9
vs
4.6
vs
4.6
s
4.5
s
4.4
s
4.3
s
4.1
s
4.0
vs
3.9
s
3.9
vs
3.7
vs
3.6
vs
3.5
vs
3.4
s
3.3
s
3.1
s
3.0
s
42 . A compound according to claim 1 , characterized in that it exhibits the following major resonances in its solid-state 13 C NMR spectrum:
Chemical Shift
(δ) (ppm)
166.6
165.9
164.6
162.6
158.5
157.4
155.5
150.2
148.7
143.9
142.5
138.8
129.8
128.7
127.7
118.4
115.9
112.0
110.4
99.3
97.0
62.5
60.0
59.1
55.1
53.6
35.3
30.9
11.7
11.0
9.6
43 . A compound according to claim 1 , characterized in that it exhibits the following major resonances in its solid-state 13 C NMR spectrum:
Chemical Shift
(δ) (ppm)
167.1
166.6
164.5
156.8
155.9
149.2
144.0
141.6
138.8
129.9
128.7
127.2
118.6
117.5
116.0
112.3
111.4
97.8
96.4
62.5
59.4
56.0
54.6
53.1
30.1
13.2
11.8
10.0
44 . A compound according to claim 1 , characterized in that it exhibits the following major resonances in its solid-state 13 C NMR spectrum:
Chemical Shift
(δ) (ppm)
164.0
154.6
149.8
146.6
142.6
140.2
136.8
126.3
116.2
111.5
95.9
58.1
52.5
10.5
7.8
45 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
46 . A method of treating a gastric acid related condition in a subject comprising administering to the subject suffering from the condition a therapeutically effective amount of the compound according to claim 1 .
47 . A method of treating a gastric acid related condition in a subject comprising administering to the subject suffering from the condition a therapeutically effective amount of the pharmaceutical composition according to claim 45 .
48 . A method of inhibiting gastric acid secretion in a subject comprising administering to the subject suffering from the condition a therapeutically effective amount of the compound according to claim 1 .
49 . A method of inhibiting gastric acid secretion in a subject comprising administering to the subject suffering from the condition a therapeutically effective amount of pharmaceutical composition according to claim 45 .
50 . A magnesium R-omeprazolato coordination compound in the solid state according to formula (II):
[Mg(solv a ) x (solv b ) y ][Mg(R-omeprazolato) 3 ] 2 .(solv c ) z (II),
wherein
solv a is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv b is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv c represents at least one solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N, wherein each solv c can be the same as or different from another solv c ;
wherein R, at each occurrence, is independently hydrogen or a C 1-6 -alkyl group;
x and y, independently of each other, are selected from the integers 0-6 inclusive such that (x+y) is not more than 8;
z is a positive rational number from 0 to 6, inclusive; and
each R-omeprazolato ligand, independently of the others, is an anionic ligand of 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole.
51 . A magnesium omeprazolato coordination compound in the solid state according to formula (IIIa):
[Mg(solv a ) x (solv b ) y ][Mg(omeprazolato) 3 ] 2 .(solv c ) z (IIIa),
wherein
solv a is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv b is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv c represents at least one solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N, wherein each solv c can be the same as or different from another solv c ;
wherein R, at each occurrence, is independently hydrogen or a C 1-6 -alkyl group;
x and y, independently of each other, are selected from the integers 0-6 inclusive such that (x+y) is not more than 8;
z is a positive rational number from 0 to 6, inclusive;
each omeprazolato ligand, independently of the others, is an anionic ligand of 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole; and
there exists an enantiomeric excess of S-omeprazolato ligands over R-omeprazolato ligands.
52 . A magnesium omeprazolato coordination compound in the solid state according to formula (IIIb):
[Mg(solv a ) x (solv b ) y ][Mg(omeprazolato) 3 ] 2 .(solv c ) z (IIIb),
wherein
solv a is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv b is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv c represents at least one solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N, wherein each solv c can be the same as or different from another solv c ;
wherein R, at each occurrence, is independently hydrogen or a C 1-6 -alkyl group;
x and y, independently of each other, are selected from the integers 0-6 inclusive such that (x+y) is not more than 8;
z is a positive rational number from 0 to 6, inclusive;
each omeprazolato ligand, independently of the others, is an anionic ligand of 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole; and
there exists an enantiomeric excess of R-omeprazolato ligands over S-omeprazolato ligands.
53 . A magnesium omeprazolato coordination compound in the solid state according to formula IIIc:
[Mg(solv a ) x (solv b ) y ][Mg(omeprazolato) 3 ] 2 .(solv c ) z (IIIc),
wherein
solv a is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv b is a solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N;
solv c represents at least one solvent molecule that is selected from the group consisting of H 2 O; ROH; RC(O)R; RC(O)OR; ROR; RC(S)R; RS(O)R; R 2 NC(O)R; and an optionally substituted 5- or 6-membered heterocyclic compound comprising at least one heteroatom selected from the group consisting of O, S, and N, wherein each solv c can be the same as or different from another solv c ;
wherein R, at each occurrence, is independently hydrogen or a C 1-6 -alkyl group;
x and y, independently of each other, are selected from the integers 0-6 inclusive such that (x+y) is not more than 8;
z is a positive rational number from 0 to 6, inclusive;
each omeprazolato ligand, independently of the others, is an anionic ligand of 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole or 6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole; and
there exists an equal number of R-omeprazolato and S-omeprazolato ligands.
54 . A magnesium omeprazolato coordination compound in the solid state according to formula IV:
[Mg(omeprazolato) 3 ]X (IV),
wherein X is a monovalent cation.