Processes for Preparing Quinoline Compounds and Pharmaceutical Compositions Containing Such Compounds
The present invention is directed to processes for making and compositions containing quinolines such as formula I or pharmaceutically acceptable salts thereof wherein: X 1 is H, Br, CI, or X2 is H, Br, CI, or n1 is 1-2; and n2 is 1-2.
1 . A process for preparing a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is H, Br, Cl, or F;
X 2 is H, Br, Cl, or F;
n1 is 1-2; and
n2 is 1-2;
the process comprising:
contacting the compound of formula g(1) with reactant z(1) to yield the compound of formula
2 . The process according to claim 1 , wherein the compound of formula g(1) is made by reacting a compound of formula f(1) with reactant y(1) to yield the compound of formula g(1):
wherein LG represents a leaving group, and each X 2 and n2 are as defined in claim 1 .
3 . The process according to claim 2 , wherein the compound of formula f(1) is made by converting compound e(1) to the compound of formula f(1):
wherein LG represents a leaving group.
4 . The process according to claim 1 , wherein reactant z(1) is made by reacting reactant z(1a) with a chlorinating agent to yield reactant z(1):
wherein X 1 is Br, Cl, or F; and n1 is 1-2.
5 . The process according to claim 1 , wherein the compound of formula I is compound IA-1:
or a pharmaceutically acceptable salt thereof, wherein:
X 1 is H, Cl, Br, or F; and
X 2 is H, Cl, Br, or F.
6 . The process according to claim 5 , wherein the compound of formula f(1) is compound f(2):
reactant y(1) is reactant (y)(2):
wherein X 2 is hydrogen or fluoro; and
the compound of formula g(1) is of formula g(2):
7 . The process according to claim 6 , wherein the reaction employs a non-nucleophilic base.
8 . The process according to claim 7 , wherein the non-nucleophilic base is an alkali metal alkoxide; and the reaction is carried out in a polar solvent.
9 . The process according to claim 8 , wherein the alkali metal alkoxide is sodium tert-butoxide, and the polar solvent is DMA.
10 . The process according to claim 8 , wherein the alkali metal alkoxide is sodium tert-pentoxide, and the polar solvent is DMA.
11 . The process according to claim 1 , wherein the compound of formula g(1) is of compound g(3):
reactant z(1) is reactant (z)(2):
and
the compound of formula I is compound IA:
12 . The process according to claim 11 , wherein the reaction is carried out in the presence of an inorganic base.
13 . The process according to claim 12 , wherein the inorganic base is K 2 CO 3 , and the solvent employed in this reaction is a combination of THF and H 2 O.
14 . A process for preparing compound IB:
from compound IA:
comprising:
(a) heating and agitating a mixture comprising compound IA and L-malic acid, methylethyl ketone, and water;
(b) cooling the mixture;
(c) vacuum distilling the mixture successively; and
(d) isolating the compound of IB by filtration.
15 . A process for preparing compound IB:
from compound IA:
comprising:
(a) heating and agitating a mixture comprising compound IA and L-malic acid, methylethyl ketone, and water,
(b) cooling the mixture;
(c) seeding the mixture with the compound of IB;
(d) vacuum distilling the mixture; and
(e) isolating the compound of IB by filtration.
16 . Compound IA or IB admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
17 . Compound IB admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
18 . Compound IB in the N-1 form admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
19 . Compound IB in the N-2 form admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
20 . Compound IB as a mixture of the N-1 form and N-2 form admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
21 . A pharmaceutical composition according to Table 1.
TABLE 1
Ingredient
% w/w
Compound I
31.68
Microcrystalline Cellulose
38.85
(Avicel PH102)
Lactose anhydrous 60 M
19.42
Hydroxypropyl Cellulose, EXF
3.00
Croscarmellose Sodium
3.00
Total Intra-granular
95.95
Silicon dioxide, Colloidal PWD
0.30
Croscarmellose Sodium
3.00
Magnesium Stearate
0.75
Total
100.00
22 . A pharmaceutical composition according to Table 2.
TABLE 2
Ingredient
(% w/w)
Compound I
25.0-33.3
Microcrystalline Cellulose, NF
q.s
Hydroxypropyl Cellulose, NF
3
Poloxamer, NF
0-3
Croscarmellose Sodium, NF
6.0
Colloidal Silicon Dioxide, NF
0.5
Magnesium Stearate, NF
0.5-1.0
Total
100
23 . A pharmaceutical composition according to Table 2A.
TABLE 2A
Ingredient
% w/w
Compound IB (10 % drug load as
12.67
Compound IA)
MCC
51.52
Lactose
25.76
Hydroxypropyl cellulose
3.0
Croscarmellose Sodium
6.0
Colloidal Silicon Dioxide
0.3
Magnesium Stearate
0.75
Total
100
24 . A pharmaceutical composition according to Table 3.
TABLE 3
Ingredient
mg/unit dose
Compound IB (10 % drug
25
load as Compound IA)
Silicified Microcrystalline
196.75
Cellulose
Croscannellose sodium
12.5
Sodium starch glycolate
12.5
Fumed Silica
0.75
Stearic acid
2.5
Total FM Weight
250
25 . A pharmaceutical composition according to Table 4.
TABLE 4
Ingredient
mg/unit dose
Compound IB (50% drug
100
load as Compound IA)
Silicified Microcrystalline
75.40
Cellulose
Croscarmellose sodium
10.00
Sodium Starch Glycolate
10.00
Fumed silica
0.6
Stearic Acid
4.0
Total Fill Weight
200
26 . A pharmaceutical composition according to Table 5.
TABLE 5
mg/unit dose
Ingredient
50 mg
Compound IB (10% drug
63.35
load as Compound IA)
Microcrystalline Cellulose
95.39
Croscarmellose sodium
9.05
Sodium starch glycolate
9.05
Fumed Silica
0.54
Stearic acid
3.62
Total Fill Weight
181.00
27 . A pharmaceutical composition according to Table 6.
TABLE 6
mg/unit dose
Ingredient
60 mg
Compound IB
73.95
Microcrystalline Cellulose
114.36
Croscarmellose sodium
10.85
Sodium starch glycolate
10.85
Fumed Silica
0.65
Stearic acid
4.34
Total Fill Weight
217.00
28 . The pharmaceutical composition of claims 20 - 27 admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
29 . The pharmaceutical composition of claims 20 - 27 admixed with 50 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
30 . The pharmaceutical composition of claims 20 - 27 admixed with 25 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
31 . The pharmaceutical composition of claims 20 - 27 admixed with 15 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
32 . The pharmaceutical composition of claims 20 - 27 admixed with 10 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
33 . The pharmaceutical composition of claims 20 - 27 admixed with 5 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
34 . The pharmaceutical composition of claims 20 - 27 admixed with 2.5 ppm or less of 6,7-dimethoxy-quinoline-4-ol.