Processes for Preparing Quinoline Compounds and Pharmaceutical Compositions Containing Such Compounds
AssigneeExelixis, Inc.
InventorsJo Ann Wilson, Khalid Shah
Life of this patent
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Abstract
The present invention is directed to processes for making and compositions containing quinolines such as formula I or pharmaceutically acceptable salts thereof wherein: X1 is H, Br, CI, or X2 is H, Br, CI, or n1 is 1-2; and n2 is 1-2.
Claims34
A process for preparing a compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- X1 is H, Br, Cl, or F;
- X2 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 I:
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.
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.
Compound IA or IB admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
Compound IB admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
Compound IB in the N-1 form admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
Compound IB in the N-2 form admixed with 100 ppm or less of 6,7-dimethoxy-quinoline-4-ol.
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.
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
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
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
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
- Croscarmellose sodium
- 12.5
- Sodium starch glycolate
- 12.5
- Fumed Silica
- 0.75
- Stearic acid
- 2.5
- Total Fill Weight
- 250
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
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
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
Dependencies are inferred from the claim text.