IP Library › Granted Patent US 9,447,065

Granted Patent B2

US 9,447,065 · App. 14/351,190 · Granted Sep 20, 2016

Pharmaceutical composition

Inventors: Yasuhiro Iwata (Aichi, JP); Kaoru Shimada (Aichi, JP); Yoshiyuki Okumura (Aichi, JP); Mayumi Kashino (Aichi, JP); Hiromitsu Yoshida (Aichi, JP)

Assignee: RaQualia Pharma Inc.

C07D311/58 A61K9/1617 A61K9/1652 A61K9/205 A61K9/2013 A61K31/352 A61K47/48969 B82Y5/00 C08B37/0015 C08L5/16 A61K9/1623 A61K9/2018 A61K9/2054

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Quick Facts

Patent No.: US 9,447,065
App. No.: 14/351,190
Granted: Sep 20, 2016
Kind: B2

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Abstract

The present invention provides a pharmaceutical composition which prevents from decreasing the blood exposure of the third generation coxib-drugs, a process for preparing the said pharmaceutical composition and its use. It has been founded in this invention that adding a basic amine or a basic amino acid, or a cyclodextrin to the third generation coxib-drug can afford a pharmaceutical composition which can prevent from decreasing the blood exposure, AUC and bioavailability. The pharmaceutical composition of the present invention has also good stability, which is useful for drugs. Namely, the technological thought that adding a basic amine or a basic amino acid, or a cyclodextrin to the third generation coxib-drug can prevent from decreasing the blood exposure, AUC and bioavailability has been established in this invention.

Claims (240)

1. A pharmaceutical composition comprising a third-generation coxib-compound or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition contains at least one excipient selected from a basic amine, a basic amino acid, and a cyclodextrin in the range of 0.5% (weight/whole pharmaceutical composition weight) or more.

2. The pharmaceutical composition according to claim 1 , wherein at least one excipient selected from a basic amine, a basic amino acid, and a cyclodextrin is contained in the range of 5 to 70% (weight/whole pharmaceutical composition weight).

3. The pharmaceutical composition according to claim 1 , wherein the third-generation coxib-compound is a compound represented by the formula (I):

wherein X is selected from O, S and NR a ;

wherein R a is selected from hydrido, C 1 -C 3 -alkyl, (optionally substituted phenyl)-methyl, and phenylmethyl; wherein the phenyl ring is substituted by 1 to 3substituents independently selected from C 1 -C 6 -alkyl, hydroxyl, halo, C 1 -C 6 -haloalkyl, nitro, cyano, C 1 -C 6 -alkoxy and C 1 -C 6 -alkylamino;

wherein R is carboxyl;

wherein R″ is selected from hydrido and C 2 -C 6 -alkenyl;

wherein R 1 is selected from C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, nitro, cyano and cyano-C 1 -C 3 -alkyl;

wherein R 2 is one or more radicals independently selected from hydrido; halo; C 1 -C 6 -alkyl; C 2 -C 6 -alkenyl; C 2 -C 6 -alkynyl; halo-C 2 -C 6 -alkynyl; phenyl-C 1 -C 6 -alkyl; phenyl-C 2 -C 6 -alkynyl; phenyl-C 2 -C 6 -alkenyl; C 1 -C 3 -alkoxy; methylenedioxy; C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl; C 1 -C 3 -alkylthio; C 1 -C 3 -alkylsulfinyl; phenyloxy; phenylthio; phenylsulfinyl; C 1 -C 3 -haloalkyl-C 1 -C 3 -hydroxyalkyl; phenyl-C 1 -C 3 -alkoxy-C 1 -C 1 -C 3 -alkyl; C 1 -C 3 -haloalkyl; C 1 -C 3 -haloalkoxy; C 1 -C 3 -haloalkylthio; C 1 -C 3 -hydroxyalkyl; hydroxyimino-C 1 -C 3 -alkyl; C 1 -C 6 -alkylamino; nitro; cyano; amino; amino sulfonyl; N-(C 1 -C 6 -alkyl)aminosulfonyl; N-arylaminosulfonyl; N-heteroarylaminosulfonyl; N-(phenyl-C 1 -C 6 -alkyl)aminosulfonyl; N-(heteroaryl-C 1 -C 6 -alkyl)aminosulfonyl; phenyl-C 1 -C 3 -alkylsulfonyl; 5- to 8-membered heterocyclylsulfonyl; C 1 -C 6 -alkylsulfonyl; phenyl; optionally substituted phenyl substituted by one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and methylthiosulfonyl; 5- to 9-membered heteroaryl; chloro substituted thienyl; phenyl-C 1 -C 6 -alkylcarbonyl; phenylcarbonyl; 4-chlorophenylcarbonyl; 4-hydroxyphenylcarbonyl; 4-trifluoromethylphenylcarbonyl; 4-methoxyphenylcarbonyl; aminocarbonyl; formyl; and C 1 -C 6 -alkylcarbonyl;

wherein the A ring atoms A 1 , A 2 , A 3 are carbon and A 4 is carbon or nitrogen, or wherein R 2 together with ring A forms a naphthyl, benzofurylphenyl, or quinolyl radical;

or an isomer thereof.

4. The pharmaceutical composition according to claim 1 , wherein the third-generation coxib-compound is selected from the group consisting of

6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid;

7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid;

6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[[N-(2-furylmethy)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-[[N-(2-phenylethy)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid; and

6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;

or an isomer thereof.

5. The pharmaceutical composition according to claim 1 , wherein the third-generation coxib-compound is selected from the group consisting of

6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

(S)-6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

2-trifluoromethyl-2H-naphtho[2,3-b]pyran-3-carboxylic acid;

6-chloro-7-(4-nitrophenoxy)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

(S)-6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

6-chloro-2-trifluoromethyl-4-phenyl-2H-1-benzopyran-3-carboxylic acid;

6-(4-hydroxybenzoyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1-benzothiopyran-3-carboxylic acid;

6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;

6-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;

6,7-difluoro-1,2-dihydro-2-trifluoromethyl-3-quinolinecarboxylic acid;

6-chloro-1,2-dihydro-1-methyl-2-trifluoromethyl-3-quinolinecarboxylic acid;

6-chloro-2-trifluoromethyl-1,2-dihydro[1,8]naphthyridin-3-carboxylic acid; and

(S)-6-chloro-1,2-dihydro-2-trifluoromethyl-3-quinolinecarboxylic acid;

or an isomer thereof.

6. The pharmaceutical composition according to claim 1 , wherein the basic amine or the basic amino acid is tromethamine, triethanolamine, diethanolamine, monoethanolamine, glucosamine, galactosamine, fructosamine, meglumine, N-ethyl glucamine, lysine, arginine, histidine, tryptophan or ornithine; and

the cyclodextrin is β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sodium sulfobutylether-β-cyclodextrin (SBECD).

7. The pharmaceutical composition according to claim 1 , wherein the basic amine or the basic amino acid is tromethamine, meglumine, lysine, or arginine; and

the cyclodextrin is β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

8. A process for preparing a pharmaceutical composition, as defined in claim 1 , wherein the process comprises a step for combining

a third-generation coxib-compound or an isomer thereof, or a pharmaceutically acceptable salt thereof; and

a basic amine or a basic amino acid, or a cyclodextrin.

9. The process for preparing a pharmaceutical composition, as defined in claim 1 , wherein the process comprises combining

a third-generation coxib-compound or an isomer thereof, or a pharmaceutically acceptable salt thereof; and

a basic amine or a basic amino acid, or a cyclodextrin;

with at least one carrier;

and subjecting the combination to grinding or milling, or granulation.

10. The process according to claim 8 , wherein the process further comprises compressing the pharmaceutical composition into a solid dosage form.

11. The pharmaceutical composition according to claim 2 , wherein the third-generation coxib-compound is a compound represented by the formula (I):

wherein X is selected from O, S and NR a ;

wherein R is carboxyl;

wherein R″ is selected from hydrido and C 2 -C 6 -alkenyl;

wherein R 1 is selected from C 1 -C 3 -perfluoroalkyl, chloro, C 1 -C 6 -alkylthio, nitro, cyano and cyano-C 1 -C 3 -alkyl;

wherein R 2 is one or more radicals independently selected from hydrido; halo; C 1 -C 6 -alkyl; C 2 -C 6 -alkenyl; C 2 -C 6 -alkynyl; halo-C 2 -C 6 -alkynyl; phenyl-C 1 -C 6 -alkyl; phenyl-C 2 -C 6 -alkynyl; phenyl-C 2 -C 6 -alkenyl; C 1 -C 3 -alkoxy; methylenedioxy; C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl; C 1 -C 3 -alkylthio; C 1 -C 3 -alkyl sulfinyl; phenyloxy; phenylthio; phenylsulfinyl; C 1 -C 3 -haloalkyl-C 1 -C 3 -hydroxyalkyl; phenyl-C 1 -C 3 -alkoxy-C 1 -C 3 -alkyl; C 1 -C 3 -haloalkyl; C 1 -C 3 -haloalkoxy; C 1 -C 3 -haloalkylthio; C 1 -C 3 -hydroxyalkyl; hydroxyimino -C 1 -C 3 -alkyl; C 1 -C 6 -alkylamino; nitro; cyano; amino; aminosulfonyl; N-(C 1 -C 6 -alkyl)aminosulfonyl; N-arylaminosulfonyl; N-heteroarylaminosulfonyl; N-(phenyl-C 1 -C 6 -alkyl)aminosulfonyl; N-(heteroaryl-C 1 -C 6 -alkyl)aminosulfonyl; phenyl-C 1 -C 3 -alkylsulfonyl; 5- to 8-membered heterocyclylsulfonyl; C 1 -C 6 -alkylsulfonyl; phenyl; optionally substituted phenyl substituted by one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and methylthiosulfonyl; 5- to 9-membered heteroaryl; chloro substituted thienyl; phenyl-C 1 -C 6 -alkylcarbonyl; phenylcarbonyl; 4-chlorophenylcarbonyl; 4-hydroxyphenylcarbonyl; 4-trifluoromethylphenylcarbonyl; 4-methoxyphenylcarbonyl; aminocarbonyl; formyl; and C 1 -C 6 -alkylcarbonyl;

wherein the A ring atoms A 1 , A 2 , A 3 are carbon and A 4 is carbon or nitrogen, or wherein R 2 together with ring A forms a naphthyl, benzofurylphenyl, or quinolyl radical;

or an isomer thereof.

12. The pharmaceutical composition according to claim 2 , wherein the third-generation coxib-compound is selected from the group consisting of