IP Library › Granted Patent US 8,143,276

Granted Patent B2

US 8,143,276 · App. 11/895,088 · Granted Mar 27, 2012

4-thio substituted quinoline and naphthyridine compounds

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Quick Facts

Patent No.: US 8,143,276
App. No.: 11/895,088
Granted: Mar 27, 2012
Kind: B2

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Abstract

The present invention relates to 4-thio substituted quinoline and naphthyridine derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 4-thio substituted quinoline or naphthyridine derivative.

Claims (143)

1. A compound of the formula II:

wherein:

X is C—H;

r is 0 to 6;

s is 0 to 6;

n is 0 to 3;

A is selected from an aryl group;

each R 2 is —(CH 2 ) v —N(R 22 )(R 23 ) wherein:

each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

v is 0 to 6;

p is 1

R 3 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, a heterocyclic group, —(CH 2 ) x C(O)R 31 , —(CH 2 ) x C(O)N(R 32 )(R 33 ), (CH 2 ) x C(O)OR 31 ,

R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and

a heterocyclic group;

R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and

x is 0 to 6;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein A is phenyl.

3. The compound of claim 2 , having the formula III a :

wherein:

R 1a and R 1b are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, —(CH 2 ) r —O—R 11 , —(CH 2 ) r —N(R 12 )(R 13 ) 3 , —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) r , —N(R 11 )SO 2 R 11 , —(CH 2 ) r —SR 11 , —(CH 2 ) r —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 , —(CH 2 ) r OC(O)—(CH 2 ) s N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ), cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and a heterocyclic group;

each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

each R 14 is independently selected from H, alkyl, —OH, —O-alkyl, —O-aryl, —O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

r is 0 to 6;

s is 0 to 6;

R 2a is —(CH 2 ) v —N(R 22 )(R 23 ) wherein:

v is 0 to 6; and

p is 0 to 3.

4. The compound of claim 3 , wherein R 1a is selected from H, —NH 2 , halo, alkyl, and —O-alkyl.

5. The compound of claim 1 , having a chemical formula selected from:

6. A method of treating infection with Hepatitis C virus comprising administering a pharmaceutically effective amount of a compound of the formula II:

wherein:

X is C—H;

r is 0 to 6;

s is 0 to 6;

n is 0 to 3;

A is an aryl group;

each R 2 is —(CH 2 ) v —N(R 22 )(R 23 ), wherein:

v is 0 to 6;

p is 1; 0 to 3

R 3 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl,

a heterocyclic group, —(CH 2 ) x C(O)R 31 , —(CH 2 ) x C(O)N(R 32 )(R 33 ), and (CH 2 ) x C(O)OR 31 ,

R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

x is 0 to 6;

or a pharmaceutically acceptable salt or hydrate thereof.

7. The method of claim 6 , wherein A is phenyl.

8. The method of claim 7 , comprising administering a pharmaceutically effective amount of a compound of the formula III a :

wherein:

R 1a and R 1b are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, —(CH 2 ) r —O—R 11 ,

—(CH 2 ) r —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) r —N(R 11 )SO 2 R 11 , —(CH 2 ) r —SR 11 ,

—(CH 2 ) r —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 , —(CH 2 ) r OC(O)—(CH 2 ) s N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ), cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and a heterocyclic group;

each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

r is 0 to 6;

s is 0 to 6;

R 2a is —CH 2 ) v —N(R 22 )(R 23 ); wherein:

v is 0 to 6;

p is 1.

9. The method of claim 8 , wherein R 1a and R 2a are independently selected from H, —NH 2 , halo, alkyl, and —O-alkyl, and R 2a is selected from H and halo.

10. The method of claim 6 , comprising administering a pharmaceutically effective amount of a compound having a chemical formula selected from:

11. A compound of the formula II:

wherein:

X is C—R 1 ;

each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —(CH 2 ) r O—R 11 , —(CH 2 ) r —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 )., C(O)R 14 , —(CH 2 ) r —N(R 11 )SO 2 R 11 , —(CH 2 ) r —SR 11 , —(CH 2 ) r —C(O)R 14 , —(CH 2 ) r C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 , —(CH 2 ) r OC(O)—(CH 2 ) s N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ), cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and a heterocyclic group;

may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

r is 0 to 6;

s is 0 to 6;

n is 0 to 3;

A is selected from an aryl group;

each R 2 is —(CH 2 ) v —N(R 22 )(R 23 ) wherein:

v is 0 to 6;

p is 1;

R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and

a heterocyclic group;

R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

x is 0 to 6;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 wherein A is phenyl.

13. The compound of claim 12 , having the formula III a :

wherein:

R 1a and R 1b are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, —(CH 2 ) r —O—R 11 , —(CH 2 ) r —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) r , —N(R 11 )SO 2 R 11 , —(CH 2 ) r —SR 11 , —(CH 2 ) r —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 , —(CH 2 ) r OC(O)—(CH 2 ) s N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ), cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and a heterocyclic group;

each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

r is 0 to 6;

s is 0 to 6;

R 2a is —(CH 2 ) v —N(R 22 )(R 23 ) wherein:

v is 0 to 6; and

p is 0 to 3.

14. The compound of claim 13 , wherein R 1a is selected from H, —NH 2 , halo, alkyl, and —O-alkyl.

15. A method of treating infection with Hepatitis C virus comprising administering a pharmaceutically effective amount of a compound of the formula II:

wherein:

X is C—R 1 ;

each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —(CH 2 ) r —O—R 11 , —(CH 2 ) r —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) r , —N(R 11 )SO 2 R 11 , —(CH 2 ) r —SR 11 , —(CH 2 ) r , —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ) s —C(O)R 14 , —(CH 2 ) r OC(O)—(CH 2 ) s N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ), cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and a heterocyclic group;

r is 0 to 6;

s is 0 to 6;

n is 0 to 3;

A is an aryl group;

each R 2 is —(CH 2 ) v —N(R 22 )(R 23 ), wherein:

v is 0 to 6;

p is 1;

R 3 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl,

a heterocyclic group, —(CH 2 ) x C(O)R 31 , —(CH 2 ) x C(O)N(R 32 )(R 33 ), and (CH 2 ) x C(O)OR 31 ,

R 31 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

x is 0 to 6;

or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein A is phenyl.

17. The method of claim 15 , comprising administering a pharmaceutically effective amount of a compound of the formula III a :

wherein:

R 1a and R 1b are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, —(CH 2 ) r —O—R 11 ,

—(CH 2 ) r —N(R 12 )(R 13 ), —(CH 2 ) r —N(R 11 )—(CH 2 ) s C(O)R 14 , —(CH 2 ) r —N(R 11 )SO 2 R 11 , —(CH 2 ) r —SR 11 ,

—(CH 2 ) r —C(O)R 14 , —(CH 2 ) r —C(O)—(CH 2 ) s OR 11 , —(CH 2 ) r —C(O)—(CH 2 ) s N(R 12 )(R 13 ), —(CH 2 ) r O—(CH 2 ) s —C(O)R 14 , —(CH 2 ) r OC(O)—(CH 2 ) s N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13) , cycloalkyl, cycloalkenyl, halo, phosphate, phosphonate, aryl and a heterocyclic group;

each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

r is 0 to 6;

s is 0 to 6;

R 2a is —(CH 2 ) v —N(R 22 )(R 23 ) wherein:

v is 0 to 6; and

p is 1.

18. The method of claim 15 , wherein R 1a and R 2a are independently selected from H, —NH 2 , halo, alkyl, and —O-alkyl, and R 2a is selected from H and halo.

Assignments (2)

LICENSE Recorded Apr 7, 2008

From: XTL BIOPHARMACEUTICALS LTD.

To: PRESIDIO PHARMACEUTICALS, INC.

Reel/Frame 020762/0273 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 20, 2007

From: YANG, ZHEN; FATHI, REZA; ZHU, QIANG; CHO, HYUN-JOON; LIN, YIXIN; SANDRASAGRA, ANTHONY; WOBBE, C RICHARD

To: XTL BIOPHARMACEUTICALS LTD.

Reel/Frame 020275/0950 →