Cell adhesion-inhibiting antiinflammatory compounds

• US 6,579,882 B2
• Filed: 03/06/2001
• Issued: 06/17/2003
• Est. Priority Date: 06/04/1998
• Status: Expired due to Fees

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Patel, Meena V., Condroski, Kevin R., Freeman, Jennifer C., Boyd, Steven A., Staeger, Michael A., McCarty, Catherine M., Bhatia, Pramila, Lartey, Kraig, Stout, David M., Mort, Nicholas A., Gunawardana, Indrani W., Zhu, Gui-Dong, Stewart, Andrew O., Arendsen, David L.
• Primary Examiner(s): Aulakh, Charanjit S.
• Application Number:
  US09/799,729
• Publication Number:
  US 20010020030A1
• Time in Patent Office: 833 Days
• Field of Search: 514/258, 544/278
• US Class Current: 514/260.1
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Compounds having Formula I

are useful for treating inflammation. Also disclosed are pharmaceutical compositions comprising compounds of Formula I, and methods of inhibiting/treating inflammatory diseases in a mammal.

Claims

1. A compound having Formula I

or a pharmaceutically acceptable salt thereof, where

E and G are independently selected from

(1) nitrogen and

(2) N⁺—

O⁻

;

F is carbon;

Z is S(O)_t where t is an integer 0-2;

Y is carbon;

L_A is —

S(O)_t;

X_A is selected from

(1) halo,

(2) alkyl of one to ten carbons optionally substituted with 1, 2, or 3 substituents independently selected from

(a) oxo,

(b) cycloalkyl of three to ten carbons,

(c) —

CO₂R₇ where R₇ is selected from

(i) hydrogen and

(ii) alkyl of one to ten carbons optionally substituted with 1, or aryl and

cycloalkyl of three to ten carbons,

(d) —

NR₈R₉ where R₈ and R₉ are independently selected from

(i) hydrogen,

(ii) alkyl of one to six carbons optionally substituted with 1 or 2 substituents independently selected from

—

OH,

aryl,

heterocycle,

cycloalkyl of three to ten carbons, and

—

NR_AR_B where R_A and R_B are independently selected from

hydrogen and

alkyl of one to six carbons optionally substituted with 1 or 2 substituents selected from —

OH,

(iii) alkanoyl where the alkyl part is of one to to ten carbons,

(iv) cycloalkyl of three to ten carbons,

(v) alkoxy,

(vi) heterocycle, and

(vii) aryl,

 

where (vi) and (vii) are substituted with 1 or 2 substituents independently selected from

alkyl of one to six carbons and

halo,

(e) —

C(W)R₁₀ where W is O or R₁₀ is selected from

(i) hydrogen,

(ii) alkyl of one to ten carbons optionally substituted with 1, or 2 substituents independently selected from

aryl and

cycloalkyl of three to ten carbons,

(iii) —

NR₈R₉, and

(iv) —

OR₇,

(f) —

OH,

(g) aryl, and

(h) heterocycle,

 

where (g) and (h) can be optionally substituted with 1,2,3,4, or 5 substituents independently selected from

(i) alkyl of one to twenty carbons,

(ii) —

NR₈R₉,

(iii) alkoxy of one to ten carbons,

(iv) thioalkoxy of one to ten carbons,

(v) halo,

(vi) perfluoroalkyl of one to three carbons,

(vii) alkenyl of two to ten carbons,

(viii) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from

alkoxy of one to ten carbons and

—

OH,

(ix) —

CO₂R₇,

(x) aryl, and

(xi) —

CHO,

(3) cycloalkyl of three to ten carbons,

(4) aryl,

(5) heterocycle

where (4) and (5) can be optionally substituted with 1,2,3,4, or 5 substituents independently selected from

(a) alkyl of one to twenty carbons,

(b) alkyl of one to ten carbons substituted with 1,2, or 3 substituents independently selected from

(i) —

OR₁₁ where R₁₁ is selected from

hydrogen,

—

C(W)R₁₂ where R₁₂ is selected from

alkyl of one to ten carbons,

cycloalkyl of three to ten carbons,

aryl, and

heterocycle, and

 

heterocycle optionally substituted with 1,2,3, or 4 substituents independently selected from

—

OH and

alkyl of one to six carbons optionally substituted with 1 or 2 substituents selected from —

OH,

(ii) alkoxy of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from

alkoxy and

alkoxyalkoxy,

(iii) spiroalkyl of three to ten carbons, and

(iv) halo,

(c) alkoxy of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from

(i) alkoxy and

(ii) alkoxyalkoxy,

(d) thioalkoxy of one to ten carbons,

(e) halo,

(f) perfluoroalkyl of one to three carbons,

(g) alkenyl of two to ten carbons optionally substituted with 1 or 2 substituents independently selected from

(i) —

C(W)R₁₀ and

(ii) —

C(W)R₁₂,

(h) —

CO₂R₇,

(i) —

NR₈R₉,

(j) aryl,

(k) —

C(W)R₁₂,

(l) —

CHO,

(m) —

C(O)NR₈R₉,

(n) —

CN,

(o) heterocycle optionally substituted with 1 or 2 substituents independently selected from

(i) alkyl of one to ten carbons and

(ii) perfluoroalkyl of one to three carbons,

(p) —

C(W)R₁₀,

(q) ethylenedioxy, and

(r) —

OCF₃,

(6) —

OR₇,

(7) hydrogen, and

(8) —

NR₈R₉;

L_B is selected from

(1) a covalent bond,

(2) —

O—

,

(3) —

S(O)_t—

,

(4) —

NR6—

,

(5) —

C(W)—

, and

(6) —

C(═

NR₁₃)—

where R₁₃ is selected from

(a) hydrogen,

(b) —

NO₂,

(c) —

CN, and

(d) —

OR₁₄ where R₁₄ is selected from

(i) hydrogen,

(ii) aryl, and

(iii) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from

aryl and

—

C(O)R₁₅ where R₁₅ is selected from

hydrogen,

—

OH,

alkoxy, and

NR_AR_B;

X_B is alkyl of one to ten carbons optionally substituted with 1, 2 or 3 substituents independently selected from

(a) —

CO₂R₇,

(b) —

NR₈R₉,

(c) —

C(W)NR₈R₉,

(d) heterocycle,

(e) aryl optionally substituted with 1 or 2 substituents independently selected from

(i) alkyl of one to ten carbons,

(ii) —

NO₂, and

(iii) —

NR_AR_B,

(f) —

OR₁₆ where R₁₆ is selected from

(i) hydrogen and

(ii) —

C(W)NR_AR_B, and

(g) —

NR_AC(W)NR₈R₉,

R₁, R₃, and R₅ are absent and R₂ and R₄ are independently selected from

(1) hydrogen

(2) alkyl of one to six carbons optionally substituted with 1 or 2 substituents independently selected from

(a) —

OC(O)R₂₂, where R₂₂ is selected from

(i) alkyl,

(ii) alkoxy, and

(iii) NR_AR_B,

(b) alkoxy,

(c) —

OH,

(d) —

NR_AR_B,

(e) heterocycle, and

(f) aryl,

(3) —

CO₂R₇,

(4) —

C(O)NR_AR_B,

(5) —

SR₂₃ where R₂₃ is selected from

(a) hydrogen,

(b) alkyl of one to six carbons,

(c) aryl optionally substituted with 1 or 2 substituents selected from

(i) alkyl of one to six carbons and

(ii) halo,

(6) NR_AR_B,

(7) alkoxy,

(8) perfluoroalkyl of one to three carbons,

(9) —

OH, and

(10) heterocycle.

2. A compound according to claim 1 where

E and G are nitrogen;

Z and L_A are S(O)_t where t is 0;

X_A is selected from

(1) alkyl of one to six carbons substituted with one —

CO₂R₇ or phenyl substituent,

where R₇ is alkyl of one to six carbons and

(2) heterocycle, where the heterocycle is pyridyl or 1,3,4-thiadizolyl substituted with one alkyl of one to six carbons substituent or one —

NR₈R₉ substituent,

where R₇ and R₈ are hydrogen;

L_B is a covalent bond;

X_B is alkyl of one to six carbons;

R₁, R₃, and R₅ is absent;

R₂ is selected from

(1) hydrogen,

(2) alkyl of one to six carbons substituted with one phenyl substituent, and

(3) —

CO₂R₇; and

R₄ is hydrogen.

3. A compound according to claim 2 where E and G are nitrogen, F and Y are carbon, Z and L_A are S(O)_t where t is 0;

X_A is —

CH₂CO₂CH₃, 4-methylphenyl, pyrid-2-yl, 2-methylpropyl, (phenyl)methyl, 5-methyl-1,3,4-thiadiazol-2-yl, or 5-amino-1,3,4-thiadazol-2-yl;

L_B is a covalent bond;

X_B is ethyl, R₁, R₃, and R₅ are absent; and

R₂ is hydrogen.

4. A compound according to claim 2 where E and G are nitrogen, F and Y are carbon, Z and L_A are S(O)_t where t is 0;

X_A is —

CH₂CO₂CH₃, 4-methylphenyl, pyrid-2-yl, 2-methylpropyl, (phenyl)methyl, 5-methyl-1,3,4-thiadiazol-2-yl, or 5-amino-1,3,4-thiadazol-2-yl;

L_B is a covalent bond;

X_B is ethyl, R₁, R₃, and R₅ are absent; and

R₂ is —

CH₂CO₂CH₃.

5. A compound according to claim 2 where E and G are nitrogen, F and Y are carbon, Z and L_A are S(O)_t where t is 0;

X_A is —

CH₂CO₂CH₃, 4-methylphenyl, pyrid-2-yl, 2-methylpropyl, (phenyl)methyl, 5-methyl-1,3,4-thiadiazol-2-yl, or 5-amino-1,3,4-thiadazol-2-yl;

L_B is a covalent bond;

X_B is ethyl, R₁, R₃, and R₅ are absent; and

R₂ is R₂ is (phenyl)methyl.

6. A compound according to claim 2 where E and G are nitrogen, F and Y are carbon, Z and L_A are S(O)_t where t is 0;

X_A is —

CH₂CO₂CH₃, 4-methylphenyl, pyrid-2-yl, 2-methylpropyl, (phenyl)methyl, 5-methyl-1,3,4-thiadiazol-2-yl, or 5-amino-1,3,4-thiadazol-2-yl;

L_B is a covalent bond;

X_B is ethyl, R₁, R₃, and R₅ are absent; and

R₂ is hydrogen.

7. A method for treating reperfusion injuries and inflammatory diseases in a mammal comprising administering thereto a therapeutically effective amount of a compound of claim 1.

8. A compound selected from the group consisting of

methyl 2-[(6-ethylthieno[2,3-d]pyrimidin-4-yl)thio]acetate,

6-ethyl-4-[(4-methylphenyl)thio]thieno[2,3-d]pyrimidine,

6-ethyl-4-(2-pyridinylthio)thieno[2,3-d]pyrimidine,

6-ethyl-4-[(2-methylethyl)thio]thieno[2,3-d]pyrimidine,

6-ethyl-4-[phenylmethyl)thio]thieno[2,3-d]pyrimidine,

6-ethyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]thieno[2,3-d]pyrimidine,

ethyl 6-ethyl-4-[(4-methylphenyl)thio]thieno[2,3-d]pyrimidine-6-carboxylate, and

4-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-6-ethyl-2-(phenylmethyl)thieno[2,3-d]pyrimidine.