Granted Patent B2

US 7,361,678 · App. 10/382,203 · Granted Apr 22, 2008

Abstract

Claims (145)

1. A compound of Formula (Ib)

wherein

R 1 is -hydrogen, -alkyl, or -alkenyl,

R 3 is -hydrogen or -alkyl; and

R 102 and R 104 are independently selected from the group consisting of:

a) —H;

b) -alkyl;

c) -aryl;

d) -heteroaryl;

e) -alkylene-heteroaryl-aryl;

f) -alkylene-aryl;

g) -alkylene-W 2 —R 18 ;

h) —Y 4 —NR 23 R 24 ;

i) —Y 4 —NH—C(═NR 25 )NR 23 R 24 ;

j) —Y 4 —C(═NR 25 )NR 23 R 24 ; and

k) —Y 4 —Y 5 -A 2 ;

 wherein

W 2 is —CH 2 —, —O—, —N(H), —S—, —SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—S(O) 2 —, —O—CO—,

 wherein R 19 and R 20 are independently selected from the group consisting of: -hydrogen, -aryl, -alkyl, -alkylene-aryl, alkoxy, and -alkylene-O-aryl;

R 18 is -aryl, -alkyl, -alkylene-aryl, -alkylene-heteroaryl, or -alkylene-O-aryl;

Y 5 is a direct bond, —CH 2 —, —O—, —N(H), —S—, SO 2 —, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —NHSO 2 NH—, —O—CO—,

 wherein R 27 and R 28 are independently selected from the group consisting of aryl, -alkyl, -alkylene-aryl, alkoxy, and alkyl-O-aryl;

Y 4 is

a) -alkylene;

b) -alkenylene;

c) -alkynylene;

d) -arylene;

e) -heteroarylene;

f) -cycloalkylene;

g) -heterocyclylene;

h) -alkylene-arylene;

i) -alkylene-heteroarylene;

j) -alkylene-cycloalkylene;

k) -alkylene-heterocyclylene;

l) -arylene-alkylene;

m) -heteroarylene-alkylene;

n) -cycloalkylene-alkylene;

o) -heterocyclylene-alkylene;

p) —O—;

q) —S—;

r) —(O) 2 —; or

s) —S(O)—;

 wherein said alkylene groups may optionally contain one or more O, S, S(O), or SO 2 atoms;

A 2 is

a) heterocyclyl, fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing at least one basic nitrogen atom, or

b) -imidazolyl,

R 23 , R 24 , and R 25 are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkylene-heteroaryl, alkyl, -alkylene-aryl, -alkylene-O-aryl, and -alkylene-O-heteroaryl; and R 23 and R 24 may be taken together to form a live membered ring having the formula —(CH 2 ) 3 —X 3 —(CH 2 ) r — bonded to the nitrogen atom to which R 23 and R 24 are attached

 wherein

s and t are, independently, 1, 2, or 3;

X 3 is a direct bond, —CH 2 —, —O—, —S—, —S(O) 2 —, —C(O)—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —C(O)—O—, —O—C(O)—, —NHSO 2 NH—,

 wherein R 28 and R 29 are independently selected from the group consisting of: -hydrogen, -aryl, -heteroaryl, -alkyl, -arkylene-aryl, and -alkylene-heteroaryl;

wherein

the alkyl and/or aryl groups of R 102 and R 104 may be optionally substituted 1–4 times with a substituent group selected from the group consisting of:

a) halogen;

b) perhaloalkyl;

c) alkyl;

d) cyano:

e) alkyloxy

f) aryl; and

g) aryloxy

wherein the ring or rings containing a -hetercatom in the heteroaryl, heteroarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl, or fused heteroarylheterocyclyl groups in R 102 or R 104 or in a substituent of R 102 or R 104 is a five membarnd nitrogen containing ring, and

wherein

at least one of R 102 and R 104 is a group of the formula

—Y 4 —NR 23 R 24 ,

—Y 4 —NH−C(=NR 25 )NR 23 R 24 ,

—Y 4 —C(=NR 25 )NR 23 R 24 , or

—Y 4 —Y 5 −A 2 ,

with the proviso that no more than one of R 23 , R 24 , and R 25 is aryl or heteroaryl;

or a pharmaceutically acceptable salt thereof.

2. The compound of Formula (Ib) of claim 1 , wherein R 1 is a hydrogen, methyl, ethyl, propyl, butyl, iso-butyl, 3-butenyl, tert-butyl, 2,4,4-trimethyl-pentyl, 1-ethyl-propyl, or 1-propyl-butyl, and R 3 is -hydrogen,

or a pharmaceutically acceptable salt thereof.

3. The compound of Formula (Ib) of claim 1 , wherein R 102 and R 104 are independently selected from the group consisting of:

2-(4-chlorophenyl)-ethyl,

3-(N,N′-diethyiamino)-propyl,

2-amino-ethyl,

2-(guanidinyl)-ethyl,

3-(N,N′-dimethylamino)-propyl,

3-fluoro-4-trifluoromethyl-phenyl,

4-fluoro-3-trifluoromethyl-phenyl,

4-phenyl-phenyl,

4-trifruoromethyl-benzyl,

3,4-dichloro-phenyl,

2,4-dichloro-phenyl,

benzyl,

4-phenoxy-benzyl,

3,4,5-trimethoxybenzyl,

2-(pyrrolidin-1-ethyl,

2,2′-dimethyl-3-(N,N′-dimethylamino)-propyl,

2-(N,N′-diisopropylamino)-ethyl,

4-bromo-benzyl, 4-chlorophenyl,

3,3-diphenylpropyl,

2-(biphenyl-4-yl)-acetamido

2-(SH-carbazole)-ethyl,

4-methoxyphenyl,

4-tert-butyl-phenyl, and

naphthylen-2-ylmethyl,

or a pharmaceutically salt thereof.

4. The compound of Formula (Ib) of claim 1 , wherein R 1 is -alkyl, R 3 is hydrogen; R 102 is -aryl or -alkylene-aryl substituted with at least one of a halogen, a perhaloalkyl, or an alkoxy group; and R 104 is —Y 4 —NR 23 R 24 or ——Y 4 —Y 5 -A 2 ,

or a pharmaceutically acceptable salt thereof.

5. The compound of Formula (Ib) of claim 1 , wherein

R 3 is hydrogen; and

R 102 and R 104 are independently selected from the group consisting of -aryl and -alkylene-aryl,

wherein

the alkyl or aryl groups of R 102 and R 104 are optionally substituted with at least one of a halogen, a perhaloalkyl, or an alkoxy group, and wherein at least one of R 102 and R 104 is —Y 4 —NR 23 R 24 or —Y 4 Y 5 -A 2 wherein Y 4 is alkylene,

or a pharmaceutically acceptable salt thereof.

6. A compound selected from the group consisting of:

(1) {3—[4-(2-butyl-4(4[2-(4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine;

(2) {3-[4-(4-[4-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-2-isobutyl-imidazol-1-yl)-phenoxy)-propyl}-diethyl-amine;

(3) [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(4) 3-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(5) diethyl-[3-(4-{1-[4-(4-flouro-3-trifluoromethyl-phenoxy)-phenyl]-2-methyl-1H-imidazol-4-yl}-phenoxy)-propyl]-amine;

(6) [3-(4-{2-butyl-1-[4-(3-tert-butyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(7) (3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(1ethyl-propyl)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine;

(8) {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-5-methyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine;

(9) {3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-5-propyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine;

(10) {3-[4-(5-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-5-propyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine;

(11) [3-(4-{1-[4-chloro-phenyl)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(12) [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-methyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(13) [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-propyl-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(14) [3-(4-[2,5-dibutyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(15) 2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-(2-pyrrollidin-1-yl-ethoxy)-phenyl]-1H-imidazole;

(16) [3-(4-{2-butyl-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine;

(17) [3-(4-{2-butyl-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine;

(18) (3-{4-[2-butyl-1-(4-p-tolyloxy-phenyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-diethyl-amine;

(19) [3-(4-{2-butyl-1-[4(4-fluoro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine;

(20) [3-(4-{4-[4-(3,3-diphenyl-propoxy)-phenyl]-2-isobutyl-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine; and

pharmaceutically acceptable salts thereof.

7. A compound which is [3-(4-[2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl]-phenoxy)-propyl]- diethyl-amine, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutically composition comprising a compound of Formula (Ib) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

9. A pharmaceutically composition comprising a compound of Formula (Ib) as claimed in claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

10. A pharmaceutically composition comprising a compound of Formula (Ib) as claimed in claim 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

11. A pharmaceutically composition comprising a compound of Formula (Ib) as claimed in claim 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

12. A pharmaceutically composition comprising a compound of Formula (Ib) as claimed in claim 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

13. A pharmaceutically composition comprising a compound as claimed in claim 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

14. A pharmaceutical composition comprising [3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

15. The pharmaceutical composition of claim 8 , in the form of an oral dosage or parenteral dosage unit.

16. The pharmaceutical composition of claim 8 , wherein said compound or a pharmaceutically acceptable salt thereof is a dose in a range from about 0.01 to 500 mg/kg of body weight per day.

17. The pharmaceutical composition of claim 8 , wherein said compound or a pharmaceutically acceptable salt thereof is a dose in a range from about 0.1 to 200 mg/kg of body weight per day.

18. The pharmaceutical composition of claim 8 , wherein said compound or a pharmaceutical acceptable salt thereof is a dose in a range from about 0.1 to 100 mg/kg of body weight per day.

19. The pharmaceutical composition of claim 8 , in a topical dosage form.

20. The pharmaceutical composition of claim 19 , wherein said compound or a pharmaceutically acceptable salt thereof is in a formulation ratio of 0.1% to 99% of compound to topical excipient.

21. The pharmaceutical composition of claim 8 , wherein said compound or a pharmaceutically acceptable salt thereof is in an inhaled dosage form.

22. The pharmaceutical composition of claim 21 , wherein said composition is an aerosol formulation,

23. The pharmaceutical composition of claim 21 , wherein said composition is an inhaled powder dosage form,

24. The pharmaceutical composition of claim 8 , further comprising one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgeslcs, NSAlDs, DMARDs, glucocorticolds, suitonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anficonvulsants.

Assignments (15)