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1. (WO2005066164) ANTAGONISTES DE RECEPTEUR D'OPIOIDES
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

We claim:

1. A compound of formula (I)



(I)
wherein
each of Xls X2, X3, X4, X5, X6, X7, X8, X and X10 is C, CH, or N; provided that each of rings A or B has no more than 2 nitrogen atoms;
E is O or N; provided that when E is O, R is absent from E-R ; and further provided that when E is O and R is absent, then W is not NR ;
W is O or NR7;
v is 1, 2, or 3;
R1 and R2 are independently selected from hydrogen, -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl, Ci-Cio alkylaryl, C(O)d-C8 alkyl, CO(O)Cι-C8 alkyl, SO2C!-C8 alkyl, SO2C1-C10 alkylaryl, Ci-C8 alkylheterocyclic, 8020,-03
alkylheterocyclic, Ci-Cio alkylcycloalkane, - alkoxyalkyl, (CH2)nC(O)OR8,
(CH2)nC(O)R8, (CH2)mC(O)NR8R8, and (CH2)mNSO2R8; wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclic and aryl groups are optionally substituted with one to five groups independently selected from oxo, Cι-C8 alkyl, C2-C8 alkenyl, phenyl, C]-C8 alkylaryl, C^ -Cs alkyl, CO^C Cs alkyl, C C8 alkoxy, SO Q-Cs alkyl, SO2d-C8 alkylaryl, SOa - alkylheterocyclic, C]-C10 alkylcycloalkane, (CH2)nC(O)OR8, and (CH2)nC(O)R8; and wherein R1 and R2 may optionally combine together to form a 4, 5, 6, or 7-membered nitrogen-containing heterocycle which nitrogen -containing heterocycle is optionally substituted with 1, 2, or 3 substitutents independently selected from the group consisting of oxo, amino, Cj-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cι-C8 alkoxy, phenyl, C C8 alkylaryl, C(O)C C8 alkyl, CO(O)Cι-C8 alkyl, halo, and d-C8 haloalkyl;

R and R are each independently selected from hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, phenyl, aryl, d-C8 alkylaryl;
R4 and R5 are each independently selected from hydrogen, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, d-C8 alkoxy, halo, d-C8 haloalkyl, phenyl, aryl, d-C8 alkylaryl,
(CH2)mNSO2d-C8 alkyl, (CH2)mNSO2phenyl, (CH2)mNSO2aryl, -C(O)d-C8 alkyl, and -C(O)Od-C8 alkyl; wherein each R4 and R5 is attached to its respective ring only at carbon atoms, and wherein y is 0, 1, 2, or 3; and wherein z is 0, 1, 2, or 3;
R and R are each independently selected from hydrogen, d-C8 alkyl, d-C8 alkenyl, C2-C8 alkynyl, C(O)d-C8 alkyl, hydroxy, d-C8 alkoxy, aryl, d-C8 alkylaryl, C3-C8 cycloalkyl, d-C8 alkylheterocyclic, d-do alkylcycloalkyl, -NHd-C8 alkyl,
(CH2)nC(O)OR8, (CH2)nC(O)R8, (CH2)mC(O)NR8R8, and (CH2)mNSO2R8; wherein each of the alkyl, alkenyl, cycloalkyl, heterocyclic, and aryl groups is optionally substituted with one to 3 groups independently selected from d-C8 alkyl, C2-C8 alkenyl, phenyl, and d-C8 alkylaryl; and wherein R and R optionally combine together to form a 5, 6, or 7-membered nitrogen-containing heterocycle with E and W; and wherein the nitrogen containing heterocycle is optionally substituted with 1 -2 groups independently selected from the group consisting of oxo, amino, d-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, phenyl, d-C8 alkylaryl, C(O)d-C8 alkyl, CO(O)Cι-C8 alkyl, hydroxy, d-C8 alkoxy, halo, and haloalkyl;
R8 is hydrogen, Cι-C8 alkyl, C2-C8 alkenyl, C5-C8 alkylaryl, (CH2)mNSO2C1-C8 alkyl, (CH2)mNSO aryl, -C(O)d-C8 alkyl, or -C(O)OC C8 alkyl; n is 0, 1, 2, or 3; and m is 1, 2 or 3;
or a pharmaceutically acceptable salt, solvate, enantiomer, racemate, diastereomers or mixtures thereof.

2. The compound according to claim 1 wherein the A-ring is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, and pyridazine.

3. A compound according to Claim 1 wherein the B-ring is selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, and pyridazine.

4. A compound according to Claim 1 wherein the A-ring is phenyl and the B
<
ring is pyridinyl.

5. A compound according to Claim 1 wherein the A ring is phenyl and the B ring is pyrazinyl.

6. A compound according to Claim 1 wherein the A-ring is pyridinyl and the B-ring is phenyl.

7. A compound according to Claim 1 wherein both rings A and B are phenyl.

8. A compound according to Claim 1 wherein E is a nitrogen atom.

9. A compound according to Claim 1 wherein y is 0, 1, or 2, and R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, phenyl, and benzyl.

10. A compound according to Claim 1 wherein z is 0, 1, or 2, and R5 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, phenyl, and benzyl.

1 1. A compound according to Claim 1 wherein R1 and R2 are each
independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl,

and wherein n is 1, 2, or 3.

fi 7
12. A compound according to Claim 1 wherein R and R are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and phenyl.

13. A compound according to Claim 1 wherein v is 1 or 2.

14. A compound according to Claims 1 wherein v is 2, m is 1, n is 1, y is 0 or 1 and z is 0 or 1.

15. A compound selected from the group consisting of:
6-{4-[(3-Methyl-butylamino)-methyl]-phenoxy}-nicotinimidic acid ethyl ester



N-Hydroxy-6-{4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinamidine

6- { 4-[(3-Methyl-butylamino)-methyl]-phenoxy } -nicotinamidine



{4-[5-(4,5-Dihydro-lH-imidazol-2-yl)-pyridin-2-yloxy]-benzyl}-(3-methyl-butyl)-amine



{4-[5-(4,5-Dihydro-lH-imidazol-2-yl)-pyridin-2-yloxy]-benzyl}-(2-thiophen-2yl-ethyl)amine


(3-Methyl-butyl)-{4-[5-(l,4,5,6-tetrahydro-2-yl)-pyridin-2-yloxy]-benzyl} -amine



N-Cyano-6- { 4-[(3-methyl-butylamino)-methyl]-phenoxy } -nicotinamidine



(3-Methyl-butyl)- { 4-[5-(2H-tetrazol-5-yl)-pyridin-2-yloxy]-benzyl } -amine


{4-[5-(lH-Imidazol-2-yl)-pyridin-2-yloxy]-benzyl}-(3-methyl-butyl)-amine



N-(2,2-Dimethoxy-ethyl)-6-{4-[(3-methyl-butylamino)-methyl]-phenoxy} -nicotinamidine



and a pharmaceutically acceptable salt, solvate, enantiomer, diastereomer and
diastereomeric mixture thereof.

16. A compound according to Claim 1 wherein the pharmaceutically acceptable salt is the hydrochloric acid salt, the methanesulfonic acid salt, hydrobromide salt, the bisulfate salt or tartaric acid salt.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 in association with a carrier, diluent and/or excipient.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 15 in association with a carrier, diluent and/or excipient.

19. A method for blocking a mu, kappa, delta or receptor combination (heterodimer) thereof in mammals comprising administering to a mammal requiring blocking of a mu, kappa, delta or receptor combination (heterodimer) thereof, a receptor blocking dose of a compound according to Claim 1 or a pharmaceutically acceptable salt, enantiomer, racemate, mixture of diastereomers, or solvate thereof.

20. A method of treating and/or preventing obesity and Related Diseases comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof.

21. A method of treating and/or preventing diseases related to obesity including irritable bowel syndrome, nausea, vomiting, obesity-related depression, obesity-related anxiety, smoking and alcohol addiction, sexual dysfunction, substance abuse, drug overdose, addictive behavior disorders, compulsive behaviors, metabolic diseases, and stroke, comprising administering a therapeutically effective amount of a compound of formula I.

22. A method according to Claim 20 wherein the Related Diseases is selected from the group consisting of diabetes, diabetic complications, diabetic retinopathy, atherosclerosis, hyperlipidemia, hypertriglycemia, hyperglycemia, and
hyperlipoproteinemia.

23. A method of suppressing appetite in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula I.

24. Use of a compound according to Claim 1 for the manufactrure of a medicament for the treatment of obesity and Raited Diseases.

25. Use of a compound according to Claim 15 for the treatment of weight loss comprising administering an effective dose of said compound to a person in need thereof.