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1. WO2007011810 - SPIROPIPERIDINE BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

What is claimed is:

1. A compound of formula (I)

or its tautomer (P)


wherein

Rl is selected from the group consisting of
(1) hydrogen,
(2) -Ci_iO alkyl,
(3) -C3.12 cycloalkyl,
(4) a heterocyclic group having 4 to 8 ring atoms, wherein one ring atom is a heteroatom selected from the group consisting of nitrogen, sulfur or oxygen, and (5) phenyl,
wherein said alkyl, cycloalkyl, heterocyclic or phenyl Rl moiety is optionally substituted with one or more
(a) hydrogen,
(b) halo,
(c) -OH,
(d) -CN,
(e) -Ci-IO alkyl
(f) -C3-I2 cycloalkyl,
(g) -O-Cl-iO alkyl, or
(h) phenyl; .

R2 is optionally present at one or more of the ring carbon atoms, and is selected from the group consisting of
(l) halo,
(2)-OH,
(3) -CN, and
(4) -Ci-10 alkyl;

R3 is selected from the group consisting of
(1) hydrogen,
(2) -Ci-10 alkyl,
(3) -C3-12 cycloalkyl,
(4) phenyl, and
(5) heteroaryl,
wherein said alkyl, cycloalkyl, phenyl or heteroaryl R3 moiety is optionally substituted with one or more
(a) halo,
(b) -OH,
(c) -CN,
(d) -Ci-10 alkyl,
(e) -C3-I2 cycloalkyl,
(f) -O-C3-I2 cycloalkyl,
(g) -0-Ci-io alkyl,
and said alkyl and cycloalkyl moiety is optionally
substituted with one or more
(i) halo, (ϋ)-OH,
(iii) -CN,
(iv) -C3-12 cycloalkyl,
(v) -Ci-io alkyl, or
(vi) -OCi-10 alkyl;
and pharmaceutically acceptable salts thereof, and individual enantiomers and diastereomers thereof.

2. A compound of claim 1 of formula (T), wherein Rl is optionally substituted Ci-io alkyl.

3. A compound of claim 1 of formula (I), wherein Rl is optionally substituted C3-I2 cycloalkyl.

4. A compound of claim 1, wherein R2 is present at one of the ring carbon atoms, and is halogen.

5. A compound of claim 1, wherein R3 is phenyl, wherein the phenyl is optionally substituted with one or more
(A) halo,
(B)-OH,
(C) -CN3
(D) -Ci-io alkyl, and
(E) -OCi-10 alkyl.

6. A compound of claim 1, or an enantiomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) and (F) is a compound of formula (IB)

or its tautomer (IB')


7. A compound of of claim 1 of formula (I), which is selected from the group consisting of Racemic 5(R,S)7(R,S)-8-benzyl-4-(cyclohexylamino)-l-(3-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one (diastereomer A);
Racemic 5(R,S)7(S,R)-8-benzyl-4-(cyclohexylamino)-l-(3-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one (diastereomer B);
Racemic 5(R,S)7(R,S)
-4-(cyclohexylamino)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one (diastereomer A);
Racemic 5(R,S)7(S,R)
-4-(cyclohexylamino)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one (diastereomer B);
Racemic 5(R,S)7(R,S)-8-ben2yl-4-(cyclohexylamino)-7-methyl-l -phenyl-1 ,3,8-triazaspiro[4.5]dec-3-en- 2-one (diastereomer A);
Racemic 5(R,S)7(S,R) -8-benzyl-4-(cyclohexylamino)-7-methyl-l-phenyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one (diastereomer B); Racemic 5(R,S)7(R,S)-8-(3-isopropoxybenzyl)-4-(isopropylamino)-7-methyl-l-(3-methylphenyl)-l,3,8-triazaspiro[4.5]dec-3-en-2-one (diastereomer A);
Racemic 5(R,S)7(S,R)
-8-(3-isopropoxybenzyl)-4-(isopropylamino)-7-methyl-l-(3-methylphenyl)-l,3,8-triazaspiro[4.5]dec-3-en-2-one (diastereomer B);
and enantiomers and pharmaceutically acceptable salts thereof.

8. A compound of claim 6 of formula (IB), which is selected from the group consisting of
(5R,7S)-4-(cyclohexylamino)-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5] dec-3 -en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-{[(lS,2S)-2-fluorocyclohexyl]ammo}-l-(3-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7.S)-8-(cyclobutylmethyl)-4-{[(lR,2R)-2-fluorocyclohexyl]ammo}-l-(3-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-l-(3-fluorophenyl)-7-methyl-8-(3-thienylmethyl)-l,3,8-triazaspiro[4.5]dec- 3-en-2-one;
(5R,7S)-l-(3-chlorophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)- 1 -(3 -bromophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl- 1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5i?,7)S)-4-{[(li?)-2,2-difluorocyclopentyl]amino}-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl- 1 ,3,8-triazaspiro[4.5]dec-3-en-2-one; and
(5R,7S)-4-{[(lS)-2,2-difluorocyclopentyl]amino}-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;
and pharmaceutically acceptable salts thereof.

9. A compound of claim 8, which is selected from the group consisting of
(5R,7S)-4-(cyclohexylamino)- 1 -(3 -fiuorophenyl)-8-(3 -isopropoxybenzyl)-7-methyl- 1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-{[(li?,2i?)-2-fluorocyclohexyl]amino}-l-(3-fluorophenyl)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-l-(3-chlorophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-l-(3-bromophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;

(5R,7S)-4-{[(li?)-2,2-difluorocyclopentyl]ammo}-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1 ,3,8-triazaspiro[4.5]dec-3-en-2-one; and
(5R,7S)-4-{[(lS)-2,2-difluorocyclopentyl]amino}-l-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7 -methyl-l,3,8-triazaspiro[4.5]dec-3-en-2-one;
and pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, further comprising a P450 inhibitor.

12. The pharmaceutical composition of claim 11, wherein the P450 inhibitor is ritonavir.

13. A pharmaceutical composition for the treatment of Alzheimer's Disease, comprising a therapeutically effective amount of a compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13, further comprising a P450 inhibitor.

15. The pharmaceutical composition of claim 14, wherein the P450 inhibitor is ritonavir.

16. Use of a pharmaceutical composition of any of claims 13-15 for the treatment of Alzheimer's Disease.

17. Use of a compound of any of claims 1-9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, for the manufacture of a medicament for the treatment of Alzheimer's Disease.

18. A method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method of treating Alzheimer's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a P-450 inhibitor, and a pharmaceutically acceptable carrier.

0. The method of claim 19, wherein the P450 inhibitor is ritonavir.