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1. (WO1995032953) INHIBITEURS D'ACAT A BASE D'AMIDE TETRAZOLE
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 having the Formula I


wherein R1 is selected from
(a) phenyl which is unsubstituted or is
substituted with from 1 to 3 substituents selected from
C1-C4 alkyl,
C1-C4 alkoxy,
C1-C4 alkylthio,
hydroxy,
halo,
nitro,
cyano,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from 1 to
4 carbon atoms and which is straight or
branched,
-(CH2)mNRxRy wherein m is 0 or 1, and each of
Rx and Ry is independently hydrogen or
C1-C4 alkyl;
(b) 1- or 2-naphthyl which is unsubstituted or substituted with from 1 to 3 substituents selected from
C1-C4 alkyl,
C1-C4 alkoxy,
C1-C4 alkylthio,
hydroxy, halo,
nitro,
cyano,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from 1 to
4 carbon atoms and which is straight or branched,
-(CH2)mNRxRy wherein m is 0 or 1, and each of

Rx and Ry is independently hydrogen or
C1-C4 alkyl;
(c) the group


(d) the group


wherein R8 and R9 independently are C1-C4 alkyl or phenyl, and R10 is a straight or branched
hydrocarbon group having from 1 to 18 carbon atoms which is saturated or is unsaturated containing one double bond or two nonadjacent double bonds; phenyl; phenyl substituted with from 1 to
3 substituents selected from C1-C4 alkyl,
C1-C4 alkoxy,
hydroxy,
halo, nitro,
cyano,
trifluoromethyl,
-COOH,
-COOalkyl wherein alkyl has from 1 to
4 carbon atoms and is straight or
branched,
-(CH2)mNRxRy wherein m, Rx, and Ry are as
defined above; or
a heterocyclic group selected from 2-, 3-, or

4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-, or 3-pyrazinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 3- or 4-pyridazinyl,
and the N-oxides thereof;
(e) the group


(f) a straight or branched hydrocarbon group having from 1 to 18 carbon atoms which is
saturated or is unsaturated containing one double bond or two nonadjacent double bonds;
(g) a cycloalkyl group having from 3 to
10 carbon atoms;

(h) the group



wherein ---- denotes a single or double bond;

Y and Z are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or halo;
W is oxygen or two hydrogen atoms;
R11 is hydrogen or C1-C4 alkyl, and n' is 0 or 1; or
(i) is selected from the group


wherein R12, R13, R14, and R15 are each
independently
hydrogen,
halo,
C1-C4 alkyl,
C1-C4 alkoxy,
C1-C4 alkylthio,
cycloalkylthio of 5 to 7 carbon atoms, phenylalkylthio in which alkyl is 1 to
4 carbon atoms,
substituted phenylthio, heteroarylthio, or heteroaryloxy;
and B, D, E, and G are nitrogen or carbon where one or more of B, D, and E is nitrogen;
with the proviso that when G = N, the group is attached to the nitrogen atom of Formula I at the four or five position of the pyrimidine ring (a and b);
X is unsaturated (= X) and is selected from:
(a) = O
(b) = NR5 where R5 is selected from
i) the group R4, wherein R4 is hydrogen, C1-C4 alkyl, hydroxy C1-C4 alkyl, C1-C4 alkanoyl, C3-C10 cycloalkyl, C2-C6 alkenyl, or

(CH2)m-phenyl or
wherein
the phenyl is unsubstituted or is
substituted with from 1 to
3 substituents selected from
C1-C4 alkyl,
C1-C4 alkoxy,
C1-C4 alkylthio,
phenyl,
hydroxy,
halo,
nitro,
cyano,
trifluoromethy1,
-COOH,
-COOalkyl wherein alkyl has from
1 to 4 carbon atoms and which
is straight or branched,
-(CH2)mNRxRy wherein m is 0 or 1,
and each of Rx and Ry is hydrogen or a straight chain
alkyl group having 1 to
4 carbon atoms;
R4 is heteroaryl selected from a 5- or 6-membered monocyclic or fused
bicyclic heterocyclic group
containing at least 1 to
4 heteroatoms in at least one
ring, said heteroatoms being
nitrogen, oxygen, or sulfur and
combinations thereof, said
heterocyclic group being
unsubstituted or substituted with an alkyl group having from 1 to
4 carbon atoms and the N-oxides
thereof;
or 1- or 2-naphthyl which is
unsubstituted or substituted with 1 to 3 substituents selected from
alkyl having from 1 to 4 carbon
atoms and which is straight
or branched, and
alkoxy having from 1 to 4 carbon
atoms and which is straight
or branched;
(ii) the group -ORx , wherein Rx is
hydrogen, R4, C1-C18 alkyl, C2-C18
alkenyl, C2-C18 alkynyl, or such alkyl, alkenyl, and alkynyl groups substituted with R4;
(iii) the group -NR6R7, wherein R6 is
hydrogen, C1-C4 alkyl, or phenyl
which is unsubstituted or
substituted with 1 to
3 substituents selected from
straight or branched alkyl having 1 to 4 carbon atoms, straight or
branched alkoxy having from 1 to
4 carbon atoms, halo, trifluoromethyl, cyano, and nitro; R7 is
hydrogen, C1-C4 alkyl, or heteroaryl selected from a 5- or
6-membered monocyclic or fused
bicyclic heterocyclic group
containing at least 1 to
4 heteroatoms in at least one
ring, said heteroatoms being
nitrogen, oxygen, or sulfur and
combinations thereof, said
heterocyclic group being
unsubstituted or substituted with
an alkyl group having from 1 to
4 carbon atoms and the N-oxides
thereof; or R6 and R7 together
with the nitrogen to which they
are attached from a 4- to
7-membered ring;
(iv) or NHCONH2;
wherein X is saturated (-X), it is selected from the group NR3R4, wherein R4 is also defined above, and preferably R3 and R4 are the same or different and are selected from
(a) hydrogen;
(b) C1-C4 alkyl or a cycloalkyl group having from 3 to 10 carbon atoms;
(c) when R3 = H, R4 is C1-C4 alkanoyl, benzoyl, substitued benzoyl, C2-C6 alkenyl, and those substituents previously defined for R5 = R4;
(d) R3 and R4 taken together with the nitrogen atom to which they are attached to form 5- to 7-membered monocyclic heterocycles containing 1 to 4 heteroatoms, said heteroatoms being nitrogen, oxygen, or sulfur and combinations thereof, said heterocyclic group being unsubstituted or
substituted with phenyl or an alkyl group having
1 to 4 carbon atoms; wherein R2 is a straight or branched hydrocarbon chain having from 1 to 20 carbon atoms and is saturated or is unsaturated and has one double bond or has two nonadjacent double bonds; and wherein R2 can be bonded
directly to the tetrazole ring or connected
through an oxygen or sulfur atom; pharmaceutically acceptable salts and individual enantiomeric
isomers and regioisomers of the compounds.

2. A compound of Claim 1 wherein R1 is phenyl or
substituted phenyl.

3. A compound of Claim 2 wherein R2 is C1-C20 alkyl.

4. A compound of Claim 3 wherein R2 is C6-C12 alkyl.

5. A compound of Claim 4 wherein X is -NR3R4.

6. A compound of Claim 5 which is:
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-thiomorpholin-4-yl-acetamide;
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-morpholino-4-yl-acetamide;
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-piperidin-1-yl-acetamide;
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-pyrrolidinyl-1-yl-acetamide;
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-imidazol-1-yl-acetamide;
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2-tetrazol-5-yl)-2-(4-methyl-piperazin-1-yl)- acetamide;

(±)-2-diethylamino-N-(2,6-diisopropylphenyl)- 2-(2-dodecyl-2H-tetrazol-5-yl)-acetamide;
(±)-2-[bis-(2-hydroxyethyl)-amino]-N-(2,6- diisopropylphenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)- acetamide;
(±)-N-(2,6-diisopropylphenyl)-2- dimethylamino-(2-dodecyl-2H-tetrazol-5-yl)- acetamide;
(±)-2-amino-N-(2,6-diisopropylphenyl)-2-(2- dodecyl-2H-tetrazol-5-yl)-acetamide;
(±)-N-(2,4,6-trimethoxyphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-pyrrolidin-1-yl-acetamide;
(±)-N-2,4,6-triisopropylphenyl-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-pyrrolidin-1-yl-acetamide
(±)-N-(2,4,6-trimethylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-pyrrolidin-1-yl-acetamide;
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-(homopiperidin-1-yl)- acetamide;
(±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-cyclohexylamino-acetamide;
(±)-N-(2,4,6-trichlorophenyl)-2-[2-(5-octen- 1-yl)-2H-tetrazol-5-yl]-2-isopropylaminoacetamide; and
(±)-N-(4-nitrophenyl)-2-(2-heptyl- 2H-tetrazol-5-yl)-2-(N-methylcyclopentylamino)- acetamide.

7. A compound of Claim 4 wherein X is = N-R5.

8. A compound of Claim 7 which is
N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H- tetrazol-5-yl)-2-hydroxyimino-acetamide;
E-N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H- tetrazol-5-yl)-2-methoxyimino-acetamide;

Z-N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H- tetrazol-5-yl)-2-methoxyimino-acetamide;
E-2-(2-dodecyl-2H-tetrazol-5-yl)-2- methoxyimino-N-(2,4,6-trimethoxyphenyl)-acetamide;
E-N-(2,6-diisopropylphenyl)-2-(2-(1- methylundecyl)-2H-tetrazol-5-yl)-2-methoxyimino- acetamide;
Z-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-ethoxyimino-acetamide;
E-N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-ethoxyimino-acetamide;
E-N-(2,6-diisopropylphenyl)-2-(1-dodecyl-1H- tetrazol-5-yl)-2-ethoxyimino-acetamide;
N-(2,4,6-triisopropylphenyl-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-methoxyimino-acetamide;
N-(2-methoxy-4-bromo-6-methylthiophenyl)-2- (2-ocyl-2H-tetrazol-5-yl)-2-isobutoxyimino- acetamide;
N-(2,6-diisopropylphenyl)-2-(2 dodecyl- 2H-tetrazol-5-yl)-2-hydrazono-acetamide;
N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-phenylhydrazono-acetamide;
N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-dimethylhydrazono-acetamide;
Z-N-(2,6-diisopropylphenyl)-2-(2-dodecyltetrazol-5-yl)-2-(phenylmethoxyimino)-acetamide;
E-N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H- tetrazol-5-yl)-2-(phenylmethoxyimino)-acetamide;
and
N-(2,6-diisopropylphenyl)-2-(2-dodecyl- 2H-tetrazol-5-yl)-2-aminocarbonylhydrazono- acetamide.

9. A compound of Claim 2 wherein X = 0.

10. A compound of Claim 9 which is N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H-tetrazol-5-yl)-2-oxo- acetamide.

11. A compound of Example 1 wherein R1 is naphthyl or substituted naphthyl.

12. A compound of Claim 11 wherein R2 is C1-C20 alkyl.

13. A compound of Claim 12 wherein R2 is C6-C12 alkyl.

14. A compound of Claim 13 which is
N-(6-ethylthionaphth-1-yl)-2-(2-octyl- 2H-tetrazol-5-yl)-2-ethylhydrazono-acetamide;
N-(2-n-butylthionaphth-1-yl)-2-(2-isoheptyl- 2H-tetrazol-5-yl)-2-formamido-acetamide; and
N-(7-hydroxynaphth-2-yl)-2-[2- (5-isobutyloctyl)-2H-tetrazol-5-yl]-2- (N-ethylcyclopropylamino)-acetamide .

15. A compound of Claim 1 wherein R1 is 4,6-dialkoxypyrimidin-5-yl and R2 is C6-C12 alkyl.

16. A compound of Claim 1 wherein R1 is 4-(2-chlorophenyl)-5,7-dimethylquinolin-2-yl and R2 is C6-C12 alkyl.

17. A compound of Claim 1 wherein X is -NR3R4 wherein
R3 and R4 independently are hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, hydroxy C1-C4 alkyl, or R3 and R4 taken together with the nitrogen form
pyrrolidinyl, morpholinyl, piperidinyl,
thiomorpholinyl, 4-alkylpiperazinyl, or
imidazolyl.

18. A compound of Claim 1 wherein X is -NR3R4 in which R3 is hydrogen and R4 is C1-C4 alkyl or C1-C4
alkanoyl.

19. A compound of Claim 1 wherein X is =N-R5.

20. A compound of Claim 19 wherein R5 is hydroxy or
C1-C4 alkoxy.

21. A compound of Claim 4 wherein R1 is 2,6-diisopropylphenyl and R2 is dodecyl.

22. A compound of Claim 2 wherein R1 is phenyl
substituted with one, two, or three C1-C4 alkyl groups.

23. A pharmaceutical formulation for treating hypercholesterolemia or atherosclerosis comprising an
ACAT-inhibiting effective amount of a compound of Claim 1 together with a pharmaceutically
acceptable carrier.

24. A formulation of Claim 23 wherein R1 is phenyl or substituted phenyl and R2 is C6-C12 alkyl.

25. A formulation of Claim 24 wherein R1 is 2,6-diisopropylphenyl.

26. A formulation of Claim 25 wherein R2 is dodecyl.

27. A method of treating hypercholesterolemia or
atherosclerosis comprising administering to a
mammal in need of such treatment an ACAT- inhibiting amount of a compound of Claim 1.

28. A method of Claim 27 employing a compound wherein R1 is phenyl or substituted phenyl and R2 is C6-C12 alkyl.

29. A method of Claim 28 employing a compound wherein R1 is 2,6-diisopropylphenyl and R2 is dodecyl.