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1. (WO1993017557) COMPOSES ABAISSANT LE TAUX DE CHOLESTEROL ET PRODUITS PAR BIOSYNTHESE DIRIGEE
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

WHAT IS CLAIMED IS:

1. A compound selected from structural formulae (I) and (II)



wherein R1 is selected from the group consisting of

,


,


,

,

, and

;

wherein X is selected from:
(a) H,
(b) halogen (F, Cl, Br, I),
(c) OH, and
(d) CH3;
Y is selected from:
(a) halogen (F, Cl, Br, I),
(b) OH, and
(c) CH3;
and wherein Z1, Z2 and Z3 are each independently selected from:
(a) H,
(b) C1-5alkyl,
(c) C1-5alkyl substituted with:
(i) phenyl,
(ϋ) phenyl substituted with a substituent
selected from methyl, methoxy, halogen
(Cl, Br, I, F) and hydroxy,
(iϋ) C1-5alkylcarbonyloxy,
(iv) C6-10arylcarbonyloxy,
(v) C1-5alkoxycarbonyloxy,
(vi) C6-10aryloxycarbonyloxy,
(vii)


and


(ix) or the groups (iii) to (vi) form a 5 to
10 membered mono- or bicyclic ring with
C1-5alkyl; and
a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1 wherein Z1, Z2 and Z3 are each independently selected from:
(a) H,
(b) C1-5alkyl ,
(c) C1-5alkyl substituted with phenyl , or


(d ) pivaloyl ,
(e) sodium, potassium, aluminum, calcium,
lithium, magnesium or zinc, (f) ammonia, N,N'-dibenzylethylenediamine,
diethanolamine, N-benzylphenylethylamine, or diethylamine,
(g) N-methyl-glutamine, lysine, arginine, or
ofnithine,
(h) choline,
(i) chloroprocaine or procaine,
(j) piperazine,
(k) tetramethylammonium hydroxide, and
(l) tris(hydroxymethyl)aminomethane.

3. The compound of Claim 2 wherein the compound is of structural formula (I) and R1 is
selected from:

,

, and
.

4. The compound of Claim 3 wherein X is selected from H and F; and Y is selected from F and OH,

5. The compound of Claim 3 wherein Z1, Z2 and Z3 are each hydrogen.

6. The compound of Claim 5 wherein R1 is selected from:
(a) 3-thiophene,
(b) 3-fluorophenyl, (c) 4-fluoroρhenyl,
(d) 2-fluorophenyl,
(e) 2-furyl, and
(f) 2-thiophene.

7. The compound of Claim 2 wherein the compound is of structural formula (II) and R1 is



8. A pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptaible carrier.

9. A pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound of Claim 1 in combination with a nontoxic therapeutically effective amount of a cholesterol lowering agent selected from the group consisting of: a) HMG-CoA reductase inhibitor,
b) HMG-CoA synthase inhibitor,
c) squalene epoxidase inhibitor,
d) probucol,
e) niacin, f) gemfibrozil,
g) clofibrate,
h) LDL-receptor gene inducer, and
i) a pharmaceutically acceptable non-toxic
cationic polymer capable of binding bile
acids in a non-resorbable form in the
gastrointestinal tract.

10. A pharmaceutical composition comprising a unit dose of a compound of Claim 1 and a nontoxic therapeutically effective amount of an HMG-CoA
reductase inhibitor.

11. A method of treating hypercholesterolemia comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of Claim 1.

12. A method of inhibiting squalene synthase comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of Claim 1.

13. A method for inhibiting fungal growth comprising applying to the area where growth is to be controlled an antifungally effective amount of a compound of Claim 1.

14. A method for treating cancer comprising administration to a subject in need of such treatment a non-toxic therapeutically effective amount of a
compound of Claim 1.

15. A method of treating hypercholesterolemia comprising the administration to a subject in need of such treatment 20 to 100 mg of a compound of Claim 1.

16. A method for inhibiting fungal growth in a living organism in need of such treatment comprising the oral, systemic or parenteral administration of a non-toxic antifungally effective amount of a compound of Claim 1.

17. A process for the formation of a
compound of Claim 1 of structural formula (I) wherein Z1, Z2, and Z3 are each H, comprising the addition of a compound of Formula (III) selected from the group consisting of:

(a) R1-CO2H; and
(b) R1-CH2-CHNH2CO2H:

at a concentration of 0.01 mM to 100 mM, wherein R1 is selected from

;


;

;

;

; and

;

and wherein X is selected from:
(a) H,
(b) halogen (F, Cl, Br, I),
(c) OH, and
(d) CH3;

and Y is selected from:
(a) halogen (F, Cl, Br, I ) ,
(b) OH, and
(c) CH3;

to a Zaragozic Acid A producing culture and incubating for 48 to 120 hours at 20 to 30ºC at a pH less than 8 and isolating the product of Formula (I) from the culture broth.

18. The process of Claim 17 wherein the Zaragozic Acid A producing culture is:
(a) MF5453,
(b) MF5565,
(c) MF5599,
(d) MF5572,
(e) MF5573,
or a mutant having essentially the same characteristics as one of the above.

19. The process of Claim 18 wherein R1 is selected from:

,


, and

.

20. The process of Claim 19 wherein X is selected from H and F and Y is selected from F and OH.

21. The process of Claim 18 wherein an inhibitor of phenylalanine ammonium lyase is added to the culture broth.

22. The process of Claim 18 wherein the cells of the Zaragozic Acid A producing culture are homogenized before the addition of the compound of Formula (III).

23. The process of Claim 18 wherein the cells of the Zaragozic Acid A producing culture are treated with toluene before the addition of the compound of Formula (III).

24. The process of Claim 18 wherein the cells of the Zaragozic Acid A producing culture are washed after growth and resuspended in an aqueous medium before the addition of the compound of Formula (III).

25. A process for the formation of a compound of Claim 1 of structural formula (II) wherein Z1, Z2 and Z3 are each hydrogen, comprising the.
addition of a compound of formula (III) selected from the group consisting of:
(a) R1-CO2H, and
(b) R1-CH2-CHNH2CO2H;
wherein R1 is selected from:

;


;

;

;

; and

;

wherein X is selected from the group consisting of:
(a) hydrogen,
(b) halogen, wherein halogen is selected from the group:
(i) F,
(ϋ) Cl,
(iii) Br, and
(iv) I,
(c) hydroxy, and
(d) methyl;
and wherein Y is selected from the group consisting of:

(a) halogen, wherein halogen is selected from the group:
(i) F,
(ϋ) Cl,
(iii) Br, and
(iv) I,
(b) hydroxy, and
(c) methyl;
to a Zaragozic Acid C producing culture and isolating the product compound of Claim 1 from the culture broth.

26. The process according to Claim 25 wherein the Zaragozic Acid C producing culture is:
(a) MF5465 (ATCC 74011),
(b) MF5701 (ATCC 74165),
(c) MF5703 (ATCC 74166),
or a mutant having essentially the same characteristics as one of the above.

27. The process according to Claim 25 wherein R1 is:


28. The process according to Claim 27 wherein R1 is: