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Paramétrages

Paramétrages

1. WO2005068421 - NITRO-OXY-DERIVES DE LA PROSTAGLANDINE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

CLAIMS

A compound of - general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof


wherein R is the prostaglandin residue of formula (II):


wherein

the symbol - - - represents a single bond or a double bond;

L is selected from the following groups:

-
,
,

-
,
;

X is -O- -S- or -NH-;

Y is a bivalent radical having the following meaning: a)

straight or branched C1-C20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T, wherein T is

-OC(O)(C1-C10alkyl)-ONO2 or -O(C1-C10alkyl)-ONO2;

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched C1-C10 alkyl;

b)


c)


wherein n is an integer from 0 to 20, and n1 is an integer from 1 to 20;

d)


wherein

X1 = -OCO- or -COO- and R2 is H or CH3;

Z is -(CH)n1- or the bivalent radical defined above under b)

n1 is as defined above and n2 is an integer from 0 to

2;

e)


wherein:

Y1 is -CH2-CH2-(CH2)n2-; or -CH=CH-(CH2)n2-;

Z is -(CH)n1- or the bivalent radical defined above under b)

n1, n2,R2 and Xi are as defined above;

f)


wherein:

n1 and R2 are as defined above, R3 is H or -COCH3;

with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the -ONO2 group is bound to -(CH2)n1;

g)


,


wherein X2 is -O- or -S-, n3 is an integer from 1 to 6 and R2 is as defined above;

h)


wherein:

n4 is an integer from 0 to 10;

n5 is an integer from 1 to 10;

R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl;

wherein the -ONO2 group is linked to


wherein n is as defined above;

Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from

, , , , ,




, , , , ,




,
,



2. A compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof wherein R, L, X are as defined in claim 1 and Y is a bivalent radical having the following meaning:

straight or branched C1-C20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T, wherein T is

-OC(O)(C1-C10 alkyl)-ONO2 or -O(C1-C10 alkyl)-ONO2;

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched C1-C10 alkyl;

b)


c)


wherein n is an integer from 0 to. 20, and n1 is an integer from 1 to 20;

d)


wherein:

n1 is as defined above and n2 is an integer from 0 to 2;

Xi = -OCO- or -COO- and R2 is H or CH3;

e)


wherein:

n1, n2,R2 and X1 are as defined above;

Y1 is -CH2-CH2- or -CH=CH-(CH2)n2-;

f)


wherein:

n1 and R2 are as defined above, R3 is H or -COCH3;

with the proviso that when Y is selected from the bivalent radicals mentioned under b) -f), the -ONO2 group is bound to

-(CH2)n1;

g)



wherein X2 is -O- or -S-, n is an integer from 1 to 6 and R2 is as defined above;

h)


wherein:

n4 is an integer from 0 to 10;

n5 is an integer from 1 to 10;

R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl;

wherein the -ONO2 group is linked to


wherein n5 is as defined above;

Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur,

and is selected from

, , , , ,




, , , ,





,
,



3. A compound of general formula (I) according to claim 1 or 2, wherein L is selected from the following groups:


,


;

4. A compound of general formula (I) according to anyone of the claims from 1 to 3, wherein the residue R is selected from the group consisting of travoprost, unoprostone and cloprostenol;

5. A compound of general formula (I) according to claim 1 or 2 wherein the residue R is latanoprost.

6. A compound of general formula (I) according to anyone of the claims from 1 to 5, wherein X is -O- or -S-.

7. A compound of general formula (I) according to anyone of the claims from 1 to 6, wherein Y is a bivalent radical having the following meaning:

a) straight or branched C2-C6 alkylene, being optionally substituted with -ONO2 or T, wherein T is as defined in claim 1;

b)


wherein n is an integer from 0 to 5, and n1 is an integer from 1 to 5;

g)



wherein X2 is -O- or -S-, n3 is 1, R2 is as defined in claim 1.

8. A compound of general formula (I) according to anyone of the claims from 1 to 6 wherein Y is a bivalent radical having the following meaning:

a) straight or branched C2-C6 alkylene being substituted with -ONO2 or T, wherein T is as defined in claim 1;

b)


wherein n is 0, and n is 1;

g)


wherein X2 is -O- or -S-, n3 is 1, R is hydrogen;

9. A compound of formula (I) according to anyone of the claims from 1 to 6 wherein Y is a bivalent radical having the following meaning:

d)


wherein

X1 = -OCO- or -COO- and R2 is H or CH3;

Z is -(CH)n1- or the bivalent radical defined in claim

1 under b) wherein n is an integer from 0 to 5;

n1 is an integer from 1 to 5 and n2 is an integer from

0 to 2;

e)


wherein:

Y1 is -CH2-CH2-(CH2)n2-; or -CH=CH-(CH2)n2- ;

Z is -(CH)n1- or the bivalent radical defined above under b)

n1, n2 , R2 and X1 are as defined above;

f )


wherein :

n1 and R2 are as defined above, R3 is H or COCH3 ; with the proviso that when Y is selected from the bivalent radicals mentioned under b)-f), the -ONO2 group is bound to -(CH2)n1;

h)


wherein:

n is an integer from 0 to 3;

n5 is an integer from 1 to 3;

R4, R5, R6, R7 are the same and are H;

and wherein the -ONO2 group is linked to


Y2 is a 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or two atoms of nitrogen and selected for example from

, , , ;






10. A compound according to claim 1, selected from the group consisting of:







15. 11. A process for preparing a compound of general formula

(I) as defined in claim 1, which process comprises: i) reacting a compound of formula (III).


wherein

L is as defined in claim 1; P is H or a hydroxylic protecting group and W is -OH, Cl, or -OC(O)R1 wherein R1 is a linear or branched C1-C5 alkyl;

with a compound of formula (IV) Z-Y-Q wherein Y is as defined in claim 1, Z is HX or Z1, being X as defined in claim 1 and Z1 selected from the group consisting of:

chlorine, bromine , iodine, mesyl, tosyl;

Q is -ONO2 or Z1 and

ii) when Q is Z1, converting the compound obtained in the step i) into nitro derivative by reaction with a nitrate source and

iii) optionally deprotecting the compounds obtained in step i) or ii).

12. A compound of general formula (I) according to claims 1-10 for use as a medicament.

13. Use of a compound according to claims 1-10 for the preparation of a medicament for treating glaucoma and ocular hypertension.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) and/or a salt or stereoisomer thereof as defined in claims 1-10.

15. A pharmaceutical composition according to claim 14 in a suitable form for the topical administration.

16. A pharmaceutical composition according to claims 14-15 for the treatment of glaucoma and ocular hypertension.

17. A pharmaceutical composition according to claims 15- 16, wherein the compound of general formula (I) is administered as a solution, suspension or emulsion in an ophthalmically acceptable vehicle.

18. A method for treating glaucoma or ocular hypertension, said method consisting in contacting an effective intraocular pressure reducing amount of a pharmaceutical composition according to claims 14-17, with the eye in order to reduce eye pressure and to maintain said pressure on a reduced level.

19. A pharmaceutical composition comprising a mixture of a compound of formula (I) as defined in claim 1 and (i) a beta-blocker or (ii) a carbonic anhydrase inhibitor or (iii) an adrenergic agonist or a nitrooxy derivative thereof.

20. A pharmaceutical composition comprising a mixture of a compound of formula (I) as defined in claim 1 and timolol or a nitrooxy derivative thereof.