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1. WO1993017017 - GUANIDINES SUBSTITUEES PAR [(BENZODIOXANNE, BENZOFURANNE OU BENZOPYRANNE)-ALKYLAMINO]ALKYLE, UTILES COMME VASOCONSTRICTEURS SELECTIFS

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

[ EN ]

Claims
1. A compound having the formula

,



a pharmaceutically acceptable acid addition salt thereof, or a stereochemically isomeric form thereof, wherein

X is O, CH2 or a direct bond;
R1 is hydrogen or C1-6alkyl;
R2 is hydrogen, C1-6alkyl, C3-6alkenyl or C3-6alkynyl;
R3 is hydrogen or C1-6alkyl; or
R2 and R3 taken together form a bivalent radical of formula -(CH2)m- wherein m is 4 or 5; or
R1 and R2 taken together form a bivalent radical of formula -CH=CH- or of formula

-(CH2)n-, wherein n is 2, 3 or 4; or
R3 may represent a bond when R1 and R2 taken together form a bivalent radical of formula -CH=CH-CH=, -CH=CH-N=, or -CH=N-CH=, wherein one or two hydrogen atoms can be replaced by halo, Cι-6alkyl, Cι-6alkyloxy, cyano, amino, mono- or di(C1-6alkyl)amino, mono- or di(C3-6Cycloalkyl)amino, aminocarbonyl,

C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino;
R4 is hydrogen or C1-6alkyl;
Alk1 is a bivalent C1-3alkanediyl radical;
A is a bivalent radical of formula :
,

,

,


, or

;


wherein each R5 is hydrogen or C1-4alkyl;
wherein each R6 is hydrogen or C1-4alkyl;
Alk2 is C2-15alkanediyl or C5-7cycloalkanediyl;
and each p is 0, 1 or 2;
R7 and R8 each independently are hydrogen, halo, C1-6alkyl, C3-6alkenyl,
C3-6alkynyl, hydroxy, C1-6alkyloxy, cyano, aminoC1-6alkyl, carboxyl,
C1-6alkyloxycarbonyl, nitro, amino, aminocarbonyl, C1-6alkylcarbonylamino, or mono- or di(C1-6alkyl)amino;
provided that [2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyI]amino]ethyl guanidine is excluded.
2. A compound according to claim 1, wherein Alk1 is CH2.

3. A compound according to claim 1, wherein X is CH2 and wherein R7 and R8 each independently are hydrogen, halo, C1-6alkyl, C1-6alkyloxy, hydroxy, cyano, nitro, aminoC1-6alkyI, amino, C1-6alkylcarbonylamino.

4. A compound according to claim 2 or 3 wherein A is a bivalent radical of formula (a), wherein R6 is hydrogen.

5. A compound according to claim 4, wherein the compound is N-[(3,4-dihydro-2H-1- benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine, a stereochemically isomeric form thereof, or a pharmaceutically acceptable acid addition salt thereof.

6. A composition comprising a pharmaceutically acceptable carrier and as an active ingredient an effective vasoconstricting amount of a compound of formula (I) as claimed in any of claims 1 to 5.

7. A process of preparing a composition as claimed in claim 6 characterized in that a therapeutically effective amount of a compound as defined in any of claims 1 to 5 is intimately mixed with a pharmaceutically acceptable carrier.

8. A compound as claimed in any of claims 1 to 5 for use as a medicine.

9. An intermediate of formula (IX-a)

,



the pharmaceutically acceptable acid addition salts thereof, and the stereochemically isomeric forms thereof, wherein
X is O, CH2 or a direct bond;
R2 is hydrogen, C1-6alkyl, C3-6alkenyl or C3-6alkynyl;
R3 is hydrogen or C1-6alkyl; or
R2 and R3 may be taken together to form a bivalent radical of formula -(CH2)m-, wherein m is 4 or 5;
R4 is hydrogen or C1-6alkyl;
Alk 1 is a bivalent C 1-3alkanediyl radical;
A is a bivalent radical of formula :

,

,


, or



wherein each R5 is hydrogen or C1 -4alkyl;
wherein each R6 is hydrogen of C 1-4alkyl;
Alk2 is C2-15alkanediyl or C5-7cycloalkanediyl;

and each p is 0, 1 or 2;
R7 and R8 each independently are hydrogen, halo, C1-6alkyl, C3-6alkenyl,
C3-6alkynyl, hydroxy, C1-6alkyloxy, cyano, aminoC1-6alkyl, carboxyl,
C1-6alkyloxycarbonyl, nitro, amino, aminocarbonyl, C1-6alkylcarbonylamino, or mono- or di(C1-6aIkyI)amino.

10. A process for preparing a compound as claimed in claim 1 characterized by
a) N-alkylating a diamine of formula (II) wherein X, A, R4, R7 and R8 are as defined in claim 1, with a reagent of formula (III) wherein R1, R2 and R3 are as defined in claim 1 and wherein W1 is a reactive leaving group;

b) reductively N-alkylating an aminoderivative of formula (VI) wherein A, R1, R2 and R3 are as defined in claim 1, with an appropriate aldehyde of formula (V) wherein X, R4, R7 and R8 are as defined in claim 1 and wherein r is 0, 1 or 2;


c) N-alkylating an amine of formula (VI), with an intermediate of formula (VII), wherein X, Alk1, R4, R7 and R8 are as defined in claim 1 and wherein W2 is a reactive leaving group;

d) debenzylating an intermediate of formula (VIII) wherein R1, R2, R3, R4, R6, R7, R8, X, Alk1 and Alk2 are as defined in claim 1, thus yielding compounds of formula (I-a)


e) hydrolyzing an intermediate of formula (IX-a) wherein R1, R2, R3, R4, R6, R7, R8, X, Alk1 and A are as defined in claim 1, thus yielding compounds of formula
(I-b)

f) hydrogenating a compound of formula (I-c), wherein R4, R7, R8, X, Alk1 and A are as defined in claim 1, thus yielding compounds of formula (I-d)

and optionally converting the compounds of formula (I) into each other by a
functional group transformation reaction; and, if desired, converting a compound of formula (I) into a therapeutically active non-toxic acid addition salt, or conversely, converting an acid addition salt into a free base form with alkali; and/ or preparing stereochemically isomeric forms thereof.