Antithrombotic compounds

 

The invention relates to new compounds of the formula (I):

wherein R1is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (ISO)hyalinella, tetrahydro(ISO)hyalinella, 3,4-dihydro-1H-izokhinolinom, romaniam or camphor group, and these groups optionally can be substituted by one or more substituents selected from (1-8C)alkyl or (1-8C)alkoxyl; R2and R3independently are H or (1-8C)alkyl; R4is (1-8C)alkyl or (3-8C)cycloalkyl; or R3and R4together with the nitrogen atom to which they are linked, are a nonaromatic (4-8)membered cycle, optionally containing another heteroatom, the cycle is optionally substituted (1-8C)alkyl or SO2is(1-8C)alkyl; Q is a spacer having a chain length from 10 to 70 atoms; and Z is a negatively charged oligosaccharide residue comprising from two to six monosaccharide units, the charge is compensated by positively charged counterions, or its pharmaceutically acceptable salts or prodrugs and pharmaceutical compositions having antithrombotic activity. 2 S. and 6 C.p. f-crystals.

1. The compounds of formula (I)

characterized in that

R1is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (ISO)hyalinella, tetrahydro(ISO)hyalinella, 3,4-dihydro-1H-izokhinolinom, romaniam or camphor group, these groups optionally can be substituted by one or more substituents selected from (1-8C)Akilov or (1-8C)alkoxyl;

R2and R3independently are H or (1-8C)alkyl; and

R4is (1-8C)alkyl or (3-8C)cycloalkyl or R3and R4together with the nitrogen atom to which they are linked, are a nonaromatic (4-8)membered cycle, optionally containing another heteroatom, the cycle is optionally substituted (1-8C)alkyl or SO2is(1-8C)alkyl; and

Q is a spacer having a chain length from 10 to 70 atoms;

Z is a negatively charged oligosaccharide residue comprising from two to six monosaccharide units, the charge is compensated by positively charged counterions,

or its pharmaceutically acceptable salt or its prodrug.

2. Connection on p. 1, characterized in that Z is formed from an oligosaccharide which has activity against Ha, mediated by AT-III.

3. Aedm, that Z has the formula (II)

where R5independently are OSO-3or (1-8C)alkoxyl.

5. The compound according to any one of paragraphs.1 to 4, wherein R1represents phenyl, 4-methoxy-2,3,6-trimetilfenil or naphthyl; R2is N; a is NR3R4is piperidinyloxy group.

6. The compound according to any one of paragraphs.1 to 5, characterized in that Q has the formula (III):

where W is - [1,4-phenylene-NR3-C(O)]q-(CH2)r-S-

or

- (CH2)t-S-(CH2)u-[O(CH2)2]v-O-(CH2)w-C(O)-NR3-;

a R3independently is H or (1-8C)alkyl; and

m=1-12; n=1-8; R=0-4; q=0 or 1; r=1-8; s=1-8; t=1-8; u=1-8; v=1-12; w=1-8; the total number of atoms is 10 to 70, and the fragment -[(CH2)2O]mis the end to which Q is attached to Z.

7. Connection on p. 6, wherein Q is selected from the

-[(CH2)2O]5-(CH2)2-NH-C(O)-CH2-S-CH2-;

-[(CH2)2O]5-(CH2)2-NH-C(O)-CH2-S-(CH2)2-[O(CH2)2]C-O-CH2-C(O)-NH-(CH2)4and

-[(CH2)2O]3-(CH2)2-NH-C(O)-1,4-dryer is Yu, containing as active ingredient a compound according to any one of paragraphs.1-7.

 

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