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US 2004/0019033 A1Published application
Mandelic acid derivatives and their use as throbin inhibitors
AssigneeAstraZeneca AB
InventorsTord Inghardt, Anders Johansson, Arne Svensson
Life of this patent
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Abstract
There is provided a compound of formula I 1 wherein Ra, R1, R2, Y and R3 have meanings given in the description and pharmaceutically acceptable derivatives (including prodrugs) thereof, which compounds and derivatives are useful as, or are useful as prodrugs of, competitive inhibitors of trypsin-like proteases, such as thrombin, and thus, in particular, in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.
Claims44
A compound of formula I
- 39
- wherein
- Ra represents —OH or —CH2OH;
- R1 represents one or more optional halo substituents;
- R2 represents one or two C1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted by one or more fluoro substituents;
- Y represents —CH2— or —(CH2)2—;
- and
- R3 represents a structural fragment of formula I(i) or I(ii):
- 40
- wherein
- R4 represents H or one or more fluoro substituents;
- and one or two of X1, X2, X3 and X4 represent —N— and the others represent —CH—,
- or a pharmaceutically acceptable derivative thereof.
10 more elements
A process for the preparation of a compound of formula I
- 46
- which comprises:
- (i) the coupling of a compound of formula II,
- 47
- wherein Ra represents —OH or —CH2OH;
- R1 represents one or more optional halo substituents;
- R2 represents one or two C1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted by one or more fluoro substituents;
- with a compound of formula III,
- 48
- wherein
- Y represents —CH2— or —(CH2)2—;
- and
- R3 represents a structural fragment of formula I(i) or I(ii):
- 49
- wherein
- R4 represents H or one or more fluoro substituents;
- and one or two of X1, X2, X3 and X4 represent —N— and the others represent —CH—;
- (ii) the coupling of a compound of formula IV,
- 50
- with a compound of formula V,
- R3CH2NH2 V;
- (iii) for compounds of formula I in which R1 does not represent one or more halo groups, reduction of a corresponding compound of formula Ia
- 51
- wherein R3a represents a structural fragment of formula I(iii) or I(iv):
- 52
- wherein R5 represents OR6;
- R6 represents H, C1-10 alkyl, C1-3 alkylaryl or C1-3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents);
- R7 represents C1-10 alkyl (optionally interrupted by one or more oxygen atoms), or C1-3 alkylaryl or C1-3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents);
- (iv) reaction of a corresponding compound of formula XVIA or XVIB,
- 53
- with a source of ammonia;
- (v) reaction of a compound of formula XIVA,
- 54
- with:
- (a) a corresponding fluorinated haloalkane;
- or
- (b) for compounds of formula I in which R2 represents —OCH2CF3, —OCH2CHF2, —OCH2CH2F or —OCH(CH2F)2, a compound of formula XIVJ,
- RxS(O)2ORy XIVJ
- wherein Rx represents C1-4 alkyl, C1-4 perfluoroalkyl or phenyl (optionally substituted by methyl, nitro or halo) and Ry represents —CH2CF3, —CH2CHF2, —CH2CH2F or —CH(CH2F)2;
- (vi) for compounds of formula I in which R1 does not represent one or more halo groups, hydrogenation of a corresponding compound of formula I in which R1 represents one or more halo groups;
- or
- (vii) deprotection of a protected derivative of a compound of formula I or a pharmaceutically acceptable derivative thereof.
39 more elements
A compound of formula II
- 55
- or a protected derivative thereof.
A compound as claimed in claim 40, where the carbon atom to which Ra is attached is in the R-configuration when Ra represents —OH, or is in the S-configuration when Ra represents —CH2OH.
A compound of formula IV
- 56
- or a protected derivative thereof.
A compound of formula VIa,
- 57
- wherein R1 represents halo and R2 represents one or two C1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted by one or more fluoro substituents, or a protected derivative thereof.
A compound of formula IXa,
- 58
- wherein R represents C1-6 alkyl or C1-3 alkylphenyl, R1 represents halo and R2 represents one or two C1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted by one or more fluoro substituents, or a protected derivative thereof.
A compound of formula IXAa,
- 59
- wherein R represents C1-6 alkyl or C1-3 alkylphenyl, R1 represents halo and R2 represents one or two C1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted by one or more fluoro substituents, or a protected derivative thereof.
A compound of formula XIVBa,
- 60
- or a phenol O-protected derivative thereof, wherein R1 represents halo and Ra represents —OH or —CH2OH.
A process for the preparation of a compound of formula Ia
- 61
- wherein Ra represents —OH or —CH2OH;
- R1 represents one or more optional halo substituents;
- R2 represents one or two C1-3 alkoxy substituents, the alkyl parts of which substituents are themselves substituted by one or more fluoro substituents;
- Y represents —CH2— or —(CH2)2—;
- R3a represents a structural fragment of formula I(iii) or I(iv):
- 62
- wherein R4 represents H or one or more fluoro substituents;
- and one or two of X1, X2, X3 and X4 represent —N— and the others represent —CH—;
- R5 represents OR6 or C(O)OR7;
- R6 represents H, C1-10 alkyl, C1-3 alkylaryl or C1-3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents);
- R7 represents C1-10 alkyl (optionally interrupted by one or more oxygen atoms), or C1-3 alkylaryl or C1-3 alkyloxyaryl (the alkyl parts of which latter two groups are optionally interrupted by one or more oxygen atoms, and the aryl parts of which latter two groups are optionally substituted by one or more substituents selected from halo, phenyl, methyl or methoxy, which latter three groups are also optionally substituted by one or more halo substituents,
- which comprises:
- (a) reaction of a corresponding compound of formula II
- 63
- with a compound of formula XV,
- 64
- (b) reaction of a corresponding compound of formula IV
- 65
- with a compound of formula XVI,
- R3aCH2NH2 XVI;
- (c) for compounds of formula Ia in which R5 represents OH, reaction of a corresponding compound of formula XVIA or XVIB,
- 66
- with hydroxylamine;
- (d) for compounds of formula Ia in which R5 represents OR6, reaction of a compound of formula XVII,
- 67
- wherein R3b represents a structural fragment of formula I(v) or I(vi):
- 68
- wherein Rb represents —CH2CH2—Si(CH3)3 or benzyl, or a tautomer thereof, with a compound of formula XVIII,
- R6ONH2 XVIII,
- or an acid addition salt thereof, followed by removal of the —C(O)ORb group;
- (e) for compounds of formula Ia in which R5 represents OH, reaction of a compound of formula XVII, as defined above, in which Rb represents benzyl with hydroxylamine, or an acid addition salt thereof;
- (f) for compounds of formula Ia in which R5 represents COOR7, reaction of a corresponding compound of formula I
- 69
- wherein R3 represents a structural fragment of formula I(i) or I(ii):
- 70
- with a compound of formula XIX,
- L1COOR7 XIX
- wherein L1 represents a leaving group;
- or
- (g) for compounds of formula Ia in which R5 represents OCH3 or OCH2CH3, reaction of a corresponding compound of formula Ia in which R5 represents OH with dimethylsulfate or diethylsulfate, respectively.
38 more elements
A compound of formula XVIA or XVIB
- 71
- or a protected derivative thereof.
A compound of formula XVII
- 72
- or a protected derivative thereof.
Dependencies are inferred from the claim text.