Blood-brain barrier-penetrant dopamine-b-hydroxylase inhibitors
AssigneeBial - Portela & Ca, S.A.
InventorsPatrício Soares Da Silva, Tino Rossi, Laszlo Erno Kiss, Alexander Beliaev, Pedro Nuno Leal Palma
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Abstract
This invention relates to: (a) compounds of formula (I) (with R1 to R5, n and A as defined herein) and pharmaceutically acceptable salts or solvates thereof that are useful as dopamine-β-hydroxylase inhibitors; (b) pharmaceutical compositions comprising such compounds, salts or solvates; (c) the use of such compounds, salts or solvates in therapy; (d) therapeutic methods of treatment using such compounds, salts or solvates; and (e) processes and intermediates useful for the synthesis of such compounds.
Claims35
A pharmaceutical composition comprising (i) a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof:
- and (ii) a pharmaceutically acceptable excipient, wherein:
- R1 is hydrogen, C1-C6 alkyl, partially or fully deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 cyanoalkyl, C1-C6 mercaptoalkyl or amino;
- R2 is hydrogen or C1-C3 alkyl;
- R3 is hydrogen or oxo;
- or R2 and R3 combine to form a structure of formula Ia:
- wherein:
- X is CH2, CR6 or N;
- is a double bond when X is CR6 or N and is a single bond when X is CH2;
- R4 is hydrogen or C1-C3 alkyl;
- R5 is hydrogen or C1-C2 alkyl;
- or R4 and R5 combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring wherein the CH2 moiety is optionally substituted with two deuterium atoms;
- R6 is hydrogen;
- A is C5-C7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl or
- wherein:
- X1 is hydrogen, halo or methyl;
- X1′ is hydrogen or halo;
- X2 is hydrogen, halo or methyl;
- X2′ is hydrogen or halo;
- X3 is hydrogen or fluoro;
- n is 0 or 1, and when n is 0 a single or double bond joins the carbon atoms to which R3 and R4 are attached.
A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof:
- wherein:
- R1 is hydrogen, C1-C6 alkyl, partially or fully deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 cyanoalkyl, C1-C6 mercaptoalkyl or amino;
- R2 is hydrogen or C1-C3 alkyl;
- R3 is hydrogen or oxo;
- or R2 and R3 combine to form a structure of formula Ia:
- wherein:
- X is CH2, CR6 or N;
- is a double bond when X is CR6 or N and is a single bond when X is CH2;
- R4 is hydrogen or C1-C3 alkyl;
- R5 is hydrogen or C1-C2 alkyl;
- or R4 and R5 combine, together with the carbon atom to which they are attached, to form a cyclopropyl ring wherein the CH2 moiety is optionally substituted with two deuterium atoms;
- R6 is hydrogen;
- A is C5-C7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl or
- wherein:
- X1 is hydrogen, halo or methyl;
- X1′ is hydrogen or halo;
- X2 is hydrogen, halo or methyl;
- X2′ is hydrogen or halo;
- X3 is hydrogen or fluoro;
- n is 0 or 1, and when n is 0 a single or double bond joins the carbon atoms to which R3 and R4 are attached
- with the proviso that the following compounds are excluded:
17-18. (canceled)
Dependencies are inferred from the claim text.