Alkyl and aryl derivatives of 1-oxa-4,9-diazaspiro undecane compounds having multimodal activity against pain

A process for the preparation of a compound of formula Ia

• wherein
• Z is —C(O)—;
• m is 1;
• n is 1, 2 or 3;
• R1 is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl or —(CH2)r—W—R1′;
• r is 0, 1 or 2;
• W is —CH2O—, —CH2C(O)NR5′—, —CH2C(O)O—, —CH2C(O)— or —C(CH3)2O—;
• R1′ is H, —CN, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl or R5;
• wherein the aryl, heterocyclyl or cycloalkyl in R1 or R1′, if substituted, also in alkylaryl or alkylheterocyclyl, are substituted with substituents selected from the group consisting of —R5, —OR5, halogen, —CN, —NO2, —NR5R5′″, —C(O)OR8, NR5C(O)R5′, —C(O)NR5R5′, —NR5S(O)2R5, ═O, —OCH2CH2OH, —NR5C(O)NR5′R5′″, —S(O)2NR5R5′, —NR5S(O)2NR5R5″, haloalkyl, haloalkoxy, —SR5, —S(O)R5 and —S(O)2R5;
• and wherein “aryl” is a monocyclic aryl and “heterocyclyl” is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring;
• X is a bond, —C(O)O—, —C(O)NR5—, —C(O)—, —O— or —C(R4R4′)—;
• R2 is H, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl;
• wherein the aryl, heterocyclyl or cycloalkyl in R2, if substituted, also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, is substituted with substituents selected from the group consisting of —R, —OR5, halogen, —CN, —NO2, —NR5R5′″, —C(O)OR5, —NR5C(O)R5′, —C(O)NR5R5′, —NR5S(O)2R5′, ═O, —OCH2CH2OH, —NR5C(O)NR5R5″, —S(O)2NR5R5′, —NR5S(O)2NR5′R5″, haloalkyl, -haloalkoxy, —SR5, —S(O)R5 and —S(O)2R5;
• and wherein “aryl” is a monocyclic aryl and “heterocyclyl” is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring;
• R3 and R3′ are independently selected from the group consisting of H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheterocyclyl, and substituted or unsubstituted alkylcycloalkyl;
• wherein the aryl, cycloalkyl and heterocyclyl as defined in R3, also in alkylaryl, alkylcycloalkyl or alkylheterocyclyl, if substituted, are substituted with substituents selected from the group consisting of —OR5, halogen, —CN, haloalkyl, haloalkoxy, —SR5, —S(O)R5 and —S(O)2R5;
• and wherein “aryl” is a monocyclic aryl and “heterocyclyl” is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring;
• R4 is H, —OR5, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, —COOR5, —CONR5R5′, —NR5COR5′, —NR5R5′″ or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted cycloalkyl,
• wherein the aryl, cycloalkyl and heterocyclyl as defined in R4, if substituted, are substituted with substituents selected from the group consisting of —OR5, halogen, —CN, haloalkyl, haloalkoxy, —SR5, —S(O)R5 and —S(O)2R5;
• and wherein “aryl” is a monocyclic aryl and “heterocyclyl” is a heterocyclic ring system of one or two saturated or unsaturated rings of which at least one ring contains one or more heteroatoms from the group consisting of nitrogen, oxygen and/or sulfur in the ring;
• R4′ is H, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl or substituted or unsubstituted C2-6 alkynyl;
• R5, R5′, and R5″ are independently selected from the group consisting of H, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl, and unsubstituted aryl and unsubstituted alkylaryl;
• and wherein “aryl” is a monocyclic aryl;
• R5′″ is H, unsubstituted C1-6 alkyl, unsubstituted C2-6 alkenyl, unsubstituted C2-6 alkynyl or -Boc;
• R8 and R8′ are independently selected from the group consisting of H, —OR5, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl and substituted or unsubstituted C2-6 alkynyl;
• wherein
• the alkyl, alkenyl and alkynyl as defined in R1, R1′, R2, R3, R3′, R4, R4′, R8, and R8′, if substituted, are substituted with substituents selected from the group consisting of —OR5, halogen, —CN, haloalkyl, haloalkoxy, —SR5, —S(O)R5, —S(O)2R5, C(O)OR5 and C(O)NR5R5′;
• with the proviso that the the following compounds are excluded from formula Ia:
• which comprises the steps
• (a) reacting a compound of formula Va
• with a compound of formula VI
• wherein LG is a leaving group,
• to obtain a compound of formula VIIa
• and
• (b) Carrying out a cyclisation of the resulting compound in a suitable solvent, in the presence of a strong base and at a temperature comprised between −78° C. and the reflux temperature.