N-PYRROLIDIN-3YL-AMIDE DERIVATIVES AS SEROTONIN AND NORADRENALIN RE-UPTAKE INHIBITORS

摘要

A compound of Formula (I) and pharmaceutically and/or veterinarily acceptable derivatives thereof, wherein: R<SUP>1</SUP> is H, C<SUB>1-6</SUB>alkyl, - C(A)D, C<SUB>3-8</SUB>cycloalkyl, aryl, het, aryl-C<SUB>1-4</SUB>alkyl or het-C<SUB>1-4</SUB>alkyl, wherein the cycloalkyl, aryl or het groups are optionally substituted; A is S or O; D is H, C<SUB>1-6</SUB>alkyl, aryl, het, aryl-C<SUB>1-4</SUB>alkyl or het-C<SUB>1-4</SUB>alkyl; aryl represents phenyl, naphthyl, anthracyl or phenanthryl; het represents an aromatic or non-aromatic 4-, 5­-or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 5- or 6- membered carbocyclic group or a second 4-, 5- or 6-membered heterocycle which contains at least one N, O or S heteroatom; R<SUP>2</SUP> is aryl<SUP>1</SUP> or het<SUP>1</SUP>, each optionally substituted; n is 1 or 2, provided that when n is 1, m is 0 or 1 and when n is 2, m is 0, wherein if m is 0, then * represents a chiral centre; R<SUP>3</SUP> is (CH<SUB>2</SUB>)<SUB>a</SUB>E, wherein a is 0, 1 or 2 and E is a group selected from: Formula (i) wherein: X is O, S, NR<SUP>12</SUP>, (CH<SUB>2</SUB>)<SUB>v</SUB> or a bond; b is 1, 2, 3 or 4; c is 1, 2 or 3; v is 1 or 2; R<SUP>10 </SUP>and <SUP>11</SUP> are each independently H or C<SUB>1-4 </SUB>alkyl; and R<SUP>12 </SUP>is H, <SUB>1-6</SUB> alkyl, C(O)C<SUB>1-6</SUB> alkyl, SO<SUB>2</SUB>-C<SUB>1-6</SUB>alkyl; and wherein one or more pairs of hydrogen atoms on adjacent carbon or nitrogen atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic; Formula (ii) a carbocyclic spiro group containing 6 to 12 carbon atoms; Formula (iii) wherein: d is 1, 2, 3 or 4; a is 1, 2 or 3; f is 1 or 2; and R<SUP>30 </SUP>is H or C<SUB>14 </SUB>alkyl; and wherein one or more pairs of hydrogen atoms on adjacent carbon atoms may be replaced by a corresponding number of double bonds, provided the ring system is not aromatic; Formula (iv) wherein: g is 0, 1, 2 or 3; J is NR<SUP>40</SUP>; and R<SUP>40 </SUP>is C(O)C<SUB>1-6</SUB> alkyl, S0<SUB>2</SUB>-C<SUB>1-6 </SUB>alkyl; Formula (v) wherein: h is 0, 1, 2 or 3; and R<SUP>50 </SUP>is H, C<SUB>1-8</SUB>alkyl, C<SUB>1-8</SUB>alkoxy, OH, halo, CF<SUB>3</SUB>, OCF<SUB>3</SUB>, SCF<SUB>3</SUB>, hydroxy-C<SUB>1-6</SUB>alkyl, C<SUB>1-4</SUB>alkoxy-C<SUB>1-6</SUB>alkyl and C<SUB>1-4</SUB>alkyl-S-C<SUB>1-4</SUB>alkyl; Formula (vi) -CH(cyclopropane)<SUB>2</SUB>; Formula (vii) C<SUB>1-6</SUB>alkyl, substituted by at least one substituent; and Formula (viii) C<SUB>3-8</SUB>cycloalkyl-C<SUB>1-6</SUB>alkyl; wherein the C<SUB>1-6</SUB>alkyl moiety is substituted at any point other than at the junction with the C<SUB>3-8</SUB>cycloalkyl moiety, by at least one substituent. The compounds exhibit activity as both serotonin and/or noradrenaline re-uptake inhibitors and therefore have utility in a variety of therapeutic areas, for example urinary incontinence.