5-HT2A receptor inverse agonists

A method for modulating by inverse agonism the activity of a human 5HT.sub.2A serotonin receptor by contacting the receptor with a compound of formula:

• ##STR27## Wherein:
• W is Me, or Et, or halogen;
• X is either Oxygen or Sulfur;
• Y is NR.sup.2 R.sup.3, or (CH.sub.2).sub.m R.sup.4, or O(CH.sub.2).sub.n R.sup.4 ;
• Z is lower alkyl (C.sub.1-6);
• m=0-4
• n=0-4
• R.sup.1 is H or lower alkyl (C.sub.1-4);
• R.sup.2 is H or lower alkyl(C.sub.1-4);
• R.sup.3 and R.sup.4 are independently a C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.5 R.sup.6, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl, SCF.sub.3 CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, and aryloxy wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, or aryloxy groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, NHCOCH.sub.3, OCF3, SMe, COOR.sup.7, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.5 R.sup.6, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl;
• R.sup.5 and R.sup.6 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.7 R.sup.8, NR.sup.7 R.sup.8, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.9, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.7 R.sup.8, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, or aryl groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.8 R.sup.9, NR.sup.8 R.sup.9, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl,
• or R.sup.5 and R.sup.6 may form part of a 5, 6 or 7 membered cyclic structure which may be either saturated or unsaturated and that may contain up to four heteroatoms selected from O, N or S and said cyclic structure may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, OCF.sub.3, SMe, COOR.sup.7, ,SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, NHCOCH.sub.3, COEt, COMe, or halogen;
• R.sup.7 may be independently selected from H or C.sub.1-6 alkyl;
• R.sup.8 and R.sup.9 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from halogen, CF.sub.3, OCF3, OEt, CCl.sub.3, Me, NO.sub.2, OH, OMe, SMe, COMe, CN, COOR.sup.7, SO.sub.3 R.sup.7, COEt, NHCOCH.sub.3, or aryl;
• an aryl moiety can be a 5 or 6 membered aromatic heterocyclic ring (containing up to 4 hetero atoms independently selected from N, O, or S) or a 6 membered aromatic non-heterocyclic ring or a polycycle.

A method for modulating by inverse agonism the activity of a human 5HT.sub.2A serotonin receptor by contacting the receptor with a compound of formula:

• ##STR28## Wherein:
• R.sup.1 and R.sup.2 are H;
• W is Br;
• X is O;
• Z is Me;
• R.sup.3 is C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.5 R.sup.6, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl, SCF.sub.3 CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, and aryloxy wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, or aryloxy groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, NHCOCH.sub.3, OCF3, SMe, COOR.sup.7, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.5 R.sup.6, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl;
• R.sup.5 and R.sup.6 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.7 R.sup.8, NR.sup.7 R.sup.8, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.9, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.7 R.sup.8, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, or aryl groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.8 R.sup.9, NR.sup.8 R.sup.9, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl,
• or R.sup.5 and R.sup.6 may form part of a 5, 6 or 7 membered cyclic structure which may be either saturated or unsaturated and that may contain up to four heteroatoms selected from O, N or S and said cyclic structure may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, NHCOCH.sub.3, COEt, COMe, or halogen;
• R.sup.7 may be independently selected from H or C.sub.1-6 alkyl;
• R.sup.8 and R.sup.9 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from halogen, CF.sub.3, OCF3, OEt, CCl.sub.3, Me, NO.sub.2, OH, OMe, SMe, COMe, CN, COOR.sup.7, SO.sub.3 R.sup.7, COEt, NHCOCH.sub.3, or aryl;
• an aryl moiety can be a 5 or 6 membered aromatic heterocyclic ring (containing up to 4 hetero atoms independently selected from N, O, or S) or a 6 membered aromatic non-heterocyclic ring or a polycycle.

A method for modulating by inverse agonism the activity of a human 5HT2A serotonin receptor by contacting the receptor with a compound of formula:

• ##STR29## Wherein:
• R.sup.1 is H;
• W is Br;
• X is O;
• Z is Me;
• n=0-4
• R.sup.4 is C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.5 R.sup.6, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl, SCF.sub.3 CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, and aryloxy wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, or aryloxy groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, NHCOCH.sub.3, OCF3, SMe, COOR.sup.7, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.5 R.sup.6, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl;
• R.sup.5 and R.sup.6 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.7 R.sup.8, NR.sup.7 R.sup.8, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.9, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.7 R.sup.8, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, or aryl groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.8 R.sup.9, NR.sup.8 R.sup.9, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl,
• or R.sup.5 and R.sup.6 may form part of a 5, 6 or 7 membered cyclic structure which may be either saturated or unsaturated and that may contain up to four heteroatoms selected from O, N or S and said cyclic structure may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, NHCOCH.sub.3, COEt, COMe, or halogen;
• R.sup.7 may be independently selected from H or C.sub.1-6 alkyl;
• R.sup.8 and R.sup.9 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from halogen, CF.sub.3, OCF3, OEt, CCl.sub.3, Me, NO.sub.2, OH, OMe, SMe, COMe, CN, COOR.sup.7, SO.sub.3 R.sup.7, COEt, NHCOCH.sub.3, or aryl;
• an aryl moiety can be a 5 or 6 membered aromatic heterocyclic ring (containing up to 4 hetero atoms independently selected from N, O, or S) or a 6 membered aromatic non-heterocyclic ring or a polycycle.

A method for modulating by inverse agonism the activity of a human 5HT2A serotonin receptor by contacting the receptor with a compound of formula:

• ##STR30## Wherein:
• W is Br;
• X is O;
• Z is Me;
• R.sup.1 is H;
• m=0-4
• R.sup.4 is C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.5 R.sup.6, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl, SCF.sub.3 CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, and aryloxy wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, aryl, or aryloxy groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.5 R.sup.6, NR.sup.5 R.sup.6, NHCOCH.sub.3, OCF3, SMe, COOR.sup.7, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.5 R.sup.6, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl;
• R.sup.5 and R.sup.6 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.7 R.sup.8, NR.sup.7 R.sup.8, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.9, SO.sub.3 R.sup.7, SO.sub.2 NR.sup.7 R.sup.8, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl wherein each of the C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, or aryl groups may be further optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, CONR.sup.8 R.sup.9, NR.sup.8 R.sup.9, NHCOCH.sub.3, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, COMe, COEt, CO-lower alkyl, SCF.sub.3, CN, C.sub.2-6 alkenyl, H, halogens, C.sub.1-4 alkoxy, C.sub.3-6 cycloalkyl, C.sub.1-6 alkyl, and aryl,
• or R.sup.5 and R.sup.6 may form part of a 5, 6 or 7 membered cyclic structure which may be either saturated or unsaturated and that may contain up to four heteroatoms selected from O, N or S and said cyclic structure may be optionally substituted by up to four substituents in any position independently selected from CF.sub.3, CCl.sub.3, Me, NO.sub.2, OH, OMe, OEt, OCF.sub.3, SMe, COOR.sup.7, SO.sub.2 NR.sup.8 R.sup.9, SO.sub.3 R.sup.7, NHCOCH.sub.3, COEt, COMe, or halogen;
• R.sup.7 may be independently selected from H or C.sub.1-6 alkyl;
• R.sup.8 and R.sup.9 are independently a H, or C.sub.1-6 alkyl, or C.sub.2-6 alkenyl, or cycloalkyl, or aryl, or CH.sub.2 aryl group and each said group may be optionally substituted by up to four substituents in any position independently selected from halogen, CF.sub.3, OCF3, OEt, CCl.sub.3, Me, NO.sub.2, OH, OMe, SMe, COMe, CN, COOR.sup.7, SO.sub.3 R.sup.7, COEt, NHCOCH.sub.3, or aryl;
• an aryl moiety can be a 5 or 6 membered aromatic heterocyclic ring (containing up to 4 hetero atoms independently selected from N, O, or S) or a 6 membered aromatic non-heterocyclic ring or a polycycle.