Preparation of 3-azabicyclo[3.1.0]hexane derivatives as glycine transporter inhibitors for enhancing cognition and treating psychoses.

Abstract

The present invention relates to substituted bicyclic [3.1.0]amines (shown as I; variables defined below; e.g. thiophene-2-carboxylic acid N-[(3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-[3-fluoro-4-(morpholin-4-yl)phenyl]amide (II)), their pharmaceutically acceptable salts, pharmaceutical compns. thereof, and their use (no data) for the enhancement of cognition and the treatment of the pos. and neg. symptoms of schizophrenia and other psychoses in mammals, including humans. Compds. of the invention analyzed by an assay for their activity in inhibiting glycine reuptake in synaptosomes have IC50 values more potent than 10 μM; no values for individual examples of I are given. For I: y = H or (R100)k-R1-(R6)m; k = 0-1; l = 0-3; m = 1-3; n = 0-4; o = 0-1; p = 0-3; q = 0-4; r = 1-2; s = 0-4; t = 0-1; u = 1-3; v = 1-3; R100 is -CH2-, -CH(C1-C3)alkyl-, -C(O)- or -SO2-. R1 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl, -(4 to 7 membered) heterocycloalkyl, -(CH2)l-(C6-C10 aryl) or -(5 to 10 membered) heteroaryl, or (5 to 10 membered) tetrahydroheteroaryl; each R6 = H, halo, -(C1-C6) alkyl-B, (C1-C7) alkoxy-D, (C2-C4)alkenoxy, (C1-C6)alkyl-OH, -OH, CN, -NO2, -CR7R8R9, - NR20R21, -NHCOalkyl(C1-C3), NHSO2alkyl(C1-C3), C(O)OR22, -R23C(O)OR22, -C(O)NH2, phenyl-E, phenoxy-F, morpholine, -NR20R21, aryl, heteroaryl, -SR24, and -SO2R25; B and D = H, OH, Ph, di-Ph or trifluoro; E and F = H, alkyl, or halo. R2 and R3 = H or (C1-C3)alkyl; R4 and R5 = H or (C1-C3) alkyl; or R4 and R5 taken together form a double bond to an O to form (C:O), or R4 and R5 are connected with 2 to 4 C atoms to form a 3-5 member carbocyclic ring; A is H or (C1-C3)alkyl-(R28)n; R28 = (C1-C3)alkoxy, -OH, -NR12R13 or -NHC(O)(C1-C4)alkyl; X is a bond, -CH2(R29)p, -C(O) or -SO2; R29 is -(C1-C3)alkyl; W is alkyl, -(C3-C6)cycloalkyl, -(3 to 7 membered) heterocycloalkyl, -(3 to 7 membered) heterocycloalkyl with 1 or 2 C:O groups, Ph, or -(5 to 7 member) heteroaryl or heterocyclic; R30 is -(C1-C4)alkyl, -(C1-C3)alkoxy, CN, -F, -Cl, -Br, -I, -NR18R19, -NHC(O)R18, -SCH3 or -C(O)CH3. Q is a bond, -CH(R31)r, -C(O) or SO2; R31 = H or (C1-C3)alkyl; Z is -(C1-C8)alkyl, -(C3-C8)cycloalkyl, -(4 to 8 member) heterocycloalkyl, Ph or -(5 to 7 membered) heteroaryl or heterocyclic; R14 is F, Cl, Br, I, V, H, -NR16R17, -OR16, -C(O)NR16R17, -(SO2)NR16R17, or NR32C:O-R33; R15 is -(C1-C3)alkyl, -(C1-C3)alkoxy, -F, -Br, -Cl, -I -OH or CN; V is -(C3-C8)cycloalkyl, -(C1-C5)alkyl, (5 to 7 membered) heterocycloalkyl, (5 to 7 membered)heterocycloalkyl substituted with 1 or 2 C:O groups or 1, 2, or 3-(C1-C5)alkyl groups; addnl. details are given in the claims. Although the methods of prepn. are not claimed, 6 example prepns. are included. For example, II was prepd. in 5 steps starting from (3-azabicyclo[3.1.0]hex-6-yl)methanol hydrochloride and involving 6-hydroxymethyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-Bu ester, 6-[[[3-fluoro-4-(morpholin-4-yl)phenyl]amino]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-Bu ester, 6-[[[3-fluoro-4-(morpholin-4-yl)phenyl][(thien-2-yl)carbonyl]amino]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-Bu ester and thiophene-2-carboxylic acid N-[(3-azabicyclo[3.1.0]hex-6-yl)methyl]-N-[3-fluoro-4-(morpholin-4-yl)phenyl]amide trifluoroacetate as intermediates. [on SciFinder(R)]