Mpzp: a small molecule corticotropin-releasing factor type 1 receptor (crf1) antogonist

A method for treating a host mammal that exhibits substance-related or substance-induced psychiatric disorders that include aversive signs and symptoms that comprises the steps of

• administering to a host mammal in need thereof a pharmaceutical composition containing a substance-related or substance-induced psychiatric disorder aversive sign and symptom lessening amount a compound of Formula I or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable diluent, and repeating the administration as needed,
• wherein
• W and Z are independently N or C, and X and Y are independently N or CH, with the proviso that at least two and no more that three of W, X, Y and Z are N;
• R1 is NR7R8 where each of R7 and R8 is independently a straight, branched or cyclic substituent that is selected from the group consisting of C1-C4 alkyl or C1-C4 alkenyl, methoxy-C1-C3 alkyl or C1-C3 alkenyl, mono-or dihydroxy-C1-C3 alkyl or C1-C3 alkenyl, N-methylamino-C1-C3 alkyl or C1-C3 alkenyl, 2- or 3-tetrahydrofuryl, and 2- or 3-tetrahydrofurfuryl, or NR7R8 together form a 5- or 6-membered ring containing zero or one oxygen atom in the ring, which ring is unsubstituted or substituted with a hydroxyl group, a hydroxymethyl group or a hydroxyethyl group;
• Ar—is
• wherein
• A is CH or N,
• R2 is selected from the group consisting of hydrido, methyl, methoxy, chloro and bromo,
• R4 is selected from the group consisting of chloro, methyl, methoxy, dimethylamino and morpholinyl,
• R5 is selected from the group consisting of hydrido, chloro and methyl, and
• R6 is selected from the group consisting of hydrido, chloro, methyl and methoxy,
• said compound exhibiting a calculated cLogD, pH 7 value of about 1.5 to about 4.5, using ACD/Labs Software v.8.14 for Solaris, a pKa value of about 4 to about 8.5, and a polar surface area of about 40 to about 70 Å2.

A method for treating a host mammal to inhibit relapse of compulsive use or behavioral disorders that comprises the steps of

• administering to a host mammal in need thereof a pharmaceutical composition containing a compulsive use or behavioral disorders relapse inhibiting amount a compound of Formula I or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable diluent, and repeating the administration as needed,
• wherein
• W and Z are independently N or C, and X and Y are independently N or CH, with the proviso that at least two and no more that three of W, X, Y and Z are N;
• R1 is NR7R8 where each of R7 and R8 is independently a straight, branched or cyclic substituent that is selected from the group consisting of C1-C4 alkyl or C1-C4 alkenyl, methoxy-C1-C3 alkyl or C1-C3 alkenyl, mono-or dihydroxy-C1-C3 alkyl or C1-C3 alkenyl, N-methylamino-C1-C3 alkyl or C1-C3 alkenyl, 2- or 3-tetrahydrofuryl, and 2- or 3-tetrahydrofurfuryl, or NR7R8 together form a 5- or 6-membered ring containing zero or one oxygen atom in the ring, which ring is unsubstituted or substituted with a hydroxyl group, a hydroxymethyl group or a hydroxyethyl group;
• Ar—is
• wherein
• A is CH or N,
• R2 is selected from the group consisting of hydrido, methyl, methoxy, chloro and bromo,
• R4 is selected from the group consisting of chloro, methyl, methoxy, dimethylamino and morpholinyl,
• R5 is selected from the group consisting of hydrido, chloro and methyl, and
• R6 is selected from the group consisting of hydrido, chloro, methyl and methoxy,
• said compound exhibiting a calculated cLogD, pH 7 value of about 1.5 to about 4.5, using ACD/Labs Software v.8.14 for Solaris, a pKa value of about 4 to about 8.5, and a polar surface area of about 40 to about 70 Å2.

A method for preventing a host mammal from exhibiting aversive signs and symptoms present during protracted abstinence or extended discontinuation syndromes as seen after cessation of compulsive activity, behaviors, or substance use that comprises the steps of

• administering to a host mammal in need thereof a pharmaceutical composition containing an aversive sign and symptom present during protracted abstinence or extended discontinuation syndrome-preventing amount a compound of Formula I or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable diluent, and repeating the administration as needed,
• wherein
• W and Z are independently N or C, and X and Y are independently N or CH, with the proviso that at least two and no more that three of W, X, Y and Z are N;
• R1 is NR7R8 where each of R7 and R8 is independently a straight, branched or cyclic substituent that is selected from the group consisting of C1-C4 alkyl or C1-C4 alkenyl, methoxy-C1-C3 alkyl or C1-C3 alkenyl, mono-or dihydroxy-C1-C3 alkyl or C1-C3 alkenyl, N-methylamino-C1-C3 alkyl or C1-C3 alkenyl, 2- or 3-tetrahydrofuryl, and 2- or 3-tetrahydrofurfuryl, or NR7R8 together form a 5- or 6-membered ring containing zero or one oxygen atom in the ring, which ring is unsubstituted or substituted with a hydroxyl group, a hydroxymethyl group or a hydroxyethyl group;
• Ar—is
• wherein
• A is CH or N,
• R2 is selected from the group consisting of hydrido, methyl, methoxy, chloro and bromo,
• R4 is selected from the group consisting of chloro, methyl, methoxy, dimethylamino and morpholinyl,
• R5 is selected from the group consisting of hydrido, chloro and methyl, and
• R6 is selected from the group consisting of hydrido, chloro, methyl and methoxy,
• said compound exhibiting a calculated cLogD, pH 7 value of about 1.5 to about 4.5, using ACD/Labs Software v.8.14 for Solaris, a pKa value of about 4 to about 8.5, and a polar surface area of about 40 to about 70 | 2.

A pharmaceutical composition that contains an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable diluent,

• wherein
• W and Z are independently N or C, and X and Y are independently N or CH, with the proviso that at least two and no more that three of W, X, Y and Z are N, such that said compound of Formula I is comprised of a core bonded to R1 and Ar substituents in which the core corresponds to structural Formula II with bond lines for substituents R1 and Ar
• wherein said core contains 3 or 4 nitrogen atoms in the rings, including the nitrogen atom shown in Formula II and core corresponds in structure to one of Formulas IIA, IIB, IIC or IID
• R1 is NR7R8 where each of R7 and R8 is independently selected from the group consisting of 2- or 3-tetrahydrofuryl, and 2- or 3-tetrahydrofurfuryl, or NR7R8 together form a 5- or 6-membered ring containing zero or one oxygen atom in the ring, which ring is unsubstituted or substituted with a hydroxyl group, a hydroxymethyl group or a hydroxyethyl group;
• Ar—is
• wherein
• A is CH or N,
• R2 is selected from the group consisting of hydrido, methyl, methoxy, chloro and bromo,
• R4 is selected from the group consisting of chloro, methyl, methoxy, dimethylamino and morpholinyl,
• R5 is selected from the group consisting of hydrido, chloro and methyl, and
• R6 is selected from the group consisting of hydrido, chloro, methyl and methoxy,
• said compound exhibiting a calculated cLogD, pH 7 value of about 1.5 to about 4.5, using ACD/Labs Software v.8.14 for Solaris, a pKa value of about 4 to about 8.5, and a polar surface area of about 40 to about 70 Å2.