Patent EA-001836-B1 (EA)
Title: Method for treating sexual dysfunction
Inventor: JIROUSEK MICHAEL R
IPC: C07D513/22
Filed: 1997-08-22
Abstract: 1. A method for inducing smooth muscle relaxation associated with sexual functioning which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of an inhibitor of the beta-proteinkinase, wherein beta-proteinkinase is indolylmaleimide or a macrocyclic bis-indolylmaleimide. 2. The method of Claim 1 wherein the inhibitor is beta-isoenzyme selective and where the isoenzyme selectivity is selected from beta-1 and beta-2 isoenzymes. 3. The method of Claim 2, wherein the beta-isoenzyme selective inhibitor has the following formula:   wherein: W is -O-, -S-, -SO-, -SO2-, -CO-, C2-C6 alkylene, substituted alkylene, C2-C6 alkenylene, -aryl-, -aryl(CH2)mO-, -heterocycle-, -heterocycle-(CH2)mO-, fused bicyclic-, -fused bicyclic-(CH2)mO, -NR<3>-, -NOR<3>-, -CONH-, or -NHCO-; X and Y are independently C1-C4 alkylene, substituted alkylene, or together X,Y, and W combine to form -(CH2)n-A-A-; R<1> are hydrogen or up to four optional substituents independently selected from halo, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, haloalkyl, nitro, -NR<4>R<5>, or -NHCO(C1-C4 alkyl); R<2> is hydrogen, CH3CO-, -NH2, or hydroxy; R<3> is hydrogen, -(CH2)maryl, -C1-C4 alkyl, -COO(C1-C4 alkyl), -CONR<4>R<5>, -(C=NH)NH2, -SO(C1-C4 alkyl), SO2(NR<4>R<5>), or -SO2(C1-C4 alkyl); R<4> and R<5> are independently hydrogen, C1-C4 alkyl, phenyl, benzyl, or combine to the nitrogen to which they are bonded to form a saturated or unsaturated 5 or 6 member ring; AA is an amino acid residue; m is independently 0,1, 2, or 3; and n is independently 2, 3, 4, or 5 or a pharmaceutically acceptable salt, prodrug or ester thereof. 4. The method of Claim 3, wherein the beta-proteinkinase isoenzyme selective inhibitor has the following formula:   wherein Z is -(CH2)p- or -(CH2)p-O-(CH2)p-; R<4> is hydroxy, -SH, C1-C4 alkyl, (CH2)maryl, -NH(aryl), -N(CH3)(CF3), -NH(CF3), or -NR<5>R<6>; R<5> is hydrogen or C1-C4 alkyl, R<6> is hydrogen, C1-C4 alkyl or benzyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. 5. The method of Claim 4 wherein the beta-proteinkinase isoenzyme selective inhibitor has the following formula:   wherein Z is -(CH2)p-; R<4> is -NR<5>R<6>, -NH(CF3), or -N(CH3)(CF3); R<5> and R<6> are independently H or C1-C4 alkyl; p is 0, 1, or 2; and m is independently 2 or 3, or a pharmaceutically acceptable salt, prodrug or ester thereof. 6. The method of Claim 3, wherein the beta-proteinkinase isoenzyme selective inhibitor comprises (S)-3,4-[N,N'-1,1'-((2"-ethoxy)-3"'(O)-4"'-(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione or its pharmaceutically acceptable acid salt. 7. A method according to Claim 6, wherein the pharmaceutically acceptable acid salt is selected from the hydrochloride salt and the mesylate salt. 8. A method for inducing vasodilation associated with sexual functioning which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of beta-proteinkinase isoenzyme selective inhibitor, which is indolylmaleide or a macrocyclic bis-indolylmaleide. 9. A method for treating a sexual dysfunction in a male which comprises administering to a male in need of such treatment, a therapeutically effective amount of beta-proteinkinase isoenzyme selective inhibitor, which is indolylmaleide or a macrocyclic bis-indolylmaleide. 10. The method of Claim 9, wherein the sexual dysfunction is impairment in penile erection. 11. The method of Claim 9 wherein the male is diabetic. 12. A method for treating a sexual dysfunction in a female which comprises administering to a female in need of such treatment, a therapeutically effective amount of beta-proteinkinase isoenzyme selective inhibitor, which is indolylmaleimide or a macrocyclic bis-indolylmaleimide. 13. The method of Claim 12 wherein the sexual dysfunction is selected from dyspareunia and vaginismus. 14. The method of Claim 8, wherein said inhibitor is the mesylate salt of (S)-3,4-[N,N'-1,1'-((2"-ethoxy)-3'"(O)-4'''(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione. 15. A method according to Claim 9, wherein said inhibitor is mesylate salt of (S)-3,4-[N,N'-1,1'-((2''-ethoxy)-3'''(O)-4'''(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione. 16. A method according to Claim 11, wherein said inhibitor is mesylate salt of (S)-3,4-[N,N'-1,1'-((2''-ethoxy)-3'''(O)-4'''(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione. 17. A method according to Claim 12, wherein said inhibitor is mesylate salt of (S)-3,4-[N,N'-1,1'-((2''-ethoxy)-3'''(O)-4'''(N,N-dimethylamino)-butane)-bis-(3,3'-indolyl)]-1(H)-pyrrole-2,5-dione.