Claims for Patent: 5,510,353

Summary for Patent: 5,510,353

Title:	Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain
Abstract:	Compounds of formula A-X--Y-NH-B wherein A is derived from optionally substituted benzothiophene, indole, 4-aza-and 7-aza-benzothiophene or-indole, A bearing in position 5 hydrogen, halogen, optionally substituted alkyl, hydroxy, nitro, amino, alkylamino, acylamino, alkoxycarbonyl, sulfamoyl, cyano, trimethylsilyl, carboxy, carbamoyl, phosphate, oxycarbamoyl, heterocyclic radical or ether or ester group, X-Y is -CR8=N- or CH(R8)-NH- wherein R8 is -H or alkyl and attached at position 3 of A, and B is a heterocyclic radical or a residue cycloalkyl, aryl, adamantyl, acyl or carbamoyl and X2 is alkylthio or NR3R10 wherein R3 is H or alkyl or R3 and R10 together with the nitrogen atom to which they are attached form a heterocyclic radical, in free form or in salt form, have pharmacological activity, e.g. for treating gastrointestinal disorders.
Inventor(s):	Rudolf K. A. Giger, Henri Mattes
Assignee:	Novartis AG
Application Number:	US08/370,038
Patent Claims:	1. A compound of the formula ##STR27## wherein R1 hydrogen; C1-6 alkyl; (C1-6 alkyl)carbonyl; or benzoyl;R5 is hydrogen; halo; C1-6 alkyl; hydroxy; nitro; amino; C1-4 alkylamino; C1-10 alkylcarbonylamino; C2-6 alkoxy-carbonyl; SO2 NRa Rb ; cyano; trimethylsilyl; C1-6 alkyl monosubstituted by --SO2 -(C1-6 alkyl), --SO2 NRa Rb, --CONRa Rb, --NH--SO2 --(C1-6 alkyl), --N (C1-6 alkyl)--SO2 --(C1-6 alkyl), --NRa Rb, C2-6 alkoxycarbonyl or --PO(C1-4 alkyl)2 ; carboxy; CONRa Rb ; --PO(C1-4 alkyl)2 ;--OCONRc Rd ; C1-6 alkoxy; C1-6 alkoxy monosubstituted by hydroxy, C1-4 alkoxy, NRa R'b, CONRa Rb, CSNRa Rb, (C1-6 alkyl)carbonyloxy or benzoyloxy; C2-6 alkenyloxy; pyridyl-carbonyloxy; (C1-6 alkyl)carbonyloxy; or benzoyloxy;and wherever they appear in the above definition of R5, each of Ra and Rb, independently, is hydrogen or C1-6 alkyl; R'b is hydrogen or C1-6 alkyl; and each of Rc and Rd, independently, is C1-6 alkyl; R7 is hydrogen, halo, C1-6 alkyl or C1-6 alkoxy; X--Y is --CR8 ═N-- or---H(R8)--NH-- where R8 is hydrogen or C1-6 alkyl; and B is a radical of formula (a) or (b), ##STR28## where n is 1 or 2; A1 is C═O or CH2 ; X1 is S; NR11 where R11 is hydrogen; or CR12 R13 where each of R12 and R13, independently, is hydrogen or C1-4 alkyl; R10 is hydrogen; C1-12 alkyl; C1-6 alkyl monosubstituted by hydroxy, aryl, aryloxy, adamantyl, a heterocyclic radical, --NH--SO2 -aryl or --NR15 --COR16 where R15 is hydrogen or C1-4 alkyl and R16 is C1-6 alkyl, C5-7 cycloalkyl, C5-7 cycloalkyl-C1-4 alkyl, aryl or aryl(C1-4 alkyl); C5-7 cycloalkyl; adamantyl; (C1-10 alkyl)-carbonyl; benzoyl; phenyl(C1-4 alkyl)carbonyl; or --CONHR14 where R14 is C1-10 alkyl or C5-7 cycloalkyl;and wherever "aryl" appears as is or in the significances "aryloxy", "--NH--SO2 -aryl" or "aryl(C1-4 alkyl)" in the above definition, it is phenyl or phenyl mono- or disubstituted by fluoro, chloro, methyl or methoxy; and wherever the term "a heterocyclic radical" appears in the above definition, it is pyridyl, imidazolyl, benzimidazolyl, pyrrolidinyl, piperidino, pyrazinyl, perhydroindolyl or a radical of formula (d) ##STR29## where E is --CH2 CH2 --,--CH2 N(R17)-- where R17 is hydrogen or C1-4 alkyl; or --(CH2)3 --where one or two hydrogens therein can be replaced by C1-6 alkyl; and E1 is --CO--or --CH2 --; and X2 is --SR20 where R20 is C1-6 alkyl; or --NR3 R'10 where either R3 is hydrogen or C1-6 alkyl and R'10 has one of the significances indicated above for R10 ; or R3 and R'10 together with the nitrogen atom to which they are attached form a heterocyclic radical as defined above;with the proviso that where B is a radical of formula (b), only one of R10 and R'10 can be other than hydrogen and X2 can be --SR20 only when R10 is hydrogen; which compound is in free base or pharmaceutically acceptable salt form. 2. A compound of claim 1 wherein each of R1 and R7 is hydrogen. 3. A compound of claim 1 wherein each of R1 and R7 is hydrogen and R5 is hydroxy or C1-6 alkoxy. 4. A compound of claim 1 wherein at least one of R1 and R7 is other than hydrogen. 5. A compound of claim 1 wherein each of R1 and R7 is hydrogen and R5 is hydrogen, hydroxy, C1-6 alkoxy, carboxy, C2-6 alkoxycarbonyl, CONRa Rb where Ra and Rb are as defined in claim 14, SO2 NH(C1-6 alkyl) or C1-6 alkyl monosubstituted by --SO2 --(C1-6 alkyl) or --PO(C1-4 alkyl)2. 6. A compound according to claim 1 which is 5-methoxy-indole-3-carboxaldehyde amino-(pentyl-amino)methylenehydrazone, in free base form or in pharmaceutically acceptable salt form. 7. A compound according to claim 1 which is 5-hydroxy-indole-3-carboxaldehydeamino(N-cyclo-hexylureido)methylenehydrazone, 5hydroxy-indole-3-carboxaldehyde amino (3-benzimidazol-2-yl-propylamino)methylenehydrazone! 5-carbamoyl-indole-3-carboxaldehydeamino(pentyl-amino)methylenehydrazone, 5-hydroxy-7-methyl-indole-3-carboxaldehyde amino(pentyl-amino)methylene-hydrazone, 1-ethyl-5-hydroxy-indole-3-carboxaldehyde amino (pentyl-amino)methylenehydrazone and 5-hydroxy-7-methyl-indole-3-carboxaldehyde amino (N-methyl-N-pentyl-amino)-methylenehydrazone, all of which are in free base form or in pharmaceutically acceptable salt form. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of claim 1, which compound is in free base or pharmaceutically acceptable salt form. 9. A method of treating a gastrointestinal motility disorder comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1, which compound is in free base or pharmaceutically acceptable salt form. 10. A method according to claim 9 wherein the disorder is irritable bowel syndrome, gastroesophageal reflux disease or constipation. 11. A method of treating a disorder associated with cephalic pain comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1, which compound is in free base or pharmaceutically acceptable salt form. 12. A method according to claim 11 wherein the disorder is migraine headaches. 13. A compound of claim 1 wherein B is a radical ##STR30## or a radical of formula (b) where R10 and X2 are as defined in claim 1. 14. The compound of claim 6 which is in pharmaceutically acceptable acid addition salt form. 15. The compound of claim 6 which is in hydrogen maleate form. 16. A compound according to claim 1 where X--Y is --CR8 ═N--. 17. A compound according to claim 1 where B is a radical of formula (b) where R10 is hydrogen and X2 is --NR3 R'10 where R3 is hydrogen or C1-4 alkyl and R'10 is C1-12 alkyl.