Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain

• US 5,510,353 A
• Filed: 01/09/1995
• Issued: 04/23/1996
• Est. Priority Date: 03/22/1991
• Status: Expired due to Term

• Current Assignee: Novartis Ag
• Original Assignee: Sandoz Inc. (Novartis Ag)
• Inventors: Mattes, Henri, Giger, Rudolf K. A.
• Primary Examiner(s): Haley, Jacqueline
• Application Number:
  US08/370,038
• Time in Patent Office: 470 Days
• Field of Search: 514/300, 514/387, 514/415, 514/226.8, 514/227.2, 514/269, 514/272, 514/255, 514/339, 514/392, 514/323, 546/113, 546/201, 546/273, 548/305, 548/496, 548/505, 548/312.1, 544/54, 544/55, 544/337, 544/405
• US Class Current: 514/300
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 333/58 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07F 7/0814 said ring is substituted at a C ring atom by Si
• CPC Class Codes: C07F 9/5728 condensed with carbocyclic rings or carbocyclic ring systems

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 ##STR1## wherein R₁₀ is H, optionally substituted alkyl, cycloalkyl, aryl, adamantyl, acyl or carbamoyl and X₂ is alkylthio or NR₃ R₁₀ 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.

Claims

1. A compound of the formula ##STR27## wherein R₁ hydrogen;

C_1-6 alkyl;

(C_1-6 alkyl)carbonyl;

or benzoyl;

R₅ is hydrogen;

halo;

C_1-6 alkyl;

hydroxy;

nitro;

amino;

C_1-4 alkylamino;

C_1-10 alkylcarbonylamino;

C_2-6 alkoxy-carbonyl;

SO₂ NR_a R_b ;

cyano;

trimethylsilyl;

C_1-6 alkyl monosubstituted by --SO₂ -(C_1-6 alkyl), --SO₂ NR_a R_b, --CONR_a R_b, --NH--SO₂ --(C_1-6 alkyl), --N (C_1-6 alkyl)--SO₂ --(C_1-6 alkyl), --NR_a R_b, C_2-6 alkoxycarbonyl or --PO(C_1-4 alkyl)₂ ;

carboxy;

CONR_a R_b ;

--PO(C_1-4 alkyl)₂ ;

--OCONR_c R_d ;

C_1-6 alkoxy;

C_1-6 alkoxy monosubstituted

by hydroxy, C_1-4 alkoxy, NR_a R'"'"'_b, CONR_a R_b, CSNR_a R_b,

(C_1-6 alkyl)carbonyloxy or benzoyloxy;

C_2-6 alkenyloxy;

pyridyl-carbonyloxy;

(C_1-6 alkyl)carbonyloxy;

or benzoyloxy;

and wherever they appear in the above definition of

R₅, each of R_a and R_b, independently, is hydrogen or C_1-6 alkyl;

R'"'"'_b is hydrogen or C_1-6 alkyl; and

each of R_c and R_d, independently, is C_1-6 alkyl;

R₇ is hydrogen, halo, C_1-6 alkyl or C_1-6 alkoxy;

X--Y is --CR₈ ═

N-- or---H(R₈)--NH-- where R₈ is hydrogen or C_1-6 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 C_1-4 alkyl;

R₁₀ is hydrogen;

C_1-12 alkyl;

C_1-6 alkyl monosubstituted by hydroxy, aryl, aryloxy, adamantyl, a heterocyclic radical, --NH--SO₂ -aryl or --NR₁₅ --COR₁₆ where R₁₅ is hydrogen or C_1-4 alkyl and R₁₆ is C_1-6 alkyl, C_5-7 cycloalkyl, C_5-7 cycloalkyl-C_1-4 alkyl, aryl or aryl(C_1-4 alkyl);

C_5-7 cycloalkyl;

adamantyl;

(C_1-10 alkyl)-carbonyl;

benzoyl;

phenyl(C_1-4 alkyl)carbonyl;

or --CONHR₁₄ where R₁₄ is C_1-10 alkyl or C_5-7 cycloalkyl;

and wherever "aryl" appears as is or in the significances "aryloxy", "--NH--SO₂ -aryl" or "aryl(C_1-4 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 C_1-4 alkyl;

or --(CH₂)₃ --where one or two hydrogens therein can be replaced by C_1-6 alkyl; and

E₁ is --CO--or --CH₂ --;

and

X₂ is --SR₂₀ where R₂₀ is C_1-6 alkyl;

or --NR₃ R'"'"'₁₀ where either R₃ is hydrogen or C_1-6 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 C_1-6 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, C_1-6 alkoxy, carboxy, C_2-6 alkoxycarbonyl, CONR_a R_b where R_a and R_b are as defined in claim 14, SO₂ NH(C_1-6 alkyl) or C_1-6 alkyl monosubstituted by --SO₂ --(C_1-6 alkyl) or --PO(C_1-4 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 C_1-4 alkyl and R'"'"'₁₀ is C_1-12 alkyl.