Polycyclic aminopyridine compounds which are acetylcholinesterase inhibitors, process for preparing them and their use

• US 5,965,569 A
• Filed: 08/12/1997
• Issued: 10/12/1999
• Est. Priority Date: 10/11/1995
• Status: Expired due to Fees

• Current Assignee: Medichem, S.A.
• Original Assignee: Medichem, S.A.
• Inventors: Contreras Lascorz, Joan, Munoz-Torrero Lopez-Ibarra, Diego, Vivas, Nuria Maria, Banos Diez, Josep Eladi, El Achab, Rachid, Gorbig Romeu, Diana Marina, Simon Fornell, Monserrat, Morral Cardoner, Jordi, Badia Sancho, Albert, Camps Garcia, Pelayo
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US08/849,709
• Time in Patent Office: 791 Days
• Field of Search: 514/289, 546/63
• US Class Current: 514/289
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 221/22 Bridged ring systems

Abstract

New polycyclic aminopyridine compounds which are acetylcholinesterase inhibitors, process for preparing them and their use. The polycyclic aminopyridine compounds correspond to the formula ##STR1## in which the various radicals have the meanings stated in the specification. The process for preparing these compounds is characterized in that ketones of general formula (II) are reacted with aminonitriles of general formula (III) and, if necessary, the compounds of formula (I) are alkylated, aralkylated or acylated, or alternatively the corresponding keto precursor is reduced. The compounds of the general formula (I) are especially suitable for the preparation of medicaments against memory disorders such as senile dementia or Alzheimer'"'"'s disease.

Claims

1. Polycyclic aminopyridine compounds of general Formula I ##STR26## and their pharmaceutically acceptable salts, in which:

R is hydrogen, alkyl, aralkyl, or acyl;

R₁ and R₂ are, independently, hydrogen, alkyl, aralkyl, alkoxy, alkoxycarbonyl, amino or amino substituted with one or two alkyl, aralkyl or acyl groups, m and n are independently 1, 2 or 3;

X is a bond between two carbons, an oxygen or sulphur atom, a group N--R₃ --in which the group R₃ has one of the meanings defined about for R--or an alkylene or alkenylene bridge containing from 1 to 5 carbon atoms and which may contain one or more substituents R₄ --which are, respectively, hydrogen, lower alkyl, alkenyl or alkylidene having one to four carbon atoms with a linear or branched chain, phenyl, phenyl substituted with one or more lower alkyl groups having one to four carbon atoms, lower alkoxy groups having one to four carbon atoms or halogen groups, aralkyl, lower alkoxy containing from one to four carbon atoms, and hydroxyl--and when X is an alkenylene group, the latter may be fused to a saturated or unsaturated carbocyclic ring system, it being possible for the ring to be substituted with one or more groups R₅ --which are lower alkyl or lower alkoxy having one to four carbon atoms, or halogen;

Y is an alkenylene bridge containing from 3 to 5 carbon atoms and which may contain one or more substituents R₄ as defined above; and

##STR27## p being an integer which is 3 or 4, q being an integer from 1 to 3 inclusive, and r being an integer from 1 to 4 inclusive, and R₆ and R₇ being substituents which are individually hydrogen, halogen, lower alkoxy or lower alkyl.

2. Compounds according to claim 1, in which R is hydrogen.

3. Compounds according to claim 1, in which m and n are both equal to one.

4. Compounds according to claim 2, of general formula ##STR28## in which A, X and Y have the meanings stated in claim 1.

5. Compounds according to claim 1, in which ##STR29## R₇ being hydrogen, halogen, or lower alkyl having 1 to 4 carbon atoms and r having the values 1 or 2.

6. Compounds according to claim 1, in which X is an ortho-phenylene group, a methylene group or a methylene group substituted with one or more groups R₄, it being possible for the said groups R₄ to be, independently, equal to lower alkyl, lower alkoxy, hydroxyl or, jointly, a lower alkylidene group.

7. Compounds according to claim 1, in which Y is an alkenylene bridge containing 3 carbon atoms, the central carbon of which can be substituted with a group R₄ which has the meaning stated in claim 1.

8. Compounds according to claim 4, of general formula ##STR30## in which R₄ can be hydrogen, lower alkyl having 1 to 4 carbon atoms or phenyl, and R₇ can be hydrogen or halogen.

9. A pharmaceutical composition which comprises an effective acetylcholinesterase-inhibiting amount of at least one of the compounds of claim 1.

13. A method of treating Alzheimer'"'"'s disease by administering a compound of claim 1 to a subject suffering from said disease.

14. Compounds according to claim 8, wherein R₇ is fluorine or chlorine.

10. A process for obtaining polycyclic aminopyridine compounds of general Formula I ##STR31## and their pharmaceutically acceptable salts, in which:

R is hydrogen, alkyl, aralkyl, or acyl;

R₁ and R₂ are, independently, hydrogen, alkyl, aralkyl, alkoxy, alkoxycarbonyl, amino or amino substituted with one or two alkyl, aralkyl or acyl groups;

m and n are independently 1, 2 or 3;

X is a bond between two carbons, an oxygen or sulphur atom, a group N--R₃ --in which the group R₃ has one of the meanings defined about for R--or an alkylene or alkenylene bridge containing from 1 to 5 carbon atoms and which may contain one or more substituents R₄ --which are, respectively, hydrogen, lower alkyl, alkenyl or alkylidene having one to four carbon atoms with a linear or branched chain, phenyl, phenyl substituted with one or more lower alkyl groups having one to four carbon atoms, lower alkoxy groups having one to four carbon atoms or halogen groups, aralkyl, lower alkoxy containing from one to four carbon atoms, and hydroxyl--and when X is an alkenylene group, the latter may be fused to a saturated or unsaturated carbocyclic ring system, it being possible for the ring to be substituted with one or more groups R₅ --which are lower alkyl or lower alkoxy having one to four carbon atoms, or halogen;

Y is an alkenylene bridge containing from 3 to 5 carbon atoms and which may contain one or more substituents R₄ as defined above; and

##STR32## p being an integer which is 3 or 4, q being an integer from 1 to 3 inclusive, and r being integer from an 1 to 4 inclusive, and R₆ and R₇ being substituents which are individually hydrogen, halogen, lower alkoxy or lower alkyl, the said process wherein ketones of general Formula (11) ##STR33## are reacted with the aminonitriles of general formula (III) ##STR34## in which general formulae (II) and (III) A, R₁ and R₂, X, Y, m and n have the meanings defined above, and, if necessary, when it is desired to obtain compounds in which R is other than hydrogen, the compounds of general structure (I) in which R is hydrogen are subjected to alkylation, aralkylation or acylation;

or, when it is desired to obtain compounds in which R₄ is an endo hydroxyl group, the corresponding keto precursor in which R₄ is an oxo group is subjected to reduction;

thereafter, if so desired, to form a pharmaceutically acceptable acid addition salt, a basic compound obtained is reacted with a suitable acid.

11. A process according to claim 10, characterized in that the starting ketones (II) correspond to the general formula ##STR35## in which X and Y have the meanings stated in claim 10.

12. A process according to claim 10, in which the reaction between the ketones (II) and the aminonitriles (III) is performed in the presence of a Lewis acid as catalyst or of a dehydrating agent.