Muscarinic agonists

• US 5,403,845 A
• Filed: 04/07/1994
• Issued: 04/04/1995
• Est. Priority Date: 08/27/1991
• Status: Expired due to Term

• Current Assignee: University of Toledo
• Original Assignee: University of Toledo
• Inventors: Dunbar, Philip G., Hoss, Wayne P., Durant, Graham J., Messer, William S. Jr.
• Primary Examiner(s): TSANG, CECILIA J
• Application Number:
  US08/224,271
• Time in Patent Office: 362 Days
• Field of Search: 544/298, 544/331, 544/332, 544/333, 544/335, 546/268, 546/277, 546/280, 546/304, 546/309-312, 546/290, 546/297, 514/256, 514/269, 514/340, 514/342, 514/336, 514/349, 514/352, 514/354, 514/356, 514/357, 514/272, 514/275
• US Class Current: 514/275
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/78 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 239/06 having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 411/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

Substituted 1,4,5,6 -tetrahydropyrimidine compositions, substituted 1,2,3,6 -tetrahydropyrimidine compositions and substituted 3,4,5,6 -tetrahydropyridine compositions are disclosed. They are useful for stimulating muscarinic receptors including, for example, treating the symptoms of cognitive disorders, especially impaired memory, which are associated with decreased acetylcholine synthesis and cholinergic cell degeneration.

Claims

1. A compound having the formula (i), (ii), or (iii) below or a pharmaceutically acceptable salt thereof, ##STR4## wherein:

A is H or NHR;

R is H, alkyl of 1-7 carbon atom, --C(O)--R¹ or C(O)OR¹ ; and

wherein Z is ##STR5## wherein X is O or S, and wherein R¹ is a monovalent hydrocarbon radical having 1-7 carbon atoms, R² is alkyl of 1-8 carbon atoms, alkylthionlkyl or alkoxyalkyl of up to 8 carbon atoms or NHR, R³ is H or --CH₃, R₄, is H or an alkyl of 1-8 carbon atoms and wherein R⁵ is H, alkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms or an alkylthio group of 1-8 carbon atoms.

2. The compound or salt of claim 1 wherein said compound or salt is that of (iii).

3. The compound or salt of claim 1 wherein said compound or salt is (i) or (ii).

4. The compound or salt of claim 3 wherein said compound or salt is (i).

5. The compound or salt of claim 3 wherein said compound or salt is (ii).

6. The compound or salt of claim 1 wherein Z is selected from I, II, III, IV, or VI.

7. The salt or compound of claim 6 wherein the salt or compound is (i) and Z is I.

8. The compound or salt of claim 2 wherein said compound or salt is that of structure (iii) with the proviso that R is --H.

9. The compound of claim 1 where Z is I.

10. The compound of claim 9 where Z is I and R² is an alkyl group of 1 to 4 carbon atoms.

11. The compound of claim 9 where Z is I and R² is cyclopropyl, 2-methyl propyl, or 1-methyl butyl.

12. The compound of claim 9 where Z is I and R² is alkoxy alkyl or alkylthioalkyl of 1-8 carbon atoms.

13. In a method of providing a therapeutic benefit to a mammal comprising administering to said mammal a drug in effective amounts to stimulate a muscarinic receptor so as to provide such benefit, the improvement wherein said drug is a compound of claim 1 or its pharmaceutically salt.

14. A pharmaceutical preparation effective for stimulating a muscarinic receptor, comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable solid or liquid carrier.

15. The compound, or salt, of claim 1 wherein said salt or compound is an M₁ muscarinic agonist.

16. The preparation of claim 14 wherein in the compound or salt Z is selected from I, II, III, IV, V, VI.

17. The preparation of claim 16 wherein said compound or salt thereof is (i).

18. The preparation of claim 17 wherein R and A are H.

19. The preparation of claim 18 wherein Z is