Neurotherapeutic use of carboxypeptidase inhibitors

• US 6,489,319 B2
• Filed: 02/14/2001
• Issued: 12/03/2002
• Est. Priority Date: 08/16/1999
• Status: Expired due to Term

• Current Assignee: Revaax Pharmaceuticals, LLC
• Original Assignee: Revaax Pharmaceuticals, LLC
• Inventors: Chaney, Michael O., Koppel, Gary A.
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US09/783,201
• Publication Number:
  US 20020028761A1
• Time in Patent Office: 657 Days
• Field of Search: 514/201, 514/210.08, 514/200, 514/209
• US Class Current: 514/210.08
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/424 condensed with heterocyclic ring systems, e.g. clavulanic acid
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/431 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/536 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5365 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5383 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/22 Anxiolytics

Abstract

Administration of inhibitors of carboxypeptidase E provides significant neurotropic effects in warm-blooded vertebrates evidenced inter alia by anxiolytic and anti-aggressive behavior and enhanced cognition. Certain β-Lactam antibiotics, most significantly, certain 1-oxa-1-dethia cephems with blood brain barrier transport, exhibit potent therapeutic neurologic activity.

Claims

1. A method of treatment of a behavioral disorder selected from aggressive disorder, obsessive-compulsive disorder, anxiety, depression, and ADHD in a patient in need of such treatment, said method comprising the step of administering to said patient an effective amount of a compound capable of inhibiting the activity of a carboxypeptidase E in the brain of said patient.

2. The method of claim 1 wherein the behavioral disorder is depression or obsessive-compulsive disorder.

3. The method of claim 1 wherein the inhibitor of carboxypeptidase E is administered as an antiaggressive agent to control impulsivity and violence in a human patient in need of said control.

4. The method of claim 1 wherein the compound is administered to a human patient suffering a behavioral disorder comprising anxiety.

5. The method of claim 1 wherein the compound is administered to a human patient suffering a behavioral disorder comprising ADHD.

6. The method of claim 1 wherein the inhibitor of carboxypeptidase E is a moxalactam or a pharmaceutically acceptable salt or ester thereof.

7. The method of claim 6 wherein the behavioral disorder is depression or obsessive-compulsive disorder.

8. The method of claim 6 wherein the inhibitor of carboxypeptidase E is administered as an antiaggressive agent to control impulsivity and violence in a human patient in need of said control.

9. The method of claim 6 wherein the compound is administered to a human patient suffering a behavioral disorder comprising anxiety.

10. The method of claim 6 wherein the compound is administered to a human patient suffering a behavioral disorder comprising ADHD.

11. The method of claim 1 wherein the inhibitor of carboxypeptidase E is a flomoxef or a pharmaceutically acceptable salt or ester thereof.

12. The method of claim 11 wherein the behavioral disorder is depression or obsessive-compulsive disorder.

13. The method of claim 11 wherein the inhibitor of carboxypeptidase E is administered as an antiaggressive agent to control impulsivity and violence in a human in need of said control.

14. The method of claim 11 wherein the compound is administered to a human patient suffering a behavioral disorder comprising anxiety.

15. The method of claim 11 wherein the compound is administered to a human patient suffering a behavioral disorder comprising ADHD.

16. The method of claim 1 wherein the inhibitor of carboxypeptidase E is a compound of the formula

wherein R is hydrogen, a salt forming group or an active ester forming group;

R¹ is hydrogen or C₁-C₄ alkoxy;

X is S, O, S═

O, SO₂, or C;

T is C₁-C₄ alkyl, halo, hydroxy, O(C₁-C₄ ) alkyl, or —

CH₂B wherein B is the residue of a nucleophile B;

H, and acyl is the residue of an organic acid AcylOH.

17. A method of enhancing cognitive function in a warm-blooded vertebrate in need thereof said method comprising the step of administering to said warm-blooded vertebrate an effective amount of t compound capable of inhibiting carboxypeptidase F in the brain of said warm-blooded vertebrate.

18. The method of claim 17 wherein the warm-blooded vertebrate is a human patient suffering from dementia or amnesia.

19. The method of claim 17 wherein the warm-blooded vertebrate is a human patient suffering from Alzheimer'"'"'s Disease.

20. The method of claim 17 wherein the inhibitor of carboxypeptidase E is a moxalactam or a phannaceutically acceptable salt or ester thereof.

21. The method of claim 17 wherein the inhibitor of carboxypeptidase E is a flomoxef or a pharmaceutically acceptable salt or ester thereof.

22. The method of claim 17 wherein the inhibitor of carboxypeptidase E is a compound of the formula

wherein R is hydrogen, a salt forming group or an active ester forming group;

R¹ is hydrogen or C₁-C₄ alkoxy;

X is S, O, S═

O, SO₂, or C;

T is C₁-C₄ alkyl, halo, hydroxy, O(C₁-C₄ ) alkyl, or —

CH₂B wherein B is the residue of a nucleophile B;

H, and acyl is the residue of an organic acid AcylOH.

23. A method for treatment of an anxiety disorder in a human patient in need of said treatment, said method comprising the step of administering to said patient an effective amount of an inhibitor of neurogenic carboxypeptidase E.

24. The method of claim 23 wherein the inhibitor of carboxypeptidase E is a moxalactam or a pharmaceutically acceptable salt or ester thereof.

25. The method of claim 23 wherein the inhibitor of carboxypeptidase E is a flomoxef or a pharmaceutically acceptable salt or ester thereof.