Treatment of pancreatitis using alpha 7 receptor-binding cholinergic agonists

• US 7,238,715 B2
• Filed: 09/30/2004
• Issued: 07/03/2007
• Est. Priority Date: 12/06/2002
• Status: Active Grant

• Current Assignee: The Feinstein Institutes For Medical Research
• Original Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.)
• Inventors: Wang, Hong, Tracey, Kevin J.
• Primary Examiner(s): Marschel; Ardin H.
• Assistant Examiner(s): Graffeo; Michel
• Application Number:
  US10/957,426
• Publication Number:
  US 20050137218A1
• Time in Patent Office: 1,006 Days
• Field of Search: 514/278
• US Class Current: 514/334
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: G01N 2333/525 Tumor necrosis factor [TNF]
• CPC Class Codes: G01N 2333/54 Interleukins [IL]
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: G01N 33/9406 Neurotransmitters
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A method of treating a patient suffering from pancreatitis comprising treating said patient with a therapeutically effective amount of a cholinergic agonist selective for an α7 nicotinic receptor in an amount sufficient to decrease the amount of the proinflammatory cytokine that is released from a macrophage wherein said condition is acute pancreatitis. The compounds of the present invention include a quaternary analog of cocaine; (1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester; a compound of formula (I), a compound of formula (II), a compound of formula (III), a compound of formula (IV), and an oligonucleotide or mimetic capable of attenuating the symptoms of acute pancreatitis wherein the oligonucleotide or mimetic consists essentially of a sequence greater than 5 nucleotides long that is complementary to an mRNA of an α7 cholinergic receptor. The variables of formulae (I), (II), (III) and (IV) are described herein

Claims

1. A method of treating a subject suffering from pancreatitis, comprising:

treating said subject with a therapeutically effective amount of a cholinergic agonist selective for an α

7 nicotinic receptor.

2. The method of claim 1 wherein said acute pancreatitis is acute edematous pancreatitis.

3. The method of claim 1 wherein said acute pancreatitis is acute hemorrhaging pancreatitis.

4. The method of claim 1 wherein said acute pancreatitis is acute necrotizing pancreatitis.

5. The method of claim 1 wherein said acute pancreatitis is infected acute pancreatitis.

6. The method of claim 1 wherein said subject is treated prophylactically for acute pancreatitis.

7. The method of claim 1, wherein the cholinergic agonist is selected from the group consisting of

a quaternary analog of cocaine;

(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester;

a compound of formula I;

8. The method of claim 1, wherein the cholinergic agonist is a compound of formula I:

9. The method of claim 8, wherein the cholinergic agonist is (−

)-spiro[1-azabicyclo[2.2.2]octane-3,5′

-oxazolidin-2′

-one]

10. The method of claim 1, wherein the cholinergic agonist is a compound of formula II:

11. The method of claim 10, wherein the cholinergic agonist is a compound of formula II wherein m is 1;

n is 0;

p is 0;

x is oxygen;

A is C(R²);

G is C(R³); and

D is C(R⁴).

12. The method of claim 10, wherein the cholinergic agonist is 5′

-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′

-(3′

H)-furo[2,3-b]pyridin].

13. The method of claim 1, wherein the cholinergic agonist is a compound of formula III:

14. The method of claim 12, wherein R₂ is

15. The method of claim 13, wherein the cholinergic agonist is a compound of formula III, wherein R₂ is attached to the 3-position of the tetrahydropyridine ring, and further wherein R₃, which is attached to the 4- or the 2- position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, acetylamino, acetoxy, and nitro.

16. The method of claim 13, wherein the cholinergic agonist is a compound selected from the group consisting of formula III, wherein R₃ is hydroxyl, and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is acetylamino and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is acetoxy and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is methoxy, and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is methoxy and wherein R₁ and R₄ are hydrogen, and further wherein R₃ is attached to the 2-position of the phenyl ring, and R₅, which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy.

17. The method of claim 13, wherein the cholinergic agonist is is selected from the group consisting of 3-2,4-dimethoxybenzylidine anabaseine (DMXB-A), 3-(4-hydroxybenzylidene)anabaseine, 3-(4-methoxybenzylidene)anabaseine, 3-(4-aminobenzylidene)anabaseine, 3-(4-hyrdoxy-2-methoxybenzylidene)anabaseine, 3-(4-methoxy-2-hydroxybenzylidene)anabaseine, trans-3-cinnamylidene anabaseine, trans-3-(2-methoxy-cinnamylidene)anabaseine and trans-3-(4-methoxycinnamylidene)anabaseine.

18. The method of claim 13, wherein the cholinergic agonist is 3-(4-hydroxy-2-methoxybenzylidene)anabasine

19. The method of claim 13, wherein the cholinergic agonist is 3-(2,4-dimethoxybenzylidene)anabaseine.

20. The method of claim 13, wherein the cholinergic agonist is trans-3-cinnamylidene anabaseine.

21. The method of claim 13, wherein the cholinergic agonist is trans-3-(2-methoxycinnamylidene)anabaseine.

22. The method of claim 13, wherein the cholinergic agonist is trans-3-(4-methoxycinnamylidene)anabaseine.

23. The method of claim 1, wherein the cholinergic agonist is a compound of formula IV:

24. The method of claim 19, wherein the cholinergic agonist is selected from a group consisting of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-hydroxyphenoxy)benzamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetamidophenoxy)benzamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide, and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulphonyl)benzamide.

25. The method of claim 19, wherein the cholinergic agonist is N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide.

26. The method of claim 1, wherein the cholinergic agonist is cocaine methiodide.