Heterocyclic analgesic compounds and methods of use thereof

• US 6,645,980 B1
• Filed: 11/20/2000
• Issued: 11/11/2003
• Est. Priority Date: 05/25/2000
• Status: Expired due to Term

• Current Assignee: Sepracor Incorporated (Sumitomo Chemical Company Limited)
• Original Assignee: Sepracor Incorporated (Sumitomo Chemical Company Limited)
• Inventors: Heffernan, Michele L. R., Cuny, Gregory D., Hauske, James R., Aquila, Brian M., Bannister, Thomas D., Shao, Liming, Wu, Xinhe, Wang, Fengjiang
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US09/717,174
• Time in Patent Office: 1,086 Days
• Field of Search: 546/158, 546/194, 546/201, 546/210, 546/213, 546/214, 546/221, 546/224, 546/225, 546/226, 546/234, 514/312, 514/318, 514/323, 514/326, 514/327, 514/329, 514/330, 514/331
• US Class Current: 514/312
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/438 The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• CPC Class Codes: A61K 31/4523 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 223/04 with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 223/10 attached in position 2
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 243/08 not condensed with other rings
• CPC Class Codes: C07D 265/30 not condensed with other rings
• CPC Class Codes: C07D 267/10 not condensed with other rings
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

One aspect of the present invention relates to novel heterocyclic compounds. A second aspect of the present invention relates to the use of the novel heterocyclic compounds as ligands for various cellular receptors, including opiate receptors, other G-protein-coupled receptors, and ion channels. An additional aspect of the present invention relates to the use of the novel heterocyclic compounds as analgesics.

Claims

1. The compound represented by 1:

5. A composition, comprising a compound of claim 1, 2, 3, or 4;

and a pharmaceutically acceptable excipient.

6. The composition of claim 5, wherein said excipient is selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, and polymeric carriers.

7. A method of treating pain, drug addiction, or tinnitus in a mammal, comprising the step of administering to a mammal in need thereof an effective amount of a composition of claim 5.

8. The method of claim 7, wherein said mammal is a primate, equine, canine or feline.

9. The method claim 7, wherein said mammal is a human.

10. The method of claim 7, wherein said composition is administered orally.

11. The method of claim 7, wherein said composition is administered intravenously.

12. The method of claim 7, wherein said composition is administered sublingually.

13. The method of claim 7, wherein said composition is administered ocularly.

2. The compound represented by 2:

3. The compound represented by 3:

4. The compound represented by 4:

14. A composition, comprising:

an excipient selected from the group consisting of cyclodextrins, liposomes, micelle forming agents, and polymeric carriers; and

a compound selected from the group consisting of;

a compound represented by A;

wherein

m is 1, 2, 3 or 4;

n is 1;

y is 1 or 2;

R₁ represents alkyl;

monocyclic or polycyclic aryl;

or cycloalkyl;

R₂ represents independently for each occurrence H;

alkyl;

fluoroalkyl;

aryl;

or cycloalkyl;

R₁ and R₂ may be connected through a covalent bond;

R₃ represents independently for each occurrence H;

alkyl;

monocyclic or polycyclic aryl;

OR₂;

OC(O)R₂;

CH₂OR₂;

or CO₂R₂;

wherein any two instances of R₃ may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;

R₄ represents H;

alkyl;

monocyclic or polycyclic aryl;

alkenyl;

or cycloalkyl;

R₅ represents independently for each occurrence H;

alkyl;

CH₂Y;

monocyclic or polycyclic aryl;

F;

OR₂;

or OC(O)R₂;

R₆ represents independently for each occurrence H;

alkyl;

CH₂Y;

monocyclic or polycyclic aryl;

F;

OR₂;

or OC(O)R₂;

Y represents independently for each occurrence OR₂, N(R₂)₂, SR₂, S(O)R₂, S(O)₂R₂, or P(O)(OR₂)₂;

a covalent bond may connect R₄ and an instance of R₅ or R₆ that is attached to the carbon chain between R₄ and the ring nitrogen explicitly shown in A;

any two geminal or vicinal instances of R₅ and R₆ may be connected through a covalent bond;

X represents C(R₃)₂; and

the stereochemical configuration at any stereocenter of a compound represented by A is R, S, or a mixture of these configurations;

a compound represented by B;

wherein

m is 1, 2, 3 or 4;

n is 1;

R₁ represents H;

alkyl;

monocyclic or polycyclic aryl;

or cycloalkyl;

R₂ represents independently for each occurrence H;

alkyl;

fluoroalkyl;

monocyclic or polycyclic aryl;

or cycloalkyl;

R₁ and R₂ may be connected through a covalent bond;

R₃ represents independently for each occurrence H;

alkyl;

monocyclic or polycyclic aryl;

OR₂;

OC(O)R₂;

CH₂OR₂;

or CO₂R₂;

wherein any two instances of R₃ may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;

R₄ represents H;

alkyl;

monocyclic or polycyclic aryl;

alkenyl;

or cycloalkyl;

R₅ represents independently for each occurrence H;

alkyl;

CH₂Y;

monocyclic or polycyclic aryl;

F;

OR₂;

or OC(O)R₂;

R₆ represents independently for each occurrence H;

alkyl;

CH₂Y;

monocyclic or polycyclic aryl;

F;

OR₂;

or OC(O)R₂;

Y represents independently for each occurrence OR₂, N(R₂)₂, SR₂, S(O)R₂, S(O)₂R₂, or P(O)(OR₂)₂;

a covalent bond may connect R₄ and an instance of R₅ or R₆ that is attached to the carbon chain between R₄ and the ring nitrogen explicitly shown in B;

any two geminal or vicinal instances of R₅ and R₆ may be connected through a covalent bond;

X represents C(R₃)₂; and

the stereochemical configuration at any stereocenter of a compound represented by B is R or S; and

a compound represented by E;

wherein

m is 1, 2, 3 or 4;

n is 1;

R₁ represents H;

alkyl;

monocyclic or polycyclic aryl;

or cycloalkyl;

R₂ represents independently for each occurrence H;

alkyl;

fluoroalkyl;

monocyclic or polycyclic aryl;

or cycloalkyl;

R₁ and R₂ may be connected through a covalent bond;

R₃ represents independently for each occurrence H;

alkyl;

monocyclic or polycyclic aryl;

OR₂;

OC(O)R₂;

CH₂OR₂;

or CO₂R₂;

wherein any two instances of R₃ may be connected by a covalent tether whose backbone consists of 1, 2, 3, or 4 carbon atoms;

R₄ represents H;

alkyl;

monocyclic or polycyclic aryl;

alkenyl;

or cycloalkyl;

R₅ represents independently for each occurrence H;

alkyl;

CH₂Y;

monocyclic or polycyclic aryl;

F;

OR₂;

or OC(O)R₂;

R₆ represents independently for each occurrence H;

alkyl;

CH₂Y;

monocyclic or polycyclic aryl;

F;

OR₂;

or OC(O)R₂;

Y represents independently for each occurrence OR₂, N(R₂)₂, SR₂, S(O)R₂, S(O)₂R₂, or P(O)(OR₂)₂;

a covalent bond may connect R₄ and an instance of R₅ or R₆ that is attached to the carbon chain between R₄ and the ring nitrogen explicitly shown in E;

any two geminal or vicinal instances of R₅ and R₆ may be connected through a covalent bond;

X represents C(R₃)₂; and

the stereochemical configuration at any stereocenter of a compound represented by E is R, S, or a mixture of these configurations.

15. A method of treating pain, drug addiction, or tinnitus in a mammal, comprising the step of administering to a mammal in need thereof an effective amount of a composition of claim 14.

16. The method of claim 15, wherein said mammal is a primate, equine, canine or feline.

17. The method claim 15, wherein said mammal is a human.

18. The method of claim 15, wherein said composition is administered orally.

19. The method of claim 15, wherein said composition is administered intravenously.

20. The method of claim 15, wherein said composition is administered sublingually.

21. The method of claim 15, wherein said composition is administered ocularly.