Substituted piperazines,(1,4) diazepines, and 2,5-diazabicyclo (2.2.1)iieptanes as histamine H1 and/or H3 antagonists or histamine H3 reverse antagonists

• US 7,615,550 B2
• Filed: 10/14/2003
• Issued: 11/10/2009
• Est. Priority Date: 10/16/2002
• Status: Expired due to Fees

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Lindon, Matthew J, Wilson, David Matthew, Heightman, Thomas Daniel, Hodgson, Simon Teanby
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US10/531,758
• Publication Number:
  US 20060025404A1
• Time in Patent Office: 2,219 Days
• Field of Search: 514/227.8, 514/235.8, 514/252.11, 514/253.09, 514/253.1, 514/253.12, 544/60, 544/120, 544/357, 544/360, 544/364
• US Class Current: 514/227.8
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 209/42 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 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/81 Amides; Imides
• CPC Class Codes: C07D 215/40 attached in position 8
• CPC Class Codes: C07D 215/46 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
• CPC Class Codes: C07D 215/50 attached in position 4
• CPC Class Codes: C07D 239/28 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 243/08 not condensed with other rings
• CPC Class Codes: C07D 265/36 condensed with one six-membered ring
• CPC Class Codes: C07D 277/62 Benzothiazoles
• CPC Class Codes: C07D 285/06 1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
• CPC Class Codes: C07D 295/088 to an acyclic saturated chain
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 295/215 : Radicals derived from nitrogen analogues of carbonic acid
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/79 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 307/85 : attached in position 2
• CPC Class Codes: C07D 311/84 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
• CPC Class Codes: C07D 317/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• 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 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 487/08 : Bridged systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems

Abstract

The present invention relates to novel piperazine and azepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurodegenerative disorders including Alzheimer'"'"'s disease.

Claims

1. A compound of formula (I):

2. A compound according to claim 1 wherein R¹ is phenyl optionally substituted by 1, 2 or 3 substituents which may be the same or different and which are selected from the group consisting of:

chlorine, fluorine, bromine;

trifluoromethyl;

methyl, ethyl, isopropyl, propyl, t-butyl (optionally substituted by COOH, COOMe or COOEt);

methoxy, butoxy, —

OCH(Me)₂, —

OC(Me)₃ (optionally substituted by COOH or COOMe);

hydroxy;

oxo;

cyano;

—

CH₂—

CN;

ethenyl (optionally substituted by COOMe);

cyclopentyl;

—

SO₂Me;

—

OCH₂CH═

CH₂;

—

S-ethyl;

N(Me)₂;

benzyl;

phenyl;

—

CO-phenyl (optionally substituted by chlorine);

—

CO-azetidinyl;

—

CO-tetrahydropyranyl;

COOH, COOMe, COOt-butyl;

—

CO-methyl, —

CO-ethyl, —

CO-isopropyl, —

CO-cyclopropyl, —

CO-cyclobutyl, —

CO-cyclopentyl, —

CO-cyclohexyl;

—

CONH₂, —

CO-pyrrolidinyl, —

CO-morpholinyl, —

CO-piperazinyl, —

CO-piperidinyl, —

CO-thiomorpholinyl (optionally substituted by methyl, fluorine and —

CH₂OMe);

or —

CH₂COphenyl groups;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 wherein R¹ is phenyl substituted by C_1-6alkylsulfonyl.

4. A compound according to claim 1 wherein R¹ is phenyl substituted by SO₂Me.

5. A compound according to claim 1 wherein R¹ is phenyl substituted by SO₂Me at the para position.

6. A compound according to claim 1 wherein —

O—

R³ is present at the para position of the phenyl group with respect to the rest of the compound.

7. A compound according to claim 1 wherein R¹³ represents isopropyl, cyclopropyl or cyclobutyl.

8. A compound according to claim 3, wherein R¹³ represents isopropyl, cyclopropyl or cyclobutyl.

9. A compound according to claim 4, wherein R¹³ represents isopropyl, cyclopropyl or cyclobutyl.

11. A pharmaceutical composition which comprises a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

12. A method of treatment of diseases of the upper respiratory tract which comprises administering to a human in need thereof an effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

13. A method of treatment according to claim 11 in which the disease is allergic rhinitis.

14. A pharmaceutical composition which comprises a compound of formula (I) as defined in claim 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

15. A method of treatment of diseases of the upper respiratory tract which comprises administering to a human in need thereof an effective amount of a compound of formula (I) as defined in claim 8 or a pharmaceutically acceptable salt thereof.

16. A method of treatment according to claim 15 in which the disease is allergic rhinitis.

17. A pharmaceutical composition which comprises a compound of formula (I) as defined in claim 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

18. A method of treatment of diseases of the upper respiratory tract which comprises administering to a human in need thereof an effective amount of a compound of formula (I) as defined in claim 9 or a pharmaceutically acceptable salt thereof.

19. A method of treatment according to claim 18 in which the disease is allergic rhinitis.

10. A compound which is 1-(4-{[1-(1-methylethyl)-4-piperidinyl]oxy}phenyl)-4-{[4-(methylsulfonyl)phenyl]carbonyl}piperazine or a pharmaceutically acceptable salt thereof.