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1. (WO2004016617) BIARYL DIAZABICYCLOALKANE AMIDES AS NICOTINIC ACETYLCHOLINE AGONISTS
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CLAIMS

1. A compound of formula I:



wherein:
A is a moiety of formula II:



D is oxygen or sulfur;
E is a single bond, oxygen, sulfur, or NR3;
Ar1 is a 5- or 6-membered aromatic heterocyclic ring having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur where not more than one of said heteroatoms is oxygen or sulfur, or
Ar1 is phenyl;
Ar2 is a 5- or 6-membered aromatic heterocyclic ring having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur where not more than one of said heteroatoms is oxygen or sulfur, or
Ar is phenyl, or
Ar2 is an 8- or 9-, or 10-membered fused aromatic carbocyclic ring or fused aromatic heterocyclic ring having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur where not more than one of said heteroatoms is oxygen or sulfur, or an 8- or 9-, or 10-membered aromatic carbocyclic ring;
the rings Ar1 and Ar2 are substituted with 0, 1, 2 or 3 substituents selected from: halogen, C,.4alkyl, C2.4alkenyl, C2.4alkynyl, CN, NO2, CF3 NR'R2, CHaNR'R2, OR2, CH2OR2 or CO2R3;
R'and R2 at each occurrence are independently selected from hydrogen, Cι_ alkyl, aryl, heteroaryl, C(O)R3, C(O)NHR3, C02R3 or SO2R3, or 1 1
R and R in combination is -(CH2)jG(CH χ- wherein G is oxygen, sulfur, NR , or a bond;
a, b and c are each 1 or 2;
j is 2, 3 or 4;
k is 0, 1 or 2, and
R3 at each occurrence is independently selected from hydrogen, d.4alkyl, aryl, or heteroaryl;
or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

2. A compound according to Claim 1, wherein D is oxygen.

3. A compound according to Claim 2, wherein E is a single bond.

4. A compound according to Claim 2, wherein E is oxygen or NR3.

5. A compound according to Claim 1, wherein A is



or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

6. A compound of Claim 1, wherein
Ar1 is a 5- or 6-membered aromatic heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur where not more than one of said heteroatoms is oxygen or sulfur, or
Ar1 is phenyl,
or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

7. A compound according to Claim 6 wherein Ar1 is a benzene ring, furan ring or thiophene ring.

8. A compound according to Claim 1, wherein
Ar is a 5- or 6-membered aromatic heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur where not more than one of said heteroatoms is oxygen or sulfur, or a phenyl,
or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

9. A compound according to Claim 8, wherein Ar2 is a benzene ring, furan ring, thiophene ring, or pyridine ring.

10. A compound according to Claim 1, wherein
the -EAr2 and the C(-D)A moieties on Ar1 are positioned in a 1,3-relationship relative to each other;
or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

11. A compound according to Claim 1, wherein Ar1 or Ar2 is substituted with 0 or 1 substituents selected from: halogen, C1.4alkyl, C2.4alkenyl, C2.4alkynyl, CN, N02, NR'R2, CH2NR'R2, OR3, CH2OR3, CO2R3 or CF3;
or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

12. A compound according to Claim 1 , wherein A is a moiety of formula II:



D is oxygen;
E is a single bond;
Ar1 is a 5- or 6-membered aromatic heterocyclic ring having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur where not more than 1 of said heteroatoms is oxygen or sulfur, or
Ar1 is phenyl Ar2 is a 5- or 6-membered aromatic heterocyclic ring having 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur where not more than 1 of said heteroatoms is oxygen or sulfur, or
Ar2 is phenyl,
or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

13. A compound of Claim 12, wherein Ar1 is a benzene ring, furan ring or thiophene ring.

14. A compound according to Claim 1, having the groups -EAr2 and -C(=0)A, positioned in a 1,3-relationship relative to each other and wherein Ar2 has 0 or 1 substituents selected from: halogen, CMaιkyl, C2.4alkenyl, C2.4alkynyl, CN, N02, NR'R2, CHZNR' R2, OR1,

CH2OR', CO2R3 or CF3;
or a diastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

15. A compound according to Claim 1, selected from:
(l,4-diazabicyclo[3.2.2]non-4-yl)(biphenyl-3-yl)methanone;
( 1 ,4-diazabicyclo[3.2.2]non-4-yl)(3-(2-pyridyl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-(3-pyridyl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-(4-pyridyl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-(furan-2-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-(furan-3-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-(thiophen-2-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-(thiophen-3-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(biphenyl-4-yl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-(2-pyridyl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-(3-pyridyl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-(4-pyridyl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-2-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-3-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-2-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-3-yl)phenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylfuran-2-yl)methanone;

,4-diazabicyclo [3.2.2]non-4-yl)(5-(2-pyridyl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(5-(3-pyridyl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(5-(4-pyridyl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(5-(furan-2-yl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(5-(furan-3-yl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(5-(thiophen-2-yl)furan-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-(thiophen-3-yl)furan-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-phenylthiophen-4-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(2-(2-pyridyl)thiophen-4-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-(3-pyridyl)thiophen-4-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-(4-pyridyl)thiophen-4-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-(furan-2-yl)thiophen-4-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-(furan-3-yl)thiophen-4-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-(thiophen-2-yl)thiophen-4-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-(thiophen-3-yl)thiophen-4-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(4-phenylfuran-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(4-(2-pyridyl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(4-(3-pyridyl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(4-(4-pyridyl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(4-(furan-2-yl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(4-(furan-3-yl)furan-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(4-(thiophen-2-yl)furan-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(4-(thiophen-3-yl)furan-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-phenylthiophen-2-yl)methanone;
,4-diazabicyclo [3.2.2]non-4-yl)(5-(2-pyridyl)thiophen-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-(3-pyridyl)thiophen-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-(4-pyridyl)thiophen-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-(furan-2-yl)thiophen-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-(furan-3-yl)thiophen-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-(thiophen-2-yl)thiophen-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(5-(thiophen-3-yl)thiophen-2-yl)methanone; ,4-diazabicyclo [3.2.2]non-4-yl)(2-phenylfuran-4-yl)methanone;

(1,4-d azabicyclo[3.2.2]non-4-yl (2-(2-pyridyl)furan-4-yl)methanone;
(1,4-d azabicyclo [3.2.2]non-4-yl (2-(3-pyridyl)furan-4-yl)methanone;
(1,4-d: azabicyclo [3.2.2]non-4-yI (2-(4-pyridyl)furan-4-yl)methanone;
(1,4-d azabicyclo[3.2.2]non-4-yl (2-(ιτιran-2-yl)furan-4-yl)methanone;
(1,4-d: azabicyclo[3.2.2]non-4-yl (2-(furan-3-yl)furan-4-yl)methanone;
(1,4-d azabicyclo [3.2.2]non-4-yl (2-(thiophen-2-yl)furan-4-yl)methanone;
(1,4-d azabicyclo [3.2.2]non-4-yl (2-(thiophen-3-yl)furan-4-yl)methanone;
(1,4-d azabicyclo[3.2.2]non-4-yl (4-phenylthiophen-2-yl)methanone;
(1,4-d azabicyclo [3.2.2]non-4-yl (4-(2-pyridyl)thiophen-2-yl)methanone;
(1,4-d azabicyclo[3.2.2]non-4-yl> (4-(3-pyridyl)thiophen-2-yl)methanone;
(1,4-d: azabicyclo[3.2.2]non-4-yl (4-(4-pyridyl)thiophen-2-yl)methanone;
(1,4-d azabicyclo [3.2.2]non-4-yl (4-(furan-2-yl)thiophen-2-yl)methanone;
(1,4-d: azabicyclo[3.2.2]non-4-yl (4-(furan-3-yl)thiophen-2-yl)methanone;
(1,4-d azabicyclo[3.2.2]non-4-yl (4-(thiophen-2-yl)thiophen-2-yl)methanone, or
(1,4-d azabicyclo[3.2.2]non-4-yl' (4-(thiophen-3-yl)thiophen-2-yl)methanone,
or a d: astereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.

16. A compound according to any one of Claims 1 to 15, for use in therapy.

17. A compound according to any one of Claims 1 to 15, for use as a medicament.

18. Use of a compound as defined in any one of claims 1 to 15, in the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders, intellectual impairment disorders, human diseases or conditions in which activation of the α7 nicotinic receptor is beneficial, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, pain, ulcerative colitis or irritable bowel syndrome.

19. A method of treatment or prophylaxis of psychotic disorders, intellectual impairment disorders, human diseases or conditions in which activation of the al nicotinic receptor is beneficial, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, anxiety, schizophrenia, mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative disorders in which there is loss of cholinergic synapse, jetlag, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, pain, or ulcerative colitis which method comprises administering a therapeutically effective amount of a compound as defined in any one of Claims 1 to 15.

20. A pharmaceutical composition comprising a compound of formula I, as defined in any one of claims 1 to 15, together with at least one pharmaceutically-acceptable excipient or diluent.

21. A process for the preparation of a compound of formula I, as defined in any one of claims 1 to 15, which comprises:
reacting a compound of formula VI:



wherein J represents halogen, or OSO2CF3 substituent at the position of ring Ar at which the bond to ring Ar2 is formed with a organometallic compound of formula VII;
Ar -M
in the presence of a organometallic catalyst and solvent.

22. A compound of formula VI:



wherein:

Ar -1 i s a benzene, furan, or thiophene ring;
J is halogen, or OSO2CF3, provided that when Ar is a benzene ring, J may only represent halogen or OSO2CF3 in a position meta or para to the carboxamide group; or an enantiomer thereof or pharmaceutically-acceptable salts thereof.

23. A compound according to Claim 22, selected from:
(l,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(5-bromothiophen-2-yl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-bromophenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-bromophenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(3-iodophenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-iodophenyl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(4-bromothiophen-2-yl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(5-bromothiophen-3-yl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;
(l,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone, and
(l,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;
or enantiomers thereof, or pharmaceutically-acceptable salts thereof.