Canadian Patents Database / Patent 2341440 Summary

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(12) Patent Application: (11) CA 2341440
(54) English Title: NOVEL COMPOUNDS
(54) French Title: NOUVEAUX COMPOSES
(51) International Patent Classification (IPC):
  • C07D 213/60 (2006.01)
  • A61K 31/165 (2006.01)
  • A61K 31/44 (2006.01)
  • A61K 31/50 (2006.01)
  • C07C 43/23 (2006.01)
  • C07C 217/74 (2006.01)
  • C07C 235/42 (2006.01)
  • C07C 235/46 (2006.01)
  • C07C 321/28 (2006.01)
  • C07C 323/21 (2006.01)
  • C07C 323/42 (2006.01)
  • C07D 207/26 (2006.01)
  • C07D 207/267 (2006.01)
  • C07D 213/61 (2006.01)
  • C07D 213/64 (2006.01)
  • C07D 237/08 (2006.01)
  • C07D 239/26 (2006.01)
  • C07D 277/24 (2006.01)
(72) Inventors (Country):
  • CLADINGBOEL, DAVID (United Kingdom)
  • HIRST, SIMON (United Kingdom)
  • CHESHIRE, DAVID (United Kingdom)
  • STOCKS, MICHAEL (United Kingdom)
(73) Owners (Country):
  • ASTRAZENECA AB (Sweden)
(71) Applicants (Country):
  • ASTRAZENECA AB (Sweden)
(74) Agent: FETHERSTONHAUGH & CO.
(45) Issued:
(86) PCT Filing Date: 1999-09-13
(87) PCT Publication Date: 2000-03-23
(30) Availability of licence: N/A
(30) Language of filing: English

(30) Application Priority Data:
Application No. Country Date
9803107-3 Sweden 1998-09-14

English Abstract




The invention relates to novel pyridyl derivatives (I), their use as
medicaments, pharmaceutical formulations including them and methods for their
preparation.


French Abstract

L'invention a trait à de nouveaux dérivés de pyridyle (I), à leur utilisation comme médicaments, à des formulations pharmaceutiques qui les contiennent et à des procédés de préparation de ceux-ci.


Note: Claims are shown in the official language in which they were submitted.


36

Claims

1. A compound of formula I:
Image
wherein;
A is a phenyl or a 5- or 6-membered heterocyclic ring containing one or more
heteroatoms
selected from nitrogen, oxygen and sulfur;
R is halogen, nitro, C1-6 alkyl, C1-6 alkoxy, (CH2)p R3 where p is 0 to 3 and
R3 is hydroxy, or
NR4R5 where R4 and R5 are independently hydrogen or C1-6 alkyl or R is
CONR4R5;
n is 0, 1,2 or 3;
X is O, S or CH2;
R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl or R1 and
R2 together
with the carbon atom to which they are attached form a C3-6 cycloalkyl group;
Ar1 is biphenyl, naphthyl or tetrahydronaphthyl, each Ar1 group being
optionally
substituted by halo, nitro, C1-6 alkyl (optionally substituted by one or more
fluorine atoms),
CN,
-Y-NR8C(O)NR9R10, -O-Y-C(O)NR9R10, -O-Y-C(S)NR9R10, -Y-C(O) NR9R10,
-Y-C(S)NR9R10, -Y-SO2NR9R10, -Y-NR9R10, SO2NR9R10, C(O)NR9R10, C(S)NR9R10,
C(O)R11, -OC(O)R11, -Y-OR11, -Y-CO2R11, SO2R13, N(R12)SO2R3, N(R12)C(O)R13 or
N(R12)CO2R13 where:
Y is a bond, C1-6 alkylene or C1-6 alkenylene;
R9 and R10 are independently hydrogen or C1-6 alkyl or together with the
nitrogen atom to
which they are attached form an optionally substituted 5- to 7-membered
heterocyclic ring
optionally containing a further heteroatom selected from nitrogen, oxygen or
sulfur;
R8, R11, R12 and R13 are independently hydrogen or C1-10 alkyl (optionally
substituted by one
or more fluorine atoms);
or a salt or solvate thereof,
~ provided that when n is zero then A is not pyridyl or pyrimidinyl.


37

2. A compound according to claim 1 in which A is phenyl, pyridine, pyrimidine,
thiazole or
pyrrolidone.
3. A compound according to claim 1 or 2 in which n is 0 or 1.
4. A compound according to any one of claims 1 to 3 in which X is O.
5. A compound according to any one of claims 1 to 4 in which R is fluoro,
nitro, methyl,
methoxy, dimethylamino, (CH2)pR3 where p is 1 and R3 is hydroxy or NR4R5 where
R4 is
hydrogen and. R5 is methyl or C1-6 alkyl, or R is or R is CONR4R5 where R4 is
hydrogen
and R5 is methyl.
6. A compound according to any one of claims 1 to 5 in which R1 and R2 are
both
hydrogen.
7. A compound according to any one of claims 1 to 6 in which Ar1 is biphenyl,
naphthyl
or tetrahydronaphthyl each having one or two substituents as defined in claim
1.
8. A compound according to claim 1 which is;
(~)-1-(Biphenyl-4-yloxy)-4-(3-(2-fluoro)pyridyl)-2-butanol,
(~)-1-(Biphenyl-4-yloxy)-4-(3-(2-methoxy)pyridyl)-2-butanol,
(~)-1-(Biphenyl-4-yloxy)-4-(3-(6-fluoro)pyridyl)-2-butanol,
(~)-1-(Biphenyl-4-yloxy)-4-(3-(6-methoxy)pyridyl)-2-butanol,
(~)-1-(Biphenyl-4-yloxy)-4-(6(1H)-pyridone-3-yl)-2-butanol,
1-(Biphenyl-4-yloxy)-4-[4-(3-fluoro)pyridyl]-2-butanol,
1-(Biphenyl-4-yloxy)-4-[(3-methoxy)-4-pyridyl]-2-butanol,
1-(Biphenyl-4-yloxy)-4-(4-pyridin-2-one)-2-butanol,
1-[(Biphenyl-4-yloxy)]-4-(4-pyridazin-3-yl)-2-butanol,
1-[(Biphenyl-4-yloxy)]-4-(pyridazin-4-yl)-2-butanol,
1-[(Biphenyl-4-yloxy)]-4-(pyrimidin-4-yl)-2-butanol,
(~)-4-(2-(Hydroxymethyl)phenyl)-1-(2-thionaphthyl)-2-butanol,
(~)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzamide,
(~)-N-Methyl-2-(4-(2-thionaphthyl)-3-hydroxybutyl)benzylamine,
(~)-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyloxy))-3-
hydroxybutyl)benzamide,
(~)-N-Methyl-2-(4-(2-(5,6,7,8-tetrahydronaphthyloxy))-3-
hydroxybutyl)benzylamine,
(~)-2-(4-(2-(5,6,7,8-Tetrahydronaphthyloxy))-3-hydroxybutyl)benzyl alcohol,


38

(1S,2RS)-4'-(2-Hydroxy-1-methyl-4-thiazol-2-yl-butoxy)-biphenyl-3-
carbonitrile,
4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-2-methoxy-phenol,
4-[4-(Biphenyl-4-yloxy)-3-hydroxy-butyl]-1-methyl-pyrrolidin-2-one,
(~)-4-[4-(Biphenyl-4-yloxy)-3-hydroxybutyl]-1-methyl-1H-pyridin-2-one,
or salts or solvates thereof.
9. A compound of formula (IA):
Image
wherein;
A is a phenyl or a 5- or 6-membered heterocyclic ring containing one or more
heteroatoms
selected from nitrogen, oxygen and sulfur;
R is halogen, nitro, C1-6 alkyl, C1-6 alkoxy, (CH2)p R3 where p is 0 to 3 and
R3 is hydroxy, or
NR4R5 where R4 and R5 are independently hydrogen or C1-6 alkyl or R is
CONR4R5;
n is 0, 1, 2 or 3;
X is O, S or CH,;
R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloalkyl or R1 and
R2 together
with the carbon atom to which they are attached form a C3-6 cycloalkyl group;
Ar1 is a fused bicyclic ring system optionally containing one or more
heteroatoms, a fused
tricyclic ring system optionally containing an oxygen atom, or Ar1 is a group
R6-R7 where
one of R6/R7 is a phenyl ring and the other is phenyl or a 5- or 6-membered
heterocyclic
ring containing one or more heteroatoms, each Ar1 group being optionally
substituted by
halo, nitro, C1-6 alkyl (optionally substituted by one or more fluorine
atoms), CN,
-Y-NR8C(O)NR9R10, -O-Y-C(O)NR9R10, -O-Y-C(S)NR9R10, -Y-C(O) NR9R10,
-Y-C(S)NR9R10, -Y-SO2NR9R10, -Y-NR9R10, SO2NR9R10, C(O)NR9R10, C(S)NR9R10,
C(O)R11, - OC(O)R11 , -Y-OR1 -Y-CO2R11, SO2R13, N(R12)SO2R13, N(R12)C(O)R13 or
N(R12)CO2R13 where:
Y is a bond, C1-6 alkylene or C2-6 alkenylene;
R9 and R10 are independently hydrogen or C1-6 alkyl or together with the
nitrogen atom to
which they are attached form an optionally substituted 5- to 7-membered
heterocyclic ring
optionally containing a further heteroatom selected from nitrogen, oxygen or
sulfur;


39

R8, R11, R12 and R13 are independently hydrogen or C1-10 alkyl (optionally
substituted by one
or more fluorine atoms);
or a pharmaceutically acceptable salt or solvate thereof for use as a
therapeutic agent,
~ provided that when n is zero then A is not pyridyl.
10. Use as claimed in claim 9, wherein the disease is asthma or rhinitis.
11. A pharmaceutical composition comprising a compound of formula I or a salt
or solvate
thereof as defined in claim 9 in association with a pharmaceutically
acceptable adjuvant,
diluent or carrier.
12. A process for the preparation of compounds of formula I which comprises:
(a) reduction of a compound of formula (II):
Image
wherein A, R, n, R1, R2, X and Ar1 is as defined in formula (I) or are
protected derivatives
thereof;
(b) for compounds of formula (I), wherein Ar1 is a group R6-R7, forming the R6-
R7 bond by
reaction of a compound of formula (III):
Image
with a compound of formula (IV):
R7-R18
(IV)





40


where A, R, n, R1, R2, R6, R7 and are as defined in formula (II), R16 is a
hydroxy protecting
group, and one of R17/R18 is triflate or halo and the other is B(OH)2 or
ZnHal; or
(c) for compounds of formula (I) where R1 and R2 are both hydrogen, reaction
of a
compound of formula (V):

Image

where A, R and n are as defined in formula (II), with a compound of formula
(VI):
MYAr1 (VI)
where Y is O, S or CH2, M is Li, Na, K, Cs or MgHal where Hal is halogen and
Ar2 is as
defined in formula (I);
or with a compound of formula (VII):
HYAr1 (VII)
where Y is as defined in formula (VI) in the presence of a base; or
(d) for compounds of formula (I), where R1 and R2 are both hydrogen, and X
represents O
or S, reaction of a compound of formula (V) or (VI), as hereinbefore defined,
with a
suitably protected and activated derivative of a diol of formula (VIII):

Image

where R, n and A are as defined in formula (II); or
(e) preparation of compounds of formula (I) wherein X represents O, from a
compound of
formula (IX):




41


Image

in which R, n, A, R1, R2, and R16 are as defined in process (b) by reaction
with a compound
of formula (VII) wherein Y represents O; or
(f) reaction of a compound of formula (X):

Image

in which A, R and n are as defined in formula (II) and Hal is halogen with a
compound of
formula (XI):

Image

in which R1, R2, X and Ar1 are as defined in formula (II) in the presence of a
suitable
catalyst, or
(g) preparation of compounds of formula (I) wherein X represents O, from a
compound of
formula (XII):

Image

in which Ar1 is as defined in formula (II) with a compound of formula (XIII):

Image




42


in which R and n are as defined in formula (II) and M is a metal, or
(h) preparation of compounds of formula (I) wherein X represents O from a
compound of
formula (XIV):

Image

in which Ar1 is as defined in formula (II) with a compound of formula (XV):

Image

in which R and n are as defined in formula (II), followed by hydrogenation of
the resulting
product using a suitable catalyst
and optionally thereafter process (a) to (h):
~ removing any protecting groups
~ converting a compound of formula (I) into a further compound of formula (I)
~ forming a pharmaceutically acceptable salt or solvate.


A single figure which represents the drawing illustrating the invention.

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Admin Status

Title Date
(86) PCT Filing Date 1999-09-13
(87) PCT Publication Date 2000-03-23
(85) National Entry 2001-02-21
Dead Application 2005-09-13

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Filing $300.00 2001-02-21
Registration of Documents $100.00 2001-03-22
Maintenance Fee - Application - New Act 2 2001-09-13 $100.00 2001-06-26
Maintenance Fee - Application - New Act 3 2002-09-13 $100.00 2002-06-17
Maintenance Fee - Application - New Act 4 2003-09-15 $100.00 2003-06-16

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Cover Page 2001-05-17 1 21
Description 2001-02-21 35 1,587
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