Tetrahydropyran derivatives and their use as therapeutic agents

Details Tetrahydropyran derivatives and their use as therapeutic agents Tetrahydropyran derivatives and their use as therapeutic agents

2001-08-20

2002-12-03

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S207000, C549S416000, C549S420000

Reexamination Certificate

active

06489343

ABSTRACT:

This invention relates to a class of tetrahydropyran compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are useful as neurokinin 1 (NK-1) receptor antagonists.
By virtue of their excellent specificity for the human NK-1 receptor, the compounds of the present invention are particularly effective examples of this class of NK-1 receptor antagonist.
The present invention provides compounds of the formula (I):
wherein
R
1
is fluorine or trifluoromethyl;
R
2
is fluorine or trifluoromethyl;
R
3
is methyl or hydroxymethyl;
R
3
represents halogen, hydlroxy, C
2-4
alkenyl, C
2-4
alynyl, N
3
, —NR
5
R
6
, —NR
a
COR
b
, —OSO
2
R
a
, —(CH
2
)
p
NR
a
(CH
2
)
q
COOR
b
, COR
a
, COOR
a
, —N═C═O, or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S which heteroaromatic ring is optionally substituted at any substitutable position by a substituent selected from ═O, ═S, halogen, hydroxy, —SH, COR
a
, CO
2
R
a
, —ZNR
5
R
6
, C
1-4
alkyl, hyclroxyeC
1-4
alkyl, fluoroC
1-4
alkyl, chloroC
1-4
alkyl, C
1-4
alkoxy, fluoroC
1-4
alkoxy or C
1-4
alkoxy substituted by a C
1-4
alkoxy or hydroxyl group, and wherein said C
2-4
alkenyl and C
2-4
alkynyl groups are optionally substituted by a substituent selected from halogen, hydroxy, N
3
, —NR
5
R
6
, —NR
a
COR
b
, —OSO
2
R
a
, —(CH
2
)
p
NR
a
(CH
2
)
q
COOR
b
, COR
a
or COOR
a
;
R
5
is hydrogen, C
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, C
2-4
alkyl substituted by a C
1-4
alkoxy or hydroxyl group, or R
5
is a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined;
R
6
is hydrogen or C
1-4
alkyl, C
3-7
cycloalkyl, C
3-7
cycloalkylC
1-4
alkyl, or C
2-4
alkyl substituted by a C
1-4
alkoxy or hydroxyl group;
or R
5
, R
6
and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, COR
e
, CO
2
R
e
, C
1-4
alkyl optionally substituted by a C
1-4
alkoxy or hydroxyl group, or C
1-4
alkoxy optionally substituted by a C
1-4
alkoxy or hydroxyl group, or a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined, or said heteroaliphatic ring is substituted by a spiro-fused lactone ring, and said heteroaliphatic ring optionally containing a double bond, which heteroaliphatic ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)
2
or a second nitrogen atom which will be part of a NH or NR
d
moiety, where R
d
is C
1-4
alkyl optionally substituted by hydroxy or C
1-4
alkoxy, and where R
e
is hydrogen, C
1-4
alkyl or benzyl;
or R
5
, R
6
and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or R
5
, R
6
and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S;
Z represents a bond, C
1-6
alkylene or C
3-6
cycloalkylene;
n is zero, 1 or 2;
p is 1 or 2; and
q is 1 or 2;
and pharmaceutically acceptable salts thereof.
A preferred class of compounds of formula (I) is that wherein R
1
is trifluoromethyl.
Another preferred class of compounds of formula (I) is that wherein R
2
is trifluoromethyl.
Also preferred is the class of compounds of formula (I) wherein R
3
is methyl.
Where —NR
5
R
6
is defined as a substituent R
4
or as a substituent on a heteroaromatic ring in the definition of R
4
, then R
5
may aptly be a C
1-4
alkyl group or a C
2-4
alkyl group substituted by a hydroxyl or C
1-2
alkoxy group, R
6
may aptly be a C
1-4
alkyl group or a C
2-4
alkyl group substituted by a hydroxyl or C
1-2
alkoxy group, or R
5
and R
6
may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a C
1-4
alkyl group or a C
2-4
alkyl group substituted by a hydroxy or C
1-2
alkoxy group. Particularly preferred heteroaliphatic rings formed by —NR
5
R
6
are azetidine, pyrolidine, piperidine, morpholine, piperazine and N-methylpiperazine, and especially piperidine.
Where the group NR
5
R
6
represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by two groups, the first substituent, where present, is preferably selected from hydroxy, CO
2
R
e
(where R
e
is hydrogen, methyl, ethyl or benzyl), or C
1-2
alkyl substituted by hydroxy. Where present, the second substituent is preferably a methyl group. Where two substituents are present, said substituents are preferably attached to the same carbon atom of the heteroaliphatic ring.
Where the group NR
5
R
6
represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by a spiro-fused lactone ring, particularly preferred examples are:
Where the group NR
5
R
6
represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR
5
R
6
represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where the group NR
5
R
6
represents a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic ring ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S, said heteroaromatic ring is preferably a five-membered ring, in particular a pyrrole, imidazole or triazole ring, a nitrogen atom of which is preferably included in the heteroaliphatic ring. Suitable examples of such fused ring systems include
Particularly suitable moieties NR
5
R
6
include those wherein NR
5
R
6
is amino, methylamino, dimethylamino, diethylamino, azetidino, pyrrolidino, piperidino, morpholino and piperazino.
Where R
4
represents an optionally substituted five or six-membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S, the heteroaromatic ring is selected from pyrrole, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole.
Preferred compounds of the present invention are those wherein R
4
is a group selected from imidazole, 1,2,3-triazole and 1,2,4-triazole.
Particularly preferred compounds of the present invention are those wherein R
4
is a group selected from imidazol-1-yl and 1,2,4-triazol-1-yl.
Where R
4
represents an optionally substituted five membered or six membered nitrogen-containing heteroaromatic ring, preferred substituents are —ZNR
5
R
6
and C
1-2
alkyl (especially methyl). With reference to the group ZNR
5
R
6
defined as a substituent on a heteroaromatic ring in the definition of R
4
, Z may be a bond or a linear, branched or cyclic group. Favourably Z is a bond or contains 1 to 4 carbon atoms and most favourably 1 to 2 carbon atoms. A particularly favourable group Z is —CH
2
—. In this instance, particularly suitable moieties NR
5
R
6
include those wherein NR
5
R
6
is amino, methylamino, dimethylamino, diethylamino, azetidino, pyrrolidino, piperidino, morpholino and piperazino. Most especially, —ZNR
5
R
6
, as a substituent on a heteroaromatic ring

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