Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-28
2002-06-18
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S234000
Reexamination Certificate
active
06407108
ABSTRACT:
This invention relates to new therapeutically useful heterocyclic compounds, to process for their preparation and to pharmaceutical compositions containing them.
It is known that inhibitors of phosphodiesterase 4 (PDE 4) are useful in the treatment of inflammatory and allergic processes such as asthma, non-steroidal antiinflammatory drugs-induced gastrointestinal damage and atopic dermatitis.
EP-A-85,840 discloses a series of triazolo-phthalazine derivatives of formula:
which are useful as anxiolytic agents.
We have now found that the presence of a pyridine ring instead of the benzo ring in the above structure, provides new compounds which inhibit cyclic phosphodiesterases, in particular type 4 cyclic phosphodiesterases and have a very low emetic activity (10-100 times less active than rolipram in inducing emesis in dogs).
Accordingly, the present invention provides a compound which is a heterocycle of formula (I):
wherein:
R
1
represents a hydrogen atom or a —(CH
2
)
m
—Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl (preferably trifluoromethyl), alkoxy, alkoxycarbonyl, C
3
-C
7
cycloalkyl, norbornyl (preferably 2-norbornyl) or phenylalkenyl group, or an aromatic croup (preferably phenyl or pyridyl) which aromatic group Y may optionally be substituted by one or more halogen atoms;
R
2
represents an aromatic group (preferably phenyl, naphthyl or thienyl) which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C
3
-C
6
cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and
R
3
represents a hydrogen or halogen atom (preferably chloro) or an alkyl group,
and pharmaceutically acceptable salts thereof.
The alkyl, haloalkyl, alkenyl or alkynyl groups and moieties, such as in the alkoxy groups, mentioned in relation to the groups R
1
-R
3
in compounds of the invention are usually “lower” alkyl, that is containing up to 6 and particularly up to 4 carbon atoms, the hydrocarbon chain being branched or straight. Examples of alkyl groups and moieties are CH
3
, C
2
H
5
, C
3
H
7
, i-C
3
H
7
, n-C
4
H
9
, i-C
4
H
9
, isoamyl and neopentyl.
When any of the groups, such as R
1
or R
2
has a chiral centre, the compounds of formula (I) exhibit optical isomerism and the isomers are within the scope of the present invention.
Examples of R
1
are the preferred alkyl groups mentioned above, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl and cyclopenthylmethyl.
Examples of R
2
are phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl and 3-nitrophenyl.
Examples of R
3
are hydrogen, alkyl or chloro, preferably in the 8- or 9-positions.
The most preferred compounds of the invention are 6-(4-fluorophenyl)-3-isobutyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, and 3-cyclobutylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine.
According to a further feature of the present invention, the heterocyclic compounds of formula (I) can be prepared from the corresponding hydrazine derivative of formula (II)
wherein
R
2
and R
3
are as defined above, by reaction with a reactive derivative of a carboxylic acid of the general formula (III):
HOOC—R
1
(III)
wherein R
1
is as defined above. The reactive derivative of the said carboxylic acid may be, for example, a halide (preferably chloride), an anhydride or a mixed anhydride.
The reaction is preferably carried out in an inert organic solvent such as methylene chloride, dioxane or tetrahydrofuran, in the presence of an organic nitrogen-containing base, e.g. triethylamine and at a temperature between −10° C. and +60° C. In the reaction, the corresponding hydrazide of general formula (IV) is first formed:
wherein R
1
, R
2
and R
3
are as defined above. A suspension of this hydrazide (IV) in an organic solvent such as dioxane, tetrahydrofuran, isopropanol or n-butanol, is heated, for example at the boiling point of the solvent, to give the corresponding heterocyclic compound of formula (I)
The hydrazine derivative of formula (II) may be prepared by:
1) reacting a hydrazone of formula (V):
wherein R
2
and R
3
are as defined above and R
4
is an alkyl group, with a phosphorus halide or phosphorus oxyhalide (preferably phosphorus oxychloride), to form the intermediate compound of formula (VI):
wherein R
2
and R
3
are as defined above and X is a chlorine or bromine atom;
2) reacting compound (VI) with an alkyl carbazate (preferably t-butyl carbazate) of formula (VII):
H
2
N—NH—COOR
5
(VII)
wherein R
5
is an alkyl group, to give the alkoxycarbonylhydrazine derivative (VIII):
wherein R
2
, R
3
and R
5
are as defined above; and
3) treating compound (VIII) with hydrogen chloride in an anhydrous solvent as ethanol.
The reaction between the hydrazone of formula (V) and a phosphorus halide or phosphorus oxyhalide is carried out with an excess of reagent at a temperature from 80° C. to 120° C., then removed the excess of reagent and poured into cold water. In this way the compound (VI) is obtained.
The reaction of (VI) with the alkyl carbazate of formula (VII) to obtain the corresponding alkoxycarbonylhydrazine derivative (VIII), is preferably carried out in the presence of an organic solvent as tetrahydrofuran or dioxan at a temperature of from 60° C. to the boiling point of the reaction medium.
The alkoxycarbonylhydrazine derivative (VIII) may, for example, be transformed into the hydrazine derivative (II) at room temperature in hydrogen chloride-ethanol saturated solution.
The hydrazone derivatives or formula (V) are known compounds which can be prepared from the corresponding 2-acylnicotinic acid by known methods described in the literature.
The inhibition of cyclic nucleotide phosphodiesterase 4 from guinea-pig hearts was performed using 96-well microtiter plates as described by Verghese et al., (Molecular Pharmacology, 47, 1164-1171 (1995)).
The results from such test are shown in Table 1.
TABLE 1
PDE4
Compound *
IC
50
(&mgr;M)
A
10
6
2
7
0.3
12
3
31
0.2
47
0.7
55
0.2
60
0.1
61
2
109
0.04
112
0.7
113
0.2
* See structures in Table 2.
Compound A is 3-isobutyl-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine, a compound included in EP-A-85,340.
As it can be seen from Table 1, the compounds of formula (I) are cyclic phosphodiesterase inhibitors, in particular type 4 cyclic AMP phosphodiesterase inhibitors. The compounds are also capable of blocking the production of some pro-inflammatory cytokines such as, for example, TNF&agr;. Thus, they can be used in the treatment of allergic, inflammatory and immunological diseases, as well as those diseases or conditions where the blockade of pro-inflammatory cytokines or the selective inhibition of PDE 4 could be of benefit.
These diseases states Include asthma, rheumatoid arthritis, osteoarthritis, osteoporosis, bone-formation disorders, glomerulonephritis, multiple sclerosis, Graves ophtalmopathy, myasthenia gravis, insulin-dependent diabetes mellitus, graft rejection, gastrointestinal disorders such as ulcerative colitis or Crohn disease, septic shock, adult distress respiratory syndrome, and skin diseases such as atopic dermatitis, contact dermatitis, acute dermatomyositis and psoriasis.
They can also be used as improvers of cerebrovascular function as well as in the treatment of other CNS related diseases such as dementia, Alzheimer's disease, depression, and as nootropic agents.
The compounds of the present invention are also of benefit when administered in combination with other drugs such as steroids and immunosuppressive agents, such as cyclosporin A, rapamycin or T-cell receptor blockers. In this case the administration of the compounds allows a reduction of the dosage of the other drugs, thus preventing th
Crespo Crespo Ma Isabel
Fernandez Garcia Andres
Gracia Ferrer Jordi
Vega Noverola Armando
Almirall Prodesfarma S.A.
Bernhardt Emily
Schneller Marina V.
Venable
LandOfFree
1,2,4-triazolo(4,3-b)pyrido(3,2-d)pyridazine derivatives and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 1,2,4-triazolo(4,3-b)pyrido(3,2-d)pyridazine derivatives and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1,2,4-triazolo(4,3-b)pyrido(3,2-d)pyridazine derivatives and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2947068