Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-05
2003-12-30
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S259200, C544S281000
Reexamination Certificate
active
06670365
ABSTRACT:
FIELD OF THE INVENTION
Classically the main mechanism of action of non-steroidal antiinflammatory drugs has been the inhibition of cyclooxygenase. This enzyme transforms the arachidonic acid in prostaglandin H
2
, that is subsequently transformed into other prostaglandins, prostacyclins or thromboxanes. Recently it has been proved the existence of two cyclooxygenase isoforms, namely COX-1 and COX-2. Although they are equivalent in a 60% of their structure, they have important functional differences.
COX-1 is a constitutive enzyme located in most of the human tissues and it is nowadays considered responsible for the maintenance of several physiological functions. It synthetizes prostanoids in response to the stimulus produced by the circulating hormones that control the physiological cellular processes (TxA
2
in platelets, PGI
2
in endothelium, PGE
2
in kidney and intestinal mucosa, etc). These hormones are necessary for the maintenance of vascular homeostasis and gastric and renal functions.
Very recently, it has been sequenced, characterized and cloned the gene for a second inducible cyclooxygenase form (COX-2). COX-2 is an inducible enzyme, usually undetectable in most of the tissues, but its expression is significantly increased during inflammatory processes. It has been demonstrated that the induction of COX-2 is located in fibroblasts, macrophages, intestinal and bronquial epithellium cells, due to the exposure to proinflammatory agents like endotoxins, cytokines and growth factors. COX-2 expression has been detected in different animal models of acute or chronic inflammation.
The discovery of inducible isoenzyme COX-2, distinct from constitutive enzyme COX-1, has renewed the interest in the development of new non-steroidal antiinflammatory drugs for inflammation therapy, as it is assumed that beneficial action of these drugs will be due to their activity over COX-2, while associated side effects will be due to their activity over COX-1. It is desirable to have new pharmaceutical antiinflammatory drugs with selective inhibition of COX-2 in preference to COX-1. These drugs, with similar antiinflammatory, antipyretic and analgesic properties to conventional non-steroidal antiinflammatory drugs, may have anticancer effects, but with a remarkable decrease of non-desired side effects. In particular, such a compound would have a reduced potential for gastrointestinal toxicity, a reduced potential of renal side effects and a highly reduced effect on bleeding times.
Patent application WO 96/31509 describes imidazo[1,2a]pyridines with 4-sulfonylphenyl radicals at the 2 position of the fused heterocyclic system as selective COX-2 inhibitors, in accordance with the general formula:
Patent applications WO 92/10190 and WO 96/03387 disclose structurally closed compounds for the treatment of inflammation.
However, the imidazo[1,2a]azines whith 4-sulfonylphenyl radicals at the 3 position (instead of the 2 position) of the fused heterocyclic system which are subject-matter of the present invention have never been chemically described before. They are found to show remarkable and unexpected selective COX-2 inhibition.
SUMMARY OF THE INVENTION
The present invention provides new substituted imidazo[1,2a]azines of formula (I), or a pharmaceutically acceptable acid addition salt and solvates thereof, wherein A and B are independently selected from N and CH, with the condition that when A is N, then B is N too; R
1
is selected from the group consisting of CH
3
and NH
2
, preferably CH
3
; R
2
and R
3
are selected from the group consisting of H, CH
3
, Cl, Br, COCH
3
and OCH
3
, preferably H; R
4
, R
5
and R
6
are each independently selected from the group consisting of H, F, Cl, Br, (C1-C3)-alkyl, trifluoromethyl, (C1-C3)-alkoxy and trifluoromethoxy. Preferably, R
4
, R
5
and R
6
are selected from the group consisting of H, methyl, isopropyl, F, Cl, methoxyl and ethoxyl.
Compounds of formula (I) wherein A is CH and B is N are preferred.
When A is CH and B is N, the imidazo[1,2a]azines of formula (I) are named imidazo[1,2a]pyrimidines, and the particular examples are listed here by a letter (Ia, Ib, . . . ). When A is N and B is N, the imidazo[1,2a]azines of formula (I) are named imidazo[1,2a]triazines, and the particular examples are listed here by two letters (Iaa, Ibb, . . . ). When A is CH and B is CH, the imidazo[1,2a]azines of formula (I) are named imidazo[1,2a]pyridines, and the particular examples are listed here by three letters (Iaaa, Ibbb, . . . ). To establish the nomenclature of those fused ring systems, it has been used the numeration hereinbelow explained, that is equivalent to that used in WO 96/31509 for compounds with a similar structure.
The compounds of formula (I) hereinbelow named are especially preferred, and their nuclear magnetic resonance chemical shifts spectra are described. The
1
H-NMR chemical shifts (&dgr;) are given in parts per million (ppm) with respect to tetramethylsilane (TMS), and NMR have been carried out on a 300 MHz spectrometer, using a suitable deuterated solvent. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quadruplet; dd, doublet of doublets; td, triplet of doublets; m, multiplet.
In the present invention the synthesis of some of the following compounds are also described:
(Ia) 2-phenyl-3-(4-methylsulfonylphenyl)imidazo [1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 3.17 (s, 3H), 6.92 (dd, 1H), 7.32-7.34 (m, 3H), 7.65-7.71 (m, 4H), 8.10 (d, 2H), 8.36 (dd, 1H), 8.62 (dd, 1H).
(Ib) 2-(4-methylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 2.35 (s, 3H), 3.17 (s, 3H), 6.91 (m, 1H), 7.14 (d, 2H), 7.56 (d, 2H), 7.69 (d, 2H), 8.10 (d, 2H), 8.35 (d, 1H), 8.60 (d, 1H).
(Ic) 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 3.18 (s, 3H), 6.93 (dd, 1H), 7.00-7.06 (m, 2H), 7.63-7.70 (m, 4H), 8.10 (d, 2H), 8.34 (dd, 1H), 8.63 (dd, 1H).
(Id) 2-(4-chlorophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (DMSO 300 MHz): &dgr; 3.31 (s, 3H), 7.09 (dd, 1H), 7.43 (d, 2H), 7.58 (d, 2H), 7.81 (d, 2H), 8.11 (d, 2H), 8.61-8.66 (m,2H).
(Ie) 2-(4-bromophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 3.18 (s, 3H), 6.97 (dd, 1H), 7.46 (d, 2H), 7.54 (d, 2H), 7.69 (d, 2H), 8.12 (d, 2H), 8.33 (d, 1H), 8.63 (d, 1H).
(If) 2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 3.17 (s, 3H), 3.82 (s, 3H), 6.88 (m, 3H), 7.60 (d, 2H), 7.70 (d, 2H), 8.10 (d, 2H), 8.35 (d, 1H), 8.58 (d, 1H).
(Ig) 2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 1.42 (t, 3H), 3.17 (s, 3H), 3.95-4.14 (m, 2H), 6.83-7.00 (m, 3H), 7.60 (d, 2H), 7.69 (d, 2H), 8.10 (d, 2H), 8.33 (dd, 1H), 8.59 (dd, 1H).
(Ih) 2-(3,4-dimethylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 2.24 (s, 3H), 2.26 (s, 3H), 3.17 (s, 3H), 6.91 (m, 1H), 7.03 (d, 1H), 7.21 (d, 1H), 7.64 (s, 1H), 7.70 (d, 2H), 8.10 (d, 2H), 8.35 (d, 1H), 8.61 (s, 1H).
(Ii) 2-(3-methyl-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 2.18 (s, 3H), 3.16 (s, 3H), 3.83 (s, 3H), 6.72 (d, 1H), 6.89 (dd, 1H), 7.31 (dd, 1H), 7,60 (s, 1H), 7.70 (d, 2H), 8.09 (d, 2H), 8.35 (dd, 1H), 8.58 (dd, 1H)
(Ij) 2-(3-fluoro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo [1,2a]pyrimidine.
1
H RMN (CDCl
3
300 MHz): &dgr; 3.19 (s, 3H), 3.90 (s, 3H), 6.88-6.93 (m, 2H), 7.37-7.46 (m, 2H), 7.71 (d, 2H), 8.13 (d, 2H), 8.32 (dd, 2H), 8.61 (dd, 1H).
(Ik) 2-(3-chloro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine.
1
H RMN (DMSO 300 MHz): &dgr; 3.31 (s, 3H), 3.85 (s, 3H), 7.06 (dd, 1H), 7.13 (d, 1H), 7.41 (dd, 1H), 7.68 (d, 1H), 7.83 (d, 2H), 8.12 (d, 2H), 8.5
Farrerons Gallemi Carles
Fernandez Garcia Andres
Fernandez Serrat Ana Maria
Gimenez Guasch Ferran
Lagunas Arnal Carmen
Balasubramanian Venkataraman
Laboratorios S.A.L.V.A.T., S.A.
Merchant & Gould P.C.
Shah Mukund J.
LandOfFree
Substituted imidazo 1,2a}azines as selective inhibitors... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted imidazo 1,2a}azines as selective inhibitors..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted imidazo 1,2a}azines as selective inhibitors... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3163506