| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 30, 2003 |
| PATENT TITLE |
Substituted imidazo 1,2a}azines as selective inhibitors of cox-2 |
| PATENT ABSTRACT |
The invention refers to new compounds of formula (I), wherein A and B are selected from the group consisting of N and CH, with the condition that when A is N, B is N; R.sup.1 is selected from the group consisting of CH.sub.3 and NH.sub.2 ; R.sup.2 and R.sup.3 are selected from the group consisting of H, CH.sub.3, Br, Cl, COCH.sub.3 and OCH.sub.3 ; and R.sup.4, R.sup.5 and R.sup.6, are selected from the group consisting of H, F, Cl, Br, (C1-C3)-alkyl, trifluoromethyl, (C1-C3)-alkoxy and trifluoromethoxy. Compounds of formula (I) are prepared by reaction of a substituted aminoazine with a substituted 2-bromo-2-(4-R.sup.1 -sulfonylphenyl)-1-phenylethanone in a polar solvent. These new compounds inhibit COX-2 with high selectivity over COX-1. They are useful for the treatment of inflamation and/or cyclooxygenase-mediated diseases, having the additional advantage of a reduced potencial for ulcerogenic effects. ##STR1## |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | April 5, 2001 |
| PATENT CT FILE DATE | July 23, 1999 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | February 17, 2000 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED | McMurray et al. Am. J. Med. Sci. 323(4): 181-189,2002. |
| PATENT CLAIMS |
What is claimed is: 1. A imidazo[1,2-a]azine of formula (I), or a pharmaceutically acceptable solvate and acid addition salt thereof, wherein R.sup.1 is selected from the group consisting of CH.sub.3 and NH.sub.2 ; R.sup.2 and R.sup.3 are selected from the group consisting of H, CH.sub.3, Cl, Br, COCH.sub.3 and OCH.sub.3 ; and R.sup.4, R.sup.5 and R.sup.6 are each independently selected from the group consisting of H, F, Cl, Br, (C.sub.1 -C.sub.3)-alkyl, trifluoromethyl, (C.sub.1 -C.sub.3)-alkoxy and trifluoromethoxy ##STR9## 2. A compound according to claim 1, wherein R.sup.4, R.sup.5, and R.sup.6 are selected from the group consisting of H, F, Cl, methyl, isopropyl, methoxy and ethoxy. 3. A compound according to claim 2, said compound being selected from the group consisting of: (Ia) 2-phenyl-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ib) 2-(4-methylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ic) 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (Id) 2-(4-chlorophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ie) 2-(4-bromophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (If) 2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ig) 2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ih) 2-(3,4-dimethylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ii) 2-(3-methyl-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrim idine; (Ij) 2-(3-fluoro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrim idine; (Ik) 2-(3-chloro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrim idine; (Il) 2-(3,4-dimethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimidine ; (Im) 7-methyl-2-(4-methylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]pyrimi dine; (In) 7-methyl-2-(3,4-dimethylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2-a]py rimidine; (Io) 2-(4-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ip) 2-(3-fluoro-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2-a]pyrimi dine; (Iq) 2-(2-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2-a]pyrimidine; (Ir) 2-(4-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2-a]pyrimidine; (Is) 2-(2-chlorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2-a]pyrimidine; (It) 2-(3-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2-a]pyrimidine; and (Iu) 2-(3-chlorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2-a]pyrimidine. 4. A compound according to claim 3, said compound being 3-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine (Ic). 5. A compound according to claim 3, said compound being 3-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)imidazo[1,2-a]pyrimidine (If). 6. A compound according to claim 3, said compound being 3-(4-methylsulfonylphenyl)-2-(4-ethoxyphenyl)imidazo[1,2-a]pyrimidine (Ig). 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1, and suitable amounts of pharmaceutically acceptable carriers. 8. A pharmaceutical composition for treating rheumatoid arthritis, comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1, and suitable amounts of pharmaceutically acceptable carriers. 9. A pharmaceutical composition for treating a cancer, comprising a therapeutically effective amount of a compound of formula (I) as defined in claim 1, and suitable amounts of pharmaceutically acceptable carriers. 10. A method of treating rheumatoid arthritis in a subject comprising administering a therapeutic amount of a compound of formula (I), as defined in claim 1. 11. A method of treating cancer in a subject comprising administering a therapeutic amount of a compound of formula (I), as defined in claim 1. 12. A method according to claim 11, wherein the cancer is colon cancer. 13. A process for preparing a imidazo[1,2-a]azine of formula (I), as defined in claim 1, comprising the condensation reaction of a substituted 2-bromo-2-(4-R.sup.1 -sulfonylphenyl)-1-phenylethanone of formula (II) with a substituted aminoazine of formula (III), in a polar solvent. ##STR10## -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
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.sub.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.sub.2 in platelets, PGI.sub.2 in endothelium, PGE.sub.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: ##STR2## 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.sup.1 is selected from the group consisting of CH.sub.3 and NH.sub.2, preferably CH.sub.3 ; R.sup.2 and R.sup.3 are selected from the group consisting of H, CH.sub.3, Cl, Br, COCH.sub.3 and OCH.sub.3, preferably H; R.sup.4, R.sup.5 and R.sup.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.sup.4, R.sup.5 and R.sup.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. ##STR3## 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. ##STR4## The compounds of formula (I) hereinbelow named are especially preferred, and their nuclear magnetic resonance chemical shifts spectra are described. The .sup.1 H-NMR chemical shifts (.delta.) 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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. .sup.1 H RMN (DMSO 300 MHz): .delta. 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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]pyrimi dine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 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]pyrimi dine. .sup.1 H RMN (DMSO 300 MHz): .delta. 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), 8.57-8.62 (m, 2H). (Il) 2-(3,4-dimethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.17 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 6.75 (d, 1H), 6.94-7.02 (m, 2H), 7.51 (d, 1H), 7.76 (d, 2H), 8.13 (d, 2H), 8.34 (dd, 1H), 8.62 (dd, 1H). (Im) 7-methyl-2-(4-methylphenyl)-3-(4-methylsulfonylphenyl)imidazo [1,2a]pyrimidine. .sup.1 H RMN (DMSO 300 MHz): .delta. 2.56 (s, 3H), 3.30 (s, 3H), 3.75 (s, 3H), 6.91-6.95 (m, 3H), 7.50 (d, 2H), 7.77 (d, 2H), 8.08 (d, 2H), 8.46 (d, 1H). (In) 7-methyl-2-(3,4-dimethylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyr imidine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 2.23 (s, 3H), 2.25 (s, 3H), 2.65 (s, 3H), 3.15 (s, 3H), 6.76 (d, 1H), 7.01 (d, 1H), 7.21 (dd, 1H), 7.62 (s, 1H), 7.67 (d, 2H), 8.06 (d, 2H), 8.20 (d, 1H). (Io) 2-(4-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimidine. .sup.1 H RMN (DMSO 300 MHz): .delta. 2.30 (s, 3H), 7.05 (dd, 1H), 7.16 (d, 2H), 7.47-7.49 (m, 4H), 7.72 (d, 2H), 7.99 (d, 2H), 8.57-8.58 (m, 2H). (Ip) 2-(3-fluoro-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimid ine. .sup.1 H RMN (DMSO 300 MHz): .delta. 3.84 (s, 3H), 7.04 (dd, 1H), 7.14 (t, 1H), 7.33 (d, 1H), 7.38 (dd, 1H), 7.50 (s, 2H), 7.74 (d, 2H), 8.01 (d, 2H), 8.54 (dd, 1H), 8.60 (dd, 1H). (Iq) 2-(2-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimidine. .sup.1 H RMN (DMSO 300 MHz): .delta. 2.12 (s, 3H), 7.11-7.27 (m, 5H), 7.39 (s, 2H), 7.55 (d, 2H), 7,86 (d, 2H), 8,20 (d, 1H), 8,64 (d, 1H). (Ir) 2-(4-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimidine. .sup.1 H RMN (DMSO 300 MHz): .delta. 6.02 (s, 2H), 6.89 (d, 1H), 7.02-7.09 (m, 4H), 7.80 (d, 2H), 8.10 (d, 2H), 8.56-8.60 (m, 2H). (Is) 2-(2-chlorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimidine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.09 (dd, 1H), 7.28 (s, 2H), 7.57-7.84 (m, 8H), 8.30 (dd, 1H), 8.67 (dd, 1H). (It) 2-(3-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimidine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.08 (s, 1H), 7.16 (s, 1H), 7.39 (m, 3H), 7.51 (s, 2H), 7.76 (d, 2H), 8.02 (d, 2H), 8.57 (d, 1H), 8.64 (s, 1H). (Iu) 2-(3-chlorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimidine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.07 (dd, 1H), 7.35-7.44 (m, 3H), 7.51 (s, 2H), 7.69 (s, 1H), 7.75 (d, 2H), 8.01 (d, 2H), 8.57 (dd, 1H), 8.64 (dd, 1H). (Iaa) 2-phenyl-3-(4-methylsulfonylphenyl)imidazo[1,2a][1,2,4]triazine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.15 (s, 3H), 7.37-7.42 (m, 3H), 7.70-7.76 (m, 2H), 7.86 (d, 2H), 8.05 (d, 2H), 8.39 (d, 1H), 8.54 (d, 1H). (Ibb) 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a][1,2,4]triazine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.15 (s, 3H), 7.09 (m, 2H), 7.72 (m, 2H), 7.85 (m, 2H), 8.07 (m, 2H), 8.39 (d, 1H), 8.55 (d, 1H). (Icc) 2-(3-fluoro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a][1,2,4 ]triazine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.16 (s, 3H), 3.93 (s, 3H), 6.95 (t, 1H), 7.42 (m, 1H), 7.55 (dd, 1H), 7.86 (d, 2H), 8.08 (d, 2H), 8.38 (d, 1H), 8.53 (d, 1H). (Idd) 2-phenyl-3-(4-aminosulfonylphenyl)imidazo[1,2a][1,2,4]triazine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.39-7.41 (m, 3H), 7.51 (s, 2H), 7.64-7.67 (m, 2H), 7.77 (d, 2H), 7.96 (d, 2H), 8.65 (m, 2H). (Iee) 2-(2-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a][1,2,4]triazine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.18-7.25 (m, 1H), 7.32-7.39 (m, 3H), 7.49-7.51 (m, 1H), 7.63-7.64 (m, 2H), 7.70-7.75 (m, 1H), 7.86-7.88 (m, 1H), 8.06 (s, 1H), 8.70-8.73 (m, 2H). (Iff) 2-(2-chlorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a][1,2,4]triazine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.35 (s, 2H), 7.44-7.60 (m, 4H), 7.65 (d, 2H), 7.84 (d, 2H), 8.72 (d, 1H), 8.77 (d, 1H). (Igg) 2-(3-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a][1,2,4]triazine. .sup.1 H RMN (DMSO 300 MHz): .delta. 2.31 (s, 3H), 7.21 (t, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.44 (s, 2H), 7.60 (s, 1H), 7.77 (d, 2H), 7.97 (d, 2H), 8.64 (s, 2H). (Ihh) 2-(3-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a][1,2,4]triazine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.18-7.25 (m, 1H), 7.43-7.46 (m, 5H), 7.78 (d, 2H), 7.99 (d, 2H), 8.66 (d, 2H). (Iaaa) 2-phenyl-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.17 (s, 3H), 6.88 (td, 1H), 7.27-7.36 (m, 4H), 7.58-7.62 (m, 2H), 7.70 (d, 2H), 7.81 (d, 1H), 8.05-8.11 (m, 3H). (Ibbb) 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.21 (s, 3H), 6.88 (m, 1H), 7.03 (t, 2H), 7.33 (t, 1H), 7.58 (m, 2H), 7.69 (d, 2H), 7.78 (d, 1H), 8.05-8.12 (m, 3H). (Iccc) 2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.17 (s, 3H), 3.82 (s, 3H), 6.78-6.90 (m, 3H), 7.27 (m, 3H), 7.52 (d, 2H), 7.65-7.74 (m, 3H), 8.02-8.12 (m, 3H). (Iddd) 2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 1.41 (t, 3H), 3.16 (s, 3H), 4.04 (q, 2H), 6.78-6.88 (m, 3H), 7.26 (ddd, 1H), 7.50 (d, 2H), 7.54-7.64 (m, 3H), 8.02-8.10 (m, 3H). (Ieee) 2-(4-isopropoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo [1,2a]pyridine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 1.34 (d, 6H), 3.17 (s, 3H), 4.56 (m, 1H), 6.82-6.88 (m, 3H), 7.27-7.33 (m, 1H), 7.52 (d, 2H), 7.70 (d, 2H), 7.78 (d, 1H), 8.04-8.11 (m, 3H). (Ifff) 2-(3-methyl-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridi ne. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 2.20 (s, 3H), 3.16 (s, 3H), 3.83 (s, 3H), 6.72 (d, 1H), 6.83 (td, 1H), 7.21-7.30 (m, 2H), 7.54 (m, 1H), 7.68-7.76 (m, 3H), 8.04-8.10 (m, 3H). (Iggg) 2-> (3-fluoro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine . .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.18 (s, 3H), 3.89 (s, 3H), 6.83 (td, 1H), 6.89 (t, 1H), 7.24-7.32 (m, 3H), 7.68-7.74 (m, 3H), 8.03 (d, 1H), 8.10 (d, 2H). (Ihhh) 2-(3-chloro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridi ne. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.17 (s, 3H), 3.91 (s, 3H), 6.82-6.87 (m, 2H), 7.26-7.37 (m, 2H), 7.68-7.74 (m, 4H), 8.04 (d, 1H), 8.10 (d, 2H). (Iiii) 2-(3.4-dimethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 3.16 (s, 3H), 3,83 (s, 3H), 3.88 (s, 3H), 6.77 (d, 1H), 6.83 (td, 1H), 6.98 (dd, 1H), 7.29-7.34 (m, 2H), 7.72 (d, 2H), 7.78 (d, 1H), 8.05 (d, 1H), 8.10 (d, 2H). (Ijjj) 7-methyl-2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridi ne. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 2.43 (s, 3H), 3.16 (s, 3H), 3.81 (s, 3H), 6.65 (dd, 1H), 6.85 (d, 2H), 7.50 (m, 3H), 7.66 (d, 2H), 7.94 (d, 1H), 8.05 (d, 2H). (Ikkk) 6-methyl-2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridin e. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 1,41 (t, 3H), 2.32 (s, 3H), 3.18 (s, 3H), 4.03 (q, 2H), 6.84 (d, 2H), 7.15 (dd, 1H), 7.50 (d, 2H), 7.66-7.69 (m, 3H), 7.81 (s, 1H), 8.08 (d, 2H). (Illl) 6-chloro-2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridin e. .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 1.41 (t, 3H), 3.18 (s, 3H), 4.04 (q, 2H), 6.84 (d, 2H), 7.03 (dd, 1H), 7.49 (d, 2H), 7.68 (m, 3H ), 8.04 (d, 1H), 8.11 (d, 2H). (Immm) 6-bromo-2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine . .sup.1 H RMN (CDCl.sub.3 300 MHz): .delta. 1.41 (t, 3H), 3.18 (s, 3H), 4.04 (q, 2H), 6.84 (d, 2H), 7.34 (dd, 1H), 7.49 (d, 2H), 7.63-7.69 (m, 3H), 8.11 (m, 3H). (Innn) 2-(2-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 2.08 (s, 3H), 6.98 (t, 1H), 7.15-7.23 (m, 4H), 7.37 (m, 3H), 7.52 (d, 2H), 7.68 (d, 1H), 7.84 (d, 2H), 8.42 (d, 1H). (Iooo) 2-(2-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 7.01 (t, 1H), 7.14 (t, 1H), 7.27 (m, 1H), 7.38-7.42 (m, 4H), 7.54-7.74 (m, 4H), 7.89 (m, 2H), 8.28 (d, 1H). (Ippp) 2-(3-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 2.27 (s, 3H), 6.92 (t, 1H), 7.07-7.25 (m, 3H), 7.34 (m, 1H), 7.48 (s, 2H), 7.53 (s, 1H), 7.66-7.71 (m, 3H), 7.99 (d, 2H), 8.12 (dd, 1H). (Iqqq) 2-(3-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 6.93 (td, 1H), 7.09-7.15 (m, 1H), 7.32-7.39 (m, 4H), 7.57 (s, 2H), 7.68-7.74 (m, 3H), 8.01 (d, 2H), 8.11 (d, 1H). (Irrr) 2-phenyl-3-(4-aminosulfonylphenyl)imidazo[1,2alpyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 6.92 (td, 1H), 7.28-7.37 (m, 4H), 7.48 (s, 2H), 7.57 (dd, 2H), 7.66-7.71 (m, 3H), 8.00 (d, 2H), 8.11 (d, 1H). (Isss) 2-(4-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 6.92 (t, 1H), 7.18 (t, 2H), 7.35 (t, 1H), 7.55-7.59 (m, 4H), 7.67-7.72 (m, 3H), 7.99 (d, 2H), 8.12 (d, 1H). (Ittt) 2-(4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 3.75 (s, 3H), 6.90 (d, 3H), 7.33 (t, 1H), 7.48-7.51 (m, 4H), 7.64-7.71 (m, 3H), 8.00 (d, 2H), 8.10 (d, 1H). (Iuuu) 2-(3-methyl-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridin e. .sup.1 H RMN (DMSO MHz): .delta. 2.11 (s, 3H), 3.77 (s, 3H), 6.83-6.89 (m, 2H), 7.22-7.31 (m, 2H), 7.48 (m, 3H), 7.62-7.70 (m, 3H), 7.89 (d, 2H), 8.09 (d, 1H). (Ivvv) 2-(3-fluoro-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridin e. .sup.1 H RMN (DMSO 300 MHz): .delta. 3.83 (s, 3H), 6.91 (td, 1H), 7.11 (t, 1H), 7.27-7.39 (m, 3H), 7.49 (s, 2H), 7.66 (d, 1H), 7.71 (d, 2H), 8.01 (d, 2H), 8.08 (d, 1H). (Iwww) 2-(3-chloro-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridin e. .sup.1 H RMN (DMSO 300 MHz): .delta. 3.84 (s, 3H), 6.92 (td, 1H), 7.09 (m, 1H), 7.31-7.41 (m, 2H), 7.49 (s, 2H), 7.64-7.74 (m, 4H), 8.01 (d, 2H), 8.09 (d, 1H). (Ixxx) 2-(3,4-difluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. .sup.1 H RMN (DMSO 300 MHz): .delta. 6.94 (t, 1H), 7.33-7.41 (m, 3H), 7.50 (s, 2H), 7.53-7.58 (m, 1H), 7.67-7.74 (m, 3H), 8.02 (d, 2H), 8.10 (d, 1H). Compounds 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine (Ic), 2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine (If), and 2-(4-ethoxyphenyl)-3-(4-ethylsulfonylphenyl)imidazo[1,2a]pyrimidine (Ig), that have an specially selective COX-2 inhibitory activity, as shown in Table 1, are even more preferred. A suitable method for the preparation of substituted imidazo[1,2a]azines of formula (I) is object of this invention. This method includes the condensation of an aminoazine of formula (III) with a 2-bromo-2-(4-R.sup.1 -sulfonylphenyl)-1-phenylethanone of formula (II), in a polar solvent. ##STR5## Intermediates (II) and (III) are obtained from known compounds. When R.sup.1 is CH.sub.3, the new substituted imidazo[(1,2a] azines of formula (I, R.sup.1 =CH.sub.3) may be prepared according to the synthetic procedure shown in Scheme 1, that is being applied to the next three paragraphs. ##STR6## Product COX-2(IC.sub.50 ;.mu.M) COX-1(IC.sub.50 ;.mu.M) (Ia) 5.5 >50 (Ib) 10 >50 (Ic) 2.9 >50 (Id) >10 >50 (If) 1.4 25 (Ig) 1.0 50 (Ih) 2.8 >50 (Ii) 2.2 30 (Ik) 3.9 61 (In) 4.2 2 (Io) 4.5 >50 (Is) 10 100 (It) 10 50 (Iaa) 3.1 76 (Ibb) 2.2 50 (Idd) 3.8 >50 (Igg) 2.8 10 (Ihh) 10 100 (Iccc) 3.3 40 (Iddd) 3.5 80 (Ifff) 1.0 45 (Ihhh) 6.8 82 (Innn) >5 >100 (Ippp) 3.1 50 (Iqqq) >10 >100 (Iuuu) 1.7 25 Indomethacin 0.4 0.21 When R.sup.1 is CH.sub.3, R6=(C1-C3)-alkoxy and trifluoromethoxy, and R.sup.4 and R.sup.5 are independently selected from the group consisting of H, F, Cl, Br, (C1-C3)-alkyl, trifluoromethyl, (C1-C3)alkoxy and trifluoromethoxy. Also, when R.sup.1 is CH.sub.3, R.sup.6 =H, F, Cl, Br, (C1-C3)alkyl, trifluoromethyl, (C1-C3)-alkoxy and trifluoromethoxy, R.sup.4 =R.sup.5 =H. Also when R.sup.1 is CH.sub.3, R.sup.4 =R.sup.6 =(C1-C3)-alkyl and R.sup.5 =H or R.sup.5 =R.sup.6 =(C1-C3)-alkyl and R.sup.4 =H. The first step is a Friedel-Crafts acylation of the s substituted benzene compound (2) with an acyl halide (1), using dichloromethane, 1,2-dichloroethane or the substituted benzene compound as the solvent, to yield the ketone (3). The thioether of the ketone (3) is then consecutively oxidized to methylsulfone with an oxidizing agent (e.g. m-chloroperoxibenzoic acid (MCPBA), hydrogen peroxyde (H.sub.2 O.sub.2), or sodium perborate (NaBO.sub.3)), and .alpha.-brominated, to give substituted 2-bromo-2-(4-methylsulfonylphenyl)-1-phenylethanones (II, R.sup.1 =CH.sub.3) with good yields. In the last step, the bromoketones (II, R.sup.1 =CH.sub.3) were treated with an equimolar or excess amount of aminoazine (III), in a heated (e.g. refluxed) polar solvent (e.g. acetonitrile, ethanol or terbutilic alcohol), optionally in the presence of a base (e.g. potassium carbonate). Compounds (I, R.sup.1 =CH.sub.3) can be isolated as free base, or can be treated with pharmaceutically acceptable acids to give the resulting addition salts. When R.sup.1 is NH.sub.2 the new substituted imidazo[1,2a]azines of formula (I, R.sup.1 =NH.sub.2) can be prepared according to the synthetic procedure shown in Scheme 2. The substituted ketones (6) are treated first with chlorosulfonic acid to give the resulting sulfonyl chloride, and with ammonia later to yield the sulfonamides (7). Bromination of the .alpha.-carbonylic position yields the substituted 2-bromo-2-(4-aminosulfonylphenyl)-1-phenylethanones (II, R.sup.1 =NH.sub.2). These compounds are treated with an equimolar amount or excess amount of aminoazine (III), in a heated (e.g. refluxed) polar solvent (e.g. acetonitrile, ethanol or tert-butyl alcohol), optionally in the presence of a base (e.g. potassium carbonate). Compounds (I, R.sup.1 =CH.sub.3) can be isolated as free base, or can be treated with pharmaceutically acceptable acids to give the resulting addition salts. When (6) is a ketone, where R.sup.4 =F, Cl, Br, (C1-C3)-alkyl, trifluoromethyl, (C1-C3)-alkoxy and trifluoromethoxy, and R.sup.5 and R.sup.6 are independently selected from the group consisting of H, F, Cl, Br, (C1-C3)-alkyl; or R.sup.4 =R.sup.6 =H, and R.sup.5 =F, Cl, Br, (C1-C3)-alkyl, trifluoromethyl, (C1-C3)-alkoxy and trifluoromethoxy, the ketones (6) can be prepared according to the method described in Scheme 3. Aldehydes (7) afford the substituted alcohols (9) by addition of the appropriate organomagnesium reagent (8), prepared by treatment of benzyl chloride or bromide with magnesium in tetrahydrofurane or diethyl ether as a solvent. Subsequent oxidation of the substituted alcohol (9) to the ketone (6) is performed by treatment with an ##STR7## ##STR8## oxidising agent (such as pyridinium chlorochromate or aluminium tert-butoxide). The substituted imidazo[1,2a]azines of formula (I) inhibit cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2) in vitro, as shown in Table 1. Compounds (I) selectively inhibit COX-2 in preference to COX-1. Due to their high selectivity, the compounds herein described are useful as an alternative to conventional non-steroidal antiinflamatory drugs, especially when these drugs may be contra-indicated because of their ulcerogenic side effects. Compounds of formula (I) can prevent neuronal injury by inhibiting the generation of neuronal free radicals, and they can be useful for the treatment of epileptic seizures. Compounds of formula (I) previously defined are useful for the treatment of pain, fever and inflammation in a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, osteoarthritis, gout and ankylosing spondylitis, tendinitis, skin related conditions such as psoriasis, eczema, dermatitis and burns, injuries arising surgical and dental procedures. These compounds may also inhibit cellular and neoplastic transformations and metastatic tumor growth, and hence can be used in the treatment of cancer, such as colon cancer. Compounds of formula (I) can be used in the treatment and/or prevention of cyclooxygenase mediated diseases such as diabetic retinopathy and tumour angiogenesis. Compounds of formula (I) can also inhibit. prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids, and can also be useful for the treatment of dysmenorrhea and premature labour. They are also useful for the treatment of cognitive disorders such as dementia, senile dementia, Alzeihmer's disease, Pick's disease, Parkinson's disease, Creutzfeldt-Jackob disease, and for the treatment of osteoporosis. Compounds of formula (I) inhibit inflammatory processes and therefore can be useful in the treatment of asthma, allergic rhinitis, respiratory distress syndrome, gastrointestinal conditions such as Crohn's disease, gastritis, inflammatory bowel disease and ulcerative colitis; and inflammation in other diseases such as migraine, periarteritis nodosa, thyroiditis, Hodgkin's disease, sclerodoma, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Bechet's syndrome, polymyositis, gingivitis and conjuctivitis. Compounds of formula (I) can be useful for the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis, and of acute injury to the eye tissue. Unless explicitly stated otherwise, it is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment. The present invention also encompasses the pharmaceutical compositions comprising a therapeutically effective amount of any compound of formula (I), previously defined, in association with suitable amounts of pharmaceutically acceptable carriers. Among them, pharmaceutical compositions for the treatment of inflammation, for the treatment of cyclooxygenase-mediated diseases or for the selective inhibition of cyclooxygenase 2 (COX-2), are specially preferred. The pharmaceutical compositions of the present invention can be prepared by any form, known in the art, for oral, injectable, rectal or topical administration. Due to its high COX-2 selectivity, illustrated by data shown in Table 1, the compounds herein described are useful as an alternative to conventional non-steroidal antiinflamatory drugs, especially when these drugs may be contra-indicated because of their ulcerogenic side effects. Hence, another embodiment of the present invention is the use of any of the compounds of formula (I), previously defined, for the manufacture of a therapeutic agent for the treatment of inflammation, for the treatment of cyclooxygenase-mediated diseases, for the selective inhibition of cyclooxygenase 2 (COX-2), and for the treatment of cancer, particulary the colon cancer. |
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