| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 26.03.2002 |
| PATENT TITLE |
Triazole compounds and methods of making same |
| PATENT ABSTRACT |
The present invention relates to novel triazole compounds of the following formula: ##STR1## wherein R.sub.1 to R.sub.5 have the meanings provided herein. The invention further relates to combinatorial libraries containing two or more such compounds, as well as methods of preparing triazole compounds. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 29, 1999 |
| PATENT REFERENCES CITED |
Dooley et al., "An All D-Amino Acid Opioid Peptide with Central Analgesic Activity from a Combinatorial Library," Science 266:2019-2022 (1994). Eichler and Houghten, "Identification of Substrate-Analog Trypsin Inhibitors through the Screening of Synthetic Peptide Combinatorial Libraries," Biochemistry 32:11035-11041 (1993). Francis et al., "Synthesis and Benzodiazepine Binding Activity of a Series of Novel [1,2,4] Triazolo [1,5-c] quinazolin-5 (6H) -ones," J. Med. Chem. 34:281-290 (1991). Gallop et al., "Applications of Combinatorial Technologies to Drug Discovery," J. Med. Chem., 37:1233-1251 (1994). Goff et al., "Solid-Phase Synthesis of Highly Substituted Peptoid 1 (2H) -Isoquinolinones," J. Org. Chem. 60:5748-5749 (1995). Hanessian and Xie, "Polymer-Bound p-Alkoxybenzyl Trichloracetimidates: Regents for the Protection of Alcohols as Benzyl Ethers on Solid-Phase," Tetrahedron Letters, 39:733-736 (1998). Houghton et al., "Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery," Nature 354:84-86 (1991). Wilson et al., "Solid-supported syntheses of 3-thio-1,2,4-triazoles," Molecular Diversity 3:95-112 (1998). |
| PATENT CLAIMS |
We claim: 1. A single triazole compound of the formula: ##STR10## wherein: R.sub.1 is selected from the group consisting of --NHC(O)NR.sub.6 R.sub.7, --CO.sub.2 R.sub.6, --OR.sub.6, --NR.sub.6 R.sub.7, --C(O)NR.sub.6 R.sub.7, and --CH.sub.2 NR.sub.6 R.sub.7, wherein R.sub.6 is a hydrogen atom or a functionalized resin, and R.sub.7 is selcted from the group consisting of a hydrogen atom, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 substituted alkyl, C.sub.2 to C.sub.7 alkenyl, C.sub.2 to C.sub.7 substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C.sub.7 to C.sub.12 phenylalkyl, C.sub.7 to C.sub.12 substituted phenylalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle; R.sub.2 is selected from the group consisting of C.sub.1 to C.sub.12 alkylene, C.sub.1 to C.sub.12 substituted alkylene, C.sub.2 to C.sub.7 alkenylene, C.sub.2 to C.sub.7 substituted alkenylene, C.sub.2 to C.sub.7 alkynylene, C.sub.5 to C.sub.7 cycloalkylene, C.sub.5 to C.sub.7 substituted cycloalkylene, C.sub.5 to C.sub.7 cycloalkenylene, C.sub.5 to C.sub.7 substituted cycloalkenylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heterocyclene, substituted heterocyclene, heteroarylene, substituted heteroarylene, C.sub.7 to C.sub.12 phenylalkoxy, C.sub.7 to C.sub.12 substituted phenylalkoxy, the formula: --(CH.sub.2).sub.m --G--(CH.sub.2).sub.n -- wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and G is selected from phenylene and substituted phenylene, the formula: --(CH.sub.2).sub.m --NX--(CH.sub.2).sub.n -- wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and X is selected from the group consisting of a hydrogen atom, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 substituted alkyl, C.sub.1 to C.sub.7 acyl, C.sub.1 to C.sub.7 substituted acyl, C.sub.1 to C.sub.4 alkyl sulfonyl, C.sub.1 to C.sub.4 substituted alkyl sulfonyl, phenylsulfonyl, substituted phenylsulfonyl, C.sub.1 to C.sub.6 alkylaminocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C.sub.1 to C.sub.6 alkylaminothiocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl, substituted phenylaminothiocarbonyl, C.sub.1 to C.sub.7 alkoxycarbonyl, C.sub.1 to C.sub.7 substituted alkoxycarbonyl, phenoxycarbonyl and substituted phenoxycarbonyl, the formula: ##STR11## wherein n is an integer selected from 0 to 6; Y and Z are together or independently a hydrogen atom, C.sub.6 to C.sub.1 alkyl, C.sub.1 to C.sub.6 substituted alkyl, C.sub.2 to C.sub.7 alkenyl, C.sub.2 to C.sub.7 alkynyl, C.sub.2 to C.sub.7 substituted alkenyl, C.sub.2 to C.sub.7 substituted alkynyl, C.sub.1 to C.sub.7 acyl, C.sub.1 to C.sub.7 substituted acyl, C.sub.3 to C.sub.7 cycloalkyl, C.sub.3 to C.sub.7 substituted cycloalkyl, C.sub.5 to C.sub.7 cycloalkenyl, C.sub.5 to C.sub.7 substituted cycloalkenyl, a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted heteroaryl, C.sub.7 to C.sub.12 phenylalkyl, C.sub.7 to C.sub.12 substituted phenylalkyl, C.sub.7 to C.sub.12 phenylalkoxy, C.sub.7 to C.sub.12 substituted phenylalkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C.sub.2 to C.sub.7 alkylene, substituted cyclic C.sub.2 to C.sub.7 alkylene, cyclic C.sub.2 to C.sub.7 heteroalkylene, substituted cyclic C.sub.2 to C.sub.7 heteroalkylene, carboxy, protected carboxy, hydroxymethyl and protected hydroxymethyl; and G is selected from phenylene and substituted phenylene, and the formula: ##STR12## wherein J and K are each selected from the group consisting of phenylene and substituted phenylene, and m and n are independently selected from 0 and 1; R.sub.3 is selected from the group consisting of a hydrogen atom, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano, (monosubstituted)amino, protected (monosubstituted)amino, (disubstituted)amino, C.sub.1 to C.sub.7 acyl, C.sub.1 to C.sub.7 substituted acyl, C.sub.1 to C.sub.7 alkoxycarbonyl, C.sub.1 to C.sub.7 substituted alkoxycarbonyl, C.sub.1 to C.sub.7 alkylaminocarbonyl, C.sub.1 to C.sub.7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl, substituted naphthyl, C.sub.5 to C.sub.7 cycloalkyl, C.sub.5 to C.sub.7 substituted cycloalkyl, C.sub.5 to C.sub.7 cycloalkenyl and C.sub.5 to C.sub.7 substituted cycloalkenyl; R.sub.4 is selected from the group consisting of the formula: --D-phenylene-E-- wherein: D is directly attached to the triazole ring and D and E are independently selected from the group consisting of C.sub.1 to C.sub.6 alkylene, C.sub.2 to C.sub.7 alkenylene, C.sub.2 to C.sub.7 alkynylene, C.sub.1 to C.sub.6 substituted alkylene, C.sub.2 to C.sub.7 substituted alkenylene, C.sub.2 to C.sub.7 substituted alkynylene, C.sub.5 to C.sub.7 cycloalkylene, C.sub.5 to C.sub.7 substituted cycloalkylene, C.sub.5 to C.sub.7 cycloalkenylene, C.sub.5 to C.sub.7 substituted cycloalkenylene, C.sub.7 to C.sub.12 phenylalkylene, C.sub.7 to C.sub.12 substituted phenylalkylene, --R.sub.10 --O--R.sub.11 --, --NR.sub.10 R.sub.11 --, --R.sub.10 --NH--R.sub.11 --and --C(O)NR.sub.10 R.sub.11 --, wherein R.sub.10 and R.sub.11 are independently absent or present and selected from the group consisting of C.sub.1 to C.sub.6 alkylene, C.sub.1 to C.sub.6 substituted alkylene, C.sub.7 to C.sub.12 phenylalkylene and C.sub.7 to C.sub.12 substituted phenylalkylene, provided that, when D is --NR.sub.10 R.sub.11 -- or --C(O)NR.sub.10 R.sub.11 --, R.sub.11 is present and directly connected to the triazole ring; the formula: ##STR13## wherein: R.sub.8 and R.sub.9 are together or independently selected from the group consisting of a hydrogen atom, C.sub.1 to C.sub.6 alkyl, C.sub.2 to C.sub.7 alkenyl, C.sub.2 to C.sub.7 alkynyl, C.sub.1 to C.sub.6 substituted alkyl, C.sub.2 to C.sub.7 substituted alkenyl, C.sub.2 to C.sub.7 substituted alkynyl, C.sub.1 to C.sub.7 acyl, C.sub.1 C.sub.7 substituted acyl, C.sub.5 to C.sub.7 cycloalkyl, C.sub.5 to C.sub.7 substituted cycloalkyl, C.sub.5 to C.sub.7 cycloalkenyl, C.sub.5 to C.sub.7 substituted cycloalkenyl, a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted heteroaryl, C.sub.7 to C.sub.12 phenylalkyl, C.sub.7 to C.sub.12 substituted phenylalkyl, C.sub.7 to C.sub.12 phenylalkoxy, C.sub.7 to C.sub.12 substituted phenylalkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C.sub.2 to C.sub.7 alkylene, substituted cyclic C.sub.2 to C.sub.7 alkylene, cyclic C.sub.2 to C.sub.7 heteroalkylene, substituted cyclic C.sub.2 to C.sub.7 heteroalkylene, carboxy, protected carboxy, hydroxymethyl, protected hydroxymethyl, amino and amino-protecting group; and m and n are independently 0, 1, 2, 3 or 4; and and the formulae: ##STR14## wherein q is selected from 1 and 2; r is is selected from 0 and 1; s and t are independently selected from 0, 1 and 2; and R.sub.12 and R.sub.13 are independently selected from the group consisting of a hydrogen atom, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 substituted alkyl, C.sub.7 to C.sub.12 phenylalkyl, C.sub.7 to C.sub.12 substituted phenylalkyl, C.sub.1 to C.sub.7 acyl, C.sub.1 to C.sub.7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C.sub.1 to C.sub.4 alkylsulfonyl, C.sub.1 to C.sub.4 substituted alkylsulfonyl, C.sub.1 to C.sub.6 alkylaminocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C.sub.1 to C.sub.6 alkylaminothiocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and R.sub.14 is selected from a hydrogen atom, --OH, hydroxy-protecting group, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 substituted alkyl, C.sub.1 to C.sub.7 alkoxy, C.sub.1 to C.sub.7 phenylalkoxy, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; and R.sub.5 is absent or is selected from the group consisting of a hydrogen atom, a halide, --OH, --CO.sub.2 H, --CHO, --CO.sub.2 R.sub.15, --C(O)NR.sub.15 R.sub.16 and --NR.sub.15 R.sub.16, wherein R.sub.15 and R.sub.16 are independently selected from a hydrogen atom, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 substituted alkyl, phenyl, substituted phenyl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, C.sub.5 to C.sub.7 cycloalkyl, C.sub.5 to C.sub.7 substituted cycloalkyl, C.sub.5 to C.sub.7 cycloalkenyl, C.sub.5 to C.sub.7 substituted cycloalkenyl, C.sub.7 to C.sub.12 phenylalkyl, C.sub.7 to C.sub.12 substituted phenylalkyl, C.sub.1 to C.sub.7 acyl, C.sub.1 to C.sub.7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C.sub.1 to C.sub.4 alkylsulfonyl, C.sub.1 to C.sub.4 substituted alkylsulfonyl, C.sub.1 to C.sub.6 alkylaminocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C.sub.1 to C.sub.6 alkylaminothiocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl, and the formulae: ##STR15## wherein R.sub.17 and R.sub.18 are independently selected from a hydrogen atom, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 substituted alkyl, C.sub.7 to C.sub.12 phenylalkyl, C.sub.7 to C.sub.12 substituted phenylalkyl, C.sub.7 to C.sub.12 phenylalkoxy, C.sub.7 to C.sub.12 substituted phenylalkoxy C.sub.1 to C.sub.7 acyl, C.sub.1 to C.sub.7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C.sub.1 to C.sub.4 alkylsulfonyl, C.sub.1 to C.sub.4 substituted alkylsulfonyl, C.sub.1 to C.sub.6 alkylaminocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C.sub.1 to C.sub.6 alkylaminothiocarbonyl, C.sub.1 to C.sub.6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and s is an integer selected from 1 to 5; provided that, when (1) R.sub.8 and R.sub.9 are both hydrogen atoms; or (2) one of R.sub.8 and R.sub.9 is a hydrogen atom and the other is a C.sub.1 to C.sub.6 alkyl or C.sub.1 to C.sub.6 substituted alkyl where the substitution is one or more halides, R.sub.5 is not a hydrogen atom or a halide; and provided that, when one of R.sub.8 and R.sub.9 is a hydrogen atom and the other is a C.sub.2 to C.sub.7 alkenyl, R.sub.5 is not a hydrogen atom; or a pharmaceutically acceptable salt of a compound thereof. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to the synthesis of compounds comprising heterocyclic rings. In one specific embodiment, the invention provides novel triazoles as well as novel combinatorial libraries comprised of such compounds. 2. BACKGROUND INFORMATION The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested, one or more structures is selected as promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional "one-at-a-time" synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional "one-at-a-time" synthesis methods, except over a time frame of years or even decades. Faster methods are needed what allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as triazoles. Combinatorial approaches have recently been extended to "organic," or non-peptide, libraries. Zambias et al. (U.S. Pat. No. 5,712,171) describe a method of generating libraries that contain aminimides, oxazolones, sulfonylaminides and phosphonylaminides as the core structure in spatially arranged arrays. Combinatorial chemical methods have been applied to a limited number of heterocyclic compounds, as described, for example, in Wilson et al., Molecular Diversity, 3:95-112 (1998); U.S. Pat. Nos. 5,288,514; 5,324,483; and Goff et al., J. Org. Chem., 60:5748-5749 (1995). See also U.S. Pat. Nos. 5,549,974 and 5,506,337. However, the heterocyclic libraries to date contain compounds of limited diversity and complexity. Substituent limitations have been overcome for mixtures of peptides and peptidomimetics through the use of solid phase techniques versus solution-phase. An important step in the development of solid-phase techniques was the discovery of methods to prepare large numbers of individual compounds simultaneously, as described, for example, by Houghten in U.S. Pat. No. 4,631,211. These solid phase methods, however, have rarely been applied to the syntheses of complex heterocyclic structures. Therefore a need exists to develop more complex "organic" libraries based on heterocyclic medicinal compounds which would need less time and effort in the synthesis and testing required to bring an organic pharmacetical product to fruition. In short, improved methods for generating therapeutically useful heterocyclic compounds, such as triazole derivatives, are desired. Triazole compounds have been the subject of investigation in a number of different biological areas. For example, triazole derivatives have been proposed as useful: (a) as benzodiazepine receptor agonists (Francis et al., J. Med. Chem., 34:281-290 (1991); (b) in treating cardiovascular disorders (U.S. Pat. No. 5,098,920); (c) as fungicides and plant-growth regulators (U.S. Pat. No. 4,598,085); (d) as insecticides (U.S. Pat. No. 5,756,522) (e) in treating allergies; (f) in treating hypertension (U.S. Pat. No. 4,338,453); and (g) as angiotensin antagonists (U.S. Pat. No. 5,281,614). However, more complex triazole derivatives, especially with substitutions at the 1 and 2 nitrogen positions, have been difficult to attain. This invention satisfies this need and provides related advantages as well. The present invention overcomes the known limitations to classical serial organic synthesis of triazole derivatives, for example, as well as the shortcomings of combinatorial chemistry related to triazole compounds. The present invention allows for rapid generation of large diverse libraries of complex triazoles as discrete molecules or molecules bound to solid support, such as a resin. The present invention can utilize a readily available pool of building blocks that can be incorporated into the various regions of the molecule. Furthermore, the method of making the present invention allows for the use of building blocks that contain a wide range of diverse functionality. Therefore, building blocks, such as those described above, can provide libraries that consist of large numbers as well as libraries that are extremely diverse with respect to the functionality contained within those libraries. The present invention combines the techniques of solid-phase synthesis of triazoles and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new triazole compounds. SUMMARY OF THE INVENTION The present invention relates to novel triazole compounds of the following formula: ##STR2## wherein R.sub.1 to R.sub.5 have the meanings provided below (with R.sub.4 --R.sub.5 attached to either the one-position or two-position nitrogen on the triazole ring). The invention further relates to combinatorial libraries containing two or more such compounds, and to methods of generating triazole compounds |
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