Substituted cyclic compounds and mixtures comprising same

Details Substituted cyclic compounds and mixtures comprising same Substituted cyclic compounds and mixtures comprising same

1998-09-04

2001-02-20

Badio, Barbara (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

active

06191273

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compounds comprising substituted cyclic scaffolds moieties, and to mixtures comprising a plurality of such compounds. Such mixtures are particularly suited to pharmaceutical, pesticidal, industrial, chemical and other uses relating to the modulation detection or use of biological molecules or systems.
BACKGROUND OF THE INVENTION
Chemical libraries such as those provided by the present invention are useful per se and are appreciated to be valuable in and of themselves. Indeed, such libraries can be sold or leased in unaltered form. Moreover, such libraries generally possess biological activity themselves, e.g. antibacterial effect, or can be screened to provide useful compounds such as lead or ultimate drugs, pesticides, industrial chemical species and other useful materials.
The area of combinatorial chemistry has burgeoned recently to the point where it has begun to influence the course of drug discovery (Service, R. F.,
Science
, 1996, 272, 1266-1268). Most of the combinatorial organic synthesis to date has involved the use of solid phase methods with a very few instances of solution phase chemistry reported. Cheng, S., et al.,
J. Am. Chem. Soc
., 1996, 118, 2567-73. In most cases, solid-phase, parallel synthesis is applied to provide pooled mixtures or discrete compounds in volumes which accommodate high-throughput bioassays. Thus far, there has been scant interest in “one-pot”, essentially simultaneous functionalization of multiple sites. Ostresh, J. M., et al.,
J. Biopolymers
, 1994, 34, 1681-1689; Carell, T., et al.,
Chem. Biol
. 1995, 2, 171-83; and Shipps, G. W. Jr., et al.,
Bioorg. Med. Chem
., 1996, 4, 655-657.
There would be great benefit attained from the provision of combinatorial libraries which can be formed in solution phase, especially in essentially single reaction vessel reactions. Similar benefit would attend solution phase synthesis of such libraries under conditions which ensure representation in the product library of all possible reaction products formable under the reaction condition extant from the reactants selected for use. A further benefit would attend the preparation of such libraries from scaffold molecules possessing a relatively large number of derivatizable reaction sites. The present invention provides for the achievement of the foregoing goals.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides chemical compounds having formula Q—[(Z)
n
—L]
m
wherein:
Q is a cyclic scaffold moiety;
Z is NH, O, or S;
m is 2-10 (preferably 3-7, more preferably 3-5);
n is 0 or 1; and
L is a substituent selected from the group consisting of guanidinylarylalkyl, aminoarylalkyl, amidinylpiperazinylcarbonylalkyl, piperazinylcarbonylalkyl, amidinylpiperazinylcarbonylarylalkyl, piperazinylcarbonylarylalkyl, guanidinylalkylaminocarbonylalkyl, aminoalkylaminocarbonylalkyl, guanidinylalkylaminocarbonylarylalkyl, aminoalkylaminocarbonylarylalkyl, benzoimidazolylalkyl, amidinyl, hydroxyamidinyl, hydroxyalkylpyridinylalkyl, arylalkyl, cinnamyl, amidylalkyl, aroyl, alkyloyl, aminoalkyloyl, hydroxaminoyalkyloyl, methoxyaminothioalkyloyl, indolylaminoalkyloyl, amidylaminoalkyloyl, hydroxylcarbonylaminoalkyloyl, guanidinylaminoalkyloyl, imidazolylaminoalkyloyl, amino substituted acyl, carboxylakyl, carboxyl-substituted arylalky and carboxylalkyl-substituted arylalkyl, alkyloxycarbonylalkyl, hydroxysulfonylalkyl, alkyloxycarbonyl substituted pyrimidinyl, alkyloxycarbonyl substituted pyridinyl, carboxyl substituted pyrimidinyl, carboxyl substituted pyridinyl, guanidinylcarbonylalkyl, guanidinylcarbonylarylalkyl, guanidinylcarbonyl substituted pyrimidinyl, guanidinylcarbonyl substituted pyridinyl, alkyloxyphosphatealkyl, pyridinylalkyl, cyanoalkyl, cyanoaryl, nitroalkyl, nitroaryl, alkyloxyalkyl, phenolylalkyl, hydroxylarylalkyl, hydroxyquinolinylalkyl, alkylaminocarbonyl, arylaminocarbonyl, furanylaminocarbonyl, thiofuranylaminocarbonyl, alkylaminothiocarbonyl; arylaminothiocarbonyl, furanylaminothiocarbonyl, thiofuranylaminothiocarbonyl, pyridinylaminothiocarbonyl, 1,2,3-oxadiazolylalkyl, anthraquinone-2-carbonyl, pyrene-1-carbonyl, 5-(anthraquinone-2-carbonyl)amino-1-pentanyl, 5-(pyrene-1-carbonyl)amino-1-pentanyl, [[[2-(anthraquinone-2-carbonyl)amino]ethylamino]carbonyl]methyl, [[[2-pyrene-1-carbonyl)amino]ethylamino]carbonyl]methyl, and [5-pyrene-1-carbony
In another aspect, the present invention provides mixtures comprising at least six different chemical compounds having formula Q—[(Z)
n
—L]
m
preferably at least ten such compounds, more preferably at least 15. It is particularly preferred that such compounds be within 20 mole percent of equimolarity in the mixtures of the invention.
The present invention also provides methods for preparing combinatorial libraries. In preferred embodiments, these methods comprise the steps of reacting a cyclic scaffold moiety with at least one compound having formula L-X wherein L is as defined above and X is a leaving group.
DETAILED DESCRIPTION OF THE INVENTION
Cyclic moieties according to the invention are those in which one ring, or two or more rings are joined together to form an extended or condensed ring. Such systems include extended aromatic systems, alicyclic systems, araalicyclic systems, bicyclic systems and even spiro systems. Examples include aromatic, alicyclic and mixed aromatic-alicyclic (araalicyclic) multiple ring systems, spiro systems, bicyclic systems, non-aromatic multiple ring systems such as adamantane, decalin, steroids and terpenes, including sesquiterpenes, diterpenes, triterpenes and tetraterpenes, and multiple ring heterocyclic systems. Illustrative ring systems include, but are not limited to, naphthalene, tetrahydronaphthalene (tetralin), anthracene, phenanthrene, fluorene, pyrene, coronene, azulene, cluorene, benzonaphthene, benzo[8]annulene, pentalene, heptalane, octalene, indene, isoindene biphenyl, biphenylene and triphenylene condensed rings; spiropentane, spiro[2.4]heptane, spiro[4.5]decane, spiro[3.4]octane, dispiro[5.1.7.2]heptadecane spiro systems, bornane, norbornane, camphor, bicyclo[2.2.1]heptane, bicyclo[3.2.1]octane, 7-methylbicyclo[2.2.1]heptane and trans and cis-bicyclo[4.4.0]decane (trans and cis-decalin) bicyclic systems, carotenes, delta-3-carene, alpha-pinene, camphor, ascaridole, azulene, cadinene, beta-selinene, ambrein, beta-amyrin and lupeol terpenes; cholesterol, lanosterol, coprostanol, stigmasterol, ergosterol, calciferol, cholic acid, deoxycholic acid, estrone, estradiol, estratriol, progesterone, stilbestrol, testosterone, androsterone, deoxycorticosterone, cortisone and 17-hydroxycorticosterone steroids.
Heterocyclic moieties according to the invention are those which include aromatic systems, alicyclic systems, araalicyclic systems, bicyclic systems and even spiro systems. Examples include aromatic, alicyclic and mixed aromatic-alicyclic (araalicyclic) multiple ring systems, spiro systems, bicyclic systems, non-aromatic multiple ring systems such as adamantane, decalin, steroids and terpenes, including sesquiterpenes, diterpenes, triterpenes and tetraterpenes, and multiple ring heterocyclic systems.
A large number of heterocyclic species can be employed as scaffold molecules in the present invention. Such heterocycles can contain nitrogen, sulfur, oxygen, and/or other heteroatoms (i.e., atoms other than carbon) within a ring structure.
Illustrative oxygen-containing heterocycles include, but are not limited to, furan, 1,4-pyran, 1,2-dioxane, 1,3-dioxane, oxepin, 1,3,5,7-tetraoxocane and 1,4,8,11-tetraoxacyclotetradecane. Illustrative sulfur-containing heterocycles include, but are not limited to thiophene, thiepine, 1,4-thiazepine. Illustrative mixed heterocycles include, but are not limited to, 1,2,3-oxathiole, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,

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