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US 6,552,025 B1Granted
Diimino-piperazine derivatives for use as modulators of cell regulation
AssigneeEmory University
InventorsAlfred H. Merrill, Jr., Lisa Warden, Dennis C. Liotta
Life of this patent
Estimating the term…
Abstract
Compositions, methods of use, isolation and biosynthesis of diimino-piperazine derivatives useful for the modification of sphingolipid metabolism and other biological functions are described. The preferred derivative is 2,6-bis-(ω-aminobutyl)-3,5-diimino-piperazine. This is a naturally occurring biochemical compound isolated from cells. The diimino-piperazine derivatives are useful as therapeutic agents when administered to patients to treat diseases and disorders involving cell regulation.
Claims11
A composition comprising a diimino compound that inhibits, in a cationic form, sphingolipid metabolism;
- wherein the diimino compound has a molecular weight between 112 and 3000 Daltons;
- and wherein the diimino compound has the following structural formula:
- wherein
- R is independently H, alkyl, aryl, heteroaryl, —C(O)R, —C(NR)OR, —C(O)NR2, —C(NR)NR2, —C(NR)SR or —C(S)NR2;
- R1, R2, R3 and R4 are independently H, R, (CH2)nOR, (CH2)nNR2, CH2O(CH2)nOR, or CH2O(CH2)nNR2
- where n=1 to 6;
- and
- wherein H+ or other cationic species can form an association between any electronegative atom of the diimino compound;
- and
- wherein the term alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, typically of C1 to C18 and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl;
- and
- wherein the alkyl group can be optionally substituted with one or more moieties selected from halo, hydroxyl, carboxylic acid or ester, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected;
- and
- wherein the term aryl refers to phenyl, biphenyl, or naphthyl, and
- wherein the aryl group can be optionally substituted with one or more moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected, or protected;
- and
- wherein the aryl group can be substituted with an alkyl group as described above, and/or a halo group;
- and
- wherein the term heteroaryl refers to a cyclic moiety that includes at least one sulfur, oxygen, or nitrogen in the ring, including, but not limited to, furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl;
- and
- wherein the oxygen and nitrogen groups on the heteroaryl group can be protected or unprotected;
- and
- wherein the heteroaryl can be substituted with an alkyl group as described above;
- and,
- wherein the term “protected” refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction, or for other purposes;
- and wherein suitable protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and triisopropylsilyl.
23 more elements
A method of inhibiting sphingolipid metabolism associated with a cell signaling pathway disease or disorder, comprising administering to a patient having the disease or disorder, a therapeutic dose of a composition comprising a diimino compound in a cationic form;
- wherein the diimino compound has a molecular weight between 112 and 3000 Daltons;
- and wherein the diimino compound has the following structural formula:
- wherein
- R is independently H, alkyl, aryl, heteroaryl, —C(O)R, —C(NR)OR, —C(O)NR2, —C(NR)NR2, —C(NR)SR or —C(S)NR2;
- R1, R2, R3 and R4 are independently H, R, (CH2)nOR, (CH2)nNR2, CH2O(CH2)nOR, or CH2O(CH2)nNR2
- where n=1 to 6;
- and
- wherein H+ or other cationic species can form an association between any electronegative atom of the diimino compound;
- and
- wherein the term alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, typically of C1 to C18 and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl;
- and
- wherein the alkyl group can be optionally substituted with one or more moieties selected from halo, hydroxyl, carboxylic acid or ester, amino, alkylamino, arylamino, alkoxy, aryloxy, vitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected or protected;
- and
- wherein the term aryl refers to phenyl, biphenyl, or naphthyl, and
- wherein the aryl group can be optionally substituted with one or more moieties selected from the group consisting of halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, either unprotected, or protected;
- and
- wherein the aryl group can be substituted with an alkyl group as described above, and/or a halo group;
- and
- wherein the term heteroaryl refers to a cyclic moiety that includes at least one sulfur, oxygen, or nitrogen in the ring, including, but not limited to, furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl;
- and
- wherein the oxygen and nitrogen groups on the heteroaryl group can be protected or unprotected;
- and
- wherein the heteroaryl can be substituted with an alkyl group as described above;
- and
- wherein the term “protected” refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction, or for other purposes;
- and wherein suitable protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and triisopropylsilyl.
23 more elements
Dependencies are inferred from the claim text.