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- Nachgewiesen in: USPTO Patent Grants
- Sprachen: English
- Patent Number: 6,057,346
- Publication Date: May 02, 2000
- Appl. No: 08/353,765
- Application Filed: December 12, 1994
- Assignees: The United States of America as represented by the Department of Health and Human Services (Washington, DC)
- Claim: What is claimed is
- Claim: 1. A method of inhibiting the activity of an LTR promoter in a T cell comprising contacting said T cell containing an LTR promoter with an amount of a calcium response modifier compound effective to inhibit the activity of the LTR promoter where the calcium response modifier compound is selected from the group of calcium response modifier compounds with the formula: [equation included]
- Claim: wherein
- Claim: p is an integer of from 0 to 4;
- Claim: Ar.sup.1 and Ar.sup.2 are each aromatic moieties independently selected from the group consisting of phenyl, naphthyl, and substituted versions thereof;
- Claim: X is a linking moiety selected from the group consisting of O, S, SO.sub.2, CO, CHCN, straight chain alkyl, alkoxy, and alkosyalkyl;
- Claim: Y is a nitrogen-containing heterocyclic moiety selected from the group consisting of
- Claim: radicals of the formula ##STR6## wherein: A is N or CH;
- Claim: R.sup.1 is a member selected from the group consisting of hydrogen, --CONH.sub.2, --CONHR.sup.5, --CO.sub.2 H, --CO.sub.2 R.sup.5, and --SO.sub.2 NH.sub.2 ;
- Claim: R2 is a member selected from the group consisting of hydrogen, amino, --NHCOC.sub.6 H.sub.5, --NHCOR.sup.5, --NHCHO, --NHR.sup.5, and --N(R.sup.5).sub.2 ;
- Claim: R.sup.5 is a lower alkyl of from 1 to 6 carbon atoms, and
- Claim: (b) 1,2,4-triazolyl, pyrazinyl, purinyl, pyrimidinyl, 1,2,3-triazolo{4,5-d}-pyrimidinyl, and substituted versions thereof.
- Claim: 2. The method of claim 1 wherein the LTR promoter is an HIV LTR promoter.
- Claim: 3. The method of claim 2, wherein Y is a radical of formula (II), and A is N.
- Claim: 4. The method of claim 2, wherein Y is a radical of formula (II), A is N, and R.sup.1 is a member selected from the group consisting of hydrogen, --CONH.sub.2, --CONHR.sup.5, and --CO.sub.2 H.
- Claim: 5. The method of claim 2, wherein Y is a radical of formula (II), A is N, and R.sup.1 is --CONH.sub.2.
- Claim: 6. The method of claim 2, wherein Y is a radical of formula (II), A is N, R.sup.1 is --CONH.sub.2, and R.sup.2 is --NH.sub.2.
- Claim: 7. The method of claim 2, wherein p is an integer of from 0 to 2, Ar.sup.1 and Ar.sup.2 are both substituted phenyl, X is a linking moiety selected from the group consisting of O, CO, and CHCN, Y is a radical of formula (II), R.sup.1 is --CONH.sub.2, and R.sup.2 is --NH.sub.2.
- Claim: 8. The method of claim 2, wherein p is 1, Ar.sup.1 is 2,6-dichlorophenyl, Ar.sup.2 is 4-chlorophenyl, X is CO, Y is a radical of formula (II), A is N, R.sup.1 is --CONH.sub.2, and R.sup.2 is --NH.sub.2.
- Claim: 9. The method of claim 2, wherein p is 1, Ar.sup.1 is 2,6-dichlorophenyl, Ar.sup.2 is 4-chlorophenyl, X is CO, Y is a radical of formula (II), A is N, R.sup.1 is --CONH.sub.2, and R.sup.2 is --NHCHO.
- Claim: 10. The method of claim 2, wherein p is 1, Ar.sup.1 is 2,6-dichlorophenyl, Ar.sup.2 is 4-chlorophenyl, X is CO, Y is a radical of formula (II), A is N, R.sup.1 is --CONH.sub.2, and R.sup.2 is --NHCOCH.sub.3.
- Claim: 11. The method of claim 2, wherein p is 1, Ar.sup.1 is 2,6-dichlorophenyl, Ar.sup.2 is 4-chlorophenyl, X is CO, Y is a radical of formula (II), A is N, R.sup.1 is --CONH.sub.2, and R.sup.2 is --NHCOC.sub.6 H.sub.5.
- Claim: 12. The method of claim 2, wherein p is 1, Ar.sup.1 is 2,6-dichlorophenyl, Ar.sup.2 is 4-chlorophenyl, X is CO, Y is a radical of formula (II), A is N, R.sup.1 is --CONH.sub.2, and R.sup.2 is --NH.sub.2.
- Claim: 13. The method of claim 1, wherein said method suppresses the transition of an HIV virus from the latent to the lytic phase.
- Claim: 14. The method of claim 1, wherein said T cells are Jurkat T cells.
- Claim: 15. The method of claim 1, wherein said calcium response modifier compound is carboxyamidotriazole with the structure: ##STR7##
- Claim: 16. The method of claim 1, wherein said method further comprises inhibiting the invasion and metastasis of a malignant solid tumor.
- Claim: 17. The method of claim 1, wherein said method comprises inhibiting expression from the HIV LTR in vitro.
- Claim: 18. The method of claim 1, wherein said calcium response modifier compound is selected from the group of calcium response modifier compounds with the formula: wherein A is selected from the group consisting of N and CH, R.sup.1 is selected from the group consisting of carbamoyl, carboxyl and H, and R.sup.2 is selected from the group consisting of amino, formamido, acetamido, benzamido, and H.
- Claim: 19. The method of claim 18, wherein A is N, R.sup.1 is a carbamoyl, R.sup.2 is an amino and wherein an H is substituted for each Cl.
- Claim: 20. A method of claim 1 wherein the LTR promotor is introduced into the cell by a retrovirus.
- Claim: 21. A method of claim 1 wherein the LTR promoter is introduced into the cell by a DNA plasmid.
- Current U.S. Class: 514/359; 514/383; 514/398; 514/407; 514/396; 514/399; 514/255; 514/256; 514/258; 514/261
- Current International Class: A61K 3141; A01N 4364
- Patent References Cited: 4000197 December 1976 Barfknecht et al. ; 4289787 September 1981 Molloy et al. ; 5132315 July 1992 Kohn et al. ; 5359078 October 1994 Kohn et al.
- Other References: Horluism et al, 1991, Jap Infects Diseases vol. 164 pp. 53-60. ; Aaronson, Science 254:1146-1153 (1991). ; Berridge, et al., Nature 341:197-205 (1989). ; Chapron, et al., Biochem. Biophs. Res. Comm. 158:527-533 (1989). ; Chuvpilo et al. (1993) Nuc. Acids Res. 21(24): 5694-5704. ; Clark, et al., Cell. 65:1043-1051 (1991). ; Cole et al., Cancer Metastasis Rev. 13(1): 31-44 (1994). ; Felder, et al., J. Pharm. Exp. Therapeut. 257:967-971 (1991). ; Gusovsky, et al., J. Biol. Chem. 268:7768-7772 (1993). ; Hupe, et al., J. Biol. Chem. 266:10136-10142 (1991). ; Kohn, et al., J. Natl. Cancer Inst. 82:54-60 (1990). ; Kohn, et al., Cancer Res. 52:3208-3212 (1992). ; Lowenthal (1988) Proc. Natl. Acad. Sci. USA 85: 4468-4472. ; Masuda et al. (1993) Molecular and Cellular Biology 13(12): 7399-7407. ; Merritt, et al., J. Biol. Chem 271:515-522 (1990). ; Shaw, et al. (1988), Science 241: 202-205. ; Siekevitz et al., Science (1987) 238 (4833): 1575-1578. ; Tanaguchi, et al., J. Biol. Chem. 268:2277-2279 (1993). ; Arjona et al., "Sterochemistry of the reduction of the imino group. IV. Sterochemistry of the reduction of N-(1-phenylethyl)-1-alkyl-1-arylmethanimines," An. Quim. Ser. C 81(1):23-29 (1985). ; Freifelder, "Selective Hydrogenolysis. Dehalogenation in the Presence of N-Benzyl Linkage," J. Org. Chem. 31(11):3875-3877 (1966). ; Grethe et al., "Syntheses in the Isoquinoline Series. Synthesis of 2,3-Dihydro-4(1H)-isoquinolones," J. Org. Chem. 33(2):491-494 (1968). ; Hiroi et al., "A Highly Efficient and Recyclable Chiral Director for Asymmetric Synthesis of Sulfoxides," Chemistry Letters pp. 1595-1598 (1980). ; Hiroi et al., "Studies on Chiral Organo-Sulfur Compounds. I. Asymmetric Synthesis of Sulfoxides with Optically Active o-Aminoalkylphenol Derivatives," Chem. Pharm. Bull. 31:3471-3485 (1983). ; Kametani et al., "Studies on the Synthesis of Heterocyclic Compounds. Part 687. Asymmetric Synthesis of Salsolidine," J. Chem. Soc. Perkin Trans. 1 pp. 579-581 (1977). ; Kang et al., "Rhodium(I)-catalysed Asymmetric Hydrogenation of Imines," J. Chem. Soc. Chem. Commun. pp. 1466-1467 (1988). ; Kienzle et al., "1,5-Dihydroimidazoquinazolinones as blood platelet aggregation inhibitors," Eur. J. Med. Chem.--Chem. Ther. 17:547-556 (1982). ; Kozlov et al., "Reductive animation of 1-acetylcyclohexene by nitriles," Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk pp. 55-58 (1977. ; Mori et al., "Formic Acid Reduction. XI. Reduction of Schiff Bases," Chem. Pharm. Bull. 19:1722-1727 (1971). ; Standridge et al., "Phenylalkylamines with Potential Psychotherapeutic Utility. 1. 2-Amino-1-(2,5-dimethoxy-4-methylphenyl) butane," J. Med. Chem. 19:1400-1404 (1976). ; Standridge et al., "Phenylalkylamines with Potential Psychotherapeutic Utility. 2. Nuclear Substituted 2-Amino-1-phenylbutanes," J. Med. Chem. 22:154-162 (1980). ; Hashimoto et al., "Highly Diastereoselective Addition of Organometallic Reagents to Chiral Almines Derived from 1-(2-Methoxyphenyl) ethylamine," Synlett 9:961-962 (1995). ; Majewski and MacKinnon, "Enantioselective deprotonation of protected 4-hydroxycyclohexanones," Can. J. Chem. 72(7):1699-1704 (1994). ; Wang and Backvall, "Ruthenium-catalysed Transfer Hydrogenation of Imines by Propan-2-ol," J. Chem. Soc., Chem. Commun. pp. 980-982 (1992).
- Primary Examiner: Reamer, James H.
- Attorney, Agent or Firm: Townsend and Townsend and Crew
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