RecA inhibitors with antibiotic activity, compositions and methods of use
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-049/00
C07H-019/16
A61K-038/00
A61K-045/06
A61K-038/12
C12Q-001/18
G01N-033/50
출원번호
US-0279243
(2007-02-13)
등록번호
US-9155792
(2015-10-13)
국제출원번호
PCT/US2007/003712
(2007-02-13)
§371/§102 date
20090227
(20090227)
국제공개번호
WO2007/097940
(2007-08-30)
발명자
/ 주소
Cottarel, Guillaume
Wierzbowski, Jamey
Pal, Kollol
Kohanski, Michael
Dwyer, Daniel
Collins, James
Almstetter, Michael
Thormann, Michael
Treml, Andreas
출원인 / 주소
Trustees of Boston University
대리인 / 주소
Nixon Peabody LLP
인용정보
피인용 횟수 :
0인용 특허 :
19
초록
The present invention is directed to the use of RecA inhibitors as antibiotic agents, and provides RecA inhibitors useful in treating infections. Also provided are various compositions and methods associated with RecA inhibition.
대표청구항▼
1. A pharmaceutical composition comprising a RecA inhibitor, and at least one physiologically acceptable carrier or excipient, wherein the composition further comprises at least one antibiotic and wherein the RecA inhibitor interacts directly with the RecA protein and wherein the RecA inhibitor is s
1. A pharmaceutical composition comprising a RecA inhibitor, and at least one physiologically acceptable carrier or excipient, wherein the composition further comprises at least one antibiotic and wherein the RecA inhibitor interacts directly with the RecA protein and wherein the RecA inhibitor is selected from the group consisting of: amentoflavone, hinokiflavone, isorhamnetin, maclurin, quercetagetin, quercetin dehydrate, 3,7,4′-trihydroxyflavone, theaflavin or a compound of formula (I) or formula (II) or pharmaceutical acceptable salts thereof or combinations thereof, wherein the compound of formula (I) has the following structure: wherein:X is oxygen, sulfur, or N(R);n is 0 to 4;R1 is hydrogen, or an optionally substituted group selected from a C1-6 aliphatic group, a monocyclic 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bicyclic 8-10 membered saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each R2 is independently halogen, R3, OR3, SR3, N(R3)2, C(O)R3, C(O)OR3, NR3C(O)R3, C(O)NR3, SO2R3 NR3SO2R3 SO2N(R3)2;each R3 is independently hydrogen or an optionally substituted group selected from a C1-6 aliphatic group, a monocyclic 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bicyclic 8-10 membered saturated, partially unsaturated, or aryl ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;Q is a valence bond or a bivalent, saturated or unsaturated, straight or branched C1-6 hydrocarbon chain, wherein 0-2 methylene units of Q are independently replaced by —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —SO—, —SO2—, —NRSO2—, —SO2NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, or —NRC(O)O—;each R is independently hydrogen or an optionally substituted aliphatic group;Rx is R or OR; andRing A is an optionally substituted 3-8 membered bivalent, saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; andwherein the compound of formula (II) has the following structure: wherein:Cy1 is a an optionally substituted 5-6 membered aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;L1 is a valence bond, a C1-6 bivalent saturated, unsaturated, straight or branched hydrocarbon chain, —N(R)—, —N(R)SO2—, —N(R)SO2N(R)—, —N(R)C(O)—, —C(O)N(R)—, or —N(R)C(O)N(R)—;each R is independently hydrogen or an optionally substituted C1-6 aliphatic group;Cy2 is an optionally substituted 6-membered aryl ring having 0-2 nitrogen atoms, an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;L2 is a C1-6 bivalent saturated, unsaturated, straight or branched hydrocarbon chain, —CH2CH2C(═W)N(R)N(R)C(═W)—, —N(R)C(═W)N(R)C(═W)C(R)2W—, —C(═W)N(R)N(R)C(═W)N(R)—, —C(═W)N(R)N(R)C(═W)N(R)CH═CH2, or —C(═W)N(R)C(═W)N(R)—, wherein each W is independently oxygen or sulfur; andCy3 is an optionally substituted 6-membered aryl ring having 0-2 nitrogen atoms. 2. The pharmaceutical composition of claim 1, wherein the antibiotic is a member of the group consisting of aminoglycosides, aminomethylcyclines, aminophenicols, ansamycins, β-lactams, carbapenems, dapsones, 2,4-diaminopyrimidines, glycopeptides, glycycyclines, ketolids, lincomycins, lincosamides, macrolides, nitrofurans, oxazolidinones, peptides, polymyxins, quinolones, rifabutins, streptogramins, sulfonamides, sulfones, tetracyclines, and combinations thereof. 3. The pharmaceutical composition of claim 1, wherein the RecA inhibitor binds to at least one binding site on the RecA protein. 4. The pharmaceutical composition of claim 1, wherein the RecA inhibitor competes with hinokiflavone for binding to the RecA protein. 5. The pharmaceutical composition of claim 1, wherein the RecA inhibitor binds to more than one binding site on the RecA protein. 6. The pharmaceutical composition of claim 1, wherein the RecA inhibitor inhibits at least one activity of RecA, wherein the RecA activity is a member of the group consisting of DNA binding, monomer interaction, helicase activity, filament formation, ATP binding, ATP hydrolysis, co-protease activity, recombinase activity, and replication function. 7. The pharmaceutical composition of claim 1, wherein the RecA inhibitor inhibits ATPase activity. 8. The pharmaceutical composition of claim 1, wherein the RecA inhibitor has a IC50 of less than about 100 μg/mL, less than about 50 μg/mL, less than about 15 μg/mL, less than about 10 μg/mL, less than about 5 μg/mL, less than about 3 μg/mL, or less than about 1 μg/mL. 9. The pharmaceutical composition of claim 1, wherein X is oxygen. 10. The pharmaceutical composition of claim 1, wherein R1 has the following structure: wherein each wavy line depicts the point of attachment to Q. 11. The pharmaceutical composition of claim 1, wherein R1 has the following structure: wherein each wavy line indicates the point of attachment to Q. 12. The pharmaceutical composition of claim 1, wherein R2 is selected from the group consisting of: OH, OMe, wherein each wavy line depicts the point of attachment. 13. The pharmaceutical composition of claim 1, wherein the RecA inhibitor has any one of the following structures:
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이 특허에 인용된 특허 (19)
Grohe Klaus (Odenthal DEX) Zeiler Hans-Joachim (Velbert DEX) Metzger Karl G. (Wuppertal DEX), 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid.
Studier F. William (Stony Brook NY) Davanloo Parichehre (Basel NY CHX) Rosenberg Alan H. (Setauket NY) Moffatt Barbara A. (East Lansing MI) Dunn John J. (Bellport NY), Cloning and expression of the gene for bacteriophage T7 RNA polymerase.
Shimamura Tadakatsu (4-4 ; Nishihara 1-chome ; Shibuya-ku Tokyo JPX), Method of preventing the transmission of infection caused by methicillin-resistant Staphylococcus aureus .
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