The present invention provides Dab 9 derivatives of amphomycin-type lipopepetide antibiotics that display antimicrobial activity against Gram-positive bacteria, methods and intermediates for synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of infections.
1. A compound having the formula:
wherein R is
R 1 is selected from (C 1 -C 25 ) alkyl, (C 1 -C 25 ) alkyl substituted with one or more of the same or different R 15 groups, (C 1 -C 25 ) heteroalkyl, (C 1 -C 25 ) heteroalkyl substituted with one or more of the same or different R 15 groups, (C 5 -C 10 ) aryl, (C 5 -C 10 ) aryl substituted with one or more of the same or different R 15 groups, (C 5 -C 15 ) arylaryl, (C 5 -C 15 ) arylaryl substituted with one or more of the same or different R 15 groups, (C 5 -C 15 ) biaryl, (C 5 -C 15 ) biaryl substituted with one or more of the same or different R 15 groups, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted with one or more of the same or different R 15 groups, (C 6 -C 26 ) arylalkyl, (C 6 -C 26 ) arylalkyl substituted with one or more of the same or different R 15 groups, 6-26 membered heteroarylalkyl, and 6-26 membered heteroarylalkyl substituted with one or more of the same or different R 15 groups;
each R 15 is independently selected from —OR 16 , —SR 16 , —NR 16 R 16 , —CN, —NO 2 , —N 3 , —C(O)OR 16 , —C(O)NR 16 R 16 , —C(S)NR 16 R 16 , —C(NR 16 )NR 16 R 16 , —CHO, —R 16 CO, —SO 2 R 16 , —SOR 16 , —PO(OR 16 ) 2 , —PO(OR 16 ), —CO 2 H, —SO 3 H, —PO 3 H, halogen, and trihalomethyl;
each R 16 is independently selected from hydrogen, (C 1 -C 6 ) alkyl, (C 5 -C 10 ) aryl, 5-10 membered heteroaryl, (C 6 -C 16 ) arylalkyl, and 6-16 membered heteroarylalkyl;
R 2 is OH or NH 2 ;
PG is a protecting group; and
R 6 ′ is independently selected from at least one amino acid, —X—R 10 —NR 7 —, and —X—(CR 11 R 11 ) n —NR 7 —, wherein:
X is —C(O)—, —C(O)O—, —C(NH)—, or —S(O) 2 —;
R 7 is hydrogen or (C 1 -C 4 ) alkyl;
R 10 is independently selected from —CH 2 —, —CH═CH—, —C≡C—, —O—, —S—, —NH—, —NH—NH—, —N═N—, —C(O)—, —S(O) 2 —, —S(O) 2 —O—, —C(NH)—, (C 1 -C 6 ) alkyldiyl, (C 1 -C 6 ) alkyleno, and (C 1 -C 6 ) alkano, wherein R 10 is optionally substituted with —NR 8 R 8 , —OR 8 , —SR 8 , halogen, trihalomethyl, —CN, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 8 , amidine, guanidine, alkyl optionally substituted with one or more of the same or different R 9 , aryl optionally substituted with one or more of the same or different R 9 , arylalkyl optionally substituted with one or more of the same or different R 9 , heteroalkyl optionally substituted with one or more of the same or different R 9 , and heteroarylalkyl optionally substituted with one or more of the same or different R 9 ;
each R 8 is independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; and
each R 9 is independently selected from —NR 8 R 8 , —OR 8 , —SR 8 , halogen, trihalomethyl, —CN, —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 8 , amidine, guanidine, alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
each R 11 is independently selected from hydrogen, amino, amido, amidino, carboxy, guandino, hydroxy, sulfanyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl substituted with one or more of the same or different R 12 , (C 5 -C 10 ) aryl, (C 5 -C 10 ) aryl substituted with one or more of the same or different R 12 , (C 6 -C 13 ) arylalkyl, (C 6 -C 13 ) arylalkyl substituted with one or more of the same or different R 12 , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted with one or more of the same or different R 12 , 6-13 membered heteroarylalkyl, and 6-13 membered heteroarylalkyl substituted with one or more of the same or different R 12 ;
each R 12 is independently selected from amino, amido, amidino, carboxyl, guanidino, hydroxy, and sulfanyl;
n is an integer from 1 to 6.
2. The compound of claim 1 , wherein R 6 ′ is —X—R 10 —NR 7 — or —X—(CR 11 R 11 ) n —NR 7 — and X is —C(O)—.
3. The compound of claim 1 , wherein R 6 ′ comprises an amino acid.
4. The compound of claim 3 , wherein R 6 ′ is an amino acid.
5. The compound of claim 4 , wherein R 6 ′ is β-alanyl.
6. A method of making the compound of claim 1 , the method comprising:
a) reacting a compound having the formula (A)
to add —R 6 ′—PG to form the compound of claim 1 .
7. The compound of claim 1 , wherein the protecting group PG is tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, or benzyloxycarbonyl.
8. The compound of claim 7 , wherein PG is 9-fluorenylmethoxycarbonyl.