US2013231275A1PendingUtilityA1
Aminiothiazoles and their uses
Est. expiryDec 12, 2027(~1.4 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 31/00A61P 31/04A61P 17/10A61P 17/02C07K 5/06139A61K 38/05A61K 38/00A61K 45/06C07D 417/04A61K 31/427C07D 417/14Y02A50/30
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Claims
Abstract
The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of diseases particularly bacterial infections.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula I:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof;
wherein
R 1 is —Z—CO 2 H and -A-Z—CO 2 H;
R 1a is hydrogen, —Z—CO 2 H, and -A-Z—CO 2 H, wherein if R 1a is hydrogen, then the Z residue of R 1 is substituted by at least two CO 2 H groups; or
R 1 and R 1a , taken in combination, form a saturated, partially unsaturated or aromatic heterocycle having 4 to 7 ring atoms and having 0-3 additional ring heteroatoms selected from N, O and S, wherein the heterocycle is substituted by at least two residues independently selected from CO 2 H, —Z—CO 2 H, and -A-Z—CO 2 H;
A is indepenendently selected at each occurrence from the group consisting of a —C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —C(H)═N—, —S(O) 2 N(R 8a )—, and —S(O)N(R 8a )—;
Z is C 1 -C 10 alkylene, C 3 -C 8 cycloalkylene, C 3 -C 8 heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, each of which is optionally substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, amino, mono- and di-C 1 -C 6 alkylamino, C(O)OH, or halogen;
R 2a is selected from the group consisting of H, substituted or unsubstituted alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ;
R 2b is selected from the group consisting of absent, H and alkyl, or R 2a and R 2b may together form ═O or ═NH;
R 3 an R 12 are each, independently, selected from the group consisting of H, halogen, OR 4b , -A-J, and N(R 8a ) 2 ;
R 4a is selected from the group consisting of H, and alkyl;
R 4b is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
R 5 is selected from the group consisting of H, alkyl, and R 4b ;
J is selected from the group consisting of H, F, O-alkyl, N(R 8a ) 2 , N + (R 8a ) 3 , N(R 8a )C(O)alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CO 2 -alkyl, P(O)(OH) 2 , P(O)(O-alkyl) 2 , and a substituted nitrogen-containing heterocycle;
R 8a is absent, or selected from the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl) 2 -J, —R 4b , wherein R 8a can also cyclize with the atom to which R 8a is bonded to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times with substitutents that are the same or different; and
R 9 is selected from the group consisting of H, alkyl and CH 2 CO 2 H.
2 . The compound of claim 1 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .
3 . The compound of claim 1 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .
4 . The compound of claim 1 , wherein formula I is represented by a compound of formula II:
and pharmaceutically acceptable salts thereof.
5 . The compound of claim 1 , wherein formula I is represented by a compound of formula III:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof.
6 . The compound of claim 5 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .
7 . The compound of claim 5 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .
8 . The compound of claim 5 , wherein formula III is represented by a compound of formula IV:
9 . The compound of claim 8 , wherein
A is selected from the group consisting of —C(O)O—, C(O)—NH—, —C(O)—, —S(O) 2 —, and —S(O) 2 NH—; and Z is independently selected at each occurrence from the group consisting of C 1 -C 10 alkylene,
10 . The compound of claim 1 , wherein formula I is represented by a compound of formula V:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof, wherein
D represents a five or six membered heterocyclic ring which is saturated or aromatic, which ring comprises 0-2 additional ring heteroatoms selected from N, O or S.
11 . The compound of claim 10 , wherein R 2b , R 4b and R 5 are H, and R 4a is CH 3 .
12 . The compound of claim 10 , wherein R 2b , R 4b and R 5 are H, R 4a is CH 3 , and R 12 is CH 2 —O—CH 3 .
13 . The compound of claim 10 , wherein formula V is represented by a compound of formula VI:
14 . The compound of claim 13 , wherein
A is selected from the group consisting of —C(O)O—, C(O)—NH—, —C(O)—, —S(O) 2 —, and —S(O) 2 NH—; and Z is independently selected at each occurrence from the group consisting of C 1 -C 10 alkylene,
15 . The compound of claim 1 , wherein R 2a is OH or OAc.
16 . The compound of claim 1 , wherein the core pyridine functionality is of the following N-oxide formula:
17 . A compound selected from the group consisting of:
18 . A compound of formula VII:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, atropisomers or racemates thereof, including the pyridine N-oxide thereof;
wherein
R 1 is —Z—CO 2 H and -A-Z—CO 2 H;
R 1a is hydrogen, —Z—CO 2 H, and -A-Z—CO 2 H, wherein if R 1a is hydrogen, then the Z residue of R 1 is substituted by at least two CO 2 H groups; or
R 1 and R 1a , taken in combination, form a saturated, partially unsaturated or aromatic heterocycle having 4 to 7 ring atoms and having 0-3 additional ring heteroatoms selected from N, O and S, wherein the heterocycle is substituted by at least two residues independently selected from CO 2 H, —Z—CO 2 H, and -A-Z—CO 2 H;
A is indepenendently selected at each occurrence from the group consisting of a —C(O)—, —C(O)O—, —C(O)N(R 8a )—, —S(O) 2 —, —S(O)—, —C(H)═N—, —S(O) 2 N(R 8a )—, and —S(O)N(R 8a )—;
Z is C 1 -C 10 alkylene, C 3 -C 8 cycloalkylene, C 3 -C 8 heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, each of which is optionally substituted with one or more groups independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, amino, mono- and di-C 1 -C 6 alkylamino, C(O)OH, or halogen;
R 2 is hydrogen, C 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 0-6 alkyl, C 3-7 cycloalkylC 0-4 alkyl, arylC 0-4 alkyl, or a residue of the formula:
R 2a is selected from the group consisting of H, substituted or unsubstituted alkyl, OH, OR 4a , OC(O)R 4a , OC(O)N(R 8a ) 2 and N(R 8a ) 2 ;
R 2b is selected from the group consisting of absent, H and alkyl, or R 2a and R 2b may together form ═O or ═NH;
R 3 an R 12 are each, independently, selected from the group consisting of H, halogen, OR 4b , -A-J, and N(R 8a ) 2 ;
R 4a is selected from the group consisting of H, and alkyl;
R 4b is selected from the group consisting of alkyl and —(CH 2 —CH 2 —O—) n —R 9 , wherein n is an integer of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000 or is a mean of a plurality of integers having a value of 1-500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, or 60,000;
R 5 is selected from the group consisting of H, alkyl, and R 4b ;
J is selected from the group consisting of H, F, O-alkyl, N(R 8a ) 2 , N + (R 8a ) 3 , N(R 8a )C(O)alkyl, CO 2 H, C(═O)N(R 8a ) 2 , CO 2 -alkyl, P(O)(OH) 2 , P(O)(O-alkyl) 2 , and a substituted nitrogen-containing heterocycle;
R 8a is absent, or selected from the group consisting of H, -(alkyl)-, -(cycloalkyl)-, C(alkyl) 2 -J, —R 4b , wherein R 8a can also cyclize with the atom to which R 8a is bonded to form a 3, 4, 5, 6 or 7-membered ring that is aromatic or non-aromatic and may contain one or more heteroatoms, wherein the ring may be further substituted one or more times with substitutents that are the same or different; and
R 9 is selected from the group consisting of H, alkyl and CH 2 CO 2 H.
19 . A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of claim 1 , such that the bacterial infection is treated.
20 . A method of treating an EF-Tu associated-state comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of claim 1 , such that the EF-Tu associated state is treated.
21 . A method of treating, inhibiting or preventing the activity of EF-Tu in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of claim 1 .
22 . The method of claim 20 , wherein a bacterial infection is treated in a subject in need thereof.
23 . A method of treating, inhibiting or preventing the activity of bacteria in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of claim 1 , wherein the compound interacts with any target in the life cycle of the bacteria.
24 . The method of claim 22 , wherein the target is EF-Tu.
25 . A method of treating a bacterial infection in a subject, comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound of claim 1 , and a pharmaceutically acceptable carrier, such that the bacterial infection is treated.
26 . A method of treating a bacterial infection comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of claims 1 , in combination with a pharmaceutically effective amount of an additional therapeutic agent, such that the bacterial infection is treated.
27 . The method of claim 25 , wherein the compound of 1 and the other pharmaceutical agent are administered as part of the same pharmaceutical composition.
28 . The method of claim 25 , wherein the compound of claim 1 and the other therapeutic agent are administered as separate pharmaceutical compositions, and the compound is administered prior to, at the same time as, or following administration of the other agent.
29 . A packaged bacterial infection treatment, comprising a compound of claim 1 , packaged with instructions for using an effective amount of the compound to treat a bacterial infection.
30 . A method of treating acne in subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of a compound of claim 1 .
31 . A pharmaceutical composition comprising a compound of claim 1 , and at least one pharmaceutically acceptable carrier or diluent.
32 . The compound of claim 1 , or a salt thereof, which is selected from the group consisting ofCited by (0)
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