USRE40245EExpiredUtility
Gyrase inhibitors and uses thereof
Est. expiryDec 15, 2020(expired)· nominal 20-yr term from priority
C07D 409/04A61K 31/506A61K 45/06C07D 403/04C07D 233/56C07D 403/12C07D 401/12C07D 249/08C07D 403/14A61P 31/04C07D 235/30A61K 31/437A61K 31/423C07D 413/04A61P 43/00C07D 491/04C07D 471/14A61K 31/4709C07D 401/04A61K 31/00C07F 9/65583C07F 9/6561C07D 401/14A61P 31/00C07D 231/12A61K 31/55C07D 405/04A61K 31/4439C07D 263/58A61K 31/4184C07D 405/14A61K 31/5377C07D 471/04Y02A50/30
94
PatentIndex Score
36
Cited by
15
References
26
Claims
Abstract
The present invention relates to compounds of the formula I: or a pharmaceutically acceptable derivative or prodrug thereof. The compounds are useful as inhibitors of bacterial gyrase activity. The present invention also relates to methods for treating bacterial infections in mammala. The present invention also relates to methods for decreasing bacterial quantity in a biological sample.
Claims
exact text as granted — not AI-modified1. A compound of formula IIa or IIb:
or a pharmaceutically acceptable salt thereof, wherein:
W is nitrogen or CR a ;
R a is selected from hydrogen, halogen, —CF 3 , R 7 , —OR 7 , or —N(R 7 ) 2 ;
R 1 is an aryl or heteroaryl ring, wherein said ring is optionally substituted by up to four R 9 ; wherein an R 9 substituent in the ortho-position of R 1 taken together with R 2 may form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring having 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
R 2 and R 3 are each independently selected from R 6 , halogen, CN, SR 6 , OR 6 , N(R 6 ) 2 , NRCO 2 R 6 , NRCON (R 6 ) 2 , CON(R 6 ) 2 , NRCOR 6 , NRN(R 6 ) 2 , COR 6 , CO 2 R 6 , COCOR 6 , SO 2 R 6 , SO 2 N(R 6 ) 2 , or NRSO 2 R 6 ; or R 2 and R 3 are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
R 4 is selected from R 6 , CON(R 6 ), COR 6 , CO 2 R 6 , COCOR 6 , SO 2 R 6 , SO 2 N(R 6 ) 2 , or (CH 2 ) y R 2 ;
y is 1-6;
each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons;
Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO 2 , R 8 , OR 8 , NHR 8 , NHCOR 8 , NHCONHR 8 , COR 8 , CONHR 8 , SO 2 R 8 , NHSO 2 NHR 8 or SO 2 NHR 8 ;
each R 6 is independently selected from R 7 or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl heterocyclylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl heteroaryloxyalkyl;
each R 7 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R 7 on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms;
R 8 is a C 1 -C 4 aliphatic group, wherein two R 8 on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring ;
each R 9 is independently selected from oxo, halogen, CN, NO 2 , T n (haloalkyl), R 6 , SR 6 , OR 6 , OR 8 , N(R 6 ) 2 , CON (R 6 ) 2 , CON(R)COR 6 , COR 6 , CO 2 R 6 , CO 2 N(R 6 ) 2 , COCOR 6 , SO 2 R 6 , SO 2 N(R 6 ) 2 , N(R)T n CO 2 R 6 , N(R) T n CON(R 6 ) 2 , N(R)T n N(R 6 ) 2 , N(R)T n NRCO 2 R 6 , N(R) T n NRCON(R 6 ) 2 , N(R)T n COR 6 , N(R)T N NRCOR 6 N( R ) T n NRCOR 6 , N(R)T n SO 2 N(R 6 ) 2 , N(R)T n SO 2 R 6 , T n PO(OR 7 ) 2 , T n OPO(OR 7 ) 2 , T n SP(OR 7 ) 2 , T n PO(OR 7 ) 2 , or T n NPO (OR 7 ) 2 ;
each Q is an independently selected C 1 -C 3 branched or straight alkyl;
T is selected from —Q— or —Q m —CH(Q m —R 2 )—; and
each m and n are independently selected from zero or one.
2. The compound according to claim 1 , wherein said compound has one or more features selected from the group consisting of:
(a) R 1 is an optionally substituted aryl or heteroaryl ring;
(b) R 2 and R 3 are each independently selected from halogen, CN, CO 2 R 6 , OR 6 , or R 6 ; and
(c) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , N(R)T n CO 2 R 6 , N(R)T n NRCO 2 R 6 , N(R)T n N(R 6 ) 2 , NO 2 , T n (haloalkyl), CO 2 N(R 6 ) 2 , COR 6 , SO 2 R 6 , or SO 2 N(R 6 ) 2 .
3. The compound according to claim 2 , wherein:
(a) R 1 is an optionally substituted aryl or heteroaryl ring; (b) R 2 and R 3 are each independently selected from halogen, CN, CO 2 R 6 , OR 6 , or R 6 ; and (c) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , N(R)T n CO 2 R 6 , N(R)T n NRCO 2 R 6 , N(R)T n N(R 6 ) 2 , NO 2 , T n (haloalkyl), CO 2 N(R 6 ) 2 , COR 6 , SO 2 R 6 , or SO 2 N(R 6 ) 2 .
4. The compound according to claim 2 , wherein said compound has one or more features selected from the group consisting of:
(a) R 1 is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl;
(b) R 2 is hydrogen, alkoxy, aminoalkyl, or halogen;
(c) R 3 is hydrogen, alkoxy, aralkoxy, or halogen;
(d) R 4 is hydrogen or (CH 2 ) y R 2 ; and
(e) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , or N(R)T n CO 2 R 6 .
5. The compound according to claim 4 , wherein:
(a) R 1 is an optionally substituted ring selected from phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thienyl, pyrimidyl, imidazol-1-yl, imidazol-2-yl, pyrazol-1-yl, amino-pyrimidinyl, quinolinyl, aminobenzimidazole, or indolyl; (b) R 2 is hydrogen, alkoxy, aminoalkyl, or halogen; (c) R 3 is hydrogen, alkoxy, aralkoxy, or halogen; (d) R 4 is hydrogen or (CH 2 ) y R 2 ; and (e) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , or N(R)T n CO 2 R 6 .
6. A compound of formula IIIa or IIIb:
or a pharmaceutically acceptable salt thereof, wherein:
W is nitrogen or CR a ;
R a is selected from hydrogen, halogen, —CF 3 , R 7 , —OR 7 , or —N(R 7 ) 2 ;
Ring A is optionally substituted with up to three R 9 ; wherein when an R 9 substituent is in the ortho-position of Ring A, said R 9 substituent may be taken together with R 2 to form an optionally substituted 5-7 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
R 2 and R 3 are each independently selected from R 6 , halogen, CN, SR 6 , OR 6 , N(R 6 ) 2 , NRCO 2 R 6 , NRCON (R 6 ) 2 , CON(R 6 ) 2 , NRCOR 6 , NRN(R 6 ) 2 , COR 6 , CO 2 R 6 , COCOR 6 , SO 2 R 6 , SO 2 N(R 6 ) 2 , or NRSO 2 R 6 ; or R 2 and R 3 are taken together to form a fused, unsaturated or partially unsaturated, optionally substituted 5-8 membered ring containing 0-2 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
R 4 is selected from R 6 , CON(R 6 ), COR 6 , CO 2 R 6 , COCOR 6 , SO 2 R 6 , SO 2 N(R 6 ) 2 , or (CH 2 ) y R 2 ;
y is 1-6;
R 5 is selected from R 7 , Ar, COAr, CON(R 7 )Ar, CO 2 R , (CH 2 ) y CO 2 R, (CH 2 ) y N(R 7 ) 2 , C(═NR 10 )—N(R 7 ) 2 , C(═NR 10 )—NRCOR, C(═S)—N(R 7 ) 2 , CON(R 7 ) 2 , COR, SO 2 R, or SO 2 N(R 7 ) 2 ;
Ar is a five membered heteroaryl, heterocyclyl, or carbocyclyl ring, wherein said ring is optionally substituted by up to three substituents selected from oxo, halogen, CN, NO 2 , R 8 , OR 8 , NHR 8 , NHCOR 8 , NHCONHR 8 , COR 8 , CONHR 8 , SO 2 R 8 , NHSO 2 NHR 8 or SO 2 NHR 8 ;
each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons;
each R 6 is independently selected from R 7 or an optionally substituted group selected from alkoxy, hydroxyalkyl, heterocyclyl, heterocyclcylalkyl heterocyclylalkyl, aryl, aralkyl, aralkoxy, aryloxyalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy, or heteroarayloxyalkyl heteroaryloxyalkyl;
each R 7 is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons, or two R 7 on the same nitrogen taken together with the nitrogen optionally form a four to six member, saturated or unsaturated heterocyclic ring having one to three heteroatoms;
R 8 is a C 1 -C 4 aliphatic group, wherein two R 8 on adjacent positions of Ar, or an aryl or heteroaryl ring, may be taken together with their intervening atoms to form a three to six membered fused ring;
each R 9 is independently selected from oxo, halogen, CN, NO 2 , T n (haloalkyl), R 6 , SR 6 , OR 6 , OR 8 , N(R 6 ) 2 , CON (R 6 ) 2 , CON(R)COR 6 , COR 6 , CO 2 R 6 , CO 2 N(R 6 ) 2 , COCOR 6 , SO 2 R 6 , SO 2 N(R 6 ) 2 , N(R)T n CO 2 R 6 , N(R) T n CON(R 6 ) 2 , N(R)T n N(R 6 ) 2 , N(R)T n NRCO 2 R 6 , N(R) T n NRCON(R 6 ) 2 , N(R)T n COR 6 , N(R)T n NRCOR 6 , N(R)T n SO 2 N(R 6 ) 2 , N(R)T n SO 2 R 6 , T n PO(OR 7 ) 2 , T n OPO(OR 7 ) 2 , T nSP(OR 7 ) 2 T n SP ( OR 7 ) 2 , T n PO(OR 7 ) 2 , or T n NPO (OR 7 ) 2 ;
each Q is an independently selected C 1 -C 3 branched or straight alkyl;
T is selected from —Q— or —Q m —CH(Q m —R 2 )—;
each m and n are independently selected from zero or one; and R 10 is selected from R 7 or Ar.
7. The compound according to claim 6 , wherein said compound has one or more features selected from the group consisting of:
(a) R 2 and R 3 are each independently selected from halogen, CN, CO 2 R 6 , OR 6 , or R 6 ;
(b) R 5 is CO 2 R, COAr, COR, CON(R 7 ) 2 , Ar, (CH 2 ) y CO 2 R, or (CH 2 ) y N(R 7 ) 2 ; and
(c) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , N(R)T n CO 2 R 6 , N(R)T n NRCO 2 R 6 , N(R)T n N(R 6 ) 2 , NO 2 , T n (haloalkyl), CO 2 N(R 6 ) 2 , COR 6 , SO 2 R 6 , or SO 2 N(R 6 ) 2 .
8. The compound according to claim 7 , wherein:
(a) R 2 and R 3 are each independently selected from halogen, CN, CO 2 R 6 , OR 6 , or R 6 ; (b) R 5 is CO 2 R, COAr, COR, CON(R 7 ) 2 , Ar, (CH 2 ) CO2 R, or (CH 2 ) y N(R 7 ) 2 ; and (c) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , N(R)T n CO 2 R 6 , N(R)T n NRCO 2 R 6 , N(R)T n N(R 6 ) 2 , NO 2 , T n (haloalkyl), CO 2 N(R 6 ) 2 , COR 6 , SO 2 R 6 , or SO 2 N(R 6 ) 2 .
9. The compound according to claim 7 , wherein said compound has one or more features selected from the group consisting of:
(a) R 2 is hydrogen, alkoxy, aminoalkyl, or halogen;
(b) R 3 is hydrogen, alkoxy, aralkoxy, or halogen;
(c) R 4 is hydrogen or (CH 2 ) y R 2 ;
(d) R 5 is CON(R 7 ) 2 , Ar, (CH 2 ) y CO 2 R, or (CH 2 ) y N(R 7 ) 2 ; and
(e) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , or N(R)T n CO 2 R 6 .
10. The compound according to claim 9 , wherein:
(a) R 2 is hydrogen, alkoxy, aminoalkyl, or halogen; (b) R 3 is hydrogen, alkoxy, aralkoxy, or halogen; (c) R 4 is hydrogen or (CH 2 ) y R 2 ; (d) R 5 is CON(R 7 ) 2 , Ar, (CH 2 ) y CO 2 R, or (CH 2 ) y N(R 7 ) 2 ; and (e) R 9 is halogen, CN, oxo, R 6 , SR 6 , OR 6 , N(R 6 ) 2 , CON(R 6 ) 2 , CO 2 R 6 , CON(R)COR 6 , or N(R)T n CO 2 R 6 .
11. A compound selected from the group consisting of:
No. Ia- Structure 20 21 22 25 28 29 33 35 37 38 39 40 — — 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 68 69 70 72 76 77 80 83 84 86 88 89 91 92 93 94 98 99 100 102 103 104 105 106 107 108 109 110 111 112 113 116 117 118 119 120 121 — — 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 and 200
12. A compound selected from the group consisting of:
No. Ib- Structure 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 20 21 22 23 24 25 26 27 and 28
13. A composition comprising an effective amount of a compound according to any one of claims 1 to 10 1 - 2 , 4 , 6 - 7 and 9 , and a pharmaceutically acceptable carrier.
14. A composition according to claim 13 , wherein said compound is formulated in a pharmaceutically acceptable manner for administration to a patient.
15. The composition according to claim 13 further comprising an additional therapeutic agent selected from an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.
16. The composition according to claim 14 further comprising an additional therapeutic agent selected from an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound.
17. The composition according to claim 13 further comprising an agent that increases the susceptibility of bacterial organisms to antibiotics.
18. The composition according to claim 15 further comprising an agent that increases the susceptibility of bacterial organisms to antibiotics.
19. A method of decreasing Staphylococcus aureus, E. faecalis, or S. pneumoniae bacterial quantity in a biological sample comprising the step of contacting said biological sample with a compound according to either of claims 1 or 6 .
20. The method according to claim 19 further comprising the step of contacting said biological sample with an agent which increases the susceptibility of bacterial organisms to antibiotics.
21. A method of inhibiting gyrase Staphylococcus aureus, E. faecalis, or S. pneumoniae in a mammal, comprising the step of administering to said mammal a composition according to claim 13 .
22. A method of treating a Staphylococcus aureus, E. faecalis, or an S. pneumoniae bacterial infection in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of a composition according to claim 13 .
23. The method according to claim 22 , wherein the bacterial infection to be treated is characterized by the presence of one or more of the following: Streptococcus pneumoniae, Streptococcus pyrogenes, Enterococcus fecalis, Enterococcus faecium, Klebsiella pneumoniae, Enterobacter sps. Proteus sps. Pseudomonas aeruginosa, E. coli, Serratia marcesens, S. aureus, or Coag. Neg. Staph.
24. The method according to claim 22 , wherein the bacterial infection to be treated is selected from one or more of the following: urinary tract infections, pneumonia, prostatitis skin, and soft tissue infections, intra-abdominal infections, or infections of febrile neutropenic patients.
25. The method according to claim 22 further comprising the step of administering to said patient an antibiotic, an anti-inflammatory agent, a matrix metalloprotease inhibitor, a lipoxygenase inhibitor, a cytokine antagonist, an immunosuppressant, an anti-cancer agent, an anti-viral agent, a cytokine, a growth factor, an immunomodulator, a prostaglandin or an anti-vascular hyperproliferation compound, either as part of a multiple dosage form together with said compound or as a separate dosage form.
26. The method according to claim 22 further comprising the step of administering to said patient an agent that increases the susceptibility of bacterial organisms to antibiotics.Cited by (0)
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