4195
J . Med. Chem. 1994,37, 4195-4210
7-Azetidinylquinolones as Antibacterial Agents. 2.l Synthesis and Biological Activity of 7-(2,3-Disubstituted-l-azetidinyl)-4-oxoquinolineand -1,8-naphthyridine-3-carboxylic Acids. Properties and Structure-Activity Relationships of Quinolones with an Azetidine Moiety2 Jordi Frigola,* Antoni Torrens, Jose A. Castrillo, Josep Mas, David Vafi6, Juana M. Berrocal, Carme Calvet, Leonard0 Salgado, Jordi Redondo, Santiago Garcia-Granda,+Eduard Valenti, and Jordi R. Quintana Department of Medicinal Chemistry, Laboratorios Dr. Esteve, S. A., Av.Mare de Dku de Montserrat, 221, 08041-Barcelona, Spain, and Department of Physical Chemistry, Universidad de Oviedo, c I Julicin Claveria, s I n, 33006-Oviedo, Spain Received June 20, 1994@
A series of 7-(2,3-disubstituted-l-azetidinyl)-1,4-dihydro-6-fluoro-4-oxoquinolineand -1,8naphthyridine-3-carboxylicacids, with varied substituents at the 1-,5-, and 8-positions, was prepared to study the effects on potency and physicochemical properties of the substituent a t position 2 of the azetidine moiety. The activity of the title compounds was determined in vitro against Gram-positive and Gram-negative bacteria, and the in vivo efficacy of selected derivatives was determined using a mouse infection model. The X-ray crystal structures of 6b, 6c, and 6d were found to be in reasonable agreement with the corresponding AM1 calculated geometries. Correlations between antibacterial potency of all the synthesized 7-azetidinylquinolones and naphthyridines and their calculated electronic properties and experimental capacity factors were established. Antibacterial efficacy and pharmacokinetic and physicochemical properties of selected derivatives were compared to the relevant 7-(3-amino-l-azetidinyl) and 7-(3-amino-3-methyl-l-azetidinyl) analogues (for Part 1, see: J. Med. Chem. 1993,36, 801810). A combination of a cyclopropyl or a substituted phenyl group at N-1 and a trans-3amino-2-methyl-1-azetidinyl group at C-7 conferred the best overall antibacterial, pharmacokinetic, and physicochemical properties to the azetidinylquinolones studied. Quinolonecarboxylic acids constitute a class of extremely potent and orally active broad-spectrum antibacterial agent^.^ Most of these agents are substituted a t the 7-position by cyclic aliphatic amines, especially diamines. Norfloxacin (la),4characterized by having a piperazine moiety a t C-7, is generally considered as the first fluoroquinolone noted for significant increases in activity relative to its predecessors. Ciprofloxacin5 (lb),incorporating a cyclopropyl group, also contains a piperazine at C-7. More recently, this piperazine group has been successfully replaced with 34ethylamino)methylpyrrolidine or 3-amin~pyrrolidine~ and with 3-(aminomethy1)-3-methylpyrrolidine.' Various combinations of functionalities at C-1 and C-8 led to a number of quinolones substituted at C-7 with a 3-aminopyrrolidine group, such as tosufloxacins (2a) and clinafloxacing (2b). Other diamines such as the 3-methyl- and 3,5-dimethylpiperazinyl7-substitutedquinolones, lomefloxacinlO (3) and sparfloxacinl1(4), with enhanced in vivo properties, were brought into the market. N-l-tertButylnaphthyridines substituted at C-7 with a 2-methylpiperazine have been claimed to have better in vitro antibacterial activity than when substituted with a 3-methy1~iperazine.l~ As part of an ongoing research project in the quest for novel quinolones to improve the spectrum of activity, we have been preparing several quinolone C-7 structural analogues. These investigations led to a series of compounds substituted at the 7-position with azoles such as pyrrole (irloxacin13),or 4-methylimidazole (E+ @
Universidad de Oviedo. Abstract published in Advance ACS Abstmcts, October 15, 1994.
Chart 1
F
J
y
R,
y
H
1 R,
R,
A
R,
R,
la
ethyl
CH
H
1-piperainy1
1b
cyclopropyl
CH
H
1-piperazinyl
2a
2,4-difluorophenyl N
H
3-amino-1-pyrrolidinyl
2b
cyclopropyl
CCI
H
3-amino-1-pyrrolidinyl
3
ethyl
CF
H
3-amino-1-pynolidinyl
4
cyclopropyl
CF
NH,
3,5-dimethyl-l -piperainy1
434514) and a series of (imidazoly1)phenylmethyl substituents attached to the 7-position via a carbon-carbon bond.15 More recently, we have invested considerable effort into those C-7 groups bearing a 3-monosubstituted- and 3,3-disubstituted azetidine.l This latter series showed broad-spectrum activity, particularly against Gram-positive organisms, improved in vivo efficacy, and high blood levels in the mouse. 8-Chloro1-cyclopropylquinolones5a-b, 1-(2,4-difluorophenyl)naphthyridine 5c, and 8-chloro-l-(2,4-difluorophenyl)quinolones 5d and 6a exhibited the best overall microbiological profile. Since our previous efforts had proven that 3-aminoazetidines or 3-amino-3-methylazetidines were excel-
0022-262319411837-4195$04.50/00 1994 American Chemical Society
Frigola et al.
4196 Journal of Medicinal Chemistry, 1994, Vol. 37, No. 24
Chart 2 0
0
I
4 Rl
A
R,,
A
R,,
Sa
c-C~H,
cc1
H
CCI
NHMe
Sb
c-C,H,
CCI
Me
CH
H
5c
2,4-F,Ph
N
H
CF
H
Sd
2,4-FJ'h
CCI
Me
CH
NHEt
Scheme 1 Ph
\
R2
I
KOH
OH
7
PhAPh
0
lent replacements for the standard piperazine moiety or aminopyrrolidine moiety, our attention then shifted t o 2-substituted azetidines, in order to investigate what effect alkyl groups on position 2 of the 3-aminoazetidine ring have on the overall antibacterial potency of the molecules. The effect of two methyl groups on the 3-aminoazetidine ring was also worthy of exploration because of the increase of steric bulk and the presumed lipophilicity increase. The role that positional isomers might play on the solubility of 7-azetidinylquinolones was of particular interest, as solubility was found to be isomer-dependent for methyl-substituted pyrrolidine ring quin~lones.~ In this study, we have focused on a series of 2,3-disubstituted azetidines and several 2,2,3and 2,3,3-trisubstituted azetidines as 7-position substituents on the quinolone and naphthyridine nucleus. We report the synthesis, physicochemical properties, and antibacterial activity of this series of compounds as well as in vivo efficacy and pharmacokinetic properties in mice of several of these agents. We also have carried out the single-crystal X-ray analysis of compounds 6b-d in order to know the solid-state conformation of azetidinyl quinolones. A comparison of A M 1 derived geometrical parameters with the experimental X-ray parameters was acceptable thus providing validation for theoretical calculations. We also report here the results of an extensive quantitative structureactivity relationships2 study for the azetidinyl quinolones, including those previously published1 and the new quinolones reported in this article, and we try to rationalize these results discussing how these structureactivity relationships hold qualitatively as the substituents change at other positions of the quinolone nucleus.
-
9
loa 1Od
Table 1. Azetidine Nucleus
compd 10a 10b 1oc 10d 10e 18f 18g 18h 18i 18j 18k 181 18m 18n 180
18P 1%
isomerism
trans cis cis
trans trans cis cis
trans trans trans trans trans trans trans trans
R1 Me H H Me Me Me H H Me Me Me Me Me Me Me Me Me
R2
R3
H Me Et H Me H Me Et Me H H H H H H H H
H H H Me H H H H H Me H H H H H
H H
Nu OH OH OH OH OH NHz NHz NHz NHz NH2 NHMe NMez CHzNHz CHzNHEt CN CHzNHCOCF3 CHzN(Et)COCF3
Chemistry The 2,3-disubstituted72,2,3-trisubstituted9and 2,3,3trisubstituted aminoazetidines used in this study are new compounds that we have prepared in our laboratories.16 3-Azetidinols are key compounds in 3-aminoazetidines synthesis. Most 3-azetidinols 10 (Table 1) have been synthesized in good yields from the corresponding a-hydroxyalkene 7 (Scheme 1)via a common methodology involving generation of epoxide 9, opening of the epoxide with benzhydrylamine 11,and cyclization,
Journal of Medicinal Chemistry, 1994, Vol. 37, No. 24
7-Azetidinylquinolones as Antibacterial Agents
A
Ph 12
A
Ph
-
R,
I
,
NU
MrO
Ho+&?h Ph
R,
I
Ph
1s
14
Scheme 3
I
Ph
P hAPh
13
'"'
4197
H, ___*
Nu
Pd(OH),/C
N h-
Ph
R,
/
10
Ph
L 17
Scheme 4
Solvent
___* Base, A
R,
-
196 ISn
20
21 - 4 7
X = F, CI (See Tables I1 and Ill for Structures)
following, with E ight modifications, the procedure described by Gaertner.l' This reaction proceeds in a stereospecific way as described for trans-l-cyclohexyl2-methylazetidin-3-01,~~ thus differing from l-tert-butyl2-methylazetidin-3-01s which were obtained as two diastereomeric pairs.ln The synthesis of 2,2-dimethyl-l-(diphenylmethyl)azetidin-3-01 10e was not possible following the procedure mentioned above, because of the instability of the epoxide 9e at room temperature. The synthesis was carried out (Scheme 2) by bromination of the 3-methylbutanone tertiary carbon and substitution by benzhydrylamine to obtain 13, followed by bromination of the a-methyl and cyclization in basic medium to afford 15. The final step was achieved by reduction of ketone 15 with NaBH4 in good yield. An amino group, primary and secondary amines, as well as other nucleophiles were introduced at the 3-position of 1-benzhydrylazetidine by sequential methanesulfonate ester formation (16)and displacement with the nucleophiles to obtain 18 (Scheme 3). The methanesulfonyloxy substitution proceeded with stereospecific retention of configuration due t o the participation of the ring nitrogen via the l-azabicyclo[l.l.0lbutyl cation 17. Kinetic and stereochemical studiedg with
1-tert-but)-azeti8ine 3-tosylates and L cyclohexyl)-2phenylazetidine 3-mesylate have shown conclusively that reactions with nucleophiles proceed via a doubleinversion process, resulting in a net retention of configuration. NOE studies on compounds 10, 16, and 18 demonstrate unambiguously that nucleophilic displacements in 1-benzhydrylazetidines occur with retention of configuration. Some of the 3-aminoazetidines listed in Table 2 needed to be protected before displacement of the quinolone 'I-fluor0 group in order t o avoid reaction of the exocyclic amino group. Thus, the reaction of 18m with trifluoroacetic anhydride provided compound 18p in 82% yield. Removal of the benzhydryl group was achieved in all cases by protonation of the heterocyclic nitrogen atom, followed by hydrogenolysis over palladium hydroxide in ethanol. Following this procedure,20the corresponding salts 19a-n were obtained and could be condensed with the quinolone nuclei. Compounds 21a-n, 22a-n, 25i, and 21f-47f prepared for this study were synthesized as summarized in Scheme 4. The general method used for the preparation of 4-oxoquinolines, naphthyridines, and isothiazolopyridones 20 was adapted from synthetic routes previously reported.lIz1 The regiospecific nucleophilic aromatic
4198 Journal of Medicinal Chemistry, 1994, Vol. 37, No. 24
Frigola et al.
Table 2. Synthetic and Physical Data of the Quinolone Antibacterials Prepared for This S t u d y
compd
A
R71
R72
R73
R74
mp, "C
analysesb
method (%yield)c
NMR, 6 (DMSO-&, TFA) CzHd CsH'
log k'
8.52 7.74 0.4068 H 239-242 OH 7.79 0.3299 8.58 H 236-240 OH 8.55 7.74 0.5288 H 250-255 OH 8.57 7.77 0.5993 Me 284-290 OH 0.0457 8.52 7.75 H 222-225 NHz 8.57 7.81 0.1708 H 236-237 NHz 0.1421 8.61 7.86 Me 269-272 21j NHz 7.85 0.1790 8.65 H 208-212 21k NHMe 8.64 7.90 0.6680 H 181-185 211 NMez -0.0607 8.58 7.81 H 222-227 21m CHzNHz -0.0042 7.73 8.49 219-225 CHzNHEt H 21n 0.5176 7.69 8.57 H 215-218 22a OH 0.4618 8.59 7.69 H 235-238 OH 22b 0.6791 7.65 8.58 H 259-261 22c OH 0.6899 7.68 8.59 Me 246-251 OH 22d 0.0813 8.57 7.69 H 215-218 22g NHz 0.1399 7.64 8.60 H 230-234 22h NHz 0.1903 8.56 7.64 H 214-216 22i NHz 0.1312 7.77 8.63 Me 265-268 22j NHz 0.2923 8.65 7.77 H 241-246 NHMe 22k 0.7694 7.75 8.61 H 149-151 NMez 221 -0.0397 8.51 7.69 H 196-203 CHzNHz 22m 0.0250 7.65 8.55 209-212 CHzNHEt H 22n -0.0223 7.95 8.53 H 190-195 25i NHz a Abbreviations: Me = methyl, Et = ethyl. C, H, and N analyses where within f 0 . 4 8 of the theoretical values, except as otherwise noted. Yields are those obtained from the coupling step to final product, including deprotections when appropriate. Singlet. e Doublet. 21a 21b 21c 21d 21g 21h
CH CH CH CH CH CH CH CH CH CH CH CF CF CF CF CF CF CF CF CF CF CF CF N
H Me Et H Me Et H H H H H H Me Et H Me Et Me H H H H H Me
Me H H Me H H Me Me Me Me Me Me H H Me H H Me Me Me Me Me Me Me
substitution at C-7 of 6,7-difluoroquinolones,6,7-difluoroisothiazoloquinolones, and 7-chloro-6-fluoro-naphthyridines 20 with the appropriate azetidine 19a-n (Scheme 4) proceeded smoothly a t temperatures between 80 "C and reflux conditions, according to the general procedures A and B, t o give compounds 2147. When a trifluoroacetylated intermediate was used, this protecting group was removed in the final step. Physical properties of compounds a-d and g-n and the structures of their substituents are summarized in Table 2, and physical properties of 74trans-3-amino-2methyl-1-azetidiny1)quinolonesfin Table 3. The %monoand 3,3-disubstituted (azetidiny1)quinolones 21B-Q, 22B-Q, 23E-49E, and 231-491, prepared as described previously,l are shown in Table 4.
X-ray Crystallographic Study Among the thousands of synthesized quinolones, only a few structures have been reported using X-ray crystallography, e.g., nalidixic acid,22oxolinic acid,23pipemidic acid,24 pefloxacin salts,25 sparfloxacin,ll and ofloxacin perchlorate.26 Concerning 7-azetidinylquinolones only 6b, 642, and 6d afforded suitable crystals for X-ray analysis. We have studied the crystal structure of these compounds to improve our understanding of the drug action of quinolones. The single-crystal X-ray structures of 6b, 6c, and 6d are shown in Figures 1-3, and the cell parameters and characteristics are described in Table 5 . The main structural features are summarized here.
H131
,?I731
Figure 1. Single-crystal X-ray structure of 6b.
The quinoline ring is almost planar for all three compounds. The cyclopropyl ring is out of the plane of the quinoline ring. The angle between the cyclopropyl and the quinoline least-square planes measures 126.3(4)" (6b), 123.8(1)"(6c),and 129.8(2)"(6d). The azetidine ring is slightly off the plane determined by the quinoline. The dihedral angle between the mean plane of this ring and the quinoline ring is 9.2(3)"(6b), 16.0and 12.5(3)"(6d). (1)" (6~1, The carboxylic group has a nonionic form in compounds 6b and 6c, which is characterized by the lack of substituents in the azetidine ring. An intramolecular hydrogen bond between the carboxylic and the carbonyl
Journal of Medicinal Chemistry, 1994, Vol.37,NO.24 4199
7-Azetidinylquinolones as Antibacterial Agents
Table 3. 7-~trans-3-Amino-3-methyl-1-azetidinyl)quinolones~
compd
21f 22f 23f 24f 25f 26f 27f 28f 29f 3of 31f 32f 33f 34f 35f 36f 37f 38f 39f 40f 41f 42f 43f 44f 45f 46f 47f a
A CH CF CF CC1 N CH CF CH CF
RI
C-CBHK c-CBH~ c-C~H~ c-C~H~ c-C~H~ c-C~H~ c-C~H~ CzH5 CzH5 cc1 CzH5 N CZH5 CH CH2CHzF CF CHzCHzF CC1 CHzCHzF N CHzCHzF CH t-C4Hg CF t-C4H9 N t-C4H9 CH 4-FPh CF 4-FPh CCl 4-FPh N 4-FPh CH 2,4-FzPh CF 2,4-FzPh CC1 2,4-FzPh N 2,4-FzPh CSCHzCHz -
Rz
R3
H OH H OH H OH H OH H OH -SNH-SNHH OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH H OH
R5
mp,"C
H H NHz H H H H H H H H H H H H H H H H H H H H H H H H
241-244 234 -237 206-210 226-230 213-218 264-267 268-270 232-235 215-217 230-232 212-215 215-220 222-224 232-236 268-271 225-227 263-266 223-225 235-239 223-229 245-247 239-244 203-205 200-204 182-186 220-222 192-195
method NMR, 6 (DMSO-&, "FA) (%yield)" C2Hd C5H'
analysesb
8.61 8.61 8.33 8.73 8.60
CI,HI~FNROR.~.~H~O
8.83 8.86 8.80 8.94 8.83 8.80 8.46 8.79 8.86 8.96 8.88 8.10 8.45 8.48 8.67 8.70 8.61 8.60 8.83 8.81
7.86 7.70 7.80 7.95 7.75 7.66 7.80 7.80 7.84 8.10 7.90 7.90 7.90 7.81 7.91 7.81 8.14 8.64 7.80 7.90 8.12 8.00 7.81 7.80 8.14 7.75
log k' -0.0132 0.0755 0.0828 0.1361 -0.0304 0.0650 0.1134 -0.0915 0.0145 0.1600 -0.1061 -0.1459 -0.1024 0.0166 -0.2166 0.1399 0.2616 0.1644 0.0755 0.1875 0.2581 0.0681 0.1875 0.2644 0.3553 0.1417 -0.1195
Abbreviations: c-C~HS = cyclopropyl, 2,4-FzPh = 2,4-difluorophenyl, t-C4H9 = tert-butyl, 4-FPh = 4-fluorophenyl. b-e See Table 2. r
HI31
H13:
Hl21
033
wFigure 3. Single-crystal X-ray structure of 6d. Figure 2. Single-crystal X-ray structure of 6c.
groups forms a pseudo-six-membered ring [6b, O(32)H(32) l.OO(5) A, 0(4)-H(32) 1.67(6)A, LO-H-0 142.0(5)";6 ~0(32)-H(32) , 1.08(3) A, 0(4)-H(32) 1.47(2) A, LO-H-0 163.4(2)"]. However, the amino acid 6d has a zwitterionic character exhibiting four intermolecular hydrogen bonds [N(75)-H(751) 1.01(6)A, H(751)-0(32) 1.73(5) A,H(751)-0(4) 2.66(5) A, N(75)-H(752) 1.03(5) A, H(752)-0(32) 2.10(6) A, H(752)-0(4) 1.94(5) AI as shown in the crystal structure (Figure 4). On the other hand, the plane determined by the carbonyl and the carboxylic acid group and the plane of the quinoline ring are both almost coincident for compounds 6b and 6c [1.8(8)" and 1.0(2)",respectively]. However, the angle
between these planes is 13.9(5)" for the zwitterionic compound 6d.
Results and Discussion In vitro antibacterial activity of the new compounds described in this paper was evaluated against a variety of Gram-positive and Gram-negative bacteria. These activities were determined by conventional agar dilution procedures, and the results of these assays are summarized in Table 6. Data for five Gram-positive and six Gram-negative bacteria are reported in the table as representative examples. The data for ciprofloxacin (lb) are included for comparison. When comparing data of trans-3-amino-2-methyl series f with those of cis-3-amino-2-methyl series g, it appears that cis compounds are 1-4 times less active
4200 Journal of Medicinal Chemistry, 1994, Vol.37,No.24
Frigola et al.
Table 4. 3-Substituted- and 3,3-Disub~tituted-l-azetidinylquinolones~~~
compd 21A
A CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CF CF CF CF CF CF CF CF CF CF CF CF CF CF CF CF CF CF CF
Ri R5 c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c-CQH~ H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c-CQH~ H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c-CQH~ H c-CQH~ H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~H c - C ~ H ~NH2 c-CRH~ NH2 C-C~HB H
R13 H OH OH OH NHz NHMe NHEt NMez NHz NHMe NMez CHzNHz CHzNHEt CHzNHz CHzNHEt +NMeZEtIH OH OH OH NHz NHMe NHEt NMez NHz NHMe NMez CHzNHz CHzNHEt CHzNHz CHzNHEt +NMe3IOH NHz
R74 H H Me Et H H H H Me Me Me H H Me Me H H H Me Et H H H H Me Me Me H H Me Me Me H H Me
logk' 0.7188 0.1906 0.2148 0.6222 -0.0607 0.0215 0.0844 0.4820 -0.1249 0.0875 0.5153 -0.1549 -0.1060 -0.0782 -0.0356
compd
R5 R73 R74 logk' H NHp H -0.0264 21B H H 0.1150 21c H 0.1061 Me 21D H H -0.0773 21E H H 0.4643 21F H Me -0.1606 21G H 0.0408 Me 21H H Me -0.1805 211 H Me -0.0757 215 H Me 0.1210 21K -0.2296 H Me 21N H Me 0.0374 210 Me -0.1871 H 21P H -0.0332 Me -0.1706 H Me 21Q 21Rc H Me 0.0294 22A H 0.9074 Me 0.3030 22B H 0.3264 Me 0.1751 22c 0.5451 H 0.0128 Me H 22D 0.7591 3t3J Me 0.2107 22E -0.0438 391 H -0.0223 Me 22F 0.0390 401 H Me 0.1106 22G 0.0996 H 411 0.2546 Me 22H -0.0388 0.5843 421 H Me -0.0177 0.0969 221 H Me 431 H 0.1055 441 0.2380 22J Me 22K 0.6039 45E 0.1280 H H 22N 0.2500 -0.1960 45F H H 220 0.3448 0.2742 451 H Me 0.0063 22P -0.0438 H H 46E H 0.0792 -0.0118 Me 461 22Q -0.1033 H 22s 48E NHz 23B 0.3487 481 0.0367 Me NHz -0.0505 0.1424 H 49E 23E NHz NHZ 0.0094 491 0.3189 231 Me NHz a Previously described compounds.' Abbreviations: c-CQH~ = cyclopropyl, 2,4-FzPh = 2,4-difluorophenyl, Me = methyl, Et = ethyl, t-C4Hg = tert-butyl, 4-FPh = 4-fluorophenyl. See the Experimental Section.
24E 24F 241 25F 25H 251 255 281 291 301 311 321 331 341 351 361 36J 371 381
A CC1 cc1 cc1 N N N N CH CF CCl N CH CF CCl N CH CH CF N N CH CF cc1 N CH CF CCl CCl CCl N N CF CF CF CF
RI C-CQHG c-C~H~ C-CQH~ c-C~H~ c-CQH~ c-C~H~ c-C~H~ CZH5 CZH5 CZH5 CZH5 CHzCHzF CHzCHzF CHzCHzF CHzCHzF t-C4Hg t-C4Hg t-C4Hg t-CdHg t-C4Hg 4-FPh 4-FPh 4-FPh 4-FPh 2,4-FzPh 2,4-FzPh 2,4-FzPh 2,4-FzPh 2,4-FzPh 2,4-FzPh 2,4-F2Ph CZH5 CZH6 2,4-FzPh 2,4-FzPh _
I
than trans compounds (21g vs 21f; 22g vs 220. Additidinylquinolones previously described.l In particular, tion of a methyl group to the truns-3-amino-2-methyl the 5-amino-8-fluoroquinolone 23f and 8-chloroquiseries (21f, 22f) to obtain either the r-3-amino-transnolone 24f showed an outstanding broad spectrum. 2,3-dimethyl derivatives (21j, 22j) or the 3-amino-2,2Quantitative Structure-Activity Relationghips. dimethyl derivatives (229 resulted in a significant Chemical structures of 116 compounds (those listed in overall decrease in activity. When a 2-methyl group was Tables 2-4, except 26f, 27f, 47f, 2lR, and 22s) included substituted by a 2-ethyl group in the azetidine ring, an in this paper were built using the molecular modeling overall decrease in activity was also observed (21g vs sofiware Chem-X,27and their structures were optimized 21h; 22g vs 22h). initially by molecular mechanics using the MM2-derived The l-cyclopropyl-7-(truns-3-amino-2-methyl-l-aze- force field within Chem-X, and later by semiempirical tidinyl) series 21f-25f proved to be two times more AM1 method28interfaced with Chem-X. The conformaactive in vitro than its 3-amino-l-azetidinyl21E-24E tion selected for each compound was that with the and 3-amino-3-methyl-1-azetidinyl 211-261 counterminimum energy in AM1, which coincided with the parts, respectively. Conversely, a different effect was X-ray structure for compounds 6b, 6c, and 6d. The ESP observed in the 1-(2,4-difluorophenyl) series; for inoption within the molecular orbital package MOPAC29 stance, 7-(truns-3-amino-2-methyl-l-azetidinyl)-8-chlo- was used to calculate the electrostatic potentials of the roquinolone 45f was 2-8 times less active than its compounds. A database containing experimental (ac3-amino-1-azetidinyl counterpart 45E.l tivities, capacity factors) and calculated (energetic, structural, electronic) parameters for all the compounds In summary, the in vitro activity of the f (truns-3was built within Chem-X and transferred to the SAS30 amino-2-methyl) series with an N-1 cyclopropyl group compares very favorably with ciprofloxacin (lb), and program package for statistical analysis. A principal with the 3-monosubstituted and 3,3-disubstituted azecomponent analysis was used to select Escherichia coli
7-Azetidinylquinolones as Antibacterial Agents
Journal of Medicinal Chemistry, 1994, Vol. 37, No. 24 4201
Table 5. Crystal and Refinement Parameters for Compounds 6b-d
6b (PYRP
6d (DMSO)"
6c (DMFY ~~
formula crystal habit crystal sizelmm symmetry unit cell determination
unit cell dimension aIA blA CIA ufdeg Pfdeg ddeg packing: VIA, z Ddg ~ m - M~ , ,F(000) F1cm-l
UA technique number of reflections measured independent observed
Ci6Hi~FNz03 colorless needles 0.20 x 0.10 x 0.07 monoclinic, P2dc (150 < e
