Syntheses of new isodethiaazacephems and...

Details Syntheses of new isodethiaazacephems and... Syntheses of new isodethiaazacephems and...

1999-05-12

2002-02-19

Berch, Mark L (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S205000, C540S364000

Reexamination Certificate

active

06348454

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to syntheses of novel isodethiaazacephems and isodethiaazacephams, and their use as an potent antibacterial agent, and in particular isodethiaazacephems and isodethiaazacephams having an effective leaving group which can undergo an enzyme-initiated elimination process, so that the antibacterial activity thereof can be enhanced.
BACKGROUND OF THE INVENTION
&bgr;-Lactam antibiotics exert certain biological activity by acylating serine residues of transpeptidases so that the cross-linking of peptidoglycans does not take place [Waxman, D. J.; Strominger, J. L. Sequence of Active Site Peptides from the Penicillin-sensitive D-Alanine Carboxypeptidase of
Bacillus Subtilis. J. Biol. Chem
. 1980, 255, 3964-3976; FrËre, J. M.; Nguyen-DistËche, M.; Coyette, J.; Joris, B. Mode of Action: Interaction with the Penicillin Binding Proteins. In
The Chemistry of &bgr;-Lactams
; Page, M. I., Ed.; Blackie Academic & Professional: New York, 1992; pp 148-197]. As shown in Scheme 1, ring opening of the &bgr;-lactam nucleus would occur when cephalosporins (1) react with enzymes responsible for the cell wall synthesis of bacteria. Consequently, the substituent at the C-3′ position is liberated [Boyd, D. B. Elucidating the Leaving Group Effect in the &bgr;-Lactam Ring Opening Mechanism of Cephalosporins.
J. Org. Chem
. 1985, 50, 886-888; Boyd, D. B.; Lunn, W. H. W. Electronic Structures of Cephalosporins and Penicillins. 9. Departure of a Leaving Group in Cephalosporins.
J. Med. Chem
. 1979, 22, 778-784; Faraci, W. S.; Pratt, R. F. Elimination of a Good Leaving Group from the 3′-Position of a Cephalosporin Need Not Be Concerted with &bgr;-Lactam Ring Opening.
J. Am. Chem. Soc
. 1984, 106, 1489-1490; Page, M. L.; Proctor, P. Mechanism of &bgr;-Lactam Opening in Cephalosporins.
J. Am. Chem. Soc
. 1984, 106, 3820-3825; Grabowski, E. J. J.; Douglas, A. W.; Smith, G. B. Ammonolysis of Cephalosporins:
13
C NMR Characterization of the Intermediates from &bgr;-Lactam Ring Cleavage Prior to Loss of the 3′-Group.
J. Am. Chem. Soc
. 1985, 107, 267-268]. When the eliminated species possesses excellent leaving ability, cephalosporins (1) may exhibit profound antibacterial activity.
SUMMARY OF THE INVENTION
Accordingly, we designed and synthesized unprecedented isodethiaazacephems having the following formula (I):
wherein R
I
is hydrogen or —SO
2
R
III
, preferably —SO
2
R
III
;
R
II
is —CO
2
R
IV
or —SO
2
R
III
, preferably —CO
2
R
IV
; and
R
V
is a substituted acetamido radical;
wherein R
III
is a hydrogen, C1-C6 alkyl, aralkyl having a total carbon number of 7-12, aryl, or a halogenated C1-C6 alkyl; and R
IV
is a hydrogen, C1-C6 alkyl, aralkyl having a total carbon number of 7-12 or aryl.
We believe that the sulfone moiety, —SO
2
R
III
, at the O—3′ position of (I) could act as an effective leaving groups, and thus further enhance the antibacterial activity in comparison with that of the parent 3-(hydroxy)isodethiaazacephem (R
I
is hydrogen).
Recognizing the feasibility of 1,4-elimination in &bgr;-lactam antibiotics as shown in Scheme 1, we also synthesized novel isodethiaazacephams having the following formula (II):
wherein R
III
, R
IV
and R
V
are defined as above.
The newly designed compound (II) bears a leaving group at the C-4 position; the [1,2]-elimination process could also be initiated by bacterial enzymes (See Scheme 2).
Preferably, R
III
in the formula (I) is C1-C6 alkyl or halogenated C1-C6 alkyl, more preferably —CH
3
or —CF
3
, and most preferably, —CF
3
.
Preferably, R
III
in the formula (II) is C1-C6 alkyl, and more preferably —CH
3
.
Preferably, R
IV
in the formulas (I) and (II) is hydrogen.
Preferably, R
V
in the formulas (I) and (II) is phenylacetamido.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides new classes of &bgr;-lactams (i.e. isodethiaazacephems and isodethiaazacephams) possessing notable antibacterial activity. In the following preferred embodiments of the present invention, we synthesized compounds 3-17, in which compounds 3, 4, 9-12 and 17 are isodethiaazacephem derivatives, and compounds 5 and 16 are isodethiaazacepham derivatives. The reaction routs for the synthesis of these &bgr;-lactams are illustrated in Schemes 3-5. Compounds (±)−3, (±)−4 and (±)−5 shown as follows are prominent examples among the general structures (I) and (II):
Reagents: (a) NaN
3
, DMF, r.t. (90%); (b) CF
3
SO
2
Cl, Et
3
N, CH
2
Cl
2
, 0° C.→r.t. (90%); (c) Pd/C, H
2
, EtOAc, r.t., 7→9 (94%); (d) Pd/C, H
2
, EtOAc, r.t., 8→9 (87%); (e) PdCl
2
, H
2
, EtOH, r.t. (50%); (f) MeSO
2
Cl, pyridine, CH
2
Cl
2
, 15° C., 9→11 (45%); (g) CF
3
SO
2
Cl, pyridine, CH
2
Cl
2
, 15° C., 9→12 (30%)+13 (10%); (h) PdCl
2
, H
2
, EtOH, r.t., 11→3 (35%), 12→4 (30%).
Reagents: (a) H
2
S, Et
3
N, CH
2
Cl
2
, r.t. (55%), 8→9 (15%)+14 (40%).
Reagents: (a) MeSO
2
Cl, Et
3
N, CH
2
Cl
2
, 0° C. (85%); (b) Pd/C, H
2
, EtOAc, r.t. (90%); (c) PdCl
2
, H
2
, EtOH, r.t., 16→5 (20%)+17 (50%).
Synthesis of &bgr;-Lactams (±)−3, (±)−4, (±)−5, and (±)−10
For the synthesis of isodethiaazacephems (±)−3 and (±)−10, we treated racemic &bgr;-lactam mesylate 6 with NaN
3
in DMF at room temperature to give azido &bgr;-lactam 7 in 90% yield (Scheme 3) [Hakimelahi, G. H.; Just, G.; Ugolini, A. The Synthesis of an O-2-Isooxacephem.
Helv. Chim. Acta
1982, 65, 1368-1373]. Catalytic hydrogenation of 7 by use of Pd/C and H
2
(30-35 psi) in EtOAc at room temperature resulted in the reduction of the azide moiety and spontaneous formation of isodethiaazacephem 9 in 94% yield. Debenzylation of 9 by use of PdCl
2
and H
2
(60 psi) in EtOH produced the target isodethiaazacephem (±)−10 in 50% yield.
An alternative way to obtain 9 from azido &bgr;-lactam 7 involved two steps. Chlorination of 7 with CF
3
SO
2
Cl in Et
3
N and CH
2
Cl
2
produced chloride 8 in 90% yield [Hakimelahi, G. H.; Tsay, S.-C.; Ramezani, Z.; Hwu, J. R. Syntheses of New Isocephems and Isodethiaoxacephems as Antimicrobial Agents.
Helv. Chim. Acta
1996, 79, 813-819]. Consequent reduction of 8 by use of Pd/C and H
2
(30-35 psi) in EtOAc gave the desired compound 9 in 87% yield (Scheme 3). On the other hand, reaction of 8 with H
2
S in Et
3
N and CH
2
Cl
2
produced a mixture of isodethiaazacephem 9 (15%) and isodethiaazapenam 14 (40%) as shown in Scheme 4.
We attached a sulfonyl group onto the cephem nucleus of 9 by mesylation with MeSO
2
Cl in pyridine and CH
2
Cl
2
to give the 3-mesyloxy &bgr;-lactam 11 in 45% yield (Scheme 3). It was then hydrogenated with PdCl
2
in EtOH at 60 psi of H
2
to produce the desired isodethiaazacephem (±)−3 in 35% yield. Moreover, we treated &bgr;-lactam 9 with CF
3
SO
2
Cl in pyridine and CH
2
Cl
2
to afford a 3:1 mixture of trifluoromethanesulfonates 12 and 13 in 40% overall yield. Catalytic reduction of 12 with PdCl
2
in EtOH at 60 psi of H
2
gave the target isodethiaazacephem (±)−4 in 30% yield.
For the synthesis of isodethiaazacepham (±)−5 bearing a methylsulfonyl group at the C-4 position, we treated racemic azido &bgr;-lactam 7 with MeSO
2
Cl in Et
3
N and CH
2
Cl
2
(Scheme 5). Sulfone 15, generated in 85% yield, was treated with H
2
(30-35 psi) and Pd/C in EtOAc to give bicyclic &bgr;-lactam 16 in 90% yield through sequential reduction and lactamization. Upon further reduction with H
2
at 60 psi in the presence of PdCl
2
and EtOH, compound 16 was converted to a mixture of the desired 4-substituted isodethiaazacepham (±)−5 in 20% yield and the decarboxylated product (±)−17 in 50% yield.
Solubility and Stability of &bgr;-Lactams (+)−3, (+)−4, (±)−5, (−)−10, and (±)−17 in Water
We found that the solubility in water was 21 and 27 mg/mL for isodeth

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