CA2201736A1 - Bicyclic oxazine and thiazine oxazolidinone antibacterials - Google Patents
Bicyclic oxazine and thiazine oxazolidinone antibacterialsInfo
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- CA2201736A1 CA2201736A1 CA 2201736 CA2201736A CA2201736A1 CA 2201736 A1 CA2201736 A1 CA 2201736A1 CA 2201736 CA2201736 CA 2201736 CA 2201736 A CA2201736 A CA 2201736A CA 2201736 A1 CA2201736 A1 CA 2201736A1
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Abstract
Phenyloxazolidinone compounds of formula (I) or a pharmaceutically acceptable salt thereof characterized by a bicyclic thiazine or oxazine substituent. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
Description
W0 96115130 22 ~1 ~3 6 PCTIUS9S11~751 BICYCLIC OXAZINE AND THIAZINE OXAZOLIDINONE ANIIBACTERIALS
R--k~.o....~l of the Inv~n~
The subject invention rli~rlnses new and useful phenylo~zolitlinon~
compounds characterized by having either a bicyclic th;~7in~ or o~7in~ substituent.
The compounds are useful antimicrobial agents, eLre~;~ive against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such asmultiply-resistant staphylococci, streptococci and enterococci as well as anaerobic org~ni.~m.c such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
Tnffir~n~fion I~isclosure The present compounds are related by their phenyl~ 7Oli-linl ne ring structure to those ~ close~ in the public~tiorl~ below except that the subject compounds have either a bicyclic t~hi~7ine or osr~7~ine phenyl substituent. The instant compounds have useful ~ntih~cterial activity.
PCT/US94/08904 appli~tion discloses oxazolidinone antih~terial compounds having either a mo~pholin~ or thiomorpholine substituent.
PCT/US93/03570 applic~ti()n ~ ses oxazolitlino~s corlt~ining a substituted diazine moiety and their uses as ~ntimi~robials.
PCT/US92/08267 appli~tio~ lo8e~ substituted aryl and heteroaryl-phenyl-oxazolidinones useful as ~ntih~rterial agents.
PCT/US89/03548 applic~tion fli~loses 5'in~1Olinyl-513-~mi-lomethyloxazolidin-ones, 3-(fused-ring sub~ led)phenyl-5~ mi(lomethylc-~7oli-1inQnes, and 3-(nitrogen substituted)phenyl-5~ mitlom~t~yl~ olitlinorl~os which are useful asantibacterial agents.
Other references disclosing various n~olirlinor~es include US Patent 4,801,600, 4,921,869, Gregory W. A., et al., J. Med. Chem., 32, 1673-81 (1989);
Gregory W. A., et al., J. Med. Chem, 33, 2569-78 (1990); Wang C., et al., Tetr~hedron. 45, 1323-26 (1989); and Brittelli, et al., J. Med. Chem.. 35, 1156 (1992).
European Patent Pllhliç~tion 352,781 discloses phenyl and pyridyl substituted phenyl oxazolirlinoneR.
European Patent pnhlic~ticl~ 316,594 ~i~close~ 3-substituted styryl 35 ~ olirlinone~
European Patent Pl]hlic~tion 312,000 discloses phenylmethyl and
R--k~.o....~l of the Inv~n~
The subject invention rli~rlnses new and useful phenylo~zolitlinon~
compounds characterized by having either a bicyclic th;~7in~ or o~7in~ substituent.
The compounds are useful antimicrobial agents, eLre~;~ive against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such asmultiply-resistant staphylococci, streptococci and enterococci as well as anaerobic org~ni.~m.c such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
Tnffir~n~fion I~isclosure The present compounds are related by their phenyl~ 7Oli-linl ne ring structure to those ~ close~ in the public~tiorl~ below except that the subject compounds have either a bicyclic t~hi~7ine or osr~7~ine phenyl substituent. The instant compounds have useful ~ntih~cterial activity.
PCT/US94/08904 appli~tion discloses oxazolidinone antih~terial compounds having either a mo~pholin~ or thiomorpholine substituent.
PCT/US93/03570 applic~ti()n ~ ses oxazolitlino~s corlt~ining a substituted diazine moiety and their uses as ~ntimi~robials.
PCT/US92/08267 appli~tio~ lo8e~ substituted aryl and heteroaryl-phenyl-oxazolidinones useful as ~ntih~rterial agents.
PCT/US89/03548 applic~tion fli~loses 5'in~1Olinyl-513-~mi-lomethyloxazolidin-ones, 3-(fused-ring sub~ led)phenyl-5~ mi(lomethylc-~7oli-1inQnes, and 3-(nitrogen substituted)phenyl-5~ mitlom~t~yl~ olitlinorl~os which are useful asantibacterial agents.
Other references disclosing various n~olirlinor~es include US Patent 4,801,600, 4,921,869, Gregory W. A., et al., J. Med. Chem., 32, 1673-81 (1989);
Gregory W. A., et al., J. Med. Chem, 33, 2569-78 (1990); Wang C., et al., Tetr~hedron. 45, 1323-26 (1989); and Brittelli, et al., J. Med. Chem.. 35, 1156 (1992).
European Patent Pllhliç~tion 352,781 discloses phenyl and pyridyl substituted phenyl oxazolirlinoneR.
European Patent pnhlic~ticl~ 316,594 ~i~close~ 3-substituted styryl 35 ~ olirlinone~
European Patent Pl]hlic~tion 312,000 discloses phenylmethyl and
2 2 0 1 ~ PCT/US9S/127Sl pyridinylmethyl substituted phenyl o~7oli~1inones.
~nmmnrV of the Inv~ntiol~
In one aspect the subject invention is a compound of structural Formula I:
(CH~
(CH~\~CH2)c Rl --~(CH2)b ~N O
\tH ~
Formula I
More preferred compounds, a subset of those described by structural Formula I, are reprçsentecl by structural Formula II:
X~ Rl R1~N O
H
~ NJ~R2 Formula 11 WO96/1~130 2201 7- - PCTIUS95112751 .
or pharmaceutically acceptable salts thereof wherein:
Xis (a) O, (b) S, (c) SO, (d) SO2;
10 Rl is independently H, F, Cl or OMe;
R2 is (a) hydrogen, (b) Cl-C8 aLkyl optionally substitllte~ with one or more of the following:
F, Cl, hydroxy, Cl-C8 alkoxy, C1-C8 acyloxy~
(c) C3-C6 cycloaLkyl, ll5 (d) amino, (e) Cl-C8 aLkylamino, (f~ Cl-C8 diaLkylamino, (g) C1-C8 alkoxy;
a is 0 to 3;
20 bis0to2;
c is 0 to 2 (provided b and c cannot both be 0);
d is 0 to 2; and e is 0 to 2 (provided d and e cannot both be 0).
In another aspect, the subject invention is directed toward a method for treating microbial infection~ in humans or other warm-blooded ~nim~ by ~lmini~tering to a p~tient in need thereof an e~,~ive amount of a compound of Formula I or II as described above. The compound can be ~rlmini~3tered in a pharm~ellt.ic~l composition either orally, parenterally or topically. Preferably the compound is ~mini~tered in an amount of from about 0.1 to about 100 mg/kg of body weight/day, more preferably, from about 3.0 to about 50 mg/l;g of body weight/day.
ne~S~ile-l ne~crilDtioll of the Tnv~ntion The present invention discloses novel substituted bicyclic oxazinyl- or thiazinylphenylo~slirlinor~eæ of structural Formula I and II as described above.
wo 96115130 ~0 1 73 ~ PCT/US9S/127Sl The compounds are useful ~ntimir.~,obial agents, effective ~in~t a number oi~
human and veterin~ry pathogei~s,`particularly aerobic gram-positive bacteria, including multiply-resistant staphylococci and streptococci, as well as anaerobic org~niRmR such as bacteroides and clostridia species, and acid-fast bacteria such as as Mycobacterium tuberculosis and other mycob~ctPrial species.
"Alkyl" means carbon atom chains having the lPRign~te-l number of carbon atoms which can be either straight rh~ined or br~nr.he~l "Alkoxy" means the ~lesign~te~l number of carbon atoms ~tt~r.hed to an oxygen forming such groups as metho~ry (-OCH3), ethyloxy, butyloxy, etc. and isomeric forms thereof.
"Acyloxy" means the ~esign~tecl number of carbon atoms to form an organic acid where the OH group has been deleted, such as acetyl, CH3 CO-; benzoyl, C6 H5CO-.
CycloaL~yl" means the ~eRign~te~l number of carbon atoms forming cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. and isomeric forms thereo "Amino" means an NH2, "aL~ylamino" is where one of the hydrogen positions is replaced by an aL~yl and "diaL~ylamino" is where both hydrogens are replaced by an aL~yl group.
"Pharmaceutically acceptable salts" are acid ~ ition salts which can be prepared by any of the art recogni7.e~1 means. Typical, acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosph~te, ~cet~te, propionate, l~ct~te, m~l~te, sllrrin~te, tartrate, cyr.lohPY~neslllf~m~tes, meth~nPsulfonates, ethanes11lfon~tes, bpn~rpnpslllfon~tes~ tolueneslllforl~tes, fumarates and otherpharmaceutically acceptable couter ions for ~Tnines Preferably X is S.
The Rl substituents are preferably both fluorine and, more preferably, fluorine and hydrogen.
The R2 substituent is preferably hydrogen, methyl, dichloromethyl, hydroxymethyl or methoxy. More preferably R2 is hydrogen, mpth~y or methyl. It is most preferred that R2 is methyl.
The preferred absolute configuration at C-5 of the oxazolidinone ring of compounds rl~ime-l in this invention is as represented in the structures of Formula I
and II. This absolute configuration is called (S) under the Cahn-Ingold-Prelog nomellrl~t~lre system. It is this (s)-pn~ntiomer which is pharmacologically active.
The racemic mixture is useful in the same way and for the same purpose as the pure (S)-enantiomer; the diference is that twice as much racemic material must be WO96/lS130 2201 736 PC~IUS95~12751 used to produce the ~ame ~ntih~cterial effect. It will be apparent to one ~killed in the art that when an ~tltlition~l chiral center(s) is present in the bicyclic ~ 7;n~ or thi~ine fr~ment of compounds of structural Formula I and II, then diastereomers are po~ihle These diastereomers, in racemic and ~n~ntinm~rically enriched forms, 5 are also within the scope of the compounds of Formula I and II of the invention.
P~felled compounds of Formula I are (S)-N-[[3-[3-fluoro-4-[(15,45)-2-oxa-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-7O1i~1inyl]methyl]~et~mi~ mple 1);
(S)-N-[[3-[3-fluoro4-[( lS,4S)-2-thia-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-110 oxazolidinyl]methyl]~cet~mi-le (~ mple 2);
(S)-N-[[3-[3-fluoro-4-[(lS,4S)-2-thia-2,2-dioxo-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-o~7.oli-1inyl]methyl]acetamide (Example 3);
(S)-N-[[3-t3-fluoro~-(tetrahydro-lN-thieno[3,4~]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-o~7oli-linyl]methyl]acet~mi-le (Example 4) (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4~]pyrrol-5(3EI)-yl)phenyl]-2-oxo-5-7O~ inyl]methyl]acet~mi~le, S-oxide (F~rAmple 5) (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4~]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-olr~7.0li~linyl]methyl]~et~mi~e~ S,S-dioxide (F.~r~mr]e 6) cis-(S)-N-[[3-[3-fluoro4-[3-oxa-7azabicyclo[3 .3.0]octane-7-yl]phenyl]-2-oxo-5-2'0 oxazolidinyl]methyl]acehmi~e (F'~m~ple 7) (S)-N-[[3-[3-fluoro-4-[(~R,4R)-2-thia-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]~cet~3m~
(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.2.0]heptan-6-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]s~cet~mi~
(S)-N-[[3-[3-fluoro4-(3-thia-6-azabicyclo[3.2.0]heptan-6-yl)phenyl]-2-oxo-5-701irlinyl]methyl]~cet~mi~;
(S)-N-[[3-[3-fluoro-4-(3-thia-7-azabicyclo[3.3. 1]nonan-7-yl)phenyl]-2-oxo-5-o~ 7O1klinyl]methyl]~cet~mi-1e;
(S)-N-[[3-[3-fluoro-4-(3-thia-9-azabicyclo[3.3. l]nonan-9-yl)phenyl]-2-oxo-5-o~7.oli~inyl]methyl]~et~micle;
(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.2. 1]octan-6-y])phenyl]-2-oxo-5-oxazolidinyl]methyl]acet~mi~e;
(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.3. 1]nonan-6-yl)phenyl]-2-oxo-5-o~ 7.ol i tl i n yl]methyl] acetamide;
(S)-N-[[3-[3-fluoro-4-(7-thia-3-azabicyclo[4.2. 1]nonan-3-yl)phenyl]-2-oxo-5-o~7oli~linyl]methyl]acehmitl~;
Wo 96/15130 ~ 6 PcrluS9Sl12751 (S)-N-[[3-[3-fluoro4-(9-thia-~3-az~i~$clo[3.3. l]nonan-3-yl)phenyl]-2-oxo-5-~r~7~Qli~inyl]methyl]acet~mirle;
(S)-N-[[3-[3-fluoro-4-(3-oxa-6-azabicyclo[3.2.0]heptan-6-yl)phenyl]-2-oxo-5-n~r~701il1inyl]methyl]~et~mi~le;
(S)-N-[[3-[3-fluoro-4-(6-oxa-3-azabicyclo[3. 1. l]heptan-3-yl)phenyl]-2-oxo-5-0~7Qlillinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-(3-oxa-7-azabicyclo[3.3. l]nonan-7-yl)phenyl]-2-oxo-5-0~701itlinyl]methyl]~- et~micle;
(S)-N-[[3-[3-fluoro-4-(3-oxa-9-azabicyclo[3.3. l]nonan-9-yl)phenyl]-2-oxo-5-10 o~7oli~1inyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-(9-oxa-3-azabicyclo[3.3. l]nonan-3-yl)phenyl]-2-oxo-5-nx~701i~1inyl]methyl]~-~etS3mi-1e;
(S)-N-[[3-[3-fluoro-4-(2-oxa-5-azabicyclo[2.2 .2]octan-5-yl)phenyl]-2-oxo-5-oY~701i~inyl]methyl]acetamide;
15 (S)-N-[[3-[3-fluoro-4-(2-oxa-6-azabicyclo[3.2. l]octan-6-yl)phenyl]-2-oxo-5-n~7.oli~inyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-(3-oxa-7-azabicyclo[4.2.0]octan-7-yl)phenyl]-2-oxo-5-n~ 7oli~inyl]methyl]Qcehmide;
(S)-N-[[3-[3-fluoro-4~3-oxa-8-azabicyclo[3.2. l]octan-8-yl)phenyl]-2-oxo-5-20 0~701itlinyl]methyl]A-et~mitl~;
(S)-N-[[3-[3-fluoro-4-(6-oxa-2-azabicyclo[3.2. l]octan-2-yl)phenyl]-2-oxo-5-0~7QIirlinyl]methyl]~cet~mi-1e (S)-N-[[3-[3-fluorQ-4-(8-oxa-3-azabicyclo[3.2. l]octan-3-yl)phenyl]-2-oxo-5-n~701i~inyl]methyl]acet~mi~1e; and 26 (S)-N-[[3-[3-fluoro-4-[(lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-o~r~7oli~1inyl]methyl]acet~mif1~? .
The most preferred compound i~ (S)-N-[[3-[3-fluoro-4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-o~r~7.oli-1inyl]methyl]~cehmid~ (Example 2).
30 (S)-N-[[3-[3-fluoro-4-(tetrahydro-lN-thieno[3,4~]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acet~mide (Example 4) (s)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3~4~]pyrl ol-5(3~1)-yl)phenyl]-2-oxo-5-n~,~701itlinyl]methyl]acet~mitle, S,S-dioxide (Example 6) r The pharmaceutical compositio~ of this invention may be prepared by 35 comhininF the compounds of Formula I or II of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically wo 96/15130 2 2 Q I ~ ~-6 - PClfUS9S112751 acceptable adjuvants and ~ ipient~ employing standard and conv~ntio~l techniques. Solid form compositiorl~ infll~(1e powders, t~hlet~, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one sllhst~nce which may also filnc~ion as a tlilll~nt, flavoring agent, solllhili7er~ lubricant, 5 suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
Inert solid carriers inçlll~e m~gne~i~lm carbonate, m~gne~ium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic m~teri~l~, low m~lting wax, cocoa butter, and the like. Liquid form compositions in~ e solutions, susp~n~ion~ and emnl~i(m.q. For example, there may be provided solutions of the compounds of this lLO invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally cont~ining suitable convent.ion~l coloring agents, flavoring agents, st~hili~rs and thi~kaninF agents.
Preferably, the pharmaceutical composition is provided employing co~ ;on~l te~hniques in unit dosage form cont~ining effective or appropriate 15 amounts of the active component, that is, the compound of Formula I according to this invention.
The quantity of active component, that is the compound of Formula I or II
according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular applic~tio~, 20 the potency of the particular compound, the desired con~ntration. Generally, the quantity of active component will range between 0.5~ to 90~o by weight of the composition.
In therapeutic use for treating, or comh~tting~ bacterial infectiorl~ in warm-blooded ~nim~l~, the compounds or pharmaceutical compo~iti()n~ thereof will be 26 ~lmini~tered orally and/or parenterally at a dosage to obtain and m~int~in a concentration, that is, an amount, or blood-level of active component in the animal undergoing tre~tm~nt which will be ~ntih~t~rially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body 30 weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage ~lmini~tered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be .~m~ller than the 36 optimum and the daily dosage may be progressively increased during the course of tre~tment depending on the particular situation. If desired, the daily dose may also wo 96/15130 2 2 Q 1 7 ~ 6 PCT/US95/127Sl be divided into multiple doses for ~-lmini~tration, e.g., two to four times per a The compounds of Formula I or II according to this invention are ~lminictered parenterally, i.e., by injection, for exa~nple, by intravenous injection or by other parenteral routes of jq~mini~ctration. Pharmaceutical compositions for 5 parenteral ~lminiAtration will generally contain a pharmaceutically acceptableamount of the compound according to Formula I or II as a soluble salt (acid ~d~itio~ salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3-7. Suitable buffering agents 10 in~ e, for ~mple, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglllc~mine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compound according to Formula I generally will be dissolved in the carrier in an amount sllff~çiçnt to provide a pharmaceutically acceptableinjectable concentration in the range of about 1 mg/ml to about 400 mg/ml of solu-16 tion. The resulting liquid pharmaceutical composition will be ~-lmini.ctçred so as to obtain the above-mentioned ~ntih~ctPrially effective amount of dosage.
The plerelled method of preparation of Y~olitlincmçs of Formula I and II in çn~ntiom-3rically pure form is depicted in Charts I-IV..
As shown in Chart I, bicyclic ~ 7in~s and thi~:inçc (comm~rcially available 20 or known in the literature), such as (lS,4S)-2-oxa-6-azabicyclo[2.2.1]heptane (X = O) and (lS,4S)-2-thia-5-azabicyclo[2.2.1]heptane (X = S) of structure 1, are reacted with a function~li7e~1 nitrobenzene 2 (Y = halogen or trifluorom~th~nçslllfon~te) in the presence of a suitable base such as N,N-diiso~r~pylethylamine and in a suitable solvent such as acetonitrile, tetrahydrofuran (THF) or ethyl acetate at ambient to 25 reflux temperature to provide the adducts 3. When X = O, the nitro group of 3 is then reduced by catalytic hydrogen~tion in the presence of a suitable catalyst such as 10% palladium on carbon or W-2 Raney nickel, and in a suitable solvent such as ethyl acetate, tetrahydioru~dn, aqueous tetrahyd~oruldn~ meth~nol and mixtures thereof, to furnish the ~nilinçs 4. In the case where X = S, the nitro group of 3 can 30 be reduced by the action of sodium hydrosulfite in aqueous tetrahydrofuran atambient temperature to ~5 C to give the ~nilinçs 4. Alternatively, reduction of the nitro group of 3 (X = S) can be ~ccomplished by catalytic hydrogeIl~tioI- in thepresence of a suitable catalyst, such as platinum on sulfide carbon or W-2 Raneynickel, and in an appropriate solvent system, for example aqueous tetrahydrofuran.
~nmmnrV of the Inv~ntiol~
In one aspect the subject invention is a compound of structural Formula I:
(CH~
(CH~\~CH2)c Rl --~(CH2)b ~N O
\tH ~
Formula I
More preferred compounds, a subset of those described by structural Formula I, are reprçsentecl by structural Formula II:
X~ Rl R1~N O
H
~ NJ~R2 Formula 11 WO96/1~130 2201 7- - PCTIUS95112751 .
or pharmaceutically acceptable salts thereof wherein:
Xis (a) O, (b) S, (c) SO, (d) SO2;
10 Rl is independently H, F, Cl or OMe;
R2 is (a) hydrogen, (b) Cl-C8 aLkyl optionally substitllte~ with one or more of the following:
F, Cl, hydroxy, Cl-C8 alkoxy, C1-C8 acyloxy~
(c) C3-C6 cycloaLkyl, ll5 (d) amino, (e) Cl-C8 aLkylamino, (f~ Cl-C8 diaLkylamino, (g) C1-C8 alkoxy;
a is 0 to 3;
20 bis0to2;
c is 0 to 2 (provided b and c cannot both be 0);
d is 0 to 2; and e is 0 to 2 (provided d and e cannot both be 0).
In another aspect, the subject invention is directed toward a method for treating microbial infection~ in humans or other warm-blooded ~nim~ by ~lmini~tering to a p~tient in need thereof an e~,~ive amount of a compound of Formula I or II as described above. The compound can be ~rlmini~3tered in a pharm~ellt.ic~l composition either orally, parenterally or topically. Preferably the compound is ~mini~tered in an amount of from about 0.1 to about 100 mg/kg of body weight/day, more preferably, from about 3.0 to about 50 mg/l;g of body weight/day.
ne~S~ile-l ne~crilDtioll of the Tnv~ntion The present invention discloses novel substituted bicyclic oxazinyl- or thiazinylphenylo~slirlinor~eæ of structural Formula I and II as described above.
wo 96115130 ~0 1 73 ~ PCT/US9S/127Sl The compounds are useful ~ntimir.~,obial agents, effective ~in~t a number oi~
human and veterin~ry pathogei~s,`particularly aerobic gram-positive bacteria, including multiply-resistant staphylococci and streptococci, as well as anaerobic org~niRmR such as bacteroides and clostridia species, and acid-fast bacteria such as as Mycobacterium tuberculosis and other mycob~ctPrial species.
"Alkyl" means carbon atom chains having the lPRign~te-l number of carbon atoms which can be either straight rh~ined or br~nr.he~l "Alkoxy" means the ~lesign~te~l number of carbon atoms ~tt~r.hed to an oxygen forming such groups as metho~ry (-OCH3), ethyloxy, butyloxy, etc. and isomeric forms thereof.
"Acyloxy" means the ~esign~tecl number of carbon atoms to form an organic acid where the OH group has been deleted, such as acetyl, CH3 CO-; benzoyl, C6 H5CO-.
CycloaL~yl" means the ~eRign~te~l number of carbon atoms forming cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. and isomeric forms thereo "Amino" means an NH2, "aL~ylamino" is where one of the hydrogen positions is replaced by an aL~yl and "diaL~ylamino" is where both hydrogens are replaced by an aL~yl group.
"Pharmaceutically acceptable salts" are acid ~ ition salts which can be prepared by any of the art recogni7.e~1 means. Typical, acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, phosph~te, ~cet~te, propionate, l~ct~te, m~l~te, sllrrin~te, tartrate, cyr.lohPY~neslllf~m~tes, meth~nPsulfonates, ethanes11lfon~tes, bpn~rpnpslllfon~tes~ tolueneslllforl~tes, fumarates and otherpharmaceutically acceptable couter ions for ~Tnines Preferably X is S.
The Rl substituents are preferably both fluorine and, more preferably, fluorine and hydrogen.
The R2 substituent is preferably hydrogen, methyl, dichloromethyl, hydroxymethyl or methoxy. More preferably R2 is hydrogen, mpth~y or methyl. It is most preferred that R2 is methyl.
The preferred absolute configuration at C-5 of the oxazolidinone ring of compounds rl~ime-l in this invention is as represented in the structures of Formula I
and II. This absolute configuration is called (S) under the Cahn-Ingold-Prelog nomellrl~t~lre system. It is this (s)-pn~ntiomer which is pharmacologically active.
The racemic mixture is useful in the same way and for the same purpose as the pure (S)-enantiomer; the diference is that twice as much racemic material must be WO96/lS130 2201 736 PC~IUS95~12751 used to produce the ~ame ~ntih~cterial effect. It will be apparent to one ~killed in the art that when an ~tltlition~l chiral center(s) is present in the bicyclic ~ 7;n~ or thi~ine fr~ment of compounds of structural Formula I and II, then diastereomers are po~ihle These diastereomers, in racemic and ~n~ntinm~rically enriched forms, 5 are also within the scope of the compounds of Formula I and II of the invention.
P~felled compounds of Formula I are (S)-N-[[3-[3-fluoro-4-[(15,45)-2-oxa-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-7O1i~1inyl]methyl]~et~mi~ mple 1);
(S)-N-[[3-[3-fluoro4-[( lS,4S)-2-thia-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-110 oxazolidinyl]methyl]~cet~mi-le (~ mple 2);
(S)-N-[[3-[3-fluoro-4-[(lS,4S)-2-thia-2,2-dioxo-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-o~7.oli-1inyl]methyl]acetamide (Example 3);
(S)-N-[[3-t3-fluoro~-(tetrahydro-lN-thieno[3,4~]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-o~7oli-linyl]methyl]acet~mi-le (Example 4) (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4~]pyrrol-5(3EI)-yl)phenyl]-2-oxo-5-7O~ inyl]methyl]acet~mi~le, S-oxide (F~rAmple 5) (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4~]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-olr~7.0li~linyl]methyl]~et~mi~e~ S,S-dioxide (F.~r~mr]e 6) cis-(S)-N-[[3-[3-fluoro4-[3-oxa-7azabicyclo[3 .3.0]octane-7-yl]phenyl]-2-oxo-5-2'0 oxazolidinyl]methyl]acehmi~e (F'~m~ple 7) (S)-N-[[3-[3-fluoro-4-[(~R,4R)-2-thia-5-azabicyclo[2.2. 1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]~cet~3m~
(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.2.0]heptan-6-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]s~cet~mi~
(S)-N-[[3-[3-fluoro4-(3-thia-6-azabicyclo[3.2.0]heptan-6-yl)phenyl]-2-oxo-5-701irlinyl]methyl]~cet~mi~;
(S)-N-[[3-[3-fluoro-4-(3-thia-7-azabicyclo[3.3. 1]nonan-7-yl)phenyl]-2-oxo-5-o~ 7O1klinyl]methyl]~cet~mi-1e;
(S)-N-[[3-[3-fluoro-4-(3-thia-9-azabicyclo[3.3. l]nonan-9-yl)phenyl]-2-oxo-5-o~7.oli~inyl]methyl]~et~micle;
(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.2. 1]octan-6-y])phenyl]-2-oxo-5-oxazolidinyl]methyl]acet~mi~e;
(S)-N-[[3-[3-fluoro-4-(2-thia-6-azabicyclo[3.3. 1]nonan-6-yl)phenyl]-2-oxo-5-o~ 7.ol i tl i n yl]methyl] acetamide;
(S)-N-[[3-[3-fluoro-4-(7-thia-3-azabicyclo[4.2. 1]nonan-3-yl)phenyl]-2-oxo-5-o~7oli~linyl]methyl]acehmitl~;
Wo 96/15130 ~ 6 PcrluS9Sl12751 (S)-N-[[3-[3-fluoro4-(9-thia-~3-az~i~$clo[3.3. l]nonan-3-yl)phenyl]-2-oxo-5-~r~7~Qli~inyl]methyl]acet~mirle;
(S)-N-[[3-[3-fluoro-4-(3-oxa-6-azabicyclo[3.2.0]heptan-6-yl)phenyl]-2-oxo-5-n~r~701il1inyl]methyl]~et~mi~le;
(S)-N-[[3-[3-fluoro-4-(6-oxa-3-azabicyclo[3. 1. l]heptan-3-yl)phenyl]-2-oxo-5-0~7Qlillinyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-(3-oxa-7-azabicyclo[3.3. l]nonan-7-yl)phenyl]-2-oxo-5-0~701itlinyl]methyl]~- et~micle;
(S)-N-[[3-[3-fluoro-4-(3-oxa-9-azabicyclo[3.3. l]nonan-9-yl)phenyl]-2-oxo-5-10 o~7oli~1inyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-(9-oxa-3-azabicyclo[3.3. l]nonan-3-yl)phenyl]-2-oxo-5-nx~701i~1inyl]methyl]~-~etS3mi-1e;
(S)-N-[[3-[3-fluoro-4-(2-oxa-5-azabicyclo[2.2 .2]octan-5-yl)phenyl]-2-oxo-5-oY~701i~inyl]methyl]acetamide;
15 (S)-N-[[3-[3-fluoro-4-(2-oxa-6-azabicyclo[3.2. l]octan-6-yl)phenyl]-2-oxo-5-n~7.oli~inyl]methyl]acetamide;
(S)-N-[[3-[3-fluoro-4-(3-oxa-7-azabicyclo[4.2.0]octan-7-yl)phenyl]-2-oxo-5-n~ 7oli~inyl]methyl]Qcehmide;
(S)-N-[[3-[3-fluoro-4~3-oxa-8-azabicyclo[3.2. l]octan-8-yl)phenyl]-2-oxo-5-20 0~701itlinyl]methyl]A-et~mitl~;
(S)-N-[[3-[3-fluoro-4-(6-oxa-2-azabicyclo[3.2. l]octan-2-yl)phenyl]-2-oxo-5-0~7QIirlinyl]methyl]~cet~mi-1e (S)-N-[[3-[3-fluorQ-4-(8-oxa-3-azabicyclo[3.2. l]octan-3-yl)phenyl]-2-oxo-5-n~701i~inyl]methyl]acet~mi~1e; and 26 (S)-N-[[3-[3-fluoro-4-[(lR,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-o~r~7oli~1inyl]methyl]acet~mif1~? .
The most preferred compound i~ (S)-N-[[3-[3-fluoro-4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-o~r~7.oli-1inyl]methyl]~cehmid~ (Example 2).
30 (S)-N-[[3-[3-fluoro-4-(tetrahydro-lN-thieno[3,4~]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acet~mide (Example 4) (s)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3~4~]pyrl ol-5(3~1)-yl)phenyl]-2-oxo-5-n~,~701itlinyl]methyl]acet~mitle, S,S-dioxide (Example 6) r The pharmaceutical compositio~ of this invention may be prepared by 35 comhininF the compounds of Formula I or II of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically wo 96/15130 2 2 Q I ~ ~-6 - PClfUS9S112751 acceptable adjuvants and ~ ipient~ employing standard and conv~ntio~l techniques. Solid form compositiorl~ infll~(1e powders, t~hlet~, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one sllhst~nce which may also filnc~ion as a tlilll~nt, flavoring agent, solllhili7er~ lubricant, 5 suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
Inert solid carriers inçlll~e m~gne~i~lm carbonate, m~gne~ium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic m~teri~l~, low m~lting wax, cocoa butter, and the like. Liquid form compositions in~ e solutions, susp~n~ion~ and emnl~i(m.q. For example, there may be provided solutions of the compounds of this lLO invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally cont~ining suitable convent.ion~l coloring agents, flavoring agents, st~hili~rs and thi~kaninF agents.
Preferably, the pharmaceutical composition is provided employing co~ ;on~l te~hniques in unit dosage form cont~ining effective or appropriate 15 amounts of the active component, that is, the compound of Formula I according to this invention.
The quantity of active component, that is the compound of Formula I or II
according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular applic~tio~, 20 the potency of the particular compound, the desired con~ntration. Generally, the quantity of active component will range between 0.5~ to 90~o by weight of the composition.
In therapeutic use for treating, or comh~tting~ bacterial infectiorl~ in warm-blooded ~nim~l~, the compounds or pharmaceutical compo~iti()n~ thereof will be 26 ~lmini~tered orally and/or parenterally at a dosage to obtain and m~int~in a concentration, that is, an amount, or blood-level of active component in the animal undergoing tre~tm~nt which will be ~ntih~t~rially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body 30 weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage ~lmini~tered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be .~m~ller than the 36 optimum and the daily dosage may be progressively increased during the course of tre~tment depending on the particular situation. If desired, the daily dose may also wo 96/15130 2 2 Q 1 7 ~ 6 PCT/US95/127Sl be divided into multiple doses for ~-lmini~tration, e.g., two to four times per a The compounds of Formula I or II according to this invention are ~lminictered parenterally, i.e., by injection, for exa~nple, by intravenous injection or by other parenteral routes of jq~mini~ctration. Pharmaceutical compositions for 5 parenteral ~lminiAtration will generally contain a pharmaceutically acceptableamount of the compound according to Formula I or II as a soluble salt (acid ~d~itio~ salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3-7. Suitable buffering agents 10 in~ e, for ~mple, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglllc~mine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compound according to Formula I generally will be dissolved in the carrier in an amount sllff~çiçnt to provide a pharmaceutically acceptableinjectable concentration in the range of about 1 mg/ml to about 400 mg/ml of solu-16 tion. The resulting liquid pharmaceutical composition will be ~-lmini.ctçred so as to obtain the above-mentioned ~ntih~ctPrially effective amount of dosage.
The plerelled method of preparation of Y~olitlincmçs of Formula I and II in çn~ntiom-3rically pure form is depicted in Charts I-IV..
As shown in Chart I, bicyclic ~ 7in~s and thi~:inçc (comm~rcially available 20 or known in the literature), such as (lS,4S)-2-oxa-6-azabicyclo[2.2.1]heptane (X = O) and (lS,4S)-2-thia-5-azabicyclo[2.2.1]heptane (X = S) of structure 1, are reacted with a function~li7e~1 nitrobenzene 2 (Y = halogen or trifluorom~th~nçslllfon~te) in the presence of a suitable base such as N,N-diiso~r~pylethylamine and in a suitable solvent such as acetonitrile, tetrahydrofuran (THF) or ethyl acetate at ambient to 25 reflux temperature to provide the adducts 3. When X = O, the nitro group of 3 is then reduced by catalytic hydrogen~tion in the presence of a suitable catalyst such as 10% palladium on carbon or W-2 Raney nickel, and in a suitable solvent such as ethyl acetate, tetrahydioru~dn, aqueous tetrahyd~oruldn~ meth~nol and mixtures thereof, to furnish the ~nilinçs 4. In the case where X = S, the nitro group of 3 can 30 be reduced by the action of sodium hydrosulfite in aqueous tetrahydrofuran atambient temperature to ~5 C to give the ~nilinçs 4. Alternatively, reduction of the nitro group of 3 (X = S) can be ~ccomplished by catalytic hydrogeIl~tioI- in thepresence of a suitable catalyst, such as platinum on sulfide carbon or W-2 Raneynickel, and in an appropriate solvent system, for example aqueous tetrahydrofuran.
3~ The latter conditions are especially useful in that the reaction mixture is simply filtered through Celite(~ or the like to remove the catalyst and the filtrate containing WO 96115130 2a~OI 73 6 ~ PCTIUS95~127~1 the aniline 4 is directly used in the next step. To this end, the Anilin~s 4 are cu~ ed to their benzyl (R3 = CH2Ph) or methyl (R3 = CH3) carb~m~te del;vatives 6, employing standard Schotten-R~11m~nn co~litio~R or other variations known to one skilled in the art. The uret.h~ne.q 6 are then deprotonated with a suitable base 6 such as n-butyllithillm, lithium diisopropyl~mi~le, or lithium bis(trimethylsilyl)amide in a suitable solvent such as tetrahydrofuran or N,N-d;methylru~ mir~a and at a suitable tempelatul~ such as -78 to -60C to give a lithi~t,erl interm~ te which is then treated with commarcially available (-)-(R)-glycidyl butyrate. Warming to ambient tempe,cllu~e then directly affords the 5-(hyd1oxy~llethyl)~ ~7O1i~inones 6 in ].0 en~ntiom~riç~lly enriched form. Compound 6 is then Cû~ ed to the corresponding mesylate 7 (R4 = m~th~n~sulfonyl) or aryl sulfonate 7 (R4 = ArSO2, for example p-toluenesulfonyl) by the action of, for example, methanesulfonyl chloride/py-ridine or meth~nesulfonyl chloride/triethylAmine/dichloromethane orp-toluenesufonyl chloride/pyridine .
As illustrated in Chart II, the resultant sulfonate derivative 7 is then reactedwith an azide source such as sodium or potassium azide in an aprotic solvent such as N,N-dimethylform~mi-l~ (DMF) or 1-methyl-2-pyrrolidinone, optionally in the presence of a catalyst such as 18-crown-6, at a temperature of 50-90 C to afford the azide 8. The azide i8 then reduced by hydrogçn~t.ion with p~ m on carbon or a ~0 platinum catalyst in an a~rop.iate solvent such as ethyl ~cet~te or m~th~nol to give the corresponding amine 9. Alternatively, and preferably in the case where X =
S, the azide can be reduced by tre~tTn~nt with a trivalent phosphorus compound such as triphenylphosphin~ in a suitable solvent such as tetrahyd-~ruldn followed by the ~ 1it.ion of water. Alternatively, the mesylate or aryl slllfon~te group of compounds 7 can be rli~pl~r.ed with potassium phth~limitle in ~retollitrile at reflux temperature to give the interrn~ te pht.h~limi~l~ lO. The phth~limicle 10 is then deprotected by tre~tnnent with aqueous methyl amine in r~ g ethanol to afford the amine 9. In yet another alternative, the mesylate 7 is reacted with z~Tn7nor1illm hydroxide in hot isopropanol or isopropanol/tetrahydl.,ru dn, ~lere~.dbly in a sealed reaction vessel, to directly give the amine 9. The amine 9 is then acylated by reactions known to those skilled in the art to give oxazoli~inon~s of structure 11.
For example, the amine can be reacted with an acid chloride or anhydride in a basic solvent such as pyridine at a temperature ranging from -30 to 30 C to provide the acylated compound 11 (R2 = optionally substituted alkyl). It will be apparent to one skilled in the art that other acyl groups within the scope of this in~vention can be WO 96/15130 2 2 0 1 7 3 e~ 3~ ~ ~ PCI'IUS9S/127Sl readily appended to the amine 9 by standard acylation techniques, for examp~ose highli~htecl in March, J. "Advanced Organic Chlomi~tryll~ 4th ed.; John Wiley & Sons:
New York, 1992; pp 417~25, to give ~ ition~l examples of 11. The compounds of structure 11 represent examples of bicyclic ~ 7ine- and thi~7ine-substituted oy~7olillinone ~ntih~t-?ri~l agents of Formula II, which are the subject of this invention.
As shown in Chart III, the ~7olif~inones 11, th~m~lves e~mrle~ of antibacterial agents of Formula II, can be further elaborated to additional compounds of Formula II. Spe~ific~lly, 11 (X = S) can be ~ i7e-1 to the 10 corresponding sl71f ~i-1e(s) 12 (X = SO) with sodium metaperiodate in a mixture of water and meth~nol It will be apparent to one skilled in the art that both endo-and exo- slllfir)~i~les are possible, and both i~omeric forms, as well as mixtures thereof, are within the scope of this invention. In addition, compounds 11 or 12 can be o~irli7e~l to the corresponding sulfones 13 (X = S02) by tre~tment with 4-15 methylmorpholine N-oxide and catalytic osmium tetroxide in aqueous ~- etc r e. It will be apparent to those skilled in the art that alternative con~litiol-~ for o~ i7.ing 11 (X - S) to 12 or 13 are known, for ~Y~mrle those highli~hte/l in March, J.
"Advanced Organic Chemi~t~y", 4th ed.; John Wiley & Sons: New York, 1992; pp 1201-1202.
As shown in Chart IV synthe~i~ of compounds which incorporate a thienopyrrolidine begins with reduction of the diester 14 to the diol 15 using lithium aluminum hydride as the reducing agent. Compound 15 is then converted to the bis-mesylate 16 by reaction with m~t~nesulfonyl chloride and a trialkylamine base.
Cytli7.~tion of 16 to the thienopyrrolidine 17 is carried out by reaction with sodium 25 sulfide, and compound 17 is debenzylated to the thienopyrrole 18 by reaction with hydrogen in the presence of a suitable catalyst such as palladium on carbon. Thecompound of example 4 is then prepared from 18 by following the procedures outlined in Charts I and II (but sub~Li~ 18 for 1). The compounds of Examples 5 and 6 are prepared by o~ tio~ of the compound of ~ mple 4, using the same 30 procedures as shown in Chart III.
Antimicrobial activity was tested in vivo using a Murine Assay procedure.
Groups of female mice were injected intraperito~e~lly with bacteria which were thawed just prior to use and suspended in brain heart infusion with 4~o Brewer'syeast UC9213 (Staphylococcus aureus) or brain hear infusion (Streptococcus species).
35 Antibiotic tre~trn~nt a six dose levels per drug was ~lmini~tered on hour and five WO96/15130 ~ 1 7~ PCTlUS9S/127Sl hours after infection by either oral or subcutaneous routes. Survival was observed daily for six days. ED50 values based on mortality ratios were calculated using probit analysis. The subject compounds were compared ~in~t a well-known ~nt,imi~robial (Vanc.~llly~ ) as a control. The data is shown in Table 1.
Table 1 In Viuo A~;liv;~y ~;n~t S. aunE~ls UC~199213 ED~;o (mg/kg) Example No.
mI~le, POVancomycin, SC
7.7 11.2 2 4.2 4.0
As illustrated in Chart II, the resultant sulfonate derivative 7 is then reactedwith an azide source such as sodium or potassium azide in an aprotic solvent such as N,N-dimethylform~mi-l~ (DMF) or 1-methyl-2-pyrrolidinone, optionally in the presence of a catalyst such as 18-crown-6, at a temperature of 50-90 C to afford the azide 8. The azide i8 then reduced by hydrogçn~t.ion with p~ m on carbon or a ~0 platinum catalyst in an a~rop.iate solvent such as ethyl ~cet~te or m~th~nol to give the corresponding amine 9. Alternatively, and preferably in the case where X =
S, the azide can be reduced by tre~tTn~nt with a trivalent phosphorus compound such as triphenylphosphin~ in a suitable solvent such as tetrahyd-~ruldn followed by the ~ 1it.ion of water. Alternatively, the mesylate or aryl slllfon~te group of compounds 7 can be rli~pl~r.ed with potassium phth~limitle in ~retollitrile at reflux temperature to give the interrn~ te pht.h~limi~l~ lO. The phth~limicle 10 is then deprotected by tre~tnnent with aqueous methyl amine in r~ g ethanol to afford the amine 9. In yet another alternative, the mesylate 7 is reacted with z~Tn7nor1illm hydroxide in hot isopropanol or isopropanol/tetrahydl.,ru dn, ~lere~.dbly in a sealed reaction vessel, to directly give the amine 9. The amine 9 is then acylated by reactions known to those skilled in the art to give oxazoli~inon~s of structure 11.
For example, the amine can be reacted with an acid chloride or anhydride in a basic solvent such as pyridine at a temperature ranging from -30 to 30 C to provide the acylated compound 11 (R2 = optionally substituted alkyl). It will be apparent to one skilled in the art that other acyl groups within the scope of this in~vention can be WO 96/15130 2 2 0 1 7 3 e~ 3~ ~ ~ PCI'IUS9S/127Sl readily appended to the amine 9 by standard acylation techniques, for examp~ose highli~htecl in March, J. "Advanced Organic Chlomi~tryll~ 4th ed.; John Wiley & Sons:
New York, 1992; pp 417~25, to give ~ ition~l examples of 11. The compounds of structure 11 represent examples of bicyclic ~ 7ine- and thi~7ine-substituted oy~7olillinone ~ntih~t-?ri~l agents of Formula II, which are the subject of this invention.
As shown in Chart III, the ~7olif~inones 11, th~m~lves e~mrle~ of antibacterial agents of Formula II, can be further elaborated to additional compounds of Formula II. Spe~ific~lly, 11 (X = S) can be ~ i7e-1 to the 10 corresponding sl71f ~i-1e(s) 12 (X = SO) with sodium metaperiodate in a mixture of water and meth~nol It will be apparent to one skilled in the art that both endo-and exo- slllfir)~i~les are possible, and both i~omeric forms, as well as mixtures thereof, are within the scope of this invention. In addition, compounds 11 or 12 can be o~irli7e~l to the corresponding sulfones 13 (X = S02) by tre~tment with 4-15 methylmorpholine N-oxide and catalytic osmium tetroxide in aqueous ~- etc r e. It will be apparent to those skilled in the art that alternative con~litiol-~ for o~ i7.ing 11 (X - S) to 12 or 13 are known, for ~Y~mrle those highli~hte/l in March, J.
"Advanced Organic Chemi~t~y", 4th ed.; John Wiley & Sons: New York, 1992; pp 1201-1202.
As shown in Chart IV synthe~i~ of compounds which incorporate a thienopyrrolidine begins with reduction of the diester 14 to the diol 15 using lithium aluminum hydride as the reducing agent. Compound 15 is then converted to the bis-mesylate 16 by reaction with m~t~nesulfonyl chloride and a trialkylamine base.
Cytli7.~tion of 16 to the thienopyrrolidine 17 is carried out by reaction with sodium 25 sulfide, and compound 17 is debenzylated to the thienopyrrole 18 by reaction with hydrogen in the presence of a suitable catalyst such as palladium on carbon. Thecompound of example 4 is then prepared from 18 by following the procedures outlined in Charts I and II (but sub~Li~ 18 for 1). The compounds of Examples 5 and 6 are prepared by o~ tio~ of the compound of ~ mple 4, using the same 30 procedures as shown in Chart III.
Antimicrobial activity was tested in vivo using a Murine Assay procedure.
Groups of female mice were injected intraperito~e~lly with bacteria which were thawed just prior to use and suspended in brain heart infusion with 4~o Brewer'syeast UC9213 (Staphylococcus aureus) or brain hear infusion (Streptococcus species).
35 Antibiotic tre~trn~nt a six dose levels per drug was ~lmini~tered on hour and five WO96/15130 ~ 1 7~ PCTlUS9S/127Sl hours after infection by either oral or subcutaneous routes. Survival was observed daily for six days. ED50 values based on mortality ratios were calculated using probit analysis. The subject compounds were compared ~in~t a well-known ~nt,imi~robial (Vanc.~llly~ ) as a control. The data is shown in Table 1.
Table 1 In Viuo A~;liv;~y ~;n~t S. aunE~ls UC~199213 ED~;o (mg/kg) Example No.
mI~le, POVancomycin, SC
7.7 11.2 2 4.2 4.0
4 4.3 6 10.0 1~; 6 3.5 It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that the use of alternative bicyclic r~ ines and thi~7:ine~s known in the patent and open lite~LLu~e allows for 20 the preparation of ~ 1itior~1 examples of structural Formula I.
WO 96/15130 2 2 O. 1 ,7 3, 6` ~ PCT/US9S/12751 EXAMPLE 1~ N-rr3-r4-r(1~.4S)-2-n~-5-~7~hicyclor~ ~.1lhe~t~n-5-vll-3- ~
flllnroI~h~r~yll-~-n~n-5-n~ 7~o~ mf~thyllacet~m~
Step 1: 4-r(1l~,4.O-~-n~-5-~7~hicyclor2.2.1lhe~t~n-5-yll-3-fluoro~itrob~n7~ne A mixture of comm~rcially available (LS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
WO 96/15130 2 2 O. 1 ,7 3, 6` ~ PCT/US9S/12751 EXAMPLE 1~ N-rr3-r4-r(1~.4S)-2-n~-5-~7~hicyclor~ ~.1lhe~t~n-5-vll-3- ~
flllnroI~h~r~yll-~-n~n-5-n~ 7~o~ mf~thyllacet~m~
Step 1: 4-r(1l~,4.O-~-n~-5-~7~hicyclor2.2.1lhe~t~n-5-yll-3-fluoro~itrob~n7~ne A mixture of comm~rcially available (LS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
5 hydrochloride (0.200 g, 1.47 mmol), dipotassium hydrogen phosphate (1.030 g, 5.90 mmol) and 3,4-difluoronitrobenzene (0.195 mL, 1.77 mmol) in dimethyl sulfoxide (6 mL) was stirred at ambient tempeLdLule under a N2 atmosphere. TLC analysis (5%
MeOH/CHC13) after 3 h revealed the starting nitrobenzene was consumed. The reaction mixture was diluted with H2O and (60 mL) and extracted with CHCl3. The 10 combined organic extracts were washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. Chromatography over silica gel (60 g), eluting with a gradient of 0-2% MeOH/CHCl3, afforded, after concentration of appropriate fractions, 0.314 g (90%) of the title compound as ayellow solid with mp 106.5-108 C and MS(EI) 238 (M+).
Step 2: N-(~rbobPn7~yln~y)-4-r(1l~.4S)-2-oxa-5-~7~hicyclor~.2. llh~t~n-5-yll-3-fluoro~nilin~
A solution of 4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluoronitrobenzene (0.160 g, 0.672 mmol) in 3:1 THF/H2O (4 mL) was treated with 20 acetic acid (0.115 mL) and then 10% palladium/carbon (0.020 g) under a N2 stream.
The atmosphere was replaced with H2 (balloon) by repeated evacuation and fillingand the mixture stirred at ambient tempelalu~e. After 2 h, TLC analysis (6%
CH3CN/CHCl3) revealed the reduction to be complete. The reaction ~ ure was filtered through Celite~) and the filtrate imme~ t~ly placed under an atmosphere of 25 N2 and treated with K2CO3 (0.464 g, 3.36 mmol) followed by benzyl chloroformate (0.117 mL, 0.864 mmol). TLC analysis (6% CH3CN/CHCl3) after 0.5 h revealed the reaction to be complete. The reaction l~lu.e was concentrated under reduced pressure and chromatographed over silica gel (20 g), eluting with a gradient of 1-5%
CH3CN/CHCl3. Concentration of appropriate fractions afforded 0.226 g (98 %) of the 30 title compound as a white solid with mp 120-121 C and MS(EI) 342 (M+).
Step 3: (R)-r3-r4-r(1 1~.4S)-2-n~-5-~hicyclor2.2. 1lhel~tan-5-yll-3-fluoroph~nvll-~-n~n-5-ox~oli~ yllm~th~nol A solution of N-(carbobenzyloxy)-4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-35 yl]-3-fluoro~nilin~ (0.169 g, 0.494 mmol) in dry THF (2 mL) was cooled to -78 C
under a N2 atmosphere and then treated with n-butyllithium (0.312 mL of a 1.6 M
WO 96/151~0 22 û 1 7 3 6 PCTIUS9Sl~751 sollltion in h~Y~nl~, 0.499 mmol). After stirring 10 min at -78 C, the reaction mixture was treated with (R)-glycidyl butyrate (0.070 mL, 0.499 mmol). When the lit.ion was cornplete-tl, the cooling bath was removed and the ..~;~lule allowed to stir at ~mhi~nt tempe,~tuSe ovqrniE~ht, during which time an of~-~hite pr3~i~itate 5 appeared. TLC analysis (6% MeOH/CHCL3) revealed the reaction to be complete.
The re~rtior~ llli~tU' ~ was treated with ca. 5 drops of saturated aqueous NH4Cl, which made the re~tion ~ a a homogeneous sollltion The reaction lllixlure was concç..t.dted under reduced pLe~jule to an off-white solid. Chromatography over æilica gel, eluting with a gradient of 1-5% MeOH/CHCl3, afforded, after 10 co~cen~ration of a~propL;ate fractions, 0.116 g (84%) of the title compound as a white solid with mp 138-140 C and MS(EI) 308 (M+). In addition, 0.018 g (10%) of a second component, identified as the butyrate ester of the title compound by 1HNMR analysis, was obtained as an amber oil.
15 Step 4: (~)-rr3-r4-r(15.45)-2-n~-6-~7.~hicyclor2.2.1lhel~tan-5-yll-3-fluorophenyll-2-oxo-5-~7~ yllm~0t~yllm~0th~n~?~ulfo~te A solution of (R)-[3-[4-[(lS,4S)-2-oxa-~-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-oY~7oli-linyl]m~ nol (0.765 g, 2.48 mmol) in dry CH2Cl2 (30 mL) was cooled to 0 C under a N2 atmosphere and treated with Et3N (0.518 mL, 20 3.73 mmol) followed by methanesulfonyl ~hll~rirle (0.202 mL, 2.61 mmol). TLC
analysis (5% MeOH/CHC13) after 0.5 h revealed the reaction to be complete. The reaction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo to give 0.992 g (ca. 100%) of the title compound as a tan solid.
An analytical sample was prepared by la.;~ tion from 5% CH2Cl2/i-PrOH.
25 This sample had mp 124.5-126 C and MS(EI) 386 (M+).
Step 5: (R)-rr3-r4-r~1S.4S)-2-oxa-5-~7 ~hicyclor2.2.1lhel~tan-5-yl1-3-fluorophenyll-2--~--5-oxazolirlinyllm~t.~yll~
A solution of (R)-[t3-[4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-30 fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methaneslllfon~te (0.869 g, 2.26 mmol) in dry DMF (10 mL) was tretaed with solid NaN3 (0.732 g, 11.3 mmol) at ambient tempe~ture under N2. The llli~tUl`e was then heated to 65 C and reaction progress monitored by TLC. After 7.5 h at this tempe~alu~e, TLC analysis (5%
MeOH/CHCl3) revealed the re~rtio~ to complete. The reaction mixture was diluted 36 with EtOAc (100 mL), washed with H20 (3 x 15 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.692 g (92%) of the title WO 96/15130 2 2 0 1 ~ t,, PCT/US9S/12751 compound as a tan solid. An analytical sample was prepared by recryst~ A~
from 1:1 EtOAc/hexane as an off-white solid with mp 101-102.5 C and MS(EI) 333 (M+) 5 Step 6: (S)-N-rr3-r4-r(1.~.4.0-2-~1~A-5-A~Ahicyclor2.2.1lheptAn-5-yll-3-flll- roI)h~r~yll-2-oxo-5-~l~rA~ yllm~,thyllacet,Amitl~
A sollltion of (R)-[[3-[4-[(lS,4S)-2-oxa-6-azabicyclo[2.2. 1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-o~rA7oli-linyl]methyl]azide (0.652 g, 1.96 mmol) in MeOH (20 mL) and CH2C12 (10 mL) was treated with 10% palladium/carbon (0.095 g) under a 10 N2 stream. The atmosphere was then replaced with H2 (balloon) by repeated evacuation and filling and the mixture stirred at ambient temperature under H2.
After 3 h, TLC analysis (5% MeOH/CHC13) revealed the reduction to be complete.
The reaction mixture was filtered through Celite~ and the filtrate concentrated under reduced pressure. The crude 5-(Aminom~t~lyl)r~rA~oli~inone was dissolved in 15 CH2C12 (20 mL) and treated with pyridine (0.190 mL, 2.35 mmol) and then acetic anhydride (0.222 mL, 2.35 mmol). After 0.5 h, TLC analysis (5% MeOH/CHC13) in(lic~te~l the acetylation to be complete. The reaction mixture was washed withH2O and brine, dried over Na2SO4, filtered and co~c~ntrated in uacuo to give an off-white solid. ChromAtography over silica gel (70 g), eluting with a gradient of 1-3%
20 MeOH/CHC13, afforded, after concentration of apyropL;ate fractions, 0.517 g (76%) of the title o~oli~inone AntihActerial agent as a white solid with mp 60-65 C and MS(EI) 349 (M+).
EXAMPLE 2: (S)-N-rr3-r3-fluoro4-r(l,C~4C~ t~jA_5_A7Ahicyclor2.2.1lheDt~n-5 25 ylll~h~rlyll 2 ~l~ro-5 l~lrAs:olitlir~yllm~tl~yllA~f~tAmitl~
Step 1: 4-r(l.~.4.0-2-thiA-5 A7Ahicyclor~ heptan-5-yll-3-fluoronitrobenzene A mixture of commercially available (lS,4S)-2-thia-5-azabicyclo[2.2.1]heptane (0.500 g, 3.30 mmol), diisol~ropylethylamine (1.434 mL, 8.24 mmol) and 3,4-30 difluoronitrobenzene (0.437 mL, 3.96 mmol) in dry acetonitrile (15 mL) was heated to reflux tempeldtule under a N2 atmosphere for 1 h and then cooled to ambient temperature overnight. The reActior~ nli~ e was co~centrated under reduced pressure to give a yellow syrup. ChromAtography over silica gel (50 g), eluting with chlorofo..ll, afforded, after concentration of appropriate fr~ctior c, 0.700 g (84%) of 35 the title compound as a yellow solid with mp 97-98 C and MS(EI) 254 (M+).
wo 96/15130 2~Ui 7~ PCT~SgSIl27Sl Step 2: N~ rbob~n7,yl-~v)~-r(1.~,4S)-2-thi~-6-sl~hicvclor2.2.1lheptan-~-y1l-3-fl~ ro~niline A solution of 4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluoronitrobenzene (1.64 g, 6.46 mmol) in 20~o H20/TE3[F (50 mL) was treated with 5 platinum on sulfide carbon (0.200 g) under a N2 stream. The atmosphere was replaced with H2 (balloon) by repeated ev~cll~tio~ and filling. After 12 h TLC
analysis revealed a ~i~nifiç~nt amount of starting material still r~m~in~ The re~ tio~ n~ixture was transferred to a Parr apparatus and ~h~k~n under 45 psi H2.
TLC analysis after 2 h intlir~te~ some starting material still r~m~ine-l The reaction 10 ~li~t.l~ was filtered through Celite~ and the filtrate, cont~inin~ a mixture of the desired aniline interme~ te and starting nitrobenzene derivative, was cooled to 0 C
and treated with NaHCO3 (2.170 g, 25.8 mmol) and benzyl chloroformate (1.02 mL, 7.10 mmol). After 0.5 h the reaction ~ r~ was con~.lt.ated under reduced pressure to a yellow/green syrup. This material was dissolved in CHC13, washed 15 with H2O and brine, dried over Na2SO4, filtered and cor~ntrated in vacuo.
Filtration through a plug of silica gel, eluting with 20-30% EtOAc/l~ ne, afforded, after concentration of apl~ru~iate fr~rtion.~, a ll~ re of starting nitrobenzenederivative and the title compound. This m~tPri~l taken-up in 20% H20/THF (50 mL) and treated with W-2 Raney nickel (ca. 0.400 g). The reaction ll~ u~e was 20 .~h~k~n on a Parr apparatus under 45 psi H2. After 3 h the re~tion mixture was filtered through Celite~ and the filtrate cooled to 0 C and treated with NaHCO3(2.00 g, 23.8 mmol) followed by benzyl chloroformate (0.600 mL, 4.1L9 mmol). After 0.5 h the reaction ..~ure was concentrated under reduced pre~s2jule and the residue chrom~tographed over silica gel (125 g), eluting with 10-20% EtOAc/he~ne, to afford, after concentration of a~ iate fractions, 2.20 g (95~o) of the title compound as a yellow solid mp 91-93 C and MS(EI) 358 (M+).
Step 3: (R)-r3-r4-r( 1.~.A.~)-2-thi~-5-azabicyclor2.2. 1lhel~tan-5-yll-3-fluorophenyll-2-oxo-5-~ olidinyllmethanol A~ ltirm of N-(carbobenzyloxy)-4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluoro~niline (0.359 g, 1.00 mmol) in dry THF (4 mL) under N2 was cooled to -78 C and then treated with n-butyllithillm (0.633 mL of a 1.6 M solution in h~n~, 1.01 mmol). The re~rtion mixture was stirred at -78 C for 15 min and then treated with (R)-glycidyl buly~ate (0.151 mL, 1.00 mmol). When the ~ 1ition was coInplete, the cooling bath was removed and the reaction mixture allowed to warm to ambienttemperature overnight. TLC analysis (5~o MeOFlCHC13) in(li~ted the reaction was wo 96/15130 2 2 0 1 7 ~ 6 PCTIUS9S1127Sl compl~te but a small amount of the butyrate ester of the title compound was--present. The Atl-litioT~ of 5 drops of ~a 25 w~t.% solllticn of NaOMe/MeOH, followed by stirring for 20 min at room temperature, was effective in COIlV~ g this interm~ te to the title compound. The reaction l~ U' a was treated with G saturated aqueous NH4Cl (10 drops) and then c-~ncentrated under reduced pressure to an oil. This m~teriAl was dissolved in CH2Cl2 and washed with H20 and brine, dried over Na2S04, filtered and co~ntrated in vacuo to give a crude product.
Chrom~tography over silica gel (50 g), eluting with 1-3% MeOH/CHC13, afforded, after concentration of al ~lop~iate fractions, 0.132 g (41~fo) of the title compound as 10 an oil. Trituration with EtOAc afforded a precipitate, which was i~ol~te~l and dried zn vacuo to give an off-white solid with mp 156-157 C and MS(EI) 324 (M+).
Step 4: (~)-rr3-r4-r(15.4S)-2-thi~ 7~hicyclor2.2.1lhe~tan-5-yll-3-fl uoroph ~ vll-2-n~n-6-~ 7.f 1 i ~ yllm ~tllyllm ~t.h fl n f~811 1 fi~n ~ te A Eolllti~ n of (R)-[3-[4-[( lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-o~ olillinyl]methanol (1.68 g, 5.19 mmol) in dry CH2Cl2 (100 mL) under N2 was cooled to O C and treated with Et3N (0.793 mL, 5.70 mmol) followed by meth~ne~ulfonyl chloride (0.442 mL, 5.70 mmol). After 0.5 h at this tempel~ul~e, the re~ctior appeared to be complete by TLC analysis (55~o 20 MeOH/CHCl3). The mixture was washed with H20, saturated aqueous NaHCO3 and brine, dried over Na2S04, filtered and concentrated in vacuo to give 1.65 g (79%) of the title compound as a white solid with mp 139-142 C and MS(EI) 402 (M+).
5 Step 5: (S)-N-rr3-r3-fluoro-4-r(1S.4.0-2-thi~-5-~7slhi-~clor2.2.1lhe~ts~n-5-yllph~r~yll-~-n~--5-mr~7o~ yllm~sthyll~t~mi~1~
A mixture of (R)-[[3-[4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-o~r~70li~inyl]methyl]m.st~neslllfo~te (1.56 g, 3.88 mmol), 1:1 THF/i-PrOH (4 mL) and 30% NH40H (4 mL) was heated to 95 C in a sealed tube 30 for 14 h and then cooled to ambient temperature. TLC analysis (5~o MeOH/CHCl3) revealed the reaction to be complete. The mixture was diluted with CH2Cl2 (75 mL), washed with saturated aqueous NaHC03 (15 mL) and brine (15 mL), dried over Na2S04, filtered and corl~Pntrated under reduced pressure to give a syrup. The crude 5-(~minolnethyl)o~7.oli-1ino~ interme~ te was dissolved in CH2C12 (75 mL) 85 and treated with pyridine (0.345 mL, 4.27 mmol) and acetic anhydride (0.403 mL, 4.27 mmol) at ambient temperature. After 1 h, TLC analysis (5~o MeOH/CHC13) wo 96/l5l30 2 ~ ~ ~ 73 G PCTlUS9S1127Sl in~ t~ the acetylation to be complete The r~ction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to an amber solid. Chrom~tography over silica gel (125 g), eluting with 1-3% MeOH/CHC13, afforded, after conc~ntration of a~pro~l;ate fr~cti-n,q, 1.23 g (87~o) 5 of the title o~701i~1inone ~ntih~r,t~rial agent as a solid with mp 90-95 C and MS(EI) 365 (M+).
EXAMPLE 3: (S)-N-rr3-r3-fluoro-4-r(1.~.A.~)-2-thia-2.2-~ -5-~7~hiCyclor2.2.llh~pt~n-5-yll~henyll-2-n~l-5-~ inyllm~th-yllacet~mi(1e A solution of (S)-N-[[3-[3-fluoro-4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]~cet~mi~ie (0.300 g, 0.82 mmol) in 25~fo H2O/acetone (16 mL) was treated at ambient tempeldlure with 4-methylmorpholine-N-oxide (0.288 g, 2.47 mmol) followed by osmium tetro~ide (0.102 mL of a 2.5 wt.%
solution in tert-butanol, 0.008 mmol). After 18 h, TLC analysis (10% MeOH/CHCl3)1.5 revealed the o~ tion was complete. The reaction ~ u~e was treated with saturated aqueous NaHSO3 and then extracted with CHCl3. The comhine~l organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chrom~tographed over silica gel (10 g), eluting with 1-3~ MeOH/CHCl3, to afford, after concentration of appropriate 20 frArtion.~, 0.321 g (98~o) of the title o~ litlinon~ ~ntih~terial agent as a white solid with mp 95-105 C.
EXAMPLE 4: (s)-N-rr3-r3-fluoro-4-(tetrahydro-l F~-t~ nor3 4-c~yrrol-5(3H)-yl)phenyll-2-oxo-5~ 7~ yllmethyllacet~mide Step 1: cis-1-(Ph~ylm~thyl)-3.4-pyrrolitlin~dimethanol (cis)-1-(Phenylmethyl)-3,4-pyrroli-lin.q-lic~rboxylic acid, dimethyl ester was prepared according to the procedure of Y. Terao, et al (Chem. Pharm. Bull., 1985, 33, 2762-66). To a stirred soll7tion of this diester (12.14 g, 43.8 mmol) in dry THF (175 mL) 30 under N2 cooled to 0 C was added dropwise a solution of lithium aluminum hydride (lM in THF, 87 mL, 87 mmol) over 15 min. The reaction mixture was stirred at 0 C for 1 h, then at RT for 18 h. The re~ctio~ mixture was cooled to 0 C and q~ herl with successive ~ ition of H20 (3.2 mL), 5 N NaOH (3.2 mL) and H20 (11.7 mL). The reaction ~ lure became very thick and stirring was difficult. The35 reaction mixture was diluted with ether (500 mL) and filtered through a small pad of celite. The filter cake was washed with ether (250 mL). The filtrate was washed WO 96/lSl30 ~ ~; s PC~/US9S/1275 with H2O (1 x 300 mL) and the organics were dried (MgSO4), filtered and concçntrated to afford 9.3 g (41.8 mmol, 96%) of the desired diol and a thick yellow oil. Used without further purification. HRMS (FAB) calcd for C13HlgN02+H
222.1494, found 222.1490.
Step 2: cis-1-(Ph~rlylm~th~yl)-3.4-~li(m~t~ lfor~vlt~yy)m~th~ yrroli,1in~?
To a stirred sollltion of cis-1-(phenylmethyl)-3,4-pyrrolir~ine-limPtl~nol (9.2 g, 41.6 mmol) in CH2Cl2 (240 mL) cooled to 0 C was added triethylamine (29 mL, 208.1 mmol) followed by methanesulfonyl chloride (8.1 mL, 104.0 mmol). The re~ction 10 l~ lu~`e was stirred at 0 C for 15 min, then at RT for 1.5 h. The reaction mixture was poured into H2O (240 mT-) and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1 x 100 mL). The combined organics were dried (MgSO4), filtered and concçntrated. The residue was purified by flash chrom~tography using ethyl acetate as the eluent to afford 14.2 g (37.5 mmol, 90%) 15 of the desired bis-mesylate as a thick yellow oil. HRMS (EI) calcd for C15H23NO6S2 377.0967, found 377.0968.
Step 3: T-TP~r~h,ydro-5-(~?h~r~ylm~th~yl)-l ~-thienor3.4-cll~yrrole To a stirred solution of cis-1-(phenylmethyl)-3,4-20 di(methylsulfonyloxy)methyl~y~,olidine (9.2 g, mmol), in dry DMSO (48 mL) wasadded anhydrous sodium sulfide (5.7 g, 73.3 mmol). The dark re~tio~ mixture was heated at 120 C for 18 h. The cooled reaction ll~ e was poured into ice H20 (150 mL). The resulting mixture was extracted with ether (3 x 200mL). The comhine~l organics were dried (MgSO4), filtered and collcentrated. The resulting25 residue was purified by flash chroln~graphy using ethyl acetate as the eluent to afford 4.2 g (19.1 mmol, 78%) of the desired product as a thick yellow oil. HRMS(EI) calcd for C13H17NS 219.1082, found 219.1080. Anal. Calcd for C13H17NS: C, 71.19; H, 7.81; N, 6.39. Found: C, 70.82; H, 7.83; N, 6.35.
30 Step 4: ~hydro~ -thi~?nor3.4-cll?yrrole. ~h~y~lrorhl~ride To a stirred solution of hexahydro-5-(phenylmethyl)-lN-t_ieno[3,4-c]pyrrole (1.2 g, 5.3 mmol) in CH2Cl2 (21 mL) cooled to 0 C was added dropwise via syringe 1-chloroethylchlorofo~ ate (1.15 mL, 10.7 mmol). The reaction mixture was stirred at 0 C for 20 min, then at RT for 90 min. The reaction mixture was concentrated.
35 The resulting residue was purified by flash chromatography using 25 % ethyl acetate in h~ne as the eluent to afford 611.3 mg (2.6 mmol, 49%) of 1-WO96/15130 22 ~1 73fi - ` PCTJUS9S~12751 chloroethylcarb~m~te. The column was then washed with 20~o mPt.hflnnlic slm~nonis~
i~ CHCl3 to afford 160.5 mg (1.24 mmol, 23 %) of desired ~nine as the free base.The 1-chloroethylcarbamate (611.3 mg, 2.6 m~nol) was dissolved in meth~nol (15 mL) and heated at refLux for 90 min. The cooled reaction mixture was concçntrated toafford 408.0 mg (2.5 mmol, 47~o) of the desired amine as the HCl salt (based on chlorocarbamte). mp 149-151 C; HRMS (EI) calcd for C6HllNS 129.0612, found 129.0614. Anal. Calcd for C6Hl2ClNS: C, 43.50; H, 7.30; N, 8.45; Cl: 21.39; S:
19.35. Found: C, 43.39; H, 7.23; N, 8.24; Cl: 21.08; S: 19.12.
lLO Step 5: 5-(~-Flll-)ro 4-~itro~h~t~yl) h~ lro 1~ thi~nor3.4~l~vrrole To a stirred suspension of hexahydro-5-~H-thieno[3,4-c]pyrrole, hydrochloride (147.3 mg, 0.89 mmol) in ~etonitrile (5 mL) was added 3,4-fluoronitrobenzene (0.11 mL, 0.98 mmol) followed by diisopropylethyl amine (0.36 mL, 2.05 mmol). The homogeneous re~- tion mixture was heated at reflux for 18 h. The cooled reaction16 mixture was co~c~ontrated. The resulting residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NH4Cl (1 x 25 mL). The aqueous layer was extracted with EtOAc (1 x 30 mL). Combined organics were washed with sa~uLdted NaHC03 (1 x 40 mL), brine (1 x 40 mL), dried (MgSO4), filtered and concentrated.The residue was purified by flash chroIn~tQgraphy using 20 ~ EtOAc in h~ne as the eluent to afford 202.5 mg (0.75 m nol, 89%) of the desired nitro compound as a bright yellow solid. mp 107-109 C; Anal. calcd for C12H13FN2O2S: C, 53.72; H, 4.88; N, 10.44; S: 11.95. Found: C, 53.38; H, 5.03; N, 10.34; S: 11.89.
Step 6: 3-r3-Fluoro-4-(tetr~l~y lro-1 Fr-thi~nor3.4~lpyrrol-5(3~) yl)~he~yl-~rh~mi~ l phenylmethylester To a stirred suspension of 5-(2-fluoro-4-nitrophenyl)-hexahydro-~H-thieno[3,4-c]pyrrole (1.44 g, 5.4 mmol) in eth~nol (70 mL) was added 2 M aqueous CuSO4 (2.9mL). This mixture was cooled to 0 C and sodium borohydride (1.10 g, 26.8 mmol) was added portionwise. (Caution: Very exothermic!) The dark reaction mixture was then heated at reflux for 2 h. The cooled re~ction l~ Ul~ was partitioned between EtOAc and H2O. The phases were separated. The aqueous phase was extracted with EtOAc (3 x 100 nT ). The combined organics were dried (MgSO4), filtered and conce~ ted. The resulting dark residue was dissolved in acetone/H20(2:1, 60 mL). This stirred eollltion was cooled to 0 C and solid NaEIC03 (1.35 g, 36 16.1 mmol) was added followed by benzylchloroformate (1.9 mL, 13.4 mmol). The reaction mixture was stirred at 0 C for 15 min, then at RT for 2 h. The reaction WO 96/15130 2 2 r~ ; PCT/US951127SI
mixture was qllan~.he~l bly c7ar3e~ul ~ ition of 10 % aqueou6 NaHS04 (30 mL). ~ereaction mixture was poured into EtOAc (250 mL) and the phases were separated.
The aqueous layer wa~ extracted with EtOAc (1 x 100 mL). The comhined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by 5 flash chromatography using 20% EtOAc in ha~na to afford 1.6 g (4.3 mmol, 81 %) of the desired carbamate: mp 101-102 C; Anal. Calcd for C20H21FN2O2S: C, 64.50; H,5.68; N, 7.52; S: 8.61. Found: C, 64.33; H, 5.56; N, 7.53; S: 8.61.
Step 7: (5R)-3-r3-Fluoro-4-(tet.r~h*ydro-1 Fr-thiannr3.4~1~vrrol-S(.
yl)ph.qrlyll-5-(h,yrlrn~ymath~yl)-~-n~7.nlir~innna To stirred solution of 3-[3-fluoro-4-(tetrahydro-lN-thieno[3,4-c]pyrrol-5(3N)-yl)phenylcarbamic acid, phenylmethyl ester (1.36 g, 3.6 mmol) dry THF (14 mL) under N2 cooled to -78 C was added n-butylithillm (1.6 M in ha~ ~ne, 2.4 mL, 3.8 mmol). The reaction mixture was stirred at -78 C for 35 min and then R-(-)-15 glycidylbuly~ate (0.54 mL, 3.8 mmol) was added. The re~tion mixture was stirred at -78 C for 30 min, then at RT overnight. A thick L,re~ te had formed. The reaction mixture was qllen~.ha~l with sa~ ated aqueous NH4Cl (14 mL) and poured into EtOAc (50 mL). The phases were separated. The organic layer was washed with saturated aqueous NaHCO3 (1 x 30 mL), brine (1 x 30 mL), dried (MgSO4), 20 filtered and con~antrated. The residue was purified by flash chrom~tography using EtOAc as the eluent to afford 801.6 mg (2.4 mmol, 65%) of the desired product. mp 165-167 C; Anal. Calcd for C16H19FN2O3S: C, 56.79; H, 5.66; N, 8.28; S: 9.48.
Found: C, 56.88; H, 5.74; N, 8.21; S: 9.33.
25 Step 8: (fi~)-3-r3-Fluoro-4-(tetr~y~lro-1 Fr-thi~nor3.4~lDyrrol-5(3~l)-yl)l~har~
5-rr(mat~y~ fnT~y~ math~yll-~ 7~ in~na To a stirred solution of (5R)-3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)phenyl]-5-(hydro~ylllethyl)-2-olr~7.oli-1inone (656.5 mg, 1.9 mmol) in CH2C12 (20 mL) cooled to 0 C was added triethylamine (0.41 mL, 2.9 mmol) followed by 30 meth~ne.~ulfonylchloride (0.18 mL, 2.3 mmol). The re~ctio~ l~luLa was stirred at 0 C for 15 min, then at RT for 18 h. The reaction lllix~ula was poured into H20 (20 mL). the phases were separated. The aqueous layer was extracted with CH2Cl2 (1 x 50 mL). The combined organic layers were dried (MgSO4), filtered and concantrated. the residue was triturated with ether/heY~na and solid was isolated 35 by filtration and dried to aford 773.9 mg (1.9 mmol, 96%) of the desired mesylate.
mp 148-150 C; Anal. Calcd for C17H21FN2O5S2: C, 49.03; H, 5.08; N, 6.73; S:
= ~
WO 96/15 130 .2 ~ ~ t 7 ~ 6 . PC'rlUS9S/127Sl 1~.40. Found: C, 48.56; H, 5.12; N, 6.48, S; 15.41. Found: C, 48.46; H, 5.25; N, 6.38.
Step 9: (.O-N-rr3-r3-fluoro-4-(tetr~ydro~ -thi~nor3.4~1pyrrol-5(.
yl)~heIlyll-2-n~-5-o~,7olidinyllm~l;hyllace~m;~l~
A stirred suspension of (5R)-3-[3-fluoro-4-(tetrahydro-~I~-thieno[3,4-c]pyrrol-5-(3E~)-J yl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-c.Y~7o~ inone (208.5 mg, 0.5 mmol) in THF (3 ~) and methAnoli-! ~mmoni~ (3 mL) was heated in a sealed tube at 100 C
for 48 h. (The reaction n~lul~ became homogenous at about 80 C.) The cooled re~ct!io~ e was corlsentrated and the resulting residue was dissolved in CH2Cl2 (5 mL) and cooled to 0 C. To this stirred suspension was added pyridine (0.12 mL, 1.5 mmol) followed by acetic anhydride (60 IIL, 0.6 mmol). The homogeneous reaction mi~u~a was stirred at 0 C for 15 min, then at RT for 1 h then concantrated. The residue was pu~fied by flash chromAtography using 7 %
l!; meth~nol in EtOAc as the eluent to afford 148.2 mg (0.4 mmol, 78~o) of the desired ~cet~micle mp 143-144 C; KF-H20: 0.52% Anal. Calcd for C18H22FN303S plus 0.52% H2O: C, 56.68; H, 5.87; N, 11.01; S: 8.40. Found: C, 56.31; H, 5.90; N, 10.74;
S: 8.30.
EXAMPLE 5: (S)-N-rr3-r3-fluoro-4-(tetrah~ydro-1 Fr-t~hi~-nor3.4~l}~yrrol-5(.~Fr)yl)~?hanyll-2-oxo-5-~ yllm~thyllacet~mi~a S-~
To a stirred solution of (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-oxazoldinyl]methyl]acet~mitle (216.8 mg, 0.57 mmol) in methanol (4 mL) and H2O (4 mL) cooled to 0 C was added sodium metaperiodate (134.4 mg, 0.63 mmol). The reaction Illi~U~e~ was stirred at 0 C for 1 h, then at RT for 18 h.
The solid p r~ on was removed by filtration. The solid was washed with CHC13 (50 mL). The filtrate was washed wit,h H2O (1 x 30 mL). The aqueous layer was extracted with CHCl3 (2 x 25 mL). The combined organic layers were dried (MgSO4), filtered and cor~c~nt.rated. The residue waæ purified by flash chrorn~tography using 7~o met~nol in CH2C12 as the eluent to afford 195.7 mg (0.5 mmol, 87 % ) of the desired sulfoxide. mp 162-164 C; HRMS (EI) calcd for C18H22FN3O4S 395.1315, found 395.1309. KF-H2O: 2.87 % Anal. ~Calcd for C18H22FN3O4S plus 2.87 % H2O: C, 53.09; H, 5.76; N, 10.32; S: 7.87. Found: C, 35 53.07; H, 6.01; N, 10.20; S: 7.87.
WO 96/l5l30 2 2 0 1 7 3 ~ t ~ ; PCT/US9S/l27Sl EXA~LE 6~ N-rr3-r3-fluoro-4-(tetr~.vflro-1~-thi.?nor3.4~1pyrrol-5(3ZO- ~
yl)~)h~T~yll-~-oxo-5-o~r~7.nli~ yllm-?t.~yll~t,~mitl.s. S.S-~
To a stirred solution of (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-5 yl)phenyl]-2-oxo-5-~ ol~inyl]methyl]acetamide (213.9 mg, 0.56 mmol) in 25 %
acetone/H2O (8 mL) was added N-methylmorpholine-N-oxide (198.1 mg, 1.7 mmol) followed by osmium tetroxide in tert-butanol (2.5 % by wt.) (30 ~lL, 0.08 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was qn~n~hed by careful addition of saturated sodium bisulfite (8 mL). The mixture was poured into 10 CH2Cl2 (50 mL) and the phases were separated. The aqueous phase was extractedwith CH2Cl2 (2 x 25 mL). The combined organic layers were washed with brine (1 x30 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography using 7 % methanol in CHCl3 as the eluent to afford 194.3 mg (0.47 mmol, 84 ~o) of desired sulfone. mp 135-137 C; HRMS (EI) calcd for 15 C18H22FN3O5S 411.1264, found 411.1263. KF-H2O: 1.10 ~o. Anal. Calcd for Cl8H22FN3O5S plus 1.10 % H2O: C, 51.96; H, 5.45 N, 10.10; S: 7.71. Found: C, 51.73; H, 5.62; N, 9.96; S: 7.75.
EXAMPLE 7: ~iR-(S)-N-rr3-r3-fluoro-4-r3-~ -7azabicyclor3.3.0loctane-7-20 yllph~r~yll-2-oxo-5-~ 7olitlirlyllmf!th~yllace~mitl~
Following the general procedure of EXAMPLE 2 and m~king noncritical variations but sub~LiLuLi~lg hexahydro-lH-furo(3,4-c)pyrrole (Miller, A.D. U.S. Patent 3,976,632 1976). (2.33 g, 20.66 mmol) for (lS, 4S)-2-thia-5-azabicyclo[2.2.1]heptane, the title 25 compound is obtained, mp 124-126C.
~ r. ..~ i }~
WO96tlS130 2~1 736 PCTIUS9511~7Sl ~ Chart I
Y~NO2 R~No2 ///
Fl~--NH, ~1~HN 0113 1. RL~
/2. ~ o FI~NJ~O R~NJ~O
\~ H \~H
WO 96tl5130 2 2 0 1 7 ~ ~ PCT/US9S/12751 . ~ ~
Chart II
)~ R~N O
\
R~NJ~O R~NJ~O
H o \~
N--4~ NH2 o~ 9 R. R1 R1 NJ~O
\tH O
WO 96/15130 i 7 3 ~ ~ PCT/US9S1127S 1 Chart m R1~NJ~O F~N O
\tNJ~R2 \~NJI~R2 ~>N~ o tH ~
2~
WO 96/15130 . PCT/US9S/127Sl CHART IV
~4 \~?N~
CH3S2~ N~ ~NH
Ph Ph 18
MeOH/CHC13) after 3 h revealed the starting nitrobenzene was consumed. The reaction mixture was diluted with H2O and (60 mL) and extracted with CHCl3. The 10 combined organic extracts were washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. Chromatography over silica gel (60 g), eluting with a gradient of 0-2% MeOH/CHCl3, afforded, after concentration of appropriate fractions, 0.314 g (90%) of the title compound as ayellow solid with mp 106.5-108 C and MS(EI) 238 (M+).
Step 2: N-(~rbobPn7~yln~y)-4-r(1l~.4S)-2-oxa-5-~7~hicyclor~.2. llh~t~n-5-yll-3-fluoro~nilin~
A solution of 4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluoronitrobenzene (0.160 g, 0.672 mmol) in 3:1 THF/H2O (4 mL) was treated with 20 acetic acid (0.115 mL) and then 10% palladium/carbon (0.020 g) under a N2 stream.
The atmosphere was replaced with H2 (balloon) by repeated evacuation and fillingand the mixture stirred at ambient tempelalu~e. After 2 h, TLC analysis (6%
CH3CN/CHCl3) revealed the reduction to be complete. The reaction ~ ure was filtered through Celite~) and the filtrate imme~ t~ly placed under an atmosphere of 25 N2 and treated with K2CO3 (0.464 g, 3.36 mmol) followed by benzyl chloroformate (0.117 mL, 0.864 mmol). TLC analysis (6% CH3CN/CHCl3) after 0.5 h revealed the reaction to be complete. The reaction l~lu.e was concentrated under reduced pressure and chromatographed over silica gel (20 g), eluting with a gradient of 1-5%
CH3CN/CHCl3. Concentration of appropriate fractions afforded 0.226 g (98 %) of the 30 title compound as a white solid with mp 120-121 C and MS(EI) 342 (M+).
Step 3: (R)-r3-r4-r(1 1~.4S)-2-n~-5-~hicyclor2.2. 1lhel~tan-5-yll-3-fluoroph~nvll-~-n~n-5-ox~oli~ yllm~th~nol A solution of N-(carbobenzyloxy)-4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-35 yl]-3-fluoro~nilin~ (0.169 g, 0.494 mmol) in dry THF (2 mL) was cooled to -78 C
under a N2 atmosphere and then treated with n-butyllithium (0.312 mL of a 1.6 M
WO 96/151~0 22 û 1 7 3 6 PCTIUS9Sl~751 sollltion in h~Y~nl~, 0.499 mmol). After stirring 10 min at -78 C, the reaction mixture was treated with (R)-glycidyl butyrate (0.070 mL, 0.499 mmol). When the lit.ion was cornplete-tl, the cooling bath was removed and the ..~;~lule allowed to stir at ~mhi~nt tempe,~tuSe ovqrniE~ht, during which time an of~-~hite pr3~i~itate 5 appeared. TLC analysis (6% MeOH/CHCL3) revealed the reaction to be complete.
The re~rtior~ llli~tU' ~ was treated with ca. 5 drops of saturated aqueous NH4Cl, which made the re~tion ~ a a homogeneous sollltion The reaction lllixlure was concç..t.dted under reduced pLe~jule to an off-white solid. Chromatography over æilica gel, eluting with a gradient of 1-5% MeOH/CHCl3, afforded, after 10 co~cen~ration of a~propL;ate fractions, 0.116 g (84%) of the title compound as a white solid with mp 138-140 C and MS(EI) 308 (M+). In addition, 0.018 g (10%) of a second component, identified as the butyrate ester of the title compound by 1HNMR analysis, was obtained as an amber oil.
15 Step 4: (~)-rr3-r4-r(15.45)-2-n~-6-~7.~hicyclor2.2.1lhel~tan-5-yll-3-fluorophenyll-2-oxo-5-~7~ yllm~0t~yllm~0th~n~?~ulfo~te A solution of (R)-[3-[4-[(lS,4S)-2-oxa-~-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-oY~7oli-linyl]m~ nol (0.765 g, 2.48 mmol) in dry CH2Cl2 (30 mL) was cooled to 0 C under a N2 atmosphere and treated with Et3N (0.518 mL, 20 3.73 mmol) followed by methanesulfonyl ~hll~rirle (0.202 mL, 2.61 mmol). TLC
analysis (5% MeOH/CHC13) after 0.5 h revealed the reaction to be complete. The reaction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo to give 0.992 g (ca. 100%) of the title compound as a tan solid.
An analytical sample was prepared by la.;~ tion from 5% CH2Cl2/i-PrOH.
25 This sample had mp 124.5-126 C and MS(EI) 386 (M+).
Step 5: (R)-rr3-r4-r~1S.4S)-2-oxa-5-~7 ~hicyclor2.2.1lhel~tan-5-yl1-3-fluorophenyll-2--~--5-oxazolirlinyllm~t.~yll~
A solution of (R)-[t3-[4-[(lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-30 fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methaneslllfon~te (0.869 g, 2.26 mmol) in dry DMF (10 mL) was tretaed with solid NaN3 (0.732 g, 11.3 mmol) at ambient tempe~ture under N2. The llli~tUl`e was then heated to 65 C and reaction progress monitored by TLC. After 7.5 h at this tempe~alu~e, TLC analysis (5%
MeOH/CHCl3) revealed the re~rtio~ to complete. The reaction mixture was diluted 36 with EtOAc (100 mL), washed with H20 (3 x 15 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.692 g (92%) of the title WO 96/15130 2 2 0 1 ~ t,, PCT/US9S/12751 compound as a tan solid. An analytical sample was prepared by recryst~ A~
from 1:1 EtOAc/hexane as an off-white solid with mp 101-102.5 C and MS(EI) 333 (M+) 5 Step 6: (S)-N-rr3-r4-r(1.~.4.0-2-~1~A-5-A~Ahicyclor2.2.1lheptAn-5-yll-3-flll- roI)h~r~yll-2-oxo-5-~l~rA~ yllm~,thyllacet,Amitl~
A sollltion of (R)-[[3-[4-[(lS,4S)-2-oxa-6-azabicyclo[2.2. 1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-o~rA7oli-linyl]methyl]azide (0.652 g, 1.96 mmol) in MeOH (20 mL) and CH2C12 (10 mL) was treated with 10% palladium/carbon (0.095 g) under a 10 N2 stream. The atmosphere was then replaced with H2 (balloon) by repeated evacuation and filling and the mixture stirred at ambient temperature under H2.
After 3 h, TLC analysis (5% MeOH/CHC13) revealed the reduction to be complete.
The reaction mixture was filtered through Celite~ and the filtrate concentrated under reduced pressure. The crude 5-(Aminom~t~lyl)r~rA~oli~inone was dissolved in 15 CH2C12 (20 mL) and treated with pyridine (0.190 mL, 2.35 mmol) and then acetic anhydride (0.222 mL, 2.35 mmol). After 0.5 h, TLC analysis (5% MeOH/CHC13) in(lic~te~l the acetylation to be complete. The reaction mixture was washed withH2O and brine, dried over Na2SO4, filtered and co~c~ntrated in uacuo to give an off-white solid. ChromAtography over silica gel (70 g), eluting with a gradient of 1-3%
20 MeOH/CHC13, afforded, after concentration of apyropL;ate fractions, 0.517 g (76%) of the title o~oli~inone AntihActerial agent as a white solid with mp 60-65 C and MS(EI) 349 (M+).
EXAMPLE 2: (S)-N-rr3-r3-fluoro4-r(l,C~4C~ t~jA_5_A7Ahicyclor2.2.1lheDt~n-5 25 ylll~h~rlyll 2 ~l~ro-5 l~lrAs:olitlir~yllm~tl~yllA~f~tAmitl~
Step 1: 4-r(l.~.4.0-2-thiA-5 A7Ahicyclor~ heptan-5-yll-3-fluoronitrobenzene A mixture of commercially available (lS,4S)-2-thia-5-azabicyclo[2.2.1]heptane (0.500 g, 3.30 mmol), diisol~ropylethylamine (1.434 mL, 8.24 mmol) and 3,4-30 difluoronitrobenzene (0.437 mL, 3.96 mmol) in dry acetonitrile (15 mL) was heated to reflux tempeldtule under a N2 atmosphere for 1 h and then cooled to ambient temperature overnight. The reActior~ nli~ e was co~centrated under reduced pressure to give a yellow syrup. ChromAtography over silica gel (50 g), eluting with chlorofo..ll, afforded, after concentration of appropriate fr~ctior c, 0.700 g (84%) of 35 the title compound as a yellow solid with mp 97-98 C and MS(EI) 254 (M+).
wo 96/15130 2~Ui 7~ PCT~SgSIl27Sl Step 2: N~ rbob~n7,yl-~v)~-r(1.~,4S)-2-thi~-6-sl~hicvclor2.2.1lheptan-~-y1l-3-fl~ ro~niline A solution of 4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluoronitrobenzene (1.64 g, 6.46 mmol) in 20~o H20/TE3[F (50 mL) was treated with 5 platinum on sulfide carbon (0.200 g) under a N2 stream. The atmosphere was replaced with H2 (balloon) by repeated ev~cll~tio~ and filling. After 12 h TLC
analysis revealed a ~i~nifiç~nt amount of starting material still r~m~in~ The re~ tio~ n~ixture was transferred to a Parr apparatus and ~h~k~n under 45 psi H2.
TLC analysis after 2 h intlir~te~ some starting material still r~m~ine-l The reaction 10 ~li~t.l~ was filtered through Celite~ and the filtrate, cont~inin~ a mixture of the desired aniline interme~ te and starting nitrobenzene derivative, was cooled to 0 C
and treated with NaHCO3 (2.170 g, 25.8 mmol) and benzyl chloroformate (1.02 mL, 7.10 mmol). After 0.5 h the reaction ~ r~ was con~.lt.ated under reduced pressure to a yellow/green syrup. This material was dissolved in CHC13, washed 15 with H2O and brine, dried over Na2SO4, filtered and cor~ntrated in vacuo.
Filtration through a plug of silica gel, eluting with 20-30% EtOAc/l~ ne, afforded, after concentration of apl~ru~iate fr~rtion.~, a ll~ re of starting nitrobenzenederivative and the title compound. This m~tPri~l taken-up in 20% H20/THF (50 mL) and treated with W-2 Raney nickel (ca. 0.400 g). The reaction ll~ u~e was 20 .~h~k~n on a Parr apparatus under 45 psi H2. After 3 h the re~tion mixture was filtered through Celite~ and the filtrate cooled to 0 C and treated with NaHCO3(2.00 g, 23.8 mmol) followed by benzyl chloroformate (0.600 mL, 4.1L9 mmol). After 0.5 h the reaction ..~ure was concentrated under reduced pre~s2jule and the residue chrom~tographed over silica gel (125 g), eluting with 10-20% EtOAc/he~ne, to afford, after concentration of a~ iate fractions, 2.20 g (95~o) of the title compound as a yellow solid mp 91-93 C and MS(EI) 358 (M+).
Step 3: (R)-r3-r4-r( 1.~.A.~)-2-thi~-5-azabicyclor2.2. 1lhel~tan-5-yll-3-fluorophenyll-2-oxo-5-~ olidinyllmethanol A~ ltirm of N-(carbobenzyloxy)-4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluoro~niline (0.359 g, 1.00 mmol) in dry THF (4 mL) under N2 was cooled to -78 C and then treated with n-butyllithillm (0.633 mL of a 1.6 M solution in h~n~, 1.01 mmol). The re~rtion mixture was stirred at -78 C for 15 min and then treated with (R)-glycidyl buly~ate (0.151 mL, 1.00 mmol). When the ~ 1ition was coInplete, the cooling bath was removed and the reaction mixture allowed to warm to ambienttemperature overnight. TLC analysis (5~o MeOFlCHC13) in(li~ted the reaction was wo 96/15130 2 2 0 1 7 ~ 6 PCTIUS9S1127Sl compl~te but a small amount of the butyrate ester of the title compound was--present. The Atl-litioT~ of 5 drops of ~a 25 w~t.% solllticn of NaOMe/MeOH, followed by stirring for 20 min at room temperature, was effective in COIlV~ g this interm~ te to the title compound. The reaction l~ U' a was treated with G saturated aqueous NH4Cl (10 drops) and then c-~ncentrated under reduced pressure to an oil. This m~teriAl was dissolved in CH2Cl2 and washed with H20 and brine, dried over Na2S04, filtered and co~ntrated in vacuo to give a crude product.
Chrom~tography over silica gel (50 g), eluting with 1-3% MeOH/CHC13, afforded, after concentration of al ~lop~iate fractions, 0.132 g (41~fo) of the title compound as 10 an oil. Trituration with EtOAc afforded a precipitate, which was i~ol~te~l and dried zn vacuo to give an off-white solid with mp 156-157 C and MS(EI) 324 (M+).
Step 4: (~)-rr3-r4-r(15.4S)-2-thi~ 7~hicyclor2.2.1lhe~tan-5-yll-3-fl uoroph ~ vll-2-n~n-6-~ 7.f 1 i ~ yllm ~tllyllm ~t.h fl n f~811 1 fi~n ~ te A Eolllti~ n of (R)-[3-[4-[( lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-o~ olillinyl]methanol (1.68 g, 5.19 mmol) in dry CH2Cl2 (100 mL) under N2 was cooled to O C and treated with Et3N (0.793 mL, 5.70 mmol) followed by meth~ne~ulfonyl chloride (0.442 mL, 5.70 mmol). After 0.5 h at this tempel~ul~e, the re~ctior appeared to be complete by TLC analysis (55~o 20 MeOH/CHCl3). The mixture was washed with H20, saturated aqueous NaHCO3 and brine, dried over Na2S04, filtered and concentrated in vacuo to give 1.65 g (79%) of the title compound as a white solid with mp 139-142 C and MS(EI) 402 (M+).
5 Step 5: (S)-N-rr3-r3-fluoro-4-r(1S.4.0-2-thi~-5-~7slhi-~clor2.2.1lhe~ts~n-5-yllph~r~yll-~-n~--5-mr~7o~ yllm~sthyll~t~mi~1~
A mixture of (R)-[[3-[4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-o~r~70li~inyl]methyl]m.st~neslllfo~te (1.56 g, 3.88 mmol), 1:1 THF/i-PrOH (4 mL) and 30% NH40H (4 mL) was heated to 95 C in a sealed tube 30 for 14 h and then cooled to ambient temperature. TLC analysis (5~o MeOH/CHCl3) revealed the reaction to be complete. The mixture was diluted with CH2Cl2 (75 mL), washed with saturated aqueous NaHC03 (15 mL) and brine (15 mL), dried over Na2S04, filtered and corl~Pntrated under reduced pressure to give a syrup. The crude 5-(~minolnethyl)o~7.oli-1ino~ interme~ te was dissolved in CH2C12 (75 mL) 85 and treated with pyridine (0.345 mL, 4.27 mmol) and acetic anhydride (0.403 mL, 4.27 mmol) at ambient temperature. After 1 h, TLC analysis (5~o MeOH/CHC13) wo 96/l5l30 2 ~ ~ ~ 73 G PCTlUS9S1127Sl in~ t~ the acetylation to be complete The r~ction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to an amber solid. Chrom~tography over silica gel (125 g), eluting with 1-3% MeOH/CHC13, afforded, after conc~ntration of a~pro~l;ate fr~cti-n,q, 1.23 g (87~o) 5 of the title o~701i~1inone ~ntih~r,t~rial agent as a solid with mp 90-95 C and MS(EI) 365 (M+).
EXAMPLE 3: (S)-N-rr3-r3-fluoro-4-r(1.~.A.~)-2-thia-2.2-~ -5-~7~hiCyclor2.2.llh~pt~n-5-yll~henyll-2-n~l-5-~ inyllm~th-yllacet~mi(1e A solution of (S)-N-[[3-[3-fluoro-4-[(lS,4S)-2-thia-5-azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]~cet~mi~ie (0.300 g, 0.82 mmol) in 25~fo H2O/acetone (16 mL) was treated at ambient tempeldlure with 4-methylmorpholine-N-oxide (0.288 g, 2.47 mmol) followed by osmium tetro~ide (0.102 mL of a 2.5 wt.%
solution in tert-butanol, 0.008 mmol). After 18 h, TLC analysis (10% MeOH/CHCl3)1.5 revealed the o~ tion was complete. The reaction ~ u~e was treated with saturated aqueous NaHSO3 and then extracted with CHCl3. The comhine~l organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chrom~tographed over silica gel (10 g), eluting with 1-3~ MeOH/CHCl3, to afford, after concentration of appropriate 20 frArtion.~, 0.321 g (98~o) of the title o~ litlinon~ ~ntih~terial agent as a white solid with mp 95-105 C.
EXAMPLE 4: (s)-N-rr3-r3-fluoro-4-(tetrahydro-l F~-t~ nor3 4-c~yrrol-5(3H)-yl)phenyll-2-oxo-5~ 7~ yllmethyllacet~mide Step 1: cis-1-(Ph~ylm~thyl)-3.4-pyrrolitlin~dimethanol (cis)-1-(Phenylmethyl)-3,4-pyrroli-lin.q-lic~rboxylic acid, dimethyl ester was prepared according to the procedure of Y. Terao, et al (Chem. Pharm. Bull., 1985, 33, 2762-66). To a stirred soll7tion of this diester (12.14 g, 43.8 mmol) in dry THF (175 mL) 30 under N2 cooled to 0 C was added dropwise a solution of lithium aluminum hydride (lM in THF, 87 mL, 87 mmol) over 15 min. The reaction mixture was stirred at 0 C for 1 h, then at RT for 18 h. The re~ctio~ mixture was cooled to 0 C and q~ herl with successive ~ ition of H20 (3.2 mL), 5 N NaOH (3.2 mL) and H20 (11.7 mL). The reaction ~ lure became very thick and stirring was difficult. The35 reaction mixture was diluted with ether (500 mL) and filtered through a small pad of celite. The filter cake was washed with ether (250 mL). The filtrate was washed WO 96/lSl30 ~ ~; s PC~/US9S/1275 with H2O (1 x 300 mL) and the organics were dried (MgSO4), filtered and concçntrated to afford 9.3 g (41.8 mmol, 96%) of the desired diol and a thick yellow oil. Used without further purification. HRMS (FAB) calcd for C13HlgN02+H
222.1494, found 222.1490.
Step 2: cis-1-(Ph~rlylm~th~yl)-3.4-~li(m~t~ lfor~vlt~yy)m~th~ yrroli,1in~?
To a stirred sollltion of cis-1-(phenylmethyl)-3,4-pyrrolir~ine-limPtl~nol (9.2 g, 41.6 mmol) in CH2Cl2 (240 mL) cooled to 0 C was added triethylamine (29 mL, 208.1 mmol) followed by methanesulfonyl chloride (8.1 mL, 104.0 mmol). The re~ction 10 l~ lu~`e was stirred at 0 C for 15 min, then at RT for 1.5 h. The reaction mixture was poured into H2O (240 mT-) and the phases were separated. The aqueous phase was extracted with CH2Cl2 (1 x 100 mL). The combined organics were dried (MgSO4), filtered and concçntrated. The residue was purified by flash chrom~tography using ethyl acetate as the eluent to afford 14.2 g (37.5 mmol, 90%) 15 of the desired bis-mesylate as a thick yellow oil. HRMS (EI) calcd for C15H23NO6S2 377.0967, found 377.0968.
Step 3: T-TP~r~h,ydro-5-(~?h~r~ylm~th~yl)-l ~-thienor3.4-cll~yrrole To a stirred solution of cis-1-(phenylmethyl)-3,4-20 di(methylsulfonyloxy)methyl~y~,olidine (9.2 g, mmol), in dry DMSO (48 mL) wasadded anhydrous sodium sulfide (5.7 g, 73.3 mmol). The dark re~tio~ mixture was heated at 120 C for 18 h. The cooled reaction ll~ e was poured into ice H20 (150 mL). The resulting mixture was extracted with ether (3 x 200mL). The comhine~l organics were dried (MgSO4), filtered and collcentrated. The resulting25 residue was purified by flash chroln~graphy using ethyl acetate as the eluent to afford 4.2 g (19.1 mmol, 78%) of the desired product as a thick yellow oil. HRMS(EI) calcd for C13H17NS 219.1082, found 219.1080. Anal. Calcd for C13H17NS: C, 71.19; H, 7.81; N, 6.39. Found: C, 70.82; H, 7.83; N, 6.35.
30 Step 4: ~hydro~ -thi~?nor3.4-cll?yrrole. ~h~y~lrorhl~ride To a stirred solution of hexahydro-5-(phenylmethyl)-lN-t_ieno[3,4-c]pyrrole (1.2 g, 5.3 mmol) in CH2Cl2 (21 mL) cooled to 0 C was added dropwise via syringe 1-chloroethylchlorofo~ ate (1.15 mL, 10.7 mmol). The reaction mixture was stirred at 0 C for 20 min, then at RT for 90 min. The reaction mixture was concentrated.
35 The resulting residue was purified by flash chromatography using 25 % ethyl acetate in h~ne as the eluent to afford 611.3 mg (2.6 mmol, 49%) of 1-WO96/15130 22 ~1 73fi - ` PCTJUS9S~12751 chloroethylcarb~m~te. The column was then washed with 20~o mPt.hflnnlic slm~nonis~
i~ CHCl3 to afford 160.5 mg (1.24 mmol, 23 %) of desired ~nine as the free base.The 1-chloroethylcarbamate (611.3 mg, 2.6 m~nol) was dissolved in meth~nol (15 mL) and heated at refLux for 90 min. The cooled reaction mixture was concçntrated toafford 408.0 mg (2.5 mmol, 47~o) of the desired amine as the HCl salt (based on chlorocarbamte). mp 149-151 C; HRMS (EI) calcd for C6HllNS 129.0612, found 129.0614. Anal. Calcd for C6Hl2ClNS: C, 43.50; H, 7.30; N, 8.45; Cl: 21.39; S:
19.35. Found: C, 43.39; H, 7.23; N, 8.24; Cl: 21.08; S: 19.12.
lLO Step 5: 5-(~-Flll-)ro 4-~itro~h~t~yl) h~ lro 1~ thi~nor3.4~l~vrrole To a stirred suspension of hexahydro-5-~H-thieno[3,4-c]pyrrole, hydrochloride (147.3 mg, 0.89 mmol) in ~etonitrile (5 mL) was added 3,4-fluoronitrobenzene (0.11 mL, 0.98 mmol) followed by diisopropylethyl amine (0.36 mL, 2.05 mmol). The homogeneous re~- tion mixture was heated at reflux for 18 h. The cooled reaction16 mixture was co~c~ontrated. The resulting residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NH4Cl (1 x 25 mL). The aqueous layer was extracted with EtOAc (1 x 30 mL). Combined organics were washed with sa~uLdted NaHC03 (1 x 40 mL), brine (1 x 40 mL), dried (MgSO4), filtered and concentrated.The residue was purified by flash chroIn~tQgraphy using 20 ~ EtOAc in h~ne as the eluent to afford 202.5 mg (0.75 m nol, 89%) of the desired nitro compound as a bright yellow solid. mp 107-109 C; Anal. calcd for C12H13FN2O2S: C, 53.72; H, 4.88; N, 10.44; S: 11.95. Found: C, 53.38; H, 5.03; N, 10.34; S: 11.89.
Step 6: 3-r3-Fluoro-4-(tetr~l~y lro-1 Fr-thi~nor3.4~lpyrrol-5(3~) yl)~he~yl-~rh~mi~ l phenylmethylester To a stirred suspension of 5-(2-fluoro-4-nitrophenyl)-hexahydro-~H-thieno[3,4-c]pyrrole (1.44 g, 5.4 mmol) in eth~nol (70 mL) was added 2 M aqueous CuSO4 (2.9mL). This mixture was cooled to 0 C and sodium borohydride (1.10 g, 26.8 mmol) was added portionwise. (Caution: Very exothermic!) The dark reaction mixture was then heated at reflux for 2 h. The cooled re~ction l~ Ul~ was partitioned between EtOAc and H2O. The phases were separated. The aqueous phase was extracted with EtOAc (3 x 100 nT ). The combined organics were dried (MgSO4), filtered and conce~ ted. The resulting dark residue was dissolved in acetone/H20(2:1, 60 mL). This stirred eollltion was cooled to 0 C and solid NaEIC03 (1.35 g, 36 16.1 mmol) was added followed by benzylchloroformate (1.9 mL, 13.4 mmol). The reaction mixture was stirred at 0 C for 15 min, then at RT for 2 h. The reaction WO 96/15130 2 2 r~ ; PCT/US951127SI
mixture was qllan~.he~l bly c7ar3e~ul ~ ition of 10 % aqueou6 NaHS04 (30 mL). ~ereaction mixture was poured into EtOAc (250 mL) and the phases were separated.
The aqueous layer wa~ extracted with EtOAc (1 x 100 mL). The comhined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified by 5 flash chromatography using 20% EtOAc in ha~na to afford 1.6 g (4.3 mmol, 81 %) of the desired carbamate: mp 101-102 C; Anal. Calcd for C20H21FN2O2S: C, 64.50; H,5.68; N, 7.52; S: 8.61. Found: C, 64.33; H, 5.56; N, 7.53; S: 8.61.
Step 7: (5R)-3-r3-Fluoro-4-(tet.r~h*ydro-1 Fr-thiannr3.4~1~vrrol-S(.
yl)ph.qrlyll-5-(h,yrlrn~ymath~yl)-~-n~7.nlir~innna To stirred solution of 3-[3-fluoro-4-(tetrahydro-lN-thieno[3,4-c]pyrrol-5(3N)-yl)phenylcarbamic acid, phenylmethyl ester (1.36 g, 3.6 mmol) dry THF (14 mL) under N2 cooled to -78 C was added n-butylithillm (1.6 M in ha~ ~ne, 2.4 mL, 3.8 mmol). The reaction mixture was stirred at -78 C for 35 min and then R-(-)-15 glycidylbuly~ate (0.54 mL, 3.8 mmol) was added. The re~tion mixture was stirred at -78 C for 30 min, then at RT overnight. A thick L,re~ te had formed. The reaction mixture was qllen~.ha~l with sa~ ated aqueous NH4Cl (14 mL) and poured into EtOAc (50 mL). The phases were separated. The organic layer was washed with saturated aqueous NaHCO3 (1 x 30 mL), brine (1 x 30 mL), dried (MgSO4), 20 filtered and con~antrated. The residue was purified by flash chrom~tography using EtOAc as the eluent to afford 801.6 mg (2.4 mmol, 65%) of the desired product. mp 165-167 C; Anal. Calcd for C16H19FN2O3S: C, 56.79; H, 5.66; N, 8.28; S: 9.48.
Found: C, 56.88; H, 5.74; N, 8.21; S: 9.33.
25 Step 8: (fi~)-3-r3-Fluoro-4-(tetr~y~lro-1 Fr-thi~nor3.4~lDyrrol-5(3~l)-yl)l~har~
5-rr(mat~y~ fnT~y~ math~yll-~ 7~ in~na To a stirred solution of (5R)-3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)phenyl]-5-(hydro~ylllethyl)-2-olr~7.oli-1inone (656.5 mg, 1.9 mmol) in CH2C12 (20 mL) cooled to 0 C was added triethylamine (0.41 mL, 2.9 mmol) followed by 30 meth~ne.~ulfonylchloride (0.18 mL, 2.3 mmol). The re~ctio~ l~luLa was stirred at 0 C for 15 min, then at RT for 18 h. The reaction lllix~ula was poured into H20 (20 mL). the phases were separated. The aqueous layer was extracted with CH2Cl2 (1 x 50 mL). The combined organic layers were dried (MgSO4), filtered and concantrated. the residue was triturated with ether/heY~na and solid was isolated 35 by filtration and dried to aford 773.9 mg (1.9 mmol, 96%) of the desired mesylate.
mp 148-150 C; Anal. Calcd for C17H21FN2O5S2: C, 49.03; H, 5.08; N, 6.73; S:
= ~
WO 96/15 130 .2 ~ ~ t 7 ~ 6 . PC'rlUS9S/127Sl 1~.40. Found: C, 48.56; H, 5.12; N, 6.48, S; 15.41. Found: C, 48.46; H, 5.25; N, 6.38.
Step 9: (.O-N-rr3-r3-fluoro-4-(tetr~ydro~ -thi~nor3.4~1pyrrol-5(.
yl)~heIlyll-2-n~-5-o~,7olidinyllm~l;hyllace~m;~l~
A stirred suspension of (5R)-3-[3-fluoro-4-(tetrahydro-~I~-thieno[3,4-c]pyrrol-5-(3E~)-J yl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]-2-c.Y~7o~ inone (208.5 mg, 0.5 mmol) in THF (3 ~) and methAnoli-! ~mmoni~ (3 mL) was heated in a sealed tube at 100 C
for 48 h. (The reaction n~lul~ became homogenous at about 80 C.) The cooled re~ct!io~ e was corlsentrated and the resulting residue was dissolved in CH2Cl2 (5 mL) and cooled to 0 C. To this stirred suspension was added pyridine (0.12 mL, 1.5 mmol) followed by acetic anhydride (60 IIL, 0.6 mmol). The homogeneous reaction mi~u~a was stirred at 0 C for 15 min, then at RT for 1 h then concantrated. The residue was pu~fied by flash chromAtography using 7 %
l!; meth~nol in EtOAc as the eluent to afford 148.2 mg (0.4 mmol, 78~o) of the desired ~cet~micle mp 143-144 C; KF-H20: 0.52% Anal. Calcd for C18H22FN303S plus 0.52% H2O: C, 56.68; H, 5.87; N, 11.01; S: 8.40. Found: C, 56.31; H, 5.90; N, 10.74;
S: 8.30.
EXAMPLE 5: (S)-N-rr3-r3-fluoro-4-(tetrah~ydro-1 Fr-t~hi~-nor3.4~l}~yrrol-5(.~Fr)yl)~?hanyll-2-oxo-5-~ yllm~thyllacet~mi~a S-~
To a stirred solution of (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)phenyl]-2-oxo-5-oxazoldinyl]methyl]acet~mitle (216.8 mg, 0.57 mmol) in methanol (4 mL) and H2O (4 mL) cooled to 0 C was added sodium metaperiodate (134.4 mg, 0.63 mmol). The reaction Illi~U~e~ was stirred at 0 C for 1 h, then at RT for 18 h.
The solid p r~ on was removed by filtration. The solid was washed with CHC13 (50 mL). The filtrate was washed wit,h H2O (1 x 30 mL). The aqueous layer was extracted with CHCl3 (2 x 25 mL). The combined organic layers were dried (MgSO4), filtered and cor~c~nt.rated. The residue waæ purified by flash chrorn~tography using 7~o met~nol in CH2C12 as the eluent to afford 195.7 mg (0.5 mmol, 87 % ) of the desired sulfoxide. mp 162-164 C; HRMS (EI) calcd for C18H22FN3O4S 395.1315, found 395.1309. KF-H2O: 2.87 % Anal. ~Calcd for C18H22FN3O4S plus 2.87 % H2O: C, 53.09; H, 5.76; N, 10.32; S: 7.87. Found: C, 35 53.07; H, 6.01; N, 10.20; S: 7.87.
WO 96/l5l30 2 2 0 1 7 3 ~ t ~ ; PCT/US9S/l27Sl EXA~LE 6~ N-rr3-r3-fluoro-4-(tetr~.vflro-1~-thi.?nor3.4~1pyrrol-5(3ZO- ~
yl)~)h~T~yll-~-oxo-5-o~r~7.nli~ yllm-?t.~yll~t,~mitl.s. S.S-~
To a stirred solution of (S)-N-[[3-[3-fluoro-4-(tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-5 yl)phenyl]-2-oxo-5-~ ol~inyl]methyl]acetamide (213.9 mg, 0.56 mmol) in 25 %
acetone/H2O (8 mL) was added N-methylmorpholine-N-oxide (198.1 mg, 1.7 mmol) followed by osmium tetroxide in tert-butanol (2.5 % by wt.) (30 ~lL, 0.08 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was qn~n~hed by careful addition of saturated sodium bisulfite (8 mL). The mixture was poured into 10 CH2Cl2 (50 mL) and the phases were separated. The aqueous phase was extractedwith CH2Cl2 (2 x 25 mL). The combined organic layers were washed with brine (1 x30 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography using 7 % methanol in CHCl3 as the eluent to afford 194.3 mg (0.47 mmol, 84 ~o) of desired sulfone. mp 135-137 C; HRMS (EI) calcd for 15 C18H22FN3O5S 411.1264, found 411.1263. KF-H2O: 1.10 ~o. Anal. Calcd for Cl8H22FN3O5S plus 1.10 % H2O: C, 51.96; H, 5.45 N, 10.10; S: 7.71. Found: C, 51.73; H, 5.62; N, 9.96; S: 7.75.
EXAMPLE 7: ~iR-(S)-N-rr3-r3-fluoro-4-r3-~ -7azabicyclor3.3.0loctane-7-20 yllph~r~yll-2-oxo-5-~ 7olitlirlyllmf!th~yllace~mitl~
Following the general procedure of EXAMPLE 2 and m~king noncritical variations but sub~LiLuLi~lg hexahydro-lH-furo(3,4-c)pyrrole (Miller, A.D. U.S. Patent 3,976,632 1976). (2.33 g, 20.66 mmol) for (lS, 4S)-2-thia-5-azabicyclo[2.2.1]heptane, the title 25 compound is obtained, mp 124-126C.
~ r. ..~ i }~
WO96tlS130 2~1 736 PCTIUS9511~7Sl ~ Chart I
Y~NO2 R~No2 ///
Fl~--NH, ~1~HN 0113 1. RL~
/2. ~ o FI~NJ~O R~NJ~O
\~ H \~H
WO 96tl5130 2 2 0 1 7 ~ ~ PCT/US9S/12751 . ~ ~
Chart II
)~ R~N O
\
R~NJ~O R~NJ~O
H o \~
N--4~ NH2 o~ 9 R. R1 R1 NJ~O
\tH O
WO 96/15130 i 7 3 ~ ~ PCT/US9S1127S 1 Chart m R1~NJ~O F~N O
\tNJ~R2 \~NJI~R2 ~>N~ o tH ~
2~
WO 96/15130 . PCT/US9S/127Sl CHART IV
~4 \~?N~
CH3S2~ N~ ~NH
Ph Ph 18
Claims (15)
1. A compound of structural Formula I:
Formula I
or a pharmaceutically acceptable salt thereof wherein:
X is (a) O, (b) S, (c) SO, (d) SO2;
R1 is independently H, F, Cl or OMe;
R2 is (a) hydrogen, (b) C1-C8 alkyl optionally substituted with one or more of the following:
F, Cl, hydroxy, C1-C8 alkoxy, C1-C8 acyloxy, (c) C3-C6 cycloalkyl, (d) amino, (e) C1-C8 alkylamino, (f) C1-C8 dialkylamino, (g) C1-C8 alkoxy;
a is 0 to 3; b is 0 to 2; c is 0 to 2 (provided b and c cannot both be 0); d is 0 to 2;
and e is 0 to 2 (provided d and e cannot both be 0).
Formula I
or a pharmaceutically acceptable salt thereof wherein:
X is (a) O, (b) S, (c) SO, (d) SO2;
R1 is independently H, F, Cl or OMe;
R2 is (a) hydrogen, (b) C1-C8 alkyl optionally substituted with one or more of the following:
F, Cl, hydroxy, C1-C8 alkoxy, C1-C8 acyloxy, (c) C3-C6 cycloalkyl, (d) amino, (e) C1-C8 alkylamino, (f) C1-C8 dialkylamino, (g) C1-C8 alkoxy;
a is 0 to 3; b is 0 to 2; c is 0 to 2 (provided b and c cannot both be 0); d is 0 to 2;
and e is 0 to 2 (provided d and e cannot both be 0).
2. The compound of Claim 1 wherein X is S.
3. The compound of Claim 1 wherein each R1 is independently H or F.
4. The compound of Claim 3 wherein each R1 is F.
5. The compound of Claim 1 wherein R2 is hydrogen, a C1-C8 alkoxy, or a C1-C8 alkyl optionally substituted with one or more Cl or OH.
6. The compound of Claim 1 wherein R2 is methyl, dichloromethyl, hydroxymethyl, or methoxy.
7. The compound of Claim 1 which is:
a) (S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
b) (S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-thia-5-azabicycloo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; or c) (S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-thia-2,2-dioxo-5--azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
a) (S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide;
b) (S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-thia-5-azabicycloo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide; or c) (S)-N-[[3-[3-fluoro-4-[(1S,4S)-2-thia-2,2-dioxo-5--azabicyclo[2.2.1]heptan-5-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
8. The compound of Claim 1 which is the S-enantiomer form.
9. The compound of Claim 1 wherein c and b are both 1.
10. The compound of Claim 9 wherein d and e are both 1.
11. The compound of Claim 10 wherein a is 0.
12. The use of a compound of Formula I to prepare a medicament useful in treating microbial infections in a patient in need thereof by administering an effective amount of a compound of Formula I.
13. A compound of structural Formula II:
Formula II
or pharmaceutically acceptable salts thereof wherein:
X is (a) O, (b) S, (c) SO, (d) SO2;
R1 is independently H, F, Cl or OMe; and R is (a) hydrogen, (b) C1-C8 alkyl optionally substituted with one or more of the following:
F, Cl, hydroxy, C1-C8 alkoxy, C1-C8 acyloxy, (c) C3-C6 cycloalkyl, (d) amino, (e) C1-C8 alkylamino, (f) C1-C8 dialkylamino, (g) C1-C8 alkoxy.
Formula II
or pharmaceutically acceptable salts thereof wherein:
X is (a) O, (b) S, (c) SO, (d) SO2;
R1 is independently H, F, Cl or OMe; and R is (a) hydrogen, (b) C1-C8 alkyl optionally substituted with one or more of the following:
F, Cl, hydroxy, C1-C8 alkoxy, C1-C8 acyloxy, (c) C3-C6 cycloalkyl, (d) amino, (e) C1-C8 alkylamino, (f) C1-C8 dialkylamino, (g) C1-C8 alkoxy.
14. The compound of Claim 13 which is the S-enantiomer form.
15. The use of a compound of Formula II to prepare a medicament useful in treating microbial infections in warm-blooded animals by administering to a patient in need thereof an effective amount of a compound of Formula II.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33997994A | 1994-11-15 | 1994-11-15 | |
| US339,979 | 1994-11-15 | ||
| PCT/US1995/012751 WO1996015130A1 (en) | 1994-11-15 | 1995-10-31 | Bicyclic oxazine and thiazine oxazolidinone antibacterials |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2201736A1 true CA2201736A1 (en) | 1996-05-23 |
Family
ID=29405764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2201736 Abandoned CA2201736A1 (en) | 1994-11-15 | 1995-10-31 | Bicyclic oxazine and thiazine oxazolidinone antibacterials |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2201736A1 (en) |
-
1995
- 1995-10-31 CA CA 2201736 patent/CA2201736A1/en not_active Abandoned
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