5-hydroxymethyl-oxazolidin-2-one-derivatives and their uses as antibacterials

26 Pages·2013·2.71 MB·English

US008124623B2
(12) United States Patent (10) Patent No.: US 8,124,623 B2
Hubschwerlen et a1. (45) Date of Patent: Feb. 28, 2012
(54) SDE-RHIYVDARTOIXVYEMSE ATHNYDL T-HOEXIARZ OULSIEDSI ANS- 2-ONE- $8 $8
W0 W0 2007/023507 3/2007
ANTIBACTERIALS W0 W0 2008/056335 5/2008
OTHER PUBLICATIONS
(75) Inventors: Christian Hubschwerlen, Durrnenach
(FR); Hans Locher, Binningen (CH); Eustice et al., Drugs Under Experimental and Clinical Research, vol.
Philippe Panchaud, AllschWil (CH); XVI, No. 4, pp. 149-155 (1990).
Gregory et al., Journal of Medicinal Chemistry, vol. 32, 1673-1681
Jean-Luc Specklin, Kembs (FR)
(1989).
Written Opinion for International Application No. PCT/IB2007/
(73) Assignee: Actelion Pharmaceuticals Ltd., 054557, mailed Apr. 7, 2008.
AllschWil (CH) Borredon, Tetrahedron Letters, vol. 28, No. 17, pp. 1877-1880, Great
Britain, (1987).
Brickner, Current Pharmaceutical Design, vol. 2, pp. 175-194,
( * ) Notice: Subject to any disclaimer, the term of this
(1996).
patent is extended or adjusted under 35 Corey et al., Journal of the American Chemical Society, vol. 87, No.
U.S.C. 154(b) by 266 days. 6, pp. 1353-1364, Dec. 1965.
Gennaro, A., Index from “Remington: The Science and Practice of
(21) Appl.No.: 12/463,281 Pharmacy”, 20th Edition, Philadelphia College of Pharmacy and
Science, (2001).
(22) Filed: May 8, 2009 Gibson, M., Index from “Pharmaceutical Preformulation and Formu
lation”, IHS Health Group, Englewood, GO, USA, ISBN:
1574911201, (2001).
(65) Prior Publication Data
Gould, P., “Salt Selection for Basic Drugs”, International Journal of
US 2009/0247578 A1 Oct. 1, 2009 Pharmaceutics, vol. 33, pp. 201-217, Mar. 24, 1986.
Hamilton-Miller, Journal of Antimicrobial Chemotherapy, vol. 33,
pp. 197-200, (1994).
Related US. Application Data
Hubschwerlen et al., Bioorganic & Medicinal Chemistry Letters, vol.
(63) Continuation-in-part of application No. 13, pp. 4229-4233, Jul. 2003.
PCT/IB2007/054557, ?led on Nov. 9, 2007, and a (Continued)
continuation-in-part of application No.
PCT/IB2008/051854, ?led on May 9, 2008. Primary Examiner * D M Seaman
(74) Attorney, Agent, or Firm * Hunton & Williams LLP
(30) Foreign Application Priority Data
(57) ABSTRACT
The invention relates to novel chimeric antibiotics of formula
Nov. 10, 2006 (WO) ................ .. PCT/IB2006/054189
I
(51) Int. Cl.
A61K 31/04 (2006.01)
C07D 215/38 (2006.01)
(52) US. Cl. ....................... .. 514/312; 546/153; 546/159
(58) Field of Classi?cation Search ................ .. 546/159,
546/163; 514/312
See application ?le for complete search history.
(56) References Cited
U.S. PATENT DOCUMENTS
4,461,773 A 7/1984 Gregory
4,806,541 A 2/1989 Jolidon et a1. wherein
6,689,769 B2 * 2/2004 Gordeev et a1. ............. .. 514/183 R1 represents OH, OPO3H2 or OCOR5;
7,820,823 B2 * 10/2010 Hubschwerlen et al. .. 546/153
R2 represents H, OH or OPO3H2;
2004/0132764 A1* 7/2004 Locher ........................ .. 514/300
A represents N or CR6;
FOREIGN PATENT DOCUMENTS
R3 represents H or ?uorine;
EP 0216 345 4/1987 R4 is H, (Cl-C3) alkyl, or cycloalkyl;
JP 04128288 9/1990 R5 is the residue of a naturally occurring amino acid, of the
KR 2000-0067306 11/2000
enantiomer of a naturally occurring amino acid or of dim
SU 1156597 A 5/1985
ethylaminoglycine;
W0 WO 88/07998 10/1988
W0 WO 01/42242 6/2001 R6 represents H, alkoxy or halogen; and
W0 WO 02/59116 8/2002 n is 0 or 1;
W0 W0 02/064574 8/2002 and to salts (in particular pharmaceutically acceptable salts)
W0 W0 03/031443 4/2003
of compounds of formula I.
W0 W0 03/032962 4/2003
W0 W0 03/064415 8/2003 These chimeric compounds are useful in the manufacture of
W0 WO 2004/096221 11/2004 medicaments for the treatment of infections (e.g. bacterial
W0 WO 2005/023801 3/2005 infections).
WO 2005/058888 * 6/2005
W0 WO 2005/058886 6/2005 18 Claims, 1 Drawing Sheet
US 8,124,623 B2
Page 2
OTHER PUBLICATIONS International Search Report for International Application No. PCT/
IB2007/054557 mailed Apr. 7, 2008.
Hubschwerlen et al., Bioorganic & Medicinal Chemistry, vol. 1 1, pp.
Hubschwerlen et al. U.S. Appl. No. 12/063,305, ?led Feb. 8, 2008.
2313-2319, Jan. 2003. Ranaldi et al. (1996) Antimicrobial Agents and Chemotherapy 40(3):
Jacobsen et al., Journal ofthe American Chemical Society, vol. 110, 652-658.
pp. 1968-1970, Dec. 1987. Rudra et al. (2007) Bioorganic & Medicinal Chemistry Letters 17:
Kocienski, Protecting Groups, Foundations of Organic Chemistry
4778-4783.
SeriesiThieme, (1994). Vera-Cabrera et al. (2006) Antimicrobial Agents and Chemotherapy
Mitsunobu, SYHthGSISiRGVIGWS, vol. 1, pp. 1-28, Jan. 1981. 50(12): 4027-4029.
Sakurai, Bioorganic & Medicinal ChemistryLetters, vol. 8, pp. 2185 Yoon et al. (2005) Antimicrobial Agents and Chemotherapy 49(6):
2190, Jul. 1998. 2498-2500.
Vera-Cabrera et al., Antimicrobial Agents and Chemotherapy, vol.
50, No. 9, pp. 3170-3172, Sep. 2006. * cited by examiner
US. Patent Feb. 28,2012 US 8,124,623 B2
U Ex.1 M V
'1 Sagimi 1 a?gimi ‘I Bugfml
Figure i
US 8,124,623 B2
1 2
S-HYDROXYMETHYL-OXAZOLIDIN-2-ONE cally and biochemically stable chimeric molecules that bind,
DERIVATIVES AND THEIR USES AS as such, in tWo different targets have been more seldom
ANTIBACTERIALS reported. For example, oxaZolidinone-quinolone hybrids
have been reported as useful antimicrobial agents effective
CROSS-REFERENCE TO RELATED against a variety of multi-drug resistant pathogens (WO
APPLICATIONS
03/032962, WO 03/031443 andWO 2004/096221, WO 2005/
023801 and WO 2005/058888). Further, synthesis and bio
This application is a continuation-in-part of PCT/IB2007/
logical evaluation of these hybrids (Bioorg. & Med. Chem.
054557 With an international ?ling date of Nov. 9, 2007,
Which claims bene?t of PCT/IB2006/054189 ?led Nov. 10, (2003), 1 1, 2313-2319) andthe in?uence of the central spacer
2006. This application is also a continuation-in-part of PCT/ on the antibacterial activity in the structure-activity relation
IB2008/051854 With an international ?ling date of May 9, ship in the oxaZolidinone-quinolone series have also been
2008. Each of these documents are incorporated by reference reported (Bioorg. Med. Chem. Lett. (2003), 13, 4229-4233).
herein. All these derivatives contain a 4-aminomethyl-oxaZolidinone
rest as part of the oxaZolidinone pharmacophore.
FIELD OF THE INVENTION
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention concerns novel chimeric antibiotics
that are obtained from oxaZolidinone derivatives linked to a
FIG. 1 shoWs the outlook of a Western Blot plate used in
quinolone or naphthyridinone via a spacer, pharmaceutical
analyZing toxin A production in the supernatants of static
antibacterial compositions containing them and the use of 20
high density cell cultures of C. af?‘icile NC 13366.
these compounds in the manufacture of a medicament for the
treatment of infections (e.g. bacterial infections). These chi
DETAILED DESCRIPTION OF PREFERRED
meric compounds are useful antimicrobial agents effective
EMBODIMENTS
against a variety of human and veterinary pathogens includ
ing among others Gram-positive aerobic bacteria, Gram 25 It has noW been surprisingly found that the chimeric deriva
negative bacteria, anaerobic organisms and acid-fast organ
tives of formula I as de?ned hereafter are particularly effec
isms. tive antimicrobial agents that shoW effective against a variety
of multi-drug resistant bacteria.
BACKGROUND
Thus, the present invention relates to compounds of for
30
mula I
The intensive use of antibiotics has exerted a selective
evolutionary pressure on microorganisms to produce geneti
cally based resistance mechanisms. Modern medicine and
socio-economic behaviour exacerbate the problem of resis
tance development by creating sloW groWth situations for 35
pathogenic microbes, e. g. in arti?cial joints, and by support
ing long-term host reservoirs, eg in immuno-compromised
patients.
In hospital settings, an increasing number of strains of
Staphylococcus aureus, Streptococcus pneumonia, Entero 40
coccus spp., and Pseudomonas aeruginosa, major sources of
infections, are becoming multi-drug resistant and therefore
dif?cult if not impossible to treat:
S. aureus is [3-lactam, quinolone and noW even vancomycin wherein
resistant; 45 R1 represents OH, OPO3H2 or OCOR5;
S. pneumoniae is becoming resistant to penicillin, qui R2 represents H, OH or OPO3H2;
nolone and even to neW macrolides; A represents N or CR6;
Enteroccocci are quinolone and vancomycin resistant and R3 represents H or ?uorine;
[3-lactams Were never ef?cacious against these strains. R4 is H, (Cl-C3) alkyl or cycloalkyl;
Further neW emerging organisms like Acinetobacter spp. 50 R5 is the residue of a naturally occurring amino acid, of the
or C. di?icile, Which have been selected during therapy With enantiomer of a naturally occurring amino acid or of dimethy
the currently used antibiotics, are becoming a real problem in laminoglycine;
hospital settings. R6 represents H, alkoxy or halogen; and
In addition, microorganisms that are causing persistent n is 0 or 1;
infections are increasingly being recogniZed as causative 55 and to salts (in particular pharmaceutically acceptable salts)
agents or cofactors of severe chronic diseases like peptic of compounds of formula I.
ulcers or heart diseases. The compounds of formula I may contain one or more
In a chimeric molecule tWo or more molecules that exist stereogenic or asymmetric centers, such as one or more asym
separately in their native state are joined together to form a metric carbon atoms. The compounds of formula I may thus
single entity (i.e. molecule) having the desired functionality 60 be present as mixtures of stereoisomers or preferably as pure
of all of its constituent molecules. stereoisomers. Mixtures of stereoisomers may be separated in
Molecules Wherein tWo antibiotics that have tWo different a manner knoWn to a person skilled in the art. The folloWing
modes of action have been linked have been reported in the paragraphs provide de?nitions of the various chemical moi
literature (e.g. Journal of Antimicrobial Chemotherapy eties for the compounds according to the invention and are
(1994), 33, 197-200). Many of them are hoWever such that the 65 intended to apply uniformly throughout the speci?cation and
tWo antibiotic parts are released after biological activation claims unless an otherWise expressly set out de?nition pro
(e.g. central ester cleavage, beta-lactam cleavage). Chemi vides a broader or narroWer de?nition.
US 8,124,623 B2
3 4
Unless speci?ed otherwise, the term “alkyl” (Whether used R6 represents H or alkoxy; and
alone or in combination) refers to a saturated straight or n is 0 or 1;
branched chain alkyl group containing 1 to 6 carbon atoms, and to salts (in particular pharmaceutically acceptable salts)
of compounds of formula ICE.
and preferably 1 to 3 carbon atoms. Representative examples
According to a ?rst main embodiment of this invention, the
of alkyl groups include, but are not limited to, methyl, ethyl,
propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, compounds of formula I are such that n is 0. Such compounds
Will be hereafter referred to as “compounds of formula 15”.
n-pentyl, neopentyl, iso-pentyl, n-hexyl and iso-hexyl. The
According to one particular variant of the ?rst main
term “(C l-Cx)alkyl” (x being an integer) refers to a saturated embodiment, the compounds of formula 15 Will be such that
straight or branched chain alkyl group containing 1 to x they have the folloWing stereochemistry:
carbon atoms.
The term “alkoxy” refers to a saturated straight or branched
chain alkoxy group, containing 1 to 6 carbon atoms, and
preferably 1 to 3 carbon atoms. Representative examples of
alkoxy groups include, but are not limited to, methoxy,
ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-bu
toxy, tert-butoxy or n-hexyloxy. The term “(C 1 -Cx)alkoxy” (x
being an integer) refers to a straight or branched chain alkoxy
group containing 1 to x carbon atoms.
The term “halogen” refers to ?uorine, chlorine, bromine or 20
iodine, and preferably to ?uorine or chlorine.
The term “cycloalkyl”, used alone or in combination, refers
to a saturated cyclic hydrocarbon moiety containing 3 to 6 According to another variant of the ?rst main embodiment,
carbon atoms and preferably 3 to 5 carbon atoms. Represen the compounds of formula 15 Will be such that they have the
folloWing stereochemistry:
tative examples of cycloalkyl groups include, but are not 25
limited to, cyclopropyl and cyclopentyl.
When it is Written that R5 is the residue of an amino acid, it
is meant thereby that RSiCOOH is the corresponding amino
acid.
The term “pharmaceutically acceptable salts” refers to 30
non-toxic, inorganic or organic acid and/or base addition
salts, Reference can be made to “Salt selection for basic
drugs”, Int. J. Pharm. (1986), 33, 201-217.
Unless used regarding temperatures, the term “about”
35
placed before a numerical value “X” refers in the current
application to an interval extending from X minus 10% of X
to X plus 10% of X, and preferably to an interval extending
from X minus 5% ofX to X plus 5% of X. In the particular According to a second main embodiment of this invention,
case of temperatures, the term “about” placed before a tem the compounds of formula I are such that n is 1. Such com
40
perature “Y” refers in the current application to an interval pounds Will be hereafter referred to as “compounds of for
extending from the temperatureY minus 100 C. to Y plus 100 mula 16”.
C., and preferably to an interval extending fromY minus 5° C. According to a further main embodiment of this invention,
to Y plus 5° C.; besides, room temperature shall mean in the the compounds of formula I Will be such that they are also
current patent application 250 C. compounds of formula 1D
In particular, the invention relates to compounds of for 45
mula I that are also compounds of formula ICE
ICE
50
55
Wherein
R2 represents H or OHl;
wherein 60 A represents N or CR6;
R1 represents OH, OPO3H2 or OCOR5; R3 represents ?uorine;
R2 represents H, OH or OPO3H2; R4 represents H, (Cl-C3) alkyl or cycloalkyl;
A represents N or CR6; R6 represents H or alkoxy; and
R3 represents ?uorine; n is 0 or 1.
R4 represents H, (Cl-C3) alkyl or cycloalkyl; 65 According to yet another main embodiment of this inven
R5 is the residue of a naturally occurring amino acid (in tion, the compounds of formula I Will be such that they are
particular the residue of Ala); also compounds of formula IPDG
US 8,124,623 B2
6
R4 represents (C3 -C5 )cycloalkyl (and in particular cyclo
PrOPyD
The folloWing compounds of formula I are particularly
preferred.
l-cyclopropyl-6-?uoro -7- {4- [2 -?uoro -4-((R)-5 -hydroxym
ethyl-2-oxo -oxaZolidin-3-yl)-phenoxymethyl] -4 -hy
droXy-piperidin- l -yl} -4-oxo-l ,4-dihydro -quinoline-3 -
carboxylic acid;
l-cyclopropyl-6-?uoro -7- {4- [2 -?uoro -4-((R)-5 -hydroxym
ethyl-2-oxo -oxaZolidin-3-yl)-phenoxymethyl] -piperidin
l-yl } -4 -oxo- l ,4-dihydro-quinoline-3-carboxylic acid;
l-cyclopropyl-6-?uoro -7- {4- [2 -?uoro -4-((R)-5 -hydroxym
ethyl-2-oxo -oxaZolidin-3-yl)-phenoxymethyl] -4 -hy
R1 represents OH and R2 represents OPO3H2, or R1 repre
droXy-piperidin-l-yl}-4-oXo-l,4-dihydro-[1,8]naphthyri
sents OPO3H2 or OCOR5 and
dine-3-carboxylic acid;
R2 represents H, OH or OPO3H2;
7-(4- {4- [(R)-5-((S)-2-amino -propionyloXymethyl)-2-oxo
A represents N or CR6;
oXaZolidin-3 -yl] -2 -?uoro -phenoxymethyl } -4 -hydroxy
R3 represents ?uorine,
piperidin- l -yl)-l -cyclopropyl-6-?uoro-4-oxo-l ,4-dihy
R4 represents H, (Cl-C3) alkyl or cycloalkyl;
dro-quinoline-3-carboxylic acid;
R5 is the residue of a naturally occurring amino acid (in 20
l-cyclopropyl-6-?uoro -7- {4- [2 -?uoro -4-((R) -2 -oxo-5 -
particular the residue of Ala);
phosphonooxymethyl-oXaZolidin-3 -yl)-phenoxymethyl] -
R6 represents H or alkoxy; and
4-hydroxy-piperidin-l -yl} -4-oxo- l ,4-dihydro -quinoline
n is 0 or 1.
3-carboxylic acid;
According to a particular embodiment of this invention, the
25 l-cyclopropyl-6-?uoro -7- { (R)-3 -[2-?uoro-4-((R)-5 -hy
compounds of formula I Will be such that A represents N.
droXymethyl-2-oXo-oXaZolidin-3 -yl) -phenoxymethyl] -3 -
According to another particular embodiment of this inven
hydroxy-pyrrolidin-l -yl} -4-oxo- l ,4-dihydro -quinoline
tion, the compounds of formula I Will be such that A repre 3-carboxylic acid;
sents CR6. In such case, R6 Will preferably represent H or l-cyclopropyl-6-?uoro -7- { (S)-3- [2-?uoro -4-((R)-5 -hy
alkoxy (and in particular H or methoxy).
30 droXymethyl-2-oXo-oXaZolidin-3 -yl) -phenoxymethyl] -3 -
According to an important variant of this invention, the hydroxy-pyrrolidin-l -yl} -4-oxo- l ,4-dihydro -quinoline
compounds of formula I Will be such that R1 is OH. 3 -carboxylic acid;
According to another important variant of this invention, l-cyclopropyl-6-?uoro -7- { (R)-3 -[2-?uoro-4-((R)-5 -hy
the compounds of formula I Will be such that R1 is OPO3H2 or droXymethyl-2-oXo-oXaZolidin-3 -yl) -phenoxymethyl] -3 -
hydroxy-pyrrolidin-l -yl} -8-methoXy-4-oxo-l ,4-dihydro
OCOR5 . 35
According to yet another important variant of this inven quinoline-3-carboxylic acid;
tion, the compounds of formula I Will be such that R1 is H. l-cyclopropyl-6-?uoro -7- { (S)-3- [2-?uoro -4-((R)-5 -hy
According to yet another important variant of this inven droXymethyl-2-oXo-oXaZolidin-3 -yl) -phenoxymethyl] -3 -
tion, the compounds of formula I Will be such that R2 is OH. hydroxy-pyrrolidin-l -yl} -8-methoXy-4-oxo-l ,4-dihydro
According to a further important variant of this invention, 40 quinoline-3-carboxylic acid;
the compounds of formula I Will be such that R2 is OPO3H2. l-cyclopropyl-6-?uoro -7- { (R)-3 -[2-?uoro-4-((R)-5 -hy
Preferably, the amino acid residue R5 is such that droXymethyl-2 -OXO -oxaZolidin-3 -yl) -phenoxymethyl] -
R54COOH represents a natural amino acid (notably Ala). pyrrolidin-l -yl} -4-oxo- l ,4-dihydro -quinoline-3 -carboxy
Preferred compounds of formula I are also those Wherein at lic acid;
least one of the folloWing characteristics is present: 45 l-cyclopropyl-6-?uoro -7- { (S)-3- [2-?uoro -4-((R)-5 -hy
A represents CR6; droXymethyl-2 -OXO -oxaZolidin-3 -yl) -phenoxymethyl]
Rl represents OH or OPO3H2; pyrrolidin-l -yl} -4-oxo- l ,4-dihydro -quinoline-3 -carboxy
R2 represents H or OH; lic acid;
R3 represents ?uorine; l-cyclopropyl-6-?uoro -7- { (R)-3 -[2-?uoro-4-((R)-5 -hy
R4 represents (C l-C3)alkyl or cycloalkyl. 50 droXymethyl-2 -OXO -oxaZolidin-3 -yl) -phenoxymethyl] -
More preferred compounds of formula I are those Wherein pyrrolidin-l -yl} -8-methoXy-4-oxo-l ,4-dihydro -quino
at least one of the folloWing characteristics is present: line-3-carboxylic acid;
n is 0; l-cyclopropyl-6-?uoro -7- { (S)-3- [2-?uoro -4-((R)-5 -hy
A represents CR6, R6 representing H or alkoxy (and pref droXymethyl-2 -OXO -oxaZolidin-3 -yl) -phenoxymethyl] -
erably H or methoxy); 55 pyrrolidin-l -yl} -8-methoXy-4-oxo-l ,4-dihydro -quino
Rl represents OH; line-3-carboxylic acid;
R2 represents H or OH; l-cyclopropyl-6-?uoro -7- {4- [2 -?uoro -4-((R)-5 -hydroxym
R3 represents ?uorine; ethyl-2-oxo -oxaZolidin-3-yl)-phenoxymethyl] -4
R4 represents cycloalkyl. phosphonooXy-piperidin- l -yl} -4-oxo-l ,4-dihydro -quino
Even more preferred compounds of formula I are those 60 line-3-carboxylic acid;
Wherein at least one of the folloWing characteristics is l-ethyl-6-?uoro -7-{4- [2 -?uoro -4-((R)-5 -hydroXymethyl-2
present: oXo-oXaZolidin-3 -yl)-phenoxymethyl] -piperidin- l -yl} -4
n is 0; oxo- l ,4-dihydro-quinoline-3-carboxylic acid;
A represents CR6, R6 representing H or methoxy; 7-(4- {4- [(R)-5-((S)-2-amino -propionyloXymethyl)-2-oxo
Rl represents OH; oXaZolidin-3 -yl] -2 -?uoro -phenoxymethyl } -piperidin- l -
R2 represents H or OH (and notably OH); yl)-l -cyclopropyl-6-?uoro-4-oxo- l ,4-dihydro-quinoline
R3 represents ?uorine; 3-carboxylic acid;
US 8,124,623 B2
7 8
6-?uoro-7-{4-[2-?uoro-4-((R)-5-hydroxymethyl-2-oxo-ox by Campylobacterjejuni; intestinal protoZoa related to infec
aZolidin-3-yl)-phenoxymethyl] -4 -hydroxy-piperidin-1 - tion by Cryprosporidium spp.; odontogenic infection related
to infection by viridans streptococci; persistent cough related
to infection by Bordetella pertussis; gas gangrene related to
aZolidin-3-yl)-phenoxymethyl] -4 -hydroxy-piperidin-1 - 01 infection by Clostridium perfringens orBacteroides spp.; and
yl } -4 -oxo- 1 ,4-dihydro- [1 ,8]naphthyridine-3-carboxylic atherosclerosis or cardiovascular disease related to infection
acid; as Well as salts thereof (and in particular pharmaceu by Helicobacter pylom or Chlamydia pneumoniae.
tically acceptable salts thereof). Compounds of formula 1 according to the present invention
Chimeric derivatives of formula I are suitable for the use as are further useful for the preparation of a medicament for the
medicaments, particularly as antimicrobial agents, in human treatment of infections that are mediated by bacteria such as
medicine but also in veterinary medicine in the treatment of E. coli, Klebsiella pneumoniae and other Enterobacteriaceae,
species like pigs, ruminants, horses, dogs, cats and poultry. Acinetobacter spp., Stenothrophomonas nialtophilia, Neis
Chimeric derivatives of formula 1 according to the present seria meningitidis, Bacillus cereus, Bacillus anthracis,
invention are also useful for the manufacture of a medicament Corynebacterium spp., Propionibacterium aches and
for the treatment of infections (notably bacterial infections or bacteroide spp. In addition, compounds of formula I accord
protoZoal infections) and disorders related to infections (no ing to the present invention are further useful for the prepa
tably disorders related to bacterial infections or to protoZoal ration of a medicament for the treatment of infections that are
infections). mediated by Clostridim di?icile.
The compounds according to this invention are particularly Compounds of formula 1 according to the present invention
active against bacteria and bacteria-like organisms. They are 20 are further useful to treat protoZoal infections caused by Plas
therefore particularly suitable in human, as Well as in animals, modium malaria, Plasmodiufalciparum, Toxoplasma gondii,
for the prophylaxis and chemotherapy of local and systemic Pneamocystis carinli, Trypanosoma brucei and Leishmania
infections caused by these pathogens as Well as disorders spp.
related to bacterial infections comprising pneumonia, otitis The preceding lists of pathogens are to be interpreted
media, sinusitis, bronchitis, tonsillitis, and mastoiditis related 25 merely as examples and in no Way as limiting.
to infection by Streptococcus pneumoniae, Haemophilus As Well as in humans, bacterial infections can also be
in?uenzae, Moraxella catarrhalis, Staphylococcus aureus, treated in other species like pigs, ruminants, horses, dogs, cats
Enterococcusfaecalis, Ffaecium, E. casselifavus, S. epider and poultry.
midis, S. haemolyticus, or Peptostreptococcus spp.; pharyn Therefore, the compounds of formula I or their pharma
gitis, rheumatic fever, and glomerulonephritis related to 30 ceutically acceptable salts can be used for the preparation of
infection by Streptococcus pyogenes, Groups C and G. strep a medicament, and are suitable, for the prevention or treat
tococci, Corynebacterium diphtheriae, or Actinobacillus ment of bacterial infections (notably those caused by the
haemolyticuim; respiratory tract infections related to infec pathogens mentioned in the lists above).
tion by Mycoplasma pneumoniae, Legionella pneumophila, The compounds of formula I and their pharmaceutically
Streptococcus pneumoniae, Haemophilus in?uenzae, or 35 acceptable salts can be used as medicaments, eg in the form
Chlamydia pneumoniae; blood and tissue infections, includ of pharmaceutical compositions for enteral or parental
ing endocarditis and osteomyelitis, caused by S. aureus, S. administration.
haemolyticus, E. faecalis, E. faecium, E. durans, including The production of the pharmaceutical compositions can be
strains resistant to knoWn antibacterials such as, but not lim effected in a manner Which Will be familiar to any person
ited to, beta-lactams, vancomycin, aminoglycosides, quino 40 skilled in the art (see for example Mark Gibson, Editor, Phar
lones, chloramphenicol, tetracyclines and macrolides; maceutical Preformulation and Formulation, IHS Health
uncomplicated skin and soft tissue infections and abscesses, Group, EngleWood, Colo., USA, 2001; Remington, The Sci
and puerperal fever related to infection by Staphylococcus ence and Practice of Pharmacy, 20th Edition, Philadelphia
aureus, coagulase-negative staphylococci (i.e., S. epidermi College of Pharmacy and Science) by bringing the described
dis, S. haemolyticus, etc.), Streptococcus pyogenes, Strepto 45 compounds of formula I or their pharmaceutically acceptable
coccus agalactiae, Streptococcal groups C-F (minute colony salts, optionally in combination With other therapeutically
streptococci), viridans streptococci, Corynebacterium minut valuable substances, into a galenical administration form
issimum, Clostridium spp., or Bartonella henselae; uncom together With suitable, non-toxic, inert, therapeutically com
plicated acute urinary tract infections related to infection by patible solid or liquid carrier materials and, if desired, usual
Staphylococcus aureus, coagulase-negative staphylococcal 50 pharmaceutical adjuvants.
species, or Enrerococcus spp.; urethritis and cervicitis; sexu Another aspect of the invention concerns a method for the
ally transmitted diseases related to infection by Chlamydia treatment of an infection comprising the administration to the
trachomatis, Haemophilus ducreyi, Tr eponema pallidum, patient of a pharmaceutically active amount of a compound
Ureaplasma urealyticum, or Neiserria gonorrhoeae; toxin according to formula I or of a pharmaceutically acceptable
diseases related to infection by S. aureus (food poisoning and 55 salt thereof.
toxic shock syndrome), or Groups A, B, and C streptococci; Moreover, the compounds of formula I may also be used
ulcers related to infection by Helicobacter pylori; systemic for cleaning purposes, eg to remove pathogenic microbes
febrile syndromes related to infection by Borrelia recur and bacteria from surgical instruments or to make a room or
rentis; Lyme disease related to infection by Borrelia burgdor an area aseptic. For such purposes, the compounds of formula
feri; conjunctivitis, keratitis, and dacrocystitis related to 60 I could be contained in a solution or in a spray formulation.
infection by Chlamydia trachomatis, Neisseria gonorrhoeae, Any reference to a compound offormula l, 15 l, I52, 16, ID or
S. aureus, S. pneumoniae, S. pyogenes, H. in?uenzae, or List IPDG is to be understood as referring also to a salt (especially
eria spp.; disseminated Mycobacteriuim avium complex a pharmaceutically acceptable salt) of a compound of formula
(MAC) disease related to infection by Mycobacterium avium, 1, l5 1, I52, 16, 1D or IPDC respectively, as appropriate and expe
orMycobacterium intracellulare; infections caused by Myco 65 dient. Besides, any preferences indicated for the compounds
bacterium tuberculosis, M leprae, M paratuberculosis, M of formula 1 (Whether for the compounds themselves, salts
kansasii, or M chelonei; gastroenteritis related to infection thereof, compositions containing the compounds or salts
US 8,124,623 B2
10
thereof, uses of the compounds or salts thereof etc.) apply vi) According to preferred sub-embodiments of embodiments
mulalis mulandis to compounds of formula ICE, the com i) to iii), the compound of formula II NTor its pharmaceutically
pounds of formula 15, the compounds of formula 151, the acceptable salt Will be selected from:
compounds of formula 152, the compounds of formula 16, the l-cyclopropyl-6-?uoro -7- {4- [2 -?uoro -4-((R)-5 -hydroxym
compounds of formula ID and the compounds of formula ethyl-2-oxo-oxaZolidin-3-yl)-phenoxymethyl]-4-hy
IPDG' droxy-piperidin- l -yl} -4-oxo-l ,4-dihydro -quinoline-3 -
Various additional embodiments of the invention are pre carboxylic acid;
sented hereafter: l-cyclopropyl-6-?uoro -7- {4- [2 -?uoro -4-((R)-5 -hydroxym
i) According to its ?rst additional embodiment, the present ethyl-2-oxo-oxaZolidin-3-yl)-phenoxymethyl]-4-hy
invention relates to the compounds of formula II NT droxy-piperidin-l-yl}-4-oxo-l,4-dihydro-[1,8]naphthyri
dine-3-carboxylic acid;
l-cyclopropyl-6-?uoro -7- {3- [2 -?uoro -4-((R)-5 -hydroxym
IINT
ethyl-2-oxo-oxaZolidin-3-yl)-phenoxymethyl]-3 -hy
droxy-pyrrolidin- l -yl} -4-oxo-l ,4-dihydro -quinoline-3 -
carboxylic acid;
and the pharmaceutically acceptable salts thereof.
vii) According to more preferred sub-embodiments of
embodiments i) to iii), the compound of formula I INT or its
pharmaceutically acceptable salt Will be l-cyclopropyl-6
20
aZolidin-3 -yl) -phenoxymethyl] -4-hydroxy-piperidin-l -yl } -
4-oxo-l,4-dihydro-quinoline-3-carboxylic acid or a
pharmaceutically acceptable salt thereof.
Wherein 25 viii) According to one aspect of embodiments i) to vii), the
A is N or CH; and present invention Will relate to the compounds of formula I INT
n is 0 or 1; as de?ned in one of embodiments i) to vii), or the pharma
or the pharmaceutically acceptable salts thereof, for prevent ceutically acceptable salts thereof, for treating the intestinal
ing or treating intestinal diseases Which are caused by bacte diseases Which are caused by bacteria selected from
ria selected from Closlridium di?icile, Closlridium per?’in 30 Closlridium dl?icile, Closlridium pefringens and Staphylo
gens or Staphylococcus aureus. coccus aureus.
The following paragraphs provide additional de?nitions of ix) According to one preferred aspect of embodiment viii),
various terms used in the additional embodiments and are the present invention Will relate to the compounds of formula
intended to apply uniformly throughout said additional I INT as de?ned in one of embodiments i) to vii), or the phar
embodiments and the corresponding claims unless an other 35 maceutically acceptable salts thereof, for treating the intesti
Wise expressly set out de?nition provides a broader or nar nal diseases Which are caused by Closlridium dz?icile (nota
roWer de?nition. bly by a toxin producing strain of Closlridium di?icile).
The term “preventing”, “prevent” or “prevention” used x) According to another main aspect of embodiments i) to
With reference to a disease means either that said disease does vii), the present invention Will relate to the compounds of
not occur in the patient or animal, or that, although the animal 40 formula II NT as de?ned in one of embodiments i) to vii), or the
or patient is affected by the disease, part or all the symptoms pharmaceutically acceptable salts thereof, for preventing the
of the disease are either reduced or absent. intestinal diseases Which are caused by bacteria selected from
The term “treating”, “treat” or “treatment” used With ref Closlridium dl?icile, Closlridium perfringens and Staphylo
erence to a disease means either that said disease is cured in coccus aureus.
the patient or animal, or that, although the animal or patient 45 xi) According to one preferred aspect of embodiment x),
remains affected by the disease, part or all the symptoms of the present invention Will relate to the compounds of formula
the disease are either reduced or eliminated. I INT as de?ned in one of embodiments i) to vii), or the phar
ii) Preferably, the compound of formula I INT as de?ned in maceutically acceptable salts thereof, for preventing the
embodiment i), or a pharmaceutically acceptable salt thereof, intestinal diseases Which are caused by Closlridium dz?icile
Will alloW effective prevention or treatment of diarrhea dis 50 (notably by a toxin producing strain of Closlridium di?icile).
eases associated With enterotoxigenic strains of Closlridium xii) Preferably, the patients in Which the intestinal diseases
dl?icile, Closlridium per?’ingens or Staphylococcus aureus mentioned in embodiments
Without increasing the concentration of vancomycin-resistant i) to xi) are intended to be prevented Will be patients treated
enterococci (V RE) in the gut. With other antibiotics or With antiviral therapies, patients With
iii) More preferably, the compound of formula I INT as 55 an immunocompromised system such as cytotoxic chemo
de?ned in embodiment i), or a pharmaceutically acceptable therapy or organ transplant patients, elderly (65 years or
salt thereof, Will alloW effective prevention or treatment of older) patients, or patients of intensive care units or of long
diarrhea diseases associated With enterotoxigenic strains of term care facilities.
Closlridium dl?icile, Closlridium perringens or Staphylococ xiii) Yet another main embodiment of this invention relates
cus aureus and reduction of the concentration of VRE in the 60 to a method of preventing or treating in a patient an intestinal
gut. disease Which is caused by bacteria selected from
iv) Preferably, the compounds of formula INT as de?ned in Closlridium dl?icile, Closlridium perfringens and Staphylo
one of embodiments i) to iii), or the pharmaceutically accept coccus aureus, said method comprising the administration to
able salts thereof Will be such that A is CH. said patient of an effective amount of a compound of formula
v) Preferably also, the compounds of formula I INT as de?ned 65 II NT as de?ned in one of embodiments i) to vii), or of a
in one of embodiments i) to iv), or the pharmaceutically pharmaceutically acceptable salt of such a compound, for a
acceptable salts thereof, Will be such that n is l. duration suf?cient to prevent or treat the intestinal disease.
US 8,124,623 B2
11 12
xiv) Preferably, the method of embodiment xiii) Will allow xxiv) According to another aspect of embodiment xxi), the
effective prevention or treatment of diarrhea diseases associ present invention Will relate to the use of a compound of
ated With enterotoxigenic strains of Clostridium di?icile, formula IINT as de?ned in one of embodiments i) to vii), or of
Clostriditem perfringens or Staphylococcus agreus Without a pharmaceutically acceptable salt of such a compound, for
increasing the concentration of vancomycin-resistant entero the manufacture of a medicament intended to prevent an
cocci (VRE) in the gut. intestinal disease Which is caused by bacteria selected from
xv) More preferably, the method of embodiment xiii) Will Clostridium dl?icile, Clostridium perfringens and Staphylo
alloW effective prevention or treatment of diarrhea diseases coccus aureus.
associated With enterotoxigenic strains of Clostridium d?i xxv) According to one preferred aspect of embodiment
cile, Clostridiun pelfringens or Staphylococcus aureus and xxiv), the intestinal disease intended to be prevented Will be
reduction of the concentration of VRE in the gut. caused by Clostridium dz?icile (notably by a toxin producing
xvi) According to one aspect of embodiments xiii) to xv), strain of Clostridium dz?icile).
the present invention Will relate to a method of treating in a xxvi) Preferably, the patients for Which the medicament
patient an intestinal disease Which is caused by bacteria manufactured according to one of embodiments xxi) to xxv)
selected from Clostridium di?icile, Clostridium perj‘i’ingens Will be intended Will be patients treated With other antibiotics
and Staphylococcus aureus, said method comprising the or With antiviral therapies, patients With an immunocompro
administration to said patient of an effective amount of a mised system such as cytotoxic chemotherapy or organ trans
compound of formula IINT as de?ned in one of embodiments plant patients, elderly (65 years or older) patients, or patients
i) to vii), or of a pharmaceutically acceptable salt of such a of intensive care units or of long-term care facilities.
compound, for a duration suf?cient to treat the intestinal 20 xxvii) Another aspect of this invention relates to a method
disease. of preventing or treating in an animal (e.g. in a dog, a cat, a
xvii) According to one preferred aspect of embodiment pig, a coW or a horse) an intestinal disease caused by bacteria
xvi), the present invention Will relate to a method of treating selected from Clostridium di?icile, Clostridium per?’ingens
in a patient an intestinal disease Which is caused by and Staphylococcus aureus, said method comprising the
Clostridium dz?icile (notably by a toxin producing strain of 25 administration to said animal of an effective amount of a
Clostridium dl?icile). compound of formula IINTas de?ned in one of embodiment i)
xviii) According to another aspect of embodiments xiii) to to vii), or of a pharmaceutically acceptable salt of such a
xv), the present invention Will relate to a method of preventing compound, for a duration suf?cient to treat the intestinal
in a patient an intestinal disease Which is caused by bacteria disease.
selected from Clostridium d?icile, Clostridium perj‘i’ingens 30 xxviii) According to one aspect of embodiment xxvii), the
and Staphylococcus aureus, said method comprising the present invention Will relate to a method of treating in an
administration to said patient of an effective amount of a animal (e.g. in a dog, a cat, a pig, a coW or a horse) an
compound of formula IINT as de?ned in one of embodiments intestinal disease Which is caused by bacteria selected from
i) to vii), or of a pharmaceutically acceptable salt of such a Clostridium dl?icile, Clostridium pel?’ingens and Staphylo
compound, for a duration suf?cient to prevent the intestinal 35 coccus aureus, said method comprising the administration to
disease. said patient of an effective amount of a compound of formula
xix) According to one preferred aspect of embodiment IINT as de?ned in one of embodiments i) to vii), or of a
xviii), the present invention Will relate to a method of pre pharmaceutically acceptable salt of such a compound, for a
venting in a patient an intestinal disease Which is caused by duration suf?cient to treat the intestinal disease.
Clostridium dz?icile (notably by a toxin producing strain of 40 xxix) According to another aspect of embodiment xxvii),
Clostridium d?icile). the present invention Will relate to a method of preventing in
xx) Preferably, the patients subjected to a method of one of an animal (e.g. in a dog, a cat, a pig, a coW or a horse) an
embodiments xiii) to xix) Will be patients treated With other intestinal disease Which is caused by bacteria selected from
antibiotics or With antiviral therapies, patients With an immu Clostridium dl?icile, Clostridium per?’ingens and Staphlylo
nocompromised system such as cytotoxic chemotherapy or 45 coccus aureus, said method comprising the administration to
organ transplant patients, elderly (65 years or older) patients, said patient of an effective amount of a compound of formula
or patients of intensive care units or of long-term care facili I as de?ned in one of embodiments i) to vii), or of a pharma
ties. ceutically acceptable salt of such a compound, for a duration
xxi) Yet a further aspect of this invention relates to the use suf?cient to prevent the intestinal disease.
of a compound of formula IINT as de?ned in one of embodi 50 The intestinal diseases intended to be prevented or treated
ments i) to vii), or of a pharmaceutically acceptable salt of according to embodiments i) to xxix) of this invention com
such a compound, for the manufacture of a medicament prise notably diarrhea, colitis and pseudomembranous colitis.
intended to prevent or treat an intestinal disease Which is Preferably, said intestinal diseases Will be caused by
caused by bacteria selected from Clostridium di?icile, Clostridium di?icile (and especially by a toxin producing
Clostridium perfringens and Staphylococcus aureus. 55 strain of Clostridium dz?icile).
xxii) According to one aspect of embodiment xxi), the The most suitable administration route for the compounds
present invention Will relate to the use of a compound of of formula IINTused according to embodiments i) to xxix) of
formula IINTas de?ned in one of embodiments i) to vii), or of the present invention Will be the oral route. Administration
a pharmaceutically acceptable salt of such a compound, for may be daily (e.g., one to four times daily) or may be less
the manufacture of a medicament intended to treat an intes 60 frequent (e.g., once every other day or once or tWice Weekly).
tinal disease Which is caused by bacteria selected from Though the exact administration doses of a compound of
Clostridium dl?icile, Clostridiur perfringens and Staphylo formula IINT as de?ned in one of embodiments i) to vii), or of
coccus aureus. a pharmaceutically acceptable salt thereof, Will have to be
xxiii) According to one preferred aspect of embodiment determined by the treating physician or veterinarian, it is
xxii), the intestinal disease intended to be treated Will be 65 expected that an amount betWeen 0.5 and 50 mg of compound
caused by Clostridium dz?icile (notably by a toxin producing of formula IINT or pharmaceutically acceptable salt thereof
strain of Clostridium dz?icile). per kg of patient body Weight per day (for example an amount
US 8,124,623 B2
13 14
between 1 and 5 mg of compound of formula TINT or pharma General Preparation Routes:
ceutically acceptable salt thereof per kg of patient body The novel compounds of formula I can be manufactured in
Weight per day) given once or tWice daily for a duration of 3 accordance With the present invention by
to 15 days (for example for a duration of 7 to 14 days) Will be a) reacting the compound of formula T1
appropriate. 5
According to the invention, the compounds of formula I
can be prepared by the process described hereafter.
Preparation of the Compounds of Formula 1 0
Abbreviations:
The folloWing abbreviations are used throughout the speci
?cation and the examples:
AcOH acetic acid
AD-mix 0t 1,4-bis(dihydroquinine)phthalaZine, K3Fe(CN)6,
With a compound of formula 111
KZCO3 and K2OSO4.2H2O
AD-mix [3 1,4-bis(dihydroquilnidine)phthalaZine, K3Fe(CN)
6, KZCO3 and K2OSO4.2H2O Ill
Alloc allyloxycarbonyl
aq. aqueous
BnBr benZyl bromide 20
Boc tert-butoxycarbonyl
t-BuOK potassium tert-butylate
CbZ benZyloxycarbonyl
DBU 1,8-diaZabicyclo[5.4.0]undec-7-ene
25
DCM dichloromethane
DIAD diisopropyl aZodicarboxylate Wherein n, A, R3 and R4 are as de?ned in formula I and R7
DIPEA N,N-diisopropylethylamine is (C l-C3)alkylsulfonyl (e. g. methylsulfonyl), tri?uo
DMA dimethylacetamide romethylsulfonyl or arylsulfonyl (e. g. phenyl- or
30
DMAP 4-dimethylaminopyridine p-tolyl-sulfonyl) and R is OH or H, or R2 and R7 together
DMF N,N-dimethylformamide form a bond (i.e. R2 and OR7 form, together With the
DMSO dimethylsulfoxide carbon atoms that carry them, an epoxide ring), prefer
ably betWeen about 10° C. and 100° C. (more preferably
EA ethyl acetate
betWeen about 40° C. and 80° C.), in the presence of an
EDC 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydro 35
inorganic base such as K2CO3 or an organic base such as
chloride
TEA in an organic solvent (e.g. DMF);
ESl Electron Spray lonisation
or
ether or Et2O diethyl ether b) reacting a compound of formula TV
FC ?ash chromatography
40
h hour
Hex n-hexane IV
lC50 concentration that reduces the effect by 50%
MeCN acetonitrile
MCPBA meta-chloroperbenZoic acid 45 NH
MheOH methanol
MIC90 minimal inhibitory concentration to inhibit the
groWth of 290% of strains
MS Mass Spectroscopy Wherein n is as de?ned in formula I and R2 is H or OH,
50
NaOMe sodium methylate With a compound of formula V
NMP N-methylpyrrolidinone
OD595 optical density measured at 595 nM
v
org. organic o 0
55
Pd/C or Pd(OH)2/C palladium or dihydroxypalladium on R3
charcoal \ o—R8
PPh3 kiphenylpho sphine
/
rt room temperature Y A N
11.
sat. saturated 60
SiO2 silica gel
TBDMSCl tert-butyldimethylsilyl chloride
Wherein A, R3 and R4 are as de?ned in formula I, Y is
TEA triethylamine
halogen and R8 is hydrogen, BF2 or B(OC(:O)(C 1-C4)
TFA tri?uoroacetic acid alkyl)2, (C1-C5)alkyl (e.g. methyl, ethyl, n-propyl, iso
65
THF tetrahydrofuran propyl or tert-butyl), allyl, aryl-(Cl-C5)alkyl (e.g. ben
TMSCl trimethylsilyl chloride Zyl, p-nitrobenZyl or p-methoxybenZyl), tri-(Cl-Cs)