RING-FUSED THIAZOLINO 2-PYRIDONES, METHODS FOR PREPARATION THEREOF AND THEIR USE IN THE TREATMENT AND/OR PREVENTION OF A DISEASE INVOLVING GRAM-POSITIVE BACTERIA
The present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in combination with a drug against a disease involving gram-positive bacteria.
The present disclosure concerns novel ring-fused thiazolino 2-pyridones, methods for preparation thereof as well as their use in the treatment and/or prevention of a disease involving gram-positive bacteria. Further, the disclosure concerns a combination of a ring-fused thiazolino 2-pyridone and a drug against a disease involving gram-positive bacteria.
BACKGROUNDInfections and/or diseases that resist treatment with currently available drugs is an increasing problem and a serious threat to public health. Many of these infections and/or diseases involve gram-positive bacteria such as Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes and Staphylococcus saphyticus and Bacillus subtilis.
The term gram-positive originates from a laboratory staining technique named after the Danish scientist Hans Christian Gram. In this staining technique, bacteria are divided into groups of gram-positive bacteria and gram-negative bacteria depending on their ability to take up crystal violet stain. The Gram staining differentiates bacteria by the chemical and physical properties of their cell walls by detecting peptidoglycan, which is present in the cell wall of Gram-positive bacteria. Gram-positive bacteria retain the crystal violet dye, and thus are stained violet, while the Gram-negative bacteria do not. The Gram stain is almost always the first step in the preliminary identification of a bacterial organism. While Gram staining is a valuable diagnostic tool in both clinical and research settings, not all bacteria can be definitively classified by this technique. For instance, tuberculosis bacteria are neither gram-positive or gram-negative.
In addition to being classified by their staining in the Gram staining technique, bacteria may be further classified by their shape. For instance, the shapes include Cocci and Bacilli. Cocci have a spherical shape and can be either Staphylococcus (appearing like a bunch of grapes) or Streptococcus (forming a chain). Bacilli have a rod shape and can be either spore forming or non spore forming.
Examples of infection and/or disease involving gram-positive bacteria include urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, and tetanus. An important reason for the increase of these infections and/or diseases appears to be the increasing number of healthcare-associated infections (HCAI), i.e. infections acquired in or in connection with a health-care setting such as a hospital. For instance, the use of catheters and other intravascular devices frequently lead to diseases and/or infections involving gram-positive bacteria such as Staphylococcus aureus. The World Health Organization has reported that hundreds of millions of patients are affected by healthcare-associated infections worldwide each year, leading to significant mortality and financial losses for health systems. Thus, healthcare-associated infections are a widespread and significant problem that needs to be addressed.
WO 2014/185852 discloses substituted ring-fused 2-pyridones which are shown to reduce the infectivity of Chlamydia. However, the bacteria involved in Chlamydia are gram-negative.
WO2016075296 discloses ring-fused thiazolino 2-pyridones and use thereof in the treatment of a Chlamydia infection. However, the bacteria involved in Chlamydia are gram-negative.
PCT/IB2017/051999 discloses ring-fused thiazolino 2-pyridones and use thereof in the treatment of tuberculosis. However, the bacteria involved in are neither gram-positive nor gram-negative.
Many of the diseases and/or infections involving gram-positive bacteria are severe and/or drug-resistant making them a serious threat to public health. Therefore, there is a need for alternative and/or improved treatments of infections and/or diseases involving gram-positive bacteria.
It is an object of the present disclosure to provide compounds useful in the treatment and/or prevention of infections and/or diseases involving gram-positive bacteria. Further, it is an object of the present disclosure to provide compounds that may be used in combination with current therapeutic agents such as vancomycin to improve treatment and/or prevention of infections and/or diseases involving gram-positive bacteria.
SUMMARYThere is provided a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO2R6,
d) NH2,
e) H,
R2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, or I,
c) CH2OH,
d) C1-C4alkyl, and
e) NZ1Z2,
R3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy,
b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro,
c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl,
d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl
e) 2-(3-methyl)phenylmethylene,
f) benzothiophen-2-yl,
g) H,
h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
R4 is selected from the group consisting of:
a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C3-C6cycloalkyl,
c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C3-C6cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ1Z2,
g) CH2NZ1Z2,
i) C(O)OH, and
j) C(O)H,
R5 is selected from the group consisting of:
and in the above definitions:
R6 is C1-C4alkyl or phenyl,
R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl,
R8 is selected from the group consisting of OH, C1-C10alkoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or
R7 and R8 together form O(CH)2O,
R9 represents C1-C10 alkyl,
R10 represents C1-C4alkyl,
R11 represents C1-C4alkyl, or
R10 and R11 together form CH2(CH2)mCH2,
Y is O, S or N,
Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2,
n is 0 or 1,
m is 0 or 1,
p is 0, 1 or 2,
q is 0 or 1,
r is 1, and
X is S, SO or SO2,
with the proviso that the compound of Formula I is not:
- 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
- 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid.
There is also provided a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, carrier or excipient.
Further, the present disclosure provides a compound of Formula as described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament in therapy.
There is also provided a compound of Formula I or Formula IV as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a disease involving gram-positive bacteria.
There is also provided use of a compound of Formula I or Formula IV as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease involving gram-positive bacteria.
There is also provided a method for treatment and/or prevention of a disease involving gram-positive bacteria comprising administering to a mammal, such as a human or an animal, in need thereof an effective amount of a compound of Formula I or Formula IV as described herein, or a pharmaceutically acceptable salt thereof.
Further, there is provided a combination comprising:
(i) a composition comprising or consisting of a drug against a disease involving gram-positive bacteria, or a pharmaceutically acceptable salt of said drug, and
(ii) a composition comprising or consisting of a compound of Formula IV:
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO2R6,
d) NH2,
e) H,
R2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, or I,
c) CH2OH,
d) C1-C4alkyl, and
e) NZ1Z2,
R3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy,
b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro,
c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl,
d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl,
e) 2-(3-methyl)phenylmethylene,
f) benzothiophen-2-yl,
g) H,
h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
R4 is selected from the group consisting of:
a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C3-C6cycloalkyl,
c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C3-C6cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ1Z2,
g) CH2NZ1Z2,
i) C(O)OH,
j) C(O)H,
k) 3-(trifluoromethyl)phenyl, and
l) benzo[d][1,3]dioxol-5-yl,
R5 is selected from the group consisting of:
and
f) H,
and in the above definitions:
R6 is C1-C4alkyl or phenyl,
R7 is selected from the group consisting of F, Cl, Br, and CI-C4alkyl,
R8 is selected from the group consisting of OH, C1-C10alkoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or
R7 and R8 together form O(CH)2O,
R9 is selected from the group consisting of H and C1-C10 alkyl,
R10 represents C1-C4alkyl,
R11 represents C1-C4alkyl, or
R10 and R11 together form CH2(CH2)mCH2,
Y is O, S or N,
Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2,
n is 0 or 1,
m is 0 or 1,
p is 0, 1 or 2,
q is 0 or 1,
r is 0 or 1, and
X is S, SO or SO2.
There is also described a combination as described herein for use as a medicament in therapy.
There is also provided a combination as described herein for use in the treatment and/or prevention of a disease involving gram-positive bacteria.
There is also provided use of a combination as described herein for the manufacture of a medicament for the treatment and/or prevention of a disease involving gram-positive bacteria.
There is also provided a method for treatment and/or prevention of a disease involving gram-positive bacteria comprising administering to a mammal, such as a human or an animal, in need thereof an effective amount of a combination as described herein
The chemical structures depicted in
The present disclosure provides a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO2R6,
d) NH2,
e) H,
R2 is selected from the group consisting of:
a) H,
b) Cl, F, Br, or I,
c) CH2OH,
d) C1-C4alkyl, and
e) NZ1Z2,
R3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy,
b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro,
c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl,
d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl
e) 2-(3-methyl)phenylmethylene,
f) benzothiophen-2-yl,
g) H,
h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
R4 is selected from the group consisting of:
a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C3-C6cycloalkyl,
c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C3-C6cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ1Z2,
g) CH2NZ1Z2,
i) C(O)OH, and
j) C(O)H,
R5 is selected from the group consisting of:
and in the above definitions:
R6 is C1-C4alkyl or phenyl,
R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl, R8 is selected from the group consisting of OH, C1-C10alkoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or
R7 and R8 together form O(CH2)2O,
R9 represents C1-C10 alkyl,
R10 represents C1-C4alkyl,
R11 represents C1-C4alkyl, or
R10 and R11 together form CH2(CH2)mCH2,
Y is O, S or N,
Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2,
n is 0 or 1,
m is 0 or 1,
p is 0, 1 or 2,
q is 0 or 1,
r is 1, and
X is S, SO or SO2,
with the proviso that the compound of Formula I is not:
- 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
- 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid.
The term “C1-C4alkyl” denotes a straight or branched, saturated or unsaturated alkyl group of one to four carbon atoms. Examples of “C1-C4alkyl” include, but are not limited to, methyl, ethyl, vinyl, allyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.
The term “C1-C4alkoxy” denotes a C1-C4alkyl group as described herein which is linked to an oxygen atom. Examples of “C1-C4alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy and butoxy.
The term “C1-C10alkoxy” denotes a C1-C10alkyl group which is linked to an oxygen atom. The C1-C10alkyl group may be straight, branched and/or include a cycloalkyl group. The Examples of “C1-C10alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, hexoxy, pentoxy, octoxy, nonony, and decoxy.
The term “C3-C6cycloalkyl” denotes a saturated or unsaturated non-aromatic monocyclic ring composed of three, four, five or six carbon atoms. Examples of “C3-C6cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term “C3-C6cycloalkoxy” denotes a saturated or unsaturated non-aromatic monocyclic ring composed of three, four, five or six carbon atoms which is linked to an oxygen atom. Examples of “C3-C6cycloalkoxy” include, but are not limited to, cyclopropyloxy, cyclopropoxymethylene, cyclobutyloxy, cyclobutyloxymethylene, cyclopentyloxy, cyclopentyloxymethylene, cyclohexyloxy and cyclohexyloxymethylene.
The term “C1-C10alkenoxy” denotes a C1-C10alkenyl group which is linked to an oxygen atom. The C1-C10alkenyl group may be straight or branched. The Examples of C1-C10alkenoxy include, but are not limited to, allyloxy, 5-hexenyloxy or 4-methyl-3-pentenyloxy, (E)-2-heptenyloxy, (E)-2-hexenyloxy, (E)-2-pentenyloxy, (E)-2-butenyloxy, (Z)-2-heptenyloxy, (Z)-2-hexenyloxy and (Z)-2-pentenyloxy.
The term “C1-C10alkynoxy” denotes a C1-C10alkynyl group which is linked to an oxygen atom. The C1-C10alkynyl group may be straight or branched. The Examples of C1-C10alkynoxy include, but are not limited to, 5-hexynyloxy, (Z)-2-Butenyloxy 2-heptynyloxy, 2-hexynyloxy, 2-pentynyloxy, 2-butynyloxy, 3-heptynyloxy, 3-hexynyloxy, 3-pentynyloxy, 3-butynyloxy, 4-heptynyloxy, 4-hexynyloxy and 4-pentynyloxy.
The term “3-membered heterocycle” denotes a 3-membered saturated or unsaturated heterocycle. Examples of a 3-membered saturated heterocycle include, but are not limited to, aziridine, oxirane and thiirane. Examples of 3-membered unsaturated heterocycles include, but are not limited to, azirine, oxirene and thiirene.
The term “4-membered heterocycle” denotes a 4-membered saturated or unsaturated heterocycle. Examples of a 4-membered heterocycle include, but are not limited to, azetidine, oxethane and thietane.
The term “5-membered heterocycle” denotes a 5-membered saturated or unsaturated heterocycle. Examples of a 5-membered heterocycles include, but are not limited to pyrrolidine, tetrahydrofurane, thiolane, pyrrole, furane, thiophene, imidazolidine, pyrazolidine, pxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, imidazole, pyrazole, oxazole, isoxazole, thiazole, and isothiazole.
The term “6-membered heterocycle” denotes a 6-membered saturated or unsaturated heterocycle. Examples of a 6-membered heterocycles include, but are not limited to piperidine, pyridine, piperazine, morpholine, and thiomorpholine.
The drug against a disease involving gram-positive bacteria is to be understood as a drug that counteracts gram-positive bacteria. The against a disease involving gram-positive bacteria may reduce, substantially eliminate or eradicate gram-positive bacteria. The drug against a disease involving gram-positive bacteria may also be denominated a drug to treat a disease involving gram-positive bacteria.
The term infection intends a condition wherein gram-positive bacteria have entered into a mammal such as a human. The term disease is understood to be an abnormal condition of a part, organ, or system of a mammal such as a human resulting from various causes, such as infection, inflammation, environmental factors, or genetic defect, and characterized by an identifiable group of signs, symptoms, or both. The skilled person understands that there is an overlap of the terms. In this document, the term disease is understood to encompass both disease and infection. Thus, when the term disease is used it may intend disease and/or infection.
The compound of Formula I may be a compound of Formula II or Formula III:
wherein R1, R2, R3, R4, R5 and X are as defined for the compound of Formula I, or a pharmaceutically acceptable salt thereof.
The compound of Formula I may be a compound of Formula IIa, Formula IIb, Formula IIc and/or Formula IId:
wherein
R1, R2, R3, R4, R5 and X are as defined for the compound of Formula I, or a pharmaceutically acceptable salt thereof.
Further values of wherein R1, R2, R3, R4, R5, n, m, p, q, r and X will now follow. It will be appreciated that these values may be applied to any compound of Formula I, Formula II or Formula III of the present disclosure.
R1 may be C(O)OH or tetrazolyl.
In a further example, R1 is a combination C(O)OH, tetrazolyl or C(O)NHSO2R6 with imidazole. Thus, R1 may be selected from:
wherein R6 is as defined herein.
R2 may be H.
R3 may be 1-naphtyl, 9-anthryl or trifluoromethylphenyl.
R4 may be selected from:
C3-C6cycloalkyl,
C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, or
NZ1Z2,
wherein Z1 and Z2 are as defined herein. For instance, R4 may be cyclopropyl or methoxy.
X may be S or SO.
R5 may be:
wherein R7 and R8 are as defined herein. For instance, R5 may be:
wherein R7 and R8 are as defined herein. In an example, R7 may be H or methyl and/or R8 is selected form the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, 4-hydroxy-3-methyl-phenyl, 4-methoxy-3-methyl-phenyl, 4-ethoxy-3-methyl-phenyl, 4-propoxy-3-methyl-phenyl, 4-butoxy-3-methyl-phenyl, 4-pentoxy-3-methyl-phenyl, 4-hexoxy-3-methyl-phenyl, 4-heptoxy-3-methyl-phenyl, 4-Butoxyphenyl, 4-pentyloxyphenyl, 4-(2-methoxyethoxy-3-methyl-phenyl, 4-alloxy-3-methyl-phenyl, 5-Hexynyloxy-3-methyl-phenyl, 4-Isohexyloxy-3-methyl-phenyl, 4-(4′-methyl)-3′-pentenyloxy)-3-methyl-phenyl, 4-(5′-Hexenyloxy)-3-methyl-phenyl and 1-Hexyl-1H-1,2,3-triazol-4-yl.
The compound of Formula I described herein may be selected from Examples 1-27, 41-47, 49 and 50 of Table 1 of this document.
For instance, the compound of Formula I described herein may be selected from:
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Allyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(5-Hexynyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-8-[4-(4-methyl-3-pentenyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(5-Hexenyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(p-Butoxyphenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[p-(pentyloxy)phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(4-methoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(4-ethoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(heptyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)phenyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Cyclopropylmethoxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Amino-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid imidazole salt,
- 8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid imidazole salt,
- 5-Cyclopropyl-8-(4-hydroxytolyl)-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(dimethylamino)-2-(3-methyl-4-(pentyloxy)phenyl)-7-(naphtalen-1ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
- 8-(dimethylamino)-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphthalen-1-ylmethyl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylic,
- 8-(dimethylamino)-2-(4-(heptyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carbocylic acid,
- 8-(dimethylamino)-2-(3-methyl-4-((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
- 8-amino-2-(3-methyl-4-(pentyloxyphenyl)-7-naphtalen-1ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
- 8-amino-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-caraboxylic acid,
- 8-amino-2-(4-heptyloxy)-3-methylphenyl)-7-8naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxyic acid,
- 7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)Y5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid, or
- 1H-imidazol-1-ium 8-methoxy-2-(3-methyl-4((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylate,
a pharmaceutically acceptable salt of any of the foregoing compounds.
Further, the compound of Formula I as described herein may be selected from:
- 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Cyclopropylmethoxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)phenyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
- 1H-imidazol-1-ium 8-methoxy-2-(3-methyl-4((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylate,
a pharmaceutically acceptable salt of any of the foregoing compounds.
Further, the compound of Formula I as described herein may be selected from:
- 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)phenyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
a pharmaceutically acceptable salt of any of the foregoing compounds.
There is also provided a compound of Formula I as described, wherein:
R1 is selected from the group consisting of carboxylic acid and 1H-imidazol-1-ium carboxylate,
R2 is hydrogen,
R3 is selected from the group consisting of naphthalen-1-yl, 3-(trifluoromethyl)phenyl, anthracen-9-yl and naphthalen-1-yloxy,
R4 is selected from the group consisting of: cyclopropyl, methoxy, amino, dimethylamino, 3-(trifluoromethyl)phenyl, benzo[d][1,3]dioxol-5-yl, and carboxylic acid, and
R5 is selected from the group consisting of 4-(hexyloxy)-3-methylphenyl, 3-methyl-4-propoxyphenyl, 4-(heptyloxy)-3-methylphenyl, 4-methoxy-3-methylphenyl, 4-ethoxy-3-methylphenyl, 3-methyl-4-(pentyloxy)phenyl, 4-butoxy-3-methylphenyl, 4-(pentyloxy)phenyl, 4-butoxyphenyl, 1-hexyl-1H-1,2,3-triazol-4-yl, 4-(2-methoxyethoxy)-3-methylphenyl, 4-hydroxy-3-methylphenyl, 4-(allyloxy)-3-methylphenyl, 4-(hex-5-yn-1-yloxy)-3-methylphenyl, 3-methyl-4-((4-methylpentyl)oxy)phenyl, 3-methyl-4-((4-methylpent-3-en-1-yl)oxy)phenyl, 4-(hex-5-en-1-yloxy)-3-methylphenyl, 4-(cyclopropylmethoxy)-3-methylphenyl, benzyl, phenyl, 2-(m-tolyl), 2-(p-tolyl), and 2,3-dihydrobenzo[b][1,4]dioxin-6-yl,
or a pharmaceutically acceptable salt thereof.
Further, there is provided a compound of Formula I as described herein for use as a medicament in therapy.
There is also provided a compound of Formula I or Formula IV as described herein for use in the treatment and/or prevention of a disease involving gram-positive bacteria. The gram-positive bacteria may be selected from the group consisting of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any combination thereof. The disease may be a healthcare-associated infection. Examples of the disease, which may or may not be healthcare-associated, include diseases selected from the group consisting of urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, tetanus and any combination thereof. The central line associated bloodstream infection may be bacteremia or sepsis. Further, the disease may be drug-resistant such as resistant to drugs frequently used to treat diseases involving gram-positive bacteria.
There is also provided a use of a compound of Formula I or Formula IV as described herein for use in the manufacture of a medicament for the treatment and/or prevention of a disease involving gram-positive bacteria. The gram-positive bacteria may be selected from the group consisting of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any combination thereof. The disease may be a healthcare-associated infection. Examples of the disease, which may or may not be healthcare-associated, include diseases selected from the group consisting of urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, tetanus and any combination thereof. The central line associated bloodstream infection may be bacteremia or sepsis. Further, the disease may be drug-resistant such as resistant to drugs frequently used to treat diseases involving gram-positive bacteria.
There is also a method for treatment and/or prevention of a disease involving gram-positive bacteria comprising administering to a mammal, such as a human or an animal, in need thereof an effective amount of a compound of Formula I or Formula IV as described herein. The gram-positive bacteria may be selected from the group consisting of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any combination thereof. The disease may be a healthcare-associated infection. Examples of the disease, which may or may not be healthcare-associated, include diseases selected from the group consisting of urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, tetanus and any combination thereof. The central line associated bloodstream infection may be bacteremia or sepsis. Further, the disease may be drug-resistant such as resistant to drugs frequently used to treat diseases involving gram-positive bacteria.
The compound of Formula I may be provided in admixture with a pharmaceutically acceptable adjuvant, carrier or excipient thereby forming a pharmaceutical composition. Thus, the present disclosure provides a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, carrier or excipient.
The compounds of the present disclosure may possess bactericidal activity against gram-positive bacteria. Additionally or alternatively, the compounds of the present disclosure may sensitize gram-positive bacteria to treatment with a drug against gram-positive bacteria. In the latter case, the gram-positive bacteria may be affected to a little extent or no extent by treatment with the compounds of the present disclosure alone or by treatment by the drug against gram-positive bacteria alone. However, when a combination of the compounds of the present disclosure and a drug against gram-positive bacteria as described herein is used a significant bactericidal effect is achieved.
Thus, there is provided a compound as disclosed herein for use in sensitizing gram-positive bacteria to treatment with a drug against a disease involving gram-positive bacteria. There is also provided a use of a compound as described herein for the manufacture of a medicament for sensitizing gram-positive bacteria to treatment with a drug against a disease involving gram-positive bacteria. There is also provided a method for sensitizing gram-positive bacteria to treatment with a drug against a disease involving gram-positive bacteria, said method comprising administering to a patient such as a human or an animal in need thereof an effective amount of a compound as described herein.
The compound of Formula I or Formula IV as described herein may be provided in combination with a drug against a disease involving gram-positive bacteria. The combination may be provided in admixture with a pharmaceutically acceptable adjuvant, carrier or excipient thereby forming a pharmaceutical composition. It is believed that this combination will provide an alternative and/or improved way of treating a disease involving gram-positive bacteria. This alternative and/or improved way may involve lowering the dose of the drug compared to use of the drug alone when treating the disease involving gram-positive bacteria. Alternatively or additionally, this alternative and/or improved way may mitigate or at least partly overcome problems associated with drug-resistance.
Thus, there is provided a combination comprising:
(i) a composition comprising or consisting of a drug against a disease involving gram-positive bacteria, or a pharmaceutically acceptable salt of said drug, and
(ii) a composition comprising or consisting of a compound of Formula IV:
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is selected from the group consisting of:
a) C(O)OH,
b) tetrazolyl,
c) C(O)NHSO2R6,
d) NH2,
e) H,
R2 is selected from the group consisting of:
a) H,
b) Cl, F, Br or I,
c) CH2OH,
d) C1-C4alkyl, and
e) NZ1Z2,
R3 is selected from the group consisting of:
a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy,
b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro,
c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl,
d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl
e) 2-(3-methyl)phenylmethylene,
f) benzothiophen-2-yl,
g) H,
h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
R4 is selected from the group consisting of:
a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
b) C3-C6cycloalkyl,
c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
d) C3-C6cycloalkoxy,
e) a 3-, 4-, 5-, or 6-membered heterocycle,
f) NZ1Z2,
g) CH2NZ1Z2,
i) C(O)OH,
j) C(O)H,
k) 3-(trifluoromethyl)phenyl, and
l) benzo[d][1,3]dioxol-5-yl,
R5 is selected from the group consisting of:
and
f) H,
and in the above definitions:
R6 is C1-C4alkyl or phenyl,
R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl,
R8 is selected from the group consisting of OH, C1-C10alkoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or
R7 and R8 together form O(CH)2O,
R9 is selected from the group consisting of H and C1-C10 alkyl,
R10 represents C1-C4alkyl,
R11 represents C1-C4alkyl, or
R10 and R11 together form CH2(CH2)mCH2,
Y is O, S or N,
Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2,
n is 0 or 1,
m is 0 or 1,
p is 0, 1 or 2,
q is 0 or 1,
r is 0 or 1, and
X is S, SO or SO2.
Further, there is provided a combination as described herein wherein the compound of Formula IV is as described herein except that R5 is not hydrogen (H).
The compound of Formula IV may be a compound of Formula IVa or Formula IVb:
wherein R1, R2, R3, R4, R5 and X are as described herein for the compound of Formula IV.
In an example, the compound of Formula IV may be selected from Examples 28-39, 40 and 48 of Table 1 of this document.
For instance, the compound of Formula IV may be selected from:
- 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(1H-indol-5-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(2-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(3-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 6-[(9-Anthryl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-indancarboxylic acid,
- 6-[(Naphtyl) methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-indancarboxylic acid,
- 6-[(Naphtyloxy)methyl]-4-oxo-2-phenyl-7-(1,3-Dioxa-5-indanyl)-1-thia-3a-aza-3indancarboxylic acid,
- (R)-7-(naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-tiazolo[3,2,a]pyridine-3,8-dicarboxylic acid, or
- 7-(anthracen-9-ylmethyl)-8-methoxy-5-oxo-2,3-dihydro-thiazolo[3,2,a]pyridine-3-carboxylic acid,
a pharmaceutically acceptable salt of any one of the foregoing compounds.
In a further example, the compound described herein may be selected from:
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 6-[(9-Anthryl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-indancarboxylic acid,
- 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)phenyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or
a pharmaceutically acceptable salt of any of the foregoing compounds.
For instance, the compound of Formula IV may be a compound of Formula I as described herein.
The combination described herein may be provided as a single composition.
Alternatively, the combination may be provided as a kit of parts.
The combination described herein may further comprise instructions for use. For instance, the instructions for use may include instructions for separate, sequential or simultaneous use of (i) and (ii) of the combination as described herein.
The drug of the combination described herein may be an antibiotic such as an antibiotic selected from the group consisting of glycopeptide antibiotics, lipoglycopeptide antibiotics, lipopeptide antibiotics, penicillin antibiotics, oxazolidinone antibiotics, aminoglycoside antibiotics and any combination thereof. The glycopeptide antibiotics may be a semisynthetic glycopeptide antibiotics. The glycopeptide antibiotics may be vancomycin and/or teicoplanin. The lipoglycopeptide antibiotics may be telavancin. The lipopeptide antibiotics may be daptomycin. The penicillin antibiotics may be oxacillin. The oxazolidinone antibiotics may be linezolide and/or teidizolide. The semisynthetic antibiotics may be orbactiv. The aminoglycoside antibiotics may be gentamicin, tobramycin, amikacin, streptomycin, neomycin, and/or paromomycin.
It will be appreciated that teicoplanin is a mixture of several compounds, namely five major compounds (named teicoplanin A2-1 through A2-5) and four minor (named teicoplanin RS-1 through RS-4). All teicoplanins share a same glycopeptide core, termed teicoplanin A3-1—a fused ring structure to which two carbohydrates (mannose and N-acetylglucosamine) are attached. The major and minor components also contain a third carbohydrate moiety—β-D-glucosamine—and differ only by the length and conformation of a side-chain attached to it. The present disclosure encompasses all teicoplanin mixtures.
For instance, the drug of the combination described herein may be selected from the group consisting of vancomycin, oxacillin, dalbavancin, oritavancin, teicoplanin, daptomycin, linezolid, tedizolid, telavancin, gentamicin, tobramycin, amikacin, streptomycin, neomycin, and paromomycin and any combination thereof. In an example, the drug may be vancomycin, oxacillin and/or gentamicin.
The chemical structures of vancomycin, oxacillin, dalbavancin, oritavancin, teicoplanin, daptomycin, linezolid, tedizolid, telavancin, gentamicin are as described in the figures of this document.
It will be appreciated that the drug against a disease involving gram-positive bacteria as described herein may or may not also be a drug against tuberculosis bacteria such as rifampin and/or linezolid.
There is also provided a combination as described herein for use as a medicament in therapy.
There is also provided a combination as described herein for use in the treatment and/or prevention of a disease involving gram-positive bacteria. The gram-positive bacteria may be selected from the group consisting of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any combination thereof. The disease may be a healthcare-associated infection. Examples of the disease, which may or may not be healthcare-associated, include diseases selected from the group consisting of urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, tetanus and any combination thereof. The central line associated bloodstream infection may be bacteremia or sepsis. Further, the disease may be drug-resistant such as resistant to drugs frequently used to treat diseases involving gram-positive bacteria.
There is also provided a use of a combination as described herein for the manufacture of a medicament for the treatment and/or prevention of a disease involving gram-positive bacteria. The gram-positive bacteria may be selected from the group consisting of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any combination thereof. The disease may be a healthcare-associated infection. Examples of the disease, which may or may not be healthcare-associated, include diseases selected from the group consisting of urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, tetanus and any combination thereof. The central line associated bloodstream infection may be bacteremia or sepsis. Further, the disease may be drug-resistant such as resistant to drugs frequently used to treat diseases involving gram-positive bacteria.
There is also provided a method for treatment and/or prevention of a disease involving gram-positive bacteria comprising administering to a mammal, such as a human or an animal, in need thereof an effective amount of a combination as described herein. The gram-positive bacteria may be selected from the group consisting of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes, Staphylococcus saphyticus, Bacillus subtilis and any combination thereof. The disease may be a healthcare-associated infection. Examples of the disease, which may or may not be healthcare-associated, include diseases selected from the group consisting of urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, tetanus and any combination thereof. The central line associated bloodstream infection may be bacteremia or sepsis. Further, the disease may be drug-resistant such as resistant to drugs frequently used to treat diseases involving gram-positive bacteria.
The present disclosure provides an article treated with a compound as described herein or a combination as described herein. The article may be a medical device or a cosmetic device. Thus, there is also provided a medical device or cosmetic device such as an implant treated with a compound as described herein or a combination as described herein. The medical device or cosmetic device may be a catheter or an implant such as a dental implant, cochlear implant, breast implant, nose prosthesis, heart valve, pacemaker, ocular prosthesis or an injectable filler.
Further, the present disclosure provides the following compounds:
- (R)-7-(naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-tiazolo[3,2,a]pyridine-3,8-dicarboxylic acid, or
- 7-(anthracen-9-ylmethyl)-8-methoxy-5-oxo-2,3-dihydro-thiazolo[3,2,a]pyridine-3-carboxylic acid,
or a pharmaceutically acceptable salt of any of the foregoing compounds.
Salts
The compounds of the present disclosure may be provided as a pharmaceutically acceptable salt. A suitable pharmaceutically acceptable salt of a compound of the present disclosure may be, for example, a base-addition salt of a compound of the present disclosure which is sufficiently acidic, for example, a metal salt, for example, lithium, sodium, potassium, calcium, magnesium, zinc or aluminum, an ammonium salt, a salt with an organic base which affords a physiologically acceptable cation, which includes quartenary ammonium hydroxides, for example methylamine, ethylamine, diethylamine, trimethylamine, tert-butylamine, triethylamine, dibenzylamine, N,N-dibenzylethylamine, cyclohexylethylamine, tris-(2-hydroxyethyl)amine, hydroxyethyl diethylamine, (IR, 2S)-2-hydroxyinden-1-amine, morpholine, N-methylpiperidine, N-ethylpipeidine, imidazole, piperazine, methylpiperazine, adamantylamine, choline hydroxide, tetrabutylammonium hydroxide, tris-(hydroxymethyl)methylamine hydroxide, L-arginine, N-methyl D-glucamine, lysine or arginine.
In an example, there is provided an imidazole salt of the compounds of the present disclosure such as a compound of the present disclosure wherein R1 is C(O)OH, tetrazolyl or C(O)NHSO2R6. It will be appreciated that the imidazole salt is a combination of a compound of the present disclosure and imidazole.
As described herein, proton transfer may occur between the active pharmaceutical ingredient such as the compounds described herein and the counter ion of the salt. The proton transfer may take place to a varying extent.
For instance, when the R1 group of the compounds described herein is C(O)OH it may combine with imidazole to form a salt which may be depicted as shown below:
In a further example, when the R1 group of the compounds described herein is tetrazolyl it may combine with imidazole to form a salt which may be depicted as shown below:
In still a further example, when the R1 group of the compounds described herein is C(O)NHSO2R6 it may combine with imidazole to form a salt which may be depicted as shown below:
It will be appreciated that the imidazole salts of the compounds described herein wherein R1 is C(O)OH, tetrazolyl or C(O)NHSO2R6 may be depicted as shown above regardless of the extent of proton transfer.
Solvates or Hydrates
Certain compounds of the present disclosure may exist as solvates or hydrates. It is to be understood that the present disclosure encompasses all such solvates or hydrates. Compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.
Co-Crystals
In a salt, proton transfer may occur between the active pharmaceutical ingredient and the counter ion of the salt. However, in some cases there is no or only partial proton transfer and the solid is therefore not a true salt. It is accepted that the proton transfer is in fact a continuum, and can change with temperature, and therefore the point at which a salt is better described as a “co-crystal” may be subjective. The term “co-crystal” as used herein refers to multicomponent system in which there exists a host molecule or molecules (active pharmaceutical ingredient) and a guest (or co-former) molecule or molecules. The guest or co-former molecule is defined as existing as a solid at room temperature in order to distinguish the co-crystal from solvates. However, a co-crystal may itself form solvates. In a co-crystal there is generally predominance for interaction through non-ionic forces, such as hydrogen bonding. It will be appreciated that all co-crystals are included within the scope of the compounds described herein.
Polymorphs
Compounds of the present disclosure may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. Thus, it is to be understood that all polymorphs, such as mixtures of different polymorphs, are included within the scope of the compounds described herein.
Prodrugs
In addition, compounds of the present disclosure may be administered in the form of a prodrug. A prodrug is a compound which may have little or no pharmacological activity itself, but when such compound is administered into or onto the body of a patient, it is converted into a compound of Formula II. The prodrug may contain a metabolically or chemically labile acyl function such as a carboxylate ester or carbamate.
Methods of Preparation
Compounds of the present disclosure may be prepared as described in WO 2014/185833 and/or in schemes 1 to 4 below. In schemes 1 to 4, R may be an alkyl group and Ar may be an aryl such as phenyl. The aryl may optionally be substituted with one or more alkyl groups such as a methyl group. The compounds may also be prepared as described for structurally related compounds. The reactions may be carried out as in standard procedures or as described in the experimental section of this document. The sulfide of the compounds of Formula I or Formula IV may be oxidized with the aid of meta-chloroperoxybenzoic acid (mCPBA) to sulphoxide and sulphone, respectively.
It will be appreciated that some of the compounds of the present disclosure may also serve as intermediates for preparing further compounds of Formula I or Formula IV. For instance, compounds wherein R1 is C(O)OH or tetrazolyl may be used in the synthesis of a pharmaceutically acceptable salt of a compound of Formula I or Formula IV as described herein. In a further example, when R8 is OH it may be transformed into an alkoxy group.
The disclosure is further illustrated by the following non-limitative Examples.
EXAMPLES AbbreviationsBHI Brain Heart Infusion plates supplied from Fischer Scientific
calcd. calculated
CAUTI Catheter-Associated Urinary Tract Infection
C. difficile Clostridium difficile
CLABSI central line associated bloodstream infection
DCM dichloromethane
DMF dimethylformamide
DMSO dimethylsulphoxide
EA Ethyl Acetate
EtOAc Ethyl Acetate
ESI-TOF Electrospray Ionization Time of Flight Mass Spectroscopy
Gen Gentamicin
HCAI HealthCare-Associated Infection
HRMS High Resolution Mass Spectroscopy
IR infrared
MBC Minimum Bactericidal Concentration
MIC Minimum Inhibitory Concentration
ml milliliter
MRSA Methicillin-resistant Staphylococcus aureus
MW microwave
NMR Nuclear Magnetic Resonance
nd no data
nm nanometer
ns not statistically different
OD Optical density
OD600 Optical density at 600 nm
PBS Phosphate-Buffered Saline buffer
ppm part per million
Van Vancomycin
VISA Vancomycin-Intermediate Staphylococcus aureus
VRE Vancomycin-Resistant Enterococci
VRSA Vancomycin-Resistant Staphylococcus aureus
TBAF tetra-n-butylammonium fluoride
TFA trifluoroacetic acid
THF tetrahydrofurane
TLC Thin Layer Chromatography
TMS trimethylsilyl
UTI urinary tract infection
μl microliter
LOD Bacterial limit of detection
In this document, unless otherwise stated, the naming and the drawing of the chemical compounds and radicals have been made using the program Chem Doodle version 7.0.1 or version 7.0.2, or the program ChemDraw Ultra 12.0.2.1076. If the name and drawing are inconsistent, the chemical structure shall be considered to be correct.
Chemistry
General
Unless otherwise stated, all reagents and solvents were used as received from commercial suppliers. Microwave reactions were performed in sealed vessels using a Biotage® Initiator microwave synthesizer; temperatures were monitored by an internal IR probe. Automated flash column chromatography was performed using a Biotage® Isolera One system and purchased pre-packed silica gel cartridges (Biotage® SNAP Cartridge, KP-Sil). 1H- and 13C-NMR spectra were recorded, depending on instrument availability, on a Bruker Avance III 400 MHz spectrometer with a BBO-F/H Smartprobe™, a Bruker Avance III HD 600 MHz spectrometer with a CP BBO-H/F, 5 mm cryoprobe at 298 K. All spectrometers were operated by Topspin 3.5.7. Resonances are given in ppm relative to TMS, and calibrated to solvent residual signals (CDCl3: δH=7.26 ppm; δC=77.16 ppm. (CD3)2SO: δH=2.50 ppm; δC=39.51 ppm. CD3OD δH=3.31 ppm; δC=49.00 ppm). The following abbreviations are used to indicate splitting patterns: s=singlet; d=doublet; dd=double doublet; t=triplet; m=multiplet; bs=broad singlet. HRMS was performed on a mass spectrometer with ESI-TOF (ES+).
Synthesis of Compounds
The compounds of the Examples were synthesized in accordance or analogy with Schemes 1-4 disclosed herein. For instance, the compounds of the Examples were synthesized as follows.
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid and (3R)-7-Methoxy-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid was prepared according to WO2016075296.
(3R)-7-Cyclopropyl-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylic acid (17.42 mmol) was suspended in dichloromethane (190 ml) and cooled to 0° C. Oxalyl chloride (19.16 mmol, 1.70 ml) and dimethylformamide (19.16 mmol, 1.50 ml) were added at 0° C. The mixture was then stirred at room temperature for 12 minutes. 2-(trimethylsilyl)ethanol (49.53 mmol, 7.10 ml) was added slowly and the reaction was stirred for 3 hours. Completion of the reaction was confirmed by TLC. The reaction mixture was then diluted with DCM, washed with NaHCO3 (saturated, aqueous), dried (Na2SO4) and concentrated until about 200 ml dichloromethane remained. The organic layer was washed with water and the aqueous layer was extracted with DCM. The organic layers were combined, dried with Na2SO4 and concentrated. Crude product was purified on silica gel (ethyl acetate:heptane 1:1) to give TMS-ethyl ester.
NaH (3.06 mmol) was added slowly to a solution of the TMS-ethyl ester (1.70 mmol) in dry acetonitrile (15 ml) at 0° C. After 10 minutes, BrCCl3(5.11 mmol) was added dropwise. After stirring for 30 minutes, the reaction mixture was allowed to reach room temperature and stirred for further 30 minutes. 2-(TMS)ethanol (3.40 mmol) was added dropwise, and stirring was continued overnight. After completion reaction was quenched with an aqueous solution of 6 wt % KHSO4 (10 ml), diluted with H2O (10 ml) and acidified with 1 M HCl (10 ml). Aqueous layer extracted with EtOAc (20 ml×3), combined organic layers were washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield crude brominated product which was purified by flash column chromatography (Biotage, 100 g column) eluting with 10-60% EtOAc in heptane.
A microwave vial was charged with bromo compound (0.90 mmol), added MeOH (6 ml) and degassed with nitrogen for 10 minutes. Boronic ester (1.44 mmol), K2CO3(1.62 mmol) and Pd(OAc)2 (0.09 mmol) were added. The microwave vial was sealed and the reaction mixture heated under MWI at 120° C. for 10 minutes. Diluted with dichloromethane (30 ml) and acidified with 1N HCl. Organic layer was separated, dried over anhydrous sodium sulphate and evaporated to yield crude aryl alcohol product which was purified by flash column chromatography (Biotage 100 g column) eluting with 0-100% EtOAc in heptane.
Aryl alcohol compound (0.27 mmol) was dissolved in dry DMF (2 ml). Added K2CO3 (1.11 mmol) and alkyl bromide (1.11 mmol). Reaction mixture was stirred under heating at 80° C. for 2 hours. Cooled to room temperature and added EtOAc (10 ml). Washed with brine (10 ml×4) 4. Organic layer dried over anhydrous Na2SO4 and evaporated under reduced pressure to yield crude silyl ester product which was used in next step without further purification.
Silyl Ester (0.23 mmol) was dissolved in dry THF (4 ml) and added TBAF (0.47 mmol). Reaction mixture was stirred at room temperature for 2 hours. Added H2O and extracted with EtOAc (10 ml×2). Combined organic layers were dried over anhydrous sodium sulphate and evaporated to yield crude product which was purified by flash column chromatography (Biotage 10 g column) eluting with 20% MeOH in DCM. Pure compound was lyophilized from acetonitrile:water (1:3) mixture.
Example 36 was prepared from the known compound Methyl (3R)-5-bromo-7-iodo-6-[(1-naphthyl)methyl]-4-oxo-1-thia-3a-aza-3-indancarboxylate as described in J. Org. Chem (2010), 75(3), 972-975 and/or according to Scheme 3.
Imidazole Salt
An imidazole salt was prepared as follows.
8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic Acid Imidazole Salt8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, (0.11 mmol) was taken in a round bottom flask and MeOH (2 ml) was added thereby providing a suspension. Then imidazole (0.11 mmol) was added. Allowed to stir for about 2 hours. A clear reaction mixture was obtained. Solvent evaporated and the crude product was lyophilized from acetonitrile:water (3:1).
Examples 1-50
Examples 28-36 are described in J. Med Chem (2010), 53(15), 5690-5695, example 37 and 39 are described in Bioorg. Med Chem (2012), 20(9), 3128-3142, example 38 is described in Chem&Biol (2013), 20, (10), 1245-1254.
Biology
Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) Assays
To define the MIC, bacterial cultures at starting OD=0.001 at OD600 were incubated in the presence of different increasing concentrations of each compound of Examples 1-39 as described herein, or a combination of each compound of Examples 1-39 as described herein with an antibiotic overnight (18 hrs). MIC was defined by the lowest concentration of the test compound that inhibits visible growth of pathogen of interest. The optical density of the pathogen of interest culture was measured by OD600.
The MBC was defined by the lowest concentration of each compound of Examples 1-39, or a combination of each compound of Example 1-36 with an antibiotic that results in pathogen of interest death from the same cultures as MIC assay. MBC was determined colony forming units (CFUs) enumeration by serially diluting and plating bacterial cultures on BHI plates.
MIC and MBC data for each compound of examples 1-39 is provided in Table 2. The values provided in Table 2 result from the use of the compounds of Examples 1-39 alone. Thus, no antibiotic was used in Table 2.
Method for Determining the Effect of Each Compound of Examples 8, 9 and 11 on MRSA, and Also the Effect on MRSA of a Combination of Oxacillin with Each Compound of Examples 8, 9 and 11 on MRSA
The test compound of interest, i.e. the compound of Example 8, 9 or 11, was added to the bacterial inoculum MRSA (190 μl) with an OD 1, 0.1 or 0.001. The mixture (200 μL) was incubated at 37° C. for 18 h. A control without the test compound was performed in the same way. The results are shown in Table 3a.
The test compound of interest, i.e. the compound of Example 8, 9 or 11, (25 μM, 5 μL in DMSO) was added to the bacterial inoculum MRSA (190 μl) with an OD 1, 0.1 or 0.001 along with Oxacillin (9 μM, 5 μL in water). The mixture (200 μL) was incubated at 37° C. for 18 h. A control without the test compound was performed in the same way. The results are shown in Table 3b.
The effect was determined by CFU counts and is summarized in Tables 3a and 3b, respectively.
Table 3a shows the results obtained for each compound of Examples 8, 9 and 11 described herein compared with a DMSO control.
Table 3b shows the results obtained for the combination of Oxacillin with each of compound of Examples 8, 9 and 11 compared with a DMSO control also containing oxacillin.
Table 3a shows that for each OD value use of the compound of Examples 8, Example 9 and Example 11, respectively, resulted in a decrease of the number of CFUs/ml as compared to the DMSO control.
Table 3b shows that for each OD value use of a combination of oxacillin and the compound of Example 8, Example 9 or Example 11 resulted in a larger decrease in the number of CFUs/ml as compared to the control containing DMSO and oxacillin. No CFUs/ml were detected when a combination of oxacillin and the compound of Example 11 was used at OD 0.1. Further, no CFUs/ml were detected at OD 0.001 when oxacillin was used in combination with the compounds of Examples 8, 9 and 11, respectively.
A comparison of the results of Tables 3a and 3b reveals that a larger decrease in the number of detected CFUs/ml was observed for the combination of oxacillin with the compounds of Examples 8, 9 and 11, respectively, as compared to use of each of these compounds alone or use of oxacillin alone.
In this document, E+n stands for 10n. For instance, E+6 means 106.
Method for Determining the Effect of a Combination of Example 11 and Vancomycin on VRE (V583)
Compound of Example 11 (2.5 μM, 5 μL in DMSO) was added to the bacterial inoculum (190 ul) with OD 0,001 along with increasing doses of Vancomycin (in water) at increasing concentrations of the Vancomycin ranging from 1-64 μg/ml. The mixture (200 μL) was incubated at 37° C. for 18 h Controls were performed without bacteria-vehicle (DMSO), Vancomycin vehicle (water) and BHI controls that use those as treatment to the inoculum, to ensure no previous bacterial contamination in the reagents. Bacterial CFU were counted as standard methods using serial dilution plated on BHI plates to determine the effect of each treatment. Additionally, the initial bacterial inoculum was counted to determine whether the treatment had a bacteriostatic or a bacteriocidal effect. Bacterial CFU of each treatment were summarized in Table 4
Table 4 shows the results obtained for a combination of Example 11 with Vancomycin for eradication of a Vancomycin Resistant Enterococcus (VRE) strain V583.
It was observed that use of Vancomycin at a concentration below 64 μg/ml had no or no substantial effect on the bacterial growth and nor the use of only the compound of Example 11 at 2.5 μM. However, the combination of Example 11 (2.5 μM) and Vancomycin had a large effect on the number of CFU's from 2 μg/mL of Vancomycin and above.
Effect of a Combination of Gentamicin and the Compound of Example 11 on E. faecalis OG1RF
In this example, gentamicin was used in combination with the compound of Example 11, i.e. 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid.
Stand Alone Activity In Vivo Against Enterococcus Faecalis in a Mouse Model of Catheter-Associated Urinary Tract Infection (CAUTI)
Mice used in this study were six-week-old female wild-type C57BL/6Ncr mice. Mice were anesthetized by inhalation of isoflurane and implanted with a 5-mm length of platinum-cured silicone catheter. Then, mice were infected immediately following catheter implantation with 50 μl of ˜2×107 CFU of E. faecalis OG1RF in PBS (1 mL) was introduced in the bladder lumen by transurethral inoculation. 24 hours post-infection, 100 μL, 10 mg/kg of 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid (Example 30) or 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid (Example 28) in DMSO was administrated via intraperitoneally injection. Mice were sacrificed at 48 hours post-infection by cervical dislocation after anaesthesia inhalation, and the bladders were aseptically harvested. Subsequently, the silicone implant was retrieved from the bladder. Catheters were placed in 1×PBS (1 mL), sonicated for 10 min, to detach E. faecalis and bladders were homogenized in 1×PBS (1 mL). For bacterial enumeration on catheters and bladders, samples were serially diluted and plated on BHI for CFU enumeration
Additionally, the compounds of Example 14, Example 49, Example 23, and Example 50 were tested in the mouse model of E. faecalis CAUTI (
Activity of a Combination of Vancomycin and the Compound of Example 49 In Vivo Against Two Enterococcus Faecalis Strains OG1RF (Vancomycin Sensitive) and V583 (Vancomycin Resistant) in a Mouse Model of Catheter-Associated Urinary Tract Infection (CAUTI)
Mice used in this study were six-week-old female wild-type C57BL/6Ncr mice. Mice were anesthetized by inhalation of isoflurane and implanted with a 5-mm length of platinum-cured silicone catheter. Then, mice were infected immediately following catheter implantation with 50 μl of˜2×107 CFU of E. faecalis OG1RF (
Activity of a Combination of Gentamicin and the Compound of Example 49 In Vivo Against Enterococcus Faecalis Strains OG1RF in a Mouse Model of Catheter-Associated Urinary Tract Infection (CAUTI)
Mice used in this study were six-week-old female wild-type C57BL/6Ncr mice. Mice were anesthetized by inhalation of isoflurane and implanted with a 5-mm length of platinum-cured silicone catheter. Then, mice were infected immediately following catheter implantation with 50 μl of ˜2×107 CFU of E. faecalis OG1RF in PBS (1 mL) was introduced in the bladder lumen by transurethral inoculation. 24 hours post-infection, 100 μL, 2 mg/kg of Vancomycin or Example 49 (7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylic acid) or in combination in DMSO was administrated via intraperitoneally injection. Mice were sacrificed at 48 hours post-infection by cervical dislocation after anaesthesia inhalation, and the bladders were aseptically harvested. Subsequently, the silicone implant was retrieved from the bladder. Catheters were placed in 1×PBS (1 mL), sonicated for 10 min, to detach E. faecalis and bladders were homogenized in 1×PBS (1 mL). For bacterial enumeration on catheters and bladder, samples were serially diluted and plated on BHI for CFU enumeration.
In this document, to evaluate significance the .Mann-Whitney U test was used for mouse experiments, p<0.05 was considered statistically significant.*, p<0.05; *, p<0.005; *, p<0.0005; ns, values were not statistically different.
Claims
1. A compound of Formula III:
- or a pharmaceutically acceptable salt thereof,
- wherein: R1 is selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c) C(O)NHSO2R6, d) NH2, e) H,
- R2 is selected from the group consisting of: a) H, b) Cl, F, Br, or I, c) CH2OH, d) C1-C4alkyl, and e) NZ1Z2, R3 is selected from the group consisting of: a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy, b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl e) 2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl, R4 is selected from the group consisting of: a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro; b) C3-C6cycloalkyl, c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d) C3-C6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered heterocycle, f) NZ1Z2, g) CH2NZ1Z2, i) C(O)OH, and j) C(O)H, R5 is selected from the group consisting of:
- and in the above definitions: R6 is selected from the group consisting of ethyl, vinyl, allyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl, R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl, R8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, henoxy, pentoxy, octoxy, nonoxy, decoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or R7 and R8 together form O(CH2)2O, R9 represents C1-C10 alkyl, R10 represents C1-C4alkyl, R11 represents C1-C4alkyl, or R10 and R11 together form CH2(CH2)mCH2, Y is O, S or N, Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2, n is 0 or 1, m is 0 or 1, p is 0, 1 or 2, q is 0 or 1, r is 1, and X is S, SO or SO2, with the proviso that the compound of Formula III is not: 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid.
2. (canceled)
3. (canceled)
4. The compound according to claim 1, wherein:
- R1 is C(O)OH or tetrazolyl,
- R2 is H;
- R3 is 1-naphtyl, 9-anthryl or trifluoromethylphenyl, and
- R4 is C3-C6cycloalkyl, C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, or NZ1Z2,
- or a pharmaceutically acceptable salt thereof.
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. The compound according to claim 1, wherein R4 is cyclopropyl or methoxy, or a pharmaceutically acceptable salt thereof.
10. (canceled)
11. (canceled)
12. (canceled)
13. The compound according to claim 1, wherein
- R7 is methyl, and/or
- R8 is selected form the group consisting of ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, 4-hydroxy-3-methyl-phenyl, 4-methoxy-3-methyl-phenyl, 4-ethoxy-3-methyl-phenyl, 4-propoxy-3-methyl-phenyl, 4-butoxy-3-methyl-phenyl, 4-pentoxy-3-methyl-phenyl, 4-hexoxy-3-methyl-phenyl, 4-heptoxy-3-methyl-phenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-(2-methoxyethoxy)-3-methyl-phenyl, 4-alloxy-3-methyl-phenyl, 5-hexynyloxy-3-methyl-phenyl, 4-isohexyloxy-3-methyl-phenyl, 4-(4′-methyl)-3′-pentenyloxy)-3-methyl-phenyl, 4-(5′-hexenyloxy)-3-methyl-phenyl and 1-hexyl-1H-1,2,3-triazol-4-yl,
- or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1, wherein the compound is selected from the group consisting of:
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Allyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(5-Hexynyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Isohexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Methoxy-8-[4-(4-methyl-3-pentenyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(5-Hexenyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8(p-Butoxyphenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[p-(pentyloxy)phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(4-methoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(4-ethoxy-3-methyl-phenyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(4-propoxy-3-methyl-phenyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-[4-(pentyloxy)-3-methyl-phenyl]-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(heptyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-[4-(2-methoxyethoxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(4-Butoxy-3-methyl-phenyl)-5-cyclopropyl-2-oxo-4-{[m-(trifluoromethyl)phenyl]methyl}-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Cyclopropylmethoxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Amino-8-[4-(hexyloxy)-3-methyl-phenyl]-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 8-[4-(Hexyloxy)-3-methyl-phenyl]-5-methoxy-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid imidazole salt,
- 8-(1-Hexyl-1H-1,2,3-triazol-4-yl)-5-methoxy-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid imidazole salt,
- 5-Cyclopropyl-8-(4-hydroxytolyl)-4-[(1-naphtyl)methyl]-2-oxo-7-thia-1-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid,
- 8-(dimethylamino)-2-(3-methyl-4-(pentyloxy)phenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
- 8-(dimethylamino)-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphthalen-1-ylmethyl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylic,
- 8-(dimethylamino)-2-(4-(heptyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carbocylic acid,
- 8-(dimethylamino)-2-(3-methyl-4-((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
- 8-amino-2-(3-methyl-4-(pentyloxyphenyl)-7-naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid,
- 8-amino-2-(4-(hexyloxy)-3-methylphenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-caraboxylic acid,
- 8-amino-2-(4-heptyloxy)-3-methylphenyl)-7-8naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxyic acid,
- 7-(anthracen-9-ylmethyl)-8-methoxy-2-(3-methyl-4-(pentyloxy)phenyl)-5-oxo-thiazolo[3,2,a]pyridine-3-carboxylic acid, and
- 1H-imidazol-1-ium 8-methoxy-2-(3-methyl-4((4-methylpentyl)oxy)phenyl)-7-(naphtalen-1-ylmethyl)-5-oxo-thiazolo[3,2-a]pyridine-3-carboxylate,
- or a pharmaceutically acceptable salt of any of the foregoing compounds.
15. (canceled)
16. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, carrier or excipient.
17. A combination comprising:
- (i) a composition comprising a drug against a disease involving gram-positive bacteria, or a pharmaceutically acceptable salt of said drug, and
- (ii) a composition comprising a compound of Formula IV:
- or a pharmaceutically acceptable salt thereof,
- wherein: R1 is selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c) C(O)NHSO2R6, d) NH2, e) H,
- R2 is selected from the group consisting of: a) H, b) Cl, F, Br or I, c) CH2OH, d) C1-C4alkyl, and e) NZ1Z2, R3 is selected from the group consisting of: a) 1-naphtyl, 2-naphtyl, 1-naphtyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy, b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl, e) 2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl, R4 is selected from the group consisting of: a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro; b) C3-C6cycloalkyl, c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d) C3-C6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered heterocycle, f) NZ1Z2, g) CH2NZ1Z2, i) C(O)OH, j) C(O)H, k) 3-(trifluoromethyl)phenyl, and l) benzo[d][1,3]dioxol-5-yl, R5 is selected from the group consisting of:
- and f) H and in the above definitions: R6 is C1-C4alkyl or phenyl, R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl, R8 is selected from the group consisting of OH, C1-C10alkoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or R7 and R8 together form O(CH)2O, R9 is selected from the group consisting of H and C1-C10 alkyl, R10 represents C1-C4alkyl, R11 represents C1-C4alkyl, or R10 and R11 together form CH2(CH2)mCH2, Y is O, S or N, Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2, n is 0 or 1, m is 0 or 1, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1, and X is S, SO or SO2.
18. The combination according to claim 17, wherein said compound of Formula IV is selected from the group consisting of:
- 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(1H-indol-5-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(3-thienyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(2-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-8-(3-furyl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 6-[(9-Anthryl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-indancarboxylic acid,
- 6-[(Naphtyl)methyl]-4-oxo-7-[m-(trifluoromethyl)phenyl]-1-thia-3a-aza-3-indancarboxylic acid,
- 6-[(Naphtyloxy)methyl]-4-oxo-2-phenyl-7-(1,3-Dioxa-5-indanyl)-1-thia-3a-aza-3indancarboxylic acid,
- (R)-7-(naphtalen-1-ylmethyl)-5-oxo-2,3-dihydro-tiazolo[3,2,a]pyridine-3,8-dicarboxylic acid, and
- 7-(anthracen-9-ylmethyl)-8-methoxy-5-oxo-2,3-dihydro-thiazolo[3,2,a]pyridine-3-carboxylic acid,
- or a pharmaceutically acceptable salt of any of the foregoing compounds.
19. The combination according to claim 17, wherein the compound of Formula IV is a compound of Formula III:
- or a pharmaceutically acceptable salt thereof,
- wherein: R1 is selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c) C(O)NHSO2R6, d) NH2, e) H,
- R2 is selected from the group consisting of: a) H, b) Cl, F, Br, or I, c) CH2OH, d) C1-C4alkyl, and e) NZ1Z2, R3 is selected from the group consisting of: a) 1-naphtyl, 2-naphtyl, 1-napthyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy, b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl e) 2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl, R4 is selected from the group consisting of: a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro: b) C3-C6cycloalkyl, c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d) C3-C6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered heterocycle, f) NZ1Z2, g) CH2NZ1Z2, i) C(O)OH, and j) C(O)H, R5 is selected from the group consisting of:
- and in the above definitions:
- R6 is selected from the group consisting of ethyl, vinyl, allyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl,
- R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl,
- R8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, hexoxy, pentoxy, octoxy, nonoxy, decoxy, C1-C10alkenoxy, C1-C10alkenoxy and O(CH2)2OCH3, or
- R7 and R8 together form O(CH2)2O,
- R9 represents C1-C10 alkyl,
- R10 represents C1-C4alkyl,
- R11 represents C1-C4alkyl, or
- R10 and R11 together form CH2(CH2)6CH2,
- Y is O, S or N,
- Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2,
- n is 0 or 1,
- m is 0 or 1,
- p is 0, 1 or 2,
- q is 0 or 1,
- r is 1, and
- X is S, SO or SO2,
- with the proviso that the compound of Formula III is not:
- 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphtyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4,3,0]nona-3,5,8-triene-9-carboxylic acid, or
- 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid.
20. The combination according to claim 17, wherein said combination is provided as a single composition.
21. The combination according to claim 17, wherein said combination is provided as a kit of parts.
22. The combination according to claim 17, wherein said combination further comprises instructions for use.
23. The combination according to claim 17, wherein the drug against a disease involving gram-positive bacteria is an antibiotic.
24. The combination according to claim 17, wherein the drug against a disease involving gram-positive bacteria is selected from the group consisting of vancomycin, oxacillin, dalbavancin, oritavancin, teicoplanin, daptomycin, linezolid, tedizolid, telavancin, gentamicin, tobramycin, amikacin, streptomycin, neomycin, and paromomycin or any combination thereof.
25. The combination according to claim 17, wherein the drug against a disease involving gram-positive bacteria is vancomycin, oxacillin and/or gentamicin.
26.-36. (canceled)
37. A method for treatment and/or prevention of a disease involving gram-positive bacteria comprising administering to a mammal, in need thereof an effective amount of or a pharmaceutically acceptable salt thereof, wherein: and
- a compound of Formula III or an effective amount of
- a compound of Formula IV:
- R1 is selected from the group consisting of:
- a) C(O)OH, b) tetrazolyl, c) C(O)NHSO2R6, d) NH2, e) H,
- R2 is selected from the group consisting of: a) H, b) Cl, F, Br, or I, c) CH2OH, d) C1-C4alkyl, and e) NZ1Z2, R3 is selected from the group consisting of: a) 1-naphtyl, 2-naphtyl, 1-napthyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy, b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl e) 2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl, R4 is selected from the group consisting of: a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro: b) C3-C6cycloalkyl, c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d) C3-C6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered heterocycle, f) NZ1Z2, g) CH2NZ1Z2, i) C(O)OH, and j) C(O)H, R5 is selected from the group consisting of:
- and in the above definitions: R6 is selected from the group consisting of ethyl, vinyl, allyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl, R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl, R8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, henoxy, pentoxy, octoxy, nonoxy, desoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or R7 and R8 together form O(CH2)2O, R9 represents C1-C10 alkyl, R10 represents C1-C4alkyl, R11 represents C1-C4alkyl, or R10 and R11 together form CH2(CH2)mCH2, Y is O, S or N, Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2, n is 0 or 1, m is 0 or 1, p is 0, 1 or 2, q is 0 or 1, r is 1 and X is S, SO or SO2, with the proviso that the compound of Formula III is not: 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-1(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic acid:
- or a pharmaceutically acceptable salt thereof,
- wherein: R1 is selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c) C(O)NHSO2R6, d) NH2, e) H,
- R2 is selected from the group consisting of: a) H, b) Cl, F, Br or I, c) CH2OH, d) C1-C4alkyl, and e) NZ1Z2,
- R3 is selected from the group consisting of:
- a) 1-naphtyl, 2-naphtyl, 1-napthyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy,
- b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro,
- c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl,
- d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl,
- e) 2-(3-methyl)phenylmethylene,
- f) benzothiophen-2-yl,
- g) H,
- h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and
- i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl,
- R4 is selected from the group consisting of:
- a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro;
- b) C3-C6cycloalkyl,
- c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro,
- d) C3-C6cycloalkoxy,
- e) a 3-, 4-, 5-, or 6-membered heterocycle,
- f) NZ1Z2,
- g) CH2NZ1Z2,
- i) C(O)OH,
- j) C(O)H,
- k) 3-(trifluoromethyl)phenyl, and
- l) benzo[d][1,3]dioxol-5-yl,
- R5 is selected from the group consisting of:
- f) H
- and in the above definitions:
- R6 is C1-C4alkyl or phenyl,
- R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl,
- R8 is selected from the group consisting of OH, C1-C10alkoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or
- R7 and R8 together form O(CH)2O,
- R9 is selected from the group consisting of H and C1-C10 alkyl,
- R10 represents C1-C4alkyl,
- R11 represents C1-C4alkyl, or
- R10 and R11 together form CH2(CH2)mCH2,
- Y is O, S or N,
- Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2,
- n is 0 or 1,
- m is 0 or 1,
- p is 0, 1 or 2,
- q is 0 or 1,
- r is 0 or 1, and
- X is S, SO or SO2, or
- a combination according to claim 17.
38. The method according to claim 37, wherein said gram-positive bacteria are selected from the group consisting of Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococci (VRE), Enterococcus faecalis (E. faecalis), Enterococcus faecium, Vancomycin-Intermediate Staphylococcus aureus (VISA), Vancomycin-Resistant Staphylococcus aureus (VRSA), Clostridium difficile (C. difficile), Clostridium tetani, Streptococcus pyogenes, Staphylococcus saphyticus, and Bacillus subtilis or any combination thereof.
39. The method according to claim 37, wherein said disease is a healthcare associated infection.
40. The method according to claim 37, wherein said disease is selected from the group consisting of urinary tract infection (UTI), catheter associated urinary tract infection, central line associated bloodstream infection (CLABSI), pneumonia, wound associated infection, surgical site infection, bacterial endocarditis, and tetanus or any combination thereof.
41. (canceled)
42. (canceled)
43. A catheter or an implant treated with:
- a compound of Formula III or Formula IV:
- or a pharmaceutically acceptable salt thereof,
- wherein: R1 is selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c) C(O)NHSO2R6, d) NH2, e) H,
- R2 is selected from the group consisting of: a) H, b) Cl, F, Br, or I, c) CH2OH, d) C1-C4alkyl, and e) NZ1Z2, R3 is selected from the group consisting of: a) 1-naphtyl, 2-naphtyl, 1-napthyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy, b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl e) 2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl, R4 is selected from the group consisting of: a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro; b) C3-C6cycloalkyl, c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d) C3-C6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered heterocycle, f) NZ1Z2, g) CH2NZ1Z2, i) C(O)OH, and j) C(O)H, R5 is selected from the group consisting of:
- and in the above definitions: R6 is selected from the group consisting of ethyl, vinyl, allyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and phenyl, R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl, R8 is selected from the group consisting of OH, ethoxy, n-propoxy, cyclopropylmethoxy, iso-propoxy, butoxy, pentoxy, hexoxy, pentoxy, octoxy, nonoxy, decoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or R7 and R8 together form O(CH2)2O, R9 represents C1-C10 alkyl, R10 represents C1-C4alkyl, R11 represents C1-C4alkyl, or R10 and R11 together form CH2(CH2)mCH2, Y is O, S or N, Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2, n is 0 or 1, m is 0 or 1, p is 0, 1 or 2, q is 0 or 1, r is 1, and X is S, SO or SO2, with the proviso that the compound of Formula III is not: 8-Benzyl-5-cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-phenyl-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphtyl)methyl]-2-oxo-8-(m-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3.5,8-triene-9-carboxylic acid, 5-Cyclopropyl-4-[(1-naphthyl)methyl]-2-oxo-8-(p-tolyl)-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid, or 5-Cyclopropyl-8-(1,4-dioxa-2,3-dihydronaphth-6-yl)-4-[(1-naphthyl)methyl]-2-oxo-7-thia-1-azabicyclo[4.3.0]nona-3,5,8-triene-9-carboxylic acid,
- or a pharmaceutically acceptable salt thereof,
- wherein: R1 is selected from the group consisting of: a) C(O)OH, b) tetrazolyl, c) C(O)NHSO2R6, d) NH2, e) H,
- R2 is selected from the group consisting of: a) H, b) Cl, F, Br or I, c) CH2OH, d) C1-C4alkyl, and e) NZ1Z2, R3 is selected from the group consisting of: a) 1-naphtyl, 2-naphtyl, 1-napthyloxy, 9-anthryl and 9-anthryloxy each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of methyl, fluoro, chloro, bromo, cyano and methoxy, b) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro, c) phenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro, cyano and trifluoromethyl, d) aminophenyl substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of methyl, fluoro, chloro and trifluoromethyl, e) 2-(3-methyl)phenylmethylene, f) benzothiophen-2-yl, g) H, h) 2-methyl-1-aza-2-bora-1H-naphth-5-yloxy, and i) 2-methyl-1-aza-2-bora-1H-naphth-5-yl, R4 is selected from the group consisting of: a) C1-C4alkyl substituted with 0, 1, 2, 3 or 4 fluoro; b) C3-C6cycloalkyl, c) C1-C4alkoxy substituted with 0, 1, 2, 3 or 4 fluoro, d) C3-C6cycloalkoxy, e) a 3-, 4-, 5-, or 6-membered heterocycle, f) NZ1Z2, g) CH2NZ1Z2, i) C(O)OH, j) C(O)H, k) 3-(trifluoromethyl)phenyl, and l) benzo[d][1,3]dioxol-5-yl, R5 is selected from the group consisting of:
- and f) H and in the above definitions: R6 is C1-C4alkyl or phenyl, R7 is selected from the group consisting of F, Cl, Br, and C1-C4alkyl, R8 is selected from the group consisting of OH, C1-C10alkoxy, C1-C10alkenoxy, C1-C10alkynoxy and O(CH2)2OCH3, or R7 and R8 together form O(CH)2O, R9 is selected from the group consisting of H and C1-C10 alkyl, R10 represents C1-C4alkyl, R11 represents C1-C4alkyl, or R10 and R11 together form CH2(CH2)mCH2, Y is O, S or N, Z1 and Z2 each independently represents hydrogen, methyl, CH3S(O)2, C(O)OR10, C(O)NR10R11 or C(O)R10, or Z1 and Z2 together form CH2CH2CH2CH2, CH2CH2CH2, or CH2CH2CH2CH2CH2, n is 0 or 1, m is 0 or 1, p is 0, 1 or 2, q is 0 or 1, r is 0 or 1, and X is S, SO or SO2, or a combination as defined in claim 17.
44. (canceled)
45. (canceled)
Type: Application
Filed: Jun 13, 2018
Publication Date: Dec 30, 2021
Inventors: Scott Hultgren (Town and Country, MO), Jerome S. Pinkner (St. Louis, MO), Michael Gordon Caparon, Jr. (Chesterfield, MO), Ana Lidia Flores Mireles (St. Louis, MO), Fredrik Almqvist (Umeå), Pardeep Singh (Umeå), Anders Lindgren (Umeå), Aaron James Leonard Lynch (Webster Grove, MO)
Application Number: 16/619,133
