WO2016128131A1 - Beta-lactone inhibitors of phospholipase a2 and uses thereof - Google Patents
Beta-lactone inhibitors of phospholipase a2 and uses thereof Download PDFInfo
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- 0 CC*C(C(C(*(C)*(C)*)O)C(O)=O)NC(C)CC Chemical compound CC*C(C(C(*(C)*(C)*)O)C(O)=O)NC(C)CC 0.000 description 1
- JVDDZUWYDWDDOP-UHFFFAOYSA-N CCCC(C(CCCc1cc(cccc2)c2cc1)C(O)=O)O Chemical compound CCCC(C(CCCc1cc(cccc2)c2cc1)C(O)=O)O JVDDZUWYDWDDOP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
Definitions
- the present invention belongs to the field of medicinal chemistry, in particular it related to novel beta-lactone compounds useful in treatment of disease or condition associated with phospholipase A (PLA 2 ) activity.
- the phospholipase A 2 (PLA 2 ) superfamily consists of several groups of enzymes that are characterized by their ability to catalyze the hydrolysis of the ester bond at the sn- 2 position of glycerophospholipids.
- the products of the hydrolysis are a free fatty acid, for example arachidonic acid, and a lysophospholipid, both of which may generate second messengers that play important physiological roles.
- Three predominant types of PLA 2 are found in human tissues: the cytosolic (cPLA 2 ), the secreted (sPLA 2 ), and the calcium-independent (iPLA 2 ) enzymes.
- PLA 2 s The structure and the biological functions of PLA 2 s are summarized in a review article ("Phospholipase A 2 enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention" E. A. Dennis, G. Kokotos et al Chem. Rev. 2011, 111, 6130-6185).
- the calcium-independent group iPLA 2 is actually a group of cytosolic enzymes ranging from 85 to 88 kDa and expressed as several distinct splice variants of the same gene (P. K. Larsson et al J. Biol. Chem. 1998, 273, 207-214).
- the iPLA 2 enzyme contains a consensus lipase motif, Gly-Thr-Ser*-Thr-Gly, with the catalytic serine confirmed by site-directed mutagenesis (J. Tang et al J. Biol. Chem. 1997, 272, 8567-8575).
- a number of studies suggest that iPLA 2 plays important roles in numerous cell types, although they may differ from cell to cell.
- Synthetic inhibitors of the various forms of PLA 2 have attracted a lot of interest as potential novel medicinal agents, because they may regulate PLA activity and subsequently the production of various bioactive lipids.
- a variety of synthetic inhibitors are known in the art (see, for example, Chem. Rev. 2011, 111, 6130-6185). The inhibitors described in various patents are summarized in two recent articles (V. Magrioti and G. Kokotos, Expert Opinion Therapeutic Patents 2010, 20, 1-18; V. Magrioti and G. Kokotos Expert Opinion Therapeutic Patents 2013, 23, 333-344).
- iPLA 2 The most important inhibitors of iPLA 2 include bromoenol lactone (BEL), which is an irreversible inhibitor able however to inhibit proteases in addition to iPLA 2 , and polyfluoroketone compounds.
- BEL bromoenol lactone
- polyfluoroketone compounds A variety of polyfluoroketones have been described in the art (C. Baskakis et al J. Med. Chem, 2008, 51, 8027-8037; G. Kokotos et al J Med. Chem. 2010, 53, 3602-3610; V. Magrioti et al Bioorg. Med. Chem. 2013, 21, 5823-5829).
- polyfluoroketone FKGK1 1 has been used to show that iPLA 2 plays an important role in the onset and progress of multiple sclerosis-like disease (A. Kalyvas et al Brain 2009, 132, 1221-1235).
- Polyfluoroketone FKGK18 has been proposed as a candidate drug for preventing beta-cell apoptosis and diabetes (T. Ali et al PLOS ONE 2013, 8, e71748).
- the present invention relates to beta-lactone compounds as well as salts, and derivatives thereof, and compositions containing them.
- the invention further relates to uses of such compounds, salts, derivatives and compositions, such as for the inhibition of phospholipase A 2 and/or the treatment of various conditions (e.g., autoimmune conditions, neural conditions and/or inflammatory conditions).
- the present invention provides beta-lactone compounds having the formula I
- R 1 is H, F, or lower alkyl
- Ar 1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms;
- the present invention provides beta-lactone compounds having the formula I
- R 1 is H, F, or lower alkyl
- Ar 1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms;
- the present invention provides beta-lactone compounds having the formula I
- R 1 is H, F, or lower alkyl
- Ar 1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms
- R 2 is an alkyl having 1-6 carbon atoms
- the present invention provides beta-lactone compounds having the formula I
- R 1 is H
- Ar 1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms;
- the present invention provides a use of the above-mentioned compound as a medicament.
- the present invention provides a use of the above-mentioned compound for the preparation of a medicament.
- the present invention provides a method for inhibiting PLA 2 activity in a system (e.g., a cell-free system), cell or subject, said method comprising contacting said system or cell with, or administering to said subject, an effective amount of the above-mentioned compound or composition.
- the present invention provides a method for inhibiting iPLA 2 activity in a system (e.g., a cell-free system), cell or subject, said method comprising contacting said system or cell with, or administering to said subject, an effective amount of the above-mentioned compound or composition.
- a system e.g., a cell-free system
- the present invention provides a method for the preventing and/or treating an autoimmune disease or condition in a subject, said method comprising administering to said subject an effective amount of the above-mentioned compound or composition.
- the present invention provides a method for the preventing and/or treating an inflammatory disease or condition in a subject, said method comprising administering to said subject an effective amount of the above-mentioned compound.
- the present invention provides the use of the above-mentioned compound for the preparation of a medicament for inhibiting PLA 2 activity in a cell or subject.
- the present invention provides the use of the above-mentioned compound for the preparation of a medicament for inhibiting iPLA 2 activity in a cell or subject.
- the present invention provides a method for the preventing and/or treating a neural disease or condition in a subject, said method comprising administering to said subject an effective amount of the above-mentioned compound or composition.
- the present invention provides the above-mentioned compound or composition for use in the prevention and/or treatment of an autoimmune disease or condition.
- the present invention provides the above-mentioned compound or composition for use in the prevention and/or treatment of a neural disease or condition.
- the present invention provides the above-mentioned compound or composition for use in the prevention and/or treatment of an inflammatory disease or condition.
- the present invention provides a composition comprising the above- mentioned compound and a pharmaceutically acceptable carrier or excipient.
- the present invention provides a method of preparing a beta-lactone compound of the invention.
- a beta-lactone compound of the present invention can be prepared by cyclization of a beta-hydroxy carboxylic acid.
- Compounds of the invention are constructed based on beta-lactone ring with a long or medium hydrocarbon tail carrying an aryl or heteroaryl and a short hydrocarbon chain or a carbon tether bearing an acidic group.
- Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
- the present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.
- alkyl refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl etc.
- the alkyl groups are (Ci-C 2 o) alkyl groups, more preferably (C Cio) alkyl groups.
- the term "lower alkyl” refers to alkyl groups having up to 6 carbons, (Ci-C 6 ) alkyl groups.
- aryl refers to a C 6- i 2 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or biphenyl. Optionally, the term “aryl” also covers C 6- i 2 monocyclic or bicyclic hydrocarbon ring substituted with an O-alkyl group having 1 -4 carbon atoms.
- inflammatory diseases or conditions refers to the group of diseases or conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints.
- autoimmune diseases or conditions refers to the group of diseases or conditions including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantily asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes mellitus, type II diabetes mellitus, and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. Particularly the term refers to COPD, asthma, systemic lupus erythematosis, and inflammatory bowel disease.
- COPD chronic or inveterate asthma
- neural diseases or conditions refers to the group of diseases including multiple sclerosis (MS), amyotropic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Alzheimer's disease and neural injury.
- MS multiple sclerosis
- ALS amyotropic lateral sclerosis
- Parkinson's disease Huntington's disease
- Alzheimer's disease and neural injury.
- the present invention provides a composition comprising the above- mentioned compound and a pharmaceutically acceptable carrier or excipient.
- the compounds e.g., the compounds of formula I
- the compounds are effective as both injectable and oral compositions.
- Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound and a pharmaceutically acceptable diluent or carrier or excipient.
- Example 1 Synthesis and characterization of beta-lactones. General route for the synthesis of beta-lactones
- aldehyde (0.6 mmol) in anhydrous THF (2 mL) is added and the solution is stirred at 0°C for 1 h and at room temperature overnight.
- the solvent is removed under vacuum; Et 2 0 is added and washed with H 2 0.
- the aqueous phase is acidified with HC1 IN to pH 2 and then, extracted with Et 2 0.
- the organic layers are combined, washed with brine and dried.
- the solvent is removed and the product is purified by column chromatography eluting with a gradient of CHCl 3 /MeOH 95/5 to 9/1.
- G 393, 397, 399, 412, 436 are the most potent compounds in this series.
- GK436 exhibited a Xi(50) value of 0.00006 and thus is the most potent inhibitor of GVIA iPLA 2 ever reported. It is selective for GVIA iPLA 2 since it is at least 1000 times more potent for GVIA iPLA 2 than for GIVA cPLA 2 and practically does not inhibit GV sPLA 2 .
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Abstract
Novel beta-lactone compounds are described. Also described are uses thereof, such as for inhibition of phospholipase A2 activity. Therapeutic uses thereof are also described, such as for the treatment of autoimmune conditions, and/or neural conditions, and/or inflammatory conditions.
Description
BETA-LACTONE INHIBITORS OF PHOSPHOLIPASE A2 AND USES THEREOF
TECHNICAL FIELD OF THE INVENTION
The present invention belongs to the field of medicinal chemistry, in particular it related to novel beta-lactone compounds useful in treatment of disease or condition associated with phospholipase A (PLA2) activity.
BACKGROUND OF THE INVENTION
The phospholipase A2 (PLA2) superfamily consists of several groups of enzymes that are characterized by their ability to catalyze the hydrolysis of the ester bond at the sn- 2 position of glycerophospholipids. The products of the hydrolysis are a free fatty acid, for example arachidonic acid, and a lysophospholipid, both of which may generate second messengers that play important physiological roles. Three predominant types of PLA2 are found in human tissues: the cytosolic (cPLA2), the secreted (sPLA2), and the calcium-independent (iPLA2) enzymes. The structure and the biological functions of PLA2s are summarized in a review article ("Phospholipase A2 enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention" E. A. Dennis, G. Kokotos et al Chem. Rev. 2011, 111, 6130-6185).
The calcium-independent group iPLA2 is actually a group of cytosolic enzymes ranging from 85 to 88 kDa and expressed as several distinct splice variants of the same gene (P. K. Larsson et al J. Biol. Chem. 1998, 273, 207-214). The iPLA2 enzyme contains a consensus lipase motif, Gly-Thr-Ser*-Thr-Gly, with the catalytic serine confirmed by site-directed mutagenesis (J. Tang et al J. Biol. Chem. 1997, 272, 8567-8575). A number of studies suggest that iPLA2 plays important roles in numerous cell types, although they may differ from cell to cell. Several review articles summarize the role of iPLA2 in signaling and pathological conditions (J. Balsinde et al "Cellular regulation and proposed biological functions of group VIA calcium
independent phospholipase A2 in activated cells" Cell. Signalling 2005, 17, 1052- 1062; J. Balsinde et al "Calcium-independent phospholipase A2 and apoptosis" Biochim. Biophys. Acta 2006, 1761, 1344-1350; S. B. Hook et al "Role of Ca2+ - independent phospholipase A2 in cell growth and signaling" Biochem. Pharmacol. 2008, 76, 1059-1067; Lei X. et al "Group VIA Ca2+-independent phospholipase A2 (iPLA2beta) and its role in beta-cell programmed cell death" Biochimie 2010, 92, 627-637).
Synthetic inhibitors of the various forms of PLA2 have attracted a lot of interest as potential novel medicinal agents, because they may regulate PLA activity and subsequently the production of various bioactive lipids. A variety of synthetic inhibitors are known in the art (see, for example, Chem. Rev. 2011, 111, 6130-6185). The inhibitors described in various patents are summarized in two recent articles (V. Magrioti and G. Kokotos, Expert Opinion Therapeutic Patents 2010, 20, 1-18; V. Magrioti and G. Kokotos Expert Opinion Therapeutic Patents 2013, 23, 333-344). The most important inhibitors of iPLA2 include bromoenol lactone (BEL), which is an irreversible inhibitor able however to inhibit proteases in addition to iPLA2, and polyfluoroketone compounds. A variety of polyfluoroketones have been described in the art (C. Baskakis et al J. Med. Chem, 2008, 51, 8027-8037; G. Kokotos et al J Med. Chem. 2010, 53, 3602-3610; V. Magrioti et al Bioorg. Med. Chem. 2013, 21, 5823-5829). The binding mode of polyfluoroketones to iPLA2 has been studied by a combination of deuterium exchane mass spectrometry and molecular dynamics simulations (Y. H. Hsu et al J. Am. Chem. Soc. 2013, 135, 1330-1337). Polyfluoroketone FKGK1 1 has been used to show that iPLA2 plays an important role in the onset and progress of multiple sclerosis-like disease (A. Kalyvas et al Brain 2009, 132, 1221-1235). Polyfluoroketone FKGK18 has been proposed as a candidate drug for preventing beta-cell apoptosis and diabetes (T. Ali et al PLOS ONE 2013, 8, e71748). Most recently, it has been demonstrated that inhibition of iPLA2 by FKGK18 ameliorates islet infiltration and incidence of diabetes in non-obese diabetic (NOD) mice (R. Bone et al Diabetes 2015, 64, 541-554).
SUMMARY OF THE INVENTION
The present invention relates to beta-lactone compounds as well as salts, and derivatives thereof, and compositions containing them. The invention further relates to uses of such compounds, salts, derivatives and compositions, such as for the inhibition of phospholipase A2 and/or the treatment of various conditions (e.g., autoimmune conditions, neural conditions and/or inflammatory conditions).
In a first aspect, the present invention provides beta-lactone compounds having the formula I
I wherein:
R1 is H, F, or lower alkyl;
Ar1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms; R2 is an alkyl having 1-6 carbon atoms; n = 2 - 7; m = 0, 1 , 2; or isomers, enantiomeric forms, or prodrugs thereof.
I
wherein:
R1 is H, F, or lower alkyl;
Ar1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms; R2 is an alkyl having 1-6 carbon atoms; n = 2 - 5; m = 0, 1 ; or isomers, enantiomeric forms, or prodrugs thereof.
In another aspect, the present invention provides beta-lactone compounds having the formula I
I
wherein:
R1 is H, F, or lower alkyl; Ar1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms;
R2 is an alkyl having 1-6 carbon atoms; n = 2, 3; m = 0; or isomers, enantiomeric forms, or prodrugs thereof.
In another aspect, the present invention provides beta-lactone compounds having the formula I
I wherein:
R1 is H;
Ar1 is an aryl group having 6-12 carbon atoms optionally substituted with an O-alkyl group having 1-4 carbon atoms;
R2 is an alkyl having 1-6 carbon atoms; n = 2, 3; m = 0; or isomers, enantiomeric forms, or prodrugs thereof. In another aspect, the present invention provides a use of the above-mentioned compound as a medicament.
In another aspect, the present invention provides a use of the above-mentioned compound for the preparation of a medicament.
In another aspect, the present invention provides a method for inhibiting PLA2 activity in a system (e.g., a cell-free system), cell or subject, said method comprising contacting said system or cell with, or administering to said subject, an effective amount of the above-mentioned compound or composition.
In another aspect, the present invention provides a method for inhibiting iPLA2 activity in a system (e.g., a cell-free system), cell or subject, said method comprising contacting said system or cell with, or administering to said subject, an effective amount of the above-mentioned compound or composition.
In another aspect, the present invention provides a method for the preventing and/or treating an autoimmune disease or condition in a subject, said method comprising administering to said subject an effective amount of the above-mentioned compound or composition.
In another aspect, the present invention provides a method for the preventing and/or treating an inflammatory disease or condition in a subject, said method comprising administering to said subject an effective amount of the above-mentioned compound. In another aspect, the present invention provides the use of the above-mentioned compound for the preparation of a medicament for inhibiting PLA2 activity in a cell or subject.
In another aspect, the present invention provides the use of the above-mentioned compound for the preparation of a medicament for inhibiting iPLA2 activity in a cell or subject.
In another aspect, the present invention provides a method for the preventing and/or treating a neural disease or condition in a subject, said method comprising administering to said subject an effective amount of the above-mentioned compound or composition.
In another aspect, the present invention provides the above-mentioned compound or composition for use in the prevention and/or treatment of an autoimmune disease or
condition.
In another aspect, the present invention provides the above-mentioned compound or composition for use in the prevention and/or treatment of a neural disease or condition.
In another aspect, the present invention provides the above-mentioned compound or composition for use in the prevention and/or treatment of an inflammatory disease or condition.
In another aspect, the present invention provides a composition comprising the above- mentioned compound and a pharmaceutically acceptable carrier or excipient.
In another aspect, the present invention provides a method of preparing a beta-lactone compound of the invention. In an embodiment, a beta-lactone compound of the present invention can be prepared by cyclization of a beta-hydroxy carboxylic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : Inhibition curves of selected beta-lactone compounds
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the invention are constructed based on beta-lactone ring with a long or medium hydrocarbon tail carrying an aryl or heteroaryl and a short hydrocarbon chain or a carbon tether bearing an acidic group.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.
As used herein, the term "alkyl" refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl etc. Preferably, the alkyl groups are (Ci-C2o) alkyl groups, more preferably (C Cio) alkyl groups. The term "lower alkyl" refers to alkyl groups having up to 6 carbons, (Ci-C6) alkyl groups.
As used herein, the term "aryl" as used herein refers to a C6-i2 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl or biphenyl. Optionally, the term "aryl" also covers C6-i2 monocyclic or bicyclic hydrocarbon ring substituted with an O-alkyl group having 1 -4 carbon atoms.
As used herein the term "inflammatory diseases or conditions" refers to the group of diseases or conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, allergic airway disease (e.g. asthma, rhinitis), inflammatory bowel diseases (e.g. Crohn's disease, colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. Particularly the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma) and inflammatory bowel diseases.
As used herein the term "autoimmune diseases or conditions" refers to the group of diseases or conditions including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantily
asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes mellitus, type II diabetes mellitus, and complications associated therewith, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. Particularly the term refers to COPD, asthma, systemic lupus erythematosis, and inflammatory bowel disease.
As used herein the term "neural diseases or conditions" refers to the group of diseases including multiple sclerosis (MS), amyotropic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, Alzheimer's disease and neural injury.
In another aspect, the present invention provides a composition comprising the above- mentioned compound and a pharmaceutically acceptable carrier or excipient. The compounds (e.g., the compounds of formula I) may be administered in the form of pharmaceutical compositions. The compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound and a pharmaceutically acceptable diluent or carrier or excipient.
The present invention is illustrated in further details by the following non-limiting examples.
EXAMPLES
Example 1 : Synthesis and characterization of beta-lactones. General route for the synthesis of beta-lactones
General method for the synthesis of beta-hydroxy acids
0 °C, 1 h→- r.t, 16 h To a stirring solution of diisopropylamine (1 mmol) in anhydrous THF (2 mL), under argon at 0°C, a solution of n-BuLi 2.5M in hexane (1 mmol, 0.4 mL) is slowly added via syringe and the solution of LDA is stirred at 0°C for 10 minutes. The carboxylic acid (0.5 mmol) in anhydrous THF (4 mL) is now added and the solution is stirred at 0°C for 1 h. Then, aldehyde (0.6 mmol) in anhydrous THF (2 mL) is added and the solution is stirred at 0°C for 1 h and at room temperature overnight. The solvent is removed under vacuum; Et20 is added and washed with H20. The aqueous phase is acidified with HC1 IN to pH 2 and then, extracted with Et20. The organic layers are
combined, washed with brine and dried. The solvent is removed and the product is purified by column chromatography eluting with a gradient of CHCl3/MeOH 95/5 to 9/1.
3-hydroxy-2-(3-phenylpropyl)nonanoic
Oil, yield 51%; 1H NMR (CDC13) δ (ppm) 7.33-7.12 (m, 5H, Ar), 3.93-3.77 (m, 0.4H, CHOH), 3.76-3.61 (m, 0.6H, CHOH), 2.63 (t, J = 7 Hz, 2H, ArCH2), 2.54-2.37 (m, 1H, C(=0)CH), 1.83-1.56 (m, 4H, CH2), 1.55-1.40 (m, 2H, CH2), 1.40-1.15 (m, 10H, CH2), 0.90 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 180.6, 141.8, 128.3, 125.8, 72.2, 50.9, 50.6, 35.6, 35.2, 33.9, 31.7, 29.1, 28.9, 25.6, 22.6, 14.1; MS (ESI) m z (%): 291.3 [(M-H)-, 100]; HRMS: 315.1947 (M+Na)+, (315.1931).
• 3-hydroxy-2-(3-phenylpropyl)hexanoic acid
Oil, yield 28%; 1H NMR (CDC13) δ (ppm) 7.37-7.07 (m, 5H, Ar), 3.94-3.80 (m, 0.6H, CHOH), 3.79-3.67 (m, 0.4H, CHOH), 2.72-2.57 (m, 2H, ArCH2), 2.57-2.42 (m, 1H, C(=0)CH), 1.87-1.59 (m, 4H, CH2), 1.58-1.30 (m, 4H, CH2), 0.93 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 180.6, 141.9, 128.3, 125.8, 71.9, 71.8, 50.8, 50.7, 37.4, 36.1, 35.8, 29.0, 29.5, 26.3, 19.1, 18.8, 13.9; MS (ESI) m/z (%): 249.3 [(M-H)-, 100]; HRMS: 273.1475 (M+Na)+, (273.1461).
• 3-hydroxy-4-methyl-2-(3-phenylpropyl)pentanoic
Oil, yield 28%; 1H NMR (CDC13) 6 (ppm) 7.37-6.97 (m, 5H, Ar), 3.64-3.45 (m, 0.3H, CHOH), 3.45-3.25 (m, 0.7H, CHOH), 2.72-2.44 (m, 2H, ArCH2 και 0.7H, C(=0)CH), 2.43-2.27 (m, 0.3H, C(=0)CH), 1.87-1.51 (m, 5H, CH2 και CH(CH3)2), 1.01-0.79 (m, 6H, CH3); 13C NMR (CDC13) δ (ppm) 180.7, 141.8, 128.3, 125.8, 77.2, 48.3, 48.0, 35.8, 35.6, 31.8, 30.9, 29.5, 29.3, 29.0, 26.1, 19.6, 19.5, 17.5, 17.4; MS (ESI) m/z (%): 268.2 [(M+NH4+), 100].
• 3-hydroxy-2-(3-(4-methoxyphenyl)propyl)hexanoic acid
Oil, yield 46%; 1H NMR (CDC13) δ (ppm) 7.09 (d, J = 8 Hz, 2H, Ar), 6.82 (d, J - 8 Hz, 2H, Ar), 3.95-3.60 (m, 4H, OCH3 και CHOH), 2.58 (t, J = 7 Hz, 2H, ArCH2), 2.52-2.43 (m, 1H, C(=0)CH), 1.75-1.57 (m, 4H, CH2), 1.52-1.36 (m, 4H, CH2), 1.02- 0.87 (m, 3H, CH3), 13C NMR (CDC13) δ (ppm) 180.2, 157.6, 134.0, 129.2, 113.7, 71.8, 55.2, 50.9, 50.7, 37.4, 36.0, 34.8, 29.7, 29.3 28.9, 26.2, 19.1, 18.8, 13.9; MS (ESI) m/z (%): 279.2 [(M-H)-, 100].
3 -hydroxy-2-(3 -(naphthalen-2-yl)propyl)nonanoic
Oil, yield 35%; 1H NMR (CDC13) δ (ppm) 7.73-7.24 (m, 7H, Ar), 3.88-3.75 (m, 0.3H, CHOH), 3.74-3.62 (m, 0.7H, CHOH), 2.85-2.65 (m, 2H, ArCH2), 2.52-2.33 (m, 1H, C(=0)CH), 1.88-1.60 (m, 4H, CH2), 1.53-1.13 (m, 10H, CH2), 0.84 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) 6 (ppm) 180.4, 139.3, 133.5, 131.9, 127.8, 127.5, 127.4, 127.2, 126.3, 125.8, 125.1, 72.3, 51.1 , 35.8, 35.4, 31.8, 29.2, 28.9, 25.6, 22.6, 14.1; MS (ESI) m/z (%): 341.3 [(M-H)-, 100]; HRMS: 365.2090 (M+Na)+, (365.2087).
• 3-hydroxy-2-(3-(naphthalen-2-yl)propyl)hexanoic acid
Oil, yield 20%; 1H NMR (CDC13) δ (ppm) 7.81-7.25 (m, 7H, Ar), 3.90-3.80 (m, 0.3H, CHOH), 3.57-3.67 (m, 0.7H, CHOH), 2.78 (t, J = 6 Hz, 2H, ArCH2), 2.58-2.43 (m, 1H, C(=0)CH), 1.83-1.59 (m, 4H, CH2), 1.51-1.26 (m, 4H, CH2), 0.89 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 180.4, 139.2, 133.5, 131.9, 127.9, 127.5, 127.3, 127.1 , 126.3, 125.8, 125.1 , 71.9, 51.0, 37.4, 35.7, 29.3, 28.9, 19.1 , 18.8, 13.9; MS (ESI) m/z (%): 299.3 [(M-H)-, 100].
• 2-(3-([ 1 , 1 '-biphenyl]-4-yl)propyl)-3-hydroxynonanoic acid
Oil, Yield 52%; 1H NMR (CDC13) δ (ppm) 7.60-7.21 (m, 9H, Ar), 3.95-3.83 (m, 0.3H, CHOH), 3.79-3.63 (m, 0.7H, CHOH), 2.75-2.60 (m, 3H, ArCH2, C(=0)CH), 1.88-1.60 (m, 4H, CH2), 1.53-1.13 (m, 10H, CH2), 0.88 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 180.6, 140.9, 138.8, 128.8, 128.7, 127.0, 126.9, 72.3, 51.1, 35.3, 33.9, 31.8, 29.5, 29.1, 29.0, 25.6, 22.6, 14.1.
3-hydroxy-2-(3-(naphthalen-2-yl)propyl)pentan
Oil, yield 30%; 1H NMR (CDC13) δ (ppm) 7.79-7.25 (m, 7H, Ar), 3.78-3.68 (m, 0.3H, CHOH), 3.60-3.53 (m, 0.7H, CHOH), 2.75 (t, J = 6 Hz, 2H, ArCH2), 2.57-2.37 (m, 1H, C(O)CH), 1.88-1.37 (m, 6H, CH2), 0.93 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 179.1, 139.5, 133.4, 131.8, 127.7, 127.4, 127.2, 127.1, 126.2, 125.7, 124.9, 73.7, 51.1, 35.4, 35.6, 29.3, 28.9, 10.3, 9.8; MS (ESI) m/z (%): 304.2 [(M+NH4+), 100].
• 2-(l-hydroxyethyl)-5-(naphthalen-2-yl)pentanoic acid
Oil, Yield 33%; 1 H NMR (CDC13) δ (ppm) 7.84-7.25 (m, 7H, Ar), 4.07-3.96 (m, 0.5H, CHOH), 3.96-3.83 (m, 0.5H, CHOH), 2.75 (t, J = 6 Hz, 2H, ArCH2), 2.53-2.31 (m, 1H, C(=0)CH), 1.88-1.53 (m, 4H, CH2), 1.18 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 180.0, 139.4, 133.5, 131.9, 127.8, 127.5, 127.3, 127.1 , 126.3, 125.8, 125.1, 68.1, 52.9, 51.7, 35.9, 35.7, 29.3, 28.9, 21.4, 19.8; MS (ESI) m/z (%): 290.4 [(M+NH4+), 100].
• 3-hydroxy-2-(4-(naphthalen-2-yl)butyl)hexanoic acid
Oil, Yield 20%; 1H NMR (CDC13) δ (ppm) 7.81-7.25 (m, 7H, Ar), 43.91-3.81 (m, 0.5H, CHOH), 3.75-3.65 (m, 0.5H, CHOH), 2.77 (t, J = 6 Hz, 2H, ArCH2), 2.53-2.31 (m, 1H, C(=0)CH), 1.85-1.63 (m, 4H, CH2), 1.58-1.33 (m, 6H, CH2), 0.91 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 179.8, 139.8, 133.5, 131.9, 127.8, 127.6, 127.4, 127.3, 126.3, 125.8, 125.0, 71.8, 71.7, 50.7, 50.6, 37.6, 36.1, 35.8, 33.8, 31.3, 31.2, 30.9, 29.3, 28.6, 27.4, 27.0, 26.4, 24.5, 19.1 , 18.9, 13.9; MS (ESI) m/z (%): 332.2 [(M+NH4+), 100].
• 3-hydroxy-2-(4-phenylbutyl)hexanoic acid
Oil, yield 68%; Ή NMR (CDC13) δ (ppm) 7.35-7.05 (m, 5H, Ar), 3.96-3.78 (m, 0.4H, CHOC(=0)), 3.78-4.14 (m, 0.7Η, CHOC(=0)), 3.65-3.51 (m, 0.3Η, C(=0)CH), 3.22-3.59 (m, 0.6Η, C(=0)CH), 2.61 (t, 2Η, J = 7 Hz, ArCH2), 2.53-2.29 (m, 1H, C(=0)CH), 1.85-1.55 (m, 4Η, C¾), 1.55-1.27 (m, 6Η, C¾), 0.93 (t, J = 6 Hz, 3H,
CH3); 13C NMR (CDCb) δ (ppm) 179.9, 147.2, 142.3, 128.4, 128.3, 125.7, 71.9, 71.8, 50.8, 50.7, 37.6, 36.1 , 35.7, 31.4, 31.3, 29.3, 27.4, 27.0, 26.5, 19.2, 18.9, 13.9; MS (ESI) m/z (%): 282.2 [(M+NH4 +), 100].
General method for the cvclization of beta- hydroxy acids to beta-lactones
To a stirring solution of β-hydroxy acid (1 mmol) in anhydrous pyridine (1.5 mL), under argon at 0°C, p-toluenesulfonyl chloride (1 mmol) and anhydrous pyridine (1.5 mL) is added slowly via a syringe. The solution is stirred at 0°C for 1 h and kept at 4°C for 3 days. Then, Et20 is added and the organic layer is washed with 10% Na2C03, HC1 IN to pH 2 and brine. The organic layer is dried and the solvent is removed in vacuo. The product is purified by column chromatography eluting with a gradient of PE/AcOEt 95/5 to 9/1.
• 4-hexyl -3 -(3 -phenylpropyl)oxetan-2 -one
Oil, yield 75%; 1H NMR (CDCB) δ (ppm) 7.35-7.1 1 (m, 5H, Ar), 4.58-4.44 (m, 0.2H, CHOC(=0)), 4.27-4.13 (m, 0.8H, CHOC(=0)), 3.68-3.53 (m, 0.2H, C(=0)CH), 3.26-3.11 (m, 0.8H, C(=0)CH), 2.65 (t, 2H, J = 7 Hz, ArCH2), 1.93-1.66 (m, 6H, CH2), 1.40-1.22 (m, 8H, CH2), 0.89 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDCB) 6 (ppm) 171.4, 141.3, 128.4, 128.3, 126.0, 78.0, 75.6, 55.9, 52.4, 35.4, 34.4, 31.5, 28.8,
28.6, 27.3, 24.9, 22.5, 14.0; MS (ESI) m/z (%): 292.3 [(M+NH4+), 100]; HRMS: 297.1842 (M+Na)+, (297.1825).
• 3-(3-phenylpropyl)-4-propyloxetan-2-one
Oil, yield 68%; 1H NMR (CDC13) δ (ppm) 7.36-7.08 (m, 5H, Ar), 4.60-4.46 (m, 0.6H, CHOC(=0)), 4.28-4.13 (m, 0.4H, CHOC(=0)), 3.68-3.52 (m, 0.6H, C(=0)CH), 3.24-3.08 (m, 0.4H, C(=0)CH), 2.65 (t, 2H, J = 7 Hz, ArCH2), 1.89-1.31 (m, 8H, CH2), 0.96 (t, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.4, 141.4, 128.3, 125.9, 77.2, 75.4, 55.9, 52.4, 36.4, 35.4, 32.1, 29.1, 28.6, 27.3, 23.3, 18.8, 18.4, 13.7; HRMS: 233.1520 (M+Na)+, (233.1536).
• 4-isopropyl-3-(3-phenylpropyl)oxetan-2-one
Oil, yield 36%; 1H NMR (CDC13) δ (ppm) 7.32-7.07 (m, 5H, Ar), 4.19-3.97 (m, 0.2H, CHOC(=0) 3.97-3.73 (m, 0.8H, CHOC(=0)), 3.69-3.48 (m, 0.2H, C(=0)CH), 3.33-3.07 (m, 0.8H, C(=0)CH), 2.63 (t, J = 7 Hz, 3H, ArCH2), 1.86-1.62 (m, 5H, CH2 και CH(CH3)2), 1.00 (d, J = 7 Hz, 3H, CH3), 0.91 (d, J = 7 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.4, 141.3, 128.4, 128.3, 126.0, 82.7, 80.2, 53.9, 51.9, 35.5, 32.3, 28.7, 27.7, 18.0, 17.0; MS (ESI) m/z (%): 250.2 [(M+NH4+), 100].
3-(3-(4-methoxyphenyl)propyl)-4-propyloxetan-2-one
Oil, yield 65%; 1H NMR (CDC13) δ (ppm) 7.09 (d, J = 8 Hz, 2H, Ar), 6.84 (d, J = 8Hz, 2H, Ar), 4.62-4.47 (m, 0.3H, CHOC(=0)), 4.28-4.14 (m, 0.7H, CHOC(=0)), 3.79 (s, 3H, OCH3), 3.68-3.51 (m, 0.3H, C(=0)CH), 3.27-3.08 (m, 0.7H, C(=0)CH), 2.60 (t, J = 7 Hz, 2H, ArCH2), 1.83-1.59 (m, 6H, CH2), 1.50-1.36 (m, 2H, CH2), 0.97 (t, J = 7Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.4, 157.8, 133.3, 129.2, 113.8, 77.9, 75.4, 55.9, 55.2, 52.5, 36.4, 34.5, 32.1, 29.3, 28.9, 27.3, 23.3, 19.0, 18.4, 13.8; MS (ESI) m/z (%): 280.3 [(M+NH4+), 100].
• 4-hexyl-3-(3-(naphthalen-2-yl)propyl)oxetan-2-one
Oil, yield 44%; 1H NMR (CDC13) δ (ppm) 7.82-7.25 (m, 7H, Ar), 4.56-4.44 (m, 0.2H, CHOC(=0)), 4.22-4.14 (m, 0.8H, CH0C(=0)), 3.67-3.55 (m, 0.2H, C(=0)CH), 3.22-3.14 (m, 0.8H, C(=0)CH), 2.81 (t, 2H, J = 6Hz, ArCH2), 1.90-1.67 (m, 6H, CH2), 1.45-1.16 (m, 8H, CH2), 0.87 (t, J = 7Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.4, 138.8, 133.5, 132., 128.1, 127.6, 127.4, 127.0, 126.5, 126.0, 125.3, 78.0, 55.9, 35.6, 34.4, 31.6, 28.9, 28.5, 27.4, 25.0, 22.5, 14.0; MS (ESI) m/z (%): 342.2 [(M+NH4+), 100]; HRMS: 347.1986 (M+Na)+, (347.1982).
• 3-(3-(naphthalen-2-yl)propyl)-4-propyloxetan-2-one
Oil, yield 66%; 1H NMR (CDC13) δ (ppm) 7.82-7.25 (m, 7H, Ar), 4.57-4.47 (m, 0.2H, CHOC(=0)), 4.25-4.05 (m, 0.8H, CHOC(=0)), 3.67-3.56 (m, 0.2H, C(=0)CH), 3.27-3.14 (m, 0.8H, C(=0)CH), 2.82 (t, 2H, J = 6 Hz, ArCH2), 1.96-1.62 (m, 6H, CH2), 1.51-1.25 (m, 4H, CH2), 0.95 (t, J = 7 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 172.1, 171.4, 138.8, 133.5, 132.0, 128.1, 127.6, 127.4, 127.0, 126.5, 126.5, 125.3, 77.8, 75.4, 56.0, 52.6, 36.4, 35.6, 32.1, 29.7, 28.9, 28.5, 27.4, 23.4, 19.0, 18.4, 13.8, MS (ESI) m/z (%): 300.2 [(M+NH4+), 100].
• 3-(3-([ 1 , 1 '-biphenyl]-4-yl)propyl)-4-hexyloxetan-2-one
Oil, yield 57%; 1H NMR (CDC13) δ (ppm) 7.60-7.21 (m, 9H, Ar), 4.57-4.47 (m, 0.2H, CHOC(=0)), 4.25-4.16 (m, 0.8H, CHOC(=0)), 3.67-3.56 (m, 0.2H, C(=0)CH), 3.23-3.14 (m, 0.8H, C(=0)CH), 2.69 (t, 2H, J = 6 Hz, ArCH2, 1.90-1.55 (m, 6H, CH2), 1.41-1.21 (m, 8H, CH2), 0.87 (t, J = 7Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.3, 140.9, 133.5, 140.4, 128.8, 128.7, 127.2, 127.1, 127.0, 78.1, 55.9, 35.1, 34.4, 31.6, 29.1, 28.9, 28.6, 27.4, 25.5, 25.0, 22.5, 14.0; MS (ESI) m/z (%): 368.3 [(M+NH4+), 100];
• 4-ethyl-3-(3-(naphthalen-2-yl)propyl)oxetan-2-one
Oil, yield 53%; 1H NMR (CDC13) δ (ppm) 7.83-7.29 (m, 7H, Ar), 4.49-4.35 (m, 0.3H, CHOC(=0)), 4.23-4.10 (m, 0.7H, CHOC(=0)), 3.66-3.55 (m, 0.3H, C(-O)CH), 3.27-3.12 (m, 0.7H, C(=0)CH), 2.81 (t, 2H, J = 6 Hz, ArCH2), 2.07-1.58 (m, 6H, CH2), 1.00 (t, J = 7 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.3, 138.7, 133.5, 131.9, 128.0, 127.5, 127.3, 127.0, 126.4, 126.0, 125.2, 79.0, 76.8, 55.4, 52.3, 35.5, 28.5, 27.3, 23.4, 23.3, 9.8, 9.1 MS (ESI) m/z (%): 286.3 [(M+NH4+), 100].
• 4-methyl-3-(3-(naphthalen-2-yl)propyl)oxetan-2-one
Oil, yield 34%; 1H NMR (CDC13) δ (ppm) 7.83-7.25 (m, 7H, Ar), 4.78-4.66 (m, 0.3H, CHOC(=0)), 4.43-4.32 (m, 0.7H, CHOC(=0)), 3.68-3.55 (m, 0.3H, C(=0)CH), 3.24-3.13 (m, 0.7H, C(=0)CH), 2.81 (t, 2H, J = 6 Hz, ArCH2), 1.95-1.75 (m, 4H, CH2), 1.53 (d, J = 6 Hz, 3H, CH3), 1.42 (d, J = 6 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.8, 171.1, 138.7, 133.5, 132.0, 128.5, 128.0, 127.6, 127.4, 127.0, 126.5, 126.0, 125.3, 74.5, 71.6, 57.4, 52.6, 35.6, 28.7, 28.4, 27.2, 23.8, 23.4, 20.27, 15.6; MS (ESI) m/z (%): 272.2 [(M+NH4+), 100].
• 3-(4-(naphthalen-2-yl)butyl)-4-propyloxetan-2-one
Oil, yield 15%; 1H NMR (CDC13) δ (ppm) 7.83-7.25 (m, 7H, Ar), 4.58-4.44 (m, 0.2H, CHOC(=0)), 4.24-4.13 (m, 0.8H, CHOC(=0)), 3.65-3.52 (m, 0.2H, C(=0)CH), 3.20-3.08 (m, 0.8H, C(=0)CH), 2.79 (t, 2H, J = 6 Hz, ArCH2), 1.90-1.32 (m, 8H, CH2), 0.93 (t, J = 7 Hz, 3H, CH3); 13C NMR (CDC13) δ (ppm) 171.6, 139.5, 133.5, 131.9, 127.9, 127.6, 127.3, 127.2, 126.4, 126.0, 125.1, 77.9, 75.4, 56.0, 52.5,36.4, 35.6, 32.1, 31.9, 30.9, 29.7, 29.4, 27.7, 27.2, 26.5, 23.8, 22.7, 18.9, 18.4, 14.1 , 13.7; MS (ESI) m/z (%): 314.4 [(M+NH4+), 100].
• 3-(4-phenylbutyl)-4-propyloxetan-2-one
Oil, yield 50%; l NMR (CDC13) S (ppm) 7.38-7.01 (m, 5H, Ar), 4.59-4.47 (m, 0.3H, CHOC(=0)), 4.27-4.14 (m, 0.7H, CHOC(=0)), 3.65-3.51 (m, 0.3Η, C(=0)CH), 3.22-3.09 (m, 0.7Η, C(=0)CH), 2.63 (t, 2Η, J = 7 Hz, ArCH2), 1.96-1.54 (m, 6H, CH2), 1.54-1.30 (m, 4H, CH2), 0.97 (t, J = 7 Hz, 3H, CH3); ,3C NMR (CDC13) δ (ppm) 172.2, 171.5, 142.0, 142.0, 128.3, 125.8, 77.9, 75.4, 55.9, 52.5, 36.4, 35.5, 32.1, 31.1 , 31.0, 27.6, 27.1, 26.5, 23.7, 18.8, 18.3, 13.8, 13.7; MS (ESI) m/z (%): 264.2 [(M+NH4 +), 100]; HRMS: 269.1509 (M+Na)+ (269.1512).
Example 2: Inhibitory activities
In vitro inhibition of cPLA2, iPLA2 and sPLA2 was estimated using mixed micelles- based assays previously described (G. Kokotos et al J Med. Chem. 2004, 47, 3615-3628; D. Stephens et al J. Med. Chem. 2006, 49, 2821-2828; D. A. Six et al J Med. Chem. 2007, 50, 4222-4235).
Table I: Inhibition of PLA? by various beta-lactone inhibitor com ounds.
GK397 97.7 ± 1.8 77.5 ± 2.7 48.0 ± 5.3
0.0014
0.001 1 ±
GK399 96.4 ± 0.9 76.3 ± 3.6 27.0 ± 4.5
0.0002
GK410 92.7 ± 0.0 85.1 ± 0.5 29.2 ± 1.7
GK411 89.2 ± 0.0 84.7 ± 1.1 26.0 ± 9.3
0.0014 ±
GK412 97.1 ± 3.1 71.4 ± 4.5 36.2 ± 0.8
0.0005
0.00006
GK436 100 ± 84 34
0.00001
Generally, inhibition above 95% is considered satisfactory inhibiting activity. Compounds showing satisfactory inhibiting activity will be further subjected to X[(50) measurement. As indicated in table 1, G 393, 397, 399, 412, 436 are the most potent compounds in this series. Particularly, GK436 exhibited a Xi(50) value of 0.00006 and thus is the most potent inhibitor of GVIA iPLA2 ever reported. It is selective for GVIA iPLA2 since it is at least 1000 times more potent for GVIA iPLA2 than for GIVA cPLA2 and practically does not inhibit GV sPLA2.
Although the present invention has been described hereinabove by way of specific embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims.
Claims
1. A compound having the general structure I:
I wherein:
R1 is H, F, or lower alkyl;
Ar1 is an aryl group having 6 - 12 carbons optionally substituted with alkyl having 1-4 carbon atoms;
R2 is an alkyl group having 1 to 6 carbons; n = 2 - 7; m = 0, 1,
2;
or isomers, enantiomeric forms thereof.
A compound according to claim 1 wherein n = 2 - 5 and m = 0, 1 ;
3. A compound according to claim 1 wherein n = 2, 3 and m = 0;
4. A compound according to claim 1 wherein R1 is H; n = 2, 3 and m = 0;
5. The compound of claim 1, wherein said compound is one of the following:
or isomers, enantiomeric forms thereof.
or isomers, enantiomeric forms thereof.
7. A compound according to any one of claims 1 to 6 for use as a medicament.
8. A compound according to any one of claims 1 to 6 for use in the prevention or treatment of an autoimmune disease or condition in a subject.
9. A compound as claimed in claim 8 wherein said autoimmune disease or condition is associated with phospholipase A2 (PLA2) activity.
A compound as claimed in claim 8 or 9, wherein said autoimmune disease condition is diabetes type-1.
A compound as claimed in claim 8 or 9, wherein said autoimmune disease condition is diabetes type-2.
12. A compound according to any one of claims 1 to 6 for use in treatment of a neural disease or condition in a subject.
13. A compound as claimed in claim 12 wherein said neural disease or condition is associated with phospholipase A2 (PLA2) activity.
14. A compound as claimed in claim 13, wherein said neural disease or condition is neural injury.
15. A compound according to any one of claims 1 to 6 for use in treatment of an inflammatory disease or condition in a subject.
16. A compound as claimed in claim 15 wherein said inflammatory disease or condition is associated with phospholipase A2 (PLA2) activity.
17. A compound as claimed in claim 16 wherein said inflammatory disease or condition is rheumatoid arthritis.
18. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier or excipient.
19. A process for preparing a compound according to claim 1, comprising:
(a) Reacting a compound of formula (II) with an aldehyde of formula (III) to provide a beta-hydroxy acid compound of formula (IV);
(b) Subjecting the beta-hydroxy acid compound of formula (IV) to cyclization condition to obtain a compound of formula (I).
20. A compound according to claim 1, wherein said compound is 3-(3- phenylpropyl)-4-propyloxetan-2-one.
21. A compound according to claim 1, wherein said compound is 3-[(3- naphthalen-2-yl)propyl]-4-propyloxetan-2-one.
22. A compound according to claim 1, wherein said compound is 3-[3-(4- methoxyphenyl)propyl]-4-propyloxetan-2-one.
23. A compound according to claim 1 , wherein said compound is 3-[4- (naphthalen-2-yl)butyl]-4-propyloxetan-2-one.
24. A compound according to claim 1 , wherein said compound is 3-(4- phenylbutyl)-4-propyloxetan-2-one.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6057369A (en) * | 1996-01-02 | 2000-05-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid compounds |
WO2009106211A1 (en) * | 2008-02-26 | 2009-09-03 | Ludwig-Maximilians-Universität München | Beta-lactones as antibacterial agents |
-
2016
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6057369A (en) * | 1996-01-02 | 2000-05-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted (aryl, heteroaryl, arylmethyl or heteroarylmethyl) hydroxamic acid compounds |
WO2009106211A1 (en) * | 2008-02-26 | 2009-09-03 | Ludwig-Maximilians-Universität München | Beta-lactones as antibacterial agents |
Non-Patent Citations (23)
Title |
---|
A. KALYVAS ET AL., BRAIN, vol. 132, 2009, pages 1221 - 1235 |
C, BASKAKIS ET AL., J. MED CHEM, vol. 51, 2008, pages 8027 - 8037 |
CHEM. REV., vol. 111, 2011, pages 6130 - 6185 |
COREY L. COMPTON ET AL: "Antibacterial Activity of and Resistance to Small Molecule Inhibitors of the ClpP Peptidase", ACS CHEMICAL BIOLOGY, vol. 8, no. 12, 20 December 2013 (2013-12-20), US, pages 2669 - 2677, XP055269816, ISSN: 1554-8929, DOI: 10.1021/cb400577b * |
D. A. SIX ET AL., J. MED. CHEM., vol. 50, 2007, pages 4222 - 4235 |
D. STEPHENS ET AL., J. MED. CHEM., vol. 49, 2006, pages 2821 - 2828 |
E. A. DENNIS; G. KOKOTOS ET AL.: "Phospholipase A enzymes: Physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention", CHEM. REV., vol. 111, 2011, pages 6130 - 6185 |
G. KOKOTOS ET AL., J. MED. CHEM, vol. 53, 2010, pages 3602 - 3610 |
G. KOKOTOS ET AL., J. MED. CHEM., vol. 47, 2004, pages 3615 - 3628 |
J. BALSINDE ET AL.: "Calcium-independent phospholipase A and apoptosis", BIOCHIM. BIOPHYS. ACTA, vol. 1761, 2006, pages 1344 - 1350 |
J. BALSINDE ET AL.: "Cellular regulation and proposed biological functions of group VIA calcium independent phospholipase A in activated cells", CELL. SIGNALLING, vol. 17, 2005, pages 1052 - 1062 |
J. TANG ET AL., J. BIO!. CHEM., vol. 272, 1997, pages 8567 - 8575 |
KADDY CAMARA, SIDDHESH S. KAMAT, CELINA C. LASOTA, BENJAMIN F. CRAVATT, AMY R. HOWELL: "Combining cross-metathesis and activity-based protein profiling: New beta-lactone motifs for targeting serine hydrolases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 15 January 2015 (2015-01-15), pages 317 - 321, XP002757256, DOI: 10.1016/j.bmcl.2014.11.038 * |
LEI X. ET AL.: "Group VIA Ca2+-independent phospholipase Az (iPLA beta) and its role in beta-cell programmed cell death", BIOCHIMIE, vol. 92, 2010, pages 627 - 637 |
P, K. LARSSON ET AL., J, BIOL. CHEM., vol. 273, 1998, pages 207 - 214 |
R. BONE ET AL., DIABETES, vol. 64, 2015, pages 541 - 554 |
ROMAIN BEJOT; SIDDAM ANJAIAH; J. R. FALCK; CHARLES MIOSKOWSKI: "Haloenol Acetates: Versatile Reactants for Oxetan-2-one, Azetidin-2-one and Isoxazolidin-5-one Synthesis", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, no. 1, 2007, pages 101 - 107, XP002757257, DOI: 10.1002/ejoc.200600708 * |
S. B. HOOK ET AL.: "Role of Ca2+-independent phospholipase A in cell growth and signaling", BIOCHEM. PHARMACOL., vol. 76, 2008, pages 1059 - 1067 |
T. ALI ET AL., PLOS ONE, vol. 8, 2013, pages E71748 |
V, MAGRIOTI ET AL., BIOORG. MED. CHEM., vol. 21, 2013, pages 5823 - 5829 |
V. MAGRIOTI; G. KOKOTOS, EXPERT OPINION THERAPEUTIC PATENTS, vol. 23, 2013, pages 333 - 344 |
V. MAGRIOTI; O. KOKOTOS, EXPERT OPINION THERAPEUTIC PATENTS, vol. 20, 2010, pages 1 - 18 |
Y. H. HSU ET AL., J. AM. CHEM. SOC., vol. 135, 2013, pages 1330 - 1337 |
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