Patent Application
20180353476
The present invention relates in general to the field of novel C5-substituted carbapenem antibiotics, compositions containing such compounds, and methods of use in the treatment of Mycobacterium tuberculosis and non-tubercular Mycobacteria.
Without limiting the scope of the invention, its background is described in connection with the antibiotic resistance.
The 21st century is witnessing the evolution and dissemination of unprecedented levels of antimicrobial resistance and new resistance mechanisms. The evolution and dissemination of MDR, XDR, and TDR strains of Mycobacterium tuberculosis (Mtb) and the rise of nontuberculous Mycobacteria, make the development of new agents to treat these conditions crucial. Meropenem/clavulanate has been recently proposed as a potential treatment for Mtb, with the meropenem targeting the essential transpeptidase LdtMt2, and the clavulanic acid acting as a beta-lactamase inhibitor to protect the antibiotic from hydrolytic degradation by the beta-lactamase, BlaC. It is recognized, however, that meropenem is a broad spectrum antibiotic, with extensive antimicrobial activity against numerous strains. Long term administration of meropenem, as would be required in treatment of tuberculosis, would adversely affect the microbiome, and thus structural modifications of the carbapenem scaffold that could improve potency and selectivity for the mycobacterial l,d-transpeptidase would be extremely useful.
What is needed are novel compounds with improved activity, relative to meropenem, against both Mtb and Mycobacterium abscessus (Mabs).
This application concerns modified carbapenem antibiotics that exhibit enhanced activity against mycobacterial species, especially including Mycobacterium tuberculosis and Mycobacterium abscessus. These new carbapenems have a specific structural modification at the C5 position, which endows them with this improved activity. By contrast, current commercial carbapenem antibiotics all have essentially the same scaffold, with modifications occurring at the C2 position.
In one embodiment, the present invention includes a compound of formula 1, or a pharmaceutically acceptable salt thereof, comprising:
R1 is H or CH3
R2 is not H, and is CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
R3 is H, CH3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and
R4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or
R4 is an SRa, where Ra is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or
R4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups.
In one aspect, R3 is (CH2)2NH2 or (CH2)3NH2. In another aspect, Ra is a substituted pyrrolidine. In another aspect, —CO2M, is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a 30 protecting group (M represents a carboxyl protecting group). In another aspect, pharmaceutically acceptable salt is —COOM, where M is a negative charge and is balanced by a counterion. In another aspect, counterion is an alkali metal cation such as sodium, potassium, calcium, magnesium, zinc, ammonium, alkylammonium cations, tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, or meglumine, triethanolhydroammonium. In another aspect, the —CO2M group that is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a 30 protecting group (M represents a carboxyl protecting group). In another aspect, the pharmaceutically acceptable salt is acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, or undecanoate. In another aspect, the molecule comprises a biolabile ester group. In another aspect, biolabile ester group is selected from at least one of pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, or methoxymethyl. In another aspect, M is selected from an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group, or the groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups, or acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl, or (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl. In another aspect, the compound is further combined with a beta-lactamase inhibitor, clavulanic acid or avibactam (or related DBOs), or a boronic acid based beta-lactamase inhibitor. In another aspect, the compound has the formula:
In another embodiment, the present invention includes a method of making any one of compounds 1 to 11 comprising:
The method of claim 14, wherein the molecule has the formula:
R1 is H or CH3
R2 is not H, and is CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
R3 is H, CH3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and
R4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or
R4 is an SRa, where Ra is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or
R4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups
In another embodiment, the present invention includes an antibiotic compound of formula 1, or a pharmaceutically acceptable salt thereof, comprising:
R1 is H or CH3
R2 is not H, and is CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
R3 is H, CH3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and
R4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or
R4 is an SRa, where Ra is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or
R4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups; and
one or more pharmaceutically acceptable excipients. In one aspect, R3 is (CH2)2NH2 or (CH2)3NH2. In another aspect, Ra is a substituted pyrrolidine. In another aspect, —CO2M, is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a 30 protecting group (M represents a carboxyl protecting group). In another aspect, the pharmaceutically acceptable salt is —COOM, where M is a negative charge and is balanced by a counterion. In another aspect, the counterion is an alkali metal cation such as sodium, potassium, calcium, magnesium, zinc, ammonium, alkylammonium cations, tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, or meglumine, triethanolhydroammonium. In another aspect, the —CO2M group that is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a 30 protecting group (M represents a carboxyl protecting group). In another aspect, the pharmaceutically acceptable salt is acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, or undecanoate. In another aspect, the molecule comprises a biolabile ester group. pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. In another aspect, the biolabile ester group is selected from at least one of pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, or methoxymethyl. In another aspect, M is selected from an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group, or the groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups, or acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl, or (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl. In another aspect, the antibiotic and the one or more pharmaceutically acceptable excipients are formulated for oral, subcutaneous, topical, pulmonary, nasal, intraalveolar, parenteral, intravenous, peritoneal, or intramuscular administration. In another aspect, the antibiotic is further combined with a beta-lactamase inhibitor, clavulanic acid or avibactam (or related DBOs), or a boronic acid based beta-lactamase inhibitor. In another aspect, the compound has the formula:
In another embodiment, the present invention includes an method of treating a bacterial infection in a subject comprising:
contacting a bacteria with an effective amount of a compound of formula I or pharmaceutically acceptable salt thereof, comprising:
R1 is H or CH3
R2 is not H, and is CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
R3 is H, CH3, or a C1-C6 alkyl or cycloalkyl group, a heteroatom-substituted alkyl; and
R4 is a C1 to C6 alkyl, or substituted alkyl group, especially including substituents which possess positive charge, or a hydroxyl group; or
R4 is an SRa, where Ra is an unsubstituted C1 to C6 alkyl group, a substituted C1 to C6 alkyl group, or a functional group that is positively charged, or which bears a positive charge when in aqueous solution at pH 7; or
R4 is a CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl, or a heteroaryl groups; and
wherein the compound inhibits the growth of the bacterium in the subject.
In one aspect, the method further comprises adding a beta-lactamase inhibitor, clavulanic acid or avibactam (or related DBOs), or a boronic acid based beta-lactamase inhibitor. In one aspect, R3 is (CH2)2NH2 or (CH2)3NH2. In another aspect, Ra is a substituted pyrrolidine. In another aspect, —CO2M, is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a 30 protecting group (M represents a carboxyl protecting group). In another aspect, the pharmaceutically acceptable salt is —COOM, where M is a negative charge and is balanced by a counterion. In another aspect, the counterion is an alkali metal cation such as sodium, potassium, calcium, magnesium, zinc, ammonium, alkylammonium cations, tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, or meglumine, triethanolhydroammonium. In another aspect, the —CO2M group that is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a 30 protecting group (M represents a carboxyl protecting group). In another aspect, the pharmaceutically acceptable salt is acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethane sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, or undecanoate. In another aspect, the molecule comprises a biolabile ester group. pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. In another aspect, the biolabile ester group is selected from at least one of pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, or methoxymethyl. In another aspect, M is selected from an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group, or the groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups, or acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl, or (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl. In another aspect, the antibiotic and the one or more pharmaceutically acceptable excipients are formulated for oral, subcutaneous, topical, pulmonary, nasal, intraalveolar, parenteral, intravenous, peritoneal, or intramuscular administration. In another aspect, the antibiotic is further combined with a beta-lactamase inhibitor, clavulanic acid or avibactam (or related DBOs), or a boronic acid based beta-lactamase inhibitor. In another aspect, the compound has the formula:
For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which:
While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.
To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not limit the invention, except as outlined in the claims.
As used herein, the terms “administration of” or “administering a” compound refers to providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
As used herein, the terms “effective amount” or “therapeutically effective amount” refer to an amount of compound that when provided to a the subject elicits a biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. As used herein, the term “treatment” refers to the treatment of the mentioned conditions, particularly in a patient who demonstrates symptoms of the disease or disorder.
As used herein, the term “excipient” refers to one or more compatible solid or liquid filler diluents or encapsulating substances that are suitable for administration to a human subject. Some examples of substances which can serve as excipients include sugars such as lactose, glucose and sucrose; starches such as corn-starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; and alginic acid; as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, sweetening agents (including nonnutritive sweeteners such as aspartame and saccharin), tableting agents, stabilizers, antioxidants, cooling agents, and preservatives, can also be present.
As used herein, the term “pharmaceutically acceptable” refers to a carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not be deleterious to the recipient thereof.
As used herein, the term “carrier” or “vehicle” refers to a diluent, adjuvant, excipient or vehicle with which the active compound is administered. Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used. When administered to a subject, the pharmaceutically acceptable vehicles are preferably sterile. Water can be the vehicle when the active compound is administered intravenously.
Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions. Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
The present invention describes compounds with improved activity, relative to meropenem, against both Mtb and Mycobacterium abscessus (Mabs).
One molecule of the present invention has the following structure 1:
Where R1=H or CH3;
Where R2=CH3, or C1-C6 straight chain, or branched alkyl, or C3-C6 cycloalkyl group, or unsaturated alkenyl, including C═CH2;
Where R3 may be H, CH3, or a C1-C6 alkyl or cycloalkyl group; and
R4 may be SRa, where Ra=may be an unsubstituted C1 to C6 alkyl group, or substituted C1 to C6 alkyl group, especially including substituents which themselves possess a positive charge. Or alternatively Ra may be a substituted or unsubstituted cyclic or heterocylic group, especially including groups which contain 1 to 3 positive charges, an aryl or heteroaryl group, or substituted aryl or heteroaryl group, particularly including a substituted pyrrolidine.
Alternatively, R3 may be R3 may be heteroatom-substituted C1 to C4 alkyl, particularly including (CH2)2NH2, or (CH2)3NH2.
Alternatively R4 may itself be CH2ORb, where Rb=C1 to C6 alkyl or substituted alkyl groups, substituted or unsubstituted aryl or heteroaryl groups.
With respect to —CO2M, which is attached to the carbapenem nucleus at position 3, this represents a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester (M represents an ester forming group) or a carboxylic acid protected by a 30 protecting group (M represents a carboxyl protecting group).
One specific molecule is:
The pharmaceutically acceptable salts referred to above may take the form —COOM, where M is a negative charge, which is balanced by a counterion, e.g., an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions may be calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.
The pharmaceutically acceptable salts referred to above also include acid addition salts. Thus, the Formula I compounds can be used in the form of salts derived from inorganic or organic acids. Included among such salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
The pharmaceutically acceptable esters are such as would be readily apparent to a medicinal chemist, and include, for example, those described in detail in U.S. Pat. No. 4,309,438. Included within such pharmaceutically acceptable esters are those that are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and others described in detail in U.S. Pat. No. 4,479,947, relevant portions incorporated herein by reference. These are also referred to as “biolabile esters”.
Biolabile esters are biologically hydrolizable, and may be suitable for oral administration, due to good absorption through the stomach or intestinal mucosa, resistance to gastric acid degradation and other factors. Examples of biolabile esters include compounds in which M represents an alkoxyalkyl, alkylcarbonyloxyalkyl, alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl or alkylthioaryl group. These groups can be substituted in the alkyl or aryl portions thereof with acyl or halo groups. The following M species are examples of biolabile ester forming moieties: acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.
The synthetic methodology that was employed to make these new carbapenems is shown in Scheme 1.
Scheme 1 involves the preparation of carbapenems of general structure 2. The detailed synthetic methodology utilized to prepare these novel carbapenems is provided below.
Dimethyl sulfide (0.2 mol) was added to a slurry of copper (I) iodide (0.2 mol) in THF at room temperature and stirred for 10 min. The resultant solution was cooled to −50° C. and treated with methyllithium (0.4 mol, 1.6 M solution in Et2O). The reaction was then allowed to warm to −10° C. for 20 min, and cooled back to −50° C. Then compound 2 was added (as a solid), and the reaction was warmed to rt over the course of 1 h. After completion, the resulting mixture was treated with aq NH4Cl and the THF evaporated in vacuo. The resultant material was diluted with CH2Cl2 and washed with NH4Cl, water and brine, dried over sodium sulfate and concentrated.
Yield 87%, 1H NMR (400 MHz, CDCl3): δ 0.09 (s, 6H), 0.90 (s, 9H), 1.23 (d, J=6.24, 2H), 1.35 (d, J=6.07, 2H), 2.83 (m, 1H), 3.85 (m, 1H), 4.21 (m, 1H), 5.78 (s, 1H).
To a solution of compound 3 (12.0 mmol) in EtOAc (80 mL), acetic acid (6 mL) was added followed by RuCl3.3H2O (0.62 mmol) and NaOAc (3 mmol) at rt. Then freshly distilled CH3CHO (1.5 mL) was added quickly and the atmosphere was replaced with an oxygen balloon. The reaction mixture was stirred for 15 min and CH3CHO (1.5 mL) was added again. The reaction was allowed to stir for another 15 min. After the reaction was completed, diluted with EtOAc (100 mL) and the organic layer was washed by NaHCO3, water and dried over sodium sulfate then purified through column.
Yield 75%, 1H NMR (400 MHz, CDCl3): δ 0.15 (m, 6H), 0.95 (s, 9H), 1.45 (d, J=6.13, 3H), 1.98 (s, 3H), 2.12 (s, 3H), 3.18 (d, J=7.12, 1H), 4.33 (m, 1H), 6.95 (s, 1H).
To a solution of compound 4 (9.3 mol) in anhydrous CH2Cl2 (100 mL), compound 5 (18.6 mol) and ZnCl2 (4.7 mL, 1 M solution in Et2O) was added. The resulting mixture was stirred for 30 min at 40° C. After the reaction was completed, diluted with CH2Cl2 (100 mL), washed with NaHCO3, water and brine, dried over sodium sulfate, evaporated the solvent in vacuo and purified through column.
Yield 51%, 1H NMR (400 MHz, CDCl3): δ 0.18 (s, 6H), 0.98 (s, 9H), 2.23 (d, J=6.07, 3H), 2.56 (s, 3H), 3.55 (m, 1H), 4.31 (m, 1H), 5.44 (s, 2H), 7.61 (d, J=7.95, 2H), 8.35 (d, J=8.05, 2H).
To a solution of compound 6 (1.8 g) in MeOH (8 mL), HCl (8 mL, solution in water 5 M) was added and the reaction at rt and stirred for 1 h. After the reaction was completed, the solvent was evaporated in vacuo and the product was used for the next step.
Yield 95%, 1H NMR (400 MHz, CDCl3): δ 1.39 (d, J=6.12, 3H), 1.56 (s, 3H), 2.91 (d, J=10.32, 1H), 3.32 (d, J=2.56, 2H), 4.16 (s, J=5.72, 1H), 5.33 (s, 2H), 7.56 (d, J=7.96, 2H), 8.24 (d, J=8.04, 2H).
To a solution of compound 7 (3.8 mmol) in EtOAc 15 mL, Rh2(OAc)4 (0.19 mmol) was added. The reaction mixture was heated to reflux for 30 min. After the reaction was completed, the solvent was evaporated in vacuo the product was used directly for the next step.
Yield 99%, 1H NMR (400 MHz, CDCl3): δ 1.48 (q, J=6.20, 2H), 1.60 (d, J=6.04, 2H), 2.59 (q, J=16.2, 2H), 3.22 (d, J=9.88, 1H), 4.39 (m, 1H), 5.27 (m, 2.02), 7.56 (d, J=8.76, 2H), 8.25 (d, J=8.12, 2H).
To a solution of compound 8 (2 mmol) in dry acetonitrile (8 mL), diphenylphosphoryl chloride (2 mmol) and (iPr)2NEt (2 mmol) was added −40° C. The reaction mixture was stirred for 20 min and allowed to warm to −10° C. Then compound 9 (2 mmol) was added to the previous mixture followed by diisopropylethylamine (2 mmol) at −40° C. The reaction was stirred for 30 min at −40° C. Then the resulting mixture was diluted with EtOAc (30 mL), and the organic layer was washed with NaHCO3, NH4Cl and brine, concentrated in vacuo and purified by column.
Yield 35%, 1H NMR (400 MHz, CDCl3): δ 1.44 (d, J=5.72, 2H), 1.61 (d, J=3.96, 2H), 3.00 (2d, 6H), 3.15 (d, J=3.84, 1H), 3.56 (m, 2H), 4.28 (m, 1H), 5.12 (d, J=8.68, 1H), 5.22 (m, 4H), 5.30 (d, J=8.34, 1H), 5.52 (d, J=13.8, 1H), 7.45 (m, 4H), 8.23 (m, 4H).
A slurry of compound 10 (300 mg, 0.422 mmol) with Pd/C (300 mg) in EtOAc (20 mL) and buffer (pH=6, 20 mL) was shaken on a Parr hydrogenator at 50 psi H2 pressure for 90 min. The solution was then filtered through celite to remove the catalyst. The aqueous layer was separated and washed with ether, then concentrated and purified through column.
Yield 19%, 1H NMR (400 MHz, D2O): δ 1.17 (d, J=5.43, 3H), 1.83 (m, 1H), 1.92 (m, 1H), 2.75 (m, 2H), 2.93 (m, 6H), 3.28 (m, 2H), 3.65 (m, 2H), 3.85 (m, 1H), 4.12 (m, 1H).
Data on Compound 11
The following additional terms are as defined herein. The term “alkyl”, “alkenyl”, “alkynyl” and “alkylene” denotes hydrocarbon chains typically ranging from about 1 to about 12 carbon atoms in length, preferably 1 to about 6 atoms, and includes straight and branched chains. Unless otherwise noted, in one embodiment of any alkyl or alkylene referred to herein is C1-C6 alkyl (e.g., methyl or ethyl).
The term “cycloalkyl” denotes a saturated or unsaturated cyclic hydrocarbon chain, including bridged, fused, or spiro cyclic compounds, preferably comprising 3 to about 12 carbon atoms, more preferably 3 to about 8.
The term “aryl” denotes one or more aromatic rings, each of 5 or 6 core carbon atoms. Multiple aryl rings may be fused, as in naphthyl or unfused, as in biphenyl. Aryl rings may also be fused or unfused with one or more cyclic hydrocarbon, heteroaryl, or heterocyclic rings.
The term “heteroaryl” denotes an aryl group containing from one to four heteroatoms, preferably N, O, or S, or a combination thereof, which heteroaryl group is optionally substituted at carbon or nitrogen atom(s) with C1-C6 alkyl, —CF3, phenyl, benzyl, or thienyl, or a carbon atom in the heteroaryl group together with an oxygen atom form a carbonyl group, or which heteroaryl group is optionally fused with a phenyl ring. Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings. Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g., thiophenes, pyrroles, furans); 5-membered heteroaryls having two heteroatoms in 1,2 or 1,3 positions (e.g., oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heteroaryls having 3 heteroatoms; 6-membered heteroaryls with one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrine, 5,6-cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (e.g., pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heteroaryls with three heteroatoms (e.g., 1,3,5-triazine); and 6-membered heteroaryls with four heteroatoms.
The term “heterocycle” or “heterocyclic” denotes one or more rings of 5-12 atoms, preferably 5-7 atoms, with or without unsaturation or aromatic character and at least one ring atom which is not carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused.
The term “heteroatom” denotes any non-carbon atom in a hydrocarbon analog compound. Examples include oxygen, sulfur, nitrogen, phosphorus, arsenic, silicon, selenium, tellurium, tin, and boron.
The term “alkylene” denotes a divalent alkyl group as defined above, such as methylene (—CH2-), propylene (—CH2 CH2 CH2-), chloroethylene (˜CHClCH2-), 2-thiobutene —CH2 CH(SH)CH2 CH2, 1-bromo-3-hydroxyl-4-methylpentene (—CHBrCH2 CH(OH)CH(CH3)CH2-), and the like.
The term “alkenyl” denotes branched or unbranched hydrocarbon chains containing one or more carbon-carbon double bonds.
The term “alkynyl” denotes branched or unbranched hydrocarbon chains containing one or more carbon-carbon triple bonds.
The term “aryl” denotes a chain of carbon atoms which form at least one aromatic ring having preferably between about 6-14 carbon atoms, such as phenyl, naphthyl, and the like, and which may be substituted with one or more functional groups which are attached commonly to such chains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl, and the like.
The term “alkoxy” denotes —OR—, wherein R is alkyl.
The term “amido” denotes an amide linkage: —C(O)NHR (wherein R is hydrogen or alkyl).
The term “amino” denotes an amine linkage: —NR—, wherein R is hydrogen or alkyl. The term “carboxyl” denotes —C(O)O—, and the term “carbonyl” denotes —C(O)—.
The term “alkylcarboxyl” denote an alkyl group as defined above substituted with a C(O)O group, for example, CH3 C(O)O—, CH3 CH2 C(O)O—, etc.
The term “carbocycle” denotes cyclic hydrocarbon chain having about 5 to about 8 ring carbons such as cyclopentyl, cylcohexyl, etc. These groups can be optionally substituted with one or more functional groups as defined under “alkyl” above.
The term “halogen” includes chlorine, fluorine, bromine, iodine and mixtures thereof
The term “heterocycle” denotes straight chain or ring system that may contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
The term “carbamoyl” denotes the group —C(O)NH2.
The term “hydroxyalkyl” denotes an alkyl group as defined above which is substituted by a hydroxy group.
The term “alkylcarbonyl”, alone or in combination, means an acyl group derived from an alkanecarboxylic acid, i.e. alkyl-C(O)—, such as acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl etc.
It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.
It will be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.
All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.
As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. In embodiments of any of the compositions and methods provided herein, “comprising” may be replaced with “consisting essentially of” or “consisting of”. As used herein, the phrase “consisting essentially of” requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention. As used herein, the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), property(ies), method/process steps or limitation(s)) only.
The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
As used herein, words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present. The extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skill in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature. In general, but subject to the preceding discussion, a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
To aid the Patent Office, and any readers of any patent issued on this application in interpreting the claims appended hereto, applicants wish to note that they do not intend any of the appended claims to invoke paragraph 6 of 35 U.S.C. § 112, U.S.C. § 112 paragraph (f), or equivalent, as it exists on the date of filing hereof unless the words “means for” or “step for” are explicitly used in the particular claim.
For each of the claims, each dependent claim can depend both from the independent claim and from each of the prior dependent claims for each and every claim so long as the prior claim provides a proper antecedent basis for a claim term or element.
This application claims priority to U.S. Provisional Application Ser. No. 62/518,569, filed Jun. 12, 2017, the entire contents of which are incorporated herein by reference.
This invention was made with government support under AI109624 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 62518569 | Jun 2017 | US |
