Patent Grant
8232410
Tuberculosis (TB) was one of the first infectious diseases to be identified. More than fifty years of research has been directed to controlling and eliminating this disease. However, the eradication of TB is still one of the most prominent challenges for basic and clinical research scientists.
Once thought to be under control, TB case reports in the U.S. increased sharply in the early 1990's. Although, this trend has reversed and the reported numbers of new cases has steadily declined in industrialized countries, TB remains a major global public health threat. Recent statistics from the WHO estimate that there are approximately 8.4 million new cases every year with a global mortality rate of 23% or approximately 2 million deaths per year.
Poor chemotherapeutics and inadequate local-control programs contribute to the inability to manage TB and lead to the emergence of drug resistant strains of the bacteria that cause Mycobacterium tuberculosis (Mtb). A survey conducted at 58 international sites between 1996 and 1999 found exceptionally high rates of single and multidrug-resistant strains in Estonia, Latvia and Russia, and revealed that countries such as China and Iran were developing a high prevalence of multidrug-resistance (MDR-TB). See Kruuner, A., Sillastu, H., Danilovitsh, M., Levina, K., Svenson, S. B., Kallenius, G., and Hoffner, S. E. (1998) Drug resistant tuberculosis in Estonia, Int J Tuberc Lung Dis 2, 130-3. Significantly, MDR-TB is much more difficult to treat than sensitive TB, requiring administration of more expensive, second-line antibiotics for up to two years. The frequency of resistance to at least one of the first-line TB drugs (isoniazid (INH), rifampicin (RIF), pyrazinamide or ethambutol) ranged from 1.7% in Uruguay to 36.9% in Estonia. The frequency of resistance is indicative of the global problem involving not only the spread of Mtb, but also treatment.
Finally, of critical importance is the role of TB as a major opportunistic pathogen in patients with HIV/AIDS. Consequently, there is a pressing need for the development of novel TB drugs that are effective against both sensitive and resistant Mtb strains.
Likewise, new drugs are needed to treat patients infected by Francisella tulerensis, the bacteria which causes tularemia. Tularemia is primarily enzootic, however, in humans, it causes lesions and flu-like symptoms. Finding new methods of treating F. tulerensis is of great importance because it is one of the most pathogenic microorganisms presently known. As such, it is currently listed as a category A select agent by the Centers for Disease Control and Prevention because of its potential as a bioterrorism agent.
The invention relates to a molecule having formula I:
The invention also relates to a method of treating a patient infected with Mycobacterium tuberculosis or Francisella tulerensis, the method comprising administering to the patient the compound of formula I or a pharmaceutically acceptable salt thereof.
The invention relates to novel benzimidazole derivatives. These benzimidazole derivatives can be used to treat a patient infected by Mycobacterium tuberculosis or Francisella tulerensis.
The molecules have formula I:
In this formula, R1 represents NH2, NHR6, NR9R10, NR6CONR9R10, NR6CSNR9R10, OH, OR6, SH, SR6, CHO, COOR6, COR6, CH2OH, CR7R8OH, CH2OR6, CR7R8OR6, CH2NH2, CR7R8NH2, CR7R8NR9R10, alkyl, cycloalkyl, aryl, or halo.
R2 and R4 independently represent H, alkyl, cycloalkyl, or aryl. For example, R2 may represent ethyl and R4 may represent H.
R3 represents alkyl, cycloalkyl, or aryl. For example, R3 may represent tetrahydrofuranyl or ethyl.
In another aspect of the invention, R3 represents COR6.
In a preferred embodiment, when R2 represents H, R3 is not methyl.
R5 represents H, R6, OR6, SR6, NH2, NHR6, or NR9R10. R6, R7, R8, R9, and R10 independently represent alkyl, cycloalkyl, aryl, or halo. Preferably, R6, R7, R8, R9, and R10 independently represent alkyl, cycloalkyl, or aryl. More preferably, R6, R7, R8, R9, and R10 independently represent alkyl or aryl.
R2 and R3; R4 and R5; and R9 and R10, independently, may be combined to represent a heterocyclic alkyl or heterocyclic aryl ring. For example, R2 and R3 can be combined to represent a heterocyclic alkyl ring, resulting in the following structure:
Similarly, R4 and R5 can be combined to represent a heterocyclic alkyl ring, resulting in the following structure:
R7 and R8 may be combined to represent a cycloalkyl.
Alkyl groups are branched or unbranched, saturated or unsaturated, and have 1-18 carbon atoms in their longest chain. Some examples of suitable straight-chained, saturated alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl groups and dodecyl and hexadecyl. Preferred straight chain, saturated alkyl groups include methyl and ethyl.
Some examples of suitable branched, saturated alkyl groups include isopropyl, iso-butyl, sec-butyl, t-butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl (isopentyl), 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl (neopentyl), 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl groups, and 2-methyl, 5-ethyldecyl. Preferred branched, saturated alkyl groups include isopropyl and t-butyl.
Some examples of unsaturated alkyl groups include ethenyl, ethynyl, propenyl, propargyl, isopropenyl, crotyl, 1-hexenyl, and 1-octenyl.
Cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituent rings. Ring systems are monocyclic, bicyclic, tricyclic, or tetracyclic and can be bridged or non-bridged.
Some examples of carbocyclic alkyl groups include cyclobutanyl, cyclopentanyl, cyclohexanyl, and cycloheptanyl. Examples of fused carbocyclic alkyl groups include indenyl, isoindenyl. Bridged groups include bicyclo[2.2.1]heptane, bicyclo[5.2.0]nonane, and bicyclo[5.2.0]nonane.
Some examples of heterocyclic alkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholino, and oxazolidinyl. Examples of fused heterocyclic alkyl groups include benzomorpholino, benzopyrrolidinyl, indolinyl, and benzopiperidinyl.
Aryl groups can be either carbocyclic or heterocyclic.
Carbocyclic aryl groups are fused or unfused ring systems having a total of 6-16 ring members including substituent rings. A preferred unfused carbocyclic aryl group is phenyl.
Some examples of fused carbocyclic aryl groups include naphthyl, phenanthryl, anthracenyl, triphenylenyl, chrysenyl, and pyrenyl.
Heterocyclic aryl groups are fused or unfused ring systems having a total of 5-16 ring members including substituent rings.
Some examples of unfused heterocyclic aryl groups include thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Some examples of fused heterocyclic aryl groups include purinyl, 1,4-diazanaphthalenyl, indolyl, benzimidazolyl, 4,5-diazaphenanthrenyl, benzoxazolyl, isoindolyl, quinolinyl, isoquinolinyl, and benzofuranyl.
Halo substituents are fluoro, chloro, or bromo.
Each alkyl, cycloalkyl, and aryl, independently, may be unsubstituted or substituted with one or more substituent at any position. Alkyl substituents are halo, hydroxyl, OR6, SR6, NH2, NHR6, NR9R10, cycloalkyl, or aryl. Cycloalkyl substituents are halo, hydroxyl, OR6, SR6, NH2, NHR6, NR9R10, alkyl, cycloalkyl, or aryl. Aryl substituents are halo, hydroxyl, OR6, SR6, NH2, NHR6, NR9R10, alkyl, cycloalkyl, aryl, nitro, or carboxyl.
Heterocyclic alkyl and heterocyclic aryl have at least one heteroatom selected from oxygen, nitrogen, and sulfur.
X represents O, S, NH, or NR6. R6 is described above.
In the present invention, various parameters are defined (e.g. R1, R2, R3, R4, X). Within each parameter, more than one element (e.g. chemical moieties) are listed. It is to be understood that the instant invention contemplates embodiments in which each element listed under one parameter may be combined with each and every element listed under any other parameter. For example, X is identified above as representing O, S, NH, or NR6. R5 is identified above as being H, R6, OR6, SR6, NH2, NHR6, or NR9R10. Each element of X (O, S, NH or NR6) can be combined with each and every element of R5 (H, R6, OR6, SR6, NH2, NHR6, or NR9R10). For example, in one embodiment, X may be O and R5 may be H. Alternatively, X may be NH and R5 may be NR9R10, etc. Similarly, a third parameter is R4, in which the elements are defined as H, alkyl, cycloalkyl, or aryl. Each of the above embodiments may be combined with each and every element of R4. For example, in the embodiment wherein X is O and R5 is H, R4 may be H (or any other chemical moiety within the element of R4).
The compounds of this invention are limited to those that are chemically feasible and stable. Therefore, a combination of substituents or variables in the compounds described above is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
Pharmaceutically Acceptable Salts
The present invention also relates to pharmaceutically acceptable salts of the benzimidazole derivatives. The pharmaceutically acceptable salts include the conventional non-toxic salts of the benzimidazole derivatives as formed, e.g., from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the benzimidazole derivatives of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Synthesis of the Benzimidazole Derivatives
The benzimidazoles of the present invention can be synthesized by methods known in the art. The following scheme represents one approach to the synthesis of the compounds of the invention.
Scheme I shows an example of a synthesis that yields individual compounds of the invention or a library of compounds of the invention. For example, the compounds of the invention may be made using polymer-assisted solution-phase (PASP) synthesis. PASP is a parallel synthesis method for creation of a trisubstituted benzimidazoles (BAZ-1) library using 2,4-dinitro-5-fluoroaniline (1) as the starting material.
The first step involves the nucleophilic substitution of compound 1 with a secondary amine in the presence of N,N-diisopropylethylamine. The reaction produces compound 2 in high yields and purity at room temperature.
Then the acylation of the free amino group of compound 2 with an acyl or aroyl chloride takes place. This reaction occurs under reflux conditions using pyridine as the solvent.
Subsequently, reduction of the aromatic m-dinitro groups of compound 3 using HCOO−NH4+ and Pd—C generates diamine compound 4. The benzimidazole ring is formed through acid-catalyzed dehydration.
The free aromatic amino group of compound 5 is modified in different ways. To introduce diversity at the —C(X)—R5 position, anhydride, acyl chloride, sulfonyl chloride, and isocyanate are used as modifying agents. The modification of the aromatic amine moiety takes place smoothly in dry dichloromethane and all excess acylating reagents are scavenged by commercially available aminomethylated polystyrene resin (from nova-biochem) to give the desired product 6 in 80-95% yield.
Uses of the Benzimidazole Derivatives
The invention also relates to a method of treating a patient infected with Mycobacterium tuberculosis or Francisella tulerensis. The method comprises administering to the patient the compound of formula (I) or a pharmaceutically acceptable salt thereof.
The method and compounds of the invention may be employed alone, or in combination with other anti-bacterial agents. Other anti-bacterial agents include isoniazid, rifampin, pyrazinamide, rifabutin, streptomycin and ciprofloxacin. The combination of these anti-bacterial agents and the compounds of the invention will provide new agents for the treatment of tuberculosis, including MDR-TB and XDR-TB, and tularemia.
An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as used herein is any amount effective to treat a patient infected by Mtb or F. tulerensis. Modes of administration and doses can be determined by those having skill in the art. An effective amount of the compound will vary with the group of patients (age, sex, weight, etc.), the nature and severity of the condition to be treated, the particular compound administered, and its route of administration. Amounts suitable for administration to humans are routinely determined by physicians and clinicians during clinical trials.
The minimum dose of the compound is the lowest dose at which efficacy is observed. For example, the minimum dose of the compound may be about 0.1 mg/kg/day, about 1 mg/kg/day, or about 3 mg/kg/day.
The maximum dose of the compound is the highest dose at which efficacy is observed in a patient, and side effects are tolerable. For example, the maximum dose of the compound may be about 10 mg/kg/day, about 9 mg/kg/day, or about 8 mg/kg/day.
A benzimidazole derivative useful in the methods of the present invention may be administered by any method known in the art. Some examples of suitable modes of administration include oral and systemic administration. Systemic administration can be enteral or parenteral. Liquid or solid (e.g., tablets, gelatin capsules) formulations can be employed.
Parenteral administration of the benzimidazole derivative include, for example intravenous, intramuscular, and subcutaneous injections. For instance, a chemical compound may be administered to a patient by sustained release, as is known in the art. Sustained release administration is a method of drug delivery to achieve a certain level of the drug over a particular period of time.
Other routes of administration include oral, topical, intrabronchial, or intranasal administration. For oral administration, liquid or solid formulations may be used. Some examples of formulations suitable for oral administration include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, and wafers. Intrabronchial administration can include an inhaler spray. For intranasal administration, administration of a chemical compound can be accomplished by a nebulizer or liquid mist.
The chemical compound can be formulated in a suitable pharmaceutical carrier. In this specification, a pharmaceutical carrier is considered to be synonymous with a vehicle or an excipient as is understood by practitioners in the art. Examples of carriers include starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums and glycols.
The chemical compound can be formulated into a composition containing one or more of the following: a stabilizer, a surfactant, preferably a nonionic surfactant, and optionally a salt and/or a buffering agent.
The stabilizer may, for example, be an amino acid, such as for instance, glycine; or an oligosaccharide, such as for example, sucrose, tetralose, lactose or a dextran. Alternatively, the stabilizer may be a sugar alcohol, such as for instance, mannitol; or a combination thereof. Preferably the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% weight for weight of the chemical compound.
The surfactant is preferably a nonionic surfactant, such as a polysorbate. Some examples of suitable surfactants include Tween 20, Tween 80; a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001% (w/v) to about 10% (w/v).
The salt or buffering agent may be any salt or buffering agent, such as for example sodium chloride, or sodium/potassium phosphate, respectively. Preferably, the buffering agent maintains the pH of the chemical compound formulation in the range of about 5.5 to about 7.5. The salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a patient. Preferably the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM.
The chemical compound can be formulated into a composition which may additionally contain one or more conventional additives. Some examples of such additives include a solubilizer such as, for example, glycerol; an antioxidant such as for example, benzalkonium chloride (a mixture of quaternary ammonium compounds, known as “quart”), benzyl alcohol, chloretone or chlorobutanol; anaesthetic agent such as, for example a morphine derivative; or an isotonic agent etc. As a further precaution against oxidation or other spoilage, the composition may be stored under nitrogen gas in vials sealed with impermeable stoppers.
Examples have been set forth below for the purposes of illustration and to describe the best mode of the invention at the present time. The scope of the invention is not to be in any way limited by the examples set forth herein.
To a solution of 2,4-dinitro-5-fluoroaniline (1.6 g, 8.0 mmol) in 20 mL of THF, a mixture of DIPEA (1.1 g, 8.8 mmol) and diethylamine (644 mg, 8.8 mmol) in 5 mL of THF was added slowly. The reaction mixture was stirred at room temperature for 1 h. Water (100 mL) was added to give the desired product as a yellow precipitate. The product was collected by filtration and washed with water (200 mL). The filtrate was concentrated to dryness in vacuo to give the desired product (1.8 g, 90% yield) as a bright yellow solid: 1H-NMR (300 MHz, CDCl3) δ 1.96 (t, 6H, J=7.2 Hz), 3.24 (q, 4H, J=7.2 Hz), 6.08 (s, 1H), 8.75 (s, 1H); 13C NMR (75 MHz, CDCl3) δ12.1, 45.7, 102.7, 123.3, 128.2, 131.6, 147.8, 149.4; ESI MS m/z 255.1 [M+H]+.
To a solution of 1-amino-3-diethylamino-4,6-dinitrobenzene (508 mg, 2.0 mmol) in 5 mL of pyridine, 2-methoxybenzoyl chloride (680 mg, 4.0 mmol) was added. After refluxing for 5 h, 50 mL of water was added to the reaction mixture, and the precipitate was collected by filtration and washed with 200 mL of water. Recrystallization from dichloromethane and methanol gave the desired product (622 mg, 80% yield) as a yellow solid: 1H-NMR (300 MHz, CDCl3) δ 1.29 (t, 6H, J=7.2 Hz), 3.39 (q, 4H, J=7.2 Hz), 4.13 (s, 3H), 7.07 (d, 1H, J=8.1), 7.11 (t, 1H, J=9.8 Hz), 7.55 (t, 1H, J=7.8 Hz), 8.23 (d, 1H, J=8.1 Hz), 8.83 (s, 1H), 8.98 (s, 1H); ESI MS m/z 389.1 [M+H]+.
To the solution of 5-(diethylamino)-2,4-dinitro-1-(2-methoxybenzoyl)aminobenzene (388 mg, 1.0 mmol) in 10 mL of 1,4-dioxane and 10 mL of methanol, was added ammonium formate (1.5 g) and 10% Pd/C (200 mg) under nitrogen atmosphere. The reaction mixture was stirred for 30 min. The Pd/C and excess ammonium formate were filtered. Conc. HCl (10 mL) was added to the filtrate. After heating at 75° C. for 18 h, the reaction mixture was basified to pH 8 with saturated K2CO3 solution. The reaction mixture was diluted with 200 mL of ethyl acetate, washed with brine, and dried over anhydrous MgSO4. The reaction mixture was filtered and concentrated in vacuo to afford the crude product (280 mg, 90% yield). The crude product was then purified by column chromatography on silica gel using EtOAc as the eluant to afford the desired product (188 mg, 61% yield) as a brown solid: 1H-NMR (300 MHz, CDCl3) δ 1.01 (t, 6H, J=7.2 Hz), 3.01 (q, 4H, J=7.2 Hz), 4.05 (s, 3H), 6.92 (s, 1H), 7.03 (d, 1H, J=8.1 Hz), 7.11 (t, 1H, J=8.1 Hz), 7.36 (t, 1H, J=6.9), 7.41 (s, 1H), 8.52 (d, 1H, J=7.8 Hz); ESI MS m/z 311.2 [M+H]+.
The following key intermediates were prepared and characterized in the same manner as Example 1.
Brown solid; 1H-NMR (300 MHz, CDCl3) δ 0.95 (t, 6H, J=7.2 Hz), 1.2-2.2 (m, 10H), 2.82 (m, 1H), 2.92 (q, 4H, J=7.2 Hz), 6.90 (s, 1H), 7.33 (s, 1H); ESI MS m/z 287.1 [M+H]+.
Brown solid; 1H-NMR (300 MHz, CDCl3) δ 0.94 (t, 6H, J=7.2 Hz), 2.91 (q, 4H, J=7.2 Hz), 6.80 (s, 1H), 7.02 (t, 2H, J=8.7 Hz), 7.27 (s, 1H), 7.98 (ddd, 2H, J=1.8, 5.4, 8.7 Hz); ESI MS m/z 299.1 [M+H]+.
Brown solid; 1H-NMR (300 MHz, CDCl3) δ 0.92 (t, 6H, J=7.2 Hz), 2.92 (q, 4H, J=7.2 Hz), 6.85 (s, 1H), 7.32 (s, 1H), 7.41 (m, 3H), 8.01 (dd, 2H, J=1.8, 8.4 Hz); ESI MS m/z 281.1 [M+H]+.
Brown solid; 1H-NMR (300 MHz, CDCl3) δ 0.91 (t, 6H, J=7.2 Hz), 2.90 (q, 4H, J=7.2 Hz), 2.33 (s, 3H), 6.79 (s, 1H), 7.13 (d, 2H, J=7.8 Hz), 7.32 (s, 1H), 7.99 (d, 2H, J=7.8 Hz); ESI MS m/z 295.1 [M+H]+.
Brown solid; 1H-NMR (300 MHz, CDCl3) δ 0.93 (t, 6H, J=7.2 Hz), 2.92 (q, 4H, J=7.2 Hz), 4.03 (s, 3H), 6.73 (s, 1H), 6.75 (d, 2H, J=8.4 Hz), 7.10 (d, 2H, J=8.4 Hz) 7.16 (s, 1H); ESI MS m/z 311.1 [M+H]+.
Brown solid; 1H-NMR (300 MHz, CDCl3) δ 0.91 (t, 6H, J=7.2 Hz), 2.92 (q, 4H, J=7.2 Hz), 6.65 (s, 1H), 7.10 (s, 1H), 7.35 (t, 1H, J=7.5 Hz), 7.44 (t, 2H, J=4.2 Hz), 7.67 (d, 1H, J=6.3), 7.83 (m, 2H), 8.64 (m, 1H); ESI MS m/z 349.2 [M+H]+.
To a solution of 5-amino-6-diethylamino-2-(2-methoxyphenyl)-1H-benzo[d]-imidazol (200 mg, 0.64 mmol) in dichloromethane (5 mL), 2-methoxybenzoyl chloride (112 mg, 0.64 mmol) was added and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel using hexane/EtOAc (4/1) as the eluant to afford the desired product (210 mg, 78%) as a white powder: 1H-NMR (300 MHz, CDCl3) δ 1.00 (t, 6H, J=7.2 Hz), 3.05 (q, 4H, J=7.2 Hz), 3.86 (s, 3H), 4.04 (s, 3H), 6.85 (d, 2H, J=9 Hz), 7.03 (d, 1H, J=8.7 Hz), 7.13 (t, 1H, J=7.2 Hz), 7.39 (t, 1H, J=7.2 Hz), 7.66 (s, 1H), 7.91 (d, 2H, J=9 Hz), 8.88 (s, 1H); 13C NMR (75 MHz, CDCl3) δ12.9, 50.4, 55.3, 55.7, 111.4, 113.8, 117.9, 121.5, 127.8, 128.6, 129.6, 130.8, 132.8, 135.8, 149.9, 156.6, 162.1, 164.1; ESI MS m/z 445.4 [M+H]+.
5-Amino-6-diethylamino-2-(2-methoxyphenyl)-1H-benzo[d]-imidazole (187 mg, 0.6 mmol) was reacted with 4-chlorobenzoyl chloride (105 mg, 0.6 mmol) in the same manner as that described above to give the desired product (216 mg, 80% yield) as pale yellow powder: 1H-NMR (300 MHz, CDCl3) δ 0.99 (t, 6H, J=7.2 Hz), 3.05 (q, 4H, J=7.2 Hz), 4.07 (s, 3H), 7.05 (d, 1H, J=8.4 Hz), 7.11 (t, 1H, J=7.8 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.67 (s, 1H), 7.88 (d, 2H, J=8.4 Hz), 8.55 (d, 1H, J=6.9 Hz), 8.86 (s, 1H); 13C NMR (75 MHz, CDCl3) δ13.1, 50.6, 55.9, 111.5, 117.7, 121.7, 128.3, 129.0, 129.8, 131.1, 132.5, 133.9, 136.0, 137.7, 150.2, 156.7, 163.4; ESI MS m/z 449.2 [M+H]+.
5-Amino-6-diethylamino-2-(cyclohexyl)-1H-benzo[d]-imidazole (27 mg, 0.1 mmol) was reacted with benzoyl chloride (11 mg, 0.1 mmol) in the same manner as that described above to give the desired product (27 mg, 74% yield) as white powder: 1H-NMR (300 MHz, CDCl3) δ 0.98 (t, 6H, J=7.2 Hz), 1.16 (m, 3H), 1.57-1.70 (m, 5H), 1.98 (m, 2H), 2.87 (m, 1H), 3.03 (q, 4H, J=7.2 Hz), 7.57 (m, 3H), 7.57 (s, 1H), 8.00 (dd, 2H, J=1.8, 8.4 Hz), 8.96 (s, 1H); ESI MS m/z 391.0 [M+H]+.
5-Amino-6-diethylamino-2-(cyclohexyl)-1H-benzo[d]-imidazole (28 mg, 0.1 mmol) was reacted with 4-methoxybenzoyl chloride (17 mg, 0.1 mmol) in the same manner as that described above to give the desired product (33 mg, 79% yield) as white powder: 1H-NMR (300 MHz, CDCl3) δ 0.97 (t, 6H, J=7.2 Hz), 1.16 (m, 3H), 1.57-1.70 (m, 5H), 1.98 (m, 2H), 2.87 (m, 1H), 3.01 (q, 4H, J=7.2 Hz), 7.05 (d, 2H, J=8.7 Hz), 7.57 (s, 1H), 7.96 (d, 2H, J=8.7 Hz), 8.94 (s, 1H); ESI MS m/z 421.0 [M+H]+.
A suspension of 4-amino-3,5-dinitrobenzamide (543 mg, 2.4 mmol) in 4M HCl (20 mL) was refluxed overnight. The reaction mixture was cooled and the precipitated solid was filtered to give 4-amino-3,5-dinitrobenzoic acid as yellow solid: 1H-NMR (300 MHz, DMSO-d6) δ 8.80 (s, 2H). 4-Amino-3,5-dinitrobenzoic acid, thus obtained, was dissolved in SOCl2 (4 mL) and refluxed overnight. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure to remove excess SOCl2. The crude product was immediately dissolved in acetone (2.4 mL) in an ice-bath. To this solution was added dropwise NaN3 (0.29 g, 3.84 mmol) in ice-water (0.88 mL). The mixture was stirred for 20 min at 0° C. until a solid precipitated out. After dilution with ice-water (12 mL), the reaction mixture was extracted with CH2Cl2 (6 mL×2), dried over MgSO4 at 0° C. for 1 h, and filtered. The filtrate was concentrated on a rotary evaporator (below room temperature), and the residue dissolved in toluene (15 mL). After refluxing for 2 h, the reaction mixture was cooled down to room temperature, and MeOH (10 mL) was added. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane/EtOAc=1/1) to afford 4-amino-3,5-dinitro-1-(methoxycarbonyl)aminobenzene as bright red solid (292 mg, 45% yield): 1H-NMR (300 MHz, CDCl3) δ 3.73 (s, 3H), 6.60 (s, 1H), 8.30 (s, 2H), 8.64 (s, 2H); ESI MS m/z 256.9 [M+H]+.
To a suspension of 4-amino-3,5-dinitro-1-(methoxycarbonyl)aminobenzene (311 mg, 1.2 mmol) in ethanol (24 mL), was added ammonium formate (1.8 g) and 10% Pd/C (120 mg) under nitrogen. The mixture was stirred at room temperature overnight. The Pd/C and excess ammonium formate were filtered off. The filtrate was treated with the sodium bisulfite adduct of 4-bromobenzaldehyde (715 mg, 0.84 mmol) at 0° C. After the solution was stirred for 12-16 h at room temperature under nitrogen, a trace of insoluble material was removed by filtration and the filtrate was concentrated on a rotary evaporator until approximately 60-70% of the solvent was removed. To the residue an equal volume of ethyl acetate was added, and the mixture was transferred to a separatory funnel. The organic layer was separated, and the water layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the desired product (610 mg, 48% yield) as brown powder: 1H-NMR (300 MHz, CD3OD) δ 3.73 (s, 3H), 6.53 (s, 1H), 7.16 (s, 1H), 7.64 (dd, 2H, J=6.6, 1.8 Hz), 7.88 (dd, 2H, J=6.6, 1.8 Hz); ESI MS m/z 361.0 [M+H]+.
To a solution of 7-amino-5-(methoxycarbonyl)amino-2-(4-bromophenyl)-1H-benzo[d]-imidazole (60 mg, 0.17 mmol) in dichloromethane (5 mL) was added acetic anhydride (18 mg, 0.17 mmol) and the solution was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel using hexane/EtOAc (4/1) as the eluant to afford the desired product (55 mg, 80%) as a pale yellow powder: 1H-NMR (300 MHz, CD3OD) δ 2.24 (s, 3H), 3.74 (s, 3H), 7.65 (m, 3H), 7.67 (bs, 1H), 7.90 (m, 2H); ESI MS m/z 403.0 [M+H]+.
Procedure for the determination of the minimum inhibitory concentration (MIC): MIC values were determined using the microplate dilution method, previously reported [R. A. Slayden and C. E. Barry, III. “The role of KasA and KasB in the biosynthesis of meromycolic acids and isoniazid resistance in Mycobacterium tuberculosis”, Tuberculosis (Edinb) 82:149-60 (2002)].
Bacteria were cultivated in liquid medium to an optical density of ˜0.4 at 600 nm. The bacterial cultures were then prepared for testing by diluting 1:100 in liquid medium. A total of 50 μL of each culture was added to each well of a 96-well optical plate. Analogs were prepared at 60 μM in 100% DMSO. Compound stock solutions were diluted 1:2 in liquid medium and then distributed in the plate as 2-fold serial dilutions to achieve a concentration range of 200-0.2 mg/mL in a total final volume of 100 μL. The plates were incubated at 37° C. and evaluated for the presence of bacterial growth or non-growth by optical density using an inverted plate reading method. The MIC99 was determined to be the lowest concentration of compound that inhibited bacterial growth. Reported MIC values represent measurements performed independently in triplicate.
A list of active compounds is included in the Appendix section.
The following key intermediates were prepared and characterized in the same manner as Example 1(a).
Yield 92%; 1HNMR (400 MHz, CDCl3) δ 8.92 (s, 1H) 6.12 (s, 1H), 3.86 (t, 4H, J=6.2 Hz), 3.12 (t, 4H, J=6.2 Hz); ESI MS m/z 269.2 [M+H]+.
Yield 94%; 1HNMR (300 MHz, CDCl3) δ 8.84 (s, 1H) 6.43 (bs, 2H), 3.09 (t, 4H, J=5 Hz), 1.71 (m, 4H); ESI MS m/z 267.2 [M+H]+.
Yield 94% 1HNMR (400 MHz, CDCl3) δ 8.91 (s, 1H) 6.16 (s, 1H), 3.61 (t, 4H, J=5 Hz), 3.09 (t, 4H, J=4.8 Hz), 1.47 (s, 9H); ESI MS m/z 368.3 [M+H]+.
The following key intermediates were prepared and characterized in the same manner as Example 1(b).
Yield 88%; 1HNMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 8.65 (s, 1H), 3.36 (q, 4H, J=10.8 Hz), 2.38-1.30 (m, 11H), 1.26 (t, 6H, J=7.2 Hz); ESI MS m/z 365.4 [M+H]+.
Yield 67%; 1HNMR (300 MHz, CDCl3) δ 8.8 (d, 2H, J=5.8 Hz), 7.87 (d, 2H, J=4 Hz), 7.33 (d, 2H, J=4 Hz), 3.4 (q, 4H, J=10.6 Hz), 2.43 (s, 3H), 1.29 (t, 6H, J=7.2 Hz); ESI MS m/z 373.3 [M+H]+.
Yield 85%; 1HNMR (300 MHz, CDCl3) δ 11.79 (s, 1H), 8.82 (d, 2H, J=2.1 Hz), 7.96 (d, 2H, J=4.5 Hz), 7.03 (d, 2H, J=4.3 Hz), 3.39 (s, 3H), 3.41 (q, 4H, J=10.6 Hz), 1.30 (t, 6H, J=6.9 Hz); ESI MS m/z 389.3 [M+H]+.
Yield 78%; 1HNMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.82 (s, 1H), 7.94 (d, 2H, J=4.3 Hz), 7.56 (d, 2H, J=4.2 Hz), 3.41 (q, 4H, J=10.6 Hz), 1.37 (s, 9H), 1.30 (t, 6H, J=7.2 Hz); ESI MS m/z 415.4 [M+H]+.
Yield 79%; 1HNMR (300 MHz, CDCl3) δ 11.84 (s, 1H), 8.81 (s, 1H), 8.8 (s, 1H), 8.02 (d, 2H, J=7.2 Hz), 7.22 (d, 2H, J=5.2 Hz), 3.41 (q, 4H, J=10.6 Hz), 1.30 (t, 6H, J=7.2 Hz); ESI MS m/z 377.3 [M+H]+.
Yield 80%; 1HNMR (300 MHz, CDCl3) δ 11.87 (s, 1H), 8.84 (s, 1H), 8.82 (s, 1H), 8.0 (d, 2H, J=4.8 Hz), 7.63-7.55 (m, 3H), 3.41 (q, 4H, J=10.6 Hz), 1.31 (t, 6H, J=7.2 Hz); ESI MS m/z 359.3 [M+H]+.
Yield 90%; 1HNMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 8.87 (s, 1H), 8.64 (s, 1H), 3.83 (t, 4H, J=4.8 Hz), 3.28 (t, 4H, J=4.6 Hz), 2.38 (m, 1H), 2.03-1.26 (m, 11H); ESI MS m/z 379.3 [M+H]+.
Yield 87%; 1HNMR (400 MHz, CDCl3) δ 11.80 (s, 1H), 8.95 (s, 1H), 8.83 (s, 1H), 7.88 (d, 2H, J=4.2 Hz), 7.36 (d, 2H, J=4 Hz), 3.88 (t, 4H, J=4.6 Hz), 3.34 (t, 4H, J=4.6 Hz), 2.46 (s, 3H); ESI MS m/z 387.3 [M+H]+.
Yield 75%; 1HNMR (400 MHz, CDCl3) δ 11.81 (s, 1H), 8.95 (s, 1H), 8.84 (s, 1H), 7.92 (d, 2H, J=4.2 Hz), 7.57 (d, 2H, J=4.2 Hz), 3.88 (t, 4H, J=4.6 Hz), 3.34 (t, 4H, J=4.6 Hz), 1.37 (s, 9H); ESI MS m/z 429.4 [M+H]+.
Yield 70%; 1HNMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 8.90 (s, 1H), 8.67 (s, 1H), 3.62 (t, 4H, J=5.2 Hz), 3.28 (t, 4H, J=5.2 Hz), 2.38 (m, 1H), 2.03-1.26 (m, 11H); ESI MS m/z 478.5 [M+H]+.
Yield 80%; 1HNMR (300 MHz, CDCl3) δ 10.95 (s, 1H), 8.85 (s, 1H), 8.63 (s, 1H), 3.27 (t, 4H, J=4.9 Hz), 2.38 (m, 1H), 2.03-1.26 (m, 16H); ESI MS m/z 377.4 [M+H]+.
Yield 85%; 1HNMR (300 MHz, CDCl3) δ 11.69 (s, 1H), 8.90 (s, 1H), 8.79 (s, 1H), 7.95 (d, 2H, J=4.5 Hz), 7.03 (d, 2H, J=4.3 Hz), 3.90 (s, 3H), 3.32 (t, 4H, J=4.95 Hz), 1.75 (m, 6H); ESI MS m/z 401.3 [M+H]+.
Yield 83%; 1HNMR (300 MHz, CDCl3) δ 11.87 (s, 1H), 8.91 (s, 1H), 8.80 (s, 1H), 7.98 (d, 2H, J=4.8 Hz), 7.66-7.55 (m, 3H), 3.33 (t, 4H, J=4.9 Hz), 1.76 (m, 6H); ESI MS m/z 371.3 [M+H]+.
The following key intermediates were prepared and characterized in the same manner as Example 1(c).
Yield 55%; 1HNMR (300 MHz, CDCl3) δ 7.31 (s, 1H), 6.9 (s, 1H), 2.92 (m, 4H, J=10.8 Hz), 2.04 (m, 2H), 1.68 (m, 5H), 1.26 (m, 4H), 0.95 (t, 6H, J=6.9 Hz); ESI MS m/z 287.4 [M+H]+.
Yield 46%; 1HNMR (400 MHz, CDCl3) δ 7.95 (d, J=4.2 Hz, 2H), 7.21 (s, 1H), 7.12 (d, 2H, J=4 Hz), 6.77 (s, 1H), 2.84 (q, 4H, J=10.6 Hz), 2.3 (s, 3H), 0.90 (t, 6H, J=7 Hz); ESI MS m/z 295.3 [M+H]+.
Yield 52%; 1HNMR (400 MHz, CDCl3) δ 8.48 (dd, 1H), 7.37-7.29 (m, 2H), 7.48 (t, 1H, J=8 Hz), 6.97 (d, 1H, J=4.2 Hz), 6.88 (s, 1H), 3.96 (s, 3H), 2.96 (q, 4H, J=10.6 Hz), 0.97 (t, 6H, J=7 Hz); ESI MS m/z 311.3 [M+H]+.
Yield 50%; 1HNMR (400 MHz, CDCl3) δ 8.01 (d, 2H, J=2.5 Hz), 7.35 (d, 2H, J=2.5 Hz), 7.29 (s, 1H), 6.78 (s, 1H), 2.86 (q, 4H, J=10.6 Hz), 1.27 (s, 9H), 0.91 (t, 6H, J=7 Hz); ESI MS m/z 337.4 [M+H]+.
Yield 66%; 1HNMR (300 MHz, CDCl3) δ 7.23 (s, 1H), 6.81 (s, 1H), 2.81 (t, 4H, J=4.9 Hz), 2.04 (m, 1H), 1.78-1.23 (m, 16H); ESI MS m/z 299.4 [M+H]+.
The following key intermediates were prepared and characterized in the same manner as Examples 9-11.
Yield 78%; 1HNMR (300 MHz, CDCl3) δ 10.31 (s, 1H), 8.94 (s, 1H), 7.95 (d, 2H, J=4.35 Hz), 7.57 (s, 1H), 7.05 (d, 2H, J=4.35 Hz), 3.9 (s, 3H), 3.0 (m, 4H), 2.1 (s, 1H), 1.98 (m, 2H), 1.58 (m, 5H), 1.26 (m, 3H), 0.97 (t, 6H, J=7.2 Hz); ESI MS m/z 421.5 [M+H]+.
Yield 74%; 1HNMR (300 MHz, CDCl3) δ 10.3 (s, 1H), 8.96 (s, 1H), 7.98 (m, 2H), 7.57 (m, 4H), 3.03 (m, 4H, J=10.65 Hz), 1.98 (m, 2H), 1.65 (m, 5H), 1.16 (m, 4H), 0.97 (m, 6H, J=7.2 Hz); ESI MS m/z 391.5 [M+H]+.
Yield 65%; 1HNMR (300 MHz, CDCl3) δ 10.31 (s, 1H), 8.91 (s, 1H), 7.87 (d, 2H, J=4.5 Hz), 7.59 (s, 1H), 7.34 (d, 2H, J=4.2 Hz), 3.02 (m, 4H, J=10.8 Hz), 2.45 (s, 3H), 2.01 (m, 2H), 1.69 (m, 5H), 1.2 (m, 4H), 0.97 (m, 6H, J=7 Hz) ESI MS m/z 405.5 [M+H]+.
Yield 64%; 1HNMR (300 MHz, CDCl3) δ 10.26 (s, 1H), 8.77 (s, 1H), 7.88 (d, 2H, J=3.45 Hz), 7.60 (s, 1H), 7.50 (d, 2H, J=4.2 Hz), 3.02 (m, 4H, J=10.65 Hz), 2.11 (m, 2H), 1.84-1.25 (m, 9H), 0.97 (t, 6H, J=7.2 Hz); ESI MS m/z 425 [M+H]+.
Yield 61%; 1HNMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.25 (s, 1H), 7.45-7.35 (m, 5H), 5.22 (s, 2H), 2.91 (m, 4H, J=10.65 Hz), 2.11 (m, 2H), 1.84-1.62 (m, 5H), 1.38 (m, 4H), 0.90 (t, 6H, J=7.2 Hz); ESI MS m/z 421.5 [M+H]+.
Yield 63%; 1HNMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.23 (s, 1H), 7.47 (s, 1H), 4.14 (t, 2H, J=6.75 Hz), 2.92 (m, 4H, J=10.8 Hz), 2.10 (m, 2H), 1.87-1.60 (m, 7 H), 1.40-1.25 (m, 4H), 0.98 (t, 3H, J=6.15 Hz), 0.93 (t, 6H, J=7.05 Hz) ESI MS m/z 373.5 [M+H]+.
Yield 51%; 1HNMR (300 MHz, CDCl3) δ 8.50 (s, 1H), 8.22 (s, 1H), 7.48 (s, 1H), 4.18 (t, J=6.75 Hz, 2H), 2.92 (m, J=10.5 Hz, 4H), 2.10 (m, 2H), 1.87-1.60 (m, 7H), 1.40-1.39 (m, 6H), 0.96 (t, J=7.5 Hz, 3H), 0.92 (t, J=7.2 Hz, 6H); ESI MS m/z 387.5 [M+H]+.
Yield 51%; 1HNMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.23 (s, 1H), 7.48 (s, 1H), 5.84 (m, 1H), 5.11 (m, 2H), 4.23 (t, 2H, J=6.9 Hz), 2.92 (m, 4H, J=10.5 Hz), 2.47 (t, 2H, J=4.65 Hz), 2.10 (m, 2H), 1.82-1.60 (m, 5H), 1.40-1.32 (m, 4H), 0.91 (t, 6H, J=7.05 Hz); ESI MS m/z 385.2 [M+H]+.
Yield 48%; 1HNMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 9.02 (s, 1H), 7.93 (d, 2H, J=4.2 Hz), 7.57 (d, 3H, J=4.2 Hz), 3.02 (q, 4H, J=10.6 Hz), 2.68 (m, 1H), 1.92 (m, 2H), 1.67-1.53 (m, 5H), 1.38 (s, 9H), 1.24 (s, 2H), 1.26 (m, 3H), 0.97 (t, 6H, J=7 Hz); ESI MS m/z 2447.6 [M+H]+.
Yield 74%; 1HNMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.65 (s, 1H), 7.50 (s, 1H), 2.93 (q, 4H, J=10.6 Hz), 2.81 (m, 2H), 2.07-1.67 (m, 15H), 1.31 (m, 3H), 0.92 (t, 6H, J=7 Hz); ESI MS m/z 383.5 [M+H]+.
Yield 55%; 1HNMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.69 (s, 1H), 7.49 (s, 1H), 7.59 (s, 1H), 7.27-7.18 (m, 5H), 3.11 (t, 2H, J=7.6 Hz), 2.86 (q, 3H, J=10.6 Hz), 2.76 (t, 2H, J=7.6 Hz), 2.08 (m, 2H), 1.8-1.6 (m, 4H), 1.35-1.23 (m, 5H), 0.83 (t, 6H, J=7 Hz); ESI MS m/z 419.5 [M+H]+.
Yield 60%; 1HNMR (3\400 MHz, CDCl3) δ 9.45 (s, 1H), 8.73 (s, 1H), 7.51 (s, 1H), 2.94 (q, 4H, J=10.9 Hz), 2.84 (m, 1H), 2.49 (t, 2H, J=7.6 Hz), 2.10 (m, 2H), 1.84-1.65 (m, 7H), 1.48-1.25 (m, 5H), 0.96 (t, 3H, J=7.4 Hz), 0.92 (t, 6H, J=7.2 Hz); ESI MS m/z 371.5 [M+H]+.
Yield 75%; 1HNMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.73 (s, 1H), 7.52 (s, 1H), 2.94 (q, 4H, J=10.8 Hz), 2.84 (m, 1H), 2.45 (t, 2H, J=7.6 Hz), 2.10 (m, 2H), 1.84-1.65 (m, 7H), 1.48-1.25 (m, 5H), 1.06 (t, 3H, J=7.4 Hz), 0.92 (t, 6H, J=7.2 Hz); ESI MS m/z 357.5 [M+H]+.
Yield 51%; 1HNMR (300 MHz, CDCl3) δ 8.51 (s, 1H), 8.23 (s, 1H), 7.48 (s, 1H), 5.84 (m, 1H), 5.11 (m, 2H), 4.23 (t, 2H, J=6.9 Hz), 2.92 (q, 4H, J=10.5 Hz), 2.47 (t, 2H, J=4.65 Hz), 2.10 (m, 2H), 1.82-1.6 (m, 5H), 1.40-1.32 (m, 4H), 0.91 (t, 6H, J=7.05 Hz); ESI MS m/z 371.4 [M+H]+.
The following key intermediates 49 through 54 were prepared and characterized in the same manner as 7-amino-5-(methoxycarbonyl)amino-2-(4-bromophenyl)-1H-benzo[d]imidazole in Example 12(b).
Yield 55%; 1H-NMR (300 MHz, CD3OD) δ 1.29 (t, 3H, J=9 Hz), 4.16 (dd, 2H, J=14.1, 7.2 Hz), 6.51 (s, 1H), 6.61 (m, 1H), 7.05 (m, 1H), 7.13 (s, 1H), 7.67 (m, 1H); ESI MS m/z 287.0 [M+H]+.
Yield 57%; 1H-NMR (300 MHz, CD3OD) δ 3.73 (s, 3H), 3.93 (s, 3H), 6.52 (s, 1H), 7.19 (s, 1H), 8.12 (s, 4H); ESI MS m/z 341.0 [M+H]+.
Yield 54%; 1H-NMR (300 MHz, CD3OD) δ 1.30 (t, 3H, J=6.9 Hz), 4.16 (dd, 2H, J=14.4, 7.2 Hz), 6.51 (s, 1H), 7.18 (s, 1H), 7.44 (m, 3H), 8.01 (m, 2H); ESI MS m/z 297.1 [M+H]+.
Yield 53%: 1H-NMR (300 MHz, CD3OD) δ 3.72 (s, 3H), 3.85 (s, 3H), 3.99 (s, 3H), 6.51 (s, 1H), 6.66 (m, 2H), 7.17 (bs, 1H), 8.06 (d, 1H, J=9.3 Hz); ESI MS m/z 343.0 [M+H]+.
Yield 50%: 1H-NMR (300 MHz, CD3OD) δ 3.72 (s, 3H), 6.51 (s, 1H), 7.17 (m, 2H), 7.50 (m, 1H), 7.78 (m, 2H); ESI MS m/z 301.1 [M+H]+.
Yield 52%; 1H-NMR (300 MHz, CD3OD) δ 1.30 (t, 3H, J=7.2 Hz), 4.14 (dd, 2H, J=14.1, 7.2 Hz), 6.48 (s, 1H), 6.95 (m, 1H), 7.27 (t, 2H), 7.43 (m, 2H); ESI MS m/z 311.9 [M+H]+.
The following key intermediates 55 and 56 were prepared and characterized in the same manner as 7-acetylamino-5-(methoxycarbonyl)amino-2-(4-bromophenyl)-1H-benzo[d]imidazole in Example 12 (c).
Yield 85%; 1H-NMR (300 MHz, CD3OD) δ 1.30 (t, 3H, J=7.2 Hz), 2.32 (s, 3H), 4.24 (dd, 2H, J=14.4, 7.2 Hz), 7.58 (m, 3H), 7.77 (bs, 1H), 7.85 (bs, 1H), 8.10 (m, 2H); ESI MS m/z 339.1 [M+H]+.
Yield 83%: 1H-NMR (300 MHz, CD3OD) δ 2.25 (s, 3H), 3.74 (s, 3H), 6.51 (s, 1H), 7.22 (m, 1H), 7.52 (m, 1H), 7.78 (m, 5H); ESI MS m/z 343.1 [M+H]+.
This application is the U.S. National Phase of, and Applicants claim priority from, International Application Number PCT/US2008/005084 filed 21 Apr. 2008 and U.S. Provisional Patent Application No. 60/912,980 filed 20 Apr. 2007, each of which are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US2008/005084 | 4/21/2008 | WO | 00 | 12/14/2009 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2008/130669 | 10/30/2008 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 4873181 | Miyasaka et al. | Oct 1989 | A |
| 20050124678 | Levy et al. | Jun 2005 | A1 |
| 20060116412 | Ng et al. | Jun 2006 | A1 |
| Number | Date | Country |
|---|---|---|
| WO2007105023 | Sep 2007 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20100256203 A1 | Oct 2010 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60912980 | Apr 2007 | US |
