IMIDAZO[1,2-A]PYRIDINE COMPOUNDS

专利摘要:
imidazo[1,2-a]pyridine compound, synthesis and methods of using the same. embodiments related to the field of chemistry and biochemistry, and more specifically to imidazopyridine compounds, their synthesis and methods of using them. Described herein are various imidazo[1,2-a]pyridine compounds and methods of using the novel compounds to treat or prevent tuberculosis in a subject or to inhibit fungal growth in plant species. other embodiments include methods of synthesizing imized [1,2-a] pyridine compounds, such as the described imidazol [1,2-a]pyridine compounds.
公开号:BR112012010752B1
申请号:R112012010752-6
申请日:2010-11-05
公开日:2021-07-20
发明作者:Garret C.Moraski；Lowell D. Markley；George E. Davis；Marvin J. Miller
申请人:University Of Notre Dame Du Lac；Dow Agrosciences Llc；
IPC主号:

专利说明:

Government Interests
[001] This invention was made with government sponsorship under grant R01 Al 054193 granted by the National Institutes of Health. The Government has certain rights in this invention. Cross Reference With Related Applications
[002] The present application claims priority to US Provisional Patent Application Number 61/258,549, filed November 5, 2009, entitled Imidazo[1,2-a]Pyridine Compounds, Synthesis thereof, and Methods of Use thereof, the discovery is hereby incorporated by reference in its entirety. Technical Field
[003] The personifications herein related to the fields of chemistry and biochemistry, and more specifically to imidazo[1,2-a]pyridine compounds, syntheses thereof, and methods of using them. Background
[004] Worldwide, more than two billion people are infected with tuberculosis (TB), and an estimated 14,400,000 people have active TB cases. Of these active cases, 83% are located in Africa, Southeast Asia and the Western Pacific region. The global impact of TB is enormous: each year, TB kills 1.5 million people who are HIV negative and 0.2 million people who are HIV positive. New drug-resistant strains emerge every year.
[005] Current treatment for active, susceptible drugs to TB includes a carefully monitored regimen of a cocktail of rifampicin, isoniazid, pyrazinamide and ethambutol for two months, followed by an additional four months of rifampicin and isoniazid. Multidrug-resistant TB infections require a long course of therapy lasting two years or more with drugs that are expensive and poorly tolerated. Because of their duration, complexity, and cost, these regimens represent inadequate therapies for most TB cases. New therapies are urgently needed to fight TB infections, yet no new drugs have been approved to treat TB in over 40 years.
[006] Furthermore, in a different technical area, a large number of fungi are known to grow at the expense of commercially important plants that are essential for human survival. A number of fungicides have been developed for use in protecting both ornamental plants and food crops from pathogenic fungi. While many safe and effective fungicides are currently used, the evolution of pathogenic fungi and the ever-increasing pressure to use lower levels of fungicides have created the need for new fungicides. Effective antifungal treatments are urgently needed to treat harmful fungal infections in plant species. Brief Description of Drawings
[007] The personifications will be readily understood by the following detailed descriptions in conjunction with the attached drawings. The personifications are illustrated through examples and not through delimitations in the figures of the attached drawings.
[008] Figure 1 illustrates the low cost of treating a therapy for TB with a high and low dose of imidazo[1,2-a]pyridine.
[009] Figure 2 shows the SAR of particular imidazo[1,2-a]pyridine agents and some trends observed from screening the compounds in an anti-TB assay.
[0010] Figure 3 shows the SAR of particular imidazo[1,2-a]pyridine agents and some trends observed from screening the compounds in an antifungal assay.
[0011] Figure 4 shows the structures of particular imidazo[1,2-a]pyridine agents screened in figures 2 and 3. Detailed Description of Discovery Personifications
[0012] In the following detailed description, reference is made to the attached drawings which form a part thereof, which are shown by means of illustrations, embodiments that can be practiced. It is to be understood that other personifications can be used and logical or structural changes can be made without departing from the scope. For this reason, the following detailed description is not to be taken in a limiting sense, and the scope of embodiments is defined by the appended claims and their equivalents.
[0013]Multiple operations can be described as multiple discrete operations, in turn, in a way that can be useful in understanding impersonations; however, the order of description may not be interpreted to imply that these operations are order-dependent.
[0014] For the purposes of description, a phrase in the form "A/B" or in the form "A and/or B" means (A), (B), or (A and B). For the purposes of description, a phrase of the form "at least one of A, B, or C" means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B and C). For the purposes of description, a phrase in the form of “(A)B” means (B) or (AB) that is, A is an optional element.
[0015] The description may use the terms “personification” or “personifications”, each of which may refer to one or more of the same or different personifications. Furthermore, the terms “comprising”, “including”, “having”, and the like, as used in relation to personifications, are synonymous.
[0016] As used herein, the term "halogen" refers to fluorine, bromine, chlorine and iodine substituents.
[0017] As used herein, the term "alkyl" refers to a cyclic, branched or straight-line chain of an alkyl group containing only carbon and hydrogen, and unless otherwise noted contains from one to twelve atoms of carbon. That term can be further exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, pentyl, pivalyl, heptyl, adamantyl, and cyclopentyl. Alkyl groups can be either unsubstituted or substituted with one or more substituents, for example, halogen, alkyl, alkoxy, alkylthio, trifluoromethyl, acyloxy, hydroxy, mercapto, carboxy, aryloxy, aryloxy, aryl, aryl alkyl, heteroaryl, amino , alkylamino, dialkylamino, morpholino, piperidino, pyrrolidin-1-yl, piperazine-1-yl, or other functionality to form a "functionalized alkyl".
[0018] As used herein, the term "substituted alkyl" refers to an alkyl moiety including 1-4 substituents selected from halogen, het, cycloalkyl, cycloalkenyl, aryl, amino, cyano, nitro, -OQ10, -SQ10 , -S(O)2Q10, -S(O)Q10, - OS(O)2Q10, -C(=NQ10)Q10, -C(=NOQ10)Q10, -S(O)2-N=S(O )(Q10)2, -S(O)2-N=S(Q10)2, -NQ10Q10, -C(O)Q10, -C(S)Q10, -C(O)OQ10, -OC(O) Q10, -C(O)NQ10Q10, -C(S)NQ10Q10, -N(Q10)C(S)NQ10Q10, -C(O)NQ10Q10, -C(S)NQ10Q10, -C(O)C(Q16) 2OC(O)Q10, -CN, =S, -NQ10C(O)Q10, -NQ10C(O)NQ10Q10, -S(O)2NQ10Q10, -NQ10S(O)2Q10, -NQ10S(O)Q10, - NQ10SQ10, and -SNQ10Q10. Each of het, cycloalkyl, cycloalkenyl, and aryl being optionally substituted with 1-4 substituents independently selected from halogen and Q15.
As used herein, the term "cycloalkyl" refers to a cyclic alkyl moiety. Unless otherwise indicated, cycloalkyl moieties include from 3 to 8 carbon atoms.
As used herein, the term "alkene" refers to a hydrocarbon molecule with the general formula CnH2n, which contains one or more double bonds.
As used herein, the term "alkyne" refers to a moiety having the general formula C2H2n-2, corresponding to carbon chains with an included carbon-carbon triple bond.
As used herein, the term "alcohol" refers to any organic compound in which the hydroxyl group (-OH) is attached to a carbon atom of an alkyl or substituted alkyl group. The general formula for simple acyclic alcohols is CnH2n+1OH.
[0023] As used herein, the term "epoxide" refers to any class of organic compound, cyclic ethers, having a three-membered ring.
[0024] As used herein, the term "ketone" refers to an organic compound containing the carbonyl group, >C=O, to which other carbon atoms are attached.
[0025] As used herein, the term "ester" refers to the product of the reaction between a carboxylic acid and an alcohol.
As used herein, the term "ether" refers to an organic compound containing the functional group RO-R’.
As used herein, the term "aldehyde" refers to an organic compound containing a -CHO group.
[0028] As used herein, the term "nitrile" refers to any of the classes of organic compounds containing the cyano-CN radical.
[0029] As used herein, the term "thiol" refers to a molecular group that includes a bonded hydrogen and sulfur atom (-SH).
As used herein, the term "thioester" refers to a compound resulting from a sulfur bond with an acyl group having the general formula R-S-CO-R'. Thioesters are the products of esterification between a carboxylic acid and a thiol (as opposed to an alcohol in regular esters).
[0031] As used herein, the term "sulfide" refers to an organic compound containing sulfur bonded to a carbon. The term "disulfide" refers to a structural unit composed of a pair of connected sulfur atoms.
[0032] As used herein, the term "sulfone" refers to a chemical compound containing a sulfonyl functional group attached to two carbon atoms. The central sulfur atom is twice doubly bonded to oxygen and has two additional hydrocarbon substituents. The general structural formula is R-S(=O)(=)-R’ where R and R’ are the organic groups.
[0033] As used herein, the term "sulfoxide" refers to a chemical compound containing a sulfinyl functional group attached to two carbon atoms. Sulfoxides can be considered oxidized sulfides.
As used herein, the term "amine" refers to NH2, NHR, or NR2. Unless otherwise indicated R may be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, het or aryl.
As used herein, the term "starch" refers to an organic compound containing the -CONH2- group.
[0036] As used herein, the term "urea" refers to an organic compound with the chemical formula (NH2)2 CO or RNHCONHR’.
As used herein, the term "carbamate" refers to any of a group of organic compounds sharing a common functional group with the general structure -NH(CO)O-. Carbamate are esters of carbamic acid, NH2COOH. Since carbamic acid contains nitrogen attached to a carboxyl group, it is also a starch. Therefore, carbamate esters can have alkyl or aryl groups substituted on the hydrogen, or on the starch function. For example, ethyl carbamate is unsubstituted, while ethyl N-methylcarbamate has a methyl group attached to nitrogen.
[0038] As used herein, the term "nitro" refers to NO2.
As used herein, the term "aryl" refers to phenyl, substituted phenyl, naphthyl, and substituted naphthyl.
[0040] As used herein, the term "morpholine" refers to an organic chemical compound having the chemical formula O(CH2CH2)2NH. This heterocycle has characteristics of both the amine and ether functional groups. Due to the amine, morpholine is a base. Its acid conjugate is called morpholinium. For example, when morpholine is neutralized by hydrochloric acid, the morpholinium salt chloride is obtained.
[0041] As used herein, the term "thiomorpholine" refers to C4H9NS, and is a heterocycle compound containing nitrogen and sulfur. This can be considered a derivative of morpholine.
[0042] As used herein, the term "piperazine" refers to an organic compound consisting of a six-membered ring containing two opposite nitrogen atoms.
[0043] As used herein, the term "piperidine" refers to an organic compound with the molecular formula (CH2)5NH. This amine heterocycle consists of a six-membered ring containing five methylene units and one nitrogen atom.
As used herein, the term "acyl" refers to any of a group or radical of the form RCO- where R is an organic group.
As used herein, the term "furan" refers to any of a class of aromatic heterocycle compounds containing a ring of four carbon atoms and an oxygen atom; for example, C4H4O. As used herein, the term "nitrofuran" refers to a furan ring with a nitro group.
As used herein, the term "thiophene" refers to a heterocycle compound of formula C4H4S. Consisting of a flat five-membered ring, it is aromatic as indicated by its extensive substitution reactions. Related to thiophene are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one and two benzene rings, respectively. Thiophene analog compounds include furan (C4H4O) and pyrrole (C4H4NH).
[0047] As used herein, the term "imidazole" refers to an organic compound with the formula C3H4N2. This aromatic heterocycle is classified as an alkaloid. Imidazole refers to the parent compound while imidazoles are a class of heterocycles with similar ring structure but variant substituents. A nitroimidazole is an imidazole derivative that contains a nitro group.
[0048] As used herein, the term "oxazole" refers to a five-membered heterocycle having three carbon atoms, one oxygen atom, one nitrogen atom and two double bonds; the 1,3-isomer is aromatic.
[0049] As used herein, the term "oxazoline" refers to an unsaturated heterocycle compound containing a five-membered ring, two double bonds, one nitrogen and one oxygen atom; and any derivative of this compound.
[0050] As used herein, the term "thiazole" refers to any of a class of unsaturated heterocycle compounds containing a ring of three carbon atoms, a sulfur and a nitrogen atom; for example, the simplest, C3H3SN.
[0051] As used herein, the term "thiazoline" refers to an unsaturated heterocycle compound containing a five-membered ring, two double bonds, one nitrogen and one sulfur atom; and any derivative of this compound.
[0052] As used herein, the term "triazole" refers to any one of a pair of isomeric chemical compounds with the molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.
[0053] As used herein, the term "pyridine" refers to any one of a class of aromatic heterocycle compounds containing a ring of five carbon atoms and one nitrogen atom; for example, the simplest, C5H5N.
[0054] As used herein, the term "pyrazine" refers to a diazine in which the two nitrogen atoms are in the n-position.
As used herein, the term "naphthalene" refers to an aromatic, white, hydrocarbon solid having the formula C10H8 and the fused two-ring structure.
As used herein, the term "diketopiperazine" refers to a class of cyclic organic compounds that result from peptide bonds between two amine acids to form a lactam. They are the smallest possible cyclic peptides.
[0057] As used herein, the term "quinoline" refers to any of a class of aromatic heterocycle compounds containing a benzene ring fused to a ring of five carbon atoms and one nitrogen atom; for example, the simplest, C9H7N. Isoquinoline, also known as benzo[c]pyridine or 2-benzanine, is an aromatic organic heterocycle compound. This is a structural quinoline isomer. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to refer to isoquinoline derivatives.
[0058] As used herein, the term oxazolidinone refers to a class of heterocycle organic compounds containing both nitrogen and oxygen in a 5-membered ring.
[0059] As used herein, the term "heterocycle" refers to organic compounds containing at least one carbon atom, and at least one element other than carbon, such as sulfur, oxygen or nitrogen within a ring structure. These structures can comprise either simple aromatic rings or non-aromatic rings. Each monocyclic ring can be aromatic, saturated or partially unsaturated. A bicyclic ring system can include a monocyclic ring containing one or more heteroatoms fused to an aryl or cycloalkyl group. A bicyclic ring system can also include a monocyclic ring containing one or more heteroatoms fused to another monocyclic ring system.
Examples of "heterocycles" include but are not limited to pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3- pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 4-oxo-2-imidazolyl, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-ioxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5- oxazolyl, 1,2,3-oxthiazole, 1,2,3-oxidiazole, 1,2,5-oxadiazole, 2-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3-oxthiazol-1-oxide, 1,2,4- oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2, 4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4,-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5 -yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1.2 ,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-oxadiazole, 4-oxo-2-thiazolinyl, 5-methyl-1,3 ,4-thiadiazol-2-yl, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone, phthalimide, quinolinyl, morpholinyl, benzimidazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, diazinyl , triazinyl, quinolinyl, quinoxalinyl, naphthyridinyl, azetidinyl, pyrrolidinyl, hydantoinyl, oxathiolanil, dioxolanil, imidazolidinyl, azabicyclo[2.2.1]heptyl, 2-methyl-1,4dioxa-8-azaspiro[4.5]decane, 2,3 - dimethyl-1,4-dioxa-8-azaspiro[4.5]decane, 3-methyl-1,5-dioxa-9-azaspiro[5.5]undecane.
As used herein, the term "heteroaryl" refers to a mono or bicyclic het in which one or more cyclic rings are aromatic.
[0062] As used herein, the term "substituted heteroaryl" refers to a substituted heteroaryl moiety with one or more functional groups selected from halogen, alkyl, hydroxy, amino, alkoxy, cyano, and nitro.
[0063] As used herein, the term "substituted aryl" refers to an aryl moiety having 1-3 substituents selected from halogen, het, alkyl, substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, cyano, nitro, -OQ10, -SQ10, -S(O)2Q10, -S(O)Q10, -OS(O)2Q10, -C(=NQ10)Q10, -C(=NOQ10)Q10, - S(O)2-N=S(O)(Q10)2, -S(O)2-N=S(Q10)2, -NQ10Q10, -C(O)Q10, -C(S)Q10, -C(O)OQ10, - OC(O)Q10, -C(O)NQ10Q10, -C(S)NQ10Q10, -C(O)C(Q16)2OC(O)Q10, -NQ10C(O)Q10, - N(Q10)C(S)NQ10Q10, -N(Q10)C(S)Q10, -NQ10C(O)NQ10Q10, -S(O)2NQ10Q10, - NQ10S(O)2Q10, -NQ10S(O)Q10, -NQ10SQ10, and -SNQ10Q10. Het, cycloalkyl, cycloalkenyl, alkenyl, alkynyl and aryl being optionally substituted with 1-3 substituents selected from halogen and Q15.
[0064]Each Q10 is independently selected from H, alkyl, cycloalkyl, het, cycloalkenyl, and aryl. Het, cycloalkyl, cycloalkenyl, and aryl being optionally substituted with 1-3 substituents selected from halo and Q13.
[0065]Each Q11 is independently selected from H, halogen, alkyl, aryl, cycloalkyl, and het. The alkyl, aryl, cycloalkyl, and het being optionally substituted with 1-3 substituents independently selected from halogen, nitro, cyano, =S, =0, and Q14.
[0066] Each Q13 is independently selected from Q11, -OQ11, - SQ11, -S(O)2Q11, -S(O)Q11, -OS(O)2Q11, -C(=NQ11)Q11, -S (O)2-N=S(O)(Q11)2, -S(O)2-N=S(Q11)2, -SC(O)Q11, -NQ11Q11, -C(O)Q11, -C (S)Q11, -C(O)OQ11, -OC(O)Q11, - C(O)NQ11Q11, -(S)NQ11Q11, -C(O)C(Q16)2OC(O)Q10, -CN, =O, =S, -NQ11C(O)Q11, - NQ11C(S)Q11, -NQ11C(O)NQ11Q11, -NQ11C(S)NQ11Q11, -S(Q)2NQ11Q11, - NQ11S(O)2Q11, -NQ11S (O)Q11, -NQ11SQ11, -NO2, and -SNQ11Q11.
[0067] Each Q14 is independently selected from H, alkyl, cycloalkyl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, -OQ16, -SQ16 , -S(O)2Q16, - S(O)Q16, -OS(O)2Q16, -NQ16Q16, -C(O)Q16, -C(S)Q16, -C(O)OQ16, -NO2, - C(O)NQ16Q16, -C(S)NQ16Q16, -CN, -NQ16C(O)Q16, -NQ16C(S)Q16, - NQ16C(O)NQ16Q16, -NQ16C(S)NQ16Q16, -S(O)2NQ16Q16 , and -NQ16S(O)2Q16. Alkyl, cycloalkyl, and cycloalkenyl being further optionally substituted with =O or =S.
[0068] Each Q15 is independently selected from H, alkyl, cycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, - OQ16, -SQ16, -S(O)2Q16, -S(O)Q16, -OS(O)2Q16, -C(=NQ16)Q16, -S(O)2-N=S(O)(Q16) 2, -S(O)2- N=S(Q16)2, -SC(O)Q16, -NQ16Q16, -C(O)Q16, -C(S)Q16, -C(O)OQ16, -OC (O)Q16, - C(S)NQ16Q16, -C(O)C(Q16)2OC(O)Q16, -CN, -NQ16C(O)Q16, -NQ16C(S)Q16, - NQ16C(O)NQ16Q16 , -NQ16C(S)NQ16Q16, -S(O)2NQ16Q16, -NQ16S(O)2Q16, -NQ16S(O)Q16, -NQ16SQ16, -NO2, and -SNQ16Q16. The alkyl, cycloalkyl, and cycloalkenyl being further substituted with =O or =S.
[0069]Each Q16 is independently selected from H, alkyl, and cycloalkyl. Alkyl and cycloalkyl optionally include 1-3 halogens.
[0070] Characterizations of the present discovery provide new imidazopyridines, eg imidazo[1,2-a]pyridine. Certain embodiments are directed towards compounds and methods for the treatment and prevention of tuberculosis (TB). Other transpersonifications are directed towards compounds and methods for inhibiting fungal growth in plant species. In still other forms of embodiment, methods are provided for synthesizing the discovery of imidazo[1,2-a]pyridine compounds.
[0071] In embodiments, the imidazo[1,2-a]pyridine compounds of this discovery may be useful in treating or preventing tuberculosis in an individual. The in vitro activity of the discovered compounds can be assessed by standard testing procedures, for example, on H37Rv TB screens.
In embodiments, the imidazo[1,2-a]pyridine compounds described herein may be useful for treating (e.g., ameliorating or preventing) multi-drug resistant (MDR) and non-MDR TB in an individual. In an embodiment, the compound can be administered to an individual locally or systemically. In embodiments, an imidazo[1,2-a]pyridine compound can be administered parenterally, for example subcutaneously, intravenously, or intramuscularly, or it can be administered orally or by inhalation. An imidazo[1,2-a]pyridine compound can be used alone or in combination with other anti-tuberculosis agents. In one embodiment, the imidazo[1,2-a]pyridine compound can be administered in varying concentrations depending on the susceptibility of the infection to the compound being administered, the extent of the disease, whether the infection is latent or active, whether the infection is drug resistant, and the individual's general health.
[0073] In one embodiment, imidazo[1,2-a]pyridine compounds may be incorporated into a pharmaceutical composition. Personifications of the present disclosure encompass any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form or mixture of a compound of the disclosure which possesses the useful properties described herein.
[0074] In cases where the compounds are sufficiently bases or acids to form non-toxic acids or stable base salts, the use of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts within the scope of the embodiments herein include organic acid addition salts formed with salts which form a physiologically acceptable anion and inorganic salts.
[0075] Pharmaceutical compositions in accordance with the personifications of the discovery may be prepared by combining the discovered compounds with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions include powders, tablets, dispersible grains, capsules, pills and suppositories. A solid carrier can be at least one substance which can also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent. Insert solid carriers including magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, solutions of the compounds disclosed herein dissolved in water/propylene glycol systems, optionally containing conventional coloring agents, flavoring agents, stabilizers, and/or thickening agents, may be provided.
[0076] In one embodiment, a pharmaceutical composition may be provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of one or more active components. In embodiments, the amount of active ingredient (compound) in a pharmaceutical composition and dosage unit form thereof can be varied or adjusted widely depending on the particular application, the potency of the particular compound, and the desired concentration. In one embodiment, the amount of active component can range from 0.5% to 90% by weight of the composition.
[0077] In embodiments, therapeutic use for the treatment, alleviation, prevention, or combat of TB in individuals, the compounds or their pharmaceutical compositions can be administered orally, parenterally, and/or by inhalation at a dosage to obtain or maintain a concentration or blood level of an active component in the animal undergoing treatment that is therapeutically effective. In an embodiment, such a therapeutically effective amount/dosage of an active component may range from approximately 0.1 to approximately 100 mg/kg, for example, from approximately 0.1 to approximately 10 mg/kg, of body weight/day. It is to be understood that dosages may vary depending on the patient's requirements, the severity of the infection, the particular species of mycobacteria, whether the infection is latent or active, the drug resistance of the strain, the duration of the infection being treated , and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond above the upper level in order to quickly reach the desired blood level or the initial dosage may be less than ideal and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times a day.
[0078] In one embodiment, an imidazo[1,2-a]pyridine starting compound was provided and tested as an exemplary member of the novel imidazo[1,2-a]pyridine class of antituberculosis agents discovered herein. Such a compound is identified below as compound ND-8454, and the structure of the compound is shown in table 1. Imidazo[1,2-a]pyridine is a simple bicyclic compound with a nitrogen atom as a bridgehead. This class of molecules is unrepresented in the TB literature, and the framework is very attractive due to the low cost of the starting materials and the ease with which potent (<1 μg/mL) anti-TB compounds are synthesized from it.
[0079] Many of the existing clinical candidates for TB therapies are rivals to existing frameworks (eg moxifloxacin and gatifloxacin, see table 1), which result in drugs that are much more prone to emerging resistance. Other clinical candidates are complex compounds that are difficult and expensive to manufacture (eg, anti-TB candidates TMC207, PA-824, OPC-67683, and LL-3858, see Table 1).
[0080] In contrast, ND-8454, N-benzyl-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide, the initial linker based on the armature of imidazo[1,2-a]pyridine, it has an in vitro activity against TB H37Rv comparable to current clinical candidates (MIC = 0.08 μg/mL or 286 nM) and unobserved toxicity for VERO or HeLa cells (>128 and >50 μM, respectively). Table 1. Current clinical candidates for tuberculosis and ND-8454 (initial imidazo[1,2-a]pyridine ligand)

[0081] According to various embodiments, Table 2 illustrates the potency of several exemplary compounds against several individual single drug resistant TB strains.
[0082]Table 2. Potency of TB against single drug resistant strains (MIC90 in µM)

RMP = Rifampicin; INH - Isoniazid; KM = Kanamycin; SM = Streptomycin According to various embodiments, Table 3 illustrates the potency of several exemplary compounds against various multidrug-resistant (MDR) TB strains. Table 3. MDR-TB potency (MIC90 in μg/mL)

[0083] Abbreviations: H=Isoniazid, R=Rifampicin, E=Ethambutol, Z=Pyrazinamide, S=Streptomycin, C=Cycloserin, K=Kanamycin, P=para-aminosalicylic acid, Rb=Rifabutin, Th=Thioacetazone, *strains genetically different.
[0084] In personifications, the exemplary compounds described above can be synthesized according to the following general procedures. ND-8454, for example, can be made in readily available synthetic four steps from inexpensive reagents. To assess the availability and affordability potential of making this compound on a kilogram scale, the cost to scale up the ND-8454 using the following exemplary procedure was evaluated (see scheme 1, below). Diagram 1. Synthesis of ND-8454

[0085] Reagents: (a) 1,2-dimethoxyethane, reflux, 48 hours; (b) 1N LiOH, EtOH, reflux, 36 hours; (c) oxalyl chloride, CH 2 Cl 2 , DMF (cat.), room temperature, 4 hours; (d) benzylamine, Et3N, CH2Cl2, reflux, 14 hours
[0086] In this specific example of the synthesis of ND-8454, the solutions of 2-amino-4-picoline (10.0 g, 91.5 mmol) and ethyl-2-chloroacetoacetate (7.93 g, 45.8 mmol) were dissolved in 92 ml of 1 ,2-dimethoxyethane (DME) and heated for 36 h at reflux. The reaction mixture was filtered and solids (2-amino-4-picoline hydrochloride salt) were collected and washed with hexanes. The filtered liquid substance was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with 5% acetic acid solution (2x) and brine. The organic phase was collected, dried over sodium sulphate (Na2SO4), filtered and then concentrated in vacuo. The crude material obtained was purified by silica gel column chromatography with 20% ethyl acetate: CH 2 Cl 2 solvent system to give 7.8 g (78%) of ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3 - carboxylate as a solid tan mp 59-61°C; 1H NMR (300 MHz, CDCl3) 9.14 □ (d, J = 7.1 Hz, 1H), 7.34 (s, 1H), 6.78 (dd, J = 7.1, 1.7 Hz, 1H), 4.40 (q, J = 7.1, 7.1, 7.1 Hz, 2H), 2.66 (s, 3H), 2.42 (s, 3H), 1.42 (t, J = 7.1, 7.1 Hz, 3H). HRMS (EI), M+1 calculated for C12H15N2O2, 219.1155; found 219,1128. Retention time = 1.4 minutes (mobile phase: 60% water: acetonitrile). Ethyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate (6.4 g, 29.3 mmol) was dissolved in 75 ml of ethanol (95%), 1M LiOH (60 ml, 60 mmol) was added and the reaction was heated to reflux for 36 hours. The resulting solution was concentrated to dryness and then made acidic (pH~2-3) with the addition of 4N HCl; resulting solids were collected by filtration and rigorously dried to give 4.6 grams (82%) of 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid, an off-white solid. mp 180-183°C; 1H NMR (300 MHz, CD3OD) □□9.52 (d, J = 7.1 Hz, 1H), 7.73 (td, J = 1.8, 0.9, 0.9 Hz, 1H), 7.48 (dd, J = 7.1, 1.3 Hz, 1H) ), 2.81 (s, 3H), 2.63 (s, 3H). HRMS (EI), M+1 calculated for C10H11N2O2, 191.0815; found 191.0837. Retention time = 0.6 - 0.7 minutes (mobile phase: 60% water: acetonitrile).
2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylic acid (2.8 grams, 14mmol) was partially dissolved in 35 ml of anhydrous CH 2 Cl 2 and oxalyl chloride (3.3 ml, 39 mmol) was added followed by catalytic (20 µL) N'N-dimethylforamide (DMF).
[0088] The reaction was stirred under argon at room temperature for 4 hours. The clear, orange solution was concentrated to dryness and the resulting hydrochloric acid (3.6 grams, 14 mmol, yellow solid) was dissolved in 35 mL of anhydrous CH 2 Cl 2 . Triethylamine (5.9 ml, 41.9 mmol) and benzylamine (1.8 ml, 16.7 mmol) were added slowly. The reaction was heated at 50oC under argon for 16 hours. The reaction was then concentrated to dryness and the resulting solid was dissolved in ethyl acetate (EtOAc) and washed with saturated sodium bicarbonate solution (2x) and washed with brine.
[0089]The organics were collected and dried over Na2SO4, the drying agent was filtered off, and the organics were concentrated down to an oil which crystallized upon standing. The solid was purified through a column of silica gel eluting with a gradient of 1:10 (EtOAc : CH 2 Cl 2 ) to 10:1 (EtOAc : CH 2 Cl 2 ). 2.75 grams of N-benzyl-2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamide, (ND-8454, 70%) was obtained as an off-white solid. mp 166 - 167°C; 1H NMR (500 MHz, CDCl 3 ) □ 9.30 (d, J = 7.1 Hz, 1H), 7.39-7.28 (m, 5H), 7.25 (s, 1H), 6.75 (dd, J = 7.2, 1.8 Hz, 1H) , 6.05 (bs, 1H, NH), 4.69 (d, J = 5.7Hz, 2H), 2.65 (s, 3H), 2.41 (s, 3H). 13C NMR (126 MHz, CDCl 3 ) □□161.52, 146.54, 145.36, 138.30, 128.84, 127.67, 127.61, 127.35, 127.31, 115.72, 115.05, 43.42, 21.34, 16.83. HRMS (EI), M+1 calculated for C17H18N3O, 280.1444; found 280.1480. Retention time = 0.8 - 1.1 minutes (mobile phase: 60% water : acetonitrile).
[0090] In another embodiment, imidazo[1,2-a]pyridine compounds can be synthesized according to the general procedures shown in Scheme 2, below. Scheme 2: Imidazo[1,2-a]pyridine Chemistry

[0091]Reagents: (a) N-Z-succinimide, DMSO, room temperature, 4 hours, where Z=Bromine, Chlorine, or Iodine; (b) 1,2-dimethoxyethane, reflux, 48 hours; (c) 1N LiOH, EtOH, reflux, 36 hours; (d) oxalyl chloride, CH 2 Cl 2 , DMF (cat.), room temperature, 4 hours; (e) R-NH2 or R-OH, EDC-HCl, DMAP, CH3CN, 16 hours; when chloride (f) R-NH2 or R-OH, Et3N, CH2Cl2, 16 hours.
[0092] Figure 1 shows that ND-8454 can be made from readily available materials using the process described above. The active pharmaceutical ingredient can be obtained at a price range of $300-1000/kg in commercial scale. This translates to a remarkable cost of just $0.03-$0.1/day at a 100mg daily dose. Therefore, ND-8454 and similar imidazo[1,2-a]pyridine agents are very inexpensive to manufacture and can be readily made accessible to populations in need.
[0093] Embodiments of the present discovery also provide methods for treating or preventing TB infection in an individual using the compounds described herein. As used herein, the terms "tuberculosis" and "TB" refer to a mycobacterial infection, a common and frequent deadly infectious disease usually caused by Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs (like pulmonary TB), but it can also affect the central nervous system, lymphatic system, circulatory system, genitourinary system, gastrointestinal system, bones, joints, and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti also cause tuberculosis, but these species are less common in humans.
[0094] The classic symptoms of tuberculosis are a chronic cough with a smear of blood, fever, night sweats, and weight loss. Infection of other organs causes a wide range of symptoms. In some embodiments, a diagnosis of tuberculosis can be made by radiology (commonly chest x-ray), a tuberculin skin test, a blood test, as well as microscopic examination and microbiological culture of body fluids. Tuberculosis treatment is difficult and usually requires long courses of multiple antibiotics, and antibiotic resistance is a growing problem.
[0095] Approximately one third of the world population is infected with M. tuberculosis. However, most of these cases will not develop mature disease; asymptomatic, latent infection is more common. About one in ten of these latent infections will eventually progress to active disease, which, if left untreated, kills more than half of its victims. In 2004, mortality and morbidity statistics included 14.6 million chronic active cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries. In addition, an increasing number of people in the developed world are contracting tuberculosis due to compromised immune systems from immunosuppressive drugs, substance abuse, or AIDS. The distribution of tuberculosis is not uniform worldwide, with about 80% of the population in many Asian and African countries testing positive in tuberculin tests, while only 5-10% of the population in the United States of America tests positive. It is estimated that the United States of America has 25,000 new cases of TB each year, 40% of which occur in immigrants from countries where TB is endemic.
[0096] An estimated 75% of active TB cases involve pulmonary TB. Symptoms include chest pain, coughing up blood, a productive, prolonged cough for more than three weeks, fever, chills, night sweats, loss of appetite, weight loss, pallor, and frequent tendency to fatigue very easily. In the other 25% of active cases, the infection moves from the lungs, causing extrapulmonary tuberculosis. This most commonly occurs in immunosuppressed people and younger children. Extrapulmonary sites of infection include the pleura in tu berculosis pleurisy, the central nervous system in meningitis, the lymphatic system in the scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious form is disseminated TB, more commonly known as military tuberculosis. Although extrapulmonary TB is not contagious, it can coexist with pulmonary TB, which is contagious.
[0097] The primary cause of TB, Mycobacterium tuberculosis, is an aerobic, Gram-positive bacterium. In addition, the M. tuberculosis complex includes three TB-causing mycobacteria: M bovis, M. africanum and M. microti. M africanum is not widespread, but in parts of Africa it is a significant cause of tuberculosis. M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has largely eliminated this as a public health problem in developed countries. M. microti is mostly seen in immunodeficient people, although it is possible that the prevalence of this pathogen has been underestimated.
[0098]Other known pathogenic mycobacteria include Mycobacterium le prae, Mycobacterium avium and M. kansasii. The last two are part of the non-tuberculous mycobacteria (NTM) group. Non-tuberculous mycobacteria neither cause TB nor leprosy, but they cause TB-like lung disease.
[0099] Polymorphisms of specific genes in IL12B have been associated with tuberculosis susceptibility. Additionally, patients with diabetes mellitus are at increased risk of contracting tuberculosis, and they have a worse response to treatment, possibly due to poorer drug absorption. Other conditions that increase the risk include IV drug abuse; recent TB infection or a history of inadequately treated TB; chest X-rays suggestive of anterior TB, showing fibrotic lesions and nodules; silicosis; prolonged corticosteroid therapy and other immunosuppressive therapy; head and neck cancers; hematologic and reticuloendothelial diseases such as leukemia and Hodgkin's disease; end-stage kidney disease, intestinal bypass or gastrectomy; chronic malabsorption syndromes; vitamin D deficiency; and low body weight. In addition, some drugs, including drugs for rheumatoid arthritis that work by blocking tumor necrosis factor alpha, increase the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB. In personifications, an individual having one or more of these risk factors may be a suitable candidate for effective therapies that treat or prevent TB.
[00100] As discussed above, compounds conforming to embodiments of the present discovery are designed to exhibit antiTB activity. Method doses are provided, in some embodiments, for treating or preventing tuberculosis in an individual. Briefly, the method includes selecting an individual in need of treatment and administering to the individual a therapeutically effective amount of at least one compound having the formula:
or a pharmaceutically acceptable salt thereof. According to the personification, R1 = alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or heterocycle, where R1 is mono or poly substituted; R2 = alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or heterocycle, where R2 is mono or poly substituted; R3 = H, alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, acyl, substituted acyl, haloacyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or heterocycle, where R3 is mono or poly substituted, where R3 is not a methyl ester, ethyl ester, t-butyl ester, or thiazoline; and Y = CH or N anywhere in positions 5, 6, 7 or 8.
[00101] In an embodiment, another compound may have the formula: or a pharmaceutically acceptable salt thereof. According to the personification, R1 = alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or heterocycle, where R1 is mono or poly substituted; R2 = alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, where R2 is mono or poly substituted; Y = CH or N anywhere in positions 5, 6, 7, or 8; R4 = OR1, NHR1, NR1R2, NHNR1, or NHOR1.
[00102] In specific non-limiting examples, compounds may have the formula:
where: (a)R1 = 7-CH3, R2 = CH3, R4 = (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine (ND-9902); (b)R1 = 7-CH3, R2 = CH3, R4 = 4-(4-(trifluoromethyl)phenoxy)aniline (ND-9903); (c)R1 = 7-CH3, R2 = CH3, R4 = 4-(4-fluorophenoxy)benzylamine (ND-9758); (d)R1 = 7-CH3, R2 = CH3, R4 = (3-ethoxy)benzylamine (ND-9906); (e)R1 = 7-CH3, R2 = CH3, R4 = (3-isopropoxy)benzylamine (ND-9872); or (f)R1 = 6-CH3, R2 = CH3, R4 = (4-methylsulfonyl)benzylamine (ND-9965).
[00103] In personifications, when examined in vitro, it was apparent that imidazo[1,2-a]pyridine had advantages over other previously evaluated anti-TB heterocycles. For example, while the potency levels of the ester analogues (notably, benzyl and ethyl) were good in several heterocycle series (oxazolines, oxazoles, thiazolines, thiazoles and imidazo[1,2-a]pyridine, these esters were me- While the corresponding starches were anticipated to be more stable, their antiTB activities were drastically decreased, except for the benzylic imidazo[1,2-a]pyridine starches (NHCH2Ph), which were more potent. , the stability of imidazo[1,2-a]pyridine analogues in microsomes from rats, dogs and humans was vastly improved (>80% remained after a 15 minute incubation).Furthermore, unlike other heterocycle scaffolds, imidazos [1,2-a]pyridines were remarkably metabolically stable in a sham gastric juice test (>90% remains ceramin after a 15 minute incubation.
[00104] In other embodiments, imidazo[1,2-a]pyridine analogues have been generated and optimized using in vitro SAR studies to improve potency, metabolism, organism selectivity and formulation. Briefly, a set of imidazo[1,2-a]pyridine analogues were prepared and subjected to an organism selectivity and metabolism profile. Figure 2 shows the SAR of particular imidazo[1,2-a]pyridine agents and some trends observed from the screening of compounds. (See Figure 4 for the structures of the compounds referenced in Figure 2). The VERO test is a toxicity test that measures the viability of the kidney epithelial cells of an African Green Monkey when treated with the compounds being studied. The other tests include three TB H37Rv screens that differ only from the medium used: GAS for glycerol-alanine salts with ferric ammonium citrate, GAST for glycerol-alanine salts with Tween 80 instead of ferric ammonium citrate, and 7H12, the which is a non-glycerol containing medium. The microsomes were from male Sprague-Dawley rats and contained drugs that metabolize enzymes such as cytochrome P450, flavin monooxygenase, and UDP glucuronyl transferase. The simulated gastric juice test contained pepsins, and was run at pH~1.2.
[00105] In personifications, the compounds ND-8448, ND-8451 and ND-8454 were all screened against a panel of diverse organisms which included four Gram-positive strains (Bacillus subtilis, Staphylococcus aureus, MRSA Staphylococ cus aureus, VRE Enterococcus Faecalis), two Gram-negative strains (E. coli, Pseudomonas aeruginosa), one yeast (Sporobolomyces salmonicolor) and fungi (Candida albicans and Penicillium notatum), as well as five pink cance cell lines (Huvec, K-562, HeLa , PC-3 and MCF-7) and the VERO cell line to check for mammalian toxicity. Notably, these three compounds were inactive against all control organisms studied.
[00106] In one embodiment, an assessment may involve screening for imidazo[1,2-a]pyridines against TB H37Rv in at least two different test media, eg GAST (glycerol-alanine salts with Tween 80) and 7H12 (non-glycerol containing medium), to ensure potency is not adversely affected by either glycerol or Tween and is not dependent on a carbon source. Compounds that have a MIC of less than 5 µM are then screened in the VERO cell toxicity and TB LORA recovery test (a test designed to simulate the latent state of TB). The most impressive compounds that possess exceptional potency (MIC <1 μM) and a large therapeutic window (IC50 >128 μM in the VERO test) are then evaluated in rat microsomes and simulated gastric juices.
[00107] In one embodiment, compounds ND-8454, ND-8667, and ND9361 were all screened against a panel of TB strains with extreme resistance to the drug HRESPOCTh, HREPKOTh, HRESPO, and then cross screened against M. smegmatis. As illustrated below in Table 4, all three drugs were effective against strains with extreme drug resistance (XDR). Table 4: XDR-TB activity of imidazopyridine agents (MIC90 values in μg/mL)

[00108]Abbreviations: H=Isoniazid, R=Rifampicin, E=Ethambutol, Z=Pyrazinamide, S=Streptomycin, C=Cycloserin, Th=Ethionamide, K=Kanamycin, P=para-aminosalicylic acid, Rb=Rifabutin, Th= Thioacetazone, O=Ofloxacin.
[00109] In another embodiment, compounds ND-8454, ND-9652, ND-9758, ND-9872, ND-9902, ND-9903, and ND-9965 were screened against various non-tuberculous mycobacteria (NTM). As illustrated below in Table 5, all seven drugs were effective against M. avium, M. bovis BCG and M. kansasii and other non-tuberculous mycobacterial strains to a lesser extent, indicating that the imidazo[1,2-a]pyridines anti-aging agents -selective mycobacterials.
[00110]Table 5: NTM activity of imidazopyridine agents (MIC90 in µM)

[00111]As discussed above, impersonations provide a method for treating or preventing TB. The method includes selecting a subject in need of treatment and administering to the subject a therapeutically effective amount of at least one compound disclosed herein. As used herein, the term "therapeutically effective amount" includes the amount of a specific compound (such as one of the imidazo[1,2-a]pyridine compounds discovered herein, e.g. compound ND-8454) required to achieve an effect. desired in an individual being treated. For example, this may be the amount needed to treat a mycobacterial infection, such as a Mycobacterium tuberculosis, M. bovis, M. africanum, or M. microti infection in an individual, or the dose sufficient to prevent advancement, or to cause regression of the disease (such as TB), or being able to alleviate symptoms caused by the disease, pulmonary or extrapulmonary symptoms. In some embodiments, a therapeutically effective amount of an imidazo[1,2-a]pyridine compound is the dose that is sufficient to inhibit progression from latent to active TB, or to prevent reactivation of a TB infection. .
[00112] Various dosage ranges and times of administration can be adopted for the therapeutic treatment of TB in animal or human subjects with the anti-TB agents discovered herein. In an embodiment, such a therapeutically effective amount of active ingredient may be in the range of from about 0.1 to about 100 mg/kg, or more preferably about 0.1 to about 10 mg/kg, of body weight/day. Such dosages may vary depending on the patient's requirements, the severity of the disease, the duration of the disease, whether the infection is latent or active, the mycobacterial strain, whether the mycobacterium exhibits drug resistance, or particular symptoms (eg, pulmonary or extrapulmonary) of the TB being treated, and the particular compound being used. In some embodiments, the anti-TB agent may be administered in conjunction with one or more other anti-TB agents, such as rifampicin, isoniazid, pyrazinamide, ethambutol, streptomycin, ethionamide, kanamycin, cycloserine, thioacetazone, para-aminosalicylic acid, or ciprofloxacin.
[00113] In some embodiments, the anti-TB agent (eg, ND-8454) may be administered systematically, whereas in other embodiments, the anti-TB agent may be administered locally. An effective dose of a discovered anti-TB agent can be administered systematically in a variety of ways. For example, systemic administration can be by oral administration or by injection, by intravenous, intramuscular, or subcutaneous injections. Local administration (eg pulmonary) may include inhaled administration. By way of example, one method of administration to an individual's lungs may be by inhalation through the use of a nebulizer or inhaler. For example, the anti-TB agent can be formulated into an aerosol or particulate and drawn into the lungs using a standard nebulizer well known to those skilled in the art.
An effective amount of an anti-TB compound can be administered as a single dose, or in multiple doses, for example daily, or every four, eight, or twelve hours during the course of treatment. In one embodiment, a therapeutically effective amount of an anti-TB compound can be administered as a single pulse dose, as a bolus dose, or as pulse doses given overtime. In specific, non-limiting examples, boost doses of an anti-TB compound may be administered over the course of a day over the course of a week, over the course of a month, or over a course of years.
[00115] In other embodiments, the imidazo[1,2-a]pyridine compounds discovered herein are used to inhibit fungal growth in plant species. In personifications, the imidazo[1,2-a]pyridine compound may have the formula:
or a pharmaceutically acceptable salt thereof, where R 1 = alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or heterocycle, where R 1 is mono or poly substituted; R2 = alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, where R2 is mono or poly substituted; R3 = H, alkyl, substituted alkyl, cycloalkyl, functionalized alkyl, cycloheteroalkyl, acyl, substituted acyl, haloacyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or heterocycle, where R2 is mono or poly substituted, and where R3 is not a methyl ester, and Y = CH or N anywhere in the 5, 6, 7, or 8 positions. Other embodiments are fungicidal compositions comprising at least one imidazo[1,2-a]pyridine compound and a phytologically acceptable carrier . Still other embodiments are antifungal formulations which further include at least one additional compound selected from the group consisting of insecticides, and herbicides.
[00116]Other personifications are methods to control a fungal infestation. The methods can include, for example, the steps of providing at least one imidazo[1,2-a]pyridine compound as described above and applying the compound to a surface having or adjacent to a fungal infection or infestation. In personifications, the composition can include at least one additional compound selected from the group consisting of: insecticides, fungicides, and herbicides. Also discovered are methods for controlling a fungal infestation. In embodiments, the methods can include the steps of: providing at least one imidazo[1,2-a]pyridine compound as described herein and applying the compound to a surface having or adjacent to a fungal infection or infestation.
[00117] In embodiments, the imidazo[1,2-a]pyridine compounds described herein may have a significant fungicidal effect, particularly in agricultural applications, for example, for use in agricultural crops and horticultural plants. In various embodiments, the imidazo[1,2-a]pyridine compounds described herein can be used to effectively control a variety of unwanted fungi that infect crops of useful plants. In specific, non-limiting examples, antifungal activity has been demonstrated, for example against the following representative species of fungi: wheat leaf rust (Puccinia recondita tritici - PUCCRT) and wheat speckled spot (Septoria tritici - SEPTTR).
[00118]Referring to Figure 3, exemplary imidazo[1,2-a]pyridine compounds were tested in order to measure their abilities to prevent fungal infections. (Figure 4 illustrates the structures of the compounds referenced in Figure 3). In embodiments, each preventive property of the exemplary compounds was determined by treating a susceptible test plant with the exemplary imidazo[1,2-a]pyridine compound and then exposing the plant to fungal spores. The antifungal activity of imidazo[1,2-a]pyridine compounds was determined by determining the extent to which fungal disease was controlled. Compounds were formulated at rates of 200 ppm in 10vol.% acetone plus 90vol.% Triton X water (99.99 wt% deionized water 9 0.01 wt% Triton X100), giving a “formulated test compound ”. Formulated test compounds were applied to plants using a turntable sprayer equipped with two opposing atomizing nozzles that emitted approximately 1500 L/ha of spray volume.
[00119] All test plants were inoculated with fungal spores (eg PUCCRT or SEPTTR) on the day after treatment with the putative fungicide. Then, the plants were incubated in an environment favorable to the development of the disease. Disease severity was assessed from 7 to 25 days later, depending on the speed of disease development.
[00120] In a specific, non-limiting example, wheat plants (variety "Yuma") were grown from the seeds in a pot mix without a peat base soil (Metromix) until the seedlings had a fully fledged first leaf. expanded. Each pot contained 3-8 seedlings. These plants were sprayed until wet with the formulated test compounds. The next day, the leaves were inoculated with an aqueous suspension of Puccinia recondita tritici spores and the plants were kept in high humidity overnight to allow the spores to germinate and infect the leaf. The plants were then transferred to a greenhouse until the disease developed into untreated control plants. These tests were conducted at a level of 200 ppm, see example, Figure 3.
[00121] In another specific, non-limiting example, wheat plants (variety "Yuma") were grown from seeds in a 50% pasteurized soil and 50% soilless mixture until the seedlings had a fully expanded first leaf. Each pot contained 3-10 seedlings. These plants were sprayed until wet with the formulated test compound. The next day, the leaves were inoculated with an aqueous suspension of Septoria tritici spores and the plants were kept in high humidity (one day in a dark condensation chamber followed by three days in a lighted condensation chamber) to allow for the spores. to germinate and infect the leaf. The plants were then transferred to a greenhouse until the disease developed into untreated control plants. These tests were conducted at a level of 200 ppm, see example, Figure 3.
[00122] In personifications, disease control was determined by visually estimating the percentage of disease severity in treated and untreated vessels 7 to 24 days after inoculation, depending on the rate of disease development. Assessments were typically made 7 or 8 days after PUCCRT inoculation and 18 to 22 days after SEPTTR inoculation. The percentage of disease control (%DC) was calculated by: %DC = (1-% of the severity of the disease treated/% of the severity of the untreated disease)*100.
In various embodiments, the imidazo[1,2-a]pyridine compounds described herein can be applied in the form of a composition comprising one or more imidazo[1,2-a]pyridine compounds with a phytologically acceptable carrier. Compositions can include, for example, concentrate formulations which are dispersed in water or other liquid for application, or powder or granular formulations which are applied without further treatment. The compositions can be prepared according to procedures that are conventional in the art of agricultural chemistry.
[00124] The dispersions to which the imidazo[1,2-a]pyridine compounds are applied may be, in some examples, aqueous suspensions or emulsions prepared from concentrated formulations of the compounds. As water-soluble, water-suspensible, or emulsifiable formulations being either solid, usually known as wettable powders, or liquid, usually known as emulsifiable concentrates, or aqueous suspensions. In personifications, any material to which the imidazo[1,2-a]pyridine compounds can be added may be used, provided it provides the desired utility without significant interference with the fungal activity of the imidazo[1,2-a compounds ]pyridine.
[00125] In embodiments, wettable powders, which can be compacted to form water-dispersible granules, may include an intimate mixture of the active compound imidazo[1,2-a]pyridine, an inert carrier, and one or more surfactants. tes. The concentration of the imidazo[1,2-a]pyridine compound can be, for example, from about 10 percent weight/weight (%w/w) to about 90% %w/w, and can be from about 10 percent w/w. from approximately 25% to approximately 75% w/w in particular examples. In preparing exemplary wetting powder compositions, the active ingredients can be compounded with any finely divided solid, such as pyrophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, clays. montmorillonite, diatomaceous earth, purified silica, and the like. In such examples, the finally divided carrier can be grounded or mixed with the toxic substance in a volatile organic solvent. Specific, non-limiting examples of effective surfactants, for example, comprise from approximately 0.5% to approximately 10% of the wettable powder, which can be used in combination with the created compounds, including sulfonated lignins, naphthalenesulfonates, alkylbenzenesulfonates, allyl sulfates, and nonionic surfactants such as ethylene oxide adduct of alkylphenols.
[00126] In various embodiments, emulsifiable concentrates of imidazo[1,2-a]imidazo compounds disclosed herein may comprise a convenient concentration, such as from approximately 10% to approximately 50% w/w, in a liquid adequate. Briefly, an exemplary method for creating such emulsions includes the step of dissolving the compound in an inert carrier (eg, either a water-miscible solvent or a mixture of water-immiscible organic solvents or emulsifiable). In specific embodiments, concentrates can be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Specific, non-limiting examples of organic solvents that can be used include aromatics, especially the olefinic and naphthalene moieties of high boiling petroleum such as heavy aromatic naphtha and the like. In other embodiments, other organic solvents can be used, such as terpenic solvents, for example, resin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols such as 1-ethoxyethanol.
[00127] In some embodiments, emulsifiers can be used, for example, non-ionic, anionic, cationic, and amphoteric emulsifiers, or a mixture of two or more emulsifiers. Specific, non-limiting examples of nonionic emulsifiers useful in preparing emulsifiable concentrates include polyalkylene glycol ethers and alkyl condensation products, and aryl phenols, aliphatic alcohols, aliphatic amines, or fatty acids with ethylene oxide, propylene oxides such such as ethoxylated alkylphenols, and carboxylic esters solubilized with polyol or polyoxyalkylene. Specific, non-limiting examples of cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Specific, non-limiting examples of anionic emulsifiers include the oil-soluble salts (eg, calcium) of alkyl aryl sulfonic acids, oil-soluble salts of sulfated polyglycol ethers, and appropriate salts of phosphated polyglycol ether.
[00128] Specific, non-limiting examples of organic liquids that can be used in the preparation of emulsifiable concentrates include aromatic liquids such as xylene, propylbenzene fractions, or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as phthalate dioctyl, kerosene, dialkyl amides of various fatty acids; particularly the dimethyl amides of fatty glycols and glycol derivatives such as n-butyl ether, ethyl ether, or triethylene glycol methyl ether. In some embodiments, mixtures of two or more organic liquids may be used to prepare an emulsifiable concentrate. Specific, non-limiting examples of organic liquids that can be used include propylbenzene and xylene fractions. In specific, non-limiting examples, surface active dispersing agents can be used in liquid compositions in an amount from approximately 0.1 of the body percent (wt. %) to approximately 20 (wt. %) of the combined weight of the agent dispersive and active compound. In embodiments, imidazo[1,2-a]pyridine compositions may also contain compatible additives, for example plant growth regulators and other biologically active compounds used in agriculture.
[00129] According to various embodiments, aqueous suspensions may include suspensions of water-insoluble imidazo[1,2-a]pyridine compounds, dispersed in an aqueous vehicle at a concentration ranging from approximately 5% to approximately 50 %w/w. In a specific, non-limiting example, the suspension can be prepared by finely grinding the compound and mixing it vigorously into a vehicle including water and surfactants as discussed above. In embodiments, inert ingredients, such as organic salts and synthetic or natural resins, can also be added, for example, to increase the density and viscosity of the aqueous vehicle. In particular embodiments, it is effective to grind and mix the compound at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
[00130] In other embodiments, the imidazo[1,2-a]pyridine compounds can be applied as granular compositions, which are particularly useful when applying the composition to soil. Specific, non-limiting examples of granular compositions may include from about 0.5% w/w to about 10% w/w of the compound dispersed in an inert carrier that includes entirely or a large coarsely divided portion of an attapulgite, bentonite, diatomite, clay, or a similar inexpressive substance. Such compositions can be prepared, for example, by dissolving the compound in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, for example, in the range of approximately 0.5 to approximately 3 mm. In various embodiments, such compositions can also be formulated by making a mass or paste of the carrier and compound, and crushing, and drying to obtain the desired granular particle.
[00131] In other embodiments, powders which include the imidazo[1,2-a]pyridine compounds can be prepared by intimately mixing the compound in powder form with a suitable powdered agricultural carrier such as, for example, air kaolin gila, volcanic rock soil, and the like. In specific, non-limiting examples, such powders may include from approximately 1% w/w to approximately 10% w/w of the compound.
[00132] According to various embodiments, imidazo[1,2-a]pyridine compositions may contain adjuvant surfactants to improve properties such as deposition, wetting, and penetration of the compositions into target cultures and organisms. In embodiments, these adjuvant surfactants can be employed as a component of the formulation or as part of a tank mix. The amount of adjuvant surfactant can vary, in specific, non-limiting examples, from approximately 0.01 percent to approximately 1.0% volume/volume based on a volume of spray water. In particular embodiments, the amount of adjuvant surfactants can be, for example, from approximately 0.05% to approximately 0.5% volume/volume. Specific, non-limiting examples of adjuvant surfactants include ethoxylated nonyl phenols, synthetic ethoxylate or natural alcohols, salts of the sulfosuccinic acid esters, ethoxylated organosilicones, ethoxylated fatty amines, and mixtures of surfactants with mineral or vegetable oils.
[00133] In embodiments, imidazo[1,2-a]pyridine compositions may include combinations that include, for example, at least 1% of one or more imidazo[1,2-a]pyridine compounds with another agriculturally active ingredient (AI). Such additional AI may include, for example, fungicides, insecticides, nematicides, acaricides, arthropodicides, bactericides, herbicides, or combinations thereof that are compatible with the imidazo[1,2-a]pyridine compounds in selected application media . Suitably, in such embodiments, the other AI is employed as a supplemental AI for the same or a different use with plants than the created compounds. In specific, non-limiting examples, the compounds in combination may generally be present in a ratio from approximately 1:10 to approximately 100:1.
[00134]Other personifications are methods for controlling or preventing a fungal infection. These methods may include applying active imidazo[1,2-a]pyridine compounds to the locus of fungi, or to a locus in which infestation is to be prevented (eg, by applying them to a cereal or plant). of grape). In personifications, imidazo[1,2-a]pyridine compounds can be used to treat various plants at fungicidal levels while exhibiting low phytotoxicity. Also, in personifications, the compounds can be used as a protector or eradicant. In embodiments, such compounds can be applied by any of a variety of known techniques, either as compounds or as compositions including the compounds. For example, the compounds can be applied to the roots, seeds, or foliage of plants to control various fungi without damaging the commercial value of the plants. In embodiments, the materials are applied in the form of any of the commonly used formulation types, for example, as solutions, powders, wettable powders, concentrated fluids, or emulsifiable concentrates.
[00135] As described above, in personifications, imidazo[1,2-a]pyridine compounds have significant fungicidal effects, particularly for agricultural use. In particular embodiments, imidazo[1,2-a]pyridine compounds are effective for use with agricultural crops and horticultural plants, or for the prevention or treatment of fungal growth on other materials such as wood, paint, leather , or carpet backing.
[00136] In particular embodiments, imidazo[1,2-a]pyridine compounds can effectively control a variety of unwanted fungi that infect crops of useful plants. In specific embodiments, imidazo[1,2-a]pyridine compounds may have activity against a variety of fungi, including, for example, the following representative species of fungi: grape downy mildew (Plasmopara viticola - PLASVI), late blight tomato (Phytophthora infestants - PHYTIN), apple scab (Venturia inaequalis - VENTIN), wheat leaf rust (Puccinia recondita tritici - PUCCRT), wheat linear rust (Puccinia strii-formis - PUCCST), rice blast (Pyricularia oryzae - PYRIOR), cercospora beetroot (Cercospora beticola - CERCBE), wheat powdery mildew (Erysiphe graminis - ERYSGT), wheat speckled blotch (Septoria tritici - SEPTTR), rice water rot (Rhizoctonia solani - RHIZSO), wheat stain wheat leaves (Pseudocercosporella herpotrichoides - PSDCHE), peach brown rot (Monilinia fructicola - MONIFC), and wheat glume spot (Leptosphaeria nodorum - LEPTNO).
[00137] In personifications, the amount of imidazo[1,2-a]pyridine compound applied for the particular use may depend or not only on the specific active material being applied, but also on the particular desired action, from the fungal species to be controlled, and the stage of its growth, as well as the part of the plant or other product to be contacted with the active ingredient.
[00138] Although certain impersonations have been illustrated and described here, it will be appreciated by those of ordinary skill in the art that a wide variety of alternate and/or equivalent impersonations or implementations calculated to achieve the same ends can be replaced by the impersonations shown and described without departing from the scope. Those with skill in the technique will easily appreciate that impersonations can be implemented in a very wide variety of ways. This application is intended to cover any adaptations or variations of the personifications discussed here. Therefore, it is manifestly intended that personifications are limited only by claims and their equivalents.

权利要求:
Claims (28)
[0001]
1. Compound, CHARACTERIZED by the fact that it has the following formula or a pharmaceutically acceptable salt thereof:
[0002]
2. Compound according to claim 1, CHARACTERIZED by the fact that R1 is halogen or methyl, and R2 is methyl or ethyl.
[0003]
3. Compound according to claim 1, CHARACTERIZED by the fact that R1 is chlorine, and R2 is ethyl.
[0004]
4. Compound according to claim 1, CHARACTERIZED by the fact that R1 is methyl, and R2 is methyl.
[0005]
5. A compound according to claim 1, CHARACTERIZED by the fact that R 1' is methyl substituted with 1 to 4 optionally substituted substituents selected from the group consisting of heteroaryl, cycloalkyl, cycloalkenyl, and aryl.
[0006]
6. Compound, according to claim 1, CHARACTERIZED by the fact that it has the following formulas:
[0007]
7. A compound according to claim 1, CHARACTERIZED by the fact that R 1' is methyl substituted with optionally substituted aryl.
[0008]
8. Compound according to claim 7, CHARACTERIZED by the fact that aryl is substituted with 1 to 3 substituents selected from halogen, heterocycle, alkyl, substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, cyano, and nitro, wherein the heterocycle, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, and aryl are optionally substituted with 1 to 3 substituents selected from those of halogen and Q15; wherein each Q15 is independently selected from H, alkyl, cycloalkyl, heteroaryl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, -OQ16, - SQ16, - S(O)2Q16, -S(O)Q16, -OS(O)2Q16, -C(=NQ16)Q16, -S(O)2-N=S(O)(Q16)2, - S(O)2- N=S(Q16)2, -SC(O)Q16, -NQ16Q16, -C(O)Q16, -C(S)Q16, -C(O)OQ16, -OC(O) Q16, - C(S)NQ16Q16, -C(O)C(Q16)2OC(O)Q16, -CN, -NQ16(O)Q16, -NQ16C(S)Q16, - NQ16C(O)NQ16Q16, -NQ16C (S)NQ16Q16, -S(O)2NQ16Q16, -NQ16S(O)2Q16, - NQ16S(O)Q16, -NQ16SQ16, -NO2, and -SNQ16Q16, wherein the alkyl, cycloalkyl, and cycloalkenyl being further substituted with =O or =S; and wherein each Q16 is independently selected from H, alkyl, and cycloalkyl; wherein the alkyl and cycloalkyl are optionally substituted with 1 to 3 halogens.
[0009]
9. Compound according to claim 8, CHARACTERIZED by the fact that aryl is phenyl substituted with two substituents.
[0010]
A compound according to claim 9, characterized in that the phenyl is substituted with fluorine and an optionally substituted heterocycle.
[0011]
11. Compound according to claim 10, CHARACTERIZED by the fact that the heterocycle contains two nitrogens.
[0012]
12. Compound according to claim 11, CHARACTERIZED by the fact that the heterocycle is substituted with a substituent.
[0013]
13. Compound according to claim 12, CHARACTERIZED by the fact that the heterocycle is substituted with Q15.
[0014]
14. Compound according to claim 13, CHARACTERIZED by the fact that Q15 is optionally substituted phenyl.
[0015]
15. Compound according to claim 14, CHARACTERIZED by the fact that phenyl is substituted with trifluoromethyl.
[0016]
A compound according to claim 8 CHARACTERIZED in that aryl is phenyl substituted with one substituent.
[0017]
17. Compound according to claim 16, CHARACTERIZED by the fact that the phenyl is substituted with an optionally substituted heterocycle.
[0018]
18. A compound, according to claim 17, CHARACTERIZED by the fact that the heterocycle is optionally substituted piperidine.
[0019]
19. A compound according to claim 18, CHARACTERIZED by the fact that piperidine is substituted with a substituent.
[0020]
20. The compound according to claim 19, CHARACTERIZED by the fact that piperidine is substituted with Q15.
[0021]
21. A compound, according to claim 20, CHARACTERIZED by the fact that Q15 is optionally substituted phenyl.
[0022]
22. Compound according to claim 21, CHARACTERIZED by the fact that the phenyl is substituted with a substituent.
[0023]
23. Compound according to claim 22, CHARACTERIZED by the fact that phenyl is substituted with -OQ16.
[0024]
24. Compound according to claim 23, CHARACTERIZED by the fact that Q16 is alkyl optionally substituted with 1 to 3 halogens.
[0025]
25. Compound according to claim 24, CHARACTERIZED by the fact that Q16 is methyl optionally substituted with 1 to 3 halogens.
[0026]
26. Compound according to claim 25, CHARACTERIZED by the fact that Q16 is methyl substituted with 1 to 3 halogens.
[0027]
27. Compound according to claim 26, CHARACTERIZED by the fact that Q16 is methyl substituted with 3 halogens.
[0028]
28. Compound according to claim 27, CHARACTERIZED by the fact that Q16 is methyl substituted with 3 fluorine.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112012010752B1|2021-07-20|IMIDAZO[1,2-A]PYRIDINE COMPOUNDS

---

EP1910360B1|2010-03-03|Hiv reverse transcriptase inhibitors

---

TWI282335B|2007-06-11|A61k 31/437 200601 a i vhtw a61p 31/04 200601 a i vhtw

---

US20090192127A1|2009-07-30|Combination therapy comprising a diaryl urea compound and a p13, akt kinase or mtor inhibitors | for cancer treatment

---

Khalil2010|Efficient synthesis of novel 1, 2, 4-triazole fused acyclic and 21–28 membered macrocyclic and/or lariat macrocyclic oxaazathia crown compounds with potential antimicrobial activity

---

US20080045589A1|2008-02-21|Drug Combinations with Substituted Diaryl Ureas for the Treatment of Cancer

---

DE69814049T2|2004-02-19|SUBSTITUTED BENZIMIDAZOLES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

---

US20090306020A1|2009-12-10|Combination therapy comprising diaryl ureas for treating diseases

---

EP2089380B1|2016-06-29|Substituted dihydropyrazolones and use thereof as hif-prolyl-4 -hydroxylase inhibitors

---

HUE035557T2|2018-05-02|Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

---

TW200831503A|2008-08-01|Chemical compounds

---

EP2097404A1|2009-09-09|Substituted dipyridyl-dihydropyrazolones and use thereof

---

MX2012011379A|2012-11-30|Non-nucleoside reverse transcriptase inhibitors.

---

Er et al.2019|Novel substituted benzothiazole and Imidazo [2, 1-b][1, 3, 4] Thiadiazole derivatives: Synthesis, characterization, molecular docking study, and investigation of their in vitro antileishmanial and antibacterial activities

---

JP2014509616A|2014-04-21|Therapeutic imidazo [1,2-a] pyridine compounds

---

Kamal et al.2006|Anti-tubercular agents. Part 3. Benzothiadiazine as a novel scaffold for anti-Mycobacterium activity

---

CN109890388A|2019-06-14|MAChR M4Positive allosteric modulators

---

Metwally et al.2019|Design, synthesis, DNA assessment and molecular docking study of novel 2-| thiazolidin-4-one derivatives as potent antifungal agents

---

JP2021505672A|2021-02-18|Antifungal agent that is a heterocyclic substituted pyridine derivative

---

CN110035995A|2019-07-19|MAChR M4Positive allosteric modulators

---

Shtyrlin et al.2021|Isonicotinoyl hydrazones of pyridoxine derivatives: Synthesis and antimycobacterial activity

---

US20060116369A1|2006-06-01|Certain compounds, compositions, and methods

---

Asif2014|Antimicrobial potential of nicotinic acid derivatives against various pathogenic microbes

---

CN107820495A|2018-03-20|Target the new E PHA4 inhibitor of EPHA4 ligand binding domain

---

DE3508666A1|1986-09-18|HETEROCYCLIC DISULFIDES AND THEIR USE AS IMMUNO MODULATORS

同族专利:

---

公开号 | 公开日

---

CN102762556A|2012-10-31|

---

CN106866667B|2019-11-15|

---

US20180354944A1|2018-12-13|

---

CN106866667A|2017-06-20|

---

US20160318925A1|2016-11-03|

---

IL219564A|2017-01-31|

---

WO2011057145A3|2011-09-09|

---

US10913737B2|2021-02-09|

---

RU2012122653A|2013-12-10|

---

RU2608611C2|2017-01-23|

---

EP3257854A1|2017-12-20|

---

CN102762556B|2017-04-26|

---

ZA201204028B|2013-11-27|

---

HK1248676A1|2018-10-19|

---

BR112012010752A2|2020-09-15|

---

IL219564D0|2012-06-28|

---

EP2496578A4|2013-08-21|

---

WO2011057145A2|2011-05-12|

---

CN110483499A|2019-11-22|

---

IN2012DN04917A|2015-09-25|

---

EP2496578A2|2012-09-12|

---

US9908876B2|2018-03-06|

---

US9309238B2|2016-04-12|

---

US20120220457A1|2012-08-30|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

FR2525602B1|1982-04-21|1984-06-22|Synthelabo|

---

ZA839398B|1982-12-27|1985-08-28|Lilly Co Eli|Substituted imidazopyrimidines-pyrazines,and-triazines|

---

FR2593818B1|1986-02-05|1988-04-29|Synthelabo|IMIDAZO PYRIDINE ACYLAMINOMETHYL-3 DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|

---

DE4010797A1|1990-04-04|1991-10-10|Hoechst Ag|SUBSTITUTED AZOLES, METHOD FOR THE PRODUCTION THEREOF, MEANS CONTAINING THEM AND THE USE THEREOF|

---

DE4023215A1|1990-07-21|1992-01-23|Hoechst Ag|New substd. azole derivs. angiotensin II antagonists - for treating hypertension, coronary insufficiency, myocardial infarct, coronary hypertrophy, arteriosclerosis etc.|

---

JPH0539205A|1990-12-21|1993-02-19|Takeda Chem Ind Ltd|Agricultural/horticultural mixed composition|

---

JP3026845B2|1991-02-20|2000-03-27|日清製粉株式会社|Piperidine derivative|

---

US5464843A|1992-06-23|1995-11-07|G.D. Searle & Co.|Imidazo[1,2-a]pyridinyldiacid compounds for cognitive enhancement and for treatment of cognitive disorders and neutrotoxic injury|

---

US5721273A|1993-12-15|1998-02-24|Alcon Laboratories, Inc.|Use of certain 9-halo-13,14-dihydroprostaglandins to treat glaucoma and ocular hypertension|

---

AU2223495A|1994-04-15|1995-11-10|Yamanouchi Pharmaceutical Co., Ltd.|Spiro compound and medicinal composition thereof|

---

AU2935895A|1994-07-15|1996-02-16|Takeda Chemical Industries Ltd.|Tricyclic compounds, their production and use|

---

US6080767A|1996-01-02|2000-06-27|Aventis Pharmaceuticals Products Inc.|Substituted n-[phenyl]propyl amides|

---

US6323227B1|1996-01-02|2001-11-27|Aventis Pharmaceuticals Products Inc.|Substituted N-[phenyl]propyl amides|

---

JPH09249666A|1996-01-12|1997-09-22|Takeda Chem Ind Ltd|Production of tricyclic compound and its intermediate|

---

SE9700661D0|1997-02-25|1997-02-25|Astra Ab|New compounds|

---

AUPP278498A0|1998-04-03|1998-04-30|Australian Nuclear Science & Technology Organisation|Peripheral benzodiazepine receptor binding agents|

---

AU4543899A|1998-06-08|1999-12-30|Advanced Medicine, Inc.|Multibinding inhibitors of microsomal triglyceride transferase protein|

---

GB2351081A|1999-06-18|2000-12-20|Lilly Forschung Gmbh|Pharmaceutically active imidazoline compounds and analogues thereof|

---

JP2003509412A|1999-09-17|2003-03-11|シーオーアールセラピューティクスインコーポレイテッド|Factor Xa inhibitor|

---

US6632815B2|1999-09-17|2003-10-14|Millennium Pharmaceuticals, Inc.|Inhibitors of factor Xa|

---

WO2001083481A1|2000-04-27|2001-11-08|Yamanouchi Pharmaceutical Co., Ltd.|Imidazopyridine derivatives|

---

US6403588B1|2000-04-27|2002-06-11|Yamanouchi Pharmaceutical Co., Ltd.|Imidazopyridine derivatives|

---

WO2002002557A2|2000-06-30|2002-01-10|Neurogen Corporation|2-phenylimidazo[1,2-a]pyridine derivatives: a new class of gaba brain receptor ligands|

---

GB0021670D0|2000-09-04|2000-10-18|Astrazeneca Ab|Chemical compounds|

---

DE10247269A1|2002-10-10|2004-04-22|Grünenthal GmbH|New C--pyridin-3-yl)-methylamines, are nitrogen monoxide synthase inhibitors useful e.g. for treating migraine, septic shock, neurodegenerative diseases, inflammatory pain or cancer|

---

WO2004100868A2|2003-04-23|2004-11-25|Abbott Laboratories|Method of treating transplant rejection|

---

JP4503022B2|2003-12-23|2010-07-14|ファイザー・インク|New quinoline derivatives|

---

EP1748048A4|2004-05-10|2010-05-26|Banyu Pharma Co Ltd|Imidazopyridine compound|

---

US20060084806A1|2004-07-21|2006-04-20|Ramasubramanian Sridharan|Processes for the preparation of imidazo[1,2-a] pyridine derivatives|

---

CA2568850A1|2004-08-02|2006-02-16|Schwarz Pharma Ag|Indolizine carboxamides and the aza and diaza derivatives thereof|

---

US20080200473A1|2004-11-11|2008-08-21|Ferrer Internacional, S.A.|Imidazo [1,2-a]Pyridine Compounds, Compositions, Uses andMethods Thereto|

---

BRPI0519287A2|2004-12-24|2009-01-06|Astrazeneca Ab|amide derivatives|

---

WO2007015866A2|2005-07-20|2007-02-08|Kalypsys, Inc.|Inhibitors of p38 kinase and methods of treating inflammatory disorders|

---

CA2652259A1|2006-05-18|2007-11-29|Merck & Co., Inc.|Substituted esters as cannabinoid-1 receptor modulators|

---

FR2903178B1|2006-07-03|2008-10-03|Rech S De L Ecole Nationale Su|METHOD AND DEVICE FOR CLEANING SURFACES OF RUNNING WATER IN AN AIR / WATER THERMAL EXCHANGER|

---

DE602007009284D1|2006-09-29|2010-10-28|Actelion Pharmaceuticals Ltd|3-AZA-BICYCLOÄ3.1.0ÜHEXANDERIVATE|

---

CA2665214A1|2006-10-06|2008-05-29|Abbott Laboratories|Novel imidazothiazoles and imidazoxazoles|

---

CN101631786A|2006-12-20|2010-01-20|先灵公司|Novel jnk inhibitor|

---

US20080221094A1|2007-03-07|2008-09-11|Harald Bluhm|Metalloprotease inhibitors containing a squaramide moiety|

---

EP1980251A1|2007-04-13|2008-10-15|Glaxo Group Limited|Pyrrolo[3,2,1-ij]quinoline-4-one derivatives for treating tuberculosis|

---

TW200901969A|2007-06-06|2009-01-16|Smithkline Beecham Corp|Chemical compounds|

---

US8148380B2|2007-07-23|2012-04-03|Crestone, Inc.|Antibacterial amide and sulfonamide substituted heterocyclic urea compounds|

---

CA2709784A1|2007-12-21|2009-07-09|University Of Rochester|Method for altering the lifespan of eukaryotic organisms|

---

WO2009143156A2|2008-05-19|2009-11-26|Sepracor Inc.|IMIDAZO[1,2-a]PYRIDINE COMPOUNDS|

---

WO2009148961A2|2008-05-29|2009-12-10|Wisconsin Alumni Research Foundation|Drugs to prevent hpv infection|

---

WO2010019796A1|2008-08-14|2010-02-18|Chemietek, Llc|Heterocyclic amide derivatives as ep4 receptor antagonists|

---

US8198449B2|2008-09-11|2012-06-12|Bristol-Myers Squibb Company|Compounds for the treatment of hepatitis C|

---

US8293909B2|2008-09-11|2012-10-23|Bristol-Myers Squibb Company|Compounds for the treatment of hepatitis C|

---

WO2010064020A1|2008-12-04|2010-06-10|Proximagen Ltd.|Imidazopyridine compounds|

---

WO2011050245A1|2009-10-23|2011-04-28|Yangbo Feng|Bicyclic heteroaryls as kinase inhibitors|

---

CN110483499A|2009-11-05|2019-11-22|圣母大学|Imidazo [1,2-a] pyridine compounds and their and its synthesis and application method|

---

PL2547678T3|2010-03-18|2016-10-31|Anti-infective compounds|CN110483499A|2009-11-05|2019-11-22|圣母大学|Imidazo [1,2-a] pyridine compounds and their and its synthesis and application method|

---

PL2547678T3|2010-03-18|2016-10-31|Anti-infective compounds|

---

JP5931752B2|2011-02-01|2016-06-08|協和発酵キリン株式会社|Fused heterocyclic derivatives|

---

US9029389B2|2011-04-21|2015-05-12|Institut Pasteur Korea|Anti-inflammation compounds|

---

US20150126530A1|2011-10-21|2015-05-07|Torrent Pharmaceuticals Limited|Novel Substituted Imidazopyrimidines as Gpbar1 Receptor Modulators|

---

CN104619707A|2012-07-31|2015-05-13|协和发酵麒麟株式会社|Condensed ring heterocyclic compound|

---

DK3027615T3|2013-08-02|2021-10-25|Pasteur Institut Korea|ANTI-INFECTIOUS COMPOUNDS|

---

WO2015143652A1|2014-03-26|2015-10-01|Merck Sharp & Dohme Corp.|TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF|

---

CN103965193B|2014-05-30|2016-04-06|浙江司太立制药股份有限公司|N- imidazo [1,2-a] pyridine-3-amides and preparation method thereof|

---

CN104628721A|2015-01-22|2015-05-20|湖南华腾制药有限公司|Preparation method of imidazo [1, 2-a] pyridine derivative|

---

EP3316968A1|2015-07-02|2018-05-09|Janssen Sciences Ireland UC|Antibacterial compounds|

---

MX2018003294A|2015-09-17|2019-04-25|J Miller Marvin|Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection.|

---

EP3472152A1|2016-06-16|2019-04-24|Janssen Sciences Ireland Unlimited Company|Heterocyclic compounds as antibacte rials|

---

CA3026010A1|2016-06-16|2017-12-21|Janssen Sciences Ireland Unlimited Company|Heterocyclic compounds as antibacterials|

---

CN106588916A|2016-11-21|2017-04-26|浙江司太立制药股份有限公司|N- imidazo [1,2-a] pyridine-3-amide compound and preparation method thereof|

---

JP2020502110A|2016-12-16|2020-01-23|バイエル・アクチエンゲゼルシヤフト|Mesoionic imidazopyridines for use as insecticides|

---

WO2018158280A1|2017-03-01|2018-09-07|Janssen Sciences Ireland Uc|Combination therapy|

---

CN108159049B|2018-02-01|2021-01-05|中国科学院广州生物医药与健康研究院|New application of pyridine compound|

---

WO2019175737A1|2018-03-12|2019-09-19|University Of Notre Dame Du Lac|Deuterated imidazopyridines|

---

CN110759913B|2018-07-26|2022-01-28|南开大学|Indolylhydrazone derivatives, preparation method thereof and application thereof in plant virus prevention and control, sterilization and disinsection|

---

CN113480541A|2019-03-07|2021-10-08|湖南化工研究院有限公司|Process for producing imidazopyridine compound and intermediate thereof|

---

WO2020208510A1|2019-04-08|2020-10-15|Pi Industries Limited|Novel oxadiazole compounds for controlling or preventing phytopathogenic fungi|

法律状态:
2020-10-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2020-10-13| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

---

2020-12-29| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2021-01-12| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2021-05-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-07-20| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/11/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US25854909P| true| 2009-11-05|2009-11-05|

---

US61/258.549|2009-11-05|

---

US61/258,549|2009-11-05|

---

PCT/US2010/055728|WO2011057145A2|2009-11-05|2010-11-05|Imidazo[1,2-a] pyridine compounds, synthesis thereof, and methods of using same|

---