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Solid dispersions containing an apoptosis-inducing agent

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20120277210 patent thumbnailZoom

Solid dispersions containing an apoptosis-inducing agent


A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.

Browse recent Abbott Laboratories patents - Abbott Park, IL, US
Inventors: Nathaniel Catron, David Lindley, Jonathan M. Miller, Eric A. Schmitt, Ping Tong
USPTO Applicaton #: #20120277210 - Class: 51421021 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai >Hetero Ring Is Four-membered And Includes At Least One Ring Nitrogen >Additional Hetero Ring Attached Directly Or Indirectly To The Four-membered Hetero Ring By Nonionic Bonding >The Additional Hetero Ring Contains Ring Nitrogen >Polycyclo Ring System Having The Additional Hetero Ring As One Of The Cyclos



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The Patent Description & Claims data below is from USPTO Patent Application 20120277210, Solid dispersions containing an apoptosis-inducing agent.

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of provisional application Ser. No. 61/408,517, filed Oct. 29, 2010, which is hereby incorporated by reference as if set forth in its entirety.

Cross-reference is also made, without claim to benefit of priority or admission as to prior art status, to the following pending U.S. application containing subject matter related to the present application: Ser. No. 12/787,682 (U.S. 2010/0305122) titled “Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases,” the entire disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to solid dispersions comprising an apoptosis-inducing agent, to pharmaceutical dosage forms comprising such dispersions, to processes for preparing such dispersions and dosage forms and to methods of use thereof for treating diseases characterized by overexpression of anti-apoptotic Bcl-2 family proteins.

BACKGROUND OF THE INVENTION

Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system.

Evasion of apoptosis is a hallmark of cancer (Hanahan & Weinberg (2000) Cell 100:57-70). Cancer cells must overcome a continual bombardment by cellular stresses such as DNA damage, oncogene activation, aberrant cell cycle progression and harsh microenvironments that would cause normal cells to undergo apoptosis. One of the primary means by which cancer cells evade apoptosis is by up-regulation of anti-apoptotic proteins of the Bcl-2 family.

A particular type of neoplastic disease for which improved therapies are needed is non-Hodgkin's lymphoma (NHL). NHL is the sixth most prevalent type of new cancer in the U.S. and occurs primarily in patients 60-70 years of age. NHL is not a single disease but a family of related diseases, which are classified on the basis of several characteristics including clinical attributes and histology.

One method of classification places different histological subtypes into two major categories based on natural history of the disease, i.e., whether the disease is indolent or aggressive. In general, indolent subtypes grow slowly and are generally incurable, whereas aggressive subtypes grow rapidly and are potentially curable. Follicular lymphomas are the most common indolent subtype, and diffuse large-cell lymphomas constitute the most common aggressive subtype. The oncoprotein Bcl-2 was originally described in non-Hodgkin's B-cell lymphoma.

Treatment of follicular lymphoma typically consists of biologically-based or combination chemotherapy. Combination therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is routinely used, as is combination therapy with rituximab, cyclophosphamide, vincristine and prednisone (RCVP). Single-agent therapy with rituximab (targeting CD20, a phosphoprotein uniformly expressed on the surface of B-cells) or fludarabine is also used. Addition of rituximab to chemotherapy regimens can provide improved response rate and increased progression-free survival.

Radioimmunotherapy agents, high-dose chemotherapy and stem cell transplants can be used to treat refractory or relapsed NHL. Currently, there is not an approved treatment regimen that produces a cure, and current guidelines recommend that patients be treated in the context of a clinical trial, even in a first-line setting.

First-line treatment of patients with aggressive large B-cell lymphoma typically consists of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R).

Most lymphomas respond initially to any one of these therapies, but tumors typically recur and eventually become refractory. As the number of regimens patients receive increases, the more chemotherapy-resistant the disease becomes. Average response to first-line therapy is approximately 75%, 60% to second-line, 50% to third-line, and about 35-40% to fourth-line therapy. Response rates approaching 20% with a single agent in a multiple relapsed setting are considered positive and warrant further study.

Other neoplastic diseases for which improved therapies are needed include leukemias such as chronic lymphocytic leukemia (like NHL, a B-cell lymphoma) and acute lymphocyctic leukemia.

Chronic lymphoid leukemia (CLL) is the most common type of leukemia. CLL is primarily a disease of adults, more than 75% of people newly diagnosed being over the age of 50, but in rare cases it is also found in children. Combination chemotherapies are the prevalent treatment, for example fludarabine with cyclophosphamide and/or rituximab, or more complex combinations such as CHOP or R-CHOP.

Acute lymphocyctic leukemia, also known as acute lymphoblastic leukemia (ALL), is primarily a childhood disease, once with essentially zero survival but now with up to 75% survival due to combination chemotherapies similar to those mentioned above. New therapies are still needed to provide further improvement in survival rates.

Current chemotherapeutic agents elicit their antitumor response by inducing apoptosis through a variety of mechanisms. However, many tumors ultimately become resistant to these agents. Bcl-2 and Bcl-XL have been shown to confer chemotherapy resistance in short-term survival assays in vitro and, more recently, in vivo. This suggests that if improved therapies aimed at suppressing the function of Bcl-2 and Bcl-XL can be developed, such chemotherapy-resistance could be successfully overcome.

Involvement of Bcl-2 proteins in bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, CLL, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer and the like is described in International Patent Publication Nos. WO 2005/024636 and WO 2005/049593.

Involvement of Bcl-2 proteins in immune and autoimmune diseases is described, for example, by Puck & Zhu (2003) Current Allergy and Asthma Reports 3:378-384; Shimazaki et al. (2000) British Journal of Haematology 110(3):584-590; Rengan et al. (2000) Blood 95(4):1283-1292; and Holzelova et al. (2004) New England Journal of Medicine 351(14):1409-1418. Involvement of Bcl-2 proteins in bone marrow transplant rejection is disclosed in United States Patent Application Publication No. US 2008/0182845.

Compounds that occupy a binding site on Bcl-2 proteins are known. To be therapeutically useful by oral administration, such compounds desirably have high binding affinity, exhibiting for example Ki<1 nM, preferably <0.1 nM, more preferably <0.01 nM, to proteins of the Bcl-2 family, specifically Bcl-2, Bcl-XL and Bcl-w. It is further desirable that they be formulated in a manner that provides high systemic exposure after oral administration. A typical measure of systemic exposure after oral administration of a compound is the area under the curve (AUC) resulting from graphing plasma concentration of the compound versus time from oral administration.

Where aqueous solubility of Bcl-2 binding compounds is very low, the formulator faces a significant challenge in assuring acceptable oral bioavailability, which is strongly dependent on solubility in the aqueous medium of the gastrointestinal tract. This is true even where binding affinity is very high. The challenge becomes even greater when considering the need to provide an adequate drug loading in the formulation, so that a therapeutically effective dose can be administered in an acceptably small volume of formulated product.

Liquid dosage forms (including encapsulated liquids) can be useful for some drugs of low aqueous solubility, provided a suitable pharmaceutically acceptable solvent system (generally lipid-based) can be found that provides adequate drug loading without posing solubility or storage-stability issues. Other approaches that have been proposed for such drugs include solid dispersions, which bring their own challenges.

For a variety of reasons, such as patient compliance and unpleasant taste, a solid dosage form is often preferred over a liquid dosage form. In most instances, however, oral solid dosage forms of a drug provide lower bioavailability than oral solutions of the drug.

Various solutions to the challenge of low oral bioavailability have been proposed in the art. For example, Sharma & Joshi (2007) Asian Journal of Pharmaceutics 1(1):9-19 discuss various solubility enhancement strategies in preparing solid dispersions. A solvent evaporation method for preparing solid dispersions is described therein, mentioning as an example a solid dispersion of etoricoxib, prepared by a process that includes dissolving polyethylene glycol (PEG), polyvinylpyrrolidone (PVP or povidone) and the active ingredient in 2-propanol.

Apoptosis-inducing drugs that target Bcl-2 family proteins such as Bcl-2 and Bcl-XL are best administered according to a regimen that provides continual, for example daily, replenishment of the plasma concentration, to maintain the concentration in a therapeutically effective range. This can be achieved by daily parenteral, e.g., intravenous (i.v.) or intraperitoneal (i.p.) administration. However, daily parenteral administration is often not practical in a clinical setting, particularly for outpatients. To enhance clinical utility of an apoptosis-inducing agent, for example as a chemotherapeutic in cancer patients, a solid dosage form with acceptable oral bioavailability would be highly desirable. Such a dosage form, and a regimen for oral administration thereof, would represent an important advance in treatment of many types of cancer, including NHL, CLL and ALL, and would more readily enable combination therapies with other chemotherapeutics.

SUMMARY

OF THE INVENTION

There is now provided a solid dispersion comprising, in essentially non-crystalline, for example amorphous, form, a compound of Formula I:

where: R0 is halo; R1 and R2 are H or are independently methyl or methoxy; R3 and R4 are independently methyl or methoxy if R1 and R2 are H, or are H if R1 and R2 are independently methyl or methoxy; A1 and A2 are each independently CH or N; R5 is C1-4 alkyl or haloalkyl, C1-4 alkylsulfonyl or haloalkylsulfonyl, halo, nitro or cyano; X is —O— or —NH—; Y is —(CH2)n— where n is 0, 1, 2 or 3; and R6 is an unsubstituted or substituted 3- to 7-membered carbocyclic or heterocyclic ring as defined herein, or is NR7R8; wherein, if R6 is NR7R8, R7 and R8 are each independently H or R9—(CH2)m— groups, no more than one of R7 and R8 being H, where each R9 is independently a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as defined below, and each m is independently 0 or 1; and wherein, if R6 is a substituted carbocyclic or heterocyclic ring, substituents thereon are no more than two Z1 groups and/or no more than one Z2 group, Z1 groups being independently selected from (a) C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 alkylsulfonyl, C1-4 alkylsulfonylamino, C1-4 alkylcarbonyl, C1-4 alkylcarbonylamino and C1-4 alkylcarboxy, each optionally substituted with one or more substituents independently selected from halo, hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino and cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups, and Z2 being (i) a further 3- to 6-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as defined above, or (ii) NR7R8 where R7 and R8 are as defined above; or a pharmaceutically acceptable salt of such compound. The compound or salt thereof is dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant.

There is further provided a solid orally deliverable dosage form comprising such a solid dispersion, optionally together with one or more additional excipients.

There is still further provided a process for preparing a solid dispersion as described above. This process comprises: (a) dissolving (i) an active pharmaceutical ingredient (API) comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, (ii) a pharmaceutically acceptable water-soluble polymeric carrier and (iii) a pharmaceutically acceptable surfactant in a suitable solvent; and (b) removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound or salt thereof dispersed in an essentially non-crystalline form therein.

The compound present in the finished solid dispersion can be in the same chemical form (e.g., parent compound or salt) as in the API used to prepare it. Alternatively, in some embodiments the process can comprise one or more additional steps wherein the API is converted from parent compound to salt or vice versa. According to one such embodiment, the process further comprises, prior to removing the solvent, adding a base for conversion of the API in salt form to its corresponding parent compound, and optionally extracting a by-product of such conversion (e.g., a salt by-product) from the resulting mixture. According to another such embodiment, the process further comprises, prior to removing the solvent, adding an acid for conversion of the API in parent compound form to a salt, for example an acid addition salt.

There is still further provided a solid dispersion prepared by the process described above.

There is still further provided a method for treating a neoplastic, immune or autoimmune disease, comprising orally administering to a subject having the disease a therapeutically effective amount of a solid dispersion as described above, or one or more solid dosage forms comprising such a dispersion. Examples of neoplastic diseases include cancers. A specific illustrative type of cancer that can be treated according to the present method is non-Hodgkin\'s lymphoma (NHL). Another specific illustrative type of cancer that can be treated according to the present method is chronic lymphocytic leukemia (CLL). Yet another specific illustrative type of cancer that can be treated according to the present method is acute lymphocytic leukemia (ALL), for example in a pediatric patient.

Additional embodiments of the invention, including more particular aspects of those provided above, will be found in, or will be evident from, the detailed description that follows.

DETAILED DESCRIPTION

Attempts to formulate a compound of Formula I or a salt thereof as an orally deliverable dosage form have been frustrated by the very limited number of pharmaceutically acceptable liquid solvent systems providing acceptable solubility of the compound or salt, and by a tendency with all such solvent systems tested for precipitation of insoluble solids during storage. It has now been found that a more successful approach is to formulate the compound or salt as a solid dispersion. Details of that approach, by which a combination of satisfactory drug loading, acceptable stability and adequate bioavailability are all achievable with a very unpromising class of active ingredient, are disclosed herein.

A solid dispersion in accordance with the present disclosure comprises an active ingredient in an essentially non-crystalline or amorphous form, which is usually more soluble than the crystalline form. The term “solid dispersion” herein encompasses systems having small solid-state particles (e.g., essentially non-crystalline or amorphous particles) of one phase dispersed in another solid-state phase. More particularly, the present solid dispersions comprise particles of one or more active ingredients dispersed in an inert carrier or matrix in solid state, and can be prepared by melting or solvent methods or by a combination of melting and solvent methods. According to the present invention a solvent method as described herein is particularly favored.

An “amorphous form” refers to a particle without definite structure, i.e., lacking crystalline structure.

The term “essentially non-crystalline” herein means that no more than about 5%, for example no more than about 2% or no more than about 1% crystallinity is observed by X-ray diffraction analysis. In a particular embodiment, no detectable crystallinity is observed by one or both of X-ray diffraction analysis or polarization microscopy. In this regard it is to be noted that, when no detectable crsytallinity is observed, the solid dispersion referenced herein may additionally or alternatively be described as a solid solution.

A. Active Compound

Compounds of Formula I, including salts thereof, useful herein typically have very low solubility in water, being classed as essentially insoluble, i.e., having a solubility of less than about 10 μg/ml. Examples of such active ingredients are, for example, Biopharmaceutics Classification System (BCS) Class IV drug substances that are characterized by low solubility and low permeability (see “Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system”, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000). It will be recognized that aqueous solubility of many compounds is pH-dependent; in the case of such compounds the solubility of interest herein is at a physiologically relevant pH, for example a pH of about 1 to about 8. Thus, in various embodiments, the drug has a solubility in water, at least at one point in a pH range from about 1 to about 8, of less than about 10 μg/ml, in some cases less than about 1 μg/ml or even less than about 0.1 μg/ml. Illustratively, a particular compound useful herein has a solubility in water at pH 4 of <0.004 μg/ml.

Solid dispersions of the present invention comprise as active ingredient a compound of Formula I as defined above, or a pharmaceutically acceptable salt of such a compound. Optionally they may further comprise a second active ingredient, for example a therapeutic agent useful in combination therapy with the compound of Formula I as indicated hereinbelow.

In one embodiment, the compound has Formula I where R0 is chloro.

In a further embodiment, the compound has Formula I where R1 is methyl or methoxy, R2 is methyl, and R3 and R4 are each H.

In a still further embodiment, the compound has Formula I where R5 is trifluoromethyl, trifluoromethylsulfonyl, chloro, bromo or nitro. In a more particular embodiment, if A2 is —CH— then R5 is nitro; and if A2 is —N— then R5 is bromo.

In a more particular embodiment, the compound has Formula I where (a) R0 is chloro, (b) R1 is methyl or methoxy, R2 is methyl, and R3 and R4 are each H, and (c) R5 is trifluoromethyl, trifluoromethylsulfonyl, chloro, bromo or nitro.

Compounds useful herein vary considerably in the —X—Y—R6 substituent, more particularly the R6 group, of Formula I. In most embodiments, R6 is a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted as defined above.

The term “carbocyclic” herein embraces saturated and partly and fully unsaturated ring structures having 3 to 7 ring carbon atoms, including bicyclic structures. In one embodiment, R6 is a saturated carbocyclic (i.e., cycloalkyl) ring, for example but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, in each case optionally substituted as more fully described below.

The term “heterocyclic” herein embraces saturated and partly and fully unsaturated ring structures having 4 to 7 ring atoms, one or more of which are heteroatoms independently selected from N, O and S. Typically the heterocyclic ring has no more than two such heteroatoms. In one embodiment, R6 is a saturated heterocyclic ring, for example but not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imazolidinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiophanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl or tetrahydrothiopyranyl, in each case optionally substituted as more fully described below.

Where R6 is a carbocyclic or heterocyclic ring, for example a saturated ring as described immediately above, it can be unsubstituted or substituted at up to three positions on the ring. Substituents, if present, comprise no more than two Z1 groups and/or no more than one Z2 group.

Z1 groups are independently selected from (a) C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, C1-4 alkylsulfonyl, C1-4 alkylsulfonylamino, C1-4 alkylcarbonyl, C1-4 alkylcarbonylamino and C1-4 alkylcarboxy, each optionally substituted with one or more substituents independently selected from halo, hydroxy, C1-4 alkoxy, amino, C1-4 alkylamino, di-(C1-4 alkyl)amino and cyano, (b) halo, (e) hydroxy, (f) amino and (g) oxo groups. Illustrative examples of such Z1 groups include without limitation methyl, cyanomethyl, methoxy, fluoro, hydroxy, amino and methylsulfonyl.

The Z2 group, if present, is a further 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as described above. Ring Z2, if present, is typically but not necessarily saturated, and in most cases is not further substituted. In one embodiment Z2 is a saturated carbocyclic ring, for example but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment Z2 is a saturated heterocyclic ring, for example but not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imazolidinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiophanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl or tetrahydrothiopyranyl.

In some embodiments, R6 is a group NR7R8, where R7 and R8 are each independently H or R9—(CH2)m— groups, no more than one of R7 and R8 being H, where each R9 is independently a 3- to 7-membered carbocyclic or heterocyclic ring, optionally substituted with no more than two Z1 groups as defined above, and each m is independently 0 or 1. Each of rings R9 is typically but not necessarily saturated, and in most cases is unsubstituted. Illustrative carbocyclic rings at R7 and/or R8 include without limitation cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Illustrative heterocyclic rings at R7 and/or R8 include without limitation azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imazolidinyl, pyrazolidinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, thiophanyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl or tetrahydrothiopyranyl.

In particular embodiments, R6 is selected from the group consisting of 4-methoxycyclohexyl, cis-4-hydroxy-4-methylcyclohexyl, trans-4-hydroxy-4-methylcyclohexyl, 4-morpholin-4-ylcyclohexyl, (3R)-1-(methylsulfonyl)pyrrolidin-3-yl, (3R)-1-tetrahydro-2H-pyran-4-ylpyrrolidin-3-yl, tetrahydro-2H-pyran-4-yl, (3S)-tetrahydro-2H-pyran-3-yl, 4-methoxytetrahydro-2H-pyran-4-yl, 4-fluorotetrahydro-2H-pyran-4-yl, 4-aminotetrahydro-2H-pyran-4-yl, 1-(cyanomethyl)piperidin-4-yl, 4-fluoro-1-oxetan-3-ylpiperidin-4-yl, 1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl, 4-methylpiperazin-1-yl, 1,4-dioxan-2-yl, 4-methylmorpholin-2-yl and cyclopropyl(oxetan-3-yl)amino.

Compounds of Formula I may contain asymmetrically substituted carbon atoms in the R- or S-configuration; such compounds can be present as racemates or in an excess of one configuration over the other, for example in an enantiomeric ratio of at least about 85:15. The compound can be substantially enantiomerically pure, for example having an enantiomeric ratio of at least about 95:5, or in some cases at least about 98:2 or at least about 99:1.

Compounds of Formula I may alternatively or additionally contain carbon-carbon double bonds or carbon-nitrogen double bonds in the Z- or E-configuration, the term “Z” denoting a configuration wherein the larger substituents are on the same side of such a double bond and the term “E” denoting a configuration wherein the larger substituents are on opposite sides of the double bond. The compound can alternatively be present as a mixture of Z- and E-isomers.

Compounds of Formula I may alternatively or additionally exist as tautomers or equilibrium mixtures thereof wherein a proton shifts from one atom to another. Examples of tautomers illustratively include keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine and the like.



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stats Patent Info
Application #
US 20120277210 A1
Publish Date
11/01/2012
Document #
13282773
File Date
10/27/2011
USPTO Class
51421021
Other USPTO Classes
51425304, 5142345, 51425211, 51425409, 5142352, 51425217, 5142282
International Class
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Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai   Hetero Ring Is Four-membered And Includes At Least One Ring Nitrogen   Additional Hetero Ring Attached Directly Or Indirectly To The Four-membered Hetero Ring By Nonionic Bonding   The Additional Hetero Ring Contains Ring Nitrogen   Polycyclo Ring System Having The Additional Hetero Ring As One Of The Cyclos