S-Nitrosothiol-mediated hyperbranched polyesters

Description

BACKGROUND

Nitric oxide (NO) is an endogenously produced diatomic free radical that mediates angiogenesis (J. P. Cooke, Atherosclerosis Suppl., 2003, 4, 53-600, blood pressure regulation (D. D. Rees, R. M. Palmer and S. Moncada, Proc. Natl. Acad. Sci., 1989, 86, 3375-3378), wound healing (J.-d. Luo and A. F. Chen, Acta Pharmacol. Sin., 2005, 26, 259-264; M. R. Schïffer, U. Tantry, S. S. Gross, H. L. Wasserkrug and A. Barbul, J. Surg. Res., 1996, 63, 237-240), and the immune response (C. Bogdan, Nat. Immunol., 2001, 2, 907-916; J. MacMicking, Q.-w. Xie and C. Nathan, Annu. Rev. Immunol., 1997, 15, 323-350). Due to its relatively short biological half-life (seconds) and reactive nature, the synthesis of scaffolds capable of controlled NO storage and release is important for helping further understand NO's role in physiology and developing NO-based therapeutics (A. W. Carpenter and M. H. Schoenfisch, Chem. Soc. Rev., 2012, 41, 3742-3752; P. N. Coneski and M. H. Schoenfisch, Chem. Soc. Rev., 2012, 41, 3753-3758; S. P. Nichols, W. L. Storm, A. Koh and M. H. Schoenfisch, Adv. Drug Delivery Rev., 2012, 64, 1177-1188; D. A. Riccio and M. H. Schoenfisch, Chem. Soc. Rev., 2012, 41, 3731-3741). To date, N-diazeniumdiolates and S-nitrosothiols (RSNOs) represent the most widely employed NO donors because of their spontaneous NO-release characteristics under physiological conditions (pH 7.4, 37° C.) (D. A. Riccio and M. H. Schoenfisch, Chem. Soc. Rev., 2012, 41, 3731-3741). S-Nitrosothiol-based NO donors are attractive as potential therapeutics due to their low toxicity and endogenous nature (P. N. Coneski and M. H. Schoenfisch, Poly. Chem., 2011, 2, 906-913). S-Nitrosothiols are readily synthesized via the reaction of free thiols with nitrosating agents (e.g., NaNO₂/HCl). The ensuing NO release is tunable and triggered via several decomposition pathways, including exposure to light, heat, and copper ions (D. Lyn H Williams, Chem. Soc. Rev., 1985, 14, 171-196).

Recent research has focused on the synthesis of macromolecular NO-release scaffolds to enhance NO payloads and enable greater tunability of the NO-release kinetics relative to that achieved using small molecule NO donors (H. P. Zhang, G. M. Annich, J. Miskulin, K. Stankiewicz, K. Osterholzer, S. I. Merz, R. H. Bartlett and M. E. Meyerhoff, J. Am. Chem. Soc., 2003, 125, 5015-5024; Y. Lu, D. L. Slomberg, B. Sun and M. H. Schoenfisch, Small, 2013, 9, 2189-2198.; D. L. Slomberg, Y. Lu, A. D. Broadnax, R. A. Hunter, A. W. Carpenter and M. H. Schoenfisch, ACS Appl. Mater. Interfaces, 2013, 5, 9322-9329; Y. Lu, D. L. Slomberg, A. Shah and M. H. Schoenfisch, Biomacromolecules, 2013, 14, 3589-3598; B. Sun, D. L. Slomberg, S. L. Chudasama, Y. Lu and M. H. Schoenfisch, Biomacromolecules, 2012, 13, 3343-3354; Y. Lu, B. Sun, C. Li and M. H. Schoenfisch, Chem. Mater., 2011, 23, 4227-4233; E. M. Hetrick, J. H. Shin, N. A. Stasko, C. B. Johnson, D. A. Wespe, E. Holmuhamedov and M. H. Schoenfisch, ACS Nano, 2008, 2, 235-246; Z. R. Zhou, G. M. Annich, Y. D. Wu and M. E. Meyerhoff, Biomacromolecules, 2006, 7, 2565-2574; M. C. Frost and M. E. Meyerhoff, J. Biomed. Mater. Res., Part A, 2005, 72A, 409-419; N. A. Stasko, T. H. Fischer and M. H. Schoenfisch, Biomacromolecules, 2008, 9, 834-841; R. J. Soto, L. Yang and M. H. Schoenfisch, ACS Appl. Mater. Interfaces, 2016, 8, 2220-2231; B. V. Worley, D. L. Slomberg and M. H. Schoenfisch, Bioconjugate Chem., 2014, 25, 918-927; T. Liu, W. Zhang, X. Yang and C. Li, J. Colloid Interface Sci., 2015, 459, 115-122). Dendritic polymeric scaffolds exhibit attractive characteristics as macromolecular scaffolds due to their high density of exterior functional groups available for further modifications (Y. Lu, D. L. Slomberg, A. Shah and M. H. Schoenfisch, Biomacromolecules, 2013, 14, 3589-3598; B. Sun, D. L. Slomberg, S. L. Chudasama, Y. Lu and M. H. Schoenfisch, Biomacromolecules, 2012, 13, 3343-3354; N. A. Stasko, T. H. Fischer and M. H. Schoenfisch, Biomacromolecules, 2008, 9, 834-841; B. V. Worley, D. L. Slomberg and M. H. Schoenfisch, Bioconjugate Chem., 2014, 25, 918-927). For example, polyamidoamine (PAMAM) dendrimers functionalized with RSNOs demonstrated large NO storage and tunable NO release kinetics by simply varying the steric structure of the thiol modification. Thiols with a compact structure exhibited extended NO-release kinetics compared to branched thiol structures (N. A. Stasko, T. H. Fischer and M. H. Schoenfisch, Biomacromolecules, 2008, 9, 834-841). While these NO-releasing dendrimers displayed antiplatelet activity, the scaffold toxicity against mammalian cells and poor biodegradability may hinder their utility for certain biomedical applications (N. A. Stasko, T. H. Fischer and M. H. Schoenfisch, Biomacromolecules, 2008, 9, 834-841).

Polyesters represent an alternative polymeric NO-release scaffold with potentially useful biodegradation properties (T. Liu, W. Zhang, X. Yang and C. Li, J. Colloid Interface Sci., 2015, 459, 115-122; P. N. Coneski, K. S. Rao and M. H. Schoenfisch, Biomacromolecules, 2010, 11, 3208-3215; V. B. Damodaran and M. M. Reynolds, J. Mater. Chem., 2011, 21, 5870-5872; A. B. Seabra, D. Martins, M. M. S. G. Simoes, R. da Silva, M. Brocchi and M. G. de Oliveira, Artif. Organs, 2010, 34, E204-E214). Seabra et al. reported the synthesis of S-nitrosothiol-modified polyesters via the condensation of 3-mercapto-1,2-propanediol and mercaptosuccinic acid, followed by a nitrosation reaction (A. B. Seabra, D. Martins, M. M. S. G. Simoes, R. da Silva, M. Brocchi and M. G. de Oliveira, Artif. Organs, 2010, 34, E204-E214). The resulting NO donor-modified polyesters were blended with poly(methyl methacrylate) to yield coatings that released ˜40 nmol NO cm⁻²over 72 h. Yapor et al. subsequently developed citrate-based S-nitrosothiol-modified polyesters capable of storing ˜0.45 μmol NO mg⁻¹polymer (J. P. Yapor, A. Lutzke, A. Pegalajar-Jurado, B. H. Neufeld, V. B. Damodaran and M. M. Reynolds, J. Mater. Chem. B, 2015, 3, 9233-9241). Of practical relevance, the tedious material preparation and relatively low NO storage capacities of these scaffolds limit their utility.

Hyperbranched polyesters are a family of polymers with multivalent structures and diverse exterior functionalities (B. I. Voit and A. Lederer, Chem. Rev., 2009, 109, 5924-5973). In contrast to their dendrimer counterparts, the synthesis of hyperbranched polyesters is more straightforward as they proceed via one-pot reactions (B. I. Voit and A. Lederer, Chem. Rev., 2009, 109, 5924-5973). Bis(hydroxymethyl)propionic acid (bis-MPA) has been widely utilized as a building unit in creating hyperbranched polyesters with a high density of modifiable exterior hydroxyl groups and good solubility in organic solvents for subsequent chemical functionalization steps (Y. L. Xiao, H. Hong, A. Javadi, J. W. Engle, W. J. Xu, Y. A. Yang, Y. Zhang, T. E. Barnhart, W. B. Cai and S. Q. Gong, Biomaterials, 2012, 33, 3071-3082; N. Feliu, M. V. Walter, M. I. Montanez, A. Kunzmann, A. Hult, A. Nystrom, M. Malkoch and B. Fadeel, Biomaterials, 2012, 33, 1970-1981; A. Carlmark, E. Malmstrom and M. Malkoch, Chem. Soc. Rev., 2013, 42, 5858-5879; E. Malmström, M. Johansson and A. Hult, Macromolecules, 1995, 28, 1698-1703). Easy synthesis, biodegradability, and solubility in organic solvents have led many research groups to evaluate the potential of these polymers for biomedical application (Y. L. Xiao, H. Hong, A. Javadi, J. W. Engle, W. J. Xu, Y. A. Yang, Y. Zhang, T. E. Barnhart, W. B. Cai and S. Q. Gong, Biomaterials, 2012, 33, 3071-3082; N. Feliu, M. V. Walter, M. I. Montanez, A. Kunzmann, A. Hult, A. Nystrom, M. Malkoch and B. Fadeel, Biomaterials, 2012, 33, 1970-1981; M. Prabaharan, J. J. Grailer, S. Pilla, D. A. Steeber and S. Q. Gong, Biomaterials, 2009, 30, 5757-5766; X. H. Zeng, Y. N. Zhang and A. M. Nystrom, Biomacromolecules, 2012, 13, 3814-3822; K. Karatasos, J. Phys. Chem. B, 2013, 117, 2564-2575). For example, Feliu et al. demonstrated that bis-MPA-based polyesters exhibited excellent biodegradability and were non-toxic compared to PAMAM dendrimers (N. Feliu, M. V. Walter, M. I. Montanez, A. Kunzmann, A. Hult, A. Nystrom, M. Malkoch and B. Fadeel, Biomaterials, 2012, 33, 1970-1981). Based on these two characteristics, bis-MPA-based hyperbranched polyesters are now being utilized for cancer-targeted drug delivery and non-invasive positron emission tomography (PET) imaging applications (Y. L. Xiao, H. Hong, A. Javadi, J. W. Engle, W. J. Xu, Y. A. Yang, Y. Zhang, T. E. Barnhart, W. B. Cai and S. Q. Gong, Biomaterials, 2012, 33, 3071-3082). The facile chemical modification and excellent biocompatibility of bis-MPA-based hyperbranched polyesters suggest that they may be useful for NO-release applications.

Despite the interest in hyperbranched polyesters for biomedical applications due to the ease of synthesis, biodegradability, and solubility of these polymers, the development and use of hyperbranched polyesters for NO-release applications has remained elusive. Accordingly, there remains a need for NO-donor modified hyperbranched polymers and methods of making and using same.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to degradable polymers useful in, for example, delivering nitric oxide to a target and/or treating a disorder in a subject.

Disclosed are degradable polymers comprising: (a) a biodegradable polymer backbone; (b) at least one nitric oxide linker moiety pendant from the polymer backbone; and (c) at least one nitric oxide molecule covalently bonded to the nitric oxide linker moiety.

Also disclosed are polymers comprising: (a) a biodegradable polymer backbone; and (b) at least one nitric oxide linker moiety pendant from the polymer backbone.

Also disclosed are methods of making a polymer, the method comprising: (a) reacting a polymer comprising at least one hydroxyl group and acryloyl halide to form a vinyl-functionalized polymer; and (b) reacting the vinyl-functionalized polymer with a dinucleophile to form a polymer scaffold, thereby making the polymer.

Also disclosed are methods of making a degradable polymer, the method comprising the step of functionalizing a polymer scaffold with a nitric oxide donor, wherein the polymer scaffold comprises: (a) a biodegradable polymer backbone; and (b) at least one nitric oxide linker moiety pendant from the polymer backbone, thereby making the degradable polymer.

Also disclosed are methods of delivering nitric oxide to a target, the method comprising: (a) administering to the target an effective amount of a degradable polymer comprising: (i) a biodegradable polymer backbone; (ii) at least one nitric oxide linker moiety pendant from the polymer backbone; and (iii) at least one nitric oxide molecule covalently bonded to the nitric oxide linker moiety; and (b) exposing the degradable polymer to at least one of heat, light, copper, a free thiol, and/or a proton source, thereby delivering nitric oxide to the target.

Also disclosed are methods for the treatment of a disorder in a subject, the method comprising the step of administering to the subject an effective amount of a degradable polymer comprising: (a) a biodegradable polymer backbone; (b) at least one nitric oxide linker moiety pendant from the polymer backbone; and (c) at least one nitric oxide molecule covalently bonded to the nitric oxide linker moiety.

Also disclosed are medical devices comprising a nitric oxide-releasing polymeric film, wherein the polymer film comprises an effective amount of at least one polymer comprising: (a) a polymer backbone; (b) at least one nitric oxide linker moiety pendant from the polymer backbone; and (c) at least one nitric oxide molecule covalently bonded to the nitric oxide linker moiety.

Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of at least one degradable polymer comprising: (a) a biodegradable polymer backbone; (b) at least one nitric oxide linker moiety pendant from the polymer backbone; and (c) at least one nitric oxide molecule covalently bonded to the nitric oxide linker moiety, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

FIG. 1 shows a representative image illustrating the structure of a hyperbranched polymer consisting of three different structural units—dendritic (D), linear (L), and terminal (T).

FIG. 2 shows representative ¹³C-NMR spectra of hyperbranched polyesters G2-HP (top), G3-HP (middle), and G4-HP (bottom).

FIG. 3 shows representative ¹H NMR spectra for G2-HP (1), acrylate-HP (2); 1,2-ethanedithiol (ET)-HP (3), 2,3-butanedithiol (BT)-HP (4), and dithiothreitol (DTT)-modified G2-HP (5).

FIG. 4A and FIG. 4B show representative UV-vis spectra of S-nitrosothiol-modified hyperbranched polyesters measured in acetone (0.1 mg/mL). Specifically, a comparison between G2-HP-DTT and G2-HP-AC (4A) and characteristic S-nitrosothiol bands (4B) are shown.

FIG. 5A and FIG. 5B show representative images illustrating total nitric oxide release from G2-HP-ET/NO (1), G2-HP-BT/NO (2), and G2-HP-DTT/NO (3) in either 0.2 mg/mL CuBr₂solution (37° C., pH 7.4) (5A) or DTPA-supplemented PBS solution shielded from light (37° C., pH 7.4) (5B).

FIG. 6A and FIG. 6B show representative ¹H NMR spectra of G3-HP-DTT (6A) and G4-HP-DTT (6B).

FIG. 7 shows representative GPC chromatograms of G2-HP-DTT (A), G3-HP-DTT (B), and G4-HP-DTT (C).

FIG. 8A-D show representative FTIR spectra for G3-HP-DTT (8A), G3-HP-AC (8B), G3-HP-DTT/NO (8C), and nitrosated G3-HP-AC (8D).

Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

Before the present compounds, compositions, articles, systems, devices, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation.

A. Definitions

As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

As used herein, the term “catalytically effective” refers to the amount of a catalyst that is sufficient to facilitate a reaction (e.g., atom-transfer radical polymerization as disclosed herein).

As used herein, the term “polymer” refers to a relatively high molecular weight organic compound, natural or synthetic, whose structure can be represented by a repeated small unit, the monomer (e.g., monomethacryloxypropyl terminated polydimethylsiloxane.). Synthetic polymers are typically formed by addition or condensation polymerization of monomers.

As used herein, the term “copolymer” refers to a polymer formed from two or more different repeating units (monomer residues). By way of example and without limitation, a copolymer can be an alternating copolymer, a random copolymer, a block copolymer, or a graft copolymer. It is also contemplated that, in certain aspects, various block segments of a block copolymer can themselves comprise copolymers.

As used herein, the term “molecular weight” (MW) refers to the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12).

As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more —OCH₂CH₂O— units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more —CO(CH₂)₈CO— moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “alkylamino” specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like. When “alkyl” is used in one instance and a specific term such as “alkylalcohol” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “alkylalcohol” and the like.

This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA¹where A¹is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA′-OA²or —OA¹-(OA²)_a-OA³, where “a” is an integer of from 1 to 200 and A¹, A², and A³are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C═C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” also includes “heteroaryl,” which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term “non-heteroaryl,” which is also included in the term “aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by the formula —NA¹A², where A¹and A²can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)₂where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A′ or —C(O)OA¹, where A¹can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula -(A¹O(O)C-A²-C(O)O)_a— or -(A¹O(O)C-A²-OC(O))_a—, where A¹and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA², where A¹and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula -(A¹O-A²O)_a—, where A¹and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen” or “halide”, as used herein can be used interchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

The term “heterocycle,” as used herein refers to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Heterocycle includes pyridinde, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A², where A¹and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “azide” or “azido” as used herein is represented by the formula —N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by the formula —CN.

The term “thiol” as used herein is represented by the formula —S— or —SH.

“R¹,” “R²,” “R³,” “Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group is independently halogen; —(CH₂)_0-4R^◯; —(CH₂)_0-4OR^◯; —O(CH₂)_0-4R^◯, —O—(CH₂)_0-4C(O)OR^◯; —(CH₂)_0-4CH(OR^◯)₂; —(CH₂)_0-4SR^◯; —(CH₂)_0-1Ph, which may be substituted with R^◯; —(CH₂)_0-4O(CH₂)_0-4Ph which may be substituted with R^◯; —CH═CHPh, which may be substituted with R^◯; —(CH₂)_0-4O(CH₂)_0-1-pyridyl which may be substituted with R^◯; —NO₂; —CN; —N₃; —(CH₂)_0-4N(R^◯)²; —(CH₂)_0-4N(R^◯)C(O)R^◯; —N(R^◯)C(S)R^◯); —(CH₂)_0-4N(R^◯)C(O)NR^◯₂; —N(R^◯)C(S)NR^◯₂; —(CH₂)_0-4N(R^◯)C(O)OR^◯; —N(R^◯)N(R^◯)C(O)R^◯; —N(R^◯)N(R^◯)C(O)NR^◯₂; —N(R^◯)N(R^◯)C(O)OR^◯; —(CH₂)_0-4C(O)R^◯; —C(S)R^◯; —(CH₂)_0-4C(O)OR^◯; —(CH₂)_0-4C(O)SR^◯; —(CH₂)_0-4C(O)OSiR^◯₃; —(CH₂)_0-4OC(O)R^◯; —OC(O)(CH₂)_0-4SR—, SC(S)SR^◯; —(CH₂)_0-4SC(O)R^◯; —(CH₂)_0-4C(O)NR^◯₂; —C(S)NR^◯₂; —C(S)SR^◯; —SC(S)SR^◯, —(CH₂)_0-4OC(O)NR^◯₂; —C(O)N(OR^◯)R^◯; —C(O)C(O)R^◯; —C(O)CH₂C(O)R^◯; —C(NOR^◯)R^◯; —(CH₂)_0-4SSR^◯; —(CH₂)_0-4S(O)₂R^◯; —(CH₂)_0-4S(O)₂OR^◯; —(CH₂)_0-4OS(O)₂R^◯; —S(O)₂NR^◯₂; —(CH₂)_0-4S(O)R^◯; —N(R^◯)S(O)₂NR^◯₂; —N(R^◯)S(O)₂R^◯; —N(OR^◯)R^◯; —C(NH)NR^◯₂; —P(O)₂R^◯; —P(O)R^◯₂; —OP(O)R^◯₂; —OP(O)(OR^◯)₂; SiR^◯₃; —(C_1-4straight or branched)alkylene)O—N(R^◯₂; or —(C_1-4straight or branched alkylene)C(O)O—N(R^◯)₂, wherein each R^◯may be substituted as defined below and is independently hydrogen, C_1-6aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^◯, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^◯(or the ring formed by taking two independent occurrences of R^◯together with their intervening atoms), is independently halogen, —(CH₂)_0-2R^●, -(haloR^●), —(CH₂)_0-2OH, —(CH₂)_0-2OR^●, —(CH₂)_0-2CH(OR^●)₂; —O(haloR^●), —CN, —N₃, —(CH₂)_0-2C(O)R^●, —(CH₂)_0-2C(O)OH, —(CH₂)_0-2C(O)OR^●, —(CH₂)_0-2SR^●, —(CH₂)_0-2SH, —(CH₂)₀₂NH₂, —(CH₂)_0-2NHR^●, —(CH₂)_0-2NR^●₂, —NO₂, —C(O)SR^●, —(C_1-4straight or branched alkylene)C(O)OR^●, or —SSR^● wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C₁aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^◯include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R^*₂))_2-3O—, or —S(C(R^*₂))_2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C_1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*₂)_2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C_1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, —R^●, -(haloR^●), —OH, —OR^●, —O(haloR^●), —CN, —C(O)OH, —C(O)OR^●, —NH₂, —NHR^●, —NR^●₂, or —NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R^†, —NR″r₂, —C(O)R^†, —C(O)OR^†, —C(O)C(O)R^†, —C(O)CH₂C(O)R^†, —S(O)₂R^†, —S(O)₂NR^†₂, —C(S)NR^†₂, —C(NH)NR^†₂, or —N(R)S(O)₂R^†; wherein each R^† is independently hydrogen, C_1-6aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^† is independently halogen, —R^●, -(haloR^●), —OH, —OR^●, —O(haloR^●), —CN, —C(O)OH, —C(O)OR^●, —NH₂, —NHR^●, —NR^●₂, or —NO₂, wherein each R^● is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C_1-4aliphatic, —CH₂Ph, —O(CH₂)_0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4-thiazolidinedione radical in a particular compound has the structure

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regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

“Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

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Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N¹-unsubstituted, 3-A³and N¹-unsubstituted, 5-A³as shown below.

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Unless stated to the contrary, the invention includes all such possible tautomers.

It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

In some aspects, a structure of a compound can be represented by a formula:

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which is understood to be equivalent to a formula:

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wherein n is typically an integer. That is, Rⁿis understood to represent five independent substituents, R^n(a), R^n(b), R^n(c), R^n(d), R^n(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R^n(a)is halogen, then R^n(b)is not necessarily halogen in that instance.

Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental Volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B—F, C-D, C-E, and C—F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B—F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

B. Degradable Polymers

In one aspect, disclosed are degradable polymers comprising: (a) a biodegradable polymer backbone; (b) at least one nitric oxide linker moiety pendant from the polymer backbone; and (c) at least one nitric oxide molecule covalently bonded to the nitric oxide linker moiety. Without wishing to be bound by theory, a degradable polymer refers to a polymer that can be broken in a biological or non-biological environment in response to a stimulus. Examples of stimuli include, but are not limited to, heat, light, copper ions, and free thiols.

In one aspect, disclosed are polymers comprising: (a) a biodegradable polymer backbone; and (b) at least one nitric oxide linker moiety pendant from the polymer backbone.

In a further aspect, the degradable polymer is hyperbranched. In a still further aspect, the polymer is hyperbranched. Without wishing to be bound by theory, a hyperbranched polymer refers to a polymer having a densely branched structure that is imperfectly branched or irregular. In various aspects, a hyperbranched polymer has a higher functional group density per molecular unit than a straight-chain polymer or a conventional branched polymer. In various further aspects, a hyperbranched polymer that has been elaborated to several generations has an internal space. These characteristics make hyperbranched polymers attractive for a variety of applications including, but not limited to, surfactants, gelling agents, drug delivery systems, and polymeric absorbents.

1. Biodegradable Polymer Backbones

In one aspect, disclosed are degradable polymers comprising a biodegradable polymer backbone.

In a further aspect, the polymer backbone is a polyester backbone.

In a further aspect, the polymer backbone comprises at least one polyester residue.

In a further aspect, the polymer backbone comprises at least one residue having a structure represented by a formula selected from:

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wherein each occurrence of n is independently selected from 0, 1, 2, 3, or 4; wherein each of R^1aand R^1bis independently selected from —OH, C1-C4 alkyl, C1-C4 hydroxyalkyl, and —(CH₂)_nOC(O)L, provided that at least one of R^1aand R^1bis —(CH₂)_nOC(O)L; and wherein L is the nitric oxide linker moiety.

In a further aspect, the polymer backbone comprises at least one residue having a structure represented by a formula selected from:

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wherein each occurrence of n is independently selected from 0, 1, 2, 3, or 4; wherein R^1ais selected from —OH, C1-C4 alkyl, C1-C4 hydroxyalkyl, and —(CH₂)_nOC(O)L; and wherein L is the nitric oxide linker moiety.

In a further aspect, the polymer backbone comprises at least one residue having a structure represented by a formula selected from:

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wherein R^1ais selected from —OH, C1-C4 alkyl, C1-C4 hydroxyalkyl, and —(CH₂)_nOC(O)L; and wherein L is the nitric oxide linker moiety.

In a further aspect, the polymer backbone comprises at least one residue having a structure:

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wherein L is the nitric oxide linker moiety.

In a further aspect, the at least one residue is present as a repeating unit.

In a further aspect, each occurrence of n is independently selected from 0, 1, 2, 3, or 4. In a still further aspect, each occurrence of n is independently selected from 0, 1, 2, or 3. In yet a further aspect, each occurrence of n is independently selected from 0, 1, or 2. In an even further aspect, each occurrence of n is independently selected from 0 or 1. In a still further aspect, each occurrence of n is 4. In yet a further aspect, each occurrence of n is 3. In an even further aspect, each occurrence of n is 2. In a still further aspect, each occurrence of n is 1. In an even further aspect, each occurrence of n is 0.

In a further aspect, L is the nitric oxide linker moiety.

a. R^1Aand R^1BGroups

In one aspect, each of R^1aand R^1bis independently selected from —OH, C1-C4 alkyl, C1-C4 hydroxyalkyl, and —(CH₂)_nOC(O)L, provided that at least one of R^1aand R^1bis —(CH₂)_nOC(O)L.

In a further aspect, R^1ais —(CH₂)_nOC(O)Land R^1bis selected from —OH, C1-C4 alkyl, C1-C4 hydroxyalkyl, and —(CH₂)_nOC(O)L. In a still further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis selected from —OH, methyl, ethyl, n-propyl, i-propyl, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)(CH₂OH), and —(CH₂)_nOC(O)L. In yet a further aspect, R^1ais —(CH₂)_nOC(O)Land R^1bis selected from —OH, methyl, ethyl, —CH₂OH, —CH₂CH₂OH, and —(CH₂)_nOC(O)L. In an even further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis selected from —OH, methyl, —CH₂OH, and —(CH₂)_nOC(O)L.

In a further aspect, R^1ais —(CH₂)_nOC(O)Land R^1bis selected from —OH, C1-C4 alkyl, and C1-C4 hydroxyalkyl. In a still further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis selected from —OH, methyl, ethyl, n-propyl, i-propyl, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, and —CH(CH₃)(CH₂OH). In yet a further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis selected from —OH, methyl, ethyl, —CH₂OH, and —CH₂CH₂OH. In an even further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis selected from —OH, methyl, and —CH₂OH. In a still further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis —OH. In yet a further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis methyl. In an even further aspect, R^1ais —(CH₂)_nOC(O)L and R^1bis —CH₂OH.

In a further aspect, each of R^1aand R^1bis —(CH₂)_nOC(O)L.

2. Nitric Oxide Linker Moieties

In one aspect, disclosed are degradable polymers comprising at least one nitric oxide linker moiety pendant from the polymer backbone.

In a further aspect, the nitric oxide linker moiety comprises a dithiol. In a still further aspect, the nitric oxide linker moiety comprises a diamine. In yet a further aspect, the nitric oxide linker moiety comprises a single amine such as, for example, hexyl amine.

In a further aspect, the nitric oxide linker moiety is present in an amount of no more than about 2.0 μmol/mg. In a still further aspect, the nitric oxide linker moiety is present in an amount of less than about 2.0 μmol/mg. In yet a further aspect, the nitric oxide linker moiety is present in an amount of less than about 1.75 μmol/mg. In an even further aspect, the nitric oxide linker moiety is present in an amount of less than about 1.5 μmol/mg. In a still further aspect, the nitric oxide linker moiety is present in an amount of less than about 1.25 μmol/mg. In yet a further aspect, the nitric oxide linker moiety is present in an amount of less than about 1.0 μmol/mg. In an even further aspect, the nitric oxide linker moiety is present in an amount of about 2.0 μmol/mg.

In a further aspect, the nitric oxide linker moiety is present in an amount of from about 0.1 μmol/mg to about 2.0 μmol/mg. In a still further aspect, the nitric oxide linker moiety is present in an amount of from about 0.5 μmol/mg to about 2.0 μmol/mg. In yet a further aspect, the nitric oxide linker moiety is present in an amount of from about 1.0 μmol/mg to about 2.0 μmol/mg. In an even further aspect, the nitric oxide linker moiety is present in an amount of from about 1.5 μmol/mg to about 2.0 μmol/mg. In a still further aspect, the nitric oxide linker moiety is present in an amount of from about 0.1 μmol/mg to about 1.5 μmol/mg. In yet a further aspect, the nitric oxide linker moiety is present in an amount of from about 0.1 μmol/mg to about 1.0 μmol/mg. In an even further aspect, the nitric oxide linker moiety is present in an amount of from about 0.1 μmol/mg to about 0.5 μmol/mg.