阅读说明：本技术 色甘酸酯及其用途 (Cromoglycate and its use ) 是由 T·M·肖普 D·R·埃尔马列 于 2019-12-10 设计创作，主要内容包括：本文描述了对疾病或病症如阿尔茨海默病、帕金森病、亨廷顿病、缺血性中风和朊病毒病进行治疗或成像的化合物和方法,包括施用治疗有效量的色甘酸酯。(Described herein are compounds and methods for treating or imaging diseases or disorders such as alzheimer's disease, parkinson's disease, huntington's disease, ischemic stroke, and prion disease, comprising administering a therapeutically effective amount of cromoglycate.)

1. A method of treating or preventing a disease or disorder comprising administering a compound selected from the group consisting of:

wherein the disease or condition is head injury, traumatic brain injury, dementia, infection, atherosclerosis, or asthma.

2. The method of claim 1, further comprising administering a pharmaceutically acceptable carrier.

3. The method of claim 1 or 2, wherein the compound is administered orally.

4. The method of any one of claims 1-3, wherein the compound is a solid dosage form.

5. The method of any one of claims 1-4, wherein the compound is

6. The method of any one of claims 1-4, wherein the compound is

7. The method of any one of claims 1-4, wherein the compound is

8. The method of any one of claims 1-7, wherein the method is a method of treating the disease or disorder.

9. A compound having the structure:

10. a compound having the structure:

11. a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 9 or claim 10.

12. A method of treating or preventing a disease or disorder comprising administering a compound selected from the group consisting of:

wherein the disease or disorder is Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, ischemic stroke, prion disease, head injury, traumatic brain injury, dementia, infection, atherosclerosis, or asthma.

13. The method of claim 12, further comprising administering a pharmaceutically acceptable carrier.

14. The method of claim 12 or 13, wherein the compound is administered orally.

15. The method of any one of claims 12-14, wherein the compound is a solid dosage form.

16. The method of any one of claims 12-15, wherein the compound is

17. The method of any one of claims 12-15, wherein the compound is

18. The method of any one of claims 12-15, wherein the compound is

19. The method of any one of claims 12-18, wherein the method is a method of treating the disease or condition.

20. A method of imaging a disease or condition comprising administering a compound selected from the group consisting of:

wherein the disease or disorder is Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, ischemic stroke, prion disease, head injury, traumatic brain injury, dementia, infection, atherosclerosis, or asthma.

21. The method of claim 20, further comprising administering a pharmaceutically acceptable carrier.

22. The method of claim 20 or 21, wherein the compound is administered orally.

23. The method of any one of claims 20-22, wherein the compound is a solid dosage form.

24. A method of imaging a disease or condition comprising administering a compound selected from the group consisting of:

wherein the disease or condition is head injury, traumatic brain injury, dementia, infection, atherosclerosis, or asthma.

25. The method of claim 24, further comprising administering a pharmaceutically acceptable carrier.

26. The method of claim 24 or 25, wherein the compound is administered orally.

27. The method of any one of claims 24-26, wherein the compound is a solid dosage form.

Background

Cromolyn (cromolyn), also known as cromoglycic acid, has traditionally been described as a mast cell stabilizer because its action is to prevent release of mediators such as histamine and cytokines from mast cells, thereby stabilizing inflammatory cells. The prevention of mediator release is thought to be a result of indirect blockade of calcium ion entry into the sensitized mast cell membrane. Cromolyn has also been shown to inhibit the migration of other inflammatory cells, such as neutrophils, eosinophils and monocytes.

Cromolyn is commonly sold as the Sodium salt, Sodium cromoglycate (or Cromolyn Sodium) for the treatment of asthma and various allergies. In general, cromolyn is administered as a nasal spray or as an aerosolized solution using an inhaler. However, cromolyn is a highly polar molecule and therefore its bioavailability is poor even when administered by inhalation. Furthermore, many patients (especially children and the elderly) find inhalers difficult to use, and poor inhalation techniques can affect the amount of drug reaching the lungs and the response to treatment.

Therefore, there is a need to develop orally administrable cromolyn analogs.

Disclosure of Invention

Provided herein are compounds, compositions, and methods useful for treating and/or preventing diseases. In some embodiments, the method comprises administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method further comprises administering a pharmaceutically acceptable carrier.

In one aspect, the compounds disclosed herein have the structure of formula I,

wherein

R¹Is a hydroxyl group,¹⁸F or F; and

R²independently of the other, is an alkyl group,

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating or preventing a disease or disorder, comprising administering a compound having the structure of formula I,

wherein

R¹Is a hydroxyl group,¹⁸F or F; and

R²independently of the other, is an alkyl group,

or a pharmaceutically acceptable salt thereof,

wherein the disease or disorder is Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, ischemic stroke, prion disease, head injury, traumatic brain injury, dementia, infection, atherosclerosis, or asthma. In some embodiments, the method further comprises administering a pharmaceutically acceptable carrier. In some embodiments, the compound is administered orally. In certain embodiments, the compound is a solid dosage form.

Brief description of the drawings

Figure 1 is a graph showing the Time Activity Curve (TAC) of compound 6 from a brain Positron Emission Tomography (PET) imaging study.

Figure 2 is a graph showing the Time Activity Curve (TAC) of compound 5 from a brain Positron Emission Tomography (PET) imaging study.

FIG. 3 is a graph showing data from a brain Positron Emission Tomography (PET) imaging study¹⁸Graph of the Time Activity Curve (TAC) of F-cromolyn (diacid).

FIG. 4 shows the assay of Compound 2,¹⁸Inhibition of Α β 42 aggregation by F-cromolyn (diacid) and cromolyn.

Detailed Description

In certain aspects, provided herein are cromoglycates, compositions and methods related to the treatment and/or prevention of diseases or disorders (e.g., alzheimer's disease, huntington's disease, parkinson's disease, amyotrophic lateral sclerosis, stroke, ischemic stroke, prion disease, head injury, traumatic brain injury, dementia, infection, atherosclerosis, asthma).

I. Compound (I)

In certain embodiments, provided herein are compounds having the structure of formula I,

wherein

R¹Is a hydroxyl group,¹⁸F or F; and

R²is an alkyl group, and the alkyl group,

or a pharmaceutically acceptable salt thereof. In some embodiments, R²Is ethyl, and in some embodiments, R²Is a tert-butyl group.

In certain embodiments, provided herein are compounds having the structure of formula I,

wherein

R¹Is a hydroxyl group,¹⁸F or F; and

R²is an alkyl group. In some embodiments, R²Is ethyl, and in some embodiments, R²Is a tert-butyl group.

In certain embodiments, the compound is selected from the compounds identified in table 1, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from the compounds identified in table 1.

TABLE 1

Pharmaceutical compositions

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

The compositions and methods of the invention can be used to treat an individual in need thereof. In certain embodiments, the subject is a mammal, e.g., a human or non-human mammal. When administered to an animal, such as a human, the composition or compound is preferably administered in the form of a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions, such as water or physiological buffered saline or other solvents or vehicles, such as glycols, glycerol, oils (e.g., olive oil) or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for administration to a human, particularly for invasive routes of administration (i.e., routes such as infusion or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipient may be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in dosage unit forms such as tablets, capsules (including dispersible capsules and gelatin capsules), granules, lyophilizates for reconstitution, powders, solutions, syrups, suppositories, injections and the like. The composition may also be present in a transdermal delivery system, such as a skin patch. The composition may also be present in a solution suitable for topical administration, such as eye drops.

The pharmaceutically acceptable carrier may comprise a physiologically acceptable agent that, for example, acts to stabilize, increase solubility, or increase absorption of a compound (e.g., a compound of the invention). Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextran; antioxidants, such as ascorbic acid or glutathione; a chelating agent; low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical compositions (formulations) may also be liposomes or other polymeric matrices, which may contain therein, for example, a compound of the invention. For example, liposomes comprising phospholipids or other lipids are non-toxic, physiologically acceptable and metabolizable carriers that are relatively easy to prepare and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, at a reasonable benefit/risk ratio, judged by sound medicine to be suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication.

The phrase "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered Astragalus membranaceus (Fisch.) bge; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a phosphate buffer solution; and (21) other non-toxic compatible materials used in pharmaceutical formulations.

The pharmaceutical compositions (formulations) can be administered to a subject by any of a variety of routes of administration, including, for example, by oral administration [ e.g., soaking agents in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including dispersion capsules and gelatin capsules), boluses, powders, granules, pastes, administration to the tongue ]; absorption through the oral mucosa (e.g., sublingual); through the anus, rectum or vagina (e.g., pessary, cream or foam); by parenteral (including intramuscular, intravenous, subcutaneous or intrathecal injection, e.g. as a sterile solution or suspension); through the nose; through the abdominal cavity; subcutaneously; by transdermal (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment or spray applied to the skin, or as eye drops). The compounds may also be formulated as inhalants. In certain embodiments, the compound may simply be dissolved or suspended in sterile water. Detailed descriptions of suitable routes of administration and compositions suitable for use in such routes of administration can be found, for example, in U.S. Pat. nos. 6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970, and 4,172,896, and the patents cited therein.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Typically, the amount is from about 1% to about 99%, preferably from about 5% to about 70%, and most preferably from about 10% to about 30% of the active ingredient in one hundred percent.

Methods of preparing these formulations or compositions include the step of bringing into association an active compound (e.g., a compound of the invention) with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be in the form of capsules (including dispersible capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophilizates, powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or as lozenges (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwash, and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compositions or compounds may also be administered in the form of a bolus, electuary or paste.

To prepare solid dosage forms for oral administration [ capsules (including dispersion-type capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like ], the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as: sodium citrate or dicalcium phosphate, and/or any of the following carriers: (1) fillers or extenders, for example starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binding agents, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; (10) complexing agents, such as modified and unmodified cyclodextrins; and (11) a colorant. In the case of capsules (including dispersion-type capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or lactose fractions and high molecular weight polyethylene glycols and the like.

Tablets may be made by compression or molding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including both dispersible capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the pharmaceutical art). They may also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized, for example, by filtration through a sterile filter, or by inclusion of a sterilizing agent in the form of a sterile solid composition which is soluble in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition that it releases the active ingredient(s) only, or preferentially, in a particular region of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymers and waxes. The active ingredient may also be in the form of microcapsules, if appropriate with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, lyophilizates for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, and which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

Formulations of pharmaceutical compositions for oral administration may be presented as mouthwashes or as oral sprays or oral ointments.

Alternatively or additionally, the composition may be formulated for delivery through a catheter, stent, wire, or other intraluminal device. Delivery through such devices may be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Formulations suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be suitable.

Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

In addition to the active compounds, ointments, pastes, creams and gels may contain excipients, for example animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can also contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms may be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers may also be used to increase the transdermal flux of the compound. The rate of flux can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions, and the like are also contemplated as within the scope of the present invention. Exemplary ophthalmic formulations are described in U.S. publication nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074, and U.S. patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, the liquid ophthalmic preparation has properties similar to those of tears, aqueous humor or vitreous humor, or is compatible with such liquids. A preferred route of administration is topical (e.g. topical administration, such as eye drops, or administration via an implant).

The terms "parenteral administration" and "administered parenterally" as used herein mean forms of administration other than enteral and topical administration, typically by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular (subarachnoid), subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions immediately prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that can be employed in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating material (e.g., lecithin), by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using a liquid suspension of crystalline or amorphous material that is poorly water soluble. The rate of absorption of the drug then depends on its rate of dissolution, which in turn depends on the crystal size and crystalline form. Alternatively, long-term absorption of parenterally administered drug forms is achieved by dissolving or suspending the drug in an oil carrier.

Injectable depot forms (depot forms) are prepared by forming a microencapsulated matrix of the subject compounds in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of release of the drug can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

For use in the methods of the invention, the active compound may be administered as such or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The method of introduction may also be provided by a reloadable or biodegradable device. In recent years, various sustained release polymer devices have been developed and tested in vivo to control drug delivery, including protein biopharmaceuticals. A variety of biocompatible polymers, including biodegradable and non-degradable polymers, including hydrogels, can be used to form implants for sustained release of compounds at specific target sites.

The actual dosage level of the active ingredient in the pharmaceutical composition can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, and which is non-toxic to the patient.

The selected dosage level will depend upon a variety of factors well known in the medical arts, including the activity of the particular compound or combination of compounds or esters, salts or amides thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the length of treatment, other drugs, compounds and/or substances used in conjunction with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and the like.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start a dose of a pharmaceutical composition or compound at a dose below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. "therapeutically effective amount" refers to a concentration of a compound sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age and medical history of the subject. Other factors that affect an effective amount may include, but are not limited to: the severity of the patient's condition, the disease being treated, the stability of the compound, and, if desired, another type of therapeutic agent in combination with a compound of the invention. A larger total dose can be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al (1996) Harrison's Principles of Internal Medicine 13 th edition, 1814-.

In general, a suitable daily dose of active compound for use in the compositions and methods of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above.

An effective amount of the composition may be administered once daily or in divided doses throughout the day, for example 2 to 3 times daily. For example, administration of a composition according to the invention may be carried out at a frequency of, for example, 3 or more times per day, which frequency is typically maintained for at least one week, 2 weeks, 3 weeks, 4 weeks, or even 4 to 15 weeks, optionally including one or more drug withdrawal periods or repeated after a drug withdrawal period.

In certain embodiments, the compound may be administered at a dose of 1mg to 1,500mg per day, such as 5mg to 1,300mg per day, such as 10mg to 900mg per day, such as 20mg to 600mg per day, such as 40mg to 300mg per day, such as 150mg to 350mg per day, such as 40mg to 150mg per day, such as 25mg to 150mg per day, such as 2.5mg to 150mg per day, such as 20mg to 80mg per day, or such as 1mg to 30mg per day. In certain embodiments, the compound can be administered at a dose of 1,300 mg/day, 900 mg/day, 600 mg/day, 350 mg/day, 300 mg/day, 250 mg/day, 200 mg/day, 150 mg/day, 80 mg/day, 75 mg/day, 60 mg/day, 40 mg/day, 30 mg/day, 20 mg/day, 15 mg/day, 10 mg/day, 5 mg/day, or 2.5 mg/day.

The dose of the compound can be as low as 5 ng/d. In certain embodiments, a compound is administered at a dose of about 10 ng/day, about 15 ng/day, about 20 ng/day, about 25 ng/day, about 30 ng/day, about 35 ng/day, about 40 ng/day, about 45 ng/day, about 50 ng/day, about 60 ng/day, about 70 ng/day, about 80 ng/day, about 90 ng/day, about 100 ng/day, about 200 ng/day, about 300 ng/day, about 400 ng/day, about 500 ng/day, about 600 ng/day, about 700 ng/day, about 800 ng/day, about 900 ng/day, about 1 μ g/day, about 2 μ g/day, about 3 μ g/day, about 4 μ g/day, about 5 μ g/day, about 10 μ g/day, about 15 μ g/day, about 20 μ g/day, about 30 μ g/day, about 40 μ g/day, about 50 μ g/day, about 60 μ g/day, about 70 μ g/day, about 80 μ g/day, about 90 μ g/day, about 100 μ g/day, about 200 μ g/day, about 300 μ g/day, about 400 μ g/day, about 500 μ g/day, about 600 μ g/day, about 700 μ g/day, about 800 μ g/day, about 900 μ g/day, about 1 mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day, or about 50 mg/day.

The dose of active agent may range from 5ng/d to 100 mg/day. In certain embodiments, the dose of active agent may range from about 5 ng/day to about 10 ng/day, about 15 ng/day, about 20 ng/day, about 25 ng/day, about 30 ng/day, about 35 ng/day, about 40 ng/day, about 45 ng/day, about 50 ng/day, about 60 ng/day, about 70 ng/day, about 80 ng/day, about 90 ng/day, about 100 ng/day, about 200 ng/day, about 300 ng/day, about 400 ng/day, about 500 ng/day, about 600 ng/day, about 700 ng/day, about 800 ng/day, or about 900 ng/day. In certain embodiments, the dose of the compound can range from about 1 μ g/day to about 2 μ g/day, about 3 μ g/day, about 4 μ g/day, about 5 μ g/day, about 10 μ g/day, about 15 μ g/day, about 20 μ g/day, about 30 μ g/day, about 40 μ g/day, about 50 μ g/day, about 60 μ g/day, about 70 μ g/day, about 80 μ g/day, about 90 μ g/day, about 100 μ g/day, about 200 μ g/day, about 300 μ g/day, about 400 μ g/day, about 500 μ g/day, about 600 μ g/day, about 700 μ g/day, about 800 μ g/day, or about 900 μ g/day. In certain embodiments, the dose of the active agent may range from about 1 mg/day to about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, or about 900 mg/day.

In certain embodiments, the compounds are administered at pM or nM concentrations. In certain embodiments, the compound is administered at the following concentrations: about 1pM, about 2pM, about 3pM, about 4pM, about 5pM, about 6pM, about 7pM, about 8pM, about 9pM, about 10pM, about 20pM, about 30pM, about 40pM, about 50pM, about 60pM, about 70pM, about 80pM, about 90pM, about 100pM, about 200pM, about 300pM, about 400pM, about 500pM, about 600pM, about 700pM, about 800pM, about 900pM, about 1nM, about 2nM, about 3nM, about 4nM, about 5nM, about 6nM, about 7nM, about 8nM, about 9nM, about 10nM, about 20nM, about 30nM, about 40nM, about 50nM, about 60, about 70nM, about 80nM, about 90nM, about 100nM, about 300nM, about 400nM, about 600nM, about 700nM or about 900 nM.

The invention includes the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the invention. The term "pharmaceutically acceptable salts" as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of molecules making up the salt is not 1: 1. For example, a salt may comprise more than one molecule of an inorganic or organic acid per molecule of base, e.g. two molecules of hydrochloric acid per molecule of compound. As another example, the salt may comprise less than one molecule of inorganic or organic acid per molecule of base, e.g., two molecules of compound per molecule of tartaric acid.

In certain embodiments, the salts contemplated herein include, but are not limited to, L-arginine, benzphetamine (benenthamine), benzathine, betaine, calcium hydroxide, choline, dimethylethanolamine (deanol), diethanolamine, diethylamine, 2- (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine (hydrabamine), 1H-imidazole, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, the salts contemplated by the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts. In other embodiments, salts contemplated by the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts.

Pharmaceutically acceptable salts may also exist in the form of various solvates, for example with water, methanol, ethanol, dimethylformamide and the like. Mixtures of these solvates may also be prepared. The source of these solvates may be from the crystallization solvent, either inherent in the preparation or crystallization solvent or accidentally incorporated into the solvent.

As will be appreciated by those skilled in the art, the compositions of the present invention have no adverse effect when administered to a subject and may be administered to a subject daily.

Preferred embodiments of the present invention are described herein. Of course, variations, changes, modifications and substitutions of equivalents to those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations, changes, modifications, and alterations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Those skilled in the art will readily recognize a variety of non-critical parameters that may be changed, altered, or modified to produce substantially similar results. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Although each element of the present invention is described herein as comprising multiple embodiments, it is to be understood that each embodiment of a given element of the present invention can be used with various embodiments of other elements of the present invention unless otherwise specified, and each such use is intended to form a separate embodiment of the present invention.

Method III

In some embodiments, provided herein are methods for treating a disease or disorder in a subject in need thereof, comprising administering to the subject a compound disclosed herein (e.g., a compound of formula I) or a composition.

In some embodiments, the disease or disorder is selected from Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), stroke, ischemic stroke, prion disease, huntington's disease, parkinson's disease, head injury, Traumatic Brain Injury (TBI), dementia, infection, atherosclerosis, asthma, and amyloidosis-associated disorders.

An "amyloidosis-associated disorder" is a disease associated with amyloid deposition and may include, but is not limited to, alzheimer's disease, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, down's syndrome, Scrapie (scarapie), medullary thyroid cancer, isolated atrial amyloid, beta in dialysis patients₂-amyloid protein of microglobulin, inclusion body myositis, beta in muscle wasting diseases₂Amyloid deposits, as well as Langerhans diabetes type I1 insulinoma, type 2 diabetes, hereditary cerebral hemorrhage amyloidosis (the Netherlands), amyloid A (reactive), secondary amyloidosis, familial Mediterranean fever, familial amyloid nephropathy with urticaria and deafness (Weldui's (Muckle-wells) syndrome), amyloid λ L-chain or amyloid κ L-chain (idiopathic, myeloma or macroglobulinemia associated) Abeta 2M (chronic hemodialysis), ATTR (familial amyloid polyneuropathy (Portugal, Japan, Sweden)), familial amyloid cardiomyopathy (Denmark), isolated cardiac amyloid, systemic senile amyloidosis, AIAPP or amylin insulinoma, atrial natriuretic factor (isolated atrial amyloid), procalcitonin (medullary carcinoma of the thyroid), gelsolin (familial amyloidosis (finland)), cystatin C (hereditary cerebral hemorrhage with amyloidosis (iceland)), AApo-a-1 (familial amyloidosis, polyneuropathy-iowa), AApo-a-II (accelerated aging in mice), head injury (traumatic brain injury), dementia, fibrinogen-associated amyloid; and Asor or Pr P-27 (scrapie, Creutzfeld Jacob disease, GSS syndrome (Gertsmann Straussler-Scheinker syndrome), bovine spongiform encephalopathy) or humans homozygous for the apolipoprotein E4 allele, as well as disorders associated with the apolipoprotein E4 allele homozygosity or huntington's disease.

"amyloidosis" is a condition characterized by the accumulation of various insoluble fibrous proteins in the tissues of a patient. Amyloid deposits are formed by aggregation of amyloid proteins followed by further combination of aggregates and/or amyloid proteins.

There are various forms of amyloidosis, and the disease can be divided into four groups: primary amyloidosis, secondary amyloidosis, hereditary amyloidosis, and amyloidosis associated with normal aging. Primary amyloidosis (light chain amyloidosis) is associated with plasma cell abnormalities, and some patients with primary amyloidosis also have multiple myeloma (plasma cell carcinoma). The typical sites of amyloid accumulation in primary amyloidosis are the heart, lungs, skin, tongue, thyroid, intestine, liver, kidneys and blood vessels. Secondary amyloidosis may be a response to a variety of diseases that result in persistent infection or inflammation, such as tuberculosis, rheumatoid arthritis, and familial mediterranean fever. Typical sites of amyloid accumulation in secondary amyloidosis are spleen, liver, kidney, adrenal gland and lymph nodes. Hereditary amyloidosis is found in several families, particularly those from portuguese, sweden and japan. The defect in amyloid production occurs due to mutations in specific proteins in the blood. Typical sites of amyloid accumulation in hereditary amyloidosis are nerves, heart, blood vessels, and kidney.

In some embodiments of the methods described herein, the compound is administered orally. In some embodiments of the methods described herein, the compound is in a solid dosage form.

Definition of

For the purposes of the present invention, the following definitions will be used (unless explicitly stated otherwise):

the use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

The term "acyl" is well known in the art and refers to a group represented by the general formula hydrocarbyl C (O) -, preferably alkyl C (O) -.

The term "amido" is well known in the art and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl C (O) NH-.

The term "acyloxy" is art-recognized and refers to a group represented by the general formula hydrocarbyl C (O) O-, preferably alkyl C (O) O-.

The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, to which oxygen is attached. Representative alkoxy groups include methoxy, ethoxy, propoxy, t-butoxy, and the like.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond, and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," the latter of which refers to alkenyl moieties having substituents that replace a hydrogen on one or more carbons of the alkenyl. Such substituents may be present on one or more carbons, with or without inclusion in one or more double bonds. Moreover, these substituents include all substituents contemplated for alkyl groups, as described below, unless stability does not permit. For example, substitution of an alkenyl group with one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated.

"alkyl" or "alkane" is a straight or branched chain nonaromatic hydrocarbon that is fully saturated. Generally, unless otherwise defined, straight or branched chain alkyl groups have from 1 to about 20 carbon atoms, preferably from 1 to about 10 carbon atoms. Examples of linear and branched alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and tert-butyl,T-butyl, pentyl, hexyl, pentyl and octyl. C₁-C₆Straight or branched alkyl is also referred to as "lower alkyl". Alkyl groups having two open valences are sometimes referred to as alkylene groups, e.g., methylene, ethylene, propylene, and the like.

Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl moieties having substituents that replace a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, may include, for example: halogen, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, acylamino, amidine, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. The skilled person will appreciate that the moiety substituted on the hydrocarbon chain may itself be substituted, if appropriate. For example, substituents of substituted alkyl groups may include: substituted or unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate) and silyl, as well as ether, alkylthio, carbonyl (including ketones, aldehydes, carboxylates and esters), -CF₃-CN, etc. Exemplary substituted alkyl groups are described below. Cycloalkyl may be further alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl substituted alkyl, -CF₃And CN, etc.

The term "C_x-y"when used in conjunction with a chemical moiety (e.g., acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy) is intended to include groups containing from x to y carbons in the chain. For example, the term "C_x–yAlkyl "refers to substituted or unsubstituted saturated hydrocarbon groups, including straight and branched chain alkyl groups containing from x to y carbons in the chain, including haloalkyl, e.g.Trifluoromethyl, 2,2, 2-trifluoroethyl, and the like. C₀Alkyl represents hydrogen when the group is in the terminal position and a bond if it is internal. The term "C_2–yAlkenyl "and" C_2–yAlkynyl "refers to a substituted or unsubstituted unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively. When applied to heteroalkyl,' C_x-y"means that the group contains x to y carbons and heteroatoms in the chain. When applied to carbocyclic ring structures such as aryl and cycloalkyl, "C_x-y"means that the ring contains from x to y carbon atoms. When applied to heterocyclic structures, e.g. heteroaryl and heterocyclyl, ` C `_x-y"means that the ring contains x to y carbons and heteroatoms. When applied to groups having ring and chain members, e.g. aralkyl and heterocyclylalkyl groups, "C_x-y"means that the ring and chain together contain x to y carbon atoms, and appropriate heteroatoms.

As used herein, the term "alkylamino" refers to an amino group substituted with at least one alkyl group.

As used herein, the term "alkylthio" refers to a thiol group substituted with an alkyl group, and may be represented by the general formula alkyl S-.

As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls," the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may be present on one or more carbons that may or may not be included in one or more triple bonds. Moreover, these substituents include all substituents contemplated for alkyl groups, as described above, unless stability does not permit. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated.

The term "amide" as used herein refers to a group

Wherein each R is¹⁰Independently represent hydrogen or a hydrocarbyl group, or two R¹⁰Together with the N atom to which they are attached form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The terms "amine" and "amino" are well known in the art and refer to both unsubstituted and substituted amines and salts thereof, such as moieties that can be represented by the formula,

wherein each R is¹⁰Independently represent hydrogen or a hydrocarbyl group, or two R¹⁰Together with the N atom to which they are attached form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group.

As used herein, the term "aryl" includes a substituted or unsubstituted monocyclic aromatic group, wherein each atom of the ring is carbon. Preferably, the ring is a 5 to 7 membered ring, more preferably a 6 membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term "carbamate" is well known in the art and refers to a group

Wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group, e.g. alkyl, or R⁹And R¹⁰Together with the intervening atoms, form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

As used herein, the terms "carbocycle" and "carbocyclyl" refer to a saturated or unsaturated ring in which each atom of the ring is carbon. The term "carbocycle" includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include cycloalkane rings wherein all carbon atoms are saturated and cycloalkene rings comprising at least one double bond. "carbocycle" includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of the bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycles include bicyclic molecules in which two rings share one, two, or three or more atoms between them. The term "fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of the fused carbocyclic ring may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, the aromatic ring (e.g., phenyl) may be fused to a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated and aromatic bicyclic rings, where valence is allowed, is included in the definition of carbocyclic ring. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1, 5-cyclooctadiene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include decalin, naphthalene, 1,2,3, 4-tetrahydronaphthalene, bicyclo [4.2.0] octane, 4,5,6, 7-tetrahydro-1H-indene and bicyclo [4.1.0] hept-3-ene. The "carbocycle" may be substituted at any one or more positions capable of bearing a hydrogen atom.

A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "cycloalkyl" includes monocyclic and bicyclic rings. Unless otherwise defined, monocyclic cycloalkyl groups typically have from 3 to about 10 carbon atoms, more typically from 3 to 8 carbon atoms. The second ring of the bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which two rings share one, two, or three or more atoms between them. The term "fused cycloalkyl" refers to bicyclic cycloalkyl groups in which each ring shares two adjacent atoms with the other ring. The second ring of the fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. "cycloalkenyl" groups are cyclic hydrocarbons containing one or more double bonds.

As used herein, the term "carbocyclylalkyl" refers to an alkyl group substituted with a carbocyclyl.

The term "carbonate" is well known in the art and refers to the group-OCO₂-R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

As used herein, the term "carboxy" refers to a compound of the formula-CO₂And H represents a group.

As used herein, the term "ester" refers to the group-C (O) OR¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

As used herein, the term "ether" refers to a hydrocarbyl group linked to another hydrocarbyl group through an oxygen. Thus, the ether substituent of the hydrocarbyl group may be hydrocarbyl-O-. The ethers may be symmetrical or asymmetrical. Examples of ethers include, but are not limited to: heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkoxyalkyl" groups, which may be represented by the general formula alkyl-O-alkyl.

As used herein, the terms "halo" and "halogen" refer to halogens, including chlorine, fluorine, bromine, and iodine.

As used herein, the terms "heteroaralkyl" and "heteroarylalkyl" refer to an alkyl group substituted with a heteroaryl group.

As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent. Similarly to alkyl, heteroalkyl groups having two open valences are sometimes referred to as heteroalkylene groups. Preferably, the heteroatoms in the heteroalkyl group are selected from O and N.

The term "heteroaryl" includes substituted or unsubstituted aromatic monocyclic ring structures, preferably 5 to 7 membered rings, more preferably 5 to 6 membered rings, the ring structure of which comprises at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

As used herein, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The terms "heterocyclyl" and "heterocycle" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3 to 10 membered ring, more preferably a 3 to 7 membered ring, which ring structure includes at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyl" and "heterocycle" also include polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is a heterocycle, e.g., the other rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

As used herein, the term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl.

As used herein, the term "hydrocarbyl" refers to a group bonded through carbon atoms not having an ═ O or ═ S substituent, and typically has at least one carbon-hydrogen bond and a predominant carbon backbone, but may optionally include heteroatoms. Thus, for purposes of this application, groups such as methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered hydrocarbyl groups, but substituents such as acetyl (with an ═ O substituent on the attached carbon) and ethoxy (attached through oxygen rather than carbon) are not hydrocarbyl groups. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

The term "lower", when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, is intended to encompass groups in which there are ten or fewer, preferably six or fewer, non-hydrogen atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing ten or fewer, preferably six or fewer, carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituents, as defined herein, are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, respectively, whether occurring alone or in combination with other substituents, for example when describing hydroxyalkyl and aralkyl groups (in which case, for example, when calculating the carbon atoms in the alkyl substituent, the atoms in the aryl group are not calculated).

As used herein, "alleviating" refers to reducing the negative effects caused by exposure to ionizing radiation relative to a cell, organ, tissue, or organism that is exposed to the same level of radiation for the same duration of time but is untreated.

As used herein, a "therapeutically effective amount" is an amount sufficient to mitigate the effects of ionizing radiation.

The terms "polycyclyl" and "polycyclic" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings". Each ring of the polycyclic ring may be substituted or unsubstituted. In certain embodiments, each ring of the polycyclic ring contains 3 to 10 atoms in the ring, preferably 5 to 7 atoms. When a polycyclic substituent is attached through an aryl or heteroaryl ring, the substituent may be referred to herein as an aryl or heteroaryl group, and if the polycyclic substituent is attached through a cycloalkyl or heterocyclyl group, the substituent may be referred to herein as a cycloalkyl or heterocyclyl group. For example, 1,2,3, 4-tetrahydronaphthalen-1-yl is cycloalkyl and 1,2,3, 4-tetrahydronaphthalen-5-yl is aryl.

The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

The term "substituted" refers to a moiety having a substituent that replaces one or more carbons or heteroatoms of the moiety. It is understood that the term "substituted" or "substitution with … …" includes the implicit proviso that such substitution complies with the valency allowed by the substituting atom or group and that the substitution results in a stable compound, e.g., that the compound is not spontaneously transformed, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds.

In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents can be one or more and the same or different. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent, and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatom. Substituents may include any of the substituents described herein, such as halogen, hydroxy, carbonyl (e.g., carboxy, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. The skilled person will appreciate that the substituents themselves may be substituted if appropriate. Unless specifically stated to be "unsubstituted," reference herein to a chemical moiety is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

The term "sulfate" is well known in the art and refers to the group-OSO₃H or a pharmaceutically acceptable salt thereof.

The term "sulfonamide" is art-recognized and refers to a group represented by the general formula,

wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group, e.g. alkyl, or R⁹And R¹⁰Together with the intervening atoms, form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

The term "sulfoxide" is well known in the art and refers to the group-S (O) -R¹⁰Which isIn R¹⁰Represents a hydrocarbon group.

The term "sulfonate" is well known in the art and refers to the group SO₃H or a pharmaceutically acceptable salt thereof.

The term "sulfone" is well known in the art and refers to the group-S (O)₂-R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

As used herein, the term "thioalkyl" refers to an alkyl group substituted with a thiol group.

As used herein, the term "thioester" refers to the group-C (O) SR¹⁰or-SC (O) R¹⁰Wherein R is¹⁰Represents a hydrocarbon group.

As used herein, the term "thioether" is equivalent to an ether, wherein the oxygen is replaced by sulfur.

The term "urea" is well known in the art and may be represented by the general formula,

wherein R is⁹And R¹⁰Independently represent hydrogen or a hydrocarbyl group, e.g. alkyl, or any R⁹And R¹⁰And the central atoms together form a heterocyclic ring having from 4 to 8 atoms in the ring structure.

As used herein, the term "administering/dosing/administration" refers to the actual physical introduction of a composition into or onto the body of a subject (as the case may be). Any and all methods of introducing a composition into a subject are contemplated according to the present invention; the method is not dependent on any particular manner of introduction and should not be so interpreted. The manner of introduction is well known to those skilled in the art and is also exemplified herein.

As used herein, the terms "effective amount," "effective dose," "sufficient amount," "amount effective to … …," "therapeutically effective amount," or grammatical equivalents thereof, refer to an amount that satisfies the following: sufficient to produce the desired result, sufficient to ameliorate or in some way reduce symptoms or halt or reverse progression of the condition, and provide subjective relief of symptoms or an objectively identifiable improvement as indicated by a clinician or other qualified observer. Ameliorating a symptom of a particular disorder by administering a pharmaceutical composition described herein refers to any alleviation, whether permanent or temporary, persistent or transient, that may be associated with the administration of the pharmaceutical composition.

As used herein, the term "pharmaceutically acceptable" refers to compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to a subject, preferably a human subject. Preferably, the term "pharmaceutically acceptable" as used herein means approved by a regulatory agency of the federal or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

As used herein, a therapeutic agent that "prevents" a disease or disorder refers to a compound that, in a statistical sample, reduces the occurrence of the disease or disorder in a treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disease or disorder relative to an untreated control sample.

As used herein, a "subject" can be any mammal. For example, the subject can be a human, a non-human primate (e.g., monkey, baboon, or chimpanzee), a horse, a cow, a pig, a sheep, a goat, a dog, a cat, a rabbit, a guinea pig, a gerbil, a hamster, a rat, or a mouse. In some embodiments, the subject is an infant (e.g., a human infant). In some embodiments, the subject is a human.

The term "treating" is art-recognized and includes administering one or more of the subject compositions to a subject, e.g., to reduce, ameliorate, or stabilize an existing unwanted condition or side effects thereof.

Examples

The foregoing is a general description of the invention that will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the invention, and are not intended to limit the invention.

Example 1-5, 5' - [ (2-hydroxy-1, 3-propanediyl) bis (oxy)]Bis [ 4-oxo-4H-1-benzopyran- Synthesis of diethyl 2-carboxylate

Scheme 1

Briefly, a suspension of cromolyn sodium salt (1.0g,2 mmol) in EtOH (100mL) and concentrated HCl (1mL) was heated in a sealed reaction tube at 100 ℃ for 24 hours. The white solid dissolved while hot to give a clear colorless solution. It was allowed to cool to room temperature and NaHCO was added₃(1.0 g). After stirring for 30 minutes at 25 ℃, the solvent was removed by rotary evaporation. Chromatography of the crude material on silica gel using 5:95 methanol/dichloromethane afforded diethyl ester (0.8g, 76% yield); mp 154-156 ℃;¹HNMR(CDCl₃,300MHz)δ1.42(t,3H,J＝7.1Hz,CH₃),2.73(br s,1H,OH),4.44(q,4H,J＝7.1Hz,2OCH₂CH₃),4.32-4.59(m,5H,CHOH,2OCH₂) 6.80(s,2H,2 vinyl-H), 6.99(d,2H, J ═ 8.24Hz,2Aro-H),7.12(d,2H, J ═ 8.24Hz,2Aro-H),7.17(d,2H, J ═ 8.24Hz,2Aro-H),7.71(t,2H, J ═ 8.242 Aro-H).

Example 2-5, 5' - [ (2-fluoro-1, 3-propanediyl) bis (oxy)]Bis [ 4-oxo-4H-1-benzopyran-2- Synthesis of diethyl carboxylate

a) 3-bis (4-methylbenzenesulfonate) -2-fluoropropanediol

A solution of 1, 3-bis (4-methylbenzenesulfonate glycerol (2.7g,6.78 mmol) in dichloromethane (20mL) is treated at 0-5 ℃ with DAST (2.18g,13.6 mmol.) the mixture is stirred at 0-5 ℃ 30, then warmed to 25 ℃ and stirred for 16 hours the mixture is poured into a saturated solution of sodium bicarbonate (30mL) and the layers are separated, the dichloromethane layer is dried (sodium sulfate), the solvent is removed, the crude material is chromatographed on silica gel (dichloromethane) to give 0.82g (30%) of a solid, mp99-102 ℃;¹H NMR(CDCl₃),δ2.5(s,6H,CH₃),4.15(dd,4H,J＝12.3,4.6Hz,CH₂,4.8(dq,1H,J＝47,4.6,CHF),7.45(d,4H,J＝8.1Hz,Aro-H),7.75(d,4H,J＝8.4Hz,Aro-H)。

b)5,5' - (2-fluoropropane-1, 3-diyl) bis (oxy) bis (4-oxo-4H-chromene-2-carboxylic acid)

1, 3-bis (2-acetyl-3-hydroxyphenoxy) -2-fluoropropane

A mixture of 3-bis (4-methylbenzenesulfonate) -2-fluoropropanediol (1.0,2.5 mmol), 2, 6-dihydroxyacetophenone (0.76g,5.0 mmol) and potassium carbonate (0.69g) in acetonitrile (40mL) was heated at reflux for 16 h. The mixture was filtered and the filtrate was evaporated. The crude material is chromatographed on silica gel (acetonitrile/dichloromethane 5:95) to give 0.57g (40%) of product; mp 162-165 ℃;¹H NMR(d6-DMSO),δ2.5(s,6H,2CH₃),4.38(m,4H,2CH₂),5.22(br d 1H,J＝49Hz,CHF),6.45(m,4H,4Aro-H),7.28(t,2H,J＝4.55Hz,2Aro-H)。

c)5,5' - [ (2-fluoro-1, 3-propanediyl) bis (oxy) ] bis [ 4-oxo-4H-1-benzopyran-2-carboxylic acid diethyl ester

A mixture of 1, 3-bis (2-acetyl-3-hydroxyphenoxy) -2-fluoropropane (200mg,0.52 mmol) and ethyl oxalate (2mL) was added to a solution of sodium ethoxide (87mg Na) in ethanol (10mL) and benzene (10 mL). The mixture was heated at reflux for 16 h, cooled and diluted with ether (50 mL). The precipitated sodium salt was filtered, washed with diethyl ether and dried. It was then dissolved in water and acidified with 10% HCl to obtain a viscous solid. The solid was refluxed with a catalytic amount of 36% HCl in ethanol (20mL) for 1 hour. The mixture was poured into 50mL of water and extracted twice with dichloromethane (50 mL). The extracts were combined and dried. After removal of the solvent, the crude material is chromatographed on silica gel (acetonitrile/dichloromethane)Alkane 10:90) to yield 0.12g (45%) of product; mp 166-170 ℃;¹H NMR(CDCl₃),δ1.42(t,6H,J＝7.14Hz,2CH₃),4.58(q,4H,J＝7.14Hz 2CH₂),4.65(m,4H,2CH₂) 5.35(dq,1H, J ═ 46Hz, J ═ 4.4Hz, CHF),6.90(s,2H, vinyl-H), 6.95(d,2H, J ═ 8.24Hz,2Aro-H),7.13(d,2H, J ═ 8.24Hz,2Aro-H),7.17(d,2H, J ═ 8.24Hz,2Aro-H)7.6(t,2H, J ═ 8.242 Aro-H).

Or, reacting 1, 3-bis [ tolylsulfonyl) oxy]-2- [ (trifluoromethyl) sulfonyl group]Oxy-propane (9mg) in acetonitrile (0.4mL) was added to the solution containing dry K¹⁸F/Kryptofix complex (3mg K)₂CO₃7mg Kryptofix) the fluorination was carried out at 80 ℃ for 10 minutes. Subjecting the obtained 2 to [2 ]¹⁸F]Fluoropropane 1, 3-xylenesulfonate solution is passed through silica gel SepPak (using methylene chloride) into a column containing K₂CO₃(10mg) and ethyl 5-hydroxy-4-oxo-4H-chromene-2-carboxylate (10 mg). After removal of the solvent, DMSO was added and the mixture was heated at 130 ℃ for 10 minutes. 1mL of 5% HCl was added followed by 2mL of 50/50 acetonitrile 0.1M ammonium formate, filtered (Millex-LCR 0.45 μ M), and the F-18 color diglyceride was purified by HPLC (C18, 50:50 acetonitrile/0.1M ammonium formate). The synthesis was completed in 90 minutes with a yield of 20% (corrected for EOB) and a chemical purity of greater than 95%.

Example 3-5, 5' - [ (2-hydroxy-1, 3-propanediyl) bis (oxy)]Bis [ 4-oxo-4H-1-benzopyran- Synthesis of di-tert-butyl 2-carboxylate

Disodium cromoglycate (5g) dissolved in water (100mL) was acidified with 10% HCl and the resulting diacid precipitate was filtered and dried. A suspension of cromolyn diacid powder (1.0g, 2.1 mmol) in toluene (80mL) was heated to reflux. Dripping within 4 hoursN, N-dimethylformamide di-tert-butyl acetal (4.3g, 21 mmol) was added and the mixture was refluxed overnight. The reaction mixture was decanted to remove solids and the solvent was evaporated in vacuo at 50 ℃. Chromatography of the crude material on silica gel using 65:30:5 hexane/ethyl acetate/methanol gave di-tert-butyl ester (0.37g, 30% yield); mp 147-;¹H NMR(CDCl₃,400MHz)δ1.57(s,9H,CH₃),2.73(br s,1H,OH),4.32-4.59(m,4H,2OCH₂) 5.35(br d,1H, J ═ 46Hz, CHF),6.87(s,2H,2 vinyl-H), 6.93(d,2H, J ═ 8.24Hz,2Aro-H),7.12(d,2H, J ═ 8.24Hz,2Aro-H),7.14(d,2H, J ═ 8.24Hz,2Aro-H),7.57(t,2H, J ═ 8.242 Aro-H). HPLC analysis was performed on a Phenomenex Luna C18 column (250mm X4.60 mm) using 60:40 acetonitrile/0.1M ammonium formate (1mL/min) as mobile phase (Rt ═ 14 min).

Example 4-5, 5' - [ (2-fluoro-1, 3-propanediyl) bis (oxy)]Bis [ 4-oxo-4H-1-benzopyran-2- Synthesis of di-tert-butyl carboxylate

The compound of example 3 above was used for 5,5' - [ (2-hydroxy-1, 3-propanediyl) bis (oxy)]A similar procedure for di-tert-butyl bis [ 4-oxo-4H-1-benzopyran-2-carboxylate. Chromatography of the crude material on silica gel using 70:30 hexane/ethyl acetate gave di-tert-butyl ester (0.47g, 39% yield);¹H NMR(CDCl₃,400MHz)δ1.57(s,9H,CH₃),2.73(br s,1H,OH),4.32-4.59(m,4H,2OCH₂) 5.35(dq,1H, J ═ 46Hz, J ═ 4.4Hz, CHF),6.87(s,2H,2 vinyl-H), 6.93(d,2H, J ═ 8.24Hz,2Aro-H),7.12(d,2H, J ═ 8.24Hz,2Aro-H),7.14(d,2H, J ═ 8.24Hz,2Aro-H),7.57(t,2H, J ═ 8.242 Aro-H). HPLC analysis was performed on a Phenomenex Luna C18 column (250mm X4.60 mm) using 70:30 acetonitrile/0.1M ammonium formate (1mL/min) as mobile phase (Rt ═ 13.2 min).

Example 5-5, 5' - [ (2- [ 18F)]Fluoro-1, 3-propanediyl) bis (oxy)]Bis [ 4-oxo-4H-1-benzopyrene Synthesis of di-tert-butyl pyran-2-carboxylate

Di-tert-butyl hydroxytryptorate (0.5g, 0.86mg), p-toluenesulfonyl chloride (0.2g,1.76 mmol) from example 3 and 10mg DMAP (4-dimethylaminopyridine) were stirred in 20ml pyridine at 0-5 ℃ for 2 hours and then at 25 ℃ for 16 hours. The mixture was washed with cold 10% HCl until the aqueous layer was acidified and then with 10% NaHCO₃And (6) washing. Chromatography of the crude oil on silica gel using dichloromethane methanol (95:5) gave 0.48g (76%) of the tosylate ester of di-tert-butyl cromoglycate.

A solution of ditertiary butyl cromoglycate (5mg) in DMSO (0.4mL) was added to a solution containing dry K18F/Kryptofix complex (3mg K)₂CO₃7mg Kryptofix) in a 5mL vial. The reaction flask was heated at 130 ℃ for 10 minutes, cooled to 25 ℃ and diluted with 1mL of a 10:90 acetonitrile/0.1M ammonium formate mixture. Purification by HPLC (C18, 70:30 acetonitrile/0.1M ammonium formate) gave F-18 color di-tert-butyl glycolate. The synthesis was completed in 90 minutes with a yield of 40% (corrected for EOB) and a chemical purity of greater than 95%.

Example 6 brain Positron Emission Tomography (PET) imaging Studies

Using compound 5 (diethyl ester), compound 6 (di-tert-butyl ester) and¹⁸dynamic PET imaging (GE Discovery MI scanner) was performed on F-cromolyn (diacid) in rhesus monkeys.

Three kinds of¹⁸Monkey imaging of F-cromolyn analogs showed the order of brain tracer penetration to be diethyl esters>Di-tert-butyl ester>Diacids (see fig. 1,2 and 3). Diethyl ester¹⁸Color F-Glycine showed uptake in all areas of the brain, with the highest in the putamen, gray matter and cerebellum, followed by the caudate nucleus, thalamus and white matter. Uptake was immediate, reaching a maximum (2.3SUV) at 2min and washout was slow, 2SUV at 20 min, 1.5 at 60 min. Brain uptake is consistent with lipophilicity values, with a measured logD of 2.5 for diethyl ester and 3.5 for di-tert-butyl ester.

Example 7 blood analysis

Using compound 5 (diethyl ester), compound 6 (di-tert-butyl ester) and¹⁸arterial blood sampling and radioactive metabolite analysis were performed with F-cromolyn (diacid). Blood sampling display¹⁸F-diacid cromolyn is the only metabolite at 20 minutes. The tert-butyl ester is also metabolized to¹⁸F-diacid, but at a slower rate. In vitro stability tests demonstrated that hydrolysis to the diacid form appears to occur in blood.

Citation of references

All publications and patents mentioned herein are incorporated herein by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions therein, will control.

Equivalents of

While specific embodiments of the invention have been discussed, the foregoing description is illustrative only and not limiting. Many variations of the invention will become apparent to those skilled in the art upon review of the specification and claims. The full scope of the invention should be determined by reference to the appended claims, along with the full scope of equivalents to which such claims are entitled, and to the specification, along with such variations.