CHROMANOL COMPOUNDS FOR THE TREATMENT OR PREVENTION OF AGEING AND AGE-RELATED DISORDERS - Patent application

Abstract

The present invention relates to certain chromanol, quinone or hydroquinone compounds and their derivatives for the treatment or prevention of aging or idiopathic aging-related disorders such as vascular aging or reduced renal function. In particular, the present invention relates to chromanol compounds selected from (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13), 6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109), or enantiomers thereof, and pharma- ceutically acceptable salts thereof.

Description

[Technical field]

[0001] The present invention relates generally to chromanol compounds and their derivatives for the treatment or prevention of aging or age-related disorders. In particular, the present invention relates to chromanol compounds and their derivatives for the treatment or prevention of aging in general, and in particular vascular aging and / or reduced kidney function due to aging. [Background technology]

[0002] Average human lifespan in most developed countries has doubled in the past 200 years as a result of improvements in water, food, sanitation, housing, and lifestyle quality, vaccinations against infectious diseases, antibiotics, and medical care conditions. However, longer human lifespans have led to a global burden of diseases in later life. Approximately half of human deaths are attributable to age-related disorders or diseases, most notably cardiovascular disease (CVD), diabetes, chronic obstructive pulmonary disease (COPD), stroke, Alzheimer's disease, chronic kidney disease (CKD), and cancer (Chang, A., Skirbekk, V., Tyrovolas, S., Kassebaum, N. and Dieleman, J., 2019. Measuring population ageing: an analysis of the Global Burden of Disease Study 2017. The Lancet Public Health, 4(3), pp. e159-e167).

[0003] One of the most major age-related diseases affecting developed countries is cardiovascular disease (CVD). CVD is caused by vascular changes and is characterized by vasodilation dysfunction and overproduction of inflammatory markers (Camici, G., Savarese, G., Akhmedov, A. and Luscher, T., 2015. Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease. European Heart Journal, 36(48), pp. 3392-3403). Furthermore, this article shows the complexity of aging, which involves many factors.

[0004] Aging cells and organisms are thought to accumulate increased levels of oxidant-damaged nuclear and mitochondrial DNA. Increased damage to mitochondrial DNA is thought to result in impaired mitochondrial function and integrity. As a result, damaged mitochondria trigger the release of more reactive oxygen species (ROS), increasing DNA damage and initiating a vicious cycle that results in increased ROS production leading to further DNA damage. Although the role of oxidants and accumulated DNA damage in the pathogenesis of many age-related diseases is widely accepted, the clinical use of antioxidant therapy remains rather unclear.

[0005] Studies in accelerated aging animal models have shown that chronic treatment with sGC activators, PDE1 inhibitors or PDE5 inhibitors, and sildenafil failed to improve endothelium-dependent relaxation (Golshiri, K., Ataei Ataabadi, E., Rubio-Beltran, E., et al., 2021. Selective Phosphodiesterase 1 Inhibition Ameliorates Vascular Function, Reduces Inflammatory Response, and Lowers Blood Pressure in Aging Animals. Journal of Pharmacology and Experimental Therapeutics, 378(2), pp.173-183., Golshiri, K., Ataei Ataabadi, E., Brandt, R., et al., 2020. Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging. International Journal of Molecular Sciences, 21(13), p.4667).

[0006] AT1 receptor blockade with losartan had no beneficial effect on vasomotor function in an accelerated aging animal model (Wu, H., van Thiel, B., Bautista-Nino, P., et al., 2017. Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ / -mice. Clinical Science, 131(15), pp.1941-1953).

[0007] The anticancer drug rapamycin failed to preserve vasodilator function in an accelerated aging animal model (Birkisdottir, M., Jaarsma, D., Brandt, R., et al., 2021 Aging Cell, 20(2)). Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcriptional stress in premature aging DNA repair-deficient mice.

[0008] To date, only dietary restriction has been successful in improving vasomotor function in age-accelerated animal models, but dietary restriction as a lifestyle intervention in humans is limited in scope given the degree of self-restraint required.

[0009] There remains a need for new compounds for the effective treatment or prevention of aging or age-related disorders.

[0010] WO2006 / 105806A1 relates to the use of a complex mixture comprising at least a combination of a statin, a compound that inhibits the production or activity of angiotensin, an anti-inflammatory agent, and at least one antioxidant, for the prevention and / or treatment of the aging process itself and disorders caused by aging.

[0011] WO2015 / 148522A1 relates to a composition comprising nicotinamide mononucleotide for treating age-related vascular dysfunction by improving endothelial function and reducing the stiffness of large elastic arteries.

[0012] WO2012 / 116985A1 relates to a pharmaceutical composition comprising a sub-therapeutic daily dose of at least one inhibitor of the renin-angiotensin-aldosterone system and a sub-therapeutic daily dose of at least one HMG-CoA reductase inhibitor for use in preventing, reducing or reversing arterial aging in apparently healthy subjects.

[0013] All these references describe active substances and / or complex mixtures that have undesirable side effects.

[0014] It is an object of the present invention to provide compounds for the treatment or prevention of aging and / or age-related disorders, in particular for the treatment or prevention of vascular aging and / or age-related decline in kidney function. Summary of the Invention

[0015] One or more of the above objects are met by providing certain chromanol, quinone, or hydroquinone compounds for use in such treatment.

[0016] More specifically, one or more of the above objects are achieved by providing a compound according to formula (I), (II), a hydroquinone analogue of formula (II), or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of ageing or idiopathic ageing-related disorders, [ka] wherein R1 represents hydrogen or a prodrug moiety capable of being removed in living tissue; - R2 and R3 together with the N atom to which they are attached form a saturated or unsaturated non-aromatic optionally substituted 5-8 membered ring having 1-4 N, O, or S atoms and R2 and R3 together containing 3-12 carbon atoms; or or R2 is a hydrogen atom or an alkyl group having 1-6 carbon atoms, R3 is an alkyl group optionally substituted with nitrogen or oxygen, the alkyl group containing 3-12 carbon atoms, the alkyl group in R3 containing one or more non-aromatic cyclic structures, which may contain nitrogen or oxygen atoms in the ring, linear and / or branched substituents, and one or more ethylenically unsaturated groups.

[0017] In particular, the present invention provides compounds for use in the treatment and prevention of disease states associated with reduced endothelium-dependent NO-cGMP vasodilation.Preferably, the present invention provides compounds for use in preserving vascular function through EDHF rescue.

[0018] In one preferred embodiment of the invention, the treatment of aging comprises increasing the lifespan of a mammal, preferably a human.

[0019] One of ordinary skill in the art would understand that any such treatment should be considered a medical treatment, and that non-medical treatments waive entitlement to a claim for a medical treatment.

[0020] Insofar as the treatment of aging and / or the improvement of conditions associated with reduced endothelium-dependent NO-cGMP vasodilation and / or the preservation of vascular function through EDHF rescue are not considered medical treatments, the present invention also provides the use of compounds defined as for increasing longevity, improving conditions associated with reduced endothelium-dependent NO-cGMP vasodilation and / or the preservation of vascular function through EDHF rescue in a mammal. The mammal is preferably a human. Those skilled in the art will understand that any of such treatments should be considered non-medical treatments, and that medical treatments waive the right to claim for non-medical treatments.

[0021] In the present invention, compounds according to formula (II) include hydrogenated quinone (ie, hydroquinone) analogs, although quinone derivatives are preferred from a stability standpoint.

[0022] In preferred embodiments, the nitrogen may be an amine, a quaternary amine, a guanidine, or an imine, the oxygen may be a hydroxyl, a carbonyl, or a carboxylic acid, and / or the oxygen and nitrogen may together form an amide, urea, or carbamate group.

[0023] In a preferred embodiment of the compounds according to either formula (I) or formula (II), R2 and R3 together with the N atom to which they are attached form a saturated ring incorporating an additional N atom, which ring is unsubstituted or substituted with an alcohol or alkanol group having 1 to 4 carbon atoms, such as ethylol.

[0024] In another preferred embodiment, R2 is a hydrogen atom and R3 comprises a saturated cyclic structure having 4 to 7 carbon atoms and one nitrogen atom, which ring may be substituted with an alkyl group, an alcohol group, or a group having 1 to 4 carbon atoms, which may include an oxygen, a carboxylic acid, or an amine group.

[0025] In another preferred embodiment, the compound is a compound according to formula II, R2 is a hydrogen atom, and R3 has 4-6 carbon atoms and includes a cyclic structure with one nitrogen atom, the ring being unsubstituted or substituted with an alcohol or an alkanol group having 1-4 carbon atoms, such as ethylol, preferably optionally substituted with methyl, ethyl, or an alcohol substituted with methyl or ethyl.

[0026] In another preferred embodiment, the compound is a compound according to formula I, R2 is a hydrogen atom, and R3 has 4 to 7 carbon atoms and comprises a saturated cyclic structure with one nitrogen atom, the ring being unsubstituted or substituted with an alcohol or an alkanol group having 1 to 4 carbon atoms, such as ethylol, preferably optionally substituted with methyl, ethyl, or an alcohol substituted with methyl or ethyl.

[0027] According to yet another preferred embodiment, the compound is either (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13) or (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109) as a racemic mixture or as one of its enantiomers, or a pharma- ceutically acceptable salt thereof.

[0028] In the most preferred embodiment, the compound is the S-enantiomer of SUL-109, namely, S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-138). [Brief description of the drawings]

[0029] The features and advantages of the present invention will be understood with reference to the following drawings.

[0030] [Figure 1] Kaplan-Meier curves showing survival of Drosophila treated with various concentrations of SUL109: control (purple), 10 uM (blue), 100 uM (green), and 1000 uM (grey). Continuous lines represent females and dotted lines represent males. [Diagram 2] Kaplan-Meier curves showing survival of Drosophila treated with various concentrations of SUL121: control (purple), 10 uM (blue), 100 uM (green), and 1000 uM (gray). Continuous lines represent females and dotted lines represent males. [Diagram 3]Effect of chronic SUL138 treatment on ED relaxation in LM vs. EC-KO mice. Acetylcholine (Ach) dose-response curves compared to U46619 precontractions. Means are expressed as mean ± SEM per group. *: significant effect of genotype (p<0,05); #: significant effect of treatment (p<0,05); p=0,054 EC-KO control vs. EC-KO treated. [Figure 4] Pathway contribution to ACh responses in LM vehicle animals. Means are expressed as mean ± SEM per group. *: significant effect of inhibitors (p<0.05). [Diagram 5] Pathway contribution to ACh responses in KO vehicle animals. Means are expressed as mean ± SEM per group. *: significant effect of inhibitors (p<0.05). [Figure 6] Pathway contribution to ACh responses in KO SUL138 treated animals. Means are expressed as mean ± SEM per group. *: significant effect of inhibitors (p<0.05). [Figure 7] Urinary albumin and creatinine levels from 22 week old mice. Means are expressed as mean ± SEM per group. *: significant effect of genotype (p<0.05), (*): p=0.0871. [Figure 8] Urinary albumin / creatinine ratio and plasma creatinine levels (22 week old mice). Means are expressed as mean ± SEM per group. *: significant effect of genotype (p<0.05). [Figure 9] Plasma creatine levels (22 week old mice). Means are expressed as mean ± SEM per group. *: significant effect of genotype (p<0.05). [Figure 10] Creatinine levels in 24-hour urine from 21-week-old mice. Means are expressed as mean ± SEM per group. *: significant effect of genotype (p<0.05), (*): p=0.088. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] One or more of the objects of the present invention to provide a compound for the treatment or prevention of aging and / or aging-related disorders is met by providing a compound according to formula (I) or (II) as shown above, or a pharma- ceutically acceptable salt thereof.

[0032] R1 may be a substituent that is easily removed in the human body, so that the compound is a prodrug. R1 may be, for example, an amino acid derivative or an ester derivative, and generally has a molecular weight of less than 100 daltons.

[0033] In a preferred embodiment, R1 in formula (I) is hydrogen or, together with the 6-oxygen, forms an ester group having 2 to 6 carbon atoms. The ester may contain one or more ether or alcohol groups. Suitable esters are acetate, butyrate, 3-hydroxybutyrate, etc.

[0034] In a preferred embodiment of the compounds according to either formula (I) or formula (II), R2 and R3 together with the N atom to which they are attached form a saturated ring having 3 to 6 carbon atoms and incorporating one additional N atom, which ring may be substituted with 1 to 4 carbon atoms which may include oxygen, carboxylic acid, or amine groups.

[0035] More preferably, R2 and R3 together with the N atom to which they are attached form a 5- to 7-membered ring containing one additional amine group, which ring is optionally substituted with methyl, ethyl, or a methyl- or ethyl-substituted alcohol.

[0036] In another preferred embodiment, R2 is a hydrogen atom and R3 includes a cyclic structure having 3 to 6 carbon atoms and one nitrogen atom.

[0037] More preferably, R2 is a hydrogen atom and R3 comprises a 5-7 membered ring containing one additional amine group attached to the amide nitrogen, which is optionally substituted with methyl, ethyl, or a methyl or ethyl substituted alcohol.

[0038] In either case, the ring (the cyclic structure formed by R2 and R3, or by R3 alone) may be unsubstituted or substituted with an alkyl group having 1 to 4 carbon atoms, an alcohol, or an alkanol group having 1 to 4 carbon atoms, such as ethylol.

[0039] In a preferred embodiment according to the invention, the compound either according to formula (I) or according to formula (II) has a molecular weight of less than 500 Da.

[0040] In a preferred embodiment, the compound for use according to the invention is a chromanol compound according to formula I.

[0041] Certain chromanol compounds are described in WO2014 / 098586. The compounds detailed have the abbreviation SUL-XXX, where XXX is a two or three digit number. Many of these compounds are racemic mixtures, but some enantiomers have been tested as well. Suitable methods for preparing chromanol compounds according to the invention are described in WO2014 / 098586 or WO2014 / 011047.

[0042] WO2017 / 060432 A1 discloses amide derivatives of 2-hydroxy-2-methyl-4-(3,5,6-trimethyl-1,4-benzoquinone-2-yl)-butanoic acid and methods for making such compounds.

[0043] The hydrogenated quinone derivatives can be readily prepared by hydrogenation of the quinone structure.

[0044] According to yet another preferred embodiment, the compound is either (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13) or (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109) as a racemic mixture or as one of its enantiomers, or a pharma- ceutically acceptable salt thereof.

[0045] In the most preferred embodiment, the compound is the S-enantiomer of SUL-109, namely, S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-138).

[0046] The counter ion in the pharma- ceutically acceptable salt can be any counter ion known in the art.Preferably, the compound has at least one basic nitrogen, an amine, and the compound can be protonated.The counter ion is preferably a halogen, such as chloride, sulfate, citrate, formate, and the like, and is most preferably chloride.

[0047] The compounds are available as racemic mixtures or in substantially pure enantiomeric form.The compounds have one or more, typically one or two, chiral centers.

[0048] Preferably, the compound is a substantially enantiomerically pure compound. Substantially enantiomerically pure is an enantiomeric excess of about 95% or more, more preferably about 98% or more, and most preferably about 99% or more. These amounts also apply when the compound contains two or more chiral centers.

[0049] The compounds are preferably used in an effective amount to achieve treatment or prevention of aging or aging-related disorders.

[0050] The term treatment or prevention includes ameliorating the symptoms of aging and / or slowing down the progression of aging, including improving vascular and renal function.

[0051] The term "treatment" encompasses reducing the progression of a disorder and / or ameliorating the symptoms of a disorder.

[0052] In one preferred embodiment of the invention, the treatment of aging comprises increasing the lifespan of a mammal, preferably a human.

[0053] Preferably, the compounds according to the invention are for use in the treatment or prevention of age-related disorders in a mammal, which mammal is preferably a human.

[0054] Age-related disorders include vascular aging, renal function reduction, amnesia, pulmonary function reduction, etc. These disorders are idiopathic or simply associated with aging, but do not have a specific underlying disease, such as asthma, COPD, Alzheimer's disease, etc. Thus, administering the compounds of the present invention increases the quality and / or lifespan of aging mammals.

[0055] One of ordinary skill in the art would understand that any such treatment should be considered a medical treatment, and that non-medical treatments waive entitlement to a claim for a medical treatment.

[0056] Insofar as any of the above treatments, such as, for example, the treatment of aging and / or the improvement of conditions associated with reduced endothelium-dependent NO-cGMP vasodilation and / or the preservation of vascular function through EDHF rescue, are not considered medical treatments, the present invention also provides the use of compounds defined as for increasing longevity, improving conditions associated with reduced endothelium-dependent NO-cGMP vasodilation and / or the preservation of vascular function through EDHF rescue in a mammal. The mammal is preferably a human. Those skilled in the art will understand that any of such treatments should be considered non-medical treatments, and that medical treatments waive the right to claim for non-medical treatments.

[0057] In a more preferred embodiment according to the present invention, the compound either according to formula (I) or according to formula (II) is for use for the treatment or prevention of vascular aging.

[0058] The present invention provides compounds for use in the treatment or prevention of ageing disorders associated with deterioration of mitochondrial function and health.

[0059] The present invention provides compounds for use in the treatment and prevention of disease states associated with reduced endothelium-dependent NO-cGMP vasodilation.Preferably, the present invention provides compounds for use in preserving vascular function through EDHF rescue.

[0060] Even more preferably, the compound either according to formula (I) or according to formula (II) is for use for the treatment or prevention of cardiovascular disease (CVD).

[0061] In a further embodiment, the compound either according to formula (I) or according to formula (II) is for use for the treatment or prevention of reduced kidney function due to aging.

[0062] The effect is generally observed at an amount of about 1 μM in body fluids, although higher amounts are preferably used. Preferred amounts are concentrations of about 10 μM or more in vivo or in vitro, more preferably about 20 μM or more. Generally, concentrations of about 200 μM or less should be sufficient and safe in humans.

[0063] For human use, assuming a volume of distribution of 30 L, 100% availability, and a concentration of about 1 μM, this would mean a dosage of about 10 mg or more. Preferred amounts would produce a concentration of about 10 μM - for which a dosage of about 100 mg or more would be suitable. Thus, preferably, dosage forms of about 20 mg or more, preferably 50 mg or more, preferably 100 mg or more are suitable.

[0064] Generally, taking into account excipients, a solid, oral dosage form contains a maximum of about 500 mg, preferably no more than about 450 mg, of the compound.

[0065] For example, larger amounts may be administered in other liquid dosage forms using parenteral administration, such as iv.

[0066] Examples of dosage amounts that may be used are effective amounts of the compounds of the invention in dosages of 0.2 mg / kg or more, preferably in the range of about 1 mg / kg to about 100 mg / kg, or about 2 mg / kg to about 40 mg / kg of body weight, or about 3 mg / kg to about 30 mg / kg of body weight, or about 4 mg / kg to about 15 mg / kg of body weight. The compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided dosages two, three, or four times daily.

[0067] The prevention or treatment of medical or non-medical aging or age-related disorders generally requires chronic administration of active compounds, i.e., administration of active substances for a long period of time.Preferably, chronic administration will generally include administration of active compounds for at least 2 months, preferably at least 4 months, and even more preferably for 6 months or more.In further preferred embodiments, administration will include administration of active compounds for a period of 1, 2, 3, 4, 5, or 6 years or more, such as up to 10, 20, or 30 years.Administration of active substances can be for a period of up to 60 years.

[0068] Treatment for a relatively long period of time, such as several months, years, or even longer, may include daily administration of one or more oral dosage forms, such as tablets or liquid.Preferably, one oral dosage form is administered once a day.However, alternative administration regimes may be effective, such as administering every other day, for example, every day for 3 weeks, and using drug holidays, such as not administering active substance for 1 week, for at least 4 months or 6 months, or even longer, such as several years.

[0069] Thus, chronic treatment according to the present invention involves administration of an active agent for months or more, preferably years or more, with an effective amount of the compound being administered throughout that period, either periodically or intermittently as explained above.

[0070] The compounds described herein can be formulated as pharmaceutical compositions by formulation with additives such as pharma- ceutical or physiologically acceptable excipient carriers and vehicles.

[0071] Suitable pharma- ceutically or physiologically acceptable excipients, carriers, and vehicles include, for example, processing agents and drug delivery modifiers and enhancers, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-P-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and the like, as well as combinations of any two or more thereof. Other suitable pharma-ceutically acceptable excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991).

[0072] The pharmaceutical composition preferably comprises a unit dose formulation, the unit dose being a dose sufficient to have a therapeutic effect. The unit dose may be a dose administered periodically during the course of treating or suppressing a disorder.

[0073] The compounds of the present invention in dosage unit formulations containing conventional non-toxic pharmacologic or physiologically acceptable carriers, adjuvants, and vehicles can be administered enterally, orally, parenterally, sublingually, by inhalation (e.g., mist or spray), rectally, or topically, as desired. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrapedicular injection, or infusion techniques. The compounds are mixed with pharmacologic acceptable carriers, adjuvants, and vehicles suitable for the desired route of administration.

[0074] Generally, oral administration is the preferred route of administration, and formulations suitable for oral administration are the preferred formulations.

[0075] The compounds described for use herein may be administered in solid, liquid, aerosol form, or in the form of tablets, pills, powder mixtures, capsules, granules, injections, creams, solutions, suppositories, enemas, colonic irrigation, emulsions, dispersions, food premixes, and other suitable forms. The compounds may also be administered in liposomal formulations.

[0076] Injectable preparations, for example, injectable sterile aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can also be injectable sterile solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in propylene glycol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any non-irritating non-volatile oils can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0077] Suppositories for rectal administration of a drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol, which are solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum and release the drug.

[0078] The solid dosage form for oral administration can include capsules, tablets, pills, powders, and granules.The active compound in such solid dosage form can be mixed with at least one inert diluent such as sucrose, lactose, or starch.Such dosage form can also contain additional material other than the inert diluent, for example, lubricant such as magnesium stearate.In the case of capsules, tablets, and pills, dosage form can also contain buffering agent.Tablets and pills can be prepared with enteric coating in addition.

[0079] Liquid dosage forms for oral administration may include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.Such compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents.

[0080] The amount of active ingredient that can be combined with carrier material to produce a single dosage form will vary depending on the host to which the active ingredient is administered and the specific mode of administration.The selected unit dosage is usually prepared and administered to provide a specified final concentration of drug in blood, tissue, organ, or other target area of ​​the body.The effective amount for a given situation can be easily determined by routine experimentation and is within the ability and judgment of the ordinary clinician or person skilled in the art.

[0081] The invention is further illustrated by the following examples, in which reference is made to the drawings. EXAMPLES

[0082] Example 1 - Study of the effect of SUL compounds on lifespan in a Drosophila model Experimental methodology Replenishing fly stocks and bait W1118 flies were bred and housed at 25°C on a 12:12 h light / dark cycle. Flies were maintained in vials containing approximately 5 mL of Bloomington diet consisting of sucrose, yeast suspension, agar, Nigapin, and fresh yeast. Flies maintained as stocks were flicked into fresh vials weekly. Diet was stored at 18°C ​​and warmed to room temperature before use.

[0083] SUL109 and SUL121 were used to evaluate the effect of chromanol compounds on the life span of fly stocks. Compounds were tested independently. Either SUL109 or SUL121 was added to the diet to final concentrations of 10 μM, 100 μM, and 1000 μM.

[0084] Drosophila lifespan W1118 flies were anesthetized in small groups using CO. Flies were then collected at a density of 5 males and 5 females per tube.

[0085] On days 10 and 11, trapped adults were anesthetized and housed at a density of 20 males and 20 females per tube. Ten vials were used per study condition (a total of 100 males and 100 females).

[0086] During their life span, flies were transferred to new vials containing fresh food three times a week and the number and sex of dead flies were recorded.

[0087] result W1118 flies were exposed to different concentrations of chromanol compounds (SUL109 and SUL121) in the diet from the larval stage until the moment of death. The results for both SUL components show that flies exposed to higher doses of the compounds have better survival rates than the control (see Figure 1 for SUL109 and Figure 2 for SUL121).

[0088] In the current experimental setting, the effect of two of these compounds, SUL109 and SUL121, on Drosophila longevity was tested. Results show an increase in longevity associated with treatment with the SUL compounds.

[0089] Example 2 - Ercc1 - / - Study of the effects of SUL compounds on vascular and renal function in (EC-KO) mouse model background Ercc1 - / - The efficacy of the compounds according to the invention for the treatment or prevention of age-related diseases was studied in an (EC-KO) mouse model.

[0090] Ercc1 - / - The (EC-KO) mouse model has endothelial cell (EC)-specific deletion of the DNA repair endonuclease Ercc1 that results in accelerated vascular aging features and is characterized by reduced endothelium-dependent NO-cGMP vasodilation at 22 weeks of age.

[0091] Therefore, EC-KO mice are an excellent animal model for studying age-related diseases, especially vascular aging.

[0092] Experimental methodology research design EC-KO mice and corresponding littermates (LM) were fed either a SUL138-treated (30 mg SUL138 / kg BW / day) or vehicle-treated (0,015% [v / v] ethanol) diet for 8 weeks (14–22 weeks of age).

[0093] At 21 weeks of age, animals were placed in metabolic cages. After 10 hours of acclimation, 24-hour urine collection was performed. At 22 weeks of age, mice were euthanized and urine, plasma, and tissues were collected.

[0094] Vascular function Segments of thoracic aorta were isolated and mounted in a wire-myograph containing Krebs Henseleit buffer (37° C., oxygenated with 95% O 2 and 5% CO 2 ) to assess endothelium-dependent (ED) relaxation.

[0095] Contraction of thoracic aortic isolates was induced with 100 mM KCl (final concentration) to assess vascular viability.

[0096] A stable synthetic analogue of the endoperoxide prostaglandin PGH2, namely U46619, was used for precontraction. Thoracic aortic segments were washed and then precontracted with U46619 (30–60 nM final concentration; 75–100% response to 100 mM KCl) followed by the ED vasodilator acetylcholine (ACh) (10 -9 ~10 -5 A dose-response curve was shown with the final concentration of M.

[0097] To assess the contribution of different pathways to the vasodilator response, segments were incubated with inhibitors for 15 min and then precontracted with U46619. -4 The contribution of nitric oxide (NO) to vasodilator responses was assessed by addition of 100 nM (100 mM) and 10 μM (100 mM) of L-NAME, apamin, and TRAM-34 to vasodilator responses.

[0098] The acute effect of SUL138 was assessed by preincubation at 100 μM for 30 min.

[0099] renal function Urinary creatine levels were measured in samples collected at 21 weeks of age and at euthanasia (22 weeks) using the QuantiChrom Creatinine Assay Kit (1:2 sample dilution) according to the manufacturer's instructions.

[0100] Urinary albumin levels were measured in samples collected at the time of euthanasia (22 weeks) using the Mouse Albumin ELISA kit ab108792 (1:400 sample dilution) according to the manufacturer's instructions.

[0101] Plasma creatinine was measured in samples collected at the time of euthanasia (22 weeks). Samples were undiluted. The QuantiChrom Creatinine Assay Kit (1:2 sample dilution) was used according to the manufacturer's instructions.

[0102] result Figure 3 shows the effect of chronic treatment of LM and EC-KO mice with SUL138. Chronic treatment with SUL138 restored ED relaxation in EC-KO mice compared to LM control levels.

[0103] Figure 4 shows pathway contributions to ACh responses in LM control (vehicle-treated) mice. It is demonstrated that ED relaxation in LM control mice is partially NO-driven (see L-NAME curve in Figure 4) and partially EDHF-driven (see L-NAME / apamin / TRAM34 curve in Figure 4).

[0104] Pathway contributions to ACh responses were also examined in EC-KO mice (vehicle-treated). The resulting curves are shown in Figure 5. Dysfunctional endothelium in vehicle-treated EC-KO resulted in a shift toward predominantly EDHF-driven ED relaxation (see L-NAME curve in Figure 5).

[0105] The results of pathway contribution to ACh responses in SUL138-treated EC-KO mice indicated that the effect of such chronic treatment resulted from an increase in EDHF-driven ED relaxation, as shown in Figure 6 (see L-NAME curves).

[0106] However, restoration of ED relaxation in EC-KO mice occurred only after chronic treatment with SUL138; acute treatment of mice with SUL138 had no effect on ED relaxation.

[0107] Figure 7 shows urinary albumin and creatine levels in 22-week-old mice. Vehicle-treated EC-KO mice showed a trend toward decreased albuminuria and creatinine filtration at that age compared with vehicle-treated LM. The results show that chronic treatment with SUL138 significantly improved creatinine filtration in EC-KO mice.

[0108] Figure 8 shows the albumin / creatinine ratio in urine and plasma of 22-week-old mice. It is shown that the albumin / creatinine ratio in urine was significantly elevated in vehicle-treated EC-KO mice compared to vehicle-treated LM mice. Chronic treatment with SUL138 resulted in a significant improvement in the albumin / creatinine ratio in EC-KO mice.

[0109] However, no effect could be identified in plasma creatinine content in vehicle-treated EC-KO mice compared with vehicle-treated LM mice (Figure 9).

[0110] Figure 10 shows creatine levels in 24-hour urine from 21-week-old mice. Results from analysis of urine collected at 21 weeks of age, i.e., 24-hour urine, showed the same trend of decreased creatinine filtration in vehicle-treated EC-KO mice compared to vehicle-treated LM mice. Such a trend was significantly ameliorated by chronic treatment of EC-KO mice with SUL138.

[0111] conclusion It has been observed that EDHF is often replaced by NO in models of progressive endothelial dysfunction. In this study, Ercc1-deficient mouse models show partial loss of EDHF and complete loss of NO as they age strongly at 16 weeks of age.

[0112] Our results show that SUL138 delays endothelial aging. The increase in EDHF, but not NO, after chronic treatment with SUL138 suggests compensation for loss of NO. Alternatively, chronic treatment with SUL138 could increase EDHF as a direct effect.

[0113] In summary, chronic treatment with SUL138 resulted in complete preservation of vascular function through EDHF rescue in tissues isolated from an Ercc1-deficient mouse model.

[0114] Furthermore, chronic treatment with SUL138 also resulted in protection of renal function in an Ercc1-deficient mouse model.

[0115] To date, only dietary restriction has been able to improve vasomotor function in an Ercc1-deficient age-accelerated mouse model (Wu et al., 2017, CI Sci). In contrast to the effects of other drugs in endothelial dysfunction models, SUL138 produces an attenuation of persistent DNA damage accumulation, similar to the demonstrated effects of dietary restriction.

[0116] Thus, the invention has been described by reference to certain specific embodiments discussed above, it will be recognized that these embodiments are susceptible to various modifications and alternative forms well known to those skilled in the art.

[0117] In addition to those described above, further modifications can be made to the structures and techniques described herein without departing from the spirit and scope of the present invention. Thus, while specific embodiments have been described, these are merely examples and are not intended to limit the scope of the present invention.

Claims

Claim 1: A pharmaceutical composition for use in the treatment or prevention of age-related or idiopathic age-related disorders, comprising a compound according to formula (I) or formula (II), a hydroquinone analog of formula (II), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 wherein R represents hydrogen or a prodrug moiety that can be removed in living tissue; (i) R2 and R3, together with the N atom to which they are attached, form a saturated or unsaturated non-aromatic, optionally substituted 5-8 membered ring having 1-4 N, O, or S atoms, and R2 and R3, together, containing 3-12 carbon atoms; or (ii) R2 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R3 is an alkyl group optionally substituted with nitrogen or oxygen, wherein the alkyl group in R3 contains 3 to 12 carbon atoms; and wherein the alkyl group in R3 contains one or more non-aromatic cyclic structures, which may contain nitrogen or oxygen atoms in the ring, may contain linear and / or branched substituents, and may contain one or more ethylenically unsaturated groups.

2. 2. The pharmaceutical composition of claim 1, wherein R1 is hydrogen or, together with the 6-oxygen, forms an ester group having 2 to 6 carbon atoms.

3. 2. The pharmaceutical composition of claim 1, wherein the nitrogen of R2 and / or R3 may be an amine, quaternary amine, guanidine, or imine, the oxygen of R2 and / or R3 may be a hydroxyl, carbonyl, or carboxylic acid, and / or the oxygen and nitrogen of R2 and / or R3 together may form an amide, urea, or carbamate group, and preferably, the compound according to formula (I) or formula (II) has a molecular weight of less than 500 Da.

4. 2. The pharmaceutical composition of claim 1, wherein R2 and R3 in the compound according to formula (I) or formula (II) together with the N atom to which they are attached form a saturated ring incorporating an additional N atom, which ring is unsubstituted or substituted with an alcohol or alkanol group having 1 to 4 carbon atoms.

5. 2. The pharmaceutical composition of claim 1, wherein the compound is a compound according to formula (I).

6. 6. The pharmaceutical composition of claim 5, wherein R2 and R3, together with the N atom to which they are attached, form a 5- to 7-membered ring containing one additional amine group, which ring is optionally substituted with methyl, ethyl, or a methyl- or ethyl-substituted alcohol.

7. 2. The pharmaceutical composition of claim 1, wherein R2 is a hydrogen atom and R3 comprises a saturated cyclic structure having 4 to 7 carbon atoms and one nitrogen atom, which ring can be substituted with an alkyl group, an alcohol group, or a group having 1 to 4 carbon atoms which can contain oxygen, a carboxylic acid, or an amine group, preferably the compound is a compound according to formula (I), wherein R2 is a hydrogen atom and R3 comprises a cyclic structure having 4 to 6 carbon atoms and one nitrogen atom, which ring is optionally substituted with methyl, ethyl, or an alcohol substituted with methyl or ethyl.

8. 2. The pharmaceutical composition of claim 1, wherein the compound is (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13), or (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109), as a racemic mixture or as one of its enantiomers, or a pharmaceutically acceptable salt thereof.

9. 9. The pharmaceutical composition of claim 8, wherein the compound is the S-enantiomer of SUL-109: S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-138), or a pharmaceutically acceptable salt thereof.

10. 2. The pharmaceutical composition of claim 1, wherein the use is for the treatment or prevention of vascular aging, for delaying aging, and / or for the treatment or prevention of age-related decline in kidney function.

11. 10. The pharmaceutical composition of claim 1, wherein the compound is administered chronically, preferably for several months or more, more preferably for several years or more, wherein the active agent is administered and an effective amount of the compound is administered throughout substantially the entire period.

12. The compound according to claim 1, wherein said treatment or prevention is associated with a reduction in endothelium-dependent NO-cGMP vasodilation.

13. 2. The pharmaceutical composition of claim 1, wherein the treatment and prevention is associated with preservation of vascular function through EDHF rescue.

14. The pharmaceutical composition of claim 1, wherein the use is for delaying aging in mammals, preferably humans.

15. 15. The pharmaceutical composition of claim 14, wherein the slowing of aging is associated with amelioration of conditions associated with reduced endothelium-dependent NO-cGMP vasodilation and / or preservation of vascular function through EDHF rescue.

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