EP4301370A1 - Polythérapie pour la prévention, l'inhibition, le traitement ou la réduction d'anévrismes - Google Patents

Polythérapie pour la prévention, l'inhibition, le traitement ou la réduction d'anévrismes

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Publication number
EP4301370A1
EP4301370A1 EP22763970.5A EP22763970A EP4301370A1 EP 4301370 A1 EP4301370 A1 EP 4301370A1 EP 22763970 A EP22763970 A EP 22763970A EP 4301370 A1 EP4301370 A1 EP 4301370A1
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EP
European Patent Office
Prior art keywords
alkyl
kit
heterocyclyl
aryl
heteroaryl
Prior art date
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Pending
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EP22763970.5A
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German (de)
English (en)
Inventor
Hua Cai
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University of California
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University of California
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Publication of EP4301370A1 publication Critical patent/EP4301370A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • AAA Abdominal aortic aneurysm
  • AAA oxidative stress driven vascular remodeling
  • vascular remodeling characterized by matrix degradation and inflammation, resulting in expansion of abdominal aortas.
  • the only clinical intervention to treat aortic aneurysms is limited to surgical correction of large AAAs of over 5.5 cm in size, and the 30-day mortality rate is high for both endovascular aortic aneurysm repair (EVAR) and open surgical repair at 1.7-4.7%.
  • EVAR endovascular aortic aneurysm repair
  • Thoracic aortic aneurysm is a term used to describe aneurysms formed at the thoracic region of the aorta, including ascending thoracic aorta/aortic root area (about 60%), and descending thoracic aorta area (about 40%).
  • Thoracic aortic aneurysms may be caused by arteriosclerosis (atherosclerosis), increased blood pressure (hypertension), congenital diseases such as Marfan Syndrome or trauma.
  • arteriosclerosis arteriosclerosis
  • blood pressure hypertension
  • congenital diseases such as Marfan Syndrome or trauma.
  • the prevalence of TAA is around 4.2% in general population.
  • no treatment options/oral medications have been available except for surgical correction.
  • Oxidative stress-driven vascular remodeling is a common pathway shared between AAA and TAA for aneurysm formation.
  • Cerebral aneurysms develop as a result of thinned/weakened artery walls. Aneurysms often form at forks or branches in arteries because those sections of the vessel are weaker and sensitive to vascular remodeling to result in aneurysm formation. Cerebral aneurysms are one of the most common cerebrovascular diseases. If the aneurysm is severe, it can develop into a hemorrhagic stroke with cerebrovascular bleeding. Likewise to AAA/TAA, no treatment options/oral medications have been available except for surgical correction. Oxidative stress- driven vascular remodeling is a common pathway shared between AAA/TAA and cerebral aneurysm for aneurysm formation.
  • compositions, kits and methods for preventing or treating an abdominal aortic aneurysm (AAA), a thoracic aortic aneurysm (TAA), or a cerebral aneurysm In certain aspects, provided herein are pharmaceutical compositions comprising a folate compound and a calcium channel blocker. Also provided herein are kits comprising a folate compound and a calcium channel blocker.
  • the methods provided herein comprise preventing or treating aneurysms (e.g., an abdominal aortic aneurysm (AAA), a thoracic aortic aneurysm (TAA), or a cerebral aneurysm) by conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • aneurysms e.g., an abdominal aortic aneurysm (AAA), a thoracic aortic aneurysm (TAA), or a cerebral aneurysm
  • the methods comprise ameliorating at least one symptom of an aneurysm or a symptom associated with an aneurysm by conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • the symptom may be, for example, increased superoxide production, increased eNOS uncoupling activity, decreased nitric oxide (NO) bioavailability, decreased tetrahydrobiopterin (TLB) bioavailability, enlargement of blood vessels (abdominal aortas, thoracic aortas or blood vessels in the brain), increased vascular remodeling, increased elastin degradation (flattening and breakdown), increased vascular inflammation/macrophage infiltration, increased matrix metalloproteinase (MMP) activation, increased adventitial hypertrophy, or a decrease in eNOS function.
  • NO nitric oxide
  • TLB tetrahydrobiopterin
  • a folate compound and a calcium channel blocker comprising conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • provided herein are methods of increasing eNOS function, nitric oxide (NO) and/or tetrahydrobiopterin bioavailabilities in a subject afflicted with an aneurysm by conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • An aneurysm described herein may be an AAA aneurysm, a TAA aneurysm, or a cerebral aneurysm.
  • the folate compound may be represented by formula I or a pharmaceutically acceptable salt thereof, wherein: each R 1 independently is hydrogen, acyl, ester, amide, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each R 2 independently is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; each R 3 and R 4 independently is halogen, cyano, nitro, amino, hydroxyl, alkylthio, alkoxy, acyloxy, acylamino, acyl, ester, amido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; m is an integer selected from 0-3; and n is an integer selected from 0-4.
  • Each R 1 independently is hydrogen, acyl, ester, amide, or alkyl. In some embodiments, each R 1 is hydrogen.
  • Each R 2 independently may be hydrogen or alkyl. In some embodiments, each R 2 is hydrogen. M and/or n may be 0.
  • the folate compound is or a pharmaceutically acceptable salt thereof.
  • the calcium channel blocker may be a dihydropyridine compound.
  • the dihydropyridine compound is represented by formula II: or a pharmaceutically acceptable salt thereof, wherein:
  • R 5 , R 6 , R 7 , R 8 , and R 10 each independently is hydrogen, halogen, cyano, nitro, amino, hydroxyl, alkylthio, alkoxy, acyloxy, acylamino, acyl, ester, amido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; and R 9 is hydrogen, acyl, ester, amide, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • the R 6 may be alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 6 is methyl or substituted or unsubstituted phenyl. R 6 may be a phenyl, optionally substituted with halogen, haloalkyl, alkyl, or nitro.
  • the dihydropyridine compound may be represented by formula Il-a, Il-b, II-c, or II-
  • R 9 may be a hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 9 is an alkyl optionally substituted with halogen, amino, hydroxyl, alkoxy, cyano, nitro, acyl, ester, amide, alkylthio, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 9 is
  • R 10 is cyano, amino, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 10 may be methyl.
  • the dihydropyridine compound is represented by formula Il-a- 1, II-b-1, II-c-1, or II-d-1 :
  • R 5 may be an alkoxy, amino, alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 5 is alkoxy optionally substituted with halogen, cyano, nitro, amino, hydroxyl, alkylthio, alkoxy, acyloxy, acylamino, acyl, ester, amido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 5 is
  • R 7 may be an acyl, ester, amide, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R 7 is
  • the R 8 may be a hydrogen, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 8 may be a hydrogen, hydroxyl, alkoxy, alkylthio, or alkyl optionally substituted with halogen, cyano, nitro, amino, hydroxyl, alkylthio, alkoxy, acyloxy, acylamino, acyl, ester, amido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.
  • R 8 is hydrogen,
  • the dihydropyridine compound is selected from:
  • lemildipine furnidipine and iganidipine or a pharmaceutically acceptable salt thereof.
  • the dihydropyridine compound is N-(2-aminopyridine)-2-aminopyridine compound.
  • the folate compound and the dihydropyridine compound may be in the same composition.
  • the folate compound may be folic acid.
  • the calcium channel blocker may be Nifedipine.
  • the amount administered of the folate compound and the amount administered of the calcium channel blocker are therapeutically effective.
  • the folate compound and the calcium channel blocker are administered in a mass ratio of about 10:1 to about 1:10.
  • the folate compound and the calcium channel blocker may be administered in a mass ratio of about 3:1 to about 3:4.
  • the folate compound may be administered in an amount of about 1-350 mg, about 1-700 mg, about 1-1050 mg, about 1-1400 mg, or about 1-1750 mg.
  • the calcium channel block is administered in an amount of about 1-350 mg, about 1-700 mg, about 1-1050 mg, about 1-1400 mg, about 1-1750 mg, about 1-2100 mg, or about 1-2450 mg.
  • the folate compound and the calcium channel blocker may be administered simultaneously or sequentially.
  • the folate compound and the calcium channel blocker are in separate dosage forms.
  • the aneurysm may be an abdominal aortic aneurysm, cerebral aneurysm, or thoracic aortic aneurysm.
  • the folate compound and the calcium channel blocker may be administered orally.
  • Figure lA-Fig. IB shows a combination of FA with Nifedipine substantially and completely further improved efficacy of FA in attenuating incidence of aortic aneurysm in a dose-dependent manner.
  • ApoE null mice of 6-8 months old were infused with angiotensin II (Ang II, 1000 ng/mg/min) for 4 weeks in the presence of regular chew, customized chew containing folic acid (FA, 15 mg/kg/day), or customized chew containing FA and various doses of Nifedipine (1.5, 5.0, and 20 mg/kg/day).
  • Fig. 1A shows the incidence of abdominal aortic aneurysm (AAA) in cross different groups.
  • Fig. 2A-Fig. 2B shows that combination of FA with Nifedipine substantially and completely further attenuated enlargement of abdominal aortas in a dose-dependent manner.
  • ApoE null mice of 6-8 months old were infused with angiotensin II (Ang II, 1000 ng/mg/min) for 4 weeks in the presence of regular chew, customized chew containing folic acid (FA, 15 mg/kg/day), or customized chew containing FA and various doses of Nifedipine (1.5, 5.0, and 20 mg/kg/day).
  • Enlargement of abdominal aortas was monitored weekly using ultrasound.
  • Fig. 2A shows representative weekly ultrasound images taken from different experimental groups.
  • Fig. 2B shows grouped data of ultrasound measurements of abdominal aortic areas.
  • Nifedipine at doses of 1.5, 5.0 and 20 mg/kg/day substantially/completely further attenuated enlargement of abdominal aortas in a dose-dependent manner (@@p ⁇ 0.01 or @@@p ⁇ 0.001 for 1.5 mg/kg/day Nifedipine group; &&p ⁇ 0.01 or &&&p ⁇ 0.001 for 5.0 mg/kg/day Nifedipine group; $$$p ⁇ 0.001 for 20 mg/kg/day Nifedipine group).
  • Nifedipine 5.0 or 20 mg/kg/day group was significantly more effective than Nifedipine 1.5 mg/kg/day group ( ⁇ p ⁇ 0.05;
  • n 4-19.
  • Fig. 3 shows combination of FA with Nifedipine substantially and completely further attenuated vascular remodeling in a dose-dependent manner.
  • ApoE null mice of 6-8 months old were infused with angiotensin II (Ang II, 1000 ng/mg/min) for 4 weeks in the presence of regular chew, customized chew containing folic acid (FA, 15 mg/kg/day), or customized chew containing FA and various doses of Nifedipine (1.5, 5.0, and 20 mg/kg/day).
  • Fig. 4 shows combination of FA with Nifedipine substantially and completely further attenuated elastin degradation in a dose-dependent manner.
  • ApoE null mice of 6-8 months old were infused with angiotensin II (Ang II, 1000 ng/mg/min) for 4 weeks in the presence of regular chew, customized chew containing folic acid (FA, 15 mg/kg/day), or customized chew containing FA and various doses of Nifedipine (1.5, 5.0, and 20 mg/kg/day).
  • Fig. 5A-Fig. 5B shows that combination of FA and Nifedipine substantially and completely further attenuated total superoxide production and eNOS uncoupling in a dose- dependent manner.
  • ApoE null mice of 6-8 months old were infused with angiotensin II (Ang II, 1000 ng/mg/min) for 4 weeks in the presence of regular chew, or oral administration of folic acid (FA, 15 mg/kg/day) in combination with various doses of Nifedipine (1.5, 5.0, and 20 mg/kg/day).
  • Fig. 5A shows total superoxide production determined by electron spin resonance (ESR).
  • ESR electron spin resonance
  • Fig. 5B shows aortic eNOS uncoupling activity determined by ESR. The data indicate that eNOS uncoupling activity, reflected by L-NAME-inhibitable superoxide production, was completely attenuated by oral administration of FA alone or in combination with various dosing of Nifedipine.
  • Fig. 6 shows a combination of FA and Nifedipine substantially further improved NO bioavailability in a dose-dependent manner.
  • ApoE null mice were infused with Ang II, fed regular chow or chow mixed with FA (15 mg/ kg/day) or chow mixed with FA plus different concentration of Nifedipine (1.5, 5 and 20 mg/kg/day).
  • ApoE null mice of 6-8 months old were infused with angiotensin II (Ang II, 1000 ng/mg/min) for 4 weeks in the presence of regular chew, or oral administration of folic acid (FA, 15 mg/kg/day) in combination with various doses of Nifedipine (1.5, 5.0, and 20 mg/kg/day).
  • Fig. 7 shows a combination of FA and Nifedipine substantially further improved aortic FEB bioavailability in a dose-dependent manner.
  • ApoE null mice were infused with Ang II, fed regular chow or chow mixed with FA (15 mg/ kg/day) or chow mixed with FA plus different concentration of Nifedipine (1.5, 5 and 20 mg/kg/day).
  • Aortic FEB bioavailability was determined by HPLC. The data indicate that there was a significant decrease in aortic FEB levels in Ang II infused apoE null mice, which was markedly restored by oral FA administration.
  • Combination of FA with 1.5, 5 and 20 mg/kg/day of Nifedipine substantially and dose-dependently further restored FEB bioavailability.
  • *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, n 4-10.
  • a novel role of endothelial nitric oxide synthase (eNOS) has been previously established in AAA formation via sustaining oxidative stress to induce MMP activity and matrix degradation. It has been demonstrated that eNOS uncoupling mediates AAA formation in a novel model of angiotensin II (Ang II) infused hph-1 mice, in which 79% of the mice developed AAA within 2 weeks of Ang II infusion, with 14% died of ruptured aneurysm (Gao L et al., Hypertension (2012)). This is the most robust AAA model to date.
  • Ang II angiotensin II
  • DHFR dihydrofolate reductase
  • FA oral folic acid
  • the inventors have further elucidated a novel role of eNOS uncoupling in mediating thoracic aortic aneurysm (TAA) and AAA formation mFbnl cl039G/+ Marfan Syndrome (MFS) mice, targeting of which with FA diet recouples eNOS to reduce superoxide production and restore NO bioavailability, resulting in attenuated formation of TAA and AAA. Therefore, these data further confirm a significant role of uncoupled eNOS in mediating AAA and TAA formation, and demonstrate a universal efficacy of FA in attenuating AAA and TAA formation via improvement in DHFR expression to restore eNOS coupling activity.
  • TAA thoracic aortic aneurysm
  • MFS Marfan Syndrome
  • Hypertension is a risk factor for AAA, and AAA patients often have co-existing hypertension.
  • An earlier study also investigated effects on AAA formation of both low and high doses of the anti-hypertensive drug Nifedipine, which is a calcium channel blocker. While low dose of Nifedipine has no effects on blood pressure, both low and high dose of Nifedipine were able to attenuate AAA formation, via restoration of DHFR expression and inhibition of NADPH oxidase to prevent eNOS uncoupling.
  • the high dose of Nifedipine can also reduce blood pressure at the same time, hence particularly valuable to treat patients with both AAA and co-existing hypertension. Nonetheless, neither FA alone nor Nifedipine alone is sufficient to fully attenuate AAA formation.
  • the goal of the present study is to examine whether combinatory therapy of FA and Nifedipine has synergistic effects in the suppression of AAA growth with augmented efficacy.
  • Ang Il-infused apoE null mice were therefore treated with combinatory therapy of FA and various doses of Nifedipine (1.5, 5 or 20 mg//kg/day), which exhibited novel and substantially improved therapeutic effects on AAA formation in a dose-dependent manner.
  • the present invention is based, in part, on the discovery that combinatory therapy of FA and Nifedipine alleviates vascular remodeling featured by elastin degradation and adventitial hypertrophy in a dose-dependent manner in a model of AAA.
  • the protective effects on AAA incidence and related pathophysiological changes are attributed to augmented effects of combinatory therapy on restoration of eNOS function and abrogation of oxidative stress.
  • Combination of FA with various doses of Nifedipine substantially and completely further attenuated superoxide production in a dose-dependent manner while completely recoupling eNOS to restore NO bioavailability also in a dose-dependent manner.
  • the combination treatment disclosed herein can be used to prevent or treat AAA, cerebral aneurysm and/or TAA. Given the common pathway between both TAA, cerebral aneurysm and AAA, the combination treatments disclosed herein would show synergy when administered to a subject afflicted with TAA, cerebral aneurysm and/or AAA.
  • compositions comprising a folate compound and a calcium channel blocker.
  • compositions, kits, and methods of the present invention may be utilized to treat an individual in need thereof (e.g., an individual suffering from an AAA, cerebral or TAA aneurysm).
  • the individual is a mammal such as a human, or a non human mammal.
  • the composition or the compound When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • the one or more folic acid compounds and one or more calcium channel blockers e.g., Nifedipine compounds
  • a therapeutically effective amount of the one or more folic acid compounds and one or more calcium channel blockers ranges from about 0.01 - 60 mg/kg body weight, about 0.01 - 45 mg/kg body weight, about 0.01 - 30 mg/kg body weight, or about 0.01- 15 mg/kg body weight of the one or more folic acid compounds, and about 0.01 - 40 mg/kg body weight, about 0.01 - 35 mg/kg body weight, about 0.01 - 30 mg/kg body weight, about 0.01 - 25 mg/kg, about 0.01 - 20 mg/kg, about 0.01 - 15 mg/kg, about 0.01 - 10 mg/kg, about 0.01 - 5 mg/kg, or about 0.01 - 1.5 mg/kg body weight of the one or more calcium channel blockers (e.g., Nifedipine compounds).
  • the one or more calcium channel blockers e.g., Nifedipine compounds
  • the ratio of the one or more folic acid compounds to the one or more calcium channel blockers (e.g., Nifedipine compounds) that are administered ranges from about 10:1 to about 1:10. In some embodiments, the amount of the one or more folic acid compounds and one or more calcium channel blockers (e.g., Nifedipine compounds) are provided or administered in a synergistic amount or a synergistic ratio.
  • the amount of the one or more folic acid compounds administered to the subject is about 1-350 mg, about 1- 700 mg, about 1-1050 mg, about 1-1400 mg, or about 1-1750 mg
  • the amount of the one or more calcium channel blockers (e.g., Nifedipine compounds) administered to the subject is about 1-350 mg, about 1-700 mg, about 1-1050 mg, about 1-1400 mg, about 1-1750 mg, about 1-2100 mg, or about 1-2450 mg.
  • the dosages used for treatment may increase or decrease over the course of a given treatment.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans; antioxidants, such as ascorbic acid or glutathione; chelating agents, 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 preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-micro-emulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means 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.
  • materials which can serve 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 tragacanth; (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 glycerin, 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;
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host 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. Generally, out of one hundred percent, this amount will range from about 0.01 percent to about 99.99 percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • 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: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, 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,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • compositions may also comprise 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 milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as 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.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • 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.
  • 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.
  • Dosage forms for the 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 that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as 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 an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just 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. Any one of the compounds or agents disclosed herein may be administered parenterally.
  • aqueous and nonaqueous carriers examples 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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.01 to 99.99% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is 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 which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily.
  • the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1 -(2-hydroxy ethyljpyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • contemplated salts of the invention include, but are not limited to, l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethan
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabi sulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known.
  • a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow-release formulation, or administered using a device for such slow or extended release.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents. Any one of the compounds or agents disclosed herein may be administered conjointly.
  • a “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
  • a “therapeutically effective amount” or a “therapeutically effective dose” includes, but is not limited to, amounts or doses that show synergy or technical effect when administered (e.g., conjointly administered) with another compound or agent disclosed herein.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
  • substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2- O-alkyl, -0P(0)(0-alkyl)2 or -CH2-0P(0)(0-alkyl)2.
  • “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
  • alkyl refers to saturated aliphatic groups, including but not limited to C1-C1 0 straight-chain alkyl groups or C1-C1 0 branched-chain alkyl groups.
  • the “alkyl” group refers to C1-C 6 straight-chain alkyl groups or C1-C 6 branched- chain alkyl groups.
  • the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl,
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(0)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci- 30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
  • Cx- y or “Cx-C y ”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a Ci- 6 alkyl group for example, contains from one to six carbon atoms in the chain.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • amide refers to a group wherein R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein R 9 , R 10 , and R 10 ’ each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • 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.
  • carboxylate is art-recognized and refers to a group wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • fused carbocycle refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • 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 carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH-indene and bicyclo[4.1.0]hept-3-ene.
  • “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-.
  • esters refers to a group -C(0)0R 9 wherein R 9 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.
  • 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.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include 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.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include 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 heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers 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 of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group -OSChH, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl.
  • sulfoxide is art-recognized and refers to the group-S(O)-.
  • sulfonate is art-recognized and refers to the group SChH, or a pharmaceutically acceptable salt thereof.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(0)SR 9 or -SC(0)R 9 wherein R 9 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • modulate includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • pharmaceutically acceptable is art-recognized.
  • the term includes compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids.
  • Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art.
  • non-pharmaceutically acceptable salts e.g., oxalates
  • oxalates may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 2001/062726.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound.
  • prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of Formula I.
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • the method provided herein comprise preventing or treating aneurysms (e.g., AAA, a cerebral aneurysm, or TAA) by conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • aneurysms e.g., AAA, a cerebral aneurysm, or TAA
  • the methods comprise ameliorating at least one symptom or pathology of an aneurysm, comprising conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • the symptom or pathology may be, for example, increased superoxide production, increased eNOS uncoupling activity, decreased nitric oxide (NO) bioavailability, decreased tetrahydrobiopterin (H4B) bioavailability, enlargement of blood vessels (abdominal aortas, thoracic aortas or blood vessels in the brain), increased vascular remodeling, increased elastin degradation (flattening and breakdown), increased vascular inflammation/macrophage infiltration, increased matrix metalloproteinase (MMP) activation, increased adventitial hypertrophy, or a decrease in eNOS function.
  • NO nitric oxide
  • H4B tetrahydrobiopterin
  • a folate compound and a calcium channel blocker comprising conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • provided herein are methods of increasing eNOS function, and nitric oxide (NO) and tetrahydrobiopterin bioavailabilities in a subject afflicted with an aneurysm by conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • NO nitric oxide
  • tetrahydrobiopterin bioavailabilities in a subject afflicted with an aneurysm by conjointly administering a folate compound and a calcium channel blocker to a subject in need thereof.
  • the calcium channel blocker is a dihydropyridine compound.
  • folate compound is folic acid.
  • the calcium channel blocker and folate compound may be in same or separate compositions.
  • the folate compound and the dihydropyridine compound may be in the same composition.
  • the calcium channel blocker may be Nifedipine.
  • the folate compound and the calcium channel blocker are administered in therapeutically effective amounts (e.g., an amount that is or expected to be synergistic).
  • the folate compound and the calcium channel blocker may be administered in a folate compound to calcium channel blocker mass ratio of about 10:1 to about 1 : 10, or about 100: 1, about 95:1, about 90:1, about 85:1, about 80:1, about 75:1, about 70:1, about 65:1, about 60:1, about 55:1, about 50:1, about 45:1, about 40:1, about 35:1, about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24 : 1 , about 23:1, about 22 : 1 , about 21:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, about 0.95:1, about 0.9:1, about 0.85:1, about 0.8:1, about 0.75:1, about 0.7:1, about 0.65:1, about 0.6
  • the calcium channel blocker and folate compound may be administered in a calcium channel blocker to folate compound mass ratio of about 100:1, about 95:1, about 90:1, about 85:1, about 80:1, about 75:1, about 70:1, about 65:1, about 60:1, about 55:1, about 50:1, about 45:1, about 40:1, about 35:1, about 10:1 to about 1:10, such as about 30:1, about 29:1, about 28:1, about 27:1, about 26:1, about 25:1, about 24 : 1 , about23 : 1 , about 22 : 1 , about 21:1, about 20:1, about 19:1, about 18:1, about 17:1, about 16:1, about 15:1, about 14:1, about 13:1, about 12:1, about 11:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1 about 0.95:1, about 0.9:1, about 0.85:1, about 0.8:1, about 0.75:1, about 0.7:1, about 0.65:1, about
  • the folate compound is administered in an amount of about 1- 350 mg, about 1-700 mg, about 1-1050 mg, about 1-1400 mg, or about 1-1750 mg.
  • the folate compound may be administered in an amount of at least or about 0.001, 0.002, 0.003, 0.004,
  • the calcium channel blocker is administered in an amount of about 1-350 mg, about 1-700 mg, about 1-1050 mg, about 1-1400 mg, about 1-1750 mg, about 1-2100 mg, or about 1-2450 mg. In some embodiments, the calcium channel blocker is administered in an amount of at least or about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007,
  • the folate compound and the calcium channel blocker may be administered simultaneously or sequentially.
  • the folate compound and the calcium channel blocker may be administered conjointly.
  • the folate compound and the calcium channel blocker may be administered in separate dosage forms.
  • the aneurysm may be an abdominal aortic aneurysm, cerebral aneurysm, or thoracic aortic aneurysm.
  • compositions may be administered to the subject systemically, intravenously, subcutaneously, intramuscularly, orally or locally (e.g., locally to the tumor in the subject).
  • the folate compound and the calcium channel blocker are administered conjointly. In some embodiments, administering conjointly comprises administering the folate compound and the calcium channel blocker at different times. In some embodiments, administering conjointly comprises administering the folate compound and the calcium channel blocker concurrently. In some embodiments, administering conjointly comprises administering the folate compound before the calcium channel blocker. In some embodiments, administering conjointly comprises administering the folate compound after the calcium channel blocker.
  • compositions e.g., a folate compound or a calcium channel blocker
  • the compositions may be administered over any period of time effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the period of time may be at least 1 day, at least 10 days, at least 20 days, at least 30, days, at least 60 days, at least three months, at least six months, at least a year, at least three years, at least five years, at least ten years, at least 20 years, at least 30 years, at least 40 years, at least 50 years.
  • the dose may be administered when needed, sporadically, or at regular intervals.
  • the dose may be administered monthly, weekly, biweekly, triweekly, once a day, twice a day, or three times a day.
  • a dose of the composition is administered at regular intervals over a period of time.
  • a dose of the composition is administered at least once a week.
  • a dose of the composition is administered at least twice a week. In certain embodiments, a dose of the composition is administered at least three times a week. In some embodiments, a dose of the composition is administered at least once a day. In some embodiments, a dose of the composition is administered at least twice a day. In some embodiments, a dose of the composition is administered at least three times a day.
  • doses of the composition are administered for at least 1 week, for at least 2 weeks, for at least 3 weeks, for at least 4 weeks, for at least 1 month, for at least 2 months, for at least 3 months, for at least 4 months, for at least 5 months, for at least 6 months, for at least 1 year, for at least two years, at least three years, at least five years, at least 10 years, at least 20 years, at least 30 years, at least 40 years, at least 50 years.
  • Toxicity and therapeutic efficacy of the combination of the one or more folic acid compounds and one or more calcium channel blocker compounds according to the instant invention and compositions thereof can be determined using cell cultures and/or experimental animals and pharmaceutical procedures in the art. For example, one may determine the lethal dose, LC50 (the dose expressed as concentration x exposure time that is lethal to 50% of the population) or the LD50 (the dose lethal to 50% of the population), and the ED50 (the dose therapeutically effective in 50% of the population) by methods in the art.
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Folic acid compounds and calcium channel blocker compounds which exhibit large therapeutic indices are preferred.
  • While combinations of folic acid compounds and calcium channel blocker compounds that result in toxic side-effects may be used, care, may be taken to design a delivery system that targets such compounds to the site of treatment to minimize potential damage to uninfected cells and, thereby, reduce side-effects.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosages for use in humans.
  • Preferred dosages provide a range of circulating concentrations that include the ED50 with tolerated, little or no toxicity.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized.
  • Therapeutically effective amounts and dosages of one or more folic acid compounds and one or more, for example, Nifedipine compounds can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • a dosage suitable for a given subject can be determined by an attending physician or qualified medical practitioner,
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions or agents to be administered may be varied so as to obtain an amount of the active ingredient (e.g., an agent described herein) which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • an amount of the active ingredient e.g., an agent described herein
  • the selected dosage level will depend upon a variety of factors including the activity of the particular agent employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician could prescribe and/or administer doses of the compounds employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • kits comprising one or more folic acid compounds and one or more calcium channel blockers, optionally in a composition, packaged together with one or more reagents or drug delivery devices for preventing, inhibiting, reducing, or treating aneurysms in a subject.
  • the kits comprise one or more folic acid compounds and one or more calcium channel blocker compounds, optionally in one or more unit dosage forms, packaged together as a pack and/or in drug delivery device, e.g., a pre-filled syringe.
  • the one or more folic acid compounds and/or the one or more calcium channel blocker compounds may be provided in the form of a pharmaceutical composition.
  • the one or more folic acid compounds and/or the one or more calcium channel blocker compounds are provided in the form of an oral formulation, e.g., a tablet.
  • kits include a carrier, package, or container that may be compartmentalized to receive one or more containers, such as vials, tubes, and the like.
  • the kits optionally include an identifying description or label or instructions relating to its use.
  • the kits include information prescribed by a governmental agency that regulates the manufacture, use, or sale of compounds and compositions as contemplated herein.
  • Aortic aneurysms are prevalent and severe vascular diseases, with high mortality resulting from patients dying of unpredictable sudden rupture of the aneurysms.
  • No treatment options have been generally available except for surgical correction of large aneurysms, which presents considerable risk.
  • the data demonstrate that orally administrated comminatory therapy of FA and Nifedipine can serve as a robust, first-in-class, and effective treatment regime for aortic and other aneurysms.
  • Example 1 Combination of Folic Acid with Nifedipine Substantially and Completely Further Attenuates Formation of Aortic Aneurysm in a Dose-deyendent Manner
  • folic acid is highly effective in alleviating aortic aneurysm formation (both AAA and TAA) in Angiotensin II (Ang II) infused apolipoprotein E (apoE) null mice, Ang II infused hyperphenylalaninemia (hph-1) mice and Fbnl Marfan Syndrome mice, via recoupling of eNOS to attenuate superoxide production while restoring nitric oxide (NO) bioavailability, resulting in abrogated vascular remodeling. Nonetheless, FA alone is not sufficient to completely attenuate development of aortic aneurysms.
  • ESR electron spin resonance
  • Oxidative stress has been shown to play an important role in the formation of aortic aneurysms including AAA and thoracic aortic aneurysm (TAA).
  • Uncoupled endothelial nitric oxide synthase (eNOS) plays a critical role in AAA formation via sustaining oxidative stress to induce matrix metalloproteinase (MMP) activation and matrix degradation.
  • MMP matrix metalloproteinase
  • Ang II infused hph-1 mice prove to be the most robust AAA model to date.
  • FA folic acid
  • eNOS uncoupling plays a novel role in the development of AAA in Ang Il-infused apoE null mice, a well-established, classical model of AAA, while oral FA administration also effectively restored DHFR function to recouple eNOS, resulting in abrogated aneurysm formation.
  • knockout of DHFR in mice facilitating uncoupling of eNOS leads to exaggerated formation of AAA.
  • NADPH oxidase NADPH oxidase
  • eNOS uncoupling also plays a critical role in driving TAA and AAA formation in Fbnl Marfan Syndrome mice, a classical model for TAA, which can also be targeted by FA to alleviate formation of both TAA and AAA (Huang et ak, Redox Biology, (2021)).
  • Hypertension is a risk factor for aortic aneurysms, and AAA and TAA patients often have co-existing hypertension. It is also a major risk factor for cerebral aneurysm.
  • Previous studies have investigated effects on AAA formation of both low and high doses of the anti hypertensive drug Nifedipine, which is a calcium channel blocker. Low doses of Nifedipine have no effect on blood pressure, however, both low and high doses of Nifedipine can attenuate AAA formation, via restoration of DHFR and inhibition of NOX to attenuate eNOS uncoupling.
  • the high dose of Nifedipine can also reduce blood pressure at the same time, hence particularly valuable to treat aortic aneurysm patients with co-existing hypertension.
  • the combinatory therapies were robustly more effective in restoring eNOS coupling activity to improve NO bioavailability and attenuate oxidative stress, resulting in abrogated vascular remodeling characterized by elastin degradation and adventitial hypertrophy, with combination of FA with Nifedipine substantially and completely further inhibiting incidence of AAA in a dose-dependent manner from 18.75% in FA group (reduced from 85.71% in Ang II infused apoE null mice) to 12.50%, 11.76% and 0.00% respectively for groups of FA plus 1.5, 5.0 or 20 mg/kg/day Nifedipine.
  • AAA The incidence of AAA was examined in Ang II infused apoE null mice subjected to oral administration of FA alone, or combinatory therapy of FA with various doses of Nifedipine (1.5, 5 or 20 mg/kg/day). As shown in Figure 1A-1B, after 4 weeks of Ang II infusion, 85.71% (30 out of 35) of the Ang II infused apoE null mice developed AAA. Oral FA administration significantly reduced incidence of AAA to 18.75% (p ⁇ 0.001, 6 out of 32).
  • FIG. 2A shows representative ultrasound images of abdominal aortas from all experimental groups across the 4 weeks, while Figure 2B shows grouped data.
  • Figure 2A-2B shows ##p ⁇ 0.01 or ###p ⁇ 0.001 vs. apoE+Ang II of the same week).
  • Nifedipine 5.0 or 20 mg/kg/day group was significantly more effective than Nifedipine 1.5 mg/kg/day group ( ⁇ p ⁇ 0.05; %p ⁇ 0.05 or %%% p ⁇ 0.001)
  • Formation of aortic aneurysms is accompanied by extensive vascular remodeling featured by matrix degradation to allow expansion of aortas.
  • vascular remodeling To examine the extent of the vascular remodeling that occurred during AAA in the presence of various treatments, freshly isolated aortas were embedded in paraffin, sectioned and stained with hematoxylin-eosin (H&E).
  • H&E hematoxylin-eosin
  • oral administration of FA markedly attenuated vascular remodeling featured by elastic degradation and adventitial hypertrophy in Ang II infused apoE null mice.
  • Combination of FA with 1.5, 5 or 20 mg/kg/day Nifedipine substantially and completely further attenuated vascular remodeling in a dose-dependent manner.
  • Combination of FA with Nifedipine substantially and completely further attenuate elastin degradation in a dose-dependent manner
  • VVG staining was performed using aortic sections from all experimental groups. As shown in Figure 4, elastin degradation featured by flattening and breakdown was obvious in Ang II infused apoE null mice, which was significantly attenuated by oral administration of FA. Importantly, combination of FA with various doses of Nifedipine (1.5, 5 or 20 mg/kg/day) substantially and completely further attenuated elastin degradation in a dose-dependent manner.
  • FEB deficiency is indicative of eNOS uncoupling.
  • aortic 3 ⁇ 4B bioavailability from all experimental groups using HPLC.
  • Ang II induced 3 ⁇ 4B deficiency in apoE null mice was significantly abrogated by oral FA administration, while combination of FA with various doses of Nifedipine (1.5, 5 or 20 mg/kg/day) substantially further improved aortic 3 ⁇ 4B bioavailability in a dose-dependent manner.
  • the data shows herein demonstrates for the first time that combinatory therapy of FA and Nifedipine, attenuates formation of aortic aneurysm in a model of Ang Il-infused apoE null mice, with the addition of Nifedipine showing a dose-dependent effect in augmenting the efficacy of FA in treating aortic aneurysm.
  • AAA incidence determined by ultrasound definition of aortic expansion and post-mortem inspection was synergistically, as well as substantially and completely, further abrogated by combination of FA with Nifedipine in a dose-dependent manner.
  • Combinatory therapy of FA and Nifedipine substantially and completely further alleviated vascular remodeling featured by elastin degradation and adventitial hypertrophy in a dose-dependent manner.
  • Oxidative stress plays a role in the pathogenesis of AAA. Specifically, as shown by the data herein, uncoupled eNOS mediates formation of AAA by driving oxidative stress and consequent vascular remodeling. It is demonstrated that, in Ang II infused hph-1 mice, a newly established, robust model of AAA, uncoupling of eNOS mediates AAA formation that can be attenuated by FA restoration of endothelial dihydrofolate reductase (DHFR) function/FEB bioavailability to recouple eNOS.
  • DHFR endothelial dihydrofolate reductase
  • eNOS uncoupling mediates sustained oxidative stress and AAA formation that can be alleviated by oral FA administration.
  • oral FA administration is effective in reducing incidence of AAA, preventing enlargement of abdominal aorta, and alleviating maladaptive vascular remodeling. This is mediated by FA recoupling of eNOS to attenuate superoxide production while restoring NO bioavailability, resulting in abrogated oxidative stress by shutting down the enzymatic system of uncoupled eNOS .
  • the combinatory therapy further abrogated expansion of abdominal aortas in a dose-dependent manner compared to the FA alone group, with FA plus 20 mg/kg/day of Nifedipine attenuating sizes of the abdominal aortas by 100% to control levels, again confirming a substantial further improvement in the efficacy of treating AAA.
  • vascular remodeling featured by elastin degradation and adventitial hypertrophy was also substantially and completely further alleviated in FA plus Nifedipine groups in a dose-dependent manner.
  • Oral administration of FA and Nifedipine thus proves to be an effective oral medicine for the treatment of aneurysms including AAA/TAA and cerebral aneurysm which are driven by the common pathway of eNOS uncoupling/oxidative stress, with composition containing high dose of Nifedipine particularly suitable for treatment of aneurysm patients with co-existing hypertension.
  • the animals receiving Ang II infusion were anesthetized in an isoflurane chamber with 5% isoflurane, and then moved to a nose cone with sustained supply of 1.5-2% isoflurane to maintain the anesthetic state.
  • the back area between the shoulder blades was cleaned of hair and disinfected.
  • a small incision was made at the cleaned site; the osmotic mini pump (Alzet, model 2004) containing Ang II (1000 ng/kg/min, Sigma-Millipore, St. Louis, MO, USA) was subcutaneously implanted into the mice.
  • the surgical wounds were closed with surgical staples, and then animals were allowed to recover in a heated cage.
  • FA folic acid
  • Nifedipine standard chow was replaced with customized food tablets containing FA (15 mg/ kg/day) alone, or FA in combination with Nifedipine (1.5, 5 or 20 mg/kg/day) two days prior to implantation of osmotic minipumps for Ang II infusion, and throughout the study period of 4 weeks of Ang II infusion.
  • Paraffin embedded aortic sections were deparaffmized by sequential washes in xylene (2x), descending ethanol from 100%, 90%, 75% to 50%, and distilled water. Sections were stained in Verhoeff s solution for 70 min, followed by differentiation in 2% ferric chloride for 90 seconds. Sections were incubated with 5% sodium thiosulfate for 60 seconds, followed by counterstaining with Van Gieson’s solution. Sections were then subjected to dehydration with 95% and 100% alcohol, and finally washed in xylene. After drying, sections were mounted with Permount mounting media (SP15-100, Thermo-Fisher Scientific, Pittsburgh, PA, USA), and images captured by a Nikon TE2000-U fluorescent microscope.
  • Permount mounting media SP15-100, Thermo-Fisher Scientific, Pittsburgh, PA, USA
  • Aortic superoxide production was determined by electron spin resonance (ESR).
  • ESR electron spin resonance
  • freshly isolated aortas were homogenized in lysis buffer containing 1:100 protease inhibitor cocktail (MilliporeSigma, P8340), centrifuged at 12,000 rpm for 15 min, and protein supernatant collected.
  • a reduction in superoxide production with L-NAME indicates that eNOS is uncoupled producing superoxide, while an increase in superoxide production with L-NAME indicates that eNOS is coupled producing NO.
  • the ESR settings used were: Center field, 3480; Sweep width, 9G; microwave frequency, 9.78 GHz; microwave power, 21.02 mW; modulation amplitude, 2.47 G; 512 points of resolution; receiver gain, 1000.
  • Aortic nitric oxide (NO) bioavailability was determined by electron spin resonance (ESR).
  • ESR electron spin resonance
  • aortic rings were incubated with freshly prepared NO specific spin trap Fe 2+ (DETC)2 (0.5 mmol/L) colloid in modified Krebs/HEPES buffer at 37°C for 60 min, in the presence of calcium ionophore A23187 (10 mmol/L).
  • DETC NO specific spin trap Fe 2+
  • the aortic pieces were snap frozen in liquid nitrogen and loaded into a finger Dewar for analysis with ESR spectrophotometer (eScan, Bruker, Billerica, MA, USA).
  • the instrument settings used were as the followings: Center field, 3440; Sweep width, 100 G; microwave frequency, 9.796 GHz; microwave power 13.26 mW; modulation amplitude, 9.82 G; 512 points of resolution; and receiver gain 356.
  • aortic H4B levels For determination of aortic H4B levels freshly isolated aortas were lysed in 3 ⁇ 4B lysis buffer (0.1 mol/L phosphoric acid, 1 mmol/L EDTA, 10 mmol/L DLDithiothreitol), centrifuged at 12,000 rpm for 10 min, and then supernatants subjected to differential oxidation in acidic (0.2 mol/L trichloroacetic acid with 2.5% I2 and 10% KI) and alkalytic (0.1 mol/L NaOH with 0.9% I2 and 1.5% KI) solutions.
  • 3 ⁇ 4B lysis buffer 0.1 mol/L phosphoric acid, 1 mmol/L EDTA, 10 mmol/L DLDithiothreitol

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant un composé de folate et un bloqueur de canal calcique, ainsi que la méthode d'utilisation de telles compositions pharmaceutiques dans le traitement d'anévrismes.
EP22763970.5A 2021-03-02 2022-03-02 Polythérapie pour la prévention, l'inhibition, le traitement ou la réduction d'anévrismes Pending EP4301370A1 (fr)

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