US20030139458A1 - Treatment of neurodegenerative and cardiovascular disorders - Google Patents
Treatment of neurodegenerative and cardiovascular disorders Download PDFInfo
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- US20030139458A1 US20030139458A1 US10/316,145 US31614502A US2003139458A1 US 20030139458 A1 US20030139458 A1 US 20030139458A1 US 31614502 A US31614502 A US 31614502A US 2003139458 A1 US2003139458 A1 US 2003139458A1
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- 0 *=C([1*]C)[Y][2*]C Chemical compound *=C([1*]C)[Y][2*]C 0.000 description 5
- MBIPDIIUISDHQL-BXTVWIJMSA-N C.O=C(/C=C/C1=CC(O)=C(O)C=C1)OCCC1=CC=CC=C1 Chemical compound C.O=C(/C=C/C1=CC(O)=C(O)C=C1)OCCC1=CC=CC=C1 MBIPDIIUISDHQL-BXTVWIJMSA-N 0.000 description 1
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
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- 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
- A61K31/13—Amines
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- 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
- A61K31/275—Nitriles; Isonitriles
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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
Definitions
- Nitric oxide (NO)-induced and caspase 1-related neuronal loss may lead to neurodegenerative disorders associated with neonatal and adult stroke, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyothrophic lateral sclerosis, stroke, spinal injury, transplantation, multiple sclerosis, as well as hearing loss.
- No neuroprotective drug is available to these diseases. Some drugs are available for treating these diseases by enhancing the function of remaining neurons. However, no drug is very successful in slowing the progression of these disorders. Some of them even produce undesirable side effects, such as motor fluctuations and dyskinesias in Parkinson's disease. See, e.g., Quinn, et al., Neurology, 1998, 51, S25-29.
- NO-induced and caspase 1-related heart cell loss may contribute to cardiovascular disorders, including heart failure, arteriosclerosis, myocarditis, and cardiomyopathy.
- the present invention relates to a method of treating neurodegenerative and cardiovascular disorders and other disorders associated with NO-induced or caspase 1-related cell death.
- the method includes administering to the subject in need thereof one or more compounds of Formula (I):
- Each of R 1 and R 2 is C 1 8 alkylene, C 2-8 alkenylene, or deleted; each of A 1 and A 2 , independently, is aryl or heteroaryl, optionally mono- or multi-(e.g., di- or tri-) substituted with halogen, —CN, —NO 2 , —OH, —SH, —OR 3 , —SR 3 , —R 3 , —R 3 —OR 4 , —C(O)R 3 , —S(O)R 3 , —S(O) 2 R 3 , —NR 4 R 5 , —C(O)OR 3 , —C(O)NR 4 R 5 , —O(O)CR 4 , or —NR 4 (O)CR 5 , and each of X and Y, independently, is O, S, or NR 6 , wherein each R 3 is C 1-4 alkyl, and each of R 4 , R 5 ,
- alkyl refers to a monovalent hydrocarbon radical, straight-chain or branched (e.g., —CH 2 CH 2 CH 3 or —CH(CH 3 ) 2 ).
- alkylene refers to a divalent hydrocarbon radical, straight-chain or branched (e.g., —CH 2 CH 2 — or —CH 2 CH(CH 3 )—CH 3 ).
- alkenylene refers to a divalent hydrocarbon radical, straight-chain or branched, containing one or more double bonds (e.g., —CH 2 CH ⁇ CH—CH 2 — or —CH 2 CH(CH 3 )CH ⁇ CH—CH 2 —).
- aryl refers to a 6 to 12-carbon monocyclic or multicyclic (fused or separated) aromatic system wherein up to 4 atoms of each ring may be substituted.
- aryl groups include phenyl and naphthyl.
- heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system, which contains 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic (each heteroatom being O, N, or S).
- heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, quinolinyl, indolyl, and thiazolyl.
- each of X and Y is O in one subset of the compounds that can be used to practice the method of this invention.
- R 1 is a C 2-8 alkenylene and R 2 is a C 1-8 alkylene.
- each of A 1 and A 2 is aryl (e.g., phenyl), optionally substituted with halogen, —CN, —OH, —SH, —OR 3 , —SR 3 , —R 3 , —R 4 —OR, or —NR 4 R 5 .
- R 1 is a C 2-3 alkenylene (e.g., —CH ⁇ CH—), and R 2 is a C 1-3 alkylene (e.g., —CH 2 —CH 2 —).
- R 2 is a C 1-3 alkylene (e.g., —CH 2 —CH 2 —).
- caffeic acid phenethyl ester is caffeic acid phenethyl ester:
- the neurodegenerative and cardiovascular disorders that can be treated by the method of this invention result from NO-induced or caspase 1-related cell loss, as well as from decrease in the amount of dopamine or the number of dopaminergic neurons.
- Such disorders are associated with a number of diseases, e.g., neonatal and adult stroke, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyothrophic lateral sclerosis, stroke, spinal injury, transplantation, multiple sclerosis, hearing loss, heart failure, arteriosclerosis, myocarditis, cardiomyopathy, and diabetes.
- diseases e.g., neonatal and adult stroke, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyothrophic lateral sclerosis, stroke, spinal injury, transplantation, multiple sclerosis, hearing loss, heart failure, arteriosclerosis, myocarditis, cardiomyopathy, and diabetes.
- diseases e.g., neonatal and adult stroke, Parkinson's disease, Huntington's disease, Alzheimer'
- One or more of the compound described above are formulated into a pharmaceutical composition before they are administered to a subject in need of treatment of a neurodegenerative or cadiovacular disorder.
- the invention therefore also relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and one or more of the compounds described above in an amount effective for treating a neurodegenerative or cardiovascular disorder.
- the invention further relates to an article of manufacture.
- the article includes: i) a container; ii) a pharmaceutical composition containing a pharmaceutically acceptable carrier and one or more of the above-described compounds in an effective amount; and iii) a label, disposed on the container and having instructions for administration of the pharmaceutical composition for treating a neurodegenerative or cadiovacular disorder.
- the instructions can provide directions for administration of the pharmaceutical composition to a subject, e.g., for epidural, intrathecal, parenteral, or local administration.
- the compounds described above also include their salts and prodrugs, if applicable.
- Such salts can be formed between a positively charged substituent (e.g., amino) in a compound described and an anion.
- Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
- a negatively charged substituent e.g., carboxylate
- a compound described above can form a salt with a cation.
- Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion.
- Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing compounds described above.
- This invention relates to a method of treating neurodegenerative and cardiovascular disorders as well as other disorders related to NO-induced or caspase 1-related cell death by using one or more compounds of the following formula:
- a compound in which X is O or S can be prepared by reacting a precursor of the formula A 1 —R 1 —C( ⁇ X)—OH with a precursor of the formula A 2 —R 2 —YH (Y is O, S, or NH).
- Y is O, S, or NH
- the compound thus obtained can be optionally converted to an imine (i.e., X is NH or N(alkyl)), e.g., via a reaction with ammonia or an amine.
- caffeic acid phenethyl ester can be synthesized by reacting caffeic acid with excess phenethyl alcohol in a suitable solvent (e.g., benzene) under reflux in the presence of an acid catalyst (e.g., p-toluene sulfonic acid) for an extended period of time (e.g., 3 or 4 days).
- a suitable solvent e.g., benzene
- an acid catalyst e.g., p-toluene sulfonic acid
- an extended period of time e.g., 3 or 4 days.
- Pure caffeic acid phenethyl ester m.p. 126-128° C., needles
- a suitable compound of Formula (I) or its salt in an effective amount is formulated with a pharmaceutically acceptable carrier to form a pharmaceutical composition before it is administered to a subject in need of treatment of neurodegenerative and cardiovascular disorders as well as other disorders related to NO-induced or caspase 1-related cell death.
- “An effective amount” refers to the amount of the compound which is required to confer therapeutic effect on the treated subject, and can be determined based on animal and clinical studies. The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother Rep, 1966, 50, 219. Body surface area may be approximately determined from height and weight of the patient.
- Effective doses will also vary, as recognized by those skilled in the art, depending on the route of administration, the excipient usage, and the optional co-usage with other therapeutic treatments.
- pharmaceutically acceptable carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.
- the pharmaceutical composition may be administered via a parenteral route, e.g., intraperitoneally and intravenously.
- parenteral dosage forms include an active compound dissolved in phosphate buffer saline (PBS), or admixed with any other pharmaceutically acceptable carrier.
- Solubilizing agents such as cyclodextrins or other solubilizing agents well known to those familiar with the art, can also be included in the pharmaceutical composition.
- Efficacy of caffeic acid phenethyl ester on treating neurodegenerative disorders as well as other disorders related to NO-induced cell death was assessed by testing its ability to block NO-induced cell death on cultured neurons according to a method described in Du, et al., Proc Natl Acad Sci, 2001, 98, 14669-14674.
- CGN cerebellar granule neurons
- Caffeic acid phenethyl ester was evaluated for its efficacy in treating a neurodegenerative disorder in mice.
- a group of mice were administered for 9 days with caffeic acid phenethyl ester (5 or 20 mg/kg/day in 10% alcohol by oral gavage, or 40 mg/kg/day in 10% alcohol by intraperitoneal injection).
- a second group of mice were administered with 10% alcohol free of caffeic acid phenethyl ester.
- mice then received four intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (“MPTP”)-HCl (20 mg/kg of free base) in saline at 2 hour intervals in a single day, as described in Liberatore, et al., Nat Med, 1999, 5, 1403-1409.
- MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- mice Seven days after the last administration of MPTP, the mice were anesthetized by halothane inhalation. Their brains were then removed and perfusion-fixed with 4% of paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). After the fixation and subsequent cryoprotection in a 30% sucrose/phosphate buffer, the brains were frozen in liquid nitrogen and sectioned serially (40 ⁇ m) through the entire midbrain. The tissue sections were rinsed 3 times with 0.1 M PBS containing 0.1% Triton-X 100, 5 minutes each time.
- anti-TH antibody rabbit polyclonal anti-tyrosine hydroxylase (anti-TH) antibody (1:2,500, CALBIOCHEM, La Jolla, Calif.), goat biotinylated-conjugated polyclonal anti-rabbit antibody (1:250; Vector Laboratories, Burlingame, Calif.), horseradish-peroxidase conjugated avidin/biotin complex (VECTASTAIN ABC Reagent, Vector Laboratories), and successively exposed to diaminobenzidine for TH-immunohistochemistry analysis and stereological quantification of TH-positive neurons.
- the stereological method for counting TH-positive neurons is described in Triarhou, et al., J Neurocytol, 1988, 17, 221-232.
- the third group of mice only received saline, i.e., free of both caffeic acid phenethyl ester and MPTP.
- mice of the second group were approximately 49%, as compared with the mice of the third group.
- the mice in the first group showed a much higher number of TH-positive neurons (up to 100%) than the mice in the second group.
- Treatment of caffeic acid phenethyl ester alone for nine days did not significantly alter the number of TH-positive neurons.
- the striatal levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were also determined by HPLC with electrochemical detector. See, e.g., Du, et al., Proc Natl Acad Sci, 2001, 98, 14669-14674. Comparison of data from the second group of mice and the third group of mice indicates that the striatal levels of dopamine, DOPAC, and HVA in the mice of the second group decreased by 62%, 46%, and 35%, respectively, 48 hours after the administration of MPTP without treatment with caffeic acid phenethyl ester.
- DOPAC dihydroxyphenylacetic acid
- HVA homovanillic acid
- caffeic acid phenethyl ester (40 mg/kg, intraperitoneally) significantly blocked the MPTP-induced decrease in the striatal levels of dopamine and its metabolites. More specifically, the caffeic acid phenethyl ester treatment resulted in MPTP-induced reduction of the striatal dopamine, DOPAC, and HVA levels by only 3%, ⁇ 2%, and 16%, respectively.
- lactate dehydrogenase decreased during 40-minute ischaemic arrest (55.14+/ ⁇ 8.65 vs 19.33+/ ⁇ 7.4 IU/L perfusate for control and treatment, respectively; p ⁇ 0.05). See Ersahin et al., J Cardiovasc Pharmacol, 1999 October; 34(4):604-611. The results indicate that caffeic acid phenethyl ester protects myocardium against ischaemic injury and can thus be used to treat cardiac arrest.
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Abstract
Description
- Pursuant to 35 USC §119(e)(1), this application claims the benefit of prior U.S. provisional application No. 60/339,215, filed Dec. 10, 2001.
- Nitric oxide (NO)-induced and caspase 1-related neuronal loss may lead to neurodegenerative disorders associated with neonatal and adult stroke, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyothrophic lateral sclerosis, stroke, spinal injury, transplantation, multiple sclerosis, as well as hearing loss. No neuroprotective drug is available to these diseases. Some drugs are available for treating these diseases by enhancing the function of remaining neurons. However, no drug is very successful in slowing the progression of these disorders. Some of them even produce undesirable side effects, such as motor fluctuations and dyskinesias in Parkinson's disease. See, e.g., Quinn, et al., Neurology, 1998, 51, S25-29. Additionally, NO-induced and caspase 1-related heart cell loss may contribute to cardiovascular disorders, including heart failure, arteriosclerosis, myocarditis, and cardiomyopathy.
-
- Each of R1 and R2, independently, is C1 8 alkylene, C2-8 alkenylene, or deleted; each of A1 and A2, independently, is aryl or heteroaryl, optionally mono- or multi-(e.g., di- or tri-) substituted with halogen, —CN, —NO2, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, —C(O)R3, —S(O)R3, —S(O)2R3, —NR4R5, —C(O)OR3, —C(O)NR4R5, —O(O)CR4, or —NR4(O)CR5, and each of X and Y, independently, is O, S, or NR6, wherein each R3 is C1-4 alkyl, and each of R4, R5, and R6, independently, is H or C1-4 alkyl.
- The term “alkyl” refers to a monovalent hydrocarbon radical, straight-chain or branched (e.g., —CH2CH2CH3 or —CH(CH3)2). The term “alkylene” refers to a divalent hydrocarbon radical, straight-chain or branched (e.g., —CH2CH2— or —CH2CH(CH3)—CH3). The term “alkenylene” refers to a divalent hydrocarbon radical, straight-chain or branched, containing one or more double bonds (e.g., —CH2CH═CH—CH2— or —CH2CH(CH3)CH═CH—CH2—). The term “aryl” refers to a 6 to 12-carbon monocyclic or multicyclic (fused or separated) aromatic system wherein up to 4 atoms of each ring may be substituted. Examples of aryl groups include phenyl and naphthyl. The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system, which contains 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic (each heteroatom being O, N, or S). Examples of heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, quinolinyl, indolyl, and thiazolyl.
-
- The neurodegenerative and cardiovascular disorders that can be treated by the method of this invention result from NO-induced or caspase 1-related cell loss, as well as from decrease in the amount of dopamine or the number of dopaminergic neurons. Such disorders are associated with a number of diseases, e.g., neonatal and adult stroke, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyothrophic lateral sclerosis, stroke, spinal injury, transplantation, multiple sclerosis, hearing loss, heart failure, arteriosclerosis, myocarditis, cardiomyopathy, and diabetes. Thus, within the scope of this invention is use of one or more of the above-described compounds as a drug for treating these disorders.
- One or more of the compound described above are formulated into a pharmaceutical composition before they are administered to a subject in need of treatment of a neurodegenerative or cadiovacular disorder. The invention therefore also relates to a pharmaceutical composition containing a pharmaceutically acceptable carrier and one or more of the compounds described above in an amount effective for treating a neurodegenerative or cardiovascular disorder. In another aspect, the invention further relates to an article of manufacture. The article includes: i) a container; ii) a pharmaceutical composition containing a pharmaceutically acceptable carrier and one or more of the above-described compounds in an effective amount; and iii) a label, disposed on the container and having instructions for administration of the pharmaceutical composition for treating a neurodegenerative or cadiovacular disorder. The instructions can provide directions for administration of the pharmaceutical composition to a subject, e.g., for epidural, intrathecal, parenteral, or local administration.
- Also within the scope of this invention is use of one or more of the above-described compounds for the manufacture of a medicament for the treatment of the neurodegenerative and cardiovascular disorders mentioned above.
- The compounds described above also include their salts and prodrugs, if applicable. Such salts, for example, can be formed between a positively charged substituent (e.g., amino) in a compound described and an anion. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a negatively charged substituent (e.g., carboxylate) in a compound described above can form a salt with a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing compounds described above.
- The details of an embodiment of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the claims.
-
- wherein each of A1, A2, R1, R2, X, and Y is defined above.
- These compounds can be synthesized by methods well known in the art. For example, a compound in which X is O or S can be prepared by reacting a precursor of the formula A1—R1—C(═X)—OH with a precursor of the formula A2—R2—YH (Y is O, S, or NH). See, e.g., Loudon, Organic Chemistry, 3rd Ed., 1995, Benjamin/Cummings Publishinh Company, Inc., Redwood, City, Calif. The compound thus obtained can be optionally converted to an imine (i.e., X is NH or N(alkyl)), e.g., via a reaction with ammonia or an amine. See, e.g., Verardo et al., Synth Commun, 1998, 18, 1501; and Farrar, Rec. Chem. Prog. 1968, 29, 85-101.
- For instance, caffeic acid phenethyl ester can be synthesized by reacting caffeic acid with excess phenethyl alcohol in a suitable solvent (e.g., benzene) under reflux in the presence of an acid catalyst (e.g., p-toluene sulfonic acid) for an extended period of time (e.g., 3 or 4 days). Pure caffeic acid phenethyl ester (m.p. 126-128° C., needles) can be obtained after removal of excess phenethyl alcohol by distillation. See, e.g., Grunberger et al., Experientia, 1988, 44, 23-232.
- A suitable compound of Formula (I) or its salt in an effective amount is formulated with a pharmaceutically acceptable carrier to form a pharmaceutical composition before it is administered to a subject in need of treatment of neurodegenerative and cardiovascular disorders as well as other disorders related to NO-induced or caspase 1-related cell death. “An effective amount” refers to the amount of the compound which is required to confer therapeutic effect on the treated subject, and can be determined based on animal and clinical studies. The interrelationship of dosages for animals and humans (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother Rep, 1966, 50, 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. Effective doses will also vary, as recognized by those skilled in the art, depending on the route of administration, the excipient usage, and the optional co-usage with other therapeutic treatments. Examples of pharmaceutically acceptable carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.
- The pharmaceutical composition may be administered via a parenteral route, e.g., intraperitoneally and intravenously. Examples of parenteral dosage forms include an active compound dissolved in phosphate buffer saline (PBS), or admixed with any other pharmaceutically acceptable carrier. Solubilizing agents, such as cyclodextrins or other solubilizing agents well known to those familiar with the art, can also be included in the pharmaceutical composition.
- One can assess the efficacy of a compound of Formula (I) on treating a neurodegenerative or cardiovascular disorder by both in vitro and in vivo assays well known in the art. See the three actual examples provided below.
- Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications recited herein are hereby incorporated by reference in their entirety. The following specific examples, which describe biological testing of caffeic acid phenethyl ester, a compound of Formula (I), are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
- Efficacy of caffeic acid phenethyl ester on treating neurodegenerative disorders as well as other disorders related to NO-induced cell death was assessed by testing its ability to block NO-induced cell death on cultured neurons according to a method described in Du, et al., Proc Natl Acad Sci, 2001, 98, 14669-14674.
- Significant neuron cell death in a cerebellar granule neurons (CGN) culture induced by nitric oxide was found to be blocked by caffeic acid phenethyl ester in a concentration-dependent manner (IC50˜1 μM). The neuroprotective effect of caffeic acid phenethyl ester was also observed when 6-hydroxydopamine was used to induce neurotoxicity.
- Caffeic acid phenethyl ester was evaluated for its efficacy in treating a neurodegenerative disorder in mice. Three groups of eight-week-old male C57B1/6 mice (Taconic Farms Inc., Germantown, N.Y.), 5-7 per group, were used. A group of mice were administered for 9 days with caffeic acid phenethyl ester (5 or 20 mg/kg/day in 10% alcohol by oral gavage, or 40 mg/kg/day in 10% alcohol by intraperitoneal injection). As a control, a second group of mice were administered with 10% alcohol free of caffeic acid phenethyl ester. These two groups of mice then received four intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (“MPTP”)-HCl (20 mg/kg of free base) in saline at 2 hour intervals in a single day, as described in Liberatore, et al., Nat Med, 1999, 5, 1403-1409.
- Seven days after the last administration of MPTP, the mice were anesthetized by halothane inhalation. Their brains were then removed and perfusion-fixed with 4% of paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). After the fixation and subsequent cryoprotection in a 30% sucrose/phosphate buffer, the brains were frozen in liquid nitrogen and sectioned serially (40 μm) through the entire midbrain. The tissue sections were rinsed 3 times with 0.1 M PBS containing 0.1% Triton-X 100, 5 minutes each time. They were then incubated with rabbit polyclonal anti-tyrosine hydroxylase (anti-TH) antibody (1:2,500, CALBIOCHEM, La Jolla, Calif.), goat biotinylated-conjugated polyclonal anti-rabbit antibody (1:250; Vector Laboratories, Burlingame, Calif.), horseradish-peroxidase conjugated avidin/biotin complex (VECTASTAIN ABC Reagent, Vector Laboratories), and successively exposed to diaminobenzidine for TH-immunohistochemistry analysis and stereological quantification of TH-positive neurons. The stereological method for counting TH-positive neurons is described in Triarhou, et al., J Neurocytol, 1988, 17, 221-232.
- As another control, the third group of mice only received saline, i.e., free of both caffeic acid phenethyl ester and MPTP.
- The number of TH-positive neurons in the substantia nigra pars compacta (SNpc) of the mice of the second group was approximately 49%, as compared with the mice of the third group. The mice in the first group showed a much higher number of TH-positive neurons (up to 100%) than the mice in the second group. Treatment of caffeic acid phenethyl ester alone for nine days did not significantly alter the number of TH-positive neurons.
- The striatal levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were also determined by HPLC with electrochemical detector. See, e.g., Du, et al., Proc Natl Acad Sci, 2001, 98, 14669-14674. Comparison of data from the second group of mice and the third group of mice indicates that the striatal levels of dopamine, DOPAC, and HVA in the mice of the second group decreased by 62%, 46%, and 35%, respectively, 48 hours after the administration of MPTP without treatment with caffeic acid phenethyl ester. In the mice of the first group, caffeic acid phenethyl ester (40 mg/kg, intraperitoneally) significantly blocked the MPTP-induced decrease in the striatal levels of dopamine and its metabolites. More specifically, the caffeic acid phenethyl ester treatment resulted in MPTP-induced reduction of the striatal dopamine, DOPAC, and HVA levels by only 3%, −2%, and 16%, respectively.
- These results indicate that caffeic acid phenethyl ester was unexpectedly effective in protecting neurons from death caused by MPTP.
- An isolated working rabbit heart model was use to define the cardioprotective effects (function, metabolic and ultrastructure) of caffeic acid phenethyl ester during ischaemia by the method described in Choong, et al., J Cardiovasc Surg (Torino), 1993 October, 34(5):423-433. More specifically, hearts (n=7 for each group) were arrested with and exposed to reinfusion (45 min) throughout the ischaemic period with a cold (4° C.) cardioplegic solution. In an hour, caffeic acid phenethyl ester (30 mg/kg; intraperitoneal injection) significantly (p<0.05) improved the postischaemic recovery of cardiac output from 71.48+/−9.66% to 90.83+/−3.2%. The release of lactate dehydrogenase decreased during 40-minute ischaemic arrest (55.14+/−8.65 vs 19.33+/−7.4 IU/L perfusate for control and treatment, respectively; p<0.05). See Ersahin et al., J Cardiovasc Pharmacol, 1999 October; 34(4):604-611. The results indicate that caffeic acid phenethyl ester protects myocardium against ischaemic injury and can thus be used to treat cardiac arrest.
- Based on the above description, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
Claims (21)
1. A method of treating a neurodegencrative or cardiovascular disorder, comprising administering to the subject in need thereof an effective amount of a compound of the following formula:
in which
each of R1 and R2, independently, is C1-8 alkylene, C2-8 alkenylene, or deleted;
each of A1 and A2 , independently, is aryl or heteroaryl, optionally substituted with halogen, —CN, —NO2, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, —C(O)R3, —S(O)R3, —S(O)2R3, —NR4R5, —C(O)OR3, —C(O)NR4R5, —O(O)CR4 or —NR4(O)CR5; and
each of X and Y, independently, is O, S, or NR6,
wherein each R3 is C1-4 alkyl, and each of R4, R5, and R6, independently, is H or C1-4 alkyl.
2. The method of claim 1 , wherein each of X and Y, independently, is O.
3. The method of claim 2 , wherein R1 is a C2-8 alkenylene and R2 is a C1-8 alkylene.
4. The method of claim 3 , wherein R1 is a C2-3 alkenylene and R2 is a C1-3 alkylene.
5. The method of claim 4 , wherein each of A1 and A2, independently, is aryl, optionally substituted with halogen, —CN, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, or —NR4R5.
6. The method of claim 4 , wherein R1 is —CH═CH— and R2 is —CH2—CH2—.
7. The method of claim 6 , wherein each of A1 and A2, independently, is aryl, optionally substituted with halogen, —CN, —OH, —SH, —OR3, —SR3, —R3, —R3—R4, or —NR4R5.
8. The method of claim 7 , wherein each of each of A1 and A2, independently, is phenyl optionally substituted with —OH or —SH.
9. The method of claim 2 , wherein each of A1 and A2, independently, is aryl, optionally substituted with halogen, —CN, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, or —NR4R5.
10. The method of claim 9 , wherein each of A1 and A2, independently, is phenyl, optionally substituted with —OH or —SH.
11. The method of claim 1 , wherein R1 is a C2-8 alkenylene, and R2 is a C1-8 alkylene.
12. The method of claim 11 , wherein R1 is a C2-3 alkenylene, and R2 is a C1-3 alkylene
13. The method of claim 12 , wherein R1 is —CH═CH—, and R2 is —CH2—CH2—.
14. The method of claim 12 , wherein each of A1 and A2, independently, is aryl, optionally substituted with halogen, —CN, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, or —NR4R5.
15. The method of claim 14 , wherein A1 is 3,4-dihyoxyphenyl and A2 is phenyl.
16. The method of claim 15 , wherein R1 is —CH═CH—; R2 is —CH2—CH2—; and each of X and Y, independently, is O.
17. The method of claim 1 , wherein each of A1 and A2, independently, is aryl, optionally substituted with halogen, —CN, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, or —NR4R5.
18. The method of claim 17 , wherein each of A1 and A2, independently, is phenyl, optionally substituted with —OH or —SH.
19. A particle of manufacture comprising:
i) a container;
ii) an effective amount of a compound, disposed in the container, and having the following formula:
in which
each of R1 and R2, independently, is C1-8 alkylene, C2-8 alkenylene, or deleted;
each of A1 and A2, independently, is aryl or heteroaryl, optionally substituted with halogen, —CN, —NO2, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, —C(O)R3, —S(O)R3, —S(O)2R3, —NR4R5, —C(O)OR3, —C(O)NR4R5, —O(O)CR4, or —NR4(O)CR5; and
each of X and Y, independently, is O, S, or NR6,
wherein each R3 is C-4 alkyl, and each of R4, R5, and R6, independently, is H or C1-4 alkyl; and
iii) a label, disposed on the container and having instructions for treating a neurodegenerative or cardiovascular disorder.
20. The particle of manufacture of claim 19 , wherein each of X and Y, independently, is O; R1 is a C2-3 alkenylene; R2 is a C1-3 alkylene; and each of A1 and A2, independently, is aryl, optionally substituted with halogen, —CN, —OH, —SH, —OR3, —SR3, —R3, —R3—OR4, or —NR4R5.
21. The particle of manufacture of claim 20 , wherein R1 is —CH═CH—; R2 is —CH2—CH2—; A1 is 3,4-dihydroxy phenyl; and A2 is phenyl.
Priority Applications (2)
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US10/316,145 US20030139458A1 (en) | 2001-12-10 | 2002-12-10 | Treatment of neurodegenerative and cardiovascular disorders |
US12/708,401 US8575215B2 (en) | 2001-12-10 | 2010-02-18 | Treatment of neurodegenerative and cardiovascular disorders |
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US33921501P | 2001-12-10 | 2001-12-10 | |
US10/316,145 US20030139458A1 (en) | 2001-12-10 | 2002-12-10 | Treatment of neurodegenerative and cardiovascular disorders |
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US12/708,401 Continuation US8575215B2 (en) | 2001-12-10 | 2010-02-18 | Treatment of neurodegenerative and cardiovascular disorders |
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US (2) | US20030139458A1 (en) |
EP (1) | EP1461025B1 (en) |
JP (1) | JP4511183B2 (en) |
CN (1) | CN100358515C (en) |
AT (1) | ATE517617T1 (en) |
AU (1) | AU2002351341A1 (en) |
CA (1) | CA2466928A1 (en) |
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WO (1) | WO2003053425A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040167217A1 (en) * | 2003-02-26 | 2004-08-26 | Giovanni Scapagnini | Neuroprotective effects of polyphenolic compounds |
US20090227673A1 (en) * | 2006-01-13 | 2009-09-10 | Bao Ting Zhu | Method and Composition for the Treatment of Parkinson's Disease |
US20120100122A1 (en) * | 2010-10-18 | 2012-04-26 | Chemigen | Combination therapy |
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US20070208087A1 (en) | 2001-11-02 | 2007-09-06 | Sanders Virginia J | Compounds, compositions and methods for the treatment of inflammatory diseases |
SI2527315T1 (en) | 2002-05-31 | 2014-06-30 | Proteotech Inc., | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as Alzheimer's disease, type 2 diabetes and Parkinson's disease |
WO2008068751A1 (en) * | 2006-12-04 | 2008-06-12 | Novotyr Therapeutics Ltd. | Novel protein kinase modulators and therapeutic uses thereof |
EP2285774B1 (en) | 2008-06-05 | 2015-02-25 | Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. | Novel modulators of protein kinase signaling |
CN101941907B (en) * | 2010-05-28 | 2015-04-01 | 毛腾淑 | 4-tertiary butyl benzyl-3,4-dyhydroxyl cinanmate as well as application and preparation method thereof |
US8993621B2 (en) * | 2010-11-15 | 2015-03-31 | Chemigen, Inc. | Caffeic acid derivatives and their use in improving neuronal cell viability |
US9770454B2 (en) | 2013-07-14 | 2017-09-26 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | IGF-1R signaling pathway inhibitors useful in the treatment of neurodegenerative diseases |
EP3750530A1 (en) | 2015-02-05 | 2020-12-16 | TyrNovo Ltd. | Combinations of irs/stat3 dual modulators and anti-cancer agents for treating cancer |
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- 2002-12-10 EP EP02786994A patent/EP1461025B1/en not_active Expired - Lifetime
- 2002-12-10 JP JP2003554183A patent/JP4511183B2/en not_active Expired - Fee Related
- 2002-12-10 CA CA002466928A patent/CA2466928A1/en not_active Abandoned
- 2002-12-10 AU AU2002351341A patent/AU2002351341A1/en not_active Abandoned
- 2002-12-10 AT AT02786994T patent/ATE517617T1/en not_active IP Right Cessation
- 2002-12-10 CN CNB02823183XA patent/CN100358515C/en not_active Expired - Fee Related
- 2002-12-10 US US10/316,145 patent/US20030139458A1/en not_active Abandoned
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JP4511183B2 (en) | 2010-07-28 |
EP1461025A1 (en) | 2004-09-29 |
TWI335220B (en) | 2011-01-01 |
EP1461025A4 (en) | 2009-07-29 |
WO2003053425A1 (en) | 2003-07-03 |
US20100160433A1 (en) | 2010-06-24 |
US8575215B2 (en) | 2013-11-05 |
CN1589137A (en) | 2005-03-02 |
TW200301100A (en) | 2003-07-01 |
CN100358515C (en) | 2008-01-02 |
CA2466928A1 (en) | 2003-07-03 |
ATE517617T1 (en) | 2011-08-15 |
JP2005513100A (en) | 2005-05-12 |
AU2002351341A1 (en) | 2003-07-09 |
EP1461025B1 (en) | 2011-07-27 |
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