OA21248A - N'-(2-Chloro-6-Methylbenzoyl)-4-Methyl-3[2-(3-Quinolyl) Ethynyl]-Benzohydrazide for treatment of Alzheimer's disease. - Google Patents
N'-(2-Chloro-6-Methylbenzoyl)-4-Methyl-3[2-(3-Quinolyl) Ethynyl]-Benzohydrazide for treatment of Alzheimer's disease. Download PDFInfo
- Publication number
- OA21248A OA21248A OA1202300025 OA21248A OA 21248 A OA21248 A OA 21248A OA 1202300025 OA1202300025 OA 1202300025 OA 21248 A OA21248 A OA 21248A
- Authority
- OA
- OAPI
- Prior art keywords
- benzohydrazide
- ethynyl
- pharmaceutically acceptable
- chloro
- methyl
- Prior art date
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Abstract
The present invention provides a method for preventing or treating Alzheimer's disease and symptoms thereof comprising administering to a subject in need thereof a therapeutically effective amount of N' -(2-chloro-6-methylbenzoyl)-4methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or a its pharmaceutically acceptable salts, wherein the prevention and/or treatment of said disease and symptoms thereof is achieved by inhibition of amyloid-beta (AB) plaque aggregation, tau hyperphosphorylation, c-Abl kinase or a combination thereof. Also disclosed is the use of a therapeutically effective amount of Ar-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide or its pharmaceutically acceptable salts to inhibit amyloid-beta (A0) plaque aggregation, tau hyperphosphorylation. cAbl kinase or a combination thereof.
Description
A'-(2-CHLORO-6-METHYLBENZOYL)-4-METHYL-3-[2-(3-QUINOLYL) ETHYNYLJ-BENZOHYDRAZIDE FOR TREATMENT OF ALZHEIMER’S DISEASE
Field of the Invention
The présent invention provides a method for preventing or treating Alzheimer's disease and symptoms thereof comprising administering to a subject in need thereof a therapeutically effective amount of .V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide or its pharmaceutically acceptable salts, wherein the prévention and/or treatment of said disease and symptoms thereof is achieved by inhibition of amyloid-beta (Αβ) plaque aggregation, tau hyperphosphorylation, c-Abl kinase or a combination thereof. Also disclosed is the use of a therapeutically effective amount of Æ-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts to inhibit amyloid-beta (Αβ) plaque aggregation, tau hyperphosphorylation, c-Abl kinase or a combination thereof.
Background of the Invention
Alzheimer’s disease (AD) is a major neurodegenerative disorder predominantly présent in an aging population. AD is the sixth leading cause of death in the United States and the fîfth leading cause of death among Americans aged 65 and older. AD currently afflicts 5.3 million people in the United States alone.
The main features of AD are wide-spread Αβ amyloid plaques and neuronal tangles in the brain. It is known that there is a loss of synaptic plasticity resulting in cognitive déficits preceding plaque formation. Several other factors like astrogliosis, neuronal loss, and vascular alterations are also known to contribute to AD pathology. The Αβ peptide toxicity and its accumulation in brain has been partially linked to progression in many clinical studies of AD patients. The major biochemical changes that occur in AD patients are the aggregation of Αβ and abnormal processing, as well as a hyper phosphorylation of Tau.
Plaques and smaller accumulations of beta-amyloids called oligomers may contribute to the damage and death of neurons (neurodegeneration) by interfering with neuron-to-neuron communication at synapses. Tau tangles block the transport of nutrients and other essential molécules inside neurons. Although the complété sequence of events is unclear, betaamyloid may begin accumulating before abnormal tau, and increasing beta-amyloid .
accumulation is associated with subséquent increases in tau. (See Neuron 2018; 98(4):8614; JAMA Neurol 2019; 76(8):915-24).
Compounds preventing or reversing aggregation of Αβ and tau protein hyperphosphorylation therefore hold potential for the treatment of AD.
USFDA has approved five drugs for the treatment of Alzheimer’s — rivastigmine, galantamine, donepezil, memantine, and memantine combined with donepezil. With the exception of memantine, these drugs temporarily improve cognitive symptoms by increasing the amount of neurotransmitters in the brain. Memantine blocks certain receptors in the brain from excess stimulation that can damage nerve cells. The effectiveness of these drugs varies from person to person and is limited in duration. (See Alzheimer ’s Dement. 2020; 16:391-460).
Despite many years of research, no clear therapeutic options are available for AD patients. In view of above facts, the inventors of the présent invention hâve realized that there should be a pharmacologie treatment (médication) which can prevent or reverse aggregation of Αβ and tau protein hyperphosphorylation, and can provide therapeutic options for AD patients.
WO2012/098416 (“the ‘416 publication”) discloses tyrosine kinase inhibitors (e.g., Abl inhibitors) having the structural formula:
or pharmaceutically acceptable sait thereof, wherein;
ring P and ring Q are independently selected from an aryl ring having 6 to 14 carbon atoms, or a 5 to 14 membered heteroaryl ring containing one to four hetero atoms each independently selected from O, S and N, optionally substituted by one or more identical or different radicals R3, with a proviso that when ring Q is pyridyl then ring P is heteroaryl; Ri and R2 are independently selected from the group consisting of hydrogen, -Ci-8-alkyl, -C210-alkenyl, -C2-i2-alkynyl, -C3-i2-cycloalkyl, -C4-i2-cycloalkylalkyl, -C3-i2-cycloalkenyl, aryl, heteroaryl, arylalkyl and a heteroarylalkyl radical, wherein the aryl ring contains 6 to 14 carbon atoms, and the heteroaryl ring contains 5 to 14 membered ring System with one to four hetero atoms each independently selected from O, S and N, and are optionally substituted by one or more identical or different radicals R3;
X and Y are independently selected from the group consisting of C=0, C=S and SO2;
R3 is selected from the group consisting of halogen, -OH, -CN, -NO2, -N3, -Ci-8-alkyl, -C312-cycloalkyl, -(Ci-8-alkyl)-C3-i2-cycloalkyl, -heterocycloalkyl containing 3 to 12 rings atoms having one or two hetero atoms each independently selected from O, S and N, -(Ci8-aIkyl)-heterocycloalkyl containing 3 to 12 rings atoms having one or two hetero atoms each independently selected from O, S and N, -O-Ci-8-alkyl, -0-C3-i2-cycloalkyl, -O-aryl, O-heteroaryl, -C1-8 alkyl-O-Ci-salkyl, -O-Ci-salkyl-O-Ci-salkyl, -0-Ci-8alkyl-NH(Ci-8alkyl), 0-Ci_8alkyl-N(Ci_8alkyl)2, -0-Ci_8alkyl-(heteroaiyl), -C(0)-Ci_8alkyl, -COOH, - C(0)NH2, C(0)NH-Ci-8alkyl, -C(0)N(Ci-8alkyl)2, -C(0)0-Ci-8alkyl, -Ci-shaloalkyl, -C2-ioalkenyl, -C2i2alkynyl, -OC(0)-NH2, -OC(0)-NH(Ci.8alkyl), -OC(0)-N(Ci-8alkyl)2, -NH2, -NH(Cisalkyl), -N(Ci-8alkyl)2, -NH-S02-Ci-8alkyl, -N(Ci-8alkyl) -S02-Ci.8alkyl, - NH-C(0)-(Ci. salkyl), -N(Ci.8alkyl)-C(0)-(Ci.8alkyl), -NH-C(0)0-Ci-8alkyl, -N(Ci-8alkyl)-C(0)0-Ci.8alkyl, -NH-C(0)-NH2,-NH-C(0)-NH(Ci.8alkyl), -N(Ci-salkyl)-C(O)- NH(Ci.8alkyl), -N(Ci8alkyl)-C(0)-N(Ci.8alkyl)2, -NH-C(0)-NH-S02-Ci.8alkyl, -N(Ci-8alkyl)-C(0)-NHS02-Ci. salkyl, -N(Ci-8alkyl)-C(0)-N(Ci.8alkyl)-S02-Ci-8alkyl, -S-Ci-salkyl, -S(0)-Ci-8alkyl, -SO2-C1. salkyl, -S-aryl, -S(0)-aryl, S02-aryl, -SO2NH2, -SO2NH- (Ci-salkyl), -S02N(Ci.8alkyl)2; -aryl, -(Ci-4alkyl)-aryl, heteroaryl or -(Ci-salkyl)- heteroaryl group, wherein the aryl ring contains 6 to 14 carbon atoms, and the heteroaryl ring contains 5 to 14 membered ring System with one to four hetero atoms each independently selected from O, S and N, wherein each of the aforementioned R3 groups may be optionally substituted with a single group selected from the group consisting of: CMalkyl, Ci-4alkoxy, Ci-4haloalkyl, -OH, -COOH, -CN, -NO2, halo, -NH2 and -SO2NH2.
The ‘416 publication further discloses a number of spécifie compounds, their préparation, pharmaceutical compositions and their usefulness for the treatment of cancers such as chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome, melanoma, germ cell tumors, gastrointestinal stromal tumor (GIST), non-small cell lung carcinoma ( SCLC), mastocytosis, neuroblastoma, glioblastoma, astrocytoma, hepatocellular carcinoma, rénal cell cancer, breast cancer, cutaneous systemic sclerosis, prostate and colorectal cancer and other solid tumors.
After an exhaustive research, the inventors of the présent invention hâve surprisingly discovered that a compound of formula:
(referred to hereinafter as “Compound 1”), from among thousands of compounds encompassed by above Markush structure together with specifically exemplified compounds in the ‘416 publication, significantly prevents or reverse aggregation of Αβ (decreased the spread of Αβ amyloid plaques).
Hyperphosphorylated tau is a cardinal feature of AD pathology. The c-Abl activation is associated with AD tau phosphorylation both directly and through the activation of Cdk5. Hence, the use of c-Abl inhibitor could be a successful strategy for AD treatment. (Current Alzheimer Research, 2011, 8:643-651).
Thus, the présent invention provides a great hope for a médication to meet the challenges of a serious global health concem, i.e., Alzheimer’s disease.
Summary of the Invention
Problems to be solved by the Invention
As realized by the inventors of the présent invention, there is a need for a new médication, which significantly prevents or reverses aggregation of Αβ (decreases the spread of Αβ plaques) and tau hyperphosphorylation, and at the same time possesses significantly higher brain concentration for increased efficacy and good safety profile amenable to human use.
Means for solving the Problems
As a resuit of intensive studies, the présent inventors hâve found that Compound 1 significantly prevents and/or reverses aggregation of Αβ (decreases the spread of Αβ plaques) and may prevent tau hyperphosphorylation. In particular, Compound 1 of the présent invention possesses significantly higher brain to plasma concentration and excellent safety profile amenable to human use.
Thus, in one aspect, the présent invention provides:
[1] A method for preventing or treating Alzheimer’s disease and symptoms thereof comprising administering to a subject in need thereof a therapeutically effective amount of
7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts.
[2] The method according to [1], wherein 2V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts regulate levels of tau hyperphosphorylation.
[3] The method according to [1], wherein TV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts regulate levels of tau hyperphosphorylation by inhibition of c-Abl-kinase.
[4] The method according to [1], wherein TV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts prevent or reverse aggregation of Αβ (decreased the spread of Αβ plaques).
[5] The method according to [1], wherein TV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts prevent or reverse aggregation of Αβ (decreased the spread of Αβ plaques) by inhibition of c-Ablkinase.
[6] The method according to any one of [1] to [5], wherein TV-(2-chloro-6-methylbenzoyl)4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait is administered at a dose in the range of about 1.0 mg/kg to about 10.0 mg/kg.
[7] A method for inhibiting tau hyperphosphoiylation comprising administering to a subject an amount of compound sufficient to inhibit tau hyperphosphorylation, wherein said compound modulâtes an ATP-dependent enzyme, wherein said compound is N -(2-chloro6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait.
[8] A method for inhibiting, preventing or reversing aggregation of Αβ comprising administering to an amount of compound sufficient to reduce Αβ plaque, wherein said compound modulâtes an ATP-dependent enzyme, wherein said compound is N -(2-chloro6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait.
[9] The method according [7] and [8], wherein the ATP-dependent enzyme is a kinase.
[10] The method according to [9] wherein the kinase is a tyrosine kinase.
[11] The method according to [10] wherein the tyrosine kinase is c-Abl kinase.
[12] The method according to any one of [1] to [11], wherein 7V-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts is further administered in combination with an additional therapeutic agent.
[13] The method according to [12], wherein the additional therapeutic agent according is selected from memantine, donepezil (Aricept®), galantamine (Reminyl®), tacrine hydrochloride (Cognex®), or rivastigmine tartrate (Exelon®).
[14] JV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts for use in the prévention or treatment of Alzheimer's disease and symptoms thereof.
[15] A pharmaceutical composition comprising a therapeutically effective amount of N -(2chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts for use in the prévention and/or treatment of Alzheimer's disease and symptoms thereof.
[16] The pharmaceutical composition according to [15], wherein the pharmaceutical composition has a form selected from tablets, pellets, capsules, dispersible tablets, sachets, granules or syrups.
[17] The pharmaceutical composition according to [16], wherein the pharmaceutical composition is a capsule and is administered orally.
[18] The pharmaceutical composition according to [16], wherein the pharmaceutical composition is a tablet and is administered orally.
[19] The use of 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyI]benzohydrazide or its pharmaceutically acceptable salts for the manufacture of a médicament for the prévention and/or treatment of Alzheimer's disease and symptoms thereof.
[20] The c-Abl inhibitor for use in the prévention and/or treatment of Alzheimer's disease and symptoms thereof, wherein the c-Abl inhibitor is #-(2-chloro-6-methylbenzoyl)-4methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts.
[21] The tau hyperphosphorylation inhibitor for use in the prévention and/or treatment of Alzheimer's disease and symptoms thereof, wherein the tau hyperphosphorylation inhibitor is jV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts.
[22] The Αβ plaque aggregation inhibitor for use in the prévention and/or treatment of Alzheimer's disease and symptoms thereof, wherein the inhibitor is 7V-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts.
[23] A method of improving symptoms of Alzheimer’s disease in a subject comprising administering to the subject a therapeutically effective dose of #-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts to improve the symptoms in the subject, wherein the improvement is achieved by inhibition of Αβ plaque aggregation, tau hyperphosphorylation, c-Abl kinase or combination thereof.
[24] The method according to [23], wherein the compound, or its pharmaceutically acceptable salts is administered at a dosage in the range of from about 1.0 mg/kg to about 10.0 mg/kg.
[25] The method according to any one of [1] to [24] in which the symptoms of AD according are difïiculty remembering recent events or conversation, disorientation, mood and behavior, difficulty speaking, swallowing, walking or cognitive disorder.
[26] The method or use according to any of [1] to [27] wherein the percentage inhibition of c-Abl kinase is 37%.
[28] The method or use according to any of [1] to [27] wherein the percentage inhibition of c-Abl kinase is about 37%.
[29] The method or use according to any of [1] to [27] wherein the percentage inhibition of c-Abl kinase is at least 37%.
Brief Description of the Drawings
Various aspects of the présent invention are illustrated by reference to the following drawings.
Figure 1: Total Αβ content in cortex of Tg APP/PS1 Mice using ELISA.
According to the resuit of ELISA, Compound 1 at 30 and 45 mg/kg dose levels showed significant réduction in total Αβ content in cortex of Tg APP/PS1 mice compared to placebo treated group.
Figure 2: Αβ plaque load (% area fraction) in cortex of Tg APP/PS1 mice using IHC
According to the resuit of IHC, Compound 1 at 30 mg/kg dose levels significantly reduced Αβ plaque area fraction compared to placebo treated group.
Figure 3: Contextual fear conditioning (CFC): Freezing behaviour in Tg APP/PS1 mice.
According to the resuit of CFC analysis, Compound 1 showed significant increase in % freezing of mice at 30 and 45 mg/kg doses as compared to placebo treated group.
Figure 4: Αβ42 and Αβ42/Αβ4ο ratio inTgSwDI mice using ELISA
According to the resuit of ELISA, Compound 1 at 15, 30, and 45 mg/kg showed dosedependent réduction in Αβ42 and ratio of Αβ42/Αβ40. The effect on Αβ42 and ratio of Αβ42/Αβ4ο was statistically significant at doses of 30 and 45 mg/kg as compared to placebo treated group, whereas in case of nilotinib only réduction in Αβ42/40 ratio was statistically significant.
The aforementioned aspects and embodiments, and other aspects, objects, features and advantages of the présent invention will be apparent from the following detailed description.
Unless otherwise indicated, the contents of each document discussed herein is incorporated by reference in its entirety.
Detailed Description of the Invention
As used herein the following définitions apply unless clearly indicated otherwise. It should be noted that the singular forms a an and the include plural reference unless the context clearly dictâtes otherwise. As used herein, the term “about”, refers to any value which lies within the range defined by a variation of up to ±10% of the value. It should be understood that unless expressly stated to the contrary, Compound 1 chemically refers to N -(2-chloro
6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide and structurally refers to:
IV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide can be 5 prepared by following the procedure known to a person of ordinary skilled in the art, for example, the procedure disclosed in the ‘416 publication.
Surprisingly, 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide was found to be a potent c-Abl inhibitor when tested for its ability to inhibit cell prolifération of K562 cells which is a measure of ability of a compound to inhibit 10 endogenous Bcr-Abl kinase activity. The potency of Compound 1 is significantly higher which is surprising and unexpected because the similar compounds from the ‘416 publication failed to show potency at a dose of 0.1 nM as shown in below. (For experimental procedure, refer to the ‘416 publication under In-vitro Cell Prolifération Assay heading).
Table 1: In-vitro Cell Prolifération Assay data
Compound No. | Structure | % inhibition (at 0.1 nM) |
Compound 1 | / \ x1 Q \=O l' Z 'x z o=/ X | 37 |
Compound 1.10 of the ‘416 publication | Oz “O O \=o z x5 z /1 Q oJX ^X \ __ / | 0 |
Compound 1.21 of the ‘416 publication | O-5 ô ^=o 1' z z o=Ç zO | 6 |
Compound 1.50 ofthe ‘416 publication | O-5 O )=o x' z 'x z o=/ O ΓÊ O □ | 0 |
Compound 1.55 of the ‘416 publication | ϋ /=O z Ί z o=/ O X \7 U. | 0 |
Compound 1.59 of | 1 NH | 2 |
the ‘416 publication | ||
o ch3 |
Compound 1 has good brain pénétration with a ratio of concentration in brain to plasma found to be significantly higher for JV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide as compared to that for nilotinib or dasatinib. (Example 2 ofWO2017/208267, which is incorporated herein by reference in its entirety).
Table 2: Concentration of compounds in brain and plasma
Compound | Treatment (mg/kg) | Time Points (hrs) | Plasma conc. (ng of compound/mL of plasma | Brain conc. (ng of compound/g of brain tissue | Ratio of brain conc./plasma conc. |
Compound 1 | 30 | 1 | 4798±858 | 1901±959 | 0.40 |
4 | 3167±50 | 510±367 | 0.16 | ||
8 | 2715±379 | 435±157 | 0.16 | ||
Nilotinib | 100 | 1 | 31683±7958 | 380±70 | 0.01 |
4 | 38813±11635 | 487±126 | 0.01 | ||
8 | 16988±2133 | 180±46 | 0.01 |
As evidenced from the results, Compound 1 showed about 40 times (at 1 hour) higher ratio of brain to plasma concentration compared to nilotinib. Similar results were observed for Compound 1 when compared with dasatinib wherein Compound 1 showed significantly better brain pénétration than dasatinib. The results indicate that the Compound 1 shows higher brain concentration for longer duration of time compared with nilotinib and dasatinib.
Accordingly, certain embodiments of the présent invention involve uses or methods of administering Compound 1 in such a manner so as to achieve a ratio of brain/plasma concentration of from about 0.16 to about 0.40. Other embodiments involve uses or methods of administering Compound 1 in such a manner so as to achieve a ratio of brain/plasma concentration of 0.16 to 0.40. In these embodiments, the brain/plasma concentrations are measured as they are measured in the Table above.
Compound 1 is also a safe c-Abl inhibitor. Other c-Abl inhibitors are known for cardiovascular toxicity (See J Clin Oncol 33:4210-4218,2015 and Vascular Health and Risk Management 13: 293-303, 2017). In fact the approved US FDA Label for Tasigna® (nilotinib), Sprycel® (dasatinib), Iclusig® (ponatinib), Bosulif® (bosutinib) and Gleevec® (imatinib) cautions about the sever cardio-toxicity associated with them. Surprisingly, the inventors hâve found that Compound 1, at a therapeutically effective dose, is devoid of cardiovascular side effects when tested for its in vitro effect on hERG channel and its in vivo effect on ECG parameters like QT interval, QTc interval, QTcf interval and heart rate in conscious beagle dogs and guinea pig. (Examples 5 and 6 ofWO2017/208267).
Thus, according to a first aspect of the présent invention, there is provided a method for preventing or treating Alzheimer's disease and symptoms thereof comprising administering to a subject in need thereof a therapeutically effective amount of 7V-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts.
As used herein, “therapeutically effective amount” is a sufficient amount of Compound 1 or a pharmaceutically acceptable sait thereof to provide a therapeutic benefit for the treatment or management of the disease or to delay, minimize or eradicate symptoms associated with the disease.
As used herein the term pharmaceutically acceptable, refers to a compound that is not biologically or otherwise undesirable, i.e., the Compound 1 may be incorporated into a pharmaceutical formulation of the invention and administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
As used herein the term “salts”, refers to salts of an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, and the like or salts of organic acids such as, for example, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, citric acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartartic acid, or amino acids, such as glutamic acid or aspartic acid, and the like.
As used herein the term subject refers to a patient such as human suffering from Alzheimer’s disease and who needs therapeutic intervention for the treatment and prévention of AD and symptoms thereof. The patient includes the elderly, for example, those 60 years of âge and above.
Studies in an animal model of AD hâve shown that an increase in Αβ causes increase in cAbl activity in hippocampal neurons (Schlatterer SD et al, J Mol Neurosci. 2011 Nov; 45(3): 445—452). Inhibition and modulation of c-Abl tyrosine kinase has been shown to decrease tau phosphorylation and behavioral symptoms. Αβ sequence results in two major Αβ isoforms: Αβ42 (42 residue long) and Αβ40 (40 residue long). Αβ42 is the major component of amyloid plaques in AD brains, while Αβ40 is detected only in a subset of plaques. Thus, Αβ42 is the major, and sometimes only, component in amyloid plaques. (See J. Neurochem. 2013; 126, 305-311). Increased Αβ42/Αβ40 ratios appear to correlate with the early-onset familial AD cases caused by presenilin mutations (See Human Mutation 2006, 27(7): 686695). Lowering Αβ42/Αβ40 ratios in transgenic mice decreases Αβ déposition (See, The Journal of Neuroscience, 2007, 27(3):627-633). Higher neurotoxicity has been reported with samples of higher Αβ42/Αβ40 ratios (See, The EMBO Journal, 2010 29:3408-3420).
Surprisingly, Compound Ishowed a dose-dependent réduction in Αβ42 content and the Αβ42/40 ratio. Preferably, the compound disclosed herein decreases the spread of Αβ42 amyloid plaques.
In one embodiment of the présent invention, N -(2-chloro-6-methylbenzoyl)-4-methyl-3-[2(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait regulate levels of tau hyperphosphorylation in AD patients via the inhibition of c-Abl-kinase.
In another embodiment of the présent invention, N -(2-chloro-6-methylbenzoyl)-4-methyl3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait prevents or reverses aggregation of Αβ (decreases the spread of Αβ amyloid plaques) in AD patients via the inhibition of Abl-kinase
In yet another embodiment of the présent invention, JV-(2-chloro-6-methylbenzoyl)-4methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait régulâtes levels of tau hyperphosphorylation and at the same time prevents or reverses the aggregation of Αβ (decreases the spread of Αβ plaques) in AD patients via the inhibition of c-Abl-kinase.
In yet another embodiment, #-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait decreases the spread of Αβ42 amyloid plaques in AD patients via the inhibition of Abl-kinase.
In yet another embodiment of the présent invention, there is provided a method for treating and/or preventing AD and symptoms thereof, wherein jV-(2-chloro-6-methylbenzoyl)-4methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait is administered at a dose in the range of about 1.0 mg/kg to about 10.0 mg/kg.
In certain embodiments, the Compound 1 may be admimstered up to a dose of about 10 mg/kg, preferably from about 1.0 mg/kg to about 10.0 mg/kg, more preferably from about 3.0 mg/kg to about 7.0 mg/kg. In various embodiments, the dose is preferably given once per day, but may also be given in multiple doses per day, for example, once, twice, three times, or four times a day. Altematively, the dose may be given every other day or every three days, four days, or five days, as will be appreciated by the skilled practitioner. Doses of Compound 1 may be administered for a short time period, e.g., weeks, months, or for a longer time period, such as chronic administration, e.g., over several months or years.
According to another aspect of the présent invention, there is provided a method for inhibiting tau hyperphosphorylation comprising administering to a subject an amount of compound sufficient to inhibit tau hyperphosphorylation, wherein said compound modulâtes an ATP-dependent enzyme, wherein said compound is Æ-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait.
Yet another aspect of the présent invention provides a method for inhibiting, preventing or reversing aggregation of Αβ plaque comprising administering to an amount of compound sufficient to reduce Αβ plaque, wherein said compound modulâtes an ATP-dependent enzyme, wherein said compound is JV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait.
In one embodiment, the enzyme is a kinase.
In another embodiment, the kinase is a tyrosine kinase.
In another embodiment, the tyrosine kinase is c-Abl kinase.
In accordance with another embodiment, ?/-(2-chloro-6-methyIbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait is further administered in combination with an additional therapeutic agent selected from memantine, donepezil (Aricept®), galantamine (Reminyl®), tacrine hydrochloride (Cognex®), or rivastigmine tartrate (Exelon®).
In another aspect, the présent invention provides N -(2-chloro-6-methylbenzoyl)-4-methyl3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait for use in the prévention and/or treatment of Alzheimer’s disease and symptoms thereof.
In yet another aspect, the présent invention provides a pharmaceutical composition comprising a therapeutically effective amount of N -(2-chloro-6-methyIbenzoyI)-4-methyl3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait for use in the prévention and/or treatment of Alzheimer's disease and symptoms thereof.
In yet another aspect, the présent invention provides the use of 7V-(2-chloro-6methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait for the manufacture of a médicament for the prévention and/or treatment of Alzheimer's disease and symptoms thereof.
According to one embodiment, the phrase préparation of a médicament refers to the use of the dosing regimen directly as the médicament in addition to their use in any stage of the préparation of such a médicament.
According to another aspect, there is provided a c-Abl inhibitor for use in the prévention and/or treatment of Alzheimer's disease, risk of developing AD and symptoms thereof, wherein the inhibitor is 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait.
According to yet another aspect, there is provided a tau hyperphosphorylation inhibitor for use in the prévention and/or treatment of Alzheimer's disease and symptoms thereof, wherein the inhibitor is 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait.
According to yet another aspect, there is provided an Αβ plaque aggregation inhibitor for use in the prévention and/or treatment of Alzheimer's disease and symptoms thereof, wherein the inhibitor is 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait thereof.
As used herein the term “symptoms” refers to difficulty remembering recent events or conversation, disorientation, mood and behavior, difficulty speaking, swallowing, walking or cognitive disorder that affect leaming, memory, perception, problem solving, and include amnesia, dementia and delirium.
Thus, according to another aspect, the présent invention provides a method of improving symptoms of Alzheimer’s disease in a subject, comprising administering to the subject a therapeutically effective dose of 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait to effectively improve the symptoms in the subject, wherein the improvement is achieved by the inhibition of Αβ plaque aggregation, tau hyperphosphorylation, c-Abl kinase or a combination thereof
In a preferred embodiment, the effective dose of N-(2-chloro-6-methylbenzoyl)-4-methyl3-[2-(3-quinoIyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable sait ranges from about 1.0 mg/kg to about 10 mg/kg.
In a preferred embodiment, the symptoms of AD include, but are not limited to, memory loss, difficulty performing familiar tasks, problems with language, disorientation to time and place, poor or decreased judgment, problems with abstract thinking, misplacing things, change in mood or behavior, changes in personality and loss of initiative. In another preferred embodiment, the symptoms include cognitive disorder that affect leaming, memory, perception, problem solving, and include amnesia, dementia and delirium.
In a preferred embodiment, the pharmaceutical composition is meant for oral administration. The composition suitable for oral use includes, but not limited, to tablets, pellets, capsules, dispersible tablets, sachets, granules, syrup, and the like. The pharmaceutical composition of the présent invention can be obtained by conventional approaches using conventional pharmaceutically acceptable excipients well known in the art. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses pharmaceutically acceptable excipients which can be used for préparation of a suitable dosage form containing 7V-(2-ch!oro-6-methylbenzoyl)-4-methyl-3-[2-(3quinolyl)ethynyl]-benzohydrazide or a pharmaceutically acceptable salts thereof as an active ingrédient.
For example, pharmaceutically acceptable excipients suitable for tablets préparation include, but not limited to, diluents (e.g., calcium phosphate- dibasic, calcium carbonate, lactose, glucose, microcrystalline cellulose, cellulose powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch pregelatinized, or polyols such as mannitol, sorbitol, xylitol, maltitol, and sucrose), binders (e.g., starch, pregelatinized starch, carboxymethyl cellulose, sodium cellulose, microcrystalline cellulose, hydroxyproyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crospovidone, or combinations thereof), disintegrants (e.g., crosslinked cellulose, crosslinkedpolyvinylpyrrolidone (crosspovidone), sodium starch glycolate, polyvinylpyrrolidone (polyvidone, povidone), sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose sodium), hydroxypropyl cellulose, hydroxypropyl methylcellulose, xanthan gum, alginic acid, or soy polysaccharides), wetting agents (e.g., polysorbate, sodium lauryl sulphate, or glyceryl stéarate) or lubricants (e.g., sodium lauryl sulfate, talc, magnésium stéarate, sodium stearyl fumarate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, or zinc stéarate).
In another preferred embodiment, the pharmaceutical composition has a form selected from tablets, pellets, capsules, dispersible tablets, sachets, granules or syrups.
In yet another preferred embodiment, the pharmaceutical composition is a capsule and is administered orally.
In yet another preferred embodiment, the pharmaceutical composition is a tablet and is administered orally.
Biological Evaluation
Hereinafter, the présent invention is described with référencé to test examples, but the scope of the preset invention is not limited thereto. Any modification in the procedures described herein, other assays or models and modification thereon can be employed or adapted. Ail such modifications and alternative procedures are within the spirit and scope of the présent application.
Evaluation of Compound 1 in a Mouse Model of Alzheimer’s Disease
Efficacy of Compound 1 was evaluated in two transgenic mouse models- Double transgenic APP/PS1 and Triple transgenic Tg-SwDI mouse models of AD. APP/PS1 are double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PSl-dE9), both directed to CNS neurons. Both mutations are associated with early-onset Alzheimer’s disease. The humanized Mo/HuAPP695swe transgene allows the mice to secrete a human Αβ peptide. These mice may be useful in studying neurological disorders of the brain, specifically Alzheimer’s disease, amyloid plaque formation and aging. Triple transgenic TgSwDI mice express neuronally derived human amyloid beta-precursor protein, APP gene, 770 isoform, containing the Swedish mutations (Lys670—>Asn/ Met671—>Leu), Dutch (Glu693—>Gln) and lowa (Asp694—*Asn) mutations, under the control of the mouse thymus cell antigen 1, thêta, Thyl, promoter.
Study I
Six month old male APP/PS1 mice which show little overt behavioral or pathological phenotype of AD were used. Ail experiments involving animais were performed in accordance with institutional guidelines for the use and care of animais after approval from the Institutional Animal Ethics Committee (IAEC), Central Animal Facility, Indian Institute of Science. Only male mice were used for the study and were housed at ambient température of 25 °C under 12 hours light-dark cycle with free access to food chow and drinking water. Ail mice were dosed once a day, orally with placebo for Compound 1 at 30 and 45 mg/kg for a period of three months.
After completion of treatment phase, mice were subjected to behavioural assessment using CFC test, followed by biochemical estimation of brain Αβ using an enzyme-linked immunosorbent assay (ELISA) and Αβ plaque load using Immunohistochemistry (IHC).
Total Αβ content in cortex of Tg APP/PS1 mice using ELISA
The animais were (n=10/treatment) deeply anesthetized with a mixture of xylazine and ketamine (1:8), perfused with 10 mL of Ix saline for 4 minutes, their brains were excised, homogenized immediately in 0.5 mL ELISA buffer, and centrifuged at 5000xg for 15 minutes at 4 °C to precipitate the pellet. Total Αβ was estimated in the cortex of APP/PS1 mice using ELISA assay kit as per the manufacturer instruction.
Compound 1 at 30 and 45 mg/kg dose levels showed significant réduction in total Αβ content in cortex of Tg APP/PS1 mice compared to placebo treated group. (See Figure 1)
Αβ plaque load (% area fraction) in cortex of Tg APP/PS1 mice using IHC
Mouse brains (n=5/treatment) were fixed in 4% (w/v) buffered paraformaldéhyde (PFA). The brain tissues were processed for paraffin embedding and serial sections (5 μΜ thickness) were eut using microtome (Leica Biosystems Inc., Buffalo Grove, IL, USA). Sections were de-waxed by xylene treatment followed by a brief wash with chloroform to remove the residual xylene. Endogenous peroxidase activity was blocked with methanol containing hydrogen peroxide (3%, v/v) for 30 minutes. Sections were hydrated in graded alcohol followed by brief washings with water and phosphate buffered saline (10 mM, pH 7.4, PBS). The sections were pressure cooked for 10 minutes in sodium citrate buffer (pH 6.8). After cooling, the sections were washed with Phosphate-buffered saline (PBS) and incubated in normal goat sérum for 30 minutes at room température to block non-specific binding. Next, the sections were incubated with primary antibody anti-β-Amyloid, 1-16 antibody (6E10) ovemight at 4 °C. After washing with phosphate buffered saline (10 mM, pH 7.4, PBS), the sections were incubated in secondary antibody. Subsequently, the sections were washed and mounted with anti-fade mounting medium (VECTASHIELD). Image acquisition was performed using 40x/0.75 NA, Zeiss Axio Imager M2 (Cari Zeiss Microscopy, LLC, Thomwood, NY, USA).
The IHC resuit showed that compared to placebo, Compound 1 significantly reduced Αβ plaque (% area fraction) at the dose of 30 mg/kg. (See Figure 2).
Contextual fear conditioning (CFC): freezing behaviour in Tg APP/PS1 mice
The CFC test was performed using an apparatus from San Diego Instruments (CA, USA). The CFC training context was rectangular in shape, identity of the context was maintained with the presence of distinct odor (2% acetic acid, v/v). The conditioning chamber was cleaned with 70% éthanol before and after each session. Mice were housed singly and were first handled for 5 minutes for 3 days. On training day, mice (n=6/treatment) were allowed to explore the training context for 1 minute and then received 3 foot-shocks (2 s and 0.6 mA each, inter-trial interval 30 s). Contextual fear memory was assessed by retuming mice to the training context 24 hours after fear conditioning and analyzing freezing during a test period of 2 minutes. Freezing was defined as complété absence of somatic mobility other than respiratory movements. (SciRep.20\8; Sep 3; 8(1):13119).The resuit of CFC analysis showed significant increase in % freezing of mice at 30 and 45 mg/kg doses of Compound 1 as compared to placebo treated group. .These results suggest that the treatment with Compound 1 at indicated doses results in improvement in cognitive déficits in Tg APP/PS1 mice. (See Figure 3).
Study Π
Estimation of Αβ42 and Αβ42/Αβ40 ratio in TgSwDI mice using ELISA
Female TgSwDI (expresses human APP gene containing Swedish, Dutch, and lowa mutations) of 5-7 months of âge were used for the study. Animais were habituated for handling for one week prior to initiation of dosing. Ail experiments involving animais were performed in accordance with institutional guidelines for the use and care of animais after approval from the Institutional Animal Ethics Committee (IAEC), Sun Pharma Advanced Research Company (SPARC) Ltd. Mice were housed at an ambient température of 25 °C under 12 hours light-dark cycle with free access to food chow and drinking water. Animais were treated with assigned treatments p.o., o.d., for a period of 96 days. Thus, Compound 1 was given at 15, 30, and 45 mg/kg dose and nilotinib was given at 30 mg/kg dose. After completion of treatment phase, mice from each treatment group were perfused with ice-cold phosphate buffered saline (PBS, pH 7.4), brain was excised, cortex was isolated and processed for préparation of lysâtes as per protocol provided by Invitrogen ELISA kit. Estimation of Αβ42 and Αβ40 were carried out as per the instructions provided by Invitrogen 5 user manual. Ratio of Αβ42/40 was calculated.
The resuit of ELISA indicated that Compound 1 at 15, 30, and 45 mg/kg showed dosedependent réduction in Αβ42 content and the Αβ42/40 ratio. Compared to placebo group, the effect on Αβ42 content and the ratio was statistically significant at 30 and 45 mg/kg doses. Compared to placebo, nilotinib had no statistically significant réduction in Αβ42 10 content. (See Figure 4).
Claims (10)
1. N -(2-chloro-6-methylbenzoyI)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts for use in the prévention or treatment of Alzheimer’s disease and symptoms thereof.
2. A pharmaceutical composition comprising a therapeutically effective amount of N-(2chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts for use in the prévention and/or treatment of Alzheimer’s disease and symptoms thereof.
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition has a form selected from tablets, pellets, capsules, dispersible tablets, sachets, granules or syrups.
4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a capsule and is administered orally.
5. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a tablet and is administered orally.
6. The use of 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide or its pharmaceutically acceptable salts for the manufacture of a médicament for the prévention and/or treatment of Alzheimer’s disease and symptoms thereof.
7. 7V-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyl]-benzohydrazide or its pharmaceutically acceptable salts for use in inhibiting c-Abl.
8. JV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl)ethynyI]-benzohydrazide or its pharmaceutically acceptable salts for use in inhibiting tau hyperphosphorylation.
9. _V-(2-chIoro-6-methylbenzoyI)-4-methyl-3-[2-(3-quinolyl)ethynyI]-benzohydrazide or its pharmaceutically acceptable salts for use in inhibiting Αβ plaque aggregation.
10. Use of jV-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyI)ethynyl]benzohydrazide or its pharmaceutically acceptable salts in the manufacture of a médicament for use in inhibiting c-Abl, tau hyperphosphorylation or Αβ plaque aggregation.
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