Classifications

• • 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
• • 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
  • A61K31/47—Quinolines; Isoquinolines
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the invention relates to a method of treating or preventing Parkinson's disease in a subject comprising administering a compound of Formula I
• Ri is -NHC(O) C 3 _ 6 cycloalkyl and R 2 is hydrogen;
• Ri and R 2 along with the carbon atoms to which they are attached form a six membered aromatic ring, wherein the ring is substituted with one or more groups selected from hydrogen, halogen and C 1-6 alkyl;
• R 3 and R4 are independently selected from group comprising hydrogen, halogen, Q_ 3 alkyl, OC 3 alkyl, N0 2 , SCi_ 3 alkyl, d_ 3 haloalkyl, OCi_ 3 haloalkyl, and SCi_ 3 haloalkyl; or pharmaceutically acceptable salt thereof.
• c-Abl is a non-receptor protein tyrosine kinase that is implicated in various cellular processes which include regulation of cell survival, growth and motility.
• c-Abl kinase inhibitors such as imatinib (Gleevec ), nilotinib (Tasigna ), dasatinib (Sprycel ) and ponatinib (Iclusig ) have been developed and marketed for clinical use in the treatment of chronic myeloid leukemia.
• c-Abl plays an important role in oxidative stress-induced neuronal cell death (Wu et al, Cell Death Differ., 2016; 23:542-552). It has been reported that c- Abl is involved in Parkinson's disease (Gonfloni et al, Int. J. Cell Biol., 2012; 2012: 1-7). Also, c-Abl is known to be activated by dopaminergic stress and by dopaminergic neurotoxins viz.
• Parkinson disease is a common neurodegenerative disease characterized by protein accumulation in intracellular inclusions designated as Lewy bodies and Lewy neuritis and subsequent loss of dopaminergic neurons. Rare familial mutations have provided insight into this chronic, progressive neurodegenerative disease like mutation in -synuclein and LRRK2 cause autosomal-dominant PD, whereas mutations in DJ-1, PINK1 and parkin results in autosomal-recessive PD. Parkin is an E3 ubiquitin ligase, and familial mutations are thought to impair E3 ligase activity of parkin (Ko et al, PNAS, 2010; 107: 16691-16696).
• c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD viz. parkin and ⁇ -synuclein (Mahul-Mellier et al, Hum. Mol. Genet., 2014; 23:2858- 2879).
• c-Abl phosphorylates parkin on tyrosine 143. This phosphorylation inhibits parkin's E3 ubiquitin ligase activity, leading to accumulation of AIMP2 and FBPl (parkin substrates) and loss of parkin's cytoprotective function resulting in cell death (Ko et al, PNAS, 2010; 107: 16691-16696; Imam et al, J.
• c-Abl regulates clearance of ⁇ -synuclein, a synaptic protein that has been strongly implicated in the pathogenesis of PD.
• ⁇ -synuclein a synaptic protein that has been strongly implicated in the pathogenesis of PD.
• a bi-directional relationship in vivo between ⁇ -synuclein and c-Abl has been described wherein an increase in ⁇ -synuclein expression facilitates its phosphorylation and subsequent activation of c-Abl.
• c-Abl inhibitors like nilotinib are known to cross the blood-brain barrier and protect dopaminergic neurons in a mouse model of PD induced with l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine (herein referred to as MPTP) (Karuppagounder et al., Sci. Rep. 2014; 4:4874).
• MPTP l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine
• Nilotinib has been shown to increase ⁇ -synuclein clearance via the autophagy pathway and protects against ⁇ -synuclein accumulation-induced loss of dopaminergic neurons in this mouse model of PD (Hebron et al, Hum. Mol. Genet., 2013; 22:3315-3328; Imam et al, J.
• US20150087653 discloses method of treating neurodegenerative diseases comprising of administering tyrosine kinase inhibitors such as nilotinib.
• nilotinib has several major drug associated adverse effects.
• USFDA has issued a boxed warning for Tasigna ® capsules since its treatment is associated with potentially severe cardiac side effects (QT prolongation) and sudden deaths in patients.
• Dasatinib is known to cause pleural effusion and hemorrhage.
• Ponatinib is also associated with severe adverse effects which include thromboembolism and vascular occlusion.
• Imatinib is not a potent inhibitor of Abl kinase.
• imatinib and dasatinib being P-glycoprotein (p-gp) substrate, show poor brain concentration. .
• p-gp P-glycoprotein
• the invention provides method of treating or preventing Parkinson's disease in a subject comprising administering a therapeutically effective amount of a compound of Formula I,
• Ri is -NHC(O) C 3 _ 6 cycloalkyl and R 2 is hydrogen; or Ri and R 2 along with the carbon atoms to which they are attached form a six membered aromatic ring, wherein the ring is substituted with one or more groups selected from hydrogen, halogen and C 1-6 alkyl;
• R 3 and R4 are independently selected from group comprising hydrogen, halogen, C 1-3 alkyl, OCi_ 3 alkyl, N0 2 , SCi_ 3 alkyl, Ci_ 3 haloalkyl, OCi_ 3 haloalkyl, and SCi_ 3 haloalkyl; or its pharmaceutically acceptable salt thereof.
• Fig.l Photomicrographs from coronal sections showing tyrosine hydroxylase (TH)-positive neurons, showing prevention of neurodegeneration by the compound of Formula La.
• Fig.2. Percentage area of TH-positive neurons on administration of the compound of Formula
• Fig.3. Integrated density of TH-immunoreactivity on administration of the compound of Formula La.
• Fig.4 Photomicrographs from coronal sections showing tyrosine hydroxylase (TH)-positive neurons, showing prevention of neurodegeneration by the compound of Formula Lb.
• TH tyrosine hydroxylase
• Fig.5. Percentage area of TH-positive neurons on administration of the compound of Formula Lb.
• Fig.6 Integrated density of TH-immunoreactivity on administration of the compound of Formula Lb.
• the present invention provides a method of treating or preventing Parkinson's disease in a subject comprising administering a therapeutically effective amount of the compound of Formula I,
• Ri is -NHC(O) C 3 _ 6 cycloalkyl and R 2 is hydrogen; or Ri and R 2 along with the carbon atoms to which they are attached form a six membered aromatic ring, wherein the ring is substituted with one or more groups selected from hydrogen, halogen and C 1-6 alkyl;
• R 3 and R4 are independently selected from group comprising hydrogen, halogen, Q_ 3 alkyl, OCi_ 3 alkyl, N0 2 , SCi_ 3 alkyl, Ci_ 3 haloalkyl, OCi_ 3 haloalkyl, and SCi_ 3 haloalkyl; or its pharmaceutically acceptable salt thereof.
• the present invention provides a method of treating or preventing Parkinson's disease in a subject, comprising selecting a subject suffering from Parkinson's disease or at risk of developing Parkinson's disease and administering a therapeutically effective amount of a compound of Formula I.
• therapeutically effective amount of compound of Formula I refers to amount of the compound of Formula I that elicit the therapeutic effect for which it is administered.
• alkyl refers to a saturated hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, either linear or branched and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl and n-pentyl.
• C 1-6 alkyl refers that there are 1 to 6 carbon atoms in the alky chain.
• Cj.g cycloalkyl refers to a non-aromatic mono-cyclic ring system of 3 to 6 carbon atoms. Monocyclic rings include cylcopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• haloalkyl refers to alkyl chain substituted with one or more halogen radical selected from chloride, bromide, iodide and fluoride.
• the present invention provides method of treating or preventing Parkinson's disease comprising administering a therapeutically effective amount of a compound of Formula I wherein Ri in the compound of Formula I is -NHC(O) cyclopropyl and R 2 is hydrogen.
• the present invention provides a method of treating or preventing Parkinson's disease comprising administering a therapeutically effective amount of a compound of Formula I wherein, Ri and R 2 in the compound of Formula I, along with the carbon atoms to which they are attached form a six membered aromatic ring, wherein the ring is substituted with one or more groups selected from hydrogen, halogen and C 1-6 alkyl.
• the aromatic ring is substituted with hydrogen i.e. unsubstituted.
• the present invention provides a method of treating or preventing Parkinson's disease comprising administering a therapeutically effective amount of a compound of Formula I wherein, Ri and R 2 in the compound of Formula I, along with the carbon atoms to which they are attached form a six membered aromatic ring, wherein the ring is substituted with hydrogen i.e. unsubstituted; and R 3 is chloro and R 4 is methyl and are present as a substituent at 2 and 6 position in the ring.
• the present invention provides a method of treating or preventing Parkinson's disease comprising administering a therapeutically effective amount of a compound of Formula I wherein, R 3 and R4 in the compound of Formula I are selected from halogen and Ci_ 6 alkyl.
• R 3 and R4 are halogen and methyl and are present as a substituent at 2 and 6 position in the ring.
• the chemical name of some of the preferred compounds of Formula I are provided below in Table 1.
• Suitable pharmaceutically acceptable salts of the compound of the invention may be salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, and the like or 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.
• One or more hydrogen atoms of the compound of Formula I may be deuteriated i.e. substituted with a deuterium atom.
• WIPO publication WO2012098416 discloses a markush group of compounds active as c-Abl kinase inhibitors and their usefulness for the treatment of cancers like chronic myelogenous leukemia (CML).
• Compounds of Formula I of the present invention may be prepared by the processes described in WO2012098416 and WO2016185490 which are incorporated herein by reference. The inventors have found that the compound of Formula I of present invention, are potent Abl kinase inhibitors and advantageously cross the blood-brain barrier effectively resulting in a high ratio of brain to plasma concentration for the compound of Formula I and a high therapeutic index.
• the inventors have found that the compound of Formula I, at 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, QT Cf interval and heart rate in conscious beagle dogs and guinea pig.
• the compound of Formula I was found to be safe as they did not show any undue effect on ECG parameters and heart rate as described herein in examples.
• the compound of Formula I can be administered orally in the form of a suitable dosage form.
• a suitable dosage form may include tablet, pellets, capsule, sachet, pellets in sachet, pellets in capsule, powder, granules and the like.
• the compound of Formula I may be formulated in oral dosage form which may include pharmaceutically acceptable excipients which are in common knowledge of a person skilled in the art. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses pharmaceutically acceptable carriers which can be used for preparation of a suitable dosage form.
• mice were administered orally at 30 mg/kg of the compound of Formula La, 100 mg kg of nilotinib or 30 mg/kg of dasatinib.
• mice were anesthetized with isoflurane and a 0.4 mL of blood was withdrawn from retro-orbital plexus into eppendorf tubes containing 8 ⁇ L ⁇ sodium heparin as an anticoagulant (100 IU/ml) and transferred to ice containers. Blood samples were centrifuged immediately for 7 min at 8500 rpm, 4 °C.
• PBS ice- cold phosphate buffered saline
• Brain to plasma ratio was found to be significantly higher for the compound of Formula La as compared to that for nilotinib or dasatinib (see Table 3).
• C57BL/6 mice (6-8 weeks old, 25-30 g body weight) were administered orally with vehicle, the compounds of Formula La (10 or 30 mg/kg, once a day) for 7 days.
• these animals received four intraperitoneal injections of a neurotoxin, l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine (MPTP-HC1; 17 mg/kg free base; Sigma) in saline at 2 hour intervals.
• MPTP-HC1 l-methyl-4-phenyl-l,2,3,6- tetrahydropyridine
• Daily dosing with compound continued for 7 additional days after the last injection of MPTP.
• the compound was administered 6 days prior to MPTP administration, on the day of MPTP administration and 7 days after MPTP administration. All animals were sacrificed 7 days after the MPTP administration and brain tissues were processed for immunohistochemistry evaluation.
• the standard avidin-biotin method (Benno et al, Brain Res., 1982; 246:225-236) was used for the immunohistochemical detection of tyrosine hydroxylase (TH). Initially, the brains were sectioned at the substantia nigra pars compacta (SNPc) level using a cryostat and mounted on glass slides. The slides with brain sections were rinsed 3x5 minutes in 0.1 M PBS.
• the sections were first incubated for 30 minutes at room temperature with normal blocking serum in 0.1 M PBS with 0.3 % Triton X-100 and for additional 2 hours with a rabbit polyclonal antibody to mouse tyrosine hydroxylase (Invitrogen) diluted 1: 1000 in 0.1 M PBS with normal blocking serum.
• the slides with sections were further rinsed 3x5 minutes in 0.1 M PBS and incubated for 1 hour at room temperature with a biotinylated anti-rabbit antibody (Vectastain ABC kit).
• the sections were rinsed 3x5 minutes in 0.1 M PBS and incubated for 1 hour at room temperature with A and B solutions (Vectastain ® ABC kit) diluted 1 :50 in 0.1 M PBS.
• the sections were rinsed 3x5 minutes in 0.1 M PBS and incubated in the 3,3'-diaminobenzidine (DAB)/H 2 02 solution (Sigma) for approximately 5-8 minutes (the development process was checked under microscope for an optimal signal-to-noise ratio).
• the sections were first rinsed 2x5 minutes in 0.1 M PBS and then with 3x5 minutes in Milli-Q water.
• the slides were cover slipped in glycerol-gelatin solution and kept at room temperature overnight for drying after which images of the stained brain sections were captured using a camera attached to a microscope and anaslyzed using NIH ImageJ software (NIH, Bethesda, MD). Images were analyzed by converting to 8-bit resolution and optimal brightness/contrast.
• the compound of Formula La and Lb were tested for cardiovascular safety in an in vitro test to determine inhibition of hERG K + channel.
• the compounds of Formula La and Lb did not show any significant inhibition of hERG current at the concentration tested.
• Micropipette solution for whole cell patch clamp recordings was composed of : potassium aspartate, 130 mM; MgCl 2 , 5 mM; EGTA, 5 mM; ATP, 4 mM; HEPES, 10 mM; pH adjusted to 7.2 with 10N KOH. Micropipette solution was prepared in batches, aliquoted, stored frozen and a fresh aliquot thawed each day.
• the recording was performed at a temperature of 33 to 35 °C using a combination of in-line solution pre-heater, chamber heater and feedback temperature controller. Temperature was measured using a thermistor probe in the recording chamber.
• Micropipettes for patch clamp recording were made from glass capillary tubing using a P-97 micropipette puller (Sutter Instruments, Novato, CA). A commercial patch clamp amplifier was used for whole cell recordings. Before digitization, current records were low-pass filtered at one-fifth of the sampling frequency.
• Table 4 Mean percent inhibition of hERG current at each concentration of the compound of Formula La and Lb.
• Compound of Formula I.a was administered via peroral (p.o.) route at three dose levels: 5, 15, and 30 mg/kg in conscious telemetered male and female beagle dogs. Emesis occurred in two animals (1 male and 1 female) treated with the 30 mg/kg dose group of the compound of Formula I.a at 14 min following dosing. Hence, the group treated with 30 mg/kg dose was not considered for the data analysis. No emesis was observed with 5 and 15 mg/kg doses. Measurements of ECG parameters (QT interval, QT C b interval, QT C f interval) and heart rate were carried out and recorded over a period of 2 hour prior to drug administration (baseline), and continuously up to 24 hour post-administration.
• Each animal received both vehicle (placebo) and three different doses of the compound of Formula La on different days in a Latin square design, with a washout period of a minimum of 96 hr. On a separate day, one additional oral dosing of compound of Formula I. a was performed to assess plasma concentrations of the compound of Formula La at different time points, to derive pharmacokinetic (PK) parameters.
• PK pharmacokinetic
• ECG parameters QT interval, QT C interval, QT C f interval,
• heart rate Data of ECG parameters (QT interval, QT C interval, QT C f interval,) and heart rate were statistically compared as follows: Data of the placebo group at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hour time points were compared with baseline data of the same group. Data of different groups treated with the compound of Formula La were compared with the corresponding data of the placebo group. Analysis of ECG based on pooled data of male and female dogs showed that as compared to baseline, placebo treatment had no statistically significant effect on any of the ECG parameters (QT interval, QT C interval, QT C f interval) and heart rate. Compound of Formula La at 5 and 15 mg/kg doses had no effects on QT, QT C b, QT C f, durations compared with placebo. In addition, other parameter such as heart rate remained unchanged.
• the PK analysis showed a dose-dependent systemic exposure of the compound of Formula La to animals administered with different doses of the compound of Formula La.
• AUCo-inf was in the range of 1925 to 4824, 6776 to 12756, and 25927 to 46749 hrxng/mL with 5, 15, and 30 mg/kg doses of the compound of Formula La, respectively.
• C max was in the range of 1218 to 2033, 2723 to 5323, and 9825 to 9967 ng/mL with 5, 15, and 30 mg/kg doses of the compound of Formula La, respectively.

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