EA041892B1 - METHODS AND COMPOSITIONS FOR TREATMENT OF AGING-ASSOCIATED DISORDERS USING CCR3 INHIBITORS - Google Patents

Description

I. Cross-Reference to Related Applications

Under 35 U.S.C. § 119(e) this application claims priority with respect to the filing dates of: U.S. Provisional Application No. 62/482137, filed April 5, 2017; U.S. Provisional Application No. 62/560,940, filed September 20, 2017; and U.S. Provisional Application No. 62/620921, filed Jan. 23, 2018, the contents of each of which are incorporated herein by reference in their entirety.

II. Introduction

The following information is offered as a general guide only and is not intended to be considered prior art for this invention.

Aging is an important risk factor for many human diseases, including cognitive impairment, cancer, arthritis, vision loss, osteoporosis, diabetes, cardiovascular disease, and stroke. In addition to physiological synapse loss during natural aging, synapse loss is an early pathological event common to many neurodegenerative conditions and is best correlated with the neuronal and cognitive impairments associated with these conditions. Thus, aging remains the single most dominant risk factor for neurodegenerative diseases associated with dementia, such as Alzheimer's disease (AD) (Bishop, N.A. et al., Neural mechanisms of aging and cognitive decline, Nature, 464(7288), 529-535 (2010); Heeden, T. et al., Insights into the aging mind: a view from cognitive neuroscience, Nat. Rev. Neurosci., 5(2), 87-96 (2004); Mattson, M. P. et al., Aging and neuronal vulnerability, Nat. Rev. Neurosci., 7(4), 278-294 (2006)). Aging affects all tissues and functions of the body, including the central nervous system, and the decline in functions such as cognition and movement can seriously affect quality of life.

Treatment of cognitive and motor impairments associated with neurodegeneration has had limited success in preventing and reversing such impairments. Therefore, it is important to identify new therapies to maintain cognitive integrity by protecting against, combating, or reversing the effects of aging. Unfortunately, drug treatment of cognitive and motor impairments faces significant barriers. For example, it is believed that in order for therapies using small molecule drugs to be effective when used for cognitive and motor impairment, such drugs must cross the blood-brain barrier (BBB). Transport across the BBB is the exception, not the rule, and 98% of all small molecule substances fail to cross it (Pardridge, William M., The Blood-Brain Barrier: Bottleneck in Brain Drug Development, NeuroRx: The J. of the Am. Society for Experimental NeuroTherapeutics, 2:3-14, 2005). As a result, treatments for neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) are limited; in fact, patients with Alzheimer's disease have one of the highest rates of treatment failure in the clinical development of any nosology (99.6% failure over the past 20 years). (Id.; and Burke, M., Renewed focus on dementia checked by drug challenges, ChemistryWorld, Jul. 3, 2014). Those BBB-passable drugs that are approved for the treatment of cognitive diseases such as Alzheimer's disease, such as donepezil, show temporary effects and do not work in all patients (Banks, W.A., Drug Delivery to the Brain in Alzheimer's Disease: Consideration of the Blood-brain Barrier, Adv. Drug Deliv. Rev., 64(7):629-39 (2012), and Burke, M. supra). Similarly, levodopa, which relieves symptoms of Parkinson's disease such as motor deficits and crosses the BBB, eventually loses its effectiveness. An additional hurdle for drugs that cross the BBB is that making compounds more lipophilic (making them more BBB-permeable) also often results in increased clearance from the blood, resulting in decreased bioavailability. Therefore, an increase in lipophilicity shifts the area under the plasma concentration-time (AUC) curve, minimizing brain uptake (Pardridge, William M, supra).

III. The essence of the invention

The present invention overcomes these disadvantages. For example, Compound 1, a compound of this invention, showed an inability to cross the BBB at significant concentrations, yet unexpectedly resulted in a reduction in the intensity of symptoms associated with age-related neurodegeneration and age-related decreased motor activity. Thus, the mechanism of action of the compounds of this invention may be directed to the peripheral nervous system, excluding what has been considered a requirement for effective cognitive drugs, i.e. act directly on the central nervous system. Although the compounds of some embodiments of the present invention can cross the BBB at significant concentrations, their antagonistic ability for the CCL11/CCR3 pathway offers an alternative mechanism of action compared to current therapies for cognitive and motor impairments.

The compounds of this invention act as antagonists of the c-c motif of the chemokine receptor 3 (CCR3), eotaxin-1 receptor. Eotaxin-1 (CCL11) is a protein whose level increases

- 1 041892 is found in plasma during aging and which causes cognitive decline (Villeda et al., The aging systemic milieu negatively regulates neurogenesis and cognitive function, Nature, 477(7362):90-94, (2011)). Eotaxin/CC11 acts primarily on the G protein-coupled receptor CCR3, which is expressed on eosinophils in the periphery and on neurons and glial cells of the central nervous system (Xia, M. et al., Immunohistochemical Study of the β-Chemokine Receptors CCR3 and CCR5 and Their Ligands in the Normal and Alzheimer's Disease Brains, Am. J. Pathol., 153(1):31-37 (1998)). In Alzheimer's disease, there is an increase in CCR3 levels in the CNS (ibid.). Thus, the cognitive effects of CCR3 antagonization in Alzheimer's disease and related disorders would be expected to be mediated by a centrally located eotaxin-1/CCR3 interaction. However, Compound 1 (the compound of this invention) unexpectedly resulted in improved cognitive function and stimulation of neurogenesis despite its inability to cross the BBB at significant concentrations.

Methods are provided for the treatment of patients with disorders associated with aging, neurodegenerative diseases, and associated cognitive and motor decline, including, by way of example, but not limitation, Alzheimer's disease, Parkinson's disease, Lewy body dementia, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy, etc. Aspects of these methods include modulating CCR3, the major CCL11/eotaxin-1 receptor, by administering a therapeutically effective amount of the CCR3 antagonists of the invention. These methods include administering an effective therapeutic dose of CCR3 antagonists to subjects or patients, as well as monitoring specific clinical criteria. Also included are methods of treating a neurodegenerative disease and associated cognitive and motor impairment with an agent that acts peripherally, ie. does not cross the blood-brain barrier in significant concentrations, but shows improvement in disease, such as improvement in cognitive function or motor activity.

IV. Inclusion by reference

All publications, patents, and patent applications referred to in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually incorporated by reference.

V. Brief description of graphic materials

In FIG. 1A shows the number of doublecortin (BCC)-positive cells in the hippocampus of: 2-month-old and 18-month-old C57BL/6 mice injected with IgG (n=18 for both groups); 18-month-old mice treated with Compound 1 for 2 weeks at either high (n=16) or low dose (n=31); and 18-month-old mice treated with compound 1 (comp. 1) for 4 weeks at a low dose (n=16). Data shown are mean ± SOS, where *P<0.05, ***P<0.001.

In FIG. 1B shows the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the hippocampus: 2-month-old and 18-month-old C57BL/6 mice injected with IgG (n=19 for both groups); 18 month old mice treated with Compound 1 for 2 weeks at either high (n=16) or low dose (n=24). Data shown are mean±SOS, where *** P<0.001.

In FIG. 2A shows the effect of Compound 1 on the time spent by young and old C57BL/6 mice in the new (N) vs. familiar/old (F or O) branch during the Y-maze test. 2-month-old mice received IgG for 2 weeks (n=18). 18-month-old mice were injected with: IgG for 2 weeks (n=18); Compound 1 at high dose for 2 weeks (n=15); Compound 1 at low dose for 2 weeks (n=31); or Compound 1 at low dose for 4 weeks (n=16). Data shown are mean±SOS, where **P<0.05, ***P<0.01.

In FIG. 2B shows the effect of Compound 1 on the total number of visits by young and old C57BL/6 mice to the new (N) compared to the familiar/old (F or O) branch during the Y-maze test. 2-month-old mice received IgG for 2 weeks (n=18). 18-month-old mice were injected with: IgG for 2 weeks (n=18); Compound 1 at high dose for 2 weeks (n=15); Compound 1 at low dose for 2 weeks (n=31); or Compound 1 at low dose for 4 weeks (n=16). Data shown are mean ± SOS, where *P<0.05, **P<0.01, ***P<0.001.

In FIG. 3 shows the effect of Compound 1 on entry attempts (number of visits) into novel and familiar branches by C57BL/6 mice during a Y-maze test. The number of visits to each arm was plotted for each treatment group and analyzed by a paired t-test. 3-month-old mice (n=15) were infused with vehicle (nasal) subcutaneously with an Alzet mini-pump (0.5 µl/h) for four weeks with one change. Mice at 16.5 months of age were injected subcutaneously with either vehicle (nose,

- 2 041892 n=16), or compound 1 at a dose of 50 mg/ml 1 (n=16) using an Alzet mini-pump (0.5 μl/h) for four weeks with one replacement. Data shown are mean±SOS;

* P<0.05.

In FIG. 4A shows the effect of compound 1 on the mean time taken by C57BL/6 mice to find a target hole during the Barnes maze test. The mean time was plotted on a graph for each treatment group. 3-month-old mice (n=18) were infused with vehicle (nasal) subcutaneously with an Alzet mini-pump (0.5 µl/h) for four weeks with one change. Mice at 16.5 months of age were injected subcutaneously with either vehicle (nose, n=15) or compound 1 at 50 mg/ml 1 (n=15) using an Alzet mini-pump (0.5 μl/h) for four weeks with one replacement. Data shown are mean ± SOS.

In FIG. 4B shows the effect of compound 1 on the difference in latency to target hole detection between the last and first trial of the last day of the Barnes maze test in C57BL/6 mice. The difference was plotted for each treatment group and analyzed by an unpaired t-test. 3-month-old mice (n=18) were infused with vehicle (nasal) subcutaneously with an Alzet mini-pump (0.5 µl/h) for four weeks with one change. Mice at 16.5 months of age were injected subcutaneously with either vehicle (nose, n=15) or compound 1 at 50 mg/ml 1 (n=15) using an Alzet mini-pump (0.5 μl/h) for four weeks with one replacement. Data shown are mean ± SOS.

In FIG. 5 shows the effect of Compound 1 on neurogenesis in C57BL/6 mice by detecting BrdU-positive cells in all sections of the dentate gyrus. The number of cells positive for BrdU from the dentate gyrus was plotted for each treatment group and the data was analyzed by an unpaired t-test between groups of mice at 16.5 months of age. Mice at 3 months of age (n=17) were infused with vehicle (nasal) subcutaneously using an Alzet minipump (0.5 μl/h) for four weeks with one change. Mice at 16.5 months of age were injected subcutaneously with either vehicle (nose, n=17) or compound 1 at 50 mg/mL 1 (n=17) using an Alzet minipump (0.5 µl/h) for four weeks with one replacement. Data shown are mean±SOS; * P<0.05.

In FIG. 6 shows the levels of Compound 1 found in the CSF of both young (n=2) and old (n=3) groups of C57BL/6 mice (both groups were below 10 nM). Compound 1 levels were determined by mass spectrometry.

In FIG. 7 shows the distribution (measured as area under the curve (AUC)) of Compound 1 in C57B1/6JOlaHsd mouse tissues over time. The compound was labeled with a carbon-14 label and measurements were taken after 1, 24, and 168 h.

In FIG. 8 shows the pharmacokinetic profiles of Compound 1 following oral (po) administration. In the blood plasma of male 2-month-old C57B1/6 mice treated with 30 or 150 mg/kg by oral gavage, levels of Compound 1 were measured at 20 minutes, 2, 8 and 12 hours after administration. Plasma concentration after drug administration was plotted over time.

In FIG. 9 shows the effect of Compound 1 on search preference during an open field test in young C57BL/6 mice. Search preference was plotted as the ratio of time spent at the periphery versus time spent at the center; and data subjected to one-way ANOVA analysis. 2-month-old mice were administered: vehicle p/o twice a day (n=11); compound 1 p/o twice a day, 30 mg/kg (n=12); vehicle po twice daily plus recombinant mouse CCL11 (eotaxin-1 or rmE) ip (n=14); or compound 1 po twice daily 30 mg/kg plus recombinant mouse CCL11 (n=14). Data shown are mean±SOS; **P<0.01.

In FIG. 10A shows the effect of Compound 1 on time spent in novel versus familiar branches during the Y-maze test in young C57BL/6 mice. Time spent in new versus familiar branches was plotted for each treatment group and analyzed by paired t-test. 2-month-old mice were administered: vehicle p/o twice a day (n=13); compound 1 p/o twice a day, 30 mg/kg (n=14); vehicle po twice daily plus recombinant mouse CCL11 (eotaxin-1) ip (n=15); or compound 1 po twice daily, 30 mg/kg, plus recombinant mouse CCL11 (n=15). Data shown are mean±SOS; **P<0.01.

In FIG. 10B shows the effect of Compound 1 on the ratio of time spent in a novel versus familiar branch during a Y-maze test in young C57BL/6 mice. The ratios were plotted for each treatment group and subjected to post hoc Kruskal-Wallis ANOVA. 2-month-old mice were administered: vehicle p/o twice a day (n=12); compound 1 p/o twice a day, 30 mg/kg (n=14); vehicle po twice daily plus recombinant mouse CCL11 (eotaxin-1) ip (n=15); or compound 1 po twice daily, 30 mg/kg, plus recombinant mouse CCL11 (n=15). Data shown are mean±SOS; * P<0.05.

- 3 041892

In FIG. 10C shows the effect of Compound 1 on the ratio of entries to novel versus familiar branch during the Y-maze test in young C57BL/6 mice. Ratios were plotted for each treatment group and subjected to t-test analysis comparing vehicle and recombinant mouse CCL11 exposures. 2-month-old mice were administered: vehicle p/o twice a day (n=13); compound 1 p/o twice a day, 30 mg/kg (n=14); vehicle po twice daily plus recombinant mouse CCL11 (eotaxin-1) ip (n=15); or compound 1 po twice daily, 30 mg/kg, plus recombinant mouse CCL11 (n=15). Data shown are mean±SOS; * P<0.05.

In FIG. 11A shows the effect of Compound 1 on the mean delay time to target hole detection during the Barnes maze test in young C57BL/6 mice. Average delay times were plotted as units of time for each treatment group in each trial. 2-month-old mice were administered: vehicle p/o twice a day (n=13); compound 1 p/o twice a day, 30 mg/kg (n=14); vehicle po twice daily plus recombinant mouse CCL11 (eotaxin-1) ip (n=15); or compound 1 po twice daily, 30 mg/kg plus recombinant mouse CCL11 (n=15). Data shown are mean ± SOS.

In FIG. 11B shows the effect of Compound 1 on delay time to target opening in a Barnes maze test in young C57BL/6 mice. The latency times averaged over the last three trials for each treatment group were plotted and the data analyzed by an unpaired t-test. 2-month-old mice were administered: vehicle p/o twice a day (n=13); compound 1 p/o twice a day, 30 mg/kg (n=14); vehicle po twice daily plus recombinant mouse CCL11 (eotaxin-1) ip (n=15); or compound 1 po twice daily, 30 mg/kg plus recombinant mouse CCL11 (n=15). Data shown are mean±SOS; * P<0.05.

In FIG. 12A shows the effect of connection 1 on memory on a new branch in a Y-like maze, estimated by the number of entries made to the new branch considering all entries. 24-month-old mice were administered compound 1 p/o twice a day, 30 mg/kg, or vehicle. Data shown are mean±SOS; **P<0.01.

In FIG. 12B shows the effect of Compound 1 on total distance traveled in the Y-maze as a measure of locomotor activity. 24-month-old mice were administered compound 1 p/o twice a day, 30 mg/kg, or vehicle. Data shown are mean±SOS; * P<0.05.

In FIG. 13A shows the effect of Compound 1 on entry attempts (number of visits) into novel and familiar branches made by 24-month-old C57BL/6 mice during a Y-maze test. The number of visits to each arm was plotted for each treatment group and analyzed by a paired t-test. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, mice were tested with the passage of a Y-like maze. All mice received 5 consecutive days of injections of BrdU at a concentration of 50 mg/kg ip immediately before treatment. Data shown are mean±SOS; *P<0.05, **P<0.01, ***P<0.001 when compared between novel and familiar branches by paired Student's t-test.

In FIG. 13B shows the effect of Compound 1 on the ratio of entries to a novel versus familiar branch during a Y-maze test in 24-month-old mice. Ratios were plotted for each treatment group and subjected to t-test analysis comparing vehicle and Compound 1 exposures. 21 days. Three weeks later, mice were tested with the passage of a Y-like maze. All mice received 5 consecutive days of injections of BrdU at a concentration of 50 mg/kg ip immediately before treatment. Data shown are mean±SOS; * P<0.05, ** P<0.01, *** P<0.001 compared with control by Student's t-test.

In FIG. 13C shows the effect of Compound 1 on time spent in novel versus familiar branches during a Y-maze test in 24-month-old C57BL/6 mice. Time spent in novel versus familiar branches was plotted for each treatment group and analyzed by paired t-test. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, mice were tested with the passage of a Y-like maze. All mice received 5 consecutive days of injections of BrdU at a concentration of 50 mg/kg ip immediately before treatment. Data shown are mean±SOS; *P<0.05, **P<0.01, ***P<0.001 when compared between novel and familiar branches by paired Student's t-test.

In FIG. 13D shows the effect of compound 1 on the ratio of time spent in

- 4 041892 a new versus familiar branch during the Y-maze test in 24-month-old C57BL/6 mice. Ratios were plotted for each treatment group and analyzed by t-test. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, mice were tested with the passage of a Y-like maze. All mice received 5 consecutive days of injections of BrdU at a concentration of 50 mg/kg ip immediately before treatment. Data shown are mean±SOS; * P<0.05, ** P<0.01, *** P<0.001 compared with control by Student's t-test.

In FIG. 13E shows the effect of Compound 1 on mean speed during the Y-maze test in 24 month old C57BL/6 mice. Average rates were plotted for each treatment group and subjected to t-test analysis. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, mice were tested with the passage of a Y-like maze. All mice received 5 consecutive days of injections of BrdU at a concentration of 50 mg/kg ip immediately before treatment. Data shown are mean±SOS; * P<0.05, ** P<0.01, *** P<0.001 compared with control by Student's t-test.

In FIG. 14A shows the effect of compound 1 on the mean time taken by 24-month-old C57BL/6 mice to find a target hole during the Barnes maze test. The mean time was plotted on a graph for each treatment group. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, the mice were subjected to a Barnes maze test. Data shown are mean±SOS; * P<0.05 compared to control by Student's t-test.

In FIG. 14B shows the effect of Compound 1 on speed scores of 24-month-old C57BL/6 mice during the Barnes maze test, averaged over all trials for each treatment group. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, the mice were subjected to a Barnes maze test. Data shown are mean±SOS; * P<0.05 compared to control by Student's t-test.

In FIG. 15A shows the effect of Compound 1 on walking distance during the open field test in 24 month old C57BL/6 mice. The average distance traveled was plotted on a graph for each treatment group. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, the mice were tested in an open field. Data shown are mean ± SOS.

In FIG. 15B shows the effect of Compound 1 on speed during the open field test in 24 month old C57BL/6 mice. Average mouse speeds were plotted for each treatment group. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. Three weeks later, the mice were tested in an open field. Data shown are mean ± SOS.

In FIG. 16A shows the effect of compound 1 on plasma levels of the cytokine TNF-alpha in 24-month-old C57B1/6 mice. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. A trend towards lower levels of inflammatory cytokines was observed in Compound 1 treated mice compared to vehicle treated mice.

In FIG. 16B shows the effect of Compound 1 on plasma cytokine IL6 levels in 24-month-old C57B1/6 mice. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. A trend towards lower levels of inflammatory cytokines was observed in Compound 1 treated mice compared to vehicle treated mice.

In FIG. 16C demonstrates the effect of Compound 1 on the plasma levels of the cytokine Illbeta in 24-month-old C57B1/6 mice. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. A trend towards lower levels of inflammatory cytokines was observed in Compound 1 treated mice compared to vehicle treated mice.

In FIG. 16D shows the effect of Compound 1 on plasma levels of the cytokine IL5 in 24-month-old C57B1/6 mice. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. A trend towards lower levels of inflammatory cytokines was observed in Compound 1 treated mice compared to vehicle treated mice.

In FIG. 16E shows the effect of Compound 1 on plasma levels of the cytokine IL17 in 24-month-old C57B1/6 mice. Mice at 23 months of age were injected with either vehicle control or

- 5 041892 compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. A trend towards lower levels of inflammatory cytokines was observed in Compound 1 treated mice compared to vehicle treated mice.

In FIG. 17 shows the effect of Compound 1 on activated microglia in 24 month old C57B1/6 mice. Mice at 23 months of age were treated with either vehicle control or compound 1 subcutaneously 2 times a day (2 times a day) for 21 days. A trend towards lower levels of CD68+ activated microglia was observed in Compound 1 treated mice compared to vehicle treated mice.

In FIG. 18 shows the effect of compound 1 on the percentage of eosinophils among the total white blood cells (WBC) in 24-month-old C57BI/6 mice treated with saline as a control or 30 mg/kg of compound 1 for 3 weeks 2 r / day, s / c . Compound 1 reduced the endogenous, age-related increase in the level of eosinophils in the blood.

In FIG. 19 shows the effect of Compound 1 on the percentage of eosinophils in the total white blood cell count (WBC) in 3-month-old hairless mice treated with saline as a control or Compound 1 30 mg/kg for 2 weeks po. Compound 1 reduced the oxazolone-induced increase in the level of eosinophils in the blood.

In FIG. 20 shows the effect of compound 1 on the results of the spinning drum test in the study of motor coordination. 24-month-old C57 mice were given a continuous infusion of Compound 1 or vehicle via an osmotic pump for 4 weeks. The best results were observed in mice treated with compound 1, compared with mice treated with media in accordance with the binomial criterion; * P<0.05.

In FIG. 21 shows the effect of Compound 1 on T-maze memory performance. 24-month-old C57 mice were given a continuous infusion of Compound 1 or vehicle via an osmotic pump for 4 weeks. The best results were observed in mice treated with compound 1, compared with mice treated with the vehicle, according to the binomial criterion, * P<0.05.

In FIG. 22A shows the effect of compound 1 on fecal excretion during the night. 24-month-old C57 mice were given a continuous infusion of Compound 1 or vehicle via an osmotic pump for 4 weeks. The weight of the faecal pellets was measured overnight. Compound 1 treated mice excreted significantly less feces compared to vehicle treated mice by Student's t-test; * P<0.05.

In FIG. 22B shows the effect of compound 1 on drinking water consumption during the night. 24-month-old C57 mice were given a continuous infusion of Compound 1 or vehicle via an osmotic pump for 4 weeks. The total amount of water drunk was measured during the night. Compound 1 treated mice drank significantly more water compared to vehicle treated mice by Student's t-test; * P<0.05.

In FIG. 22C shows the effect of compound 1 on food intake during the night. 24-month-old C57 mice were given a continuous infusion of Compound 1 or vehicle via an osmotic pump for 4 weeks. The total amount of food eaten was measured during the night. There were no differences between the two groups in terms of total food intake during the night.

In FIG. 23 shows the effect of Compound 1 (Comp. 1) on the amount of CD68-positive (CD68+) activated microglia in the brains of 3-month-old mice treated with LPS and treated with Compound 1 for 18 days. Mice treated with Compound 1 showed reduced CD68+ immunoreactivity and therefore less gliosis.

In FIG. 24A, 24B show the effect of Compound 1 on anxiety in an open field test in 3-month-old mice treated with LPS ip for 4 weeks and treated with Compound 1 orally bid (twice daily) for 1 week. The use of LPS increased the preference for the periphery in the open field, indicating increased anxiety. The use of compound 1 reduced the level of anxiety caused by LPS in the open field. Data shown are mean±SOS; * P<0.05 by Student's t-test.

In FIG. 25A, 25B show the effect of Compound 1 on the number of entries to new and familiar branches during the Y-maze test in 3-month-old C57BL/6 mice treated with LPS. The number of visits to each arm was plotted for each treatment group and analyzed by a paired t-test. 3-month-old mice were injected intravenously with either vehicle or LPS for 6 weeks, and either vehicle control or compound 1 p.o. 2 r/day (2 times a day) for 3 weeks. Compound 1 treated mice showed a significant preference for the new branch, while vehicle treated mice did not. Data shown are mean±SOS; ***P<0.01, *P<0.05 when compared between novel and familiar branches by paired Student's t-test.

In FIG. 26A, 26B show the effect of Compound 1 on IL-1beta mRNA in the brains of 3-month-old C57BL/6 mice treated with LPS and/or Compound 1. Mice were injected ip with either vehicle

- 6 041892 as a control, or LPS for 7 weeks, and the carrier or compound 1 was administered orally 2 times a day (2 times a day) for 4 weeks. Tissues were collected and RNA was obtained from the tissues of the cerebral cortex. IL-1 beta mRNA levels were measured by qPCR and data were presented relative to vehicle as a control. There was a trend towards an increase in IL-1 beta mRNA levels with LPS administration and a significant decrease with Compound 1 administration. Data shown are mean±SOS; * P<0.05 by Student's t-test.

In FIG. 27A-27C show the effect of Compound 1 on microglial activation in the hippocampus in 3-month-old C57BL/6 mice treated with LPS and/or Compound 1. Mice received either vehicle control or LPS ip for 7 weeks, and the carrier or compound 1 was administered orally 2 times a day (2 times a day) for 4 weeks. Tissues were harvested and brain sections were subjected to immunohistochemistry for the detection of CD68, a marker of activated microglia. There was an upward trend in CD68 levels with LPS exposure and a steady downward trend with Compound 1 exposure. Data shown are mean±SOS.

In FIG. 28A-28C show the effect of Compound 1 on total microglia in the hippocampus in 3-month-old C57BL/6 mice treated with LPS and/or Compound 1. Mice received either vehicle control or LPS ip for 7 weeks, and vehicle or compound 1 was also administered orally 2 times a day (2 times a day) for 4 weeks. Tissues were harvested and brain sections were subjected to immunohistochemistry to detect Iba1, a marker of activated microglia. There was a significant increase in Iba1 when exposed to LPS and a downward trend when exposed to compound 1. Data shown are mean±SOS; *** P<0.001, * P<0.05 by Student's t-test.

In FIG. 29A, 29B show the effect of Compound 1 on total hippocampal astrocyte count in 3-month-old C57BL/6 mice treated with LPS and/or Compound 1. Mice received either vehicle control or LPS ip for 7 weeks, and vehicle or compound 1 was also administered orally 2 times a day (2 times a day) for 4 weeks. Tissues were harvested and brain sections were subjected to immunohistochemistry for the detection of GFAP, a marker for astrocytes. There was a downward trend when exposed to compound 1. Data shown are mean±SOS.

In FIG. 30A shows the exposure timeline for the MPTP mouse model of Parkinson's disease.

In FIG. 30B summarizes behavioral, biochemical, and histological evaluation criteria for the MPTP mouse model of Parkinson's disease.

In FIG. 31 shows plasma levels of eotaxin-1 in 6-month-old synuclein-overexpressing strain 61 transgenic mice. Eotaxin-1 (CCL11) levels in non-transgenic (NTg) versus synuclein (Tg) overexpressing line 61 transgenic mice were plotted at pg/ml concentrations.

In FIG. 32 summarizes the behavioral, biochemical, and histological evaluation criteria for transgenic mouse models overexpressing synuclein treated with vehicle and Compound 1.

In FIG. 33 shows human eotaxin-1 concentrations in the proteomic screen. Relative concentrations of human eotaxin-1 were measured in a commercially available affinity-based assay (SomaLogic). Plasma samples from each of 18-, 30-, 45-, 55-, and 66-year-old donors were plotted on the graph.

In FIG. 34A shows the effect of Compound 1 on inhibition of eosinophil shape change. Whole blood of people treated with Compound 1 was incubated with recombinant eotaxin to induce reshaping of eosinophils. Shape change inhibition data were plotted against plasma concentration of Compound 1.

In FIG. 34B shows the effect of Compound 1 on CCR3 internalization. Whole blood from humans treated with Compound 1 was incubated with recombinant eotaxin to drive CCR3 internalization and labeled with anti-CCR3 antibody. Compound 1 inhibition of CCR3 internalization data was plotted against plasma concentration of Compound 1.

VI. Detailed description

Aspects of the present invention include methods of treating aging-associated disorders/neurodegenerative diseases. An aging-associated disorder can manifest itself in several different ways, for example, as an aging-associated cognitive impairment and/or a physiological impairment, for example, as damage to central or peripheral organs of the body, for example, but not limited to, cell damage, tissue damage, organ dysfunction. aging-associated shortening of lifespan and carcinogenesis, with specific organs and tissues of interest including, but not limited to, skin, neuron, muscle, pancreas, brain, kidney, lung, stomach, intestines, spleen, heart, adipose tissue, testicles, ovary, uterus, liver and bone; in the form of a reduced level of neurogenesis, etc.

In some embodiments of the present invention, aging-associated

- 7 041892 shenie is an aging-associated impairment of cognitive abilities in an individual, ie. aging-associated cognitive impairment. Cognitive abilities, or cognition, are mental processes that include attention and concentration, learning complex tasks and concepts, memory (receiving, storing and retrieving new information in the short and / or long term), information processing (working with information collected five senses), visuo-spatial function (visual perception, depth perception, use of mental imagery, copying drawings, construction of objects or figures), language reproduction and comprehension, fluency (word search), problem solving, decision making, and executive functions ( planning and prioritization). The term cognitive decline refers to a gradual decline in one or more of these abilities, such as a decrease in memory, language ability, thinking, judgment, etc. The term cognitive impairment and cognitive impairment refers to a decrease in cognitive abilities compared to a healthy person, for example, a healthy person of the corresponding age, or compared to the ability of a person at an earlier point in time, for example, 2 weeks, 1, 2, 3, 6 months , 1, 2, 5 or 10 years or more prior to evaluation. Aging-associated cognitive impairments include cognitive impairments that are commonly associated with aging, including, for example, cognitive impairments associated with the natural aging process, such as mild cognitive impairment (MCI); and cognitive impairment associated with a disorder associated with aging, ie. a disorder that occurs with increasing frequency with ageing, such as a neurodegenerative condition such as Alzheimer's disease, Parkinson's disease, Lewy body dementia, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia and so on.

By the term treatment is meant that at least a reduction in the intensity of one or more of the symptoms associated with an age-related disorder affecting the subject is achieved, while the term relief is used in a broad sense to mean at least a reduction in the magnitude of a parameter, for example, a symptom associated with the disorder, to be treated. Thus, treatment also includes situations where the condition, or at least the symptoms associated therewith, are completely inhibited, e.g., prevented or terminated, e.g. terminated, such that the adult mammal no longer suffers from the disorder, or at least the symptoms that characterize the disorder. In some cases, the terms treatment, exposure, etc. relate to obtaining the desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof, and/or therapeutic in terms of partially or completely curing a disease and/or an undesirable effect related to said disease. The treatment may be any treatment of a disease in a subject and includes (a) preventing the onset of the disease in a subject who is possibly predisposed to the disease but has not yet been diagnosed with the disease;

(b) disease suppression, ie. cessation of its development; and (c) alleviating the course of the disease, ie. disease regression.

Treatment can lead to various physical manifestations, such as modulation of gene expression, increased neurogenesis, rejuvenation of tissues or organs, and so on. Treatment of an ongoing disease, when treatment stabilizes or reduces the patient's undesirable clinical symptoms, is implemented in some embodiments of the present invention. Such treatment can be performed until the complete loss of function of the affected tissues. The drug in question can be administered during the symptomatic stage of the disease and in some cases after the symptomatic stage of the disease.

In some instances where the aging-associated disorder is aging-associated cognitive decline, treatment with the methods of this invention slows or attenuates the progression of aging-associated cognitive decline. In other words, the individual's cognition declines more slowly, if at all, after treatment with the described methods compared to before or without treatment with the described methods. In some cases, treatment with the methods of this invention stabilizes the cognitive abilities of the individual. For example, the progression of cognitive decline in an individual suffering from aging-associated cognitive decline stops after treatment with the described methods. As another example, cognitive decline in an individual, eg, an individual 40 years of age or older who is predicted to suffer from aging-associated cognitive decline, is prevented after treatment by the methods described. In other words, no (further) cognitive impairment is observed. In some cases, treatment with the methods of this invention reduces or eliminates cognitive impairment.

- 8 041892 , for example, as observed in the improvement of cognitive abilities in an individual suffering from aging-associated cognitive decline. In other words, the cognitive abilities of an individual suffering from aging-associated cognitive decline after treatment with the described methods will be better than before treatment with the described methods, i. they improve after treatment. In some cases, treatment with the methods of this invention reverses the cognitive impairment. In other words, the cognitive abilities of an individual suffering from aging-associated cognitive decline are restored, for example, to the level observed during the time period when the individual was about 40 years old or less, after treatment using the described methods, for example, as evidenced by an improvement in cognitive abilities in an individual suffering from aging-associated cognitive decline.

In some instances where the aging-associated disorder is an aging-associated movement disorder or decline, treatment with the methods of the invention slows or attenuates the progression of the age-related disorder or movement loss. In other words, the individual's motor abilities decline more slowly, if at all, after treatment with the methods described, compared to before or without treatment with the methods described. In some cases, treatment with the methods of this invention stabilizes the individual's motor abilities. For example, the progression of decreased motor function in an individual suffering from aging-associated decreased motor function stops after treatment with the described methods. As another example, a decrease in motor function in an individual, for example, an individual 40 years of age or older, who is predicted to suffer from aging-associated decreased motor function, is prevented after treatment using the described methods. In other words, no (further) motor disturbances are observed. In some instances, treatment with the methods of this invention reduces or eliminates movement disorders, for example, as seen with improved motor coordination or motor abilities in an individual suffering from aging-associated motor decline. In other words, the motor abilities of an individual suffering from aging-associated motor function decline, after treatment with the described methods, become better than before treatment with the described methods, i. they improve after treatment. In some cases, treatment with the methods of this invention eliminates movement disorders. In other words, motor coordination or motor abilities of an individual suffering from aging-associated motor function decline are restored, for example, to the level observed during the time period when the individual was about 40 years old or less, after treatment using the described methods, for example, that evidenced by an improvement in motor coordination or motor abilities in an individual suffering from aging-associated motor function decline.

In some instances, treatment of an adult mammal according to the methods of this invention results in an alteration of a central organ, e.g., an organ of the central nervous system such as the brain, spinal cord, etc., which alteration may manifest itself in several different ways, e.g., as described in more detail below, including, but not limited to, molecular, structural and/or functional, for example, in the form of enhanced neurogenesis.

Methods are provided for treating dysfunction caused by a neurodegenerative disease, said method comprising administering compounds according to the formulas described below. An embodiment of the present invention includes a method for improving cognitive function or motor activity in subjects of a brain-associated disease associated with cognitive function or motor impairment, said method comprising administering a therapeutically effective amount of a compound according to the chemical formulas described below. Additional embodiments of this invention include a method of enhancing neurogenesis in subjects with a disease associated with the brain or cognitive function, which method includes the introduction of a therapeutically effective amount of a compound according to the chemical formulas described below.

Additional embodiments of this invention include a method of alleviating or treating symptoms of diseases associated with the brain or cognitive function, which method includes the introduction of a therapeutically effective amount of a compound according to the chemical formulas described below. Additional embodiments of this invention include methods of alleviating the symptoms of a disease associated with the Central nervous system, while this method includes the introduction of a therapeutically effective amount of an agent, mainly peripheral action, according to the chemical formulas described below. Further additional embodiments of the present invention include methods for improving motor activity in a subject with age-related motor dysfunction, wherein said method

- 9 041892 includes the introduction of a therapeutically effective amount of a compound according to the chemical formulas described below. The methods of the invention may also include monitoring improvement in age-related disease, including, for example, improvement in cognitive function, motor activity, neurogenesis, and the like, in a subject diagnosed with one or more of such diseases or dysfunctions.

Additional embodiments of this invention include the introduction of a therapeutically effective amount of the compounds, while the specified connection is in the form of co-crystals or salts according to the formulas described below. Additional embodiments of this invention include administering a therapeutically effective amount of a compound, said compound being in the form of single optical isomers, a mixture of single enantiomers, a racemate, or enantiomerically pure compounds. Additional embodiments of the invention also include administering a therapeutically effective amount of a compound, said compound being in the form of pharmaceutical compositions and formulations, discussed further below.

Additional embodiments of the present invention that treat impairment or decline in motor function associated with aging include modifying agents that inhibit the eotaxin/CCR3 pathway. Such modifying agents include not only compounds according to the formulas described below, but also other agents that inhibit eotaxin and CCR3. Contemplated modifying agents include, by way of example and not limitation, compounds of the formulas described below and other small molecule CCR3 inhibitors (e.g. bipiperdine derivatives as described in e.g. US Pat. No. 7,705,153; cyclic amine derivatives as described in e.g. and CCR3 antagonists as described in Pease J.E. and Horuk R., Expert Opin Drug Discov (2014), 9(5):467-83, all of which are incorporated herein by reference in their entirety); anti-eotaxin antibodies; anti-CCR3 antibodies; aptamers that inhibit the expression or function of either eotaxin or CCR3 (methods for preparing such aptamers include US Pat. Nos. 5,270,163, 5,840,867, 6,180,348); antisense oligonucleotides or siRNAs that inhibit the expression or function of either eotaxin or CCR3 (eg, as described in US Pat. No. 6,822,087); soluble CCR3 receptor protein (eg, baits); and so on.

A. Connections.

The methods of the present invention further comprise administering to the subject the following compounds. In the groups, radicals or moieties defined in this section of the Compounds, the number of carbon atoms, which is often indicated in front of the group, for example C1_ ₆ -alkyl, means an alkyl group or a radical containing from 1 to 6 carbon atoms. Typically, for groups containing two or more subgroups as described in this Compounds section, the last named group is the point of attachment of the radical, for example, thioalkyl means a monovalent radical of the formula HS-Alk-. Unless otherwise indicated below, the traditional definitions of the terms are to be followed and the usual stable atomic valences are intended and achieved in all formulas and groups.

One embodiment of the present invention further comprises administering to the subject compounds of formula 1, wherein

A represents CH ₂ , O or N-Cl_ ₆ -alkyl;

R ¹ is selected from

NHR ^{1 1} , NMeR ¹ '¹;

NHR ¹ ' ² , NMeR ¹ '²;

NHCH2-R ¹ '³;

NH-C ₃ _6-cycloalkyl, where optionally one carbon atom is replaced by a nitrogen atom, and the specified ring is optionally substituted by one or two residues selected from the group consisting of C1_ ₆ -alkyl, O-C1_ ₆ -alkyl, NHSO ₂ -phenyl, NHCONH-phenyl, halogen, CN, SO ₂ -C ₁ _6-αkyl, COO-C1_ ₆ -alkyl;

With _{a 9} or 10-bicyclic ring, where one or two carbon atoms are replaced by nitrogen atoms and the specified ring system is connected through the nitrogen atom to the main structure of formula 1, while the specified ring system is optionally substituted by one or two residues selected from the group consisting of C1_ ₆ -alkyl, COO-C1_ ₆ -alkyl, C1_ ₆ -haloalkyl, O-C1_ ₆ -alkyl, NO2, halogen, CN, NHSO ₂ -C _{1 -6} -alkyl, methoxyphenyl;

a group selected from (NHCH)pyridinyl)CH ₂ COO-C ₁ _ ₆ -αkyl, NHCH(CH ₂ O-C ₁ _ ₆ - 10 041892 alkyl)benzimidazolyl optionally substituted with halogen or CN; or

1-aminocyclopentyl optionally substituted with methyloxadiazole;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of C1-6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C1_6 haloalkyl, C1_6 alkylene-OH, C2_6 alkenylene-OH , C2-6-alkynylene-OH, CH2CON(C1-6-alkyl)2, CH2NHCONH-C3.6-picloalkyl, CN, CO-pyridinyl, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COO-C1_6- alkyl, N(SO ₂ -C _1-6 -alkyl) (CH ₂ CON(C _1-4 -alkyl) ₂ ) O-C1_ ₆ -alkyl, O-pyridinyl, SO ₂ -C ₁ . ₆ -alkyl, SO ₂ -C ₁ . ₆ -alkylene-OH, SO ₂ -C ₃ . ₆ -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C ₁ . ₆ -alkylα, SO ₂ N(C _{1 .6} -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl, or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C ₁ .6 -alkyl, NHC ₁ . _6- alkyl and =O;

R ¹ ' ¹ ' ¹ represents H, C1. ₆ -alkyl, C ₃ .6-cycloalkyl, C1. ₆ -haloalkyl, CH ₂ CON(C ₁ . ₆ -alkyl) ₂ , CH ₂ CO-azetidinyl, C ₁ _ ₆ -alkylene-C ₃ _ ₆ -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ - furanyl, C ₁ .6-alkylene-OH or thiadiazolyl optionally substituted with C _1-6 alkyl;

R ¹ ' ¹ ' ² is H, _C1-6 alkyl, SO ₂ C ₁ . ₆ -alkyl; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one N or O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group, consisting of C ₁ - ₆ -alkyl, C1. _4- alkylene-OH, OH, =O; or

R ^1'1 represents phenyl, where two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing one or two N, S or SO2 independently of each other, which replace a carbon atom in the ring, and the specified ring is optional substituted with C ₁ - ₄ -alkyl or =O;

R ¹² is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of Ci-6-alkyl, C ₂ .b-alkenyl, C ₂ .b-alkynyl, C ₃ .b-cycloalkyl, CH ₂ COO- C1_ ₆ -alkyl, CONR ¹² 1R ¹²² , COR ¹ ' ² ' ³ , COO-C1_ ₆ -alkyl, CONH ₂ , O-C1_ ₆ -alkyl, halogen, CN, SO ₂ N (C ₁ . ₆ -alkyl) ₂ or heteroaryl optionally substituted with one or two residues selected from the group consisting of _{C1_6} alkyl;

heteroaryl optionally substituted with a five- or six-membered carbocyclic non-aromatic ring independently containing two N, O, S or SO ₂ that replace a carbon atom in the ring;

aromatic or non-aromatic C _{9 or 10} -bicyclic ring, where one or two carbon atoms are replaced by N, O or S, each of which is optionally substituted by one or two residues selected from the group consisting of N(C ₁ . ₆ -alkyl) ₂ , CONH-C ₁ . ₆ -alkyl, =O;

a heterocyclic non-aromatic ring optionally substituted with pyridinyl;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCO-C ₁ . ₆ -alkyl;

R ¹²¹ represents H, _C1-6 -alkyl, C ₁ _ ₆ -alkylene-C ₃ _ ₆ -cycloalkyl, C _1-4 -alkylene-phenyl, C _1-4 alkylene-furanyl, C ₃ _ ₆ -cycloalkyl, C ₁ _ ₄ -alkylene-O-C ₁ _ ₄ -alkyl, C1_ ₆ -haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S or SO ₂ independently of each other, which replace the carbon atom in the ring, optionally substituted with 4-cyclopropylmethylpiperazinyl;

R ^{12 2} is H, _C1-6 alkyl;

R ^1'2'3 is a five- or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S or SO ₂ independently of each other, which replaces a carbon atom in the ring;

R ¹³ is selected from phenyl, heteroaryl, or indolyl, each of which is optionally substituted with one or two residues selected from the group consisting of _C1-6 alkyl, _C3-6 picloalkyl, O- _C1-6 alkyl, O- _{C1_ 6} -haloalkyl, phenyl, heteroaryl;

R ² is selected from the group consisting of _{C1_6} alkylene-phenyl, _{C1_6} alkylene naphthyl and _{C1_6} alkyleneheteroaryl, each of which is optionally substituted with one, two or three residues selected from the group consisting of _{C1_6} alkyl, _{C1_6} haloalkyl, O- _{C1_6} alkyl, O- _{C1_6} haloalkyl, halogen;

R ³ is H, C1_ ₆ alkyl;

R ⁴ is H, C1_ ₆ alkyl; or

R ³ and R ⁴ together form a CH2-CH2 group.

Another embodiment of the present invention further comprises administering to the subject compounds of formula 1 (above), wherein

A represents CH ₂ , O or NC ₁ . ₄ -alkyl;

R ¹ is selected from

NHR, NMeR;

NHR ¹ ' ² , NMeR ¹ '²;

NHCH2-R ¹ '³;

- 11 041892

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-ralorenalkyl, C1-6-alkylene -OH, C2-b-alkenylene-OH, C2-b-alkynylene-OH, CH2CON(C1-6-alkyl)2, CH2NHCONH-C3.b-cycloalkyl, CN, CO-pyridinyl, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COO-C1. _b -alkyl, N(SO ₂ -C _1-6 -alkyl) (CH ₂ CONC _1-4 -alkyl) ₂ ) OC ₁ . _b -alkyl, O-pyridinyl, SO ₂ -C ₁ . _b -alkyl, SO ₂ -C ₁ . _b -alkylene-OH, SO ₂ -C ₃ . _b -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C _1-6 -alkyl, SO ₂ N(C _1-6 -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl or a heterocyclic ring, optional substituted with one or two residues selected from the group consisting of C ₁ _ ₆ alkyl, NHC ₁ _ ₆ alkyl, ═O;

R ¹ ' ¹ ' ¹ represents H, C ₁ . _b -alkyl, C ₃ .6-cycloalkyl, C ₁ - _b -haloalkyl, CH ₂ CON (C ₁ . _b -alkyl) ₂ , CH ₂ CO-azetidinyl, C ₁ _ _b -alkylene-C ₃ _ _b -cycloalkyl , CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C ₁ .6-alkylene-OH or thiadiazolyl optionally substituted with C ₁ - _b -alkyl;

R ¹ ' ¹ ' ² is H, C1-b-alkyl, SO2C1.b-alkyl; or R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one N or O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group , consisting of C1 - _b -alkyl, C ₁ - ₄ -alkylene-OH, OH, \u003d O; or

R ^1'1 represents phenyl, where two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing one or two N, S or SO ₂ independently of each other, which replace a carbon atom in the ring, and the specified ring optionally substituted with C ₁ - ₄ -alkyl or =0;

R ¹² is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of C ₁ - _b -alkyl, C ₂ .b-alkenyl, C ₂ .b-alkynyl, C ₃ .b-cycloalkyl, CH ₂ COO -C ₁ .b-alkyl, CONR ^I2 'R ¹²² , COR ^{1 2 3} , COO-Cb-alkyl, CONH ₂ , OC ₁ . _b -alkyl, halogen, CN, SO ₂ N(C ₁ . ₄ -alkyl) ₂ or heteroaryl optionally substituted with one or two residues selected from the group consisting of C ₁ - _b -alkyl;

heteroaryl optionally substituted with a five- or six-membered carbocyclic non-aromatic ring independently containing two N, O, S or SO2 replacing a carbon atom in the ring;

R ¹²¹ represents H, C ₁ - _b -alkyl, C ₁ _ _b -alkylene-C ₃ _ _b -cycloalkyl, C ₁ - ₄ -alkylene-phenyl, C ₁ - ₄ -alkylene-furanyl, C ₃ - _b - cycloalkyl, C ₁ _ ₄ -alkylene-O-C ₁ _ ₄ -alkyl, C ₁ - _b -haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently one or two N, O, S or SO2, which replace a carbon atom in the ring, optionally substituted with 4-cyclopropylmethylpiperazinyl;

R ^{12 2} represents H, C ₁ - _b -alkyl;

R ^1'2'3 is a five- or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S or SO2 independently of each other, which replaces a carbon atom in the ring;

R ¹³ is selected from phenyl, heteroaryl or indolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C1-b-alkyl, C3-b-cycloalkyl, O-C1.b-alkyl, O-C1. b-haloalkyl, phenyl, heteroaryl, in some cases R ¹³ is selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C1- _b- alkyl, C ₃ - _b -cycloalkyl, OC ₁ . _b -alkyl, OC ₁ . _b -haloalkyl, phenyl, pyrrolidinyl;

R ² is selected from the group consisting of C ₁ - _b -alkylene-phenyl, C ₁ - _b -alkylene-naphthyl and C ₁ - _b -alkylenethiophenyl, each of which is optionally substituted with one, two or three residues selected from the group consisting of from C ₁ - _b -alkyl, C ₁ - _b -haloalkyl, OC ₁ . _b -alkyl, OC ₁ . _b -haloalkyl, halogen;

R ³ is H, C _1-4 alkyl;

R ⁴ is H, C _1-4 alkyl; or

R ³ and R ⁴ together form a CH2-CH2 group.

Another embodiment of the present invention further comprises administering to the subject compounds of formula 1 (above), wherein

A represents CH ₂ , O or NC ₁ . ₄ -alkyl;

R ¹ is selected from NHR , NMeR ;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of C1-b-alkyl, C2-b-alkenyl, C2-b-alkynyl, C1-b-haloalkyl, C1-b-alkylene -OH, C2-b-alkenylene-OH, C2-b-alkynylene-OH, CH2CON(C1.b-alkyl)2, CH2NHCONH-C3.b-cycloalkyl, CN, CO-pyridinyl, CONR ¹⁴⁴ R ^{14 2} , COO -C1. _b -alkyl, N (SO ₂ -C ₁ . _b -alkyl) (CH ₂ CON (C ₁ . ₄ -alkyl) ₂ ) OC ₁ . _b -alkyl, O-pyridinyl, SO ₂ -C ₁ . _b -alkyl, SO ₂ -C ₁ . _b -alkylene-OH, SO ₂ -C ₃ . _b -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C ₁ . _b -alkyl, SO ₂ N(C ₁ . _b -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C ₁ - _b -alkyl, NHC ₁ . _b -alkyl, =O;

R ¹ ' ¹ ' ¹ represents H, C ₁ - _b -alkyl, C ₃ - _b -cycloalkyl, C ₁ - _b -haloalkyl, CH ₂ CON(C ₁ . _b -alkyl) ₂ ,

- 12 041892

CH ₂ CO-azetidinyl, C _1-b -alkylene-C _3-b -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl,

C _1- b-alkylene-OH or thiadiazolyl optionally substituted with C _1-b alkyl;

R ¹ ' ¹ ' ² represents H, C _1-b -alkyl, SO ₂ C _1-b -alkyl; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one N or O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group, consisting of C _1-b -alkyl, C _1-4 -alkylene-OH, OH, =O; or

R ^1'1 represents phenyl, where two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing one or two N, S or SO2 independently of each other, which replace a carbon atom in the ring, and the specified ring is optional substituted with C _1-4 -alkyl or =O;

R ² is selected from the group consisting of C _{1 -b} -alkylene-phenyl, C _{1 -b} -alkylene-naphthyl and C _1-b -alkylenethiophenyl, each of which is optionally substituted with one, two or three residues selected from the group consisting of from C _1-b -alkyl, C _1-b -haloalkyl, O-C _1-b -alkyl, O-C _1-b -haloalkyl, halogen;

R ³ is H, C _1-4 alkyl;

R ⁴ is H, C _1-4 alkyl; or

R ³ and R ⁴ together form a CH2-CH2 group.

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NC _1-4 -alkyl;

R ¹ is selected from NHR ¹ ' ² , NMeR ;

R ^1'2 is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of C _1-b -alkyl, C _2-b -alkenyl, C _2-b -alkynyl, C _3-b -cycloalkyl, CH ₂ COO-C _1-b -alkyl, CONR ^{1 24} R ^{1 2 2} , COR ^{1 2 3} , COO-C _1-b -alkyl, CONH ₂ , O-C _1-b -alkyl, halogen, CN, SO ₂ N(C _1-4 -alkyl) ₂ or heteroaryl optionally substituted with one or two residues selected from the group consisting of C _1-b -alkyl;

heteroaryl optionally substituted with a five- or six-membered carbocyclic non-aromatic ring independently containing two N, O, S or SO ₂ that replace a carbon atom in the ring;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of N(C _1-b -alkyl) ₂ , CONH-C _1-b -alkyl, =0;

piperidinyl optionally substituted with pyridinyl;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCO-C _1-b -alkyl;

R ^1'2'1 is H, C1-6-alkyl, C1-6-alkylene-C3-6-cycloalkyl, C1-4-alkylene-phenyl, C1-4-alkylenefuranyl, C3-6-cycloalkyl, C1- 4-alkylene-O-C1-4-alkyl, C1-6-haloalkyl, or a five- or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S, or SO ₂ independently of each other, which replaces a carbon atom in the ring , optionally substituted with 4-cyclopropylmethylpiperazinyl;

R ^{12 2} represents H, C _1-b -alkyl;

R ^1'2'3 is a five- or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S or SO2 independently of each other, which replaces a carbon atom in the ring;

R ² is selected from the group consisting of C _1-b -alkylene-phenyl, C _1-b -alkylene-naphthyl and C _1-b -alkylenethiophenyl, each of which is optionally substituted with one, two or three residues selected from the group consisting of from C _1-b -alkyl, C _1-b -haloalkyl, 0-C _1-b -alkyl, 0-C _1-b -haloalkyl, halogen;

R ³ is H, C _1-4 alkyl;

R ⁴ is H, C _1-4 alkyl; or

R ³ and R ⁴ together form a CH2-CH2 group.

Another embodiment of the present invention further comprises administering to the subject compounds of formula 1 (above), wherein

A represents CH ₂ , O or NC _1-4 -alkyl;

R ¹ is selected from NHR ^1'2 , NMeR ^1'2 ;

R ^1'2 is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of C1-b-alkyl, C2-b-alkenyl, C2-b-alkynyl, C3-b-cycloalkyl, CH2COO-C1-b -alkyl, CONR ^{1 24} R ^{1 2 2} , COR ^{1 2 3} , C00-C _1-b -alkyl, C0NH ₂ , 0-C _1-b -alkyl, halogen, CN, SO ₂ N (C _1-4 - alkyl) ₂ or heteroaryl optionally substituted with one or two residues selected from the group consisting of C _1-b -alkyl;

heteroaryl optionally substituted with a five- or six-membered carbocyclic non-aromatic ring independently containing two N, O, S or SO ₂ replacing a carbon atom in the ring;

R ¹ ' ² ' ¹ represents H, Ci-6-alkyl, C _1-6 -alkylene-C _3-6 -cycloalkyl, C _1-4 -alkylene-phenyl, C _1-4 -alkylenefuranyl, C _3-6 -cycloalkyl, C _1-4 -alkylene-O-C _1-4 -alkyl, C _1-6 -haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently one or two N, O, S or SO ₂ that replace a carbon atom in the ring, optionally substituted with 4-cyclopropylmethylpiperazinyl;

R ¹ ' ² ' ² represents H, C _1-6 -alkyl;

R ¹ ' ² ' ³ represents a five - or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S or SO2 independently of each other, which replace a carbon atom in the ring;

R ² is selected from the group consisting of C _1-6 -alkylene-phenyl, C _1-6 -alkylene-naphthyl and C _1-6 -alkylenethiophenyl, each of which is optionally substituted with one, two or three residues selected from the group consisting of from C _1-6 alkyl, C _1-6 haloalkyl, O-C _1-6 alkyl, O-C _1-6 haloalkyl, halogen;

R ³ is H, C _1-4 alkyl;

R ⁴ is H, C _1-4 alkyl; or

R ³ and R ⁴ together form a group CH ₂ -CH ₂ '

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NC _1-4 -alkyl;

R ¹ is selected from NHCH2-R ¹ '³;

R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl, C _3-6 -cycloalkyl, O-C _1-6 alkyl, O-C _1-6 haloalkyl, phenyl, pyrrolidinyl;

R ² is selected from the group consisting of C _1-6 -alkylene-phenyl, C _1-6 -alkylene-naphthyl and C _1-6 -alkylenethiophenyl, each of which is optionally substituted with one, two or three residues selected from the group consisting of from C _1-6 alkyl, C _1-6 haloalkyl, O-C _1-6 alkyl, O-C _1-6 haloalkyl, halogen;

R ³ is H, C _1-4 alkyl;

R ⁴ is H, C _1-4 alkyl; or

R ³ and R ⁴ together form a group CH ₂ -CH ₂ '

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NC _1-4 -alkyl;

R ¹ is selected from

NHR ¹ ' ¹ , NMeR ¹ '¹;

NHR ¹ ' ² , NMeR ¹ '²;

NHCH2-R ¹ '³;

NH-C _3-6 -cycloalkyl, where optionally one carbon atom is replaced by a nitrogen atom, and the specified ring is optionally substituted by one or two residues selected from the group consisting of C _1-6 alkyl, O-C _1-6 -alkyl, NHSO _2- phenyl, NHCONH-phenyl, halogen, CN, SO ₂ -C _1-6 -alkyl, COO-C _1-6 -alkyl;

C ₉ or ₁₀ -bicyclic ring, where one or two carbon atoms are replaced by nitrogen atoms and the specified ring system is connected through the nitrogen atom to the main structure of formula 1, while the specified ring system is optionally substituted by one or two residues selected from the group consisting of C _1-6 -alkyl, COO-C _1-6 -alkyl, C _1-6 -haloalkyl, O-C _1-6 -alkyl, NO ₂ , halogen, CN, NHSO2C _1-6 -alkyl, m-methoxyphenyl;

a group selected from NHCH(pyridinyl)CH ₂ COO-C _1-6 alkyl, NHCH(CH ₂ O-C _1-6 alkyl)benzimidazolyl optionally substituted with Cl atom; or

1-aminocyclopentyl optionally substituted with methyloxadiazolyl;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of C1-6-alkyl, C1-6-haloalkyl, CH2CON(C1-6-alkyl)2, CH2NHCONH-C3-6-cycloalkyl, CN , CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COO-C1-6-alkyl, O-C _1-6 -alkyl, SO ₂ -C _1-6 -alkyl, SO ₂ -C _1-6 -alkylene -OH, SO ₂ -C _3-6 -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C _1-6 -alkyl, SO ₂ N (C _1-6 -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl, NHC _1-6 -alkyl, =O;

R ¹ ' ¹ ' ¹ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, CH ₂ CON(C _1-6 alkyl) ₂ , CH ₂ CO-azetidinyl, C _1-6 -alkylene-C _3-6 -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C _1-6 -alkylene-OH or thiadiazolyl, optionally substituted with C _1-6 -alkyl;

R ¹ ' ¹ ' ² is H, C _1-6 alkyl, SO ₂ C _1-6 alkyl; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH ₂ OH;

R ^1'2 selected from

- 14 041892 heteroaryl optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl, C _3-6 -cycloalkyl, CH ₂ COO-C _1-6 -alkyl, CONR ¹² 1R ¹²² , COO- C _1-6 -alkyl, CONH2,

O-S ₁ . ₆ -alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl or heteroaryl, optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of N(C _1-6 -alkyl) ₂ , CONH-C _1-6 -alkyl, =O;

piperidinyl optionally substituted with pyridinyl;

4,5-dihydronaphtho[2,1-d]thiazole, optionally substituted with NHCO-C _1-6 -alkyl,

R ¹ ' ² ' ¹ represents H, C1-b-alkyl;

R ¹ ' ² ' ² represents H, C _1-6 -alkyl;

R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl, C _3-6 -cycloalkyl, O- C _1-6 alkyl, O-C _1-6 haloalkyl;

R ² is selected from

C _1-6 -alkylene-phenyl or C _1-6 -alkylene-naphthyl, which are both optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl, C _1-6 -haloalkyl, O-C _1-6 alkyl, O-C _1-6 haloalkyl, halogen; or

CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen;

R ³ is H, C _1-4 alkyl;

R ⁴ is H, C _1-4 alkyl; or

R ³ and R ⁴ together form a CH2-CH2 group,

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from

NHR ^1'1 , NMeR ^1'1 ;

NHR ^1'2 , NMeR ^1'2 ;

NHCH ₂ -R ¹ '³;

NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, NHSO ₂ -phenyl, NHCONH-phenyl, halogen;

NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO ₂ -C _1-4 -alkyl, COO-C _1-4 -alkyl;

piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO ₂ -C _1-4 alkyl, m-methoxyphenyl;

dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl optionally substituted with one or two residues selected from the group consisting of C _1-4 alkyl, COO-C _1-4 alkyl, C _1-4 haloalkyl, O-C _1-4 -alkyl, NO2, halogen;

a group selected from NHCH(pyridinyl)CH ₂ COO-C _1-4 alkyl, NHCH(CH ₂ O-C _1-4 alkyl)benzimidazolyl optionally substituted with C1 atom; or

1-aminocyclopentyl optionally substituted with methyloxadiazolyl;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of C1-4-alkyl, C1-4-haloalkyl, CH2CON(C1-4-alkyl)2, CH2NHCONH-C3-6cycloalkyl, CN , CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COO-C1-4-alkyl, O-C _1-4 -alkyl, SO ₂ -C _1-4 -alkyl, SO ₂ -C _1-4 -alkylene -OH, SO ₂ -C _3-6 -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C _1-4 -alkyl, SO ₂ N (C _1-4 -alkyl) ₂ , halogen, CO-morpholinyl, CH2- pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, NHC _{1- 4} -alkyl, =O;

R ¹ ' ¹ ' ¹ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, CH ₂ CON(C _1-4 alkyl) ₂ , CH ₂ CO-azetidinyl, C _1-4 -alkylene-C _3-6 -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C _1-4 -alkylene-OH or thiadiazolyl, optionally substituted with C _1-4 -alkyl;

R ¹ ' ¹ ' ² represents H, C _1-4 -alkyl, SO ₂ C _1-4 -alkyl; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH;

R ¹ ' ² is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, C _3-6 -cycloalkyl, CH ₂ COO -C _1-4 -alkyl, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COO-C _1-4 -alkyl, CONH ₂ , O-C _1-4 -alkyl, halogen, CO-pyrrolidinyl, CO- morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxa- 15 041892 diazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of N( _C1-4 alkyl) ₂ , CONH-C _1-4 -alkyl, =O;

piperidinyl optionally substituted with pyridinyl;

4,5-dihydronaphtho[2,1-d]thiazole, optionally substituted with NHCO-C _1-4 -alkyl,

R ¹ ' ² ' ¹ represents H, C _1-4 -alkyl;

R ¹ ' ² ' ² represents H, C _1-4 -alkyl;

R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, C _3-6 -cycloalkyl, O- C _1-4 alkyl, O-C _1-4 haloalkyl;

R ² is selected from

C1-b-alkylene-phenyl or C ₁ . ₆ -alkylene-naphthyl, which are both optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, C _1-4 -haloalkyl, O-C _1-4 -haloalkyl, halogen; or

CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH2-CH2 group,

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is CH2, O or NMe;

R ¹ is selected from

NHR ¹ ' ¹ NMeR ¹ '¹;

NHR ¹ ' ² , NMeR ¹ '²;

NHCH2-R ¹ '³;

NH-piperidinyl optionally substituted with pyridinyl;

NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO ₂ -phenyl, NHCONH-phenyl, F;

NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO2Me, COO-t-Bu;

piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO2-n-Bu, m-methoxyphenyl;

dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF ₃ , OMe, NO2, F, Br;

a group selected from NHCH(pyridinyl)CH ₂ COOMe, NHCH(CH ₂ OMe)benzimidazolyl optionally substituted with a Cl atom; or

1-aminocyclopentyl optionally substituted with methyloxadiazolyl;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanil, pyrazolyl, triazolyl , tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O;

R ¹ ' ¹ ' ¹ is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH ₂ -i-Pr, CH ₂ -t-Bu, CH(CH ₃ )CH ₂ CH ₃ , CH2CHF2, CH ₂ CONMe ₂ , CH ₂ CO-azetidinyl, CH ₂ -cyclopropyl, CH ₂ -cyclobutyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, CH ₂ CH ₂ OH, or thiadiazolyl optionally substituted with a Me group;

R ¹ ' ¹ ' ² represents H, Me, Et, SO ₂ Me, SO ₂ Et; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH;

R ^1'2 is selected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH ₂ COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group;

- 16 041892 benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2,

CONHMe, =O;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCOMe,

R ¹ ' ² ' ¹ represents H, Me;

R ¹ ' ² ' ² represents H, Me;

R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF2;

R ² is selected from

CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; or

CH2-thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH2-CH2 group,

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is CH2, O or NMe;

R ¹ is selected from

NHR ^1'1 ;

NHR ^1'2 ;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO ₂ NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl , triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O;

R ¹ ' ¹ ' ¹ is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH ₂ -i-Pr, CH ₂ -t-Bu, CH(CH ₃ )CH ₂ CH ₃ , CH2CHF2, CH2CONMe2, CH2CO-azetidinyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2-pyranyl, CH2-tetrahydrofuranyl, CH2-furanyl, CH2CH2OH or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² is H, Me, Et, SO ₂ Me, SO2 Et; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH ₂ OH;

R ^1'2 is selected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH2COOEt, CONR ^1'2'1 R ^1'2'2 , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, COmorpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCOMe,

R ^1'2'1 represents H, Me;

R ^1'2'2 represents H, Me;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et;

R ³ is H;

R ⁴ is H'

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from

NHR ^1'1 , NMeR ^1'1 ;

NHR ^1'2 , NMeR ^1'2 ;

NHCH2-R ^1'3 ;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, CF ₃ , CH ₂ CONMe ₂ , CH ₂ NHCONH-pyclohexyl, CN, CONR '.'.'r'.'. ² , COOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO2-cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanil, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O;

R ¹ ' ¹ ' ¹ is H, Me, Et, Pr, Bu, cyclopropyl, CH ₂ -Pr, CH ₂ -Bu, CH(CH ₃ )CH ₂ CH ₃ , CH ₂ CHF ₂ , CH ₂ CONMe ₂ , CH ₂ CO-azetidinyl, CH ₂ -cyclopropyl, CH 2 -cyclobutyl, CH _{2 -pyranyl} , CH 2 -tetrahydrofuranyl, CH 2 -furanyl, CH 2 CH 2 OH or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² is H, Me, Et, SO ₂ Me, SO2 Et; or

R ^{1 1 1} and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH;

R ^1'2 is selected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH2COOEt, CONR ¹ '2' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCOMe;

R ^1'2'1 represents H, Me;

R ^1'2'2 represents H, Me;

R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF2;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a group CH2-CH2'

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is CH2, O or NMe;

R ¹ is selected from NHR ^1'1 , NMeR ^1'1 ;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH2-pyridinyl or imidazolidinyl, piperidinyl, oxazinanil, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O;

R ¹ ' ¹ ' ¹ is H, Me, Et, Bu, Pr, cyclopropyl, CH ₂ -Pr, CH ₂ -Bu, CH(CH ₃ )CH ₂ CH ₃ , CH2CHF2, CH2CONMe2, CH2CO-azetidinyl, CH2- cyclopropyl, CH2-cyclobutyl, CH2-pyranyl, CH2tetrahydrofuranyl, CH2 _- furanyl, _CH2CH2OH or thiadiazolyl optionally substituted with _a Me group;

R ¹ ' ¹ ' ² is H, Me, Et, SO ₂ Me, SO2 Et; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH ₂ OH;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, O, Br, Et; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a group CH2-CH2'

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

- 18 041892

R ¹ is selected from NHR ^1.1 , NMeR ;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, COnR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , CoOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanil, pyrazolyl, triazolyl , tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O;

R ¹ ' ¹ ' ¹ is H, Me, Et, Bu, Pr, cyclopropyl, CH ₂ -Pr, CH ₂ -Bu, CH(CH ₃ )CH ₂ CH ₃ , CH2CHF2, CH2CONMe2, CH2CO-azetidinyl, CH2- cyclopropyl, CH2-cyclobutyl, CH2-pyranyl, CH2-tetrahydrofuranyl, CH2-furanyl, CH2CH2OH or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² is H, Me, Et, SO ₂ Me, SO2 Et; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH ₂ OH;

R ² is as defined in Table 1 below; R ³ is H;

R ⁴ is H;

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR, NMeR ;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO ₂ NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl , triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O; And

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH;

R ² is as defined in Table 1 below;

R ³ is H;

R ⁴ is H;

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR , NMeR ¹ '¹;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF ₃ , CH ₂ CONMe ₂ , CH ₂ NnCONH-cyclohexyl, CN, CONR ^{1'1' 1} R ^1'1'2 , COOMe, COOEt, OMe, F, Cl;

R ¹ ' ¹ ' ¹ is H, Me, Et, Bu, Pr, cyclopropyl, CH ₂ -Pr, CH ₂ -Bu, CH(CH ₃ )CH ₂ CH ₃ , CH2CHF2, CH2CONMe2, CH2CO-azetidinyl, CH2- cyclopropyl, CH2-cyclobutyl, CH2-pyranyl, CH2-tetrahydrofuranyl, CH2-furanyl, CH2CH2OH or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² is H, Me, Et, SO ₂ Me, SO2 Et;

R ² is as defined in Table 1 below;

R ³ is H;

R ⁴ is H;

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is CH2, O or NMe;

R ¹ is selected from NHR, NMeR ¹ '¹;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of SO ₂ Me, SO2CH2CH2OH, SO2Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO2NMeEt;

R ¹ ' ¹ ' ¹ is H, Me, Et, Bu, Pr, cyclopropyl, CH ₂ -Pr, CH ₂ -Bu, CH(CH ₃ )CH ₂ CH ₃ , CH2CHF2, CH2CONMe2, CH2CO-azetidinyl, CH2- cyclopropyl, CH2-cyclobutyl, CH2-pyranyl, CH2-tetrahydrofuranyl, CH2-furanyl, CH2CH2OH or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² is H, Me, Et, SO ₂ Me, SO2 Et;

- 19 041892

R ² is as defined in table. 1 below;

R ³ is H;

R ⁴ is H;

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ¹ , NMeR ¹ '¹;

R ¹ ' ¹ is phenyl optionally substituted with one residue selected from the ^{group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, CONR 1-14^4-2 , COOMe ,} COOEt, OMe, SO2Me, SO ₂ CH ₂ CH ₂ OH, SO ₂ Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO ₂ NHEt, SO ₂ NMeEt, F, Cl, and additionally one residue selected from the group consisting of CO -morpholinyl, CH2-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, = O;

R ^{1 1} ' ¹ is H, Me, Et, Bu, Pr, cyclopropyl, CH ₂ -Pr, CH ₂ -Bu, CH(CH ₃ )CH ₂ CH ₃ , CH ₂ CHF ₂ , CH ₂ CONMe ₂ , CH ₂ CO-azetidinyl, CH ₂ -cyclopropyl, CH 2 -cyclobutyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH _{2 -furanyl} , CH ₂ CH ₂ OH, or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² represents H, Me, Et, SO ₂ Me, SO ₂ Et;

R ² is as defined in table. 1 below;

R ³ is H;

R ⁴ is H;

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ¹ ' ² is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH ₂ COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCOMe;

R ^1'2'1 represents H, Me;

R ^1'2'2 represents H, Me;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a group CH ₂ -CH ₂ '

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ^1'2 , NMeR ^1'2 ;

R ¹ ' ² is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, n-Pr, i-Pr, Bu, cyclopropyl, CH ₂ COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optional substituted with a Me group;

R ^1'2'1 represents H, Me; R ^1'2'2 represents H, Me;

R ² is selected from CH2-phenyl or CH2-naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH3, CF3, OCF3, F, Cl, Br, Et; or CH2-thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a group CH ₂ -CH ₂ '

Another embodiment of the present invention further comprises administering to the subject compounds of Formula 1, wherein

A is CH2, O or NMe;

R ¹ is selected from NHCH2-R ¹ '³;

R ^1.3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF2;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH2-CH2 group.

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is CH2, O or NMe;

R ¹ is selected from

NH-piperidinyl optionally substituted with pyridinyl;

NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO ₂ -phenyl, NHCONH-phenyl, F;

NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO2Me, COO-t-Bu;

piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO2-n-Bu, m-methoxyphenyl;

dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF3, OMe, NO2, F, Br;

a group selected from NHCH(pyridinyl)CH ₂ COOMe, NHCH(CH ₂ OMe)benzimidazolyl optionally substituted with a Cl atom; or

1-aminocyclopentyl optionally substituted with methyloxadiazolyl;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH2-CH2 group.

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is CH2, O or NMe;

R ¹ is selected from NHR1.2, NMeR;

R ² is as defined in table. 1 below;

R ³ is H;

R ⁴ is; And

R ¹ ' ² is selected from pyridinyl optionally substituted with one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, cyclopropyl, CONR ¹ ' ² ' ¹ R ^{1 2} ' ² , COOMe, COOEt, cOnH ₂ , OMe, Cl, Br, COpyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group;

pyrrolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt;

pyrazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl;

isoxazolyl optionally substituted with one or two residues selected from the group consisting of t-Bu, COOEt;

thiazolyl optionally substituted with one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CH2COOEt, CONR ^1.2.1 R ^1.2.2 ;

thiadiazolyl optionally substituted with one or two residues selected from the group consisting of COOEt;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCOMe; And

R ^1.2.1 is H or Me;

- 21 041892

R ¹ ' ² ' ² represents H or Me.

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in table. 1 below;

R ³ is H;

R ⁴ is; And

R ¹ ' ² is selected from pyridinyl optionally substituted with one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br;

pyrrolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt;

pyrazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl;

isoxazolyl optionally substituted with one or two residues selected from the group consisting of t-Bu, COOEt;

thiazolyl optionally substituted with one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CONR ^1.2.1 R ^1.2.2 ;

thiadiazolyl optionally substituted with one or two residues selected from the group consisting of COOEt;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O; And

R ^1.2.1 is H or Me;

R ^1.2.2 is H or Me.

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in table. 1 below;

R ³ is H;

R ⁴ is H;

R ¹ ' ² is pyridinyl optionally substituted with one or two residues selected from the group consisting of Me, Et, i-Pr, n-Bu, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br;

R ^1'2'1 represents H or Me; And

R ¹ ' ² ' ² is H or Me'

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in Table 1 below;

R ³ is H;

R ⁴ is H;

R ^1'2 is pyrrolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, COOMe, COOEt; R ¹ ' ² ' ¹ represents H or Me; And

R ^1'2'2 is H or Me'

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in Table 1 below;

R ³ is H;

R ⁴ is H;

R ^1'2 is pyrazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, cyclopropyl, COOEt, CO-pyrrolidinyl;

R ^1'2'1 represents H or Me; And

R ^1'2'2 is H or Me'

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in Table 1 below;

R ³ is H;

R ⁴ is H;

R ^1'2 is isoxazolyl optionally substituted with one or two residues selected from the group consisting of t-Bu, COOEt;

- 22 041892

R ¹ ' ² ' ¹ represents H or Me; And

R ¹ ' ² ' ² represents H or Me.

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in table. 1 below;

R ³ is H;

R ⁴ is H;

R ¹ ' ² is thiazolyl optionally substituted with one or two residues selected from the group consisting of Me, n-Pr, i-Pr, Bu, COOMe, COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² '²;

R ¹ ' ² ' ¹ represents H or Me; And

R ¹ ' ² ' ² is H or Me'

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in Table 1 below;

R ³ is H;

R ⁴ is H;

R ¹ ' ² is thiadiazolyl optionally substituted with one or two residues selected from the group consisting of COOEt;

R ^1'2'1 represents H or Me; And

R ^1'2'2 is H or Me'

A represents CH ₂ , O or NMe;

R ¹ is selected from NHR ¹ ' ² , NMeR ¹ '²;

R ² is as defined in Table 1 below;

R ³ is H;

R ⁴ is H;

R ¹ ' ² is benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of NMe ₂ , CONHMe, =O;

R ^1'2'1 represents H or Me; And

R ^1'2'2 is H or Me'

Another embodiment of this invention further comprises administering to the subject compounds of Formula 1 wherein all groups are as defined above except that

R ^1'3 is selected from phenyl optionally substituted with an OCHF2 group;

pyrazolyl optionally substituted with Me or Et;

isoxazolyl optionally substituted with a Pr group;

pyrimidinyl optionally substituted with two OMe groups;

indolyl;

oxadiazolyl optionally substituted with cyclopentyl'

Another embodiment of this invention further comprises administering to the subject compounds of formula 1 wherein all groups are as defined above except that A is CH ₂ '

Another embodiment of this invention further comprises administering to the subject compounds of Formula 1 wherein all groups are as defined above except that A is O'

Another embodiment of this invention further comprises administering to the subject compounds of Formula 1 wherein all groups are as defined above except that A is NMe'

- 23 041892

Another embodiment of this invention are compounds of formula 1, where

A is CH2, O or NMe;

R ¹ is selected from

- 24 041892

- 25 041892

- 26 041892

- 27 041892

- 28 041892

- 29 041892

R ² is selected from

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH ₂ -CH ₂ group.

Another embodiment of this invention is the compounds of formula 1, where A is as defined above;

R ³ is H;

R ⁴ is H; And

R ² is as defined in table. 1 below; And

R ¹ is selected from

- 30 041892

- 31 041892

- 32 041892

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is as defined above;

R ³ is H;

R ⁴ is H; and at

R is as defined in the table. 1 below; And

R ¹ is selected from

- 33 041892

- 34 041892

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is as defined above;

R ³ is H;

R ⁴ is H; And

R ² is as defined in table. 1 below;

R ¹ is selected from

- 35 041892

- 36 041892

- 37 041892

- 38 041892

- 39 041892

Another embodiment of this invention further includes the compounds of formula 1, where the introduction to the subject coA is as defined above;

R ³ is H;

R ⁴ is H; And

R ² is as defined in table. 1 below; And

R ¹ is selected from

- 40 041892

- 41 041892

H ₃ C- _N

Another embodiment of this invention further comprises administering compounds of formula 1 to the subject, wherein

A is as defined above;

R ³ is H;

R ⁴ is H; And

- 42 041892

TL 2 ........ G’ l. ..

R is as defined in the table. 1 below;

R ¹ is selected from

- 43 041892

R ² is one of the groups depicted below in definitions 1-4.

Table 1

Another embodiment of this invention further comprises administering to the subject compounds of Formula 1, wherein the compounds of Formula 1 are in the form of single optical isomers, mixtures of single enantiomers, or racemates, for example, in the form of enantiomerically pure compounds.

Another embodiment of this invention further comprises administering to the subject compounds of Formula 1, wherein the compounds of Formula 1 are in the form of their acid addition salts with pharmacologically acceptable acids, and optionally in the form of solvates and/or hydrates.

b. cocrystals and salts.

Additional embodiments of this invention further include the introduction

- 44 041892 co-crystals of the compounds of formula 2 (below). Generally, for groups containing two or more subgroups in this Cocrystals and Salts section, the first named subgroup is the point of attachment of the radical, e.g., a C _1-3 -alkyl-aryl substituent means an aryl group that is bonded to a C _1-3 -alkyl group , the last of which is associated with the central structure or with the group to which this substituent is attached.

where R ¹ represents C _1-6 -alkyl, C _1-6 -haloalkyl, OC _1-6 -haloalkyl, halogen;

m is 1, 2 or 3, and in some cases is 1 or 2;

R ^2a and R ^2b are each independently selected from H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _3-6 cycloalkyl, COO-C _1-6 alkyl, OC _{1 -6} -alkyl, CONR ^2b.1 , halogen;

R ^2b.1 is H, C _1-6 alkyl, C _0-4 alkyl-C _3-6 cycloalkyl, C _1-6 haloalkyl;

R ^2b.2 is H, C _1-6 alkyl; or

R ^2b.1 and R ^2b.2 together represent a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom;

R ³ is H, C _1-6 alkyl;

X is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyl tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate , and in some cases from chloride or dibenzoyl tartrate;

j is 0, 0.5, 1, 1.5 or 2, and in some cases 1 or 2;

with a co-crystal forming compound selected from the group consisting of orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L-(+)-ascorbic acid, saccharin, piperazine, 3-hydroxy-2- naphthoic acid, mucinic (galactaric) acid, pamoic (embonic) acid, stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine, in some cases from ascorbic acid, mucic acid, pamoic acid, succinamide, nicotinic acid, nicotinamide, isonicotinamide, 1-lysine, 1-proline.

Another aspect of this invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ^2a is H, C ₁ _ ₆ alkyl, C ₁ . ₆ -alkenyl, C ₁ _ ₆ -alkynyl, C ₃ . ₆ -cycloalkyl, OC ₁ . ₆ -alkyl, CONR ^2a.1 R ^2a . ² ;

R ^2a.1 is H, C1_6-alkyl, C1_6-haloalkyl; R ^2a.2 is H, C1_ ₆ alkyl;

R ^2b is H, C ₁ _ ₆ alkyl, C ₁ _ ₆ alkenyl, C ₁ _ ₆ alkynyl, C ₃ _ ₆ cycloalkyl, COO-C ₁ _ ₆ alkyl, OC ₁ _ ₆ alkyl, CONR ^2b.1 K ^2b .1, halogen;

R ^2b.1 is H, C ₁ _ ₆ alkyl, C ₀ _ ₄ alkyl-C ₃ _ ₆ cycloalkyl, C ₁ _ ₆ haloalkyl;

R ^2b.2 is H, C ₁ _ ₆ alkyl; or

R ^2b.1 and R ^2b.2 together represent C ₃ . _{a 6} -alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ^2a is H, C ₁ _ ₆ alkyl, C ₁ _ ₆ alkynyl, C ₃ . ₆ -cycloalkyl, OC ₁ . ₆ -alkyl, CONR ^2a.1 R ^2a . ² ;

R ^2a.1 is C ₁ _ ₆ -alkyl;

R ^2a.2 is H; R ^2b is H, C ₁ . ₆ -alkyl, OC ₁ . ₆ -alkyl, CONR ^2b.1 R ^2b . ² ;

R ^2b.1 is C ₁ _ ₆ alkyl, C ₀ . ₄ -alkyl-C ₃ . ₆ -cycloalkyl, C ₁ _ ₆ -haloalkyl;

R ^2b.2 is H, C ₁ . ₆ -alkyl; or

R ^2b.1 and R ^2b.2 together represent C ₃ . _{a 6} -alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ^2a is H, C ₁ _ ₄ alkyl, C ₁ _ ₄ alkynyl, C ₃ . ₆ -cycloalkyl,

O-C1_4-alkyl, C/ONR R';

R ^2a.1 is C ₁ _ ₄ alkyl;

R ^2a.2 is H;

- 45 041892

R ^2b is H, C _1-4 alkyl, O-C _1-4 alkyl, CONR ^2b 'R ^{2b 2} ;

R ^{2b 1} is C _1-4 alkyl, C _0-4 alkyl-C _3-6 cycloalkyl, C _1-4 haloalkyl;

R ^{2b 2} is H, C _1-4 alkyl; or

R ^{2b 1} and R ^{2b 2} together represent a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ^2a is H, C _1-4 alkyl, R ^2b is H, CONR ^2b 1R ^2b2

R ^{2b 1} is C _1-4 alkyl, CO _-4 alkyl-C _3- b-cycloalkyl, C _1-4 haloalkyl;

R ^{2b 2} is H, C _1-4 alkyl; or

R ^{2b 1} and R ^{2b 2} together represent a C _{3 -} b-alkylene group forming a heterocyclic ring with a nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ¹ is C _1-6 alkyl, C _1-6 haloalkyl, O-C _1-6 haloalkyl, halogen;

m is 1 or 2;

R ^2a is H, C _1-4 alkyl; R ^2b is H, CONR ^2b 1R ^2b2

R ^{2b 1} is C _1-4 alkyl, C _0-4 alkyl-C _3-6 cycloalkyl, C _1-4 haloalkyl;

R ^{2b 2} is H, C _1-4 alkyl; or

R ^{2b 1} and R ^{2b 2} together represent a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom;

R ³ is H, C _1-6 alkyl;

X is an anion selected from the group consisting of chloride or dibenzoyl tartrate;

j is equal to 1 or 2.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ^2a is H, C _1-4 alkyl; in some cases, methyl, ethyl, propyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^{2b 1} is C _1-4 alkyl, and in some cases methyl, ethyl, propyl;

R ^{2b 2} is C _1-4 alkyl, and in some cases methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ^2a is H, C _1-4 -alkyl, and in some cases methyl, ethyl, propyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^{2b 1} is C _0-4 alkyl-C _3-6 cycloalkyl;

R ^{2b 2} is H, C _1-4 alkyl, and in some cases H, methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2 to the subject, wherein

R ^2a is H, C _1-4 -alkyl, and in some cases methyl, ethyl, propyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^{2b 1} is C _1-4 haloalkyl;

R ^{2b 2} is H, C _1-4 alkyl, and in some cases H, methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of this invention further comprises administering to the subject co-crystals of compounds of formula 2 wherein R ^{2b 1} and R ^{2b 2} together are a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom, and the remaining residues are as defined above.

Another aspect of this invention further comprises administering to the subject co-crystals of compounds of Formula 2 wherein R ¹ , m, R ^2a , R ^2b , R ³ , X and j are as defined above and the co-crystal forming compound is selected from the group consisting of ascorbic acid, mucinic acid, pamoic acid, succinamide, nicotinic acid, nicotinamide, isonicotinamide, 1-lysine, 1-proline or their hydrates or hydrochlorides.

Another aspect of this invention further comprises administering to the subject co-crystals of compounds of formula 2a wherein R ^2a , R ^2b , R ³ , X and j are as defined above.

- 46 041892

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2a to the subject, wherein

R ^2a is H, C ₁ . ₄ -alkyl, and in some cases methyl, ethyl, propyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^2b '1 is C ₁ . ₄ -alkyl, and in some cases methyl, ethyl, propyl;

R ^2b ' ² is C ₁ . ₄ -alkyl, and in some cases methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2a to the subject, wherein

R ^2a is H, C ₁ . ₄ -alkyl, and in some cases methyl, ethyl, propyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^2b '1 is C ₀ . ₄ -alkyl-C ₃ . ₆ -cycloalkyl;

R ^2b ' ² is H, C ₁ . ₄ -αkyl, and in some cases H, methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of this invention further comprises administering to the subject co-crystals of compounds of formula 2a wherein R ^2a is H, C ₁ . ₄ -alkyl; in some cases, methyl, ethyl, propyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^2b '1 is C _1-4 haloalkyl;

R ^2b ' ² is H, C ₁ . ₄ -alkyl; in some cases H, methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering co-crystals of compounds of formula 2a to the subject, wherein

R ^2b '1 and R ^2b ' ² together represent C ₃ . _{a 6} -alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom; and the remaining residues are as defined above.

The free bases of the compounds of formula 2 (j=0) are often amorphous and are used in the co-crystal process, however, in some cases, salts of the compounds of formula 2 are used in the co-crystal process. Thus, another aspect of this invention is the salts of the compounds of formula 2, where

R ¹ , m, R ^2a , R ^2b , R ³ are as defined above for co-crystals; And

X is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyl tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate , and in some cases from chloride or dibenzoyl tartrate;

j is 0, 0.5, 1, 1.5 or 2, and in some cases 1 or 2.

Another aspect of this invention further comprises administering to the subject co-crystals of compounds of formula 2 wherein R ¹ , m, R ^2a , R ^2b , R ³ are as defined above for the co-crystals; And

X is an anion selected from the group consisting of chloride or dibenzoyl tartrate;

j is equal to 1 or 2.

Another aspect of the present invention further comprises administering to the subject salts of compounds of Formula 2 wherein

R ¹ , m, R ^2a , R ^2b , R ³ are as defined above for salts; And

X is chloride; and j is 2.

Another aspect of the present invention further comprises administering to the subject salts of compounds of Formula 2 wherein

R ¹ , m, R ^2a , R ^2b , R ³ are as defined above for salts; And

X is dibenzoyl tartrate; and j is 1.

Another aspect of this invention further comprises administering to the subject salts of compounds of formula 2a wherein R ^2a , R ^2b , R ³ ', X and j are as defined above.

- 47 041892

Another aspect of the present invention further comprises administering to the subject salts of compounds of formula 2a, wherein

R ^2a is H, C _1-4 alkyl; in some cases, methyl, ethyl, propyl;

R ^2b is H, CONR ^2b ' ¹ R ^2b '²;

R ^2b '1 is C _1-4 alkyl, and in some cases methyl, ethyl, propyl;

R ^2b ' ² represents C _1-4 -alkyl, and in some cases, methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering to the subject salts of compounds of formula 2a, wherein

R ^2a is H, C _1-4 alkyl, and in some cases methyl, ethyl, propyl;

R ^2b is H, CONR ^2b ' ¹ R ^2b '²;

R ^2b '1 is C _0-4 alkyl-C _3-6 cycloalkyl;

R ^2b ' ² is H, C _1-4 -αkyl, and in some cases H, methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering to the subject salts of compounds of formula 2a, wherein

R ^2a is H, C _1-4 -alkyl; in some cases, methyl, ethyl, propyl;

R ^2b is H, CONR ^2b ' ¹ R ^2b '²;

R ^2b '1 is C _1-4 haloalkyl;

R ^2b ' ² represents H, C _1-4 -αkyl; in some cases H, methyl, ethyl, propyl; and the remaining residues are as defined above.

Another aspect of this invention further comprises administering to the subject salts of compounds of formula 2a wherein R ^2b '1 and R ^2b ' ² together represent a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an atom oxygen, and the remaining residues are as defined above.

Another aspect of the present invention further comprises administering to the subject salts of compounds of formula 2a, wherein

R ¹ , m, R ^2a , R ^2b , R ³ are as defined above for salts; And

X is chloride; and j is 2.

Another aspect of the present invention further comprises administering to the subject salts of compounds of formula 2a, wherein

R ¹ , m, R ^2a , R ^2b , R ³ are as defined above for salts; And

X is dibenzoyl tartrate; and j is 1.

Another aspect of this invention are salts of compounds of formula 2a, where

R ¹ , m, R ^2a , R ^2b , R ³ are as defined above for salts; And

X is (S)-(S)-(+)-2,3-dibenzoyl tartrate; and j is 1.

With. Compositions.

Additional embodiments of this invention further include administering to the subject a pharmaceutical composition containing compounds of formula 3 wherein R ¹ is H, C _1-6 alkyl, C _0-4 alkyl-C _3-6 cycloalkyl, C _1-6 haloalkyl ;

R ² is H, C _1-6 alkyl;

X is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate;

- 48 041892 j is 1 or 2.

One embodiment of the present invention further comprises administering to the subject a pharmaceutical composition comprising compounds of formula 3, wherein

R ¹ is H, C _1-6 alkyl;

R ² is H, C _1-6 alkyl;

X is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate;

j is equal to 1 or 2.

One embodiment of the present invention further comprises administering to the subject a pharmaceutical composition comprising compounds of formula 3, wherein

R ¹ represents H, methyl, ethyl, propyl, butyl;

R ² is H, methyl, ethyl, propyl, butyl;

X is an anion selected from the group consisting of chloride or ^1A dibenzoyl tartrate, such as chloride;

j is 1 or 2, in some cases 2.

One embodiment of the present invention further comprises administering to the subject a pharmaceutical composition comprising compounds of formula 3, wherein

R ¹ represents H, methyl, ethyl, propyl, butyl;

R ² is H, methyl;

X is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate, such as chloride;

j is 1 or 2, in some cases 2.

One embodiment of the present invention further comprises administering to the subject a pharmaceutical composition comprising compounds of formula 3, wherein

R ¹ is H, methyl;

R ² is H, methyl;

X is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate, such as chloride;

j is 1 or 2, in some cases 2.

One embodiment of the invention further includes administering to the subject a pharmaceutical composition containing the compounds described in Table 1. 2, in the form of hydrochloride. An additional embodiment of the present invention further comprises administering to the subject a pharmaceutical composition containing the compounds described in Table 1. 2, in the form of dihydrochloride.

table 2

- 49 041892

- 50 041892

Another object of this invention is the introduction to the subject of a pharmaceutical dosage form of the compounds described above, and the specified dosage form is a dosage form that can be delivered orally.

Another object of this invention is the administration to a subject of a pharmaceutical dosage form of the compounds described above, which is presented in the form of a tablet, capsule, pellet, powder or granules.

Another aspect of this invention is the administration to a subject of the pharmaceutical dosage forms described above for use as a medicine.

Another object of the present invention is the use of the pharmaceutical dosage forms described above for the preparation of a medicament for the treatment of a neurodegenerative disease or pathological condition selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia and progressive supranuclear palsy.

Another scope of this invention is a method of treating and/or preventing a disease or pathological condition selected from a neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia; and progressive supranuclear palsy, characterized in that an effective amount of the pharmaceutical dosage form described above is orally administered to a subject or patient once, twice, three times, or several times a day.

- 51 041892

d. Dosage forms/ingredients.

Solid pharmaceutical compositions ready for use/ingestion derived from compounds of formula 3 include powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tablets, lozenges and lozenges. Detail:

the capsule dosage forms of this invention comprise a powdered intermediate for a compound of formula 3, an intermediate mixture containing such a powdered intermediate, pellets or granules obtained by conventional wet, dry, or melt granulation, or melt extrusion, or spray drying of a suitable intermediate , which is filled with conventional capsules, for example, hard gelatin capsules or HPMC capsules;

the capsule dosage forms described above may also contain a powdered intermediate for the compound of Formula 3 in compacted form;

capsule dosage forms according to this invention contain the compound of formula 3, suspended or diluted in a liquid or mixture of liquids;

tablet dosage forms of this invention include those tablets obtained by direct compression of a suitable finished mixture, or tableting pellets or granules obtained by conventional wet, dry or melt granulation, or extrusion or hot melt, or spray drying of a suitable intermediate mixture.

Another object of this invention is a dosage form in which a pH adjusting or buffering agent has been added to improve the stability of the active ingredient. The pH adjusting/buffering agent may be a basic amino acid which contains an amino group and has alkaline characteristics (isoelectric point, pI: 7.59-10.76), such as, for example, L-arginine, L-lysine or L-histidine . The buffering agent in the context of this invention is L-arginine. L-arginine has a particularly useful stabilizing effect on the compositions of this invention, for example by inhibiting the chemical degradation of the compounds of formula 3.

Thus, in one embodiment, this invention relates to a pharmaceutical composition (for example, an oral solid dosage form, in particular a tablet) containing a compound of formula 3 and L-arginine to stabilize the composition, in particular against chemical degradation; and one or more pharmaceutical excipients.

Generally, pharmaceutical excipients used in this invention are conventional materials such as cellulose and its derivatives, D-mannitol, corn starch, pregelatinized starch as filler, copovidone as binder, crospovidone as disintegrant, magnesium stearate in as a lubricant, colloidal anhydrous silica as a lubricant, hypromellose as a film coating agent, polyethylene as a plasticizer, titanium dioxide, red/yellow iron oxide as a pigment, and talc, etc.

In more detail, the pharmaceutical excipients may be a first and second diluent, a binder, a disintegrant, and a lubricant; additional leavening agent and additional sliding agent are optional.

Suitable diluents for the pharmaceutical composition of this invention are powdered cellulose, microcrystalline cellulose, lactose in various crystalline modifications, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, erythritol, low substituted hydroxypropyl cellulose, mannitol, starch or modified starch (for example , pregelatinized or partially hydrolysed) or xylitol. Among such diluents, mannitol and microcrystalline cellulose are sometimes used.

Diluents that find use as a second diluent are the aforementioned diluents mannitol and microcrystalline cellulose.

Lubricants suitable for the pharmaceutical composition of this invention are talc, polyethylene glycol, calcium behenate, calcium stearate, sodium stearyl fumarate, hydrogenated castor oil or magnesium stearate. In some cases, the lubricant is magnesium stearate.

Binders suitable for the pharmaceutical composition of this invention are copovidone (copolymers of vinylpyrrolidone with other vinyl derivatives), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (povidone), pregelatinized starch, stearic palmitic acid, hydroxypropyl cellulose with low degree of substitution (N-HPC), and some dosage forms use copovidone and pregelatinized starch. The aforementioned binders, pregelatinized starch and H-HPC, exhibit additional diluent and disintegrant properties and can also be used as a second diluent or disintegrant.

- 52 041892

Suitable disintegrants for the pharmaceutical composition of this invention are corn starch, crospovidone, potassium polacrilin, croscarmellose sodium, low substituted hydroxypropylcellulose (H-HPC), or pregelatinized starch; such as croscarmellose sodium.

Colloidal silicon dioxide can be used as an optional lubricant. An exemplary composition of this invention contains a mannitol diluent, microcrystalline cellulose as a diluent with additional disintegrant properties, a binder copovidone, a disintegrant croscarmellose sodium and magnesium stearate as a lubricant.

Typical pharmaceutical compositions contain (% by weight):

10-50% active ingredient 20-88% thinner 1, 5-50% thinner 2, 1-5% binder, 1-15% baking powder and 0.1-5% lubricant.

Pharmaceutical (% by mass):

compositions according to some embodiments of the invention contain

10-50% active ingredient 20-75% thinner 1, 5-30% thinner 2, 2-30% binder, 1-12% baking powder and 0.1-3% lubricant.

Pharmaceutical (% by mass):

compositions according to some embodiments of the invention contain

10-90% active ingredient 5-70% thinner 1, 5-30% thinner 2, 0-30% binder, 1-12% baking powder and 0.1-3% lubricant.

Pharmaceutical (% by mass):

compositions according to some embodiments of the invention contain

10-50% active ingredient 20-75% thinner 1, 5-30% thinner 2, 2-30% binder, 0.5-20% buffer agent, 1-12% baking powder and 0.1-3% lubricant.

- 53 041892

Pharmaceutical compositions according to some embodiments of the invention contain (% by weight):

30-70% active ingredient 20-75% thinner 1, 5-30% thinner 2, 2-30% binder, 0.5-20% buffer agent, 1-12% baking powder and 0.1-3% lubricant

In some cases, pharmaceutical compositions containing 10-90% active ingredient are used, for example 30-70% active ingredient (% by weight).

The tablet dosage form of this invention may be uncoated or coated, for example film-coated, which is obtained using suitable coatings that do not have a known negative effect on the dissolution properties of the finished dosage form. For example, tablets can be provided with a protective layer to protect against the environment surrounding the patient and clinic staff, as well as to protect against moisture, by dissolving a high molecular weight polymer such as polyvinylpyrrolidone or hydroxypropyl methylcellulose, along with plasticizers, lubricants, and optionally pigments and surfactants. active ingredients in water or an organic solvent such as acetone and spraying the resulting mixture onto the tablet cores in a coating apparatus such as a pan coater or a Wurster baffled fluidized bed coater.

In addition, agents such as beeswax, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, zein, film-forming polymers such as hydroxypropyl cellulose, ethyl cellulose and polymeric methacrylates can be applied to the tablets, provided that such coating does not have a significant effect on disintegration/dissolution of the dosage form and that the stability of the coated dosage form is not impaired.

After film coating the dosage form, the coated pharmaceutical dosage form can be coated with sugar. The sugar coating may contain sucrose, dextrose, sorbitol, and the like. or mixtures thereof. If necessary, coloring agents or clouding agents may be added to the sugar solution.

Solid dosage forms according to this invention are usually hygroscopic. They can be packaged in PVC blisters, PVDC blisters or moisture resistant packaging material such as aluminum foil blister packs, aluminum blisters, clear or frosted plastic blisters with a bag, polypropylene tubes, glass bottles and LDPE bottles, optionally containing a device with a function protection from children, or may have a means to control the first opening. The primary packaging material may contain a drying agent such as molecular sieve or silica gel to improve the chemical stability of the API. Opaque packaging such as colored blister materials, tubes, brown glass bottles, or the like can be used to increase the shelf life of the API by reducing photodegradation.

e. Doses.

The dosage range for a compound of formula 3 is usually 100 to 1000 mg, in particular 200 to 900 mg, 300 to 900 mg, or 350 to 850 mg, or 390 to 810 mg. You can enter one or two tablets, while in some cases two tablets are used to receive a daily oral dose of 100, 200, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 mg, and in some cases a dose of 350, 400, 450, 750, 800, 850 is used.

This dosage range may be provided with one tablet or two tablets; in some cases, two tablets are administered, each containing half the dose.

The active ingredient may be administered up to three times per day, for example once or twice per day. The specific dosage is 400 or 800 mg.

f. Used terms and definitions.

Terms not specifically defined in this section should be understood in the sense that is understood by experts in the art in light of this description and context. However, as used in this specification, unless otherwise indicated, the following terms have the meanings indicated and are subject to the following requirements.

The term about means 5% more or less than the specified value. Yes, about 100 min.

- 54 041892 can also be understood as 95 to 105 minutes.

When a compound of this invention is shown in the form of a chemical name and in the form of a formula, if there is a discrepancy, the formula should be followed. An asterisk may be used in subformulas to indicate a bond that is connected to the central structure of the described molecule.

Unless otherwise stated in the text of this specification and the appended claims, a given chemical formula or name includes tautomers and all stereo, optical and geometric isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.) and their racemates, as well as mixtures in various ratios of individual enantiomers, mixtures of diastereomers or mixtures of any of the above forms in which such isomers and enantiomers exist, as well as their salts, including pharmaceutically acceptable salts and solvates, such as, for example, hydrates, including solvates of free compounds or solvates salts of these compounds.

The term "substituted" in this context means that any one or more hydrogen atoms on the designated atom are replaced by a choice from the specified group, provided that the normal valence of the designated atom is not exceeded, and that such replacement results in a stable compound.

The term optionally substituted in the context of this invention means the aforementioned group optionally substituted with a low molecular weight group. Examples of low molecular weight groups considered to be chemically significant are groups consisting of 1-200 atoms. Of interest are those groups that do not adversely affect the pharmacological efficacy of the compounds. For example, these groups may include:

Straight or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted with rings, heteroatoms, or other conventional functional groups.

Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which in turn may be substituted with functional groups.

A plurality of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may be linked by one or more carbon chains, optionally interrupted by heteroatoms, which are optionally substituted by heteroatoms or other conventional functional groups.

The compounds described herein may exist as therapeutically acceptable salts. This invention includes the compounds listed above in the form of salts, including acid addition salts. Suitable salts include salts formed with organic or inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be useful in the preparation and purification of the subject compounds. Base addition salts can also be prepared and may be pharmaceutically acceptable. For a more complete overview of salt preparation and selection, see Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term "therapeutically acceptable salt" as used herein means salts or zwitterionic forms of the compounds described herein that are soluble or dispersible in water or oil and are therapeutically acceptable as described herein. Salts may be obtained during the final isolation and purification of the compounds, or separately by reacting the appropriate compound in free base form with a suitable acid. Exemplary acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylene sulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3 -phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-tosylate) and undecanoate. In addition, the basic groups in the compounds described herein may be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl-, diethyl-, dibutyl- and diamyl sulfates; decyl-, lauryl-, myristyl- and sterile chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to prepare therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric, and organic acids such as oxalic, maleic, succinic and citric. Salts can also be obtained by coordinating compounds with alkali metal or alkaline earth metal ions. Thus, this invention provides sodium, potassium, magnesium and calcium salts of the compounds described herein, and the like.

Base addition salts can be obtained during the final isolation and purification of compounds by reacting the carboxy group with a suitable base such as hydroxide,

- 55 041892 carbonate or bicarbonate of a metal cation, or with ammonia, or with an organic primary, secondary or tertiary amine. Therapeutic salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,P-dibenzylethylenediamine. Other exemplary organic amines useful in the preparation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

While the compounds of this invention may be administered as the original chemical, they may also be presented as a pharmaceutical composition. Accordingly, this document provides pharmaceutical compositions that contain one or more of the specific compounds described herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers, and optionally with one or more other therapeutic ingredients. The carrier(s) must(s) be acceptable(s) in the sense that it(they) must(s) be compatible(s) with the other components of the composition and must not(s) be harmful to the recipient. The correct formulation depends on the route of administration chosen. You can use any of the well-known methods, carriers and excipients suitable and known in this field; for example, those described in Remington's Pharmaceutical Sciences publication. The pharmaceutical compositions described herein may be prepared by any method known in the art, such as by standard mixing, dissolving, granulating, drageeing, triturating, emulsifying, encapsulating, pouring, or compressing.

Heterocyclic rings (het) include five-, six- or seven-membered saturated or unsaturated heterocyclic rings, or 5-10-membered bicyclic hetero rings, which may contain one, two or three heteroatoms selected from oxygen, sulfur and nitrogen; said ring may be linked to the molecule via a carbon atom or, if present, via a nitrogen atom. The following are examples of five-, six- or seven-membered saturated or unsaturated heterocyclic rings

Unless otherwise indicated, the heterocyclic ring may contain a keto group. Examples include

Examples of 5-10 membered bicyclic hetero rings are pyrrolysine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

Although the term heterocyclic rings includes heterocyclic aromatic groups, the term heterocyclic aromatic groups (heteroaryl) means five- or six-membered heterocyclic aromatic groups or 5-10-membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from oxygen. , sulfur and nitrogen, and which contain a sufficient number of conjugated double bonds to form an aromatic system. The ring can be connected to the molecule through a carbon atom or, if present, through a nitrogen atom. The following are examples of five- or six-membered heterocyclic aromatic groups

Examples of 5-10 membered bicyclic heteroaryl rings include pyrrolysine, indole, indolizine, isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole, benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine,

The term halogen in this context means a halogen substituent selected from fluorine, chlorine, bromine or iodine.

Term C ₁ . ₆ -αkyl (including as part of other groups) means branched and unbranched

- 56 041892 nye alkyl groups containing from 1 to 6 carbon atoms, and the term C ₁ . ₄ -alkyl means straight and branched alkyl groups containing from 1 to 4 carbon atoms. In some cases, alkyl groups containing from 1 to 4 carbon atoms are present. Examples thereof include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for the above groups. Unless otherwise indicated, the definitions of propyl, butyl, pentyl and hexyl include all possible isomeric forms of the groups in question. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and t-butyl, and so on.

Term C ₁ . ₆ -alkylene (including as part of other groups) means branched and unbranched alkylene groups containing from 1 to 6 carbon atoms, and the term C ₁ . ₄ -alkylene means branched and straight chain alkylene groups containing from 1 to 4 carbon atoms. In some instances, alkylene groups containing from 1 to 4 carbon atoms are present. Examples include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless otherwise indicated, the definitions of propylene, butylene, pentylene and hexylene also include all possible isomeric forms of the corresponding groups with the same number of carbon atoms. Thus, for example, propyl also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

The term C ₂ - ₆ -alkenyl (including as part of other groups) means branched or unbranched alkenyl groups containing from 2 to 6 carbon atoms, and the term C ₂ - ₄ -alkenyl means branched and straight alkenyl groups containing from 2 to 4 carbon atoms, provided they contain at least one double bond. In some cases, alkenyl groups containing from 2 to 4 carbon atoms are used. Examples include ethenyl or vinyl, propenyl, butenyl, pentenyl or hexenyl. Unless otherwise indicated, the definitions of propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2-, and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, and so on.

The term C ₂ _ ₆ -alkenylene (including as part of other groups) means branched and unbranched alkenylene groups containing from 2 to 6 carbon atoms, and the term C ₂ - ₄ -alkenylene means branched and straight alkenylene groups containing from 2 to 4 carbons. In some instances, alkenylene groups containing 2 to 4 carbon atoms are present. Examples include ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1, 3-dimethylpropenylene or hexenylene. Unless otherwise indicated, the definitions of propenylene, butenylene, pentenylene and hexenylene include all possible isomeric forms of the respective groups with the same number of carbon atoms. Thus, for example, propenyl also includes 1-methylethenylene, and butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.

The term C ₂ _ ₆ alkynyl (including as part of other groups) means branched and straight alkynyl groups containing from 2 to 6 carbon atoms, and the term C ₂ - ₄ alkynyl means branched and straight alkynyl groups containing from 2 to 4 carbon atoms, provided they contain at least one triple bond. In some cases, alkynyl groups containing from 2 to 4 carbon atoms are present. Examples include ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless otherwise indicated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the respective groups. Thus, for example, propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl, 1-methyl2-propynyl, and so on.

Term C ₂ . ₆ -alkynylene (including as part of other groups) means branched and unbranched alkynylene groups containing from 2 to 6 carbon atoms, and the term C ₂ - ₄ -alkynylene means branched and straight-chain alkylene groups containing from 2 to 4 carbon atoms. In some cases, alkynylene groups containing from 2 to 4 carbon atoms are present. Examples include ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1, 3-dimethylpropynylene or hexynylene. Unless otherwise indicated, the definitions of propynylene, butynylene, pentynylene, and hexynylene include all possible isomeric forms of the corresponding groups with the same number of carbon atoms. Thus, for example, propynyl also includes 1-methylethynylene, and butynylene includes 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.

Term C ₃ . ₆ -cycloalkyl (including as part of other groups) in this context means cyclic alkyl groups containing from 3 to 8 carbon atoms, and in some cases such groups are cyclic alkyl groups containing from 5 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term C ₁ _ ₆ -haloalkyl (including as part of other groups) means branched and straight chain alkyl groups containing from 1 to 6 carbon atoms, where one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine such as fluorine and chlorine such as fluorine. The term _C1-4 -haloalkyl means, respectively, branched and straight-chain alkyl groups containing from 1 to 4 carbon atoms, where one or more hydrogen atoms are replaced in the same manner as above. In some cases, C ₁ is present. ₄ -haloalkyl. Examples include CH2F, CHF2, CF ₃ .

Term C ₁ . _n -alkyl, where n is an integer from 2 to n, alone or in combination with another radical, means an acyclic saturated branched or linear hydrocarbon radical containing from 1 to n C atoms. For example, the term _{C1_5} -alkyl includes H radicals. ₃ C-, H ₃ C-CH ₂ -, H ₃ C-CH2-CH2-, H3C-CH (CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-SNCHCH3)-, H3C-CH ( CH3)—CH2—, H3C—C(CH3)2—, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, NzS-CH (CHz) -CH2-CH2-, NzC-CH2-C (CHz) 2-, NzC-C (CHz) 2-CH2-, NzC-CH (CHz) -CH (CHz) - and H ₃ C -CH2-CH(CH2CH ₃ )-.

Term C ₁ . _n -haloalkyl, where n is an integer from 2 to n, alone or in combination with another radical, means an acyclic saturated branched or linear hydrocarbon radical containing from 1 to n C atoms, where one or more hydrogen atoms are replaced by a halogen atom selected from fluorine, chlorine or bromine, such as fluorine or chlorine, such as fluorine. Examples include CH2F, CHF2, CF ₃ .

The term C _1-n -alkylene, where n is an integer from 2 to n, alone or in combination with another radical, means an acyclic linear or branched divalent alkyl radical containing from 1 to n carbon atoms. For example, the term C _1-4 alkylene includes CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH (CH3)-CH2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH3)-, -CH(CH3)-CH2-CH2-, -CH2 -CH(CH3)-CH2-, -CH2-C(CH3)2-, -C(CH3)2-CH2-, -CH(CH3)-CH(CH3)-, -CH2-CH(CH2CH3)-, -CH(CH2CH3)-CH2-, -CH(CH2CH2CH3)-, -CH(CH(CH3))2- and -C(CH3)(CH2CH3)-.

The term C _2-n -alkenyl is used for a group, as defined in the description for C _1-n -alkyl, containing at least two carbon atoms, if at least two of the specified carbon atoms of the specified group are connected to each other by a double bond.

The term C _2-n -alkynyl is used for a group as defined in the description for C _1-n -alkyl containing at least two carbon atoms, if at least two of the specified carbon atoms of the specified group are connected to each other by a triple bond.

The term C _3-n -cycloalkyl, where n is an integer from 4 to n, alone or in combination with another radical, means a cyclic saturated straight hydrocarbon radical containing from 3 to n C atoms. For example, the term C _3-7 - cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

It should be noted that in this specification and in the appended claims, the singular includes reference to the plural, unless the context clearly dictates otherwise. Thus, for example, a reference to a cell includes a plurality of such cells, and a reference to a peptide includes a reference to one or more peptides and their equivalents, such as polypeptides known to those skilled in the art, and so on.

An individual suffering from or at risk of developing age-related cognitive impairment means an individual whose age is more than about 50% of his life expectancy, such as more than 60%, such as more than 75, 80, 85, 90, 95, or even 99% of his life expectancy. life expectancy. The age of the individual depends on the animal species in question. Thus, the percentage given is based on the predicted lifespan of the species in question. For example, among humans, such individuals are individuals whose age is 50 years or more, such as 60 years or more, 70 years or more, 80 years or more, 90 years or more, and usually not older than 100 years, such as 90 years, those. whose age is from about 50 to 100, for example 50... 55... 60... 65... 70... 75... 80... 85... 90... 95... 100 years or more, or any age between 50 and 1000, and who suffer from an age-related pathological condition as described below, for example, cognitive impairment associated with the natural aging process; individuals whose age is about 50 years or more, for example, 60 years or more, 70 years or more, 80 years or more, 90 years or more, and usually not older than 100 years, i. whose age is from about 50 to 100, for example 50... 55... 60... 65... 70... 75... 80... 85... 90... 95... 100 years old who have just begun to show symptoms of an age-related pathological condition, such as cognitive impairment; individuals of any age who suffer from cognitive impairment due to age-related disease, as described below, and individuals of any age who are diagnosed with age-related disease, which is usually accompanied by cognitive impairment, while the individual has not yet begun to show symptoms of cognitive impairment. The appropriate age for non-subjects is known and provided herein.

As indicated elsewhere in this document, in some cases the subject is a mammal. Mammalian species that can be treated with the proposed methods include dogs and cats, horses, cows, sheep, etc., as well as primates, including humans. The subject methods, compositions, and reagents can also be used in animal models, including small mammals, eg, murine, lagomorphs, etc., for example, in experimental studies.

In this context and as described above, treatment refers to any of (i) prevention of a disease or disorder; or (ii) reduce or eliminate the symptoms of the disease or disorder.

Treatment can be carried out prophylactically (before the onset of the disease) or therapeutically (after the onset of the disease). The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of partially or completely curing a disease and/or an adverse effect associated with the disease.

Thus, the term treatment as used herein includes any treatment of an age-related disease or disorder in a mammal and includes (a) preventing the onset of the disease in a subject who may be predisposed to the disease but not yet diagnosed;

(b) slowing down the disease, i.e. stop its development; or (c) alleviating the disease, i.e. initiation of disease regression.

Treatment can lead to many different physical manifestations, such as modulation of gene expression, tissue or organ rejuvenation, and so on. The therapeutic agent can be administered before, during or after the onset of the disease. Of particular interest is the treatment of the current disease, when the treatment stabilizes or reduces unwanted clinical symptoms in the patient. Such treatment can be carried out until complete loss of function in the affected tissues. The therapeutic drug can be administered to a subject at a symptomatic stage of the disease and in some cases after the symptomatic stage of the disease.

In some embodiments, the condition being treated is age-related cognitive decline in an individual. Cognitive ability or cognitive function is understood as mental processes that include attention and concentration, learning complex tasks and concepts, memory (storing, storing and reproducing new information in a short and / or long period of time), information processing (working with information received through five senses), spatial vision function (visual perception, depth perception, use of mental visualization, copying images, building objects or shapes), speech production and speech comprehension, fluency (word selection), problem solving, decision making and executive functions (planning and prioritization). Cognitive decline is understood to mean a progressive decline in one or more of these abilities, such as impairment of memory, speaking skills, thinking, grading, etc. Cognitive impairment and impaired cognitive function refers to a decrease in cognitive ability compared to a healthy individual, for example, a healthy individual of the same age, or compared to the ability of this individual at an earlier point in time, for example, by 2 weeks, 1, 2, 3 , 6 months, 1, 2, 5 or 10 years earlier or more. Age-related cognitive impairment refers to cognitive impairment that is commonly associated with aging, including, for example, cognitive impairment associated with the natural aging process, such as mild cognitive impairment (MCI); and cognitive impairment associated with age-related disorder, ie. with a disorder that occurs more frequently with aging, such as a neurodegenerative disease condition such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear paralysis, ataxia, associated infirmity, etc.

g. Combinations.

The compounds of general formula 1 can be used alone or in combination with other active substances of formula 1 according to this invention. The compounds of general formula 1 can also optionally be combined with other pharmacologically active substances. They include β2-adrenergic agonists (short-term and long-term), anti-cholinergics (short-term and long-term), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated glucocorticosteroid mimetics, PDE3 inhibitors, PDE4 inhibitors, PDE7 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, PAF antagonists, lipoxin A4 derivatives, FPRL1 modulators, LTB4 receptor antagonists (BLT1, BLT2), histamine H1 receptor antagonists, histamine H4 receptor antagonists, histamine H1/H3 receptor dual antagonists, inhibitors PI3 kinases, inhibitors of non-receptor tyrosine kinases such as, for example, LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases, such as p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, inhibitors NF-kB signaling pathways, e.g. IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene biosynthesis inhibitors, e.g. 5-lipoxygenase (5-LO) inhibitors, inhibitors, inhibitors

- 59 041892 cPLA2, leukotriene A4 hydrolase inhibitors or FLAP inhibitors, non-steroidal anti-inflammatory agents (NSAIDs), CRTH2 antagonists, DPI receptor modulators, thromboxane receptor antagonists, additional CCR3 antagonists, CCR4 antagonists, CCR1 antagonists, CCR5 antagonists, CCR6 antagonists, antagonists CCR7, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists, CXCR3 antagonists, CXCR4 antagonists, CXCR2 antagonists, ^CXCR1 antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR3 antagonists, neurokinin (NK1, NK2) antagonists, sphingosine 1-phosphate receptor modulators, inhibitor sphingosine-1-phosphate lyase, adenosine receptor modulators such as, for example, A2a agonists, purinergic receptor modulators, such as, for example, P2X7 inhibitors, histone deacetylase activators (HDAC), bradykinin antagonists (BK1, BK2), TACE inhibitors, PPAR-α modulators gamma, Rho kinase inhibitors, interleukin-1-beta-converting enzyme (ICE) inhibitors, Toll modulators -like receptor (TLR), HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonists, ENaC inhibitors, melanocortin receptor modulators (MC1R, MC2R, MC3R, MC4R, MC5R), antagonists CGRP, endothelin antagonists, TNFa antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, htu-CD46 antibodies, anti-HS antibodies, anti-III-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, airway edema compounds, cough compounds, VEGF inhibitors, and combinations of two or three active substances.

In some embodiments, other active agents are betamimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, CRTH2 inhibitors, 5-LO inhibitors, histamine receptor antagonists, and SYK inhibitors, as well as combinations of two or three active agents, t .e.

betamimetics with corticosteroids, PDE4 inhibitors, CRTH2 inhibitors, or LTD4 antagonists;

phnticholinergics with betamimetics, corticosteroids, PDE4 inhibitors, CRTH2 inhibitors, or LTD4 antagonists;

corticosteroids with PDE4 inhibitors, CRTH2 inhibitors, or LTD4 antagonists;

PDE4 inhibitors with CRTH2 inhibitors or LTD4 antagonists;

CRTH2 inhibitors with LTD4 antagonists.

In these embodiments, the compounds that form the combination are co-administered to the subject. The terms co-administration and in combination include the administration of two or more therapeutic agents simultaneously, in parallel or sequentially, without any particular time limitation. In one embodiment, these agents are present in the cell or body of the subject at the same time, or exhibit their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are presented in a single composition or single unit dosage form. In other embodiments, the therapeutic agents are presented in different compositions or in different unit dosage forms. In some embodiments, the first agent may be administered before (e.g., several minutes, 15, 30, 45 minutes, 1, 2, 4, 6, 12, 24, 48 72, 96 hours, 1, 2, 3, 4, 5 , 6, 8, or 12 weeks before), simultaneously, or after (e.g., 5, 15, 30, 45 min, 1, 2, 4, 6, 12, 24, 48, 72, 96 h, 1, 2, 3 , 4, 5, 6, 8 or 12 weeks after) administration of the second therapeutic agent. Simultaneous administration of a known therapeutic drug with a pharmaceutical composition of the invention means administering the compound and the second agent at such a time that both the known drug and the composition of the invention have a therapeutic effect. Such simultaneous administration may include parallel administration (ie, at the same time), administration of the drug before or after administration of the compound in question. The routes of administration of these two agents may vary, and exemplary routes of administration are described in more detail below. Those skilled in the art can readily determine the appropriate timing, sequence, and doses of administration for particular formulations and compounds of this invention. In some embodiments, the compounds (e.g., the subject compound and at least one additional compound) are administered to the subject within twenty-4 hours of each other, e.g., within 12 hours of each other, within 6 hours of each other, within 3 hours relative to each other or within 1 hour of each other. In some embodiments, the compounds are administered within 1 hour of each other. In some embodiments, the compounds are administered substantially simultaneously. By substantially simultaneous administration is meant that said compounds are administered to a subject within about 10 minutes or less of each other, such as 5 minutes or less or 1 minute or less of each other.

h. pharmaceutical forms.

Suitable preparations for administering compounds of formula 1 and co-crystals or salt forms of formulas 2 and 2a include, for example, tablets, capsules, suppositories, solutions and powders, and the like. The content of pharmaceutically active compound(s) should be from 0.05 to 90 wt.%, for example from 0.1 to 50 wt.% of the composition as a whole. Suitable tablets can be obtained, for example, by mixing the active substance(s) with known excipients, for example with inert

- 60 041892 diluents such as calcium carbonate, calcium phosphate or lactose, with disintegrants such as corn starch or alginic acid, with binders such as starch or gelatin, with lubricants such as magnesium stearate or talc, and/or with release retardants such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also contain multiple layers.

Coated tablets can be obtained, respectively, by coating the core, obtained in the same way as tablets, using substances commonly used to obtain coatings on tablets, for example, collidone or shellac, gum crab, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibility, the core can also be made up of multiple layers. In the same way, the tablet coating can be made up of several layers to achieve sustained release, possibly through the use of the excipients mentioned above for tablets.

Syrups or elixirs containing active substances or combinations thereof according to this invention may additionally contain a sweetening agent such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer such as vanillin or orange extract. They may also contain auxiliaries or suspension thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, fatty alcohol condensates with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions are prepared in the usual manner, for example with the addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, optionally using emulsifiers and/or dispersants, and in the case of using water as a diluent, you can it is not necessary to use, for example, organic solvents as solubilizers or solubility aids, and the solutions can be transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing with carriers suitable for this purpose, such as neutral fats or polyethylene glycol, or derivatives thereof.

Excipients that can be used include, for example, water, water, pharmaceutically acceptable organic solvents such as paraffins (for example, petroleum fractions), vegetable oils (for example, peanut or sesame oil), mono- or polyfunctional alcohols (for example, ethanol or glycerin), carriers such as, for example, natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. finely divided silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose ), emulsifiers (eg, lignin, sulfite-alcohol stillage, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (eg, magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

For oral administration, tablets may obviously contain, in addition to the mentioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additional substances such as starch, for example potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used to prepare tablets. In the case of aqueous suspensions, the active substances can be combined with various flavor enhancers or coloring agents, in addition to the aforementioned auxiliary substances.

For the administration of compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a, preparations or pharmaceutical compositions which are suitable for inhalation can be used. Formulations for inhalation include powders for inhalation, metered dose aerosols containing a propellant, or inhalation solutions without a propellant. Within the scope of this invention, the term propellant-free inhalation solutions also includes concentrates or sterile inhalation solutions ready for use. Dosage forms that can be used according to this invention are described in more detail below in the following part of the description.

The inhalable powders which can be used according to the invention may contain a compound of formula 1 or a co-crystal or salt form of formulas 2 and 2a, either alone or mixed with suitable physiologically acceptable excipients.

If the active substances of the compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used to prepare such inhalation powders according to the invention: monosaccharides (e.g. glucose or arabinose) , disaccharides (eg lactose, sucrose, maltose), oligo- and polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients. In some cases, mono- or disaccharides are used, such as

- 61 041892 lactose or glucose, for example in the form of their hydrates, for example lactose, such as lactose monohydrate.

Within the scope of the inhalable powders of the present invention, said excipients have a maximum average particle size of up to 250 µm, for example from 10 to 150 µm, and including values from 15 to 80 µm. Sometimes it may be appropriate to add to the excipient mentioned above, smaller fractions of the excipient with an average particle size of 1 to 9 microns. Such smaller particle size excipients are also selected from the group of possible excipients listed above. Finally, in order to obtain powders for inhalation according to the invention, micronized active substance of the compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a, for example, with an average particle size of from 0.5 to 10 μm, including values from 1 to 5 µm. Methods for obtaining powders for inhalation according to this invention by grinding and micronization, and the final mixing of the ingredients with each other are known in the prior art.

Powders for inhalation according to this invention can be administered using inhalers known from the prior art.

Aerosols for inhalation containing a propellant according to the present invention may contain a compound of formula 1 or co-crystals or a salt form of formulas 2 and 2a dissolved in the propellant or in particulate form. Compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a may be in separate compositions or in a general composition in which either both are dissolved or both are dispersed, or in each case only one component is dissolved and the other is dispersed. Propellants that can be used to produce aerosols for inhalation are known in the art. Suitable propellant gases are selected from hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above propellants can be used alone or in mixture with each other. In some cases, the propellants are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

Aerosols for inhalation containing a propellant may also contain other ingredients such as cosolvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All of these ingredients are known in the art.

The propellant-containing inhalation aerosols of this invention mentioned above can be administered using inhalers known in the art (MDI = metered dose inhalers).

In addition, active substances that are compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a according to this invention can be administered in the form of inhalation solutions and suspensions that do not contain a propellant. The solvent used may be aqueous or alcoholic, such as an ethanol solution. The solvent may be pure water or a mixture of water and ethanol. The relative content of ethanol compared to water is not limited, but the maximum content is in some cases up to 70% by volume, for example up to 60% by volume, and including values up to 30% by volume. The rest is water. Solutions or suspensions containing a compound of formula 1 or co-crystals or a salt form of formulas 2 and 2a are adjusted to a pH of 2 to 7, for example 2 to 5, with suitable acids. The pH can be adjusted with acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, and the like. In some cases, the inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which have already formed an acid addition salt with one of the active substances. Among organic acids, ascorbic acid, fumaric acid and citric acid are used in some cases. If necessary, mixtures of the above acids can be used, in particular in the case of acids having properties other than acidifying, such as flavoring agents, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid. According to the present invention, in some cases, hydrochloric acid is used to adjust the pH.

If desired, the addition of edetic acid (EDHA) or one of its known salts, sodium edetate, as a stabilizer or complexing agent, may be omitted from these compositions. Other implementation options may contain the specified connection or specified compounds. In one embodiment, the content relative to edetate sodium is less than 100 mg/ml, such as less than 50 mg/100 ml, and including a value of less than 20 mg/100 ml. In some cases, solutions for inhalation are used, in which the content of sodium edetate is from 0 to 10 mg/100 ml. Co-solvents and/or other excipients, such as those containing hydroxyl groups or other polar groups, such as alcohols, in particular isopropyl alcohol, glycols, in in particular propylene glycol, polyethylene glycol, polypropylene glycol, ether glycol, glycerin, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The term excipients and additives in this context means any pharmacologically acceptable substance that is not an active substance, but which can be formulated with the active substance or substances in a physiologically acceptable solvent to improve the qualitative properties of the active substance composition. In some embodiments, such substances do not have a pharmacological effect, or in the context of the intended therapy, do not have a noticeable or at least undesirable pharmacological effect. Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or preservatives that provide or increase the shelf life of the finished product. pharmaceutical compositions, flavors, vitamins and/or other additives known in the art. Supplements also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

In some embodiments, excipients include antioxidants such as ascorbic acid, for example, provided it is not already used to regulate pH, vitamin A, vitamin E, tocopherols, and similar vitamins and provitamins found in the human body.

Preservatives may be used to protect the composition from contamination by pathogens. Suitable preservatives are those known in the art, in particular acetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate at a concentration known in the art. The preservatives mentioned above may be present in concentrations up to 50 mg/100 ml, for example 5 to 20 mg/100 ml.

In some embodiments, the proposed compositions contain, in addition to the solvent water and compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a, only benzalkonium chloride and sodium edetate. In one embodiment, sodium edetate is absent.

The dosage of the compounds of this invention is naturally highly dependent on the route of administration and the recipient to be treated. When administered by inhalation, compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a are highly effective even at doses in the range of a few microns. Compounds of formula 1 or co-crystals or salt forms of formulas 2 and 2a can also be used effectively in the dose range of more than a few microns. For example, the dose is a few grams.

In another aspect, the invention relates to the aforementioned pharmaceutical compositions as such, which are characterized in that they contain a compound of formula 1 or co-crystals or a salt form of formulas 2 and 2a, in particular to the aforementioned pharmaceutical compositions that can be administered by inhalation.

The following composition examples illustrate the invention without limiting its scope.

i. Examples of pharmaceutical compositions.

A) Tablets per tablet

active substance 1,2 or 2a 100 mg lactose 140 mg maize starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg

500 mg

The finely divided active substance, lactose and part of the maize starch are mixed together. The mixture is sieved, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The obtained granules, the remaining maize starch and magnesium stearate are sieved and mixed with each other. The mixture is compressed into tablets of the desired shape and size.

- 63 041892

C) Tablets per tablet

active substance 1,2 or 2a 80 mg lactose 55 mg maize starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl starch 23 mg magnesium stearate 2 mg

400 mg

The finely divided active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed with each other, the mixture is sieved and treated with the remaining corn starch and water to obtain a granulate, which is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed, and the mixture is pressed with obtaining tablets of the required size.

C) Solution for ampoules ____________________________ active substance 1,2 or 2a 50 mg sodium chloride 50 mg water for injection 5 ml

The active substance is dissolved in water at its own pH, or optionally at a pH of 5.5 to 6.5, and sodium chloride is added to form an isotonic solution. The resulting solution is filtered to remove pyrogens and, under aseptic conditions, the filtrate is transferred into ampoules, which are then sterilized and sealed. Ampoules contain 5, 25 and 50 mg of the active substance.

D) Metered aerosol _________________ active substance 1,2 or 2a 0.005 sorbitan trioleate 0.1 monofluorotrichloromethane and

TG134a : TG227 2:1 up to 100

The suspension is transferred into a conventional aerosol can with a metering valve. Preferably, each press releases 50 µl of the suspension. If necessary, the active substance can also be released in higher doses (for example, 0.02 wt.%).

E) Solutions (in mg / 100 ml) ___________________

active substance 1,2 or 2a 333.3 mg benzalkonium chloride 10.0 mg EDTK 50.0 mg HC1 (1 n.) up to pH 2.4

Such a solution can be obtained in the usual way.

F) Powder for inhalation ________________ active substance 1,2 or 2a 12 µg lactose monohydrate up to 25 mg

Powder for inhalation is obtained in the usual way by mixing the individual ingredients.

- 64 041892

j. Indications.

Methods are provided for improving cognitive function or other symptoms of a cognitive disease by treating a subject/patient diagnosed with a disease associated with impaired cognitive function. Aspects of these methods include modulating CCR3, eg, with a CCR3 modulating agent, in a manner sufficient to treat a patient's cognitive impairment disorder. These methods include the treatment of a disease associated with impaired cognitive function with an orally administered and bioavailable composition, including a composition of a compound of formula 1, a co-crystal or salt of formulas 2 or 2a, or a composition of formula 3 described above. As set forth above and described in more detail below, various disorders associated with aging, such as diseases associated with impaired cognitive function, can be treated by embodiments of the present invention. In some cases, the condition being treated is a disease associated with impaired cognitive function that is associated with neurodegeneration, for example, as evidenced by a neuronal disorder, such as one or more of the following conditions: reduced neurogeneration, for example, as manifested in a decrease in the number of BrdU or EdU-positive cells, Ki67-positive cells and Dcx-positive cells compared to unaffected tissue. A composition that modulates CCR3 can be administered to a patient/subject diagnosed with a disease associated with cognitive impairment, such as (by way of example, and not limitation) mild cognitive impairment (MCI); Alzheimer's disease; Parkinson's disease; frontotemporal dementia (FTD); Huntington's disease; amyotrophic lateral sclerosis (ALS); multiple sclerosis (PC); glaucoma; myotonic dystrophy; dementia; progressive supranuclear palsy (PNP); ataxia; multisystem atrophy; and weakness; which are further described below. The methods of the present invention may further include monitoring a reduction in the rate of progression of a neurodegenerative disease by measuring cognitive or physical improvement.

Methods are provided to improve motor coordination, function, or other symptoms of movement disorders by treating a subject/patient diagnosed with a movement disorder. Aspects of these methods include modulating CCR3, for example with a CCR3 modulating agent, in a manner sufficient to treat a patient's movement disorder. These methods include the treatment of a movement disorder with an orally administered and bioavailable composition, including a composition of a compound of Formula 1, a co-crystal or salt of Formula 2 or 2a, or a composition of Formula 3 as described above. As set forth above and described in more detail below, various disorders associated with aging, such as movement disorders, can be treated by embodiments of the present invention. In some cases, the pathological condition being treated is a motor disorder that is associated with neurodegeneration, for example, as evidenced by a neuronal disorder, such as one or more of the following conditions: reduced neurogeneration, for example, as manifested by a decrease in BrdU or EdU- positive cells, Ki67 positive cells and Dcx positive cells compared to unlesioned tissue. A composition that modulates CCR3 can be administered to a patient/subject diagnosed with a movement disorder such as (by way of example and not limitation): Parkinson's disease; parkinsonism; dementia with Lewy bodies; ataxia; dystonia; cervical dystonia; chorea; Huntington's disease, multiple system atrophy; spasticity; progressive supranuclear palsy; tardive dyskinesia; Tourette's syndrome; as well as tremor; which are further described below. The methods of the present invention may further include monitoring a reduction in the rate of progression of a neurodegenerative disease by measuring cognitive or physical improvement.

Mild Cognitive Impairment (MCI) is a mild impairment of cognitive function that manifests as problems with memory or other mental functions such as planning, following instructions, or decision-making that have deteriorated over time, while general mental function and activities of daily living are not violated. Thus, while significant neuronal death usually does not occur, neurons in the aging brain are vulnerable to age-related sublethal changes in structure, synaptic integrity, and molecular processing at the synapse that impair cognitive function. Individuals suffering from or at risk of developing aging-associated cognitive impairment who would benefit from treatment with the compounds of this invention, for example, via the methods described herein, also include individuals of any age who suffer from cognitive impairment due to the disorder. associated with aging and includes individuals of any age who are diagnosed with an aging-associated disorder that is usually accompanied by cognitive impairment, when the person has not yet shown symptoms of cognitive impairment. Examples of such aging-associated disorders include, but are not limited to, the pathological conditions listed below.

Alzheimer's disease. Alzheimer's disease is characterized by progressive, irreversible loss of cognitive function associated with an excessive amount of senile plaques in the cerebral cortex and subcortical gray matter, in addition to excess β-amyloid and neurofibrillary tangles composed of tau protein. The typical form of this disease affects older people, and its frequency increases with age. This disease accounts for more than 65% of dementia cases in the elderly.

The cause of Alzheimer's disease is not known. The disease runs in families in about 15-20% of cases. The rest, the so-called sporadic cases, are characterized by some genetic associations. The disease has an autosomal dominant genetic profile in most cases of early onset and in some cases of late onset, but with variable presentation in older age. Environmental factors are of active interest to researchers.

During the course of the disease, synapses and eventually neurons die in the cerebral cortex, hippocampus and subcortical structures (including selective cell loss in the basal nucleus of Meynert), the locus coeraleus, and the dorsal raphe nucleus (nucleus raphae dorsalis). Reduced cerebral glucose uptake and perfusion in some areas of the brain (the parietal and temporal cortex in the early stages of the disease, the prefrontal cortex in the late stages of the disease). In the pathogenesis of Alzheimer's disease, neuritic or senile plaques (consisting of neurites, astrocytes and glial cells around the amyloid nucleus) and neurofibrillary tangles (consisting of paired spiral filaments) play a role. Senile plaques and neurofibrillary tangles are found in normal aging, but they are much more common in people with Alzheimer's disease.

Parkinson's disease.

Parkinson's disease (PD) is an idiopathic, slowly progressive degenerative disease of the CNS characterized by slow and reduced range of motion (bradykinesia), muscle rigidity, tremor at rest (dystonia), muscle stiffness, and postural instability. Initially thought to be primarily a movement disorder, PD has recently been shown to cause depression and emotional changes. PD can also affect cognition, behavior, sleep, autonomic function, and sensory function. The most common cognitive impairments include impaired attention and concentration, working memory, executive function, language skills, and visuospatial function. A characteristic feature of PD are symptoms associated with reduced motor function, which usually precede those associated with cognitive impairment, which helps in the diagnosis of the disease.

In primary Parkinson's disease, pigmented neurons in the substantia nigra, locus coeruleus, and other groups of dopaminergic cells in the brainstem degenerate. The reason for this condition is not known. Loss of the substantia nigra neurons that protrude into the caudate nucleus and putamen leads to depletion of the dopamine neurotransmitter in these areas. The onset of the disease usually occurs after 40 years of age with an increase in the incidence in older age groups.

Parkinson's disease is diagnosed in about 60,000 Americans each year and currently affects about a million Americans. Although PD is not fatal in itself, its complications are the fourteenth leading cause of death in the United States. There is currently no cure for PD, and treatment is usually given to control symptoms, with surgery being indicated in more advanced, severe cases.

Treatment options for PD include the administration of pharmaceuticals to help manage motor deficits. These variants increase or replace the neurotransmitter dopamine, which has low brain concentrations in PD patients. These drugs include carbidopa/levodopa (which generate more dopamine in the brain); apomorphine, pramipexolol, ropinirole and rotingotine (dopamine agonists); selegiline and rasagiline (MAO-B inhibitors that prevent the breakdown of dopamine); entacapone and tolcapone (catechol-O-methyltransferase [COMT] inhibitors that make more levodopa available in the brain); benztropine and trihexyphenidyl (anticholinergics); and amantadine (controls tremor and rigidity). Exercise/physical therapy is also commonly prescribed to support physical and mental function.

However, existing treatment options are only aimed at managing the symptoms of PD; they do not lead to recovery and cannot prevent the progression of the disease. In addition, modern drugs tend to decrease in efficacy in the late stages of PD. The most commonly prescribed drug, levodopa, usually results in adverse effects within 5 to 10 years of starting the drug. These undesirable effects can be severe and can lead to motor fluctuations and unpredictable swaying between doses, as well as twitching/convulsive contractions (dyskinesia) that are difficult to control and are even as disabling as the intrinsic symptoms of PD. Thus, there remains a need for new therapies with new mechanisms of action that can be administered simultaneously or in combination with current drugs for the treatment of PD.

Parkinsonism.

Secondary parkinsonism (also called atypical Parkinson's disease or Parkinson's disease)

- 66 041892 plus) is the result of loss or interference with the action of dopamine in the basal ganglia caused by other idiopathic degenerative diseases, drugs or exogenous toxins. The most common cause of secondary parkinsonism is the use of antipsychotic drugs or reserpine, which cause parkinsonism by blocking dopamine receptors. Less common causes include carbon monoxide or manganese poisoning, hydrocephalus, structural lesions (tumors, infarcts affecting the midbrain or basal ganglia), subdural hematoma, and degenerative disorders including nigrostriatal degeneration. Some disorders, such as progressive supranuclear palsy (PNP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and Lewy body dementia (LBD), may present with symptoms of parkinsonism before the onset of typical symptoms necessary for a specific diagnosis, and, hence, may be labeled as Parkinsonism.

Assessment of PD progression.

Several rating scales are used to assess the progression of PD. The most widely used scores include the Unified Parkinson's Disease Rating Scale (UPDRS, which was introduced in 1987) (J. Rehabil Res. Dev., 2012, 49(8):1269-76) and the Hohn and Yar Rating Scale (Neraology, 1967, 17(5):427-42). Additional scales include the International Movement Disorder Society (MDS) Updated UPDRS (MDS-UPDRS) and the Schwab and England Activity of Daily Activity Scale (ADL).

The UPDRS scale assesses a total of 31 parameters, which are divided into three subscales:

(1) thinking, behavior and mood;

(2) daily activities; and (3) motor activity assessment.

The Hen and Yahr scale classifies PD into five stages with discrete substages:

- no signs of disease;

- symptoms on one side only;

1.5 - symptoms on one side, but also involving the neck and spine;

- symptoms on both sides without imbalance;

2.5 - mild symptoms on both sides with recovery during the resistance test;

- imbalance with mild or moderate severity of the disease;

- severe disability, but the ability to walk or stand without assistance;

- need a wheelchair or are bedridden without assistance.

Schwab and England's daily activity scale classifies BP by percentage (from 100% complete independence to 10% - complete dependence).

Frontotemporal dementia.

Frontotemporal dementia (FTD) is a pathological condition resulting from progressive depletion of the frontal lobe of the brain. Over time, degeneration can progress to the temporal lobe. Second in prevalence after Alzheimer's disease (AD), FTD accounts for 20% of cases of presenile dementia. Symptoms are divided into three groups depending on the functions of the affected frontal and temporal lobes:

a behavioral variant of FTD (poFTD), with symptoms including lethargy and aspontaneity on the one hand, and disinhibition on the other;

progressive non-fluent aphasia (PNFA), in which fluency is impaired due to difficulty in articulation, phonological and / or syntactical errors, but understanding of the word is preserved; and semantic dementia (SD), in which patients are fluent in phonology and syntax but have increasing difficulty with names and understanding words.

Other cognitive symptoms common to all patients with FTD include impaired executive function and the ability to concentrate. Other cognitive abilities, including perception, spatial skills, memory, and praxis, tend to remain unchanged. FTD can be diagnosed by observing frontal and/or anterior temporal lobe atrophy on a structural MRI scan.

There are a number of forms of FTD, any of which can be treated or prevented using the methods and compositions of this invention. For example, one form of frontotemporal dementia is semantic dementia (SD). SD is characterized by loss of semantic memory in both verbal and non-verbal areas. Patients with DM often complain of difficulty finding words. Clinical features include fluent aphasia, anomie, impaired comprehension of word meaning, and associative visual agnosia (inability to pick up semantically related images or objects). As the disease progresses, behavioral and personality changes are often similar to those seen in frontotemporal dementia, although cases of pure semantic dementia with few late behavioral symptoms have been described. Structural MRI shows a characteristic pattern of temporal lobe atrophy (predominantly on the left), with more inferior than superior lesions, and more anterior than posterior temporal lobe atrophy.

- 67 041892

As another example, another form of frontotemporal dementia is Pick's disease (PiB, also PcD). The defining characteristic of the disease is the accumulation of tau proteins in neurons, which accumulate in silver-stained spherical aggregations known as Pick bodies. Symptoms include loss of speech (aphasia) and dementia. Patients with orbitofrontal dysfunction may become aggressive and exhibit inappropriate social behavior.

They may steal or exhibit compulsive or repetitive stereotypical behaviors. Patients with dorsomedial or dorsolateral frontal dysfunction may show restlessness, apathy, or decreased spontaneity. Patients may demonstrate a lack of self-control, impaired self-awareness, and an inability to appreciate meaning.

Patients with reduced gray matter in the bilateral posterolateral orbitofrontal cortex and right anterior insula may show changes in eating habits, such as pathological sweet cravings. Patients with more focal gray matter loss in the anterolateral orbitofrontal cortex may develop hyperphagia. Although some of the symptoms may initially be alleviated, the disease progresses and patients often die within 2 to 10 years.

Huntington's disease.

Huntington's disease (HD) is a hereditary progressive neurodegenerative disorder characterized by the development of emotional, behavioral and mental disorders;

loss of intellectual or cognitive functioning; and impaired motor activity (motor disorders).

The classic signs of HD include the development of chorea—involuntary, rapid, irregular, jerky movements that may affect the face, arms, legs, or trunk—and cognitive decline, including the gradual loss of thought processing and acquired intellectual abilities. There may be impairments to memory, abstract thinking, and judgment;

misperception of time, place, or identity (disorientation);

increased arousal; and personality changes (personality disintegration).

Although symptoms usually appear during the fourth or fifth decade of life, the age at which the disease debuts is variable and ranges from early childhood to old age (eg, the seventh or eighth decade).

HD runs in families as an autosomal dominant trait. This disorder results from abnormally long sequences or repetitions of coded instructions in a gene on chromosome 4 (4p16.3). The progressive loss of nervous system function seen in HD is the result of loss of neurons in certain areas of the brain, including the basal ganglia and cerebral cortex.

Lateral amyotrophic sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, inevitably fatal neurological disease that affects motor neurons. Muscle weakness and atrophy, as well as signs of dysfunction of the anterior horn cells, are initially noted most often in the hands and less often in the feet. The site of onset is random and progression is asymmetric. Spasms are common and may precede weakness. Rarely a patient survives beyond 30 years, 50% die within 3 years of onset, 20% live 5 years and 10% live 10 years.

Diagnostic features include onset in mid or late adulthood and progressive, generalized motor impairment without sensory abnormalities. Nerve conduction velocity is not disturbed until late in the disease. Recent studies have also documented the manifestation of cognitive impairment, in particular, a decrease in direct verbal memory, visual memory, language skills and executive function.

Decreases in cell area, number of synapses, and total synapse length have been documented even in visually normal neurons from ALS patients. It is hypothesized that when core plasticity reaches its limit, continued loss of synapses can lead to functional impairment. Promoting the formation of either new synapses or preventing synapse loss may maintain neuronal function in these patients.

Multiple sclerosis.

Multiple sclerosis (MS) is characterized by various symptoms and signs of CNS dysfunction, with remissions and recurrent exacerbations. The most common symptoms are paresthesias in one or more limbs, in the trunk, or on one side of the face;

weakness or awkwardness in leg or arm movements; or visual disturbances, such as partial blindness and pain in one eye (retrobulbar neuritis

- 68 041892 optic nerve), blurred vision or scotoma.

Common cognitive impairments include impairments to memory (receiving, retaining, and retrieving new information), attention and concentration (especially distracted attention), information processing, executive function, visuospatial function, and verbal fluency. Common early symptoms are paralysis of the muscles of the eye leading to double vision (diplopia), short-term weakness of one or more limbs, slight stiffness or unusual fatigue of a limb, slight gait disturbances, difficulty controlling bladder emptying, dizziness, and mild emotional disturbances; all of the above indicate diffuse CNS involvement and often occur months or years before the disease is recognized. Excess heat can exacerbate the symptoms and signs of the disease.

The course of the disease is highly variable, unpredictable, and relapsing in most patients. Initially, months or years of remission may separate episodes of exacerbation, especially when the disease begins with retrobulbar optic neuritis. However, some patients have frequent seizures and quickly become disabled; in some patients, the course of the disease may be rapidly progressive.

Glaucoma.

Glaucoma is a common neurodegenerative disease that affects retinal ganglion cells (RGCs). Modern data confirm the existence of dissociated degeneration processes in synapses and dendrites, including in the GCS. Recent data also indicate a correlation between cognitive impairment in the elderly and glaucoma (Yochim B.P. et al., Prevalence of cognitive impairment, depression, and anxiety symptoms among older adults with glaucoma, J. Glaucoma, 2012, 21(4):250- 254).

Myotonic dystrophy.

Myotonic dystrophy (MD) is an autosomal dominant multisystem disorder characterized by dystrophic muscle weakness and myotonia. The molecular defect is an extended trinucleotide (CTG) repeat in the 3' untranslated region of the myotonin protein kinase gene on chromosome 19q. Symptoms can occur at any age and the range of clinical severity is wide. Myotonia is prominent in the muscles of the hand, and ptosis is a common feature even in mild cases. In severe cases, severe peripheral muscle weakness is noted, often with cataracts, premature baldness, a characteristic facial expression (hatchet), cardiac arrhythmia, testicular atrophy, and endocrine disorders (eg, diabetes mellitus). Mental retardation is common in severe congenital forms, while aging-related decline in frontal and temporal lobe cognition, especially language and executive functions, is seen in mild forms of impairment in adults. Persons with a severe form of the disease die at the age of a little over 50 years.

Dementia. The term dementia describes a class of disorders characterized by symptoms of impaired thinking and social ability to a degree that is severe enough to interfere with daily functioning. Other cases of dementia, in addition to the dementia seen in the later stages of the aging-associated disorders discussed above, include vascular dementia and Lewy body dementia, described below.

In vascular dementia, or multi-infarct dementia, cognitive impairment is caused by an interruption in the blood supply to the brain, usually a series of small strokes, or sometimes one large stroke preceded or followed by other smaller strokes. Vascular lesions may be the result of diffuse cerebrovascular disease, such as small vessel disease, or focal lesions, or both. Patients suffering from vascular dementia have acute or subacute cognitive impairment following an acute cerebrovascular condition followed by progressive cognitive decline. Cognitive impairments are similar to those seen in Alzheimer's disease, including impairments to language skills, memory, complex visual processing, or executive function, although the associated brain changes are not due to AD pathology, but to chronically reduced blood flow to the brain, which eventually leads to dementia. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) neuroimaging can be used to confirm a diagnosis of multi-infarct dementia in combination with assessments that include mental status testing.

Dementia with Lewy bodies.

Lewy body dementia (LBD), also known by a variety of other names, including Lewy body dementia, diffuse Lewy body disease, crusted Lewy body disease, and senile dementia of the Lewy type, is a type of dementia that is anatomically characterized by the presence of Lewy bodies (clumps of alpha -synuclein and ubiquitin protein) in neurons detected during post-mortem histological examination of the brain. The main feature of this disease is a decrease in cognitive abilities, especially executive functioning. Vigilance and short-term memory will rise and fall.

- 69 041892

Persistent or recurring visual hallucinations with vivid and detailed images are often an early diagnostic symptom. DTL is often confused in its early stages with Alzheimer's disease and/or vascular dementia, however, the distinguishing feature is that Alzheimer's disease usually has a rather gradual onset, while DTL often has a rapid or acute onset. The symptoms of LBD also include movement symptoms similar to those of Parkinson's disease. DTL differs from dementia, which sometimes occurs with Parkinson's disease, in terms of the time period during which symptoms of dementia occur relative to symptoms of Parkinson's disease. The diagnosis of Parkinson's disease with dementia (BPD) can be established if dementia begins more than a year after the onset of Parkinson's disease. The diagnosis of LBD is made when cognitive symptoms begin at the same time as, or within a year of, symptoms of Parkinson's disease.

Treatment of LTD is a complex process and requires a multifaceted approach. (Neurology, 2017, 89:1-13). Common treatments for parkinsonism, such as dopaminergic and anticholinergic drugs, can exacerbate cognitive and behavioral symptoms. Optimal treatment usually includes both pharmacological (exercise, cognitive skills training, and care-oriented education) and non-pharmacological approaches. If symptoms of cognitive impairment are present, acetylcholinesterase inhibitors (eg, rivastigmine, donepezil), as well as the NMDA receptor antagonist memantine, may be administered. In neuropsychiatric symptoms, acetylcholinesterase inhibitors may improve apathy and hallucinations. Unfortunately, antipsychotic drugs increase the risk of mortality in patients with LBD. Mobility symptoms are less responsive to dopaminergic treatment in patients with LTD and may increase the risk of developing psychosis. Levodopa can be used, but only at low threshold doses, hence there is a clear need to develop new agents for the treatment of LBD.

Progressive supranuclear palsy.

Progressive supranuclear palsy (PNP) is a brain disease that causes severe and progressive problems with gait and balance control, as well as complex eye movements and thinking problems. One of the classic signs of the disease is the inability to properly aim when looking, which occurs due to lesions in the area of the brain that coordinates eye movements. Some people describe this effect as blurry vision. Patients often exhibit mood and behavioral changes, including depression and apathy, as well as progressive mild dementia. The long name of the disorder indicates that the disorder begins slowly and continues to get worse (progressive) and causes weakness (paralysis) by damaging certain parts of the brain above the pea-like structures called nuclei that control eye movements (supranuclear). PNP was first described as a separate disorder in 1964 when three scientists published a paper distinguishing the disease from Parkinson's disease. This pathological condition is sometimes referred to as Steele-Richardson-Olynevsky syndrome, reflecting the combined names of the scientists who described the disorder. Although PNP progresses rapidly, patients do not die from PNP itself.

Ataxia.

Patients with ataxia have impaired coordination because certain areas of the nervous system that control movement and balance are affected. Ataxia can affect the fingers, hands, forearms, legs, body, speech, and eye movements. The word ataxia is often used to describe a symptom of incoordination that may be associated with infections, trauma, other diseases, or degenerative changes in the central nervous system. The term ataxia is also used to refer to a group of specific degenerative diseases of the nervous system called hereditary and sporadic ataxias, which are the main pathologies of interest to the National Ataxia Foundation.

Multisystem atrophy.

Multisystem atrophy (MSA) is a degenerative neurological disorder. MCA is associated with degeneration of nerve cells in certain areas of the brain. This cell degeneration causes problems with movement, balance, and other autonomic functions of the body, such as controlling bladder emptying or regulating blood pressure.

The causes of MSA are unknown and no specific risk factors could be identified. About 55% of cases occur in men, with a typical age of onset of the disease a few years before 50 or slightly over 60 years of age. MSA is often characterized by the same symptoms as Parkinson's disease. However, patients with MSA tend to show minimal response to dopamine drugs used to treat Parkinson's disease.

Dystonia.

Dystonia is a pathological condition that involves prolonged involuntary muscle contractions. Such contractions may present with twisting, repetitive movements. This disorder can affect the whole body or specific parts of the body and is called generalized dystonia or focal dystonia (respectively). Neck dystonia can cause prolonged or intermittent contractions of the neck muscles. There are no medicines for dystonia. Current treatments include carbidopa-levodopa, trihexyphenidyl, benztropine, tetrabenazine, diazepam, clonazepam, baclofen, physical therapy, speech therapy, stretching, massage, and invasive surgery.

Senile asthenia.

The frailty syndrome (senile asthenia) is a geriatric syndrome characterized by functional and physical impairment, including decreased mobility, muscle weakness, sluggishness, poor stamina, low physical activity, malnutrition, and involuntary weight loss. This weakening is often accompanied by and is a consequence of diseases such as cognitive dysfunction and cancer. However, senile asthenia can occur even without other diseases. People suffering from frailty have an increased risk of poor prognosis for fractures, accidental falls, comorbidities with disability, and premature death. (C. Buigues et al., Effect of a Prebiotic Formulation on Frailty Syndrome: A Randomized, Double-Blind Clinical Trial, Int. J. Mol. Sci., 2016, 17, 932). In addition, individuals suffering from frailty have a higher level of spending on maintaining their health (ibid.).

General signs of frailty can be determined using certain types of tests. For example, unintentional weight loss includes losing at least 10 pounds or more than 5% of body weight in the previous year;

muscle weakness can be identified by decreased grip strength in the lowest 20% at baseline (adjusted for gender and BMI);

physical slowness can be measured by the time it takes to walk 15 feet;

poor endurance can be determined by the individual's self-reported exhaustion; and low physical activity can be measured using a standardized questionnaire.

(Z. Palace et al., The Frailty Syndrome, Today's Geriatric Medicine 7(1), at 18 (2014).)

In some embodiments of this invention, the methods and compositions of this invention find use in slowing the progression of a cognitive, motor, or other age-related impairment associated with aging. In other words, the individual's cognitive, motor, and other abilities decline more slowly after treatment with the described methods, compared to before or without treatment with the described methods. In some such cases, contemplated treatments include measuring the progression of decline in cognitive, motor, or other age-related abilities following treatment and determining that the progression of decline in said abilities is slowing down. In some such cases, the determination is made by comparison with a benchmark, such as the rate of decline in an individual's ability prior to treatment, for example, as determined by measuring cognitive, motor or other age-related abilities at two or more time points prior to administration of the drug in question.

The methods and compositions of this invention also find use in stabilizing the cognitive, motor or other abilities of an individual, for example an individual suffering from aging-associated cognitive decline or an individual who is at risk of developing aging-associated cognitive decline. For example, an individual may exhibit some aging-associated cognitive impairment, wherein the progression of cognitive impairment observed prior to treatment with the described methods will be halted after treatment with the described methods. As another example, an individual may be at risk of developing aging-associated cognitive decline (e.g., the individual may be 50 years of age or older or may be diagnosed with an aging-associated disorder) and the individual's cognitive abilities do not substantially change, t .e. cognitive decline could not be detected after treatment with the described methods compared to prior treatment with the described methods.

The methods and compositions of this invention also find use in the reduction of cognitive, motor or other age-related impairment in an individual suffering from an age-associated disorder. In other words, in an individual, after treatment with the described methods, the reduced capacity is increased. For example, the cognitive ability of an individual is increased, for example, 2 times or more, 5 times or more, 10 times or more, 15 times or more, 20 times or more, 30 times or more, or 40 times or more times, including 50-fold or more, 60-fold or more, 70-fold or more, 80-fold or more, 90-fold or more or 100-fold or more increase, after treatment with the described methods regarding cognitive abilities, which are observed in the individual prior to treatment using the described methods.

In some instances, treatment with the disclosed methods and compositions restores cognitive, motor, or other abilities in an individual suffering from an aging-associated decline in cognitive or motor function, for example, to levels seen during

- 71 041892 the time when the individual was about 40 years old or less. In other words, cognitive or motor impairments are suppressed.

k. Methods for diagnosing and monitoring improvement in a neurodegenerative-associated disease.

One of skill in the art would understand that among the many methods for diagnosing and monitoring disease progression and improvement in a neurodegenerative disease in subjects suffering from a neurodegenerative disease, the following types of assessments can be used alone or in combination. The following types of methods are provided as examples and are not limited to the methods listed. One skilled in the art will appreciate that other methods of disease monitoring may be useful in the practice of this invention. These methods are also provided by the methods of the present invention.

i. General cognitive function.

The methods of the invention further include methods for monitoring the effect of a drug or treatment on a subject in the treatment of cognitive impairment and/or age-related dementia, said method comprising comparing cognitive function before and after treatment. Those skilled in the art will recognize that there are well known methods for assessing cognitive function. For example, and not by way of limitation, this method may include assessment of cognitive function based on medical history, family history, physical and neurological examinations by clinicians who specialize in dementia and cognitive function, laboratory tests, and neuropsychological evaluation. Additional embodiments contemplated by the present invention include assessment of consciousness, such as the use of the Glasgow Coma Scale (EMV);

mental status assessment, including the Abbreviated Mental Status Scale (AMTS) or the Mini Mental Status Assessment Scale (MMSE) (Folstein et al., J. Psychiatr. Res., 1975, 12:1289-198);

cumulative evaluation of higher functions;

measurement of intracranial pressure, for example, using an examination of the fundus.

In one embodiment of the present invention, the results of a peripheral nervous system examination can be used to assess cognitive function, including any of the following: smell, visual fields and visual acuity, eye and pupil movements (sympathetic and parasympathetic nervous system), sensory function of the face, strength muscles of the face and shoulder girdle, hearing, taste, movement and reflexes of the pharynx, movement of the tongue, which can be checked individually (for example, visual acuity can be checked using the Snellen chart; a neurological hammer is used to evaluate reflexes, including the mandibular reflex, reflex from the biceps tendon muscles and triceps, knee tendon reflex, achilles reflex, and plantar reflex (i.e. Babinski's symptom) muscle strength - often on an MRC scale of 1 to 5 muscle tone and signs of rigidity.

ii. Multiple sclerosis.

In addition to monitoring the improvement in symptoms associated with cognitive function, progression or improvement in multiple sclerosis (MS) associated neurodegeneration can be monitored using techniques well known to those skilled in the art. By way of example, and not limitation, monitoring can be done using techniques such as cerebrospinal fluid (CSF) monitoring; magnetic resonance imaging (MRI) to detect lesions and the formation of demyelinating plaques; evoked potential studies; and gait monitoring.

Analysis of the CSF can be performed, for example, by lumbar puncture to obtain data on the pressure, appearance and composition of the CSF. Normal values usually vary within the following ranges: pressure (70-180 mm H ₂ O); appearance transparent and colorless; total protein (15-60 mg/100 ml); the level of IgG is 3-12% of the total protein; glucose level is 50-80 mg/100 ml; the number of cells is 0-5 leukocytes in the absence of erythrocytes; chloride (110-125 mg-equiv/l). Altered results may indicate the presence or progression of PC.

MRI is another technique that can be performed to monitor the progression or improvement of a disease. Typical criteria for monitoring PC by MRI include the appearance of patchy areas of abnormal white matter in the cerebral hemisphere and paraventricular areas, lesions present in the cerebellum and/or brainstem, and in the cervical or thoracic regions of the spinal cord.

Evoked potentials can be used to monitor progression and improvement in MS in subjects. Evoked potentials measure the deceleration of electrical impulses such as visual evoked response (VER), brainstem auditory evoked response (BAER), and somatosensory evoked response (SSER). Abnormal responses may indicate that the conduction velocity in the central sensory pathways is reduced.

- 72 041892

Gait monitoring can also be used to assess the progression and improvement of patients with MS. PC is often accompanied by decreased mobility and an altered gait due in part to fatigue. Monitoring can be performed, for example, using mobile monitoring devices worn on subjects (Moon, Y. et al., Monitoring gait in multiple sclerosis with novel wearable motion sensors, PLOS One, 12(2):e0171346 (2017)) .

iii. Huntington's disease.

In addition to monitoring the improvement in the intensity of symptoms associated with cognitive function, the progression or improvement of neurodegeneration associated with Huntington's disease (HD) can be monitored using techniques well known to those skilled in the art. By way of example, and not limitation, monitoring can be done using techniques such as motor function assessment, behavioral assessment, functional assessment, and imaging.

Examples of motor function that can be monitored as a sign of disease progression or improvement include chorea and dystonia, rigidity, bradykinesia, oculomotor dysfunction, and gait/balance changes. Techniques for monitoring these signs are well known to those skilled in the art (see Tang C. et al., Monitoring Huntington's disease progression through preclinical and early stages, Neurodegener Dis. Manag., 2(4):421-35 (2012)) .

The presence of psychiatric symptoms of HD provides an opportunity to monitor the progression and improvement of the disease. For example, a psychiatric diagnosis can be performed to determine if the subject is suffering from depression, irritability, agitation, anxiety, apathy, and psychosis with paranoia (ibid.).

Functional assessment can also be used to monitor progression or improvement in a condition. Methods of assessment using a general functional scale have been reported (ibid.), and in some groups of patients with HD, the score often decreases by one point per year.

MRI or PET may also be used to monitor progression or improvement in disease. For example, in HD there is a loss of striatal projection neurons, and in subjects it is possible to control the change in the number of such neurons. Techniques for detecting neuronal changes in subjects with HD include visualization of dopamine D ₂ receptor binding (ibid.).

iv. BASS.

In addition to monitoring the improvement in symptoms associated with cognitive function, the progression or improvement of neurodegeneration associated with amyotrophic lateral sclerosis (ALS) can be monitored using techniques well known to those skilled in the art. By way of example, and not limitation, monitoring can be done using techniques such as functional assessment; determination of muscle strength; measurement of respiratory function; measurement of loss of lower motor neurons (LMN); and measurement of upper motor neuron (UMN) dysfunction.

Functional assessment can be performed using a functional scale well known to those skilled in the art, such as the ALS Functional Rating Scale (ALSFRS-R), which assesses symptoms related to bulbar function, limbs, and respiration. Rate of change data is useful for predicting survival and progression or improvement. Another measurement includes the Combined Assessment of Function and Survival (CAFS), ranking clinical outcomes in subjects by combining survival time with changes in the ALSFRS-R (Simon N.G. et al., Quantifying Disease Progression in Amyotrophic Lateral Sclerosis, Ann Neural, 76:643-57 (2014)).

Muscle strength can be tested and quantified using the combined Manual Muscle Testing (MMT) scoring. This entails averaging measurements from multiple muscle groups using the Medical Research Council (MRC) Muscle Strength Rating Scale (ibid.). Among other techniques, manual dynamometry (HHD) can be used (ibid.).

Respiratory function can be assessed with portable spirometry devices used to obtain forced vital capacity (FVC) at baseline to predict disease progression or improvement. In addition, peak inspiratory pressure, nasal inspiratory pressure (SNIP), and evening FVC can be determined and applied to monitor progression/improvement (ibid.).

Loss of lower motor neurons is another indicator that can be used to monitor disease progression or improvement in ALS. The neurophysiological index can be determined by measuring compound muscle activity potentials (CMAPs) in motor nerve conduction studies, which parameters include CMAP amplitude and F-wave frequency (ibid. and de Carvalho M. et al., Nerve conduction studies in amyotrophic lateral sclerosis Muscle Nerve, 23:344-352 (2000)). The number of lower motor neuron units (MUNE) can also be estimated. MUNE analysis evaluates the number of residual motor axons supplying the muscle,

- 73 041892 by assessing the contribution of individual motor units to the maximum response of CMAP, which is used to determine the progression or improvement in the disease. (Simon N.G. et al., supra). Additional techniques for determining LMN loss include nerve excitability analysis, electrical impedance myography, and the use of muscle ultrasound to detect changes in muscle thickness (ibid.).

Upper motor neuron dysfunction is another indicator that can be used to monitor disease progression or improvement in ALS. Methods for determining dysfunction include MRI or PET scanning of the brain and spinal cord, transcranial magnetic stimulation; and determination of biomarker levels in cerebrospinal fluid (CSF).

v. Glaucoma.

In addition to monitoring the improvement in symptoms associated with cognitive function, progression or improvement in glaucoma-associated neurodegeneration can be monitored using techniques well known to those skilled in the art. By way of example, and not limitation, monitoring can be done using techniques such as intraocular pressure; assessment of the condition of the optic nerve head or optic nerve head for lesions; assessment of the visual field in case of loss of peripheral vision; and visualization of the optic nerve head and retina for topographic analysis.

vi. Progressive supranuclear palsy (PNP).

In addition to monitoring the improvement in symptoms associated with cognitive function, progression or improvement in neurodegeneration associated with progressive supranuclear palsy (PSP) can be monitored using techniques well known to those skilled in the art. By way of example, and not limitation, monitoring can be done using techniques such as functional assessment (Daily Activity Rating Scale or ADL); motor activity assessment; definition of psychiatric symptoms; and volumetric and functional magnetic resonance imaging (MRI).

A subject's level of function in terms of independence, partial dependence on others, or complete dependence may be useful in determining progression or improvement in disease (see Duff, K. et al., Functional impairment in progressive supranuclear palsy, Neurology, 80:380- 84 (2013)). The Progressive Supranuclear Palsy Rating Scale (PSPRS) is a rating scale that includes twenty-eight measurements in six categories: activities of daily living (according to history); behavior; bulbar functions, oculomotor functions, limb movements, and gait/midline. The result obtained varies from 0 to 100 points. Six parameters are scored from 0 to 2 points, and twenty-two parameters are scored from 0 to 4 points for a total of 100 points. PSPRS scores are practical measurements and reliable indicators of patient survival. They are also sensitive to disease progression and useful for monitoring disease progression or improvement (Golbe L.I. et al., A clinical rating scale for progressive supranuclear palsy, Brain, 130:1552-65, (2007)).

The ADL section of the UPDRS (Uniform Parkinson's Disease Rating Scale) can also be used to quantify functional activity in patients with PSP. (Duff K. et al., supra). Similarly, the Schwab and England Activity Scale of Daily Activity (SE-ADL) can be used to assess independence (ibid.). In addition, motor function sections of the UPDRS are useful as a reliable parameter for assessing disease progression in patients with PNP. The motor function section could contain, for example, 27 different parameters to quantify motor function in patients with PNP. Examples of such parameters include rest tremor, rigidity, finger tapping, posture and gait). Progression or improvement in a subject's condition can also be assessed by a baseline neuropsychological assessment performed by trained medical personnel using the Neuropsychiatric Assessment (NPI) questionnaire to determine the frequency and severity of behavioral abnormalities (e.g., delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, and impaired motor behavior) (ibid.).

Functional MRI (fMRI) may also be performed to monitor disease progression and improvement. fMRI is a technique that uses MRI to measure changes in brain activity in specific areas of the brain, usually based on blood flow to those areas. It is believed that blood flow correlates with the activation of an area of the brain. Patients with neurodegenerative disorders such as PNP may have physical or mental activity tests before or during an MRI scan. By way of example, and not limitation, the tests can be a well-known approach to force control in which patients are asked to exert force on the arm most affected by PNP, and maximal voluntary contraction (MVC) is measured using fMRI immediately after the test. Burciu, R.G. et al., Distinct patterns of brain activity in progressive supranuclear palsy and Parkinson's disease, Mov. Discord.,

- 74 041892

30(9):1248-58 (2015)).

Volumetric MRI is a technique that uses MRI scanners to determine differences in volume in a specific area of the brain. This can be done, for example, by comparing different disorders or by determining differences in the volume of a brain region in a patient over time. Volume MRI can be used to determine disease progression or improvement in neurodegenerative disorders such as PNP. This technique is well known to those skilled in the art. (Messina D. et al., Patterns of brain atrophy in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy, Parkinsonism and Related Disorders, 17(3):172-76 (2011)). Examples of brain regions that can be measured include, but are not limited to, intracranial volume, cerebral cortex, cerebellar cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, lateral ventricles, third ventricle, fourth ventricle, and brain stem.

vii. Neurogenesis.

There are reports of non-invasive methods for assessing neurogenesis. (Tamura Y. et al., J. Neurosci. (2016), 36(31):8123-31). Positron emission tomography (PET) expelled with [ ¹⁸ F]FLT radioisotope tracer, in combination with probenecid, an inhibitor of the transfer of substances across the BBB, allows the tracer to accumulate in neurogenic areas of the brain. Such imaging allows the assessment of neurogenesis in patients who are being treated for a neurodegenerative disease.

viii. Parkinson's disease and motor function.

Several rating scales are used to assess the progression of PD. The most widely used scales include the Uniform Parkinson's Disease Rating Scale (UPDRS, which was introduced in 1987) (J. Rehabil Res. Dev., 2012, 49(8):1269-76), and the Hoehn and Yahr scale (Neurology , 1967, 17(5):427-42). Additional scales include the International Movement Disorder Society (MDS) Updated UPDRS (MDS-UPDRS) and the Schwab and England Activity of Daily Activity Scale (ADL).

The UPDRS scale assesses a total of 31 parameters, which are divided into three subscales:

(1) thinking, behavior and mood;

(2) daily activities; and (3) motor activity assessment.

The Hen and Yahr scale classifies PD into five stages with discrete substages:

- no signs of disease;

- symptoms on one side only;

1.5 - symptoms on one side, but also involving the neck and spine;

- symptoms on both sides without imbalance;

2.5 - mild symptoms on both sides with recovery during the resistance test;

- imbalance with mild or moderate severity of the disease;

- severe disability, but the ability to walk or stand without assistance;

- need a wheelchair or are bedridden without assistance.

Schwab and England's daily activity scale classifies PD by percentage (from 100% complete independence to 10% - complete dependence).

General motor function can be assessed using commonly used scales, including the General Motor Function (GMF) Scale. Three components are analyzed using this scale: dependence, pain and insecurity (Aberg A.C. et al. (2003), Disabil. Rehabil., 2003 May, 6, 25(9):462-72.). Motor function can also be assessed using home monitoring sensors or wearable sensors. For example, gait (speed of movement, variability, stiffness of the leg) can be measured using an accelerometer;

posture (torso tilt) - using a gyroscope;

leg movement - with the help of an accelerometer;

hand movement - with the help of an accelerometer and a gyroscope;

tremor (amplitude, frequency, duration, asymmetry) - using an accelerometer;

falling - using an accelerometer;

freezing of gait - using an accelerometer;

dyskinesia - using an accelerometer, gyroscope and inertial sensors;

bradykinesia (duration and frequency) - using an accelerometer and a gyroscope; and aphasia (degree) - using a microphone.

(Pastorino M. et al., Journal of Physics: Conference Series, 450 (2013), 012055.)

l. Reagents, devices and kits.

Reagents, devices, and kits thereof are also provided for practicing one or more of the methods described above. The described reagents, devices and kits may

- 75 041892 vary greatly. Reagents and devices of interest include those mentioned above in relation to methods of administering compounds of formula 1 to a subject.

In addition to the above components, the kits described will further include instructions for practicing the methods described. These instructions may be present in the described kits in various forms, one or more of which may be present in the kit. One of the forms these instructions may take is printed information on a suitable carrier or substrate, such as a sheet or pieces of paper on which the information is printed, in the package of a kit, in a package insert, etc. Yet another medium may be a computer-readable medium, such as a floppy disk, CD, portable flash drive, etc., on which the information is recorded. Another tool that can be used is a website address that can be used on the Internet to access information at a remote site. Any convenient means can be present in the kits.

VII. Examples

The following examples are given by way of illustration and not limitation.

A. Pharmaceutical drug.

Pharmaceutical compositions that are administered to subjects with a cognitive or neurodegenerative disease, which consist of the compounds, co-crystals and salts described above, can be synthesized, manufactured and formulated using the examples described in US Patent Application Publication No. 2013/0266646, 2016/0081998, patent US No. 8278302, 8653075, RE45323, 8742115, 9233950 and 8680280, which are incorporated herein by reference in their entirety. In addition, pharmaceutical compositions can be prepared as described in the examples below.

1. Tablet formulation - wet granulation.

Copovidone is dissolved in ethanol at ambient temperature to obtain a granulation liquid. The CCR3 antagonist active ingredient, lactose and a portion of the crospovidone are mixed in a suitable mixer to form a premix. The pre-mixture is moistened with the granulation liquid and then granulated. The wet granulate is optionally sifted through a 1.6-3.0 mm sieve. The granulate is dried at 45°C in a suitable dryer to a residual moisture content corresponding to a loss of 1-3% on drying. The dried granulate is sifted through a sieve with a mesh size of 1.0 mm. The granulate is mixed with part of the crospovidone and microcrystalline cellulose in a suitable mixer. Magnesium stearate is added to this mixture after sifting through a 1.0 mm sieve to remove lumps. Subsequently, the final mixture is prepared by final mixing in a suitable mixer and compressed into tablets. You can get the following tablet composition.

Component mg/tablet %/tablet Active substance 28,500 30.0 Crospovidone 1,500 1.6 Lactose 28,000 29.5 Copovidone 3,000 3.2 Total (granulate) 61,000 64.3 Microcrystalline cellulose 31,000 32.6 Crospovidone 2,500 2.6 Magnesium stearate 0.500 0.5 Total 95,000 100,000

2. Tablet formulation - wet granulation.

The CCR3 antagonist active ingredient, lactose, a portion of the HCC, polyethylene glycol, lactose and a portion of the crospovidone are mixed in a suitable mixer to form a premix. The resulting premixture is heated in a high shear mixer and then

- 76 041892 granulate. The hot granulate is cooled to room temperature and sieved through a 1.0 mm sieve. The granulate is mixed with part of the crospovidone and microcrystalline cellulose in a suitable mixer. Magnesium stearate is added to this mixture after sifting through a 1.0 mm sieve to remove lumps. Subsequently, the final mixture is prepared by final mixing in a suitable mixer and compressed into tablets. You can get the following tablet composition.

Component mg/tablet %/tablet Active substance 28,500 30.0 Crospovidone 1,500 1.6 Lactose 11,000 11.6 Polyethylene glycol 14,300 15.1 MSS 5,700 6.0 Total (granulate) 61,000 64.3 Microcrystalline cellulose 31,000 32.6 Crospovidone 2,500 2.6 Magnesium stearate 0.500 0.5 Total 95,000 100,000

3. Formulation of tablets - hot melt granulation.

The CCR3 antagonist active ingredient, mannitol, polyethylene glycol and a portion of crospovidone are mixed in a suitable mixer to form a premix. The resulting pre-blend is heated in a high shear mixer and then granulated. The hot granulate is cooled to room temperature and sieved through a 1.0 mm sieve. The granulate is mixed with part of the crospovidone and mannitol in a suitable mixer. Magnesium stearate is added to this mixture after sifting through a 1.0 mm sieve to remove lumps. Subsequently, the final mixture is prepared by final mixing in a suitable mixer and compressed into tablets. You can get the following tablet composition.

Component mg/tablet %/tablet Active substance 28,500 30.0 Crospovidone 1,500 1.6 Mannitol 16,700 17.6 Polyethylene glycol 14,300 15.1 Total (granulate) 61,000 64.3 Mannitol 31,000 32.6 Crospovidone 2,500 2.6 Magnesium stearate 0.500 0.5 Total 95,000 100,000

- 77 041892

4. Tablet formulation - hot melt extrusion.

The CCR3 antagonist active ingredient and stearic palmitic acid are mixed in a suitable mixer to form a premix. The premix is extruded into a twin screw extruder and then granulated. The granulate is sifted through a sieve with a mesh size of 1.0 mm. The granulate is mixed with mannitol and crospovidone in a suitable mixer. Magnesium stearate is added to this mixture after sifting through a 1.0 mm sieve to remove lumps. Subsequently, the final mixture is prepared by final mixing in a suitable mixer and compressed into tablets. You can get the following tablet composition.

Component mg/tablet %/tablet Active substance 28,500 30.0 Stearic Palmitic Acid 27,500 28.9 Total (granulate) 56,000 58.9 Mannitol 32,600 34.3 Crospovidone 5,600 5.9 Magnesium stearate 0.800 0.9 Total 95,000 100,000

5. Formulation of tablets - hot melt extrusion.

The CCR3 antagonist active ingredient and stearic palmitic acid are mixed in a suitable mixer to form a premix. The premix is extruded into a twin screw extruder and then granulated. The granulate is sifted through a sieve with a mesh size of 1.0 mm. The granulate is directly filled into hard capsules. You can get the following composition of the capsule.

Component mg/tablet %/tablet Active substance 70,000 70.0 Stearic Palmitic Acid 30,000 30.0 Total (granulate) 100,000 100.0 Capsule 90,000 - Total 190,000 100,000

6. Formulation of tablets-rolling.

The CCR3 antagonist active ingredient, the mannitol and crospovidone portion and the magnesium stearate are mixed in a suitable mixer to form a premix. The resulting pre-mixture is compacted with a roller press and then granulated. Optionally, the granulate is sieved through a sieve with a mesh size of 0.8 mm. The granulate is mixed with part of the mannitol and crospovidone in a suitable mixer. Magnesium stearate is added to this mixture after sifting through a 1.0 mm sieve to remove lumps. Subsequently, the final mixture is prepared by final mixing in a suitable mixer and compressed into tablets. You can get the following tablet composition.

- 78 041892

Component mg/tablet %/tablet Active substance 28,500 30.0 Crospovidone 1,400 1.5 Mannitol 34,600 36.4 Magnesium stearate 0.500 0.5 Total (granulate) 65,000 68.4 Mannitol 27,000 28.4 Copovidone 1,600 1.7 Crospovidone 0.950 1.0 Magnesium stearate 0.450 0.5 Total 95,000 100,000

7. Formulation of tablets - rolling.

The CCR3 antagonist active ingredient and magnesium stearate are mixed in a suitable blender to form a premix. The resulting pre-mixture is compacted with a roller press and then granulated. Optionally, the granulate is sieved through a sieve with a mesh size of 0.8 mm. The granulate is mixed with mannitol and croscarmellose sodium in a suitable mixer. Magnesium stearate is added to this mixture after sifting through a 1.0 mm sieve to remove lumps. Subsequently, the final mixture is prepared by final mixing in a suitable mixer and compressed into tablets. You can get the following tablet composition.

Component mg/tablet %/tablet Active substance 114.200 66.0 Magnesium stearate 1,800 1.0 Total (granulate) 116,000 67.0 Mannitol 51,000 29.5 Croscarmellose sodium 3,500 2.0 Magnesium stearate 2,500 1.5 Total 173,000 100,000

8. Formulation of tablets - rolling.

The CCR3 antagonist active ingredient and magnesium stearate are mixed in a suitable blender to form a premix. The resulting pre-mixture is compacted with a roller press and then granulated. Optionally, the granulate is sieved through a sieve with a mesh size of 0.8 mm. The granulate is mixed with microcrystalline cellulose and crospovidone in a suitable mixer. Magnesium stearate is added to this mixture after sifting through a 1.0 mm sieve to remove lumps. Subsequently, the final mixture is prepared by final mixing in a suitable mixer and compressed into tablets. You can get the following tablet composition.

- 79 041892

Component mg/tablet %/tablet Active substance 114.200 66.0 Magnesium stearate 1,800 1.0 Total (granulate) 116,000 67.0 MSS 51,000 29.5 Crospovidone 3,500 2.0 Magnesium stearate 2,500 1.5 Total 173,000 100,000

9. Formulation of coated tablets.

Tablet cores according to the above formulations can be used to make film-coated tablets. Hydroxypropyl methylcellulose, polyethylene glycol, talc, titanium dioxide and iron oxide are suspended in purified water in a suitable mixer at ambient temperature to obtain a coating suspension. The tablet cores are coated with the coating suspension to increase in weight by about 3% to obtain film-coated tablets. The following film coating composition can be obtained.

Component mg/tablet %/tablet Hypromellose 2.40 48.0 Polyethylene glycol 6000 0.70 14.0 Titanium dioxide 0.90 18.0 Talc 0.90 18.0 Iron oxide red 0.10 2.0 Purified water (volatile component) - - Total 5.00 100.0

b. Drawing up the introduction of compositions.

The test product of this invention (compound 1) corresponded to the following chemical structure.

CONNECTION 1

Those skilled in the art will appreciate that the compounds, co-crystals, salts, and formulations described earlier in the above sections may also be used in these examples.

Compound 1 was produced in film-coated tablets of 100, 200 and 400 mg, biconvex, round or oval in shape and pale red in color. The tablets were made by a dry granulation process, wherein the tablets contained microcrystalline cellulose, hydrogen phosphate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red and iron oxide yellow as inactive ingredients. Placebo tablets corresponding to the study product were made by direct compression, while these tablets contained the same inactive ingredients.

With. Preclinical examples.

1. Materials and methods.

(a) Implantation of a subcutaneous osmotic pump.

Alzet mini-pumps were filled, prepared and numbered by mouse ID the day before implantation to allow priming at 37° C. and account for treatment blindness. The pumps were implanted in the dorsal region, slightly behind the shoulder blades and somewhat lateral to the midline. Mice were anesthetized with 3-5% isoflurane using a vaporizer and regulator in an induction chamber, then transferred to the site of the procedure and provided with a breathing circuit to maintain anesthesia with a concentration of isoflurane 1-3%. An ophthalmic ointment was applied to the eyes to prevent the cornea from drying out. Mice were injected subcutaneously with meloxicam 5 mg/kg. Hair was removed from the incision area with small sharp scissors and the area was cleaned by alternating treatments with 70% isopropanol and betadine. A 0.5-1 cm incision was made and a hemostat was inserted to expand the subcutaneous tissue and create a pocket for the pump. The pump was inserted into the pocket, and the wound was closed with wound clamps. All surgical instruments were autoclaved prior to first use on the day of surgery. The instruments were then sterilized in a glasperlene sterilizer between animals. Mice were placed in a clean recovery cage partially placed on a heating pad until fully recovered and able to move. Mice were tested for induction of anesthesia by hind toe pinching and monitoring of respiration. Mice were monitored after surgery every 15 min until recovery. The mice were given a second dose of meloxicam the next day. If signs of infection were observed, mice received subcutaneously 5 mg/kg Baytril per day until the infection disappeared.

(b) Open field test.

The open field test is used to evaluate general motor activity and exploratory behavior in a new environment. Before testing, mice were transferred to the experimental room for at least 30 min to adapt to the conditions of the experimental room (in low light). The test site is a 50x50 cm square area. Mice were placed in the center of the test site and monitored for 15 minutes. The period of time spent in the peripheral and central zones, as well as rearing behavior, were analyzed. Between tests, 70% ethanol was used to clean all surfaces.

(c) Y-like maze.

The test with the passage of a large Y-like maze assesses short-term memory of familiarity with a particular context. Before testing, mice were transferred to the experimental room for at least 30 min to adapt to the conditions of the experimental room (in low light). For the initial training trial, the mouse was placed at the end of one arm of the large Y-maze, designated as the start arm (arm length: 15 inches). The third branch of the maze was blocked, allowing the mouse to freely explore two of the three branches (starting branch and familiar branch) for 5 min. Each branch contains spatial labels. An hour later, the mouse was again placed in the maze in the starting branch and allowed to explore all three branches with the third branch unlocked (new branch). Movements inside and outside of each branch were tracked using automatic tracking software (CleverSys). Testing was performed in low light, with the apparatus cleaned with 70% ethanol between tests.

(d) Barnes' Maze.

The modified Barnes maze was used to assess spatial functioning/episodic learning and memory. The Barnes maze device consists of a round platform 122 cm in diameter with 40 exit holes, each 5 cm in diameter, located along three rings with different distances from the center of the platform. An exit box is attached to one of the holes, while all holes remain open. Bright light and air flow were used in the maze to provide adverse stimuli to encourage escape. Visual marks were placed on all four sides of the maze. For mice, a series of 4 or 5 trials was performed with intervals between trials of approximately 10 minutes, with the maximum duration of each trial being 90 or 120 seconds. For each trial, mice were placed in the center of the maze. After 10 s, the mice were allowed to explore the area, and ended the trial if the mouse found and entered the exit box before the end of the trial. Mice that could not find an exit box were led to the box, allowed to enter, and given 30 s to stay before returning to their home cage. The training was carried out for 4 days. The data that was recorded and analyzed included speed, exit delay, and distance travelled.

- 81 041892

Mice were divided into groups of 4-5 mice each with balanced treatment groups.

For example, mice in group 1 were run for 4 trials, then mice in group 2 were run for 4 trials, and so on until all groups had completed the trials. Between tests, 70% ethanol was used to clean all surfaces.

(e) Rotating drum.

Mice were trained on a rotating drum for 3 trials of 100 seconds each, with the rotating drum being a test for motor coordination. Success or failure was recorded in the last trial, with success being determined by holding on the drum to fall >90 s. A binomial test was used to compare success rates between control and compound-treated mice.

(f) T-like maze.

The water maze was filled with water at least 24 hours before the test to allow the water to reach room temperature. The water was painted with white latex paint so that the animals were visible for tracking and for the possibility of using a hidden platform. Two different visual marks were placed at the end of both T-arms of the T-maze insert. On day 1, 4 trials were performed on the animals, each with a visible platform and a 30-minute interval between trials. The animals were given 60 seconds to reach the platform. If they did not reach the platform during this time, they were directed to it and left for 5 seconds before being removed from the pallet. The target branches were changed after every third mouse, and the same number of changes in the right and left target branches were applied to mice in both treatment groups. After each trial, mice were placed in an empty cage with blue bedding and allowed to dry under a red light lamp before being placed back in their home cage. Day 2 was the test day when the animals were subjected to the same test consisting of 4 trials each with a 30 min interval between trials, but with a hidden platform. Animals were scored for correct or incorrect selection and for time delay to reach the platform, with a binomial test used to compare success rates between control and compound-treated mice. All tests were recorded using TopScan.

(g) Protein quantitation.

CCL11 protein levels were measured in mouse plasma by sandwich ELISA. Plasma for analysis was diluted in a ratio of 1:10. (Mouse CCL1/Eotaxin Duo Set ELISA kit, Mouse CCLH/Eotaxin Duo Set ELISA kit, R&D Systems, Minneapolis, MN.)

Human CCL11 in human plasma was measured using the SomaLogic aptamer-based assay (SOMAscan from SomaLogic, Inc., Boulder, Colorado) (Gold L. et al. (2010), Aptamer-Based Multiplexed Proteomic Technology for Biomarker Discovery, PLOS ONE, 5(12):el5004).

Panels of circulating cytokines in mouse plasma were analyzed using Luminex. The Luminex assay was serviced by Eve Technologies (Calgary, Alberta, Canada).

(h) mRNA quantification.

Quickly frozen hemispheres were dissected through the cortex, hippocampus, striatum, and thalamus. The bark was divided into three homogeneous parts and one part was used for RNA isolation. RNA was isolated using a Prolink RNA mini kit (Thermo Fisher Scientific # 12183025). cDNA was obtained using the Taqman RT kit (Thermo Fisher Sci # N8080234). qPCR was run on a Quant Studio 6 using custom Taqman multiplex primers for IL-1 beta and GAPDH. All samples were collected together on one plate and analyzed first for ddCT against their endogenous control and then against the control group.

(i) Quantification of compound 1 by HPLC/MS.

Compound levels were measured by MS/MS with Quintara (Hayward, CA).

(j) Flow analysis Eosinophil count.

200 µl of whole blood was collected at the time of perfusion and sent to the Charles River Clinical Pathology Department (Shrewsbury, Massachusetts) for hematological analysis with eosinophil counting using FACS (fluorescence activated cell sorter).

Change in the shape of eosinophils (ESC).

ESC measures the shape change of human eosinophils activated with human eotaxin-1 (PreProTech, Rocky Hill, NJ) compared to native eosinophils. The change is defined as the change in forward scatter measured by FACS (Fluorescence Activated Cell Sorter). The mean forward scatter of the autofluorescence population (eosinophils) for each sample was determined in combination with the mean of each set of samples in triplicate. Methods for determining ESC have been previously described and known in the art.

Internalization of CCR3 receptors.

The CCR3 receptor internalization assay is based on FACS and uses human eotaxin-1 (PreProTech, Rocky Hill, NJ) and anti-human CCR3 antibody labeled with APC (R&D

- 82 041892

Systems, Minneapolis, MN) or an IgG2A isotype control antibody to monitor internalization of CCR3 receptors in human eosinophils induced by human eotaxin-1 compared to naive eosinophils. The median of APC fluorescence intensity units for each sample was determined along with the average value of each set of samples in triplicate. Methods for monitoring the internalization of the CCR3 receptor have been previously described and known in the art.

(k) Histology.

Mice were sacrificed the day after the end of behavior testing. Pain relief was induced with 2,2,2-tribromoethanol and mice were subsequently transcardially perfused with 0.9% saline. The brain was dissected and sagittally cut into two equal halves. One half was flash frozen for later use on dry ice and the other half was fixed in 4% paraformaldehyde in PBS for use in immunohistochemistry. After two days of fixation, the cerebral hemispheres were transferred to 30% sucrose in PBS and replaced two days later. The cerebral hemispheres were dissected at 30 μm on a microtome at -22°C. Brain sections were stored in a cryoprotective medium at -20° C. until needed for staining. Blocking was performed on free floating sections in the appropriate serum at 10% serum in PBST 0.5%. Primary antibodies were incubated overnight at 4°C. For light microscopy, the following antibodies were used at these concentrations: DCX, 1:200, Santa Cruz BioTech, CD68, 1:1000. AbD Serotec. Secondary biotinylated antibodies were applied the next day at a concentration of 1:300. Visualization of staining was achieved by reaction with the ABC kit (Vector) and diaminobenzidine (Sigma). Dehydration of the fixed sections was achieved with ethanol and xylene. Images were taken on a Leica light microscope at 5x magnification.

For fluorescent microscopy, the following antibodies were used at these concentrations: GFAP, 1:500, DAKO; Iba1, 1:1000, Wako; and BrdU, 1:500, AbCam. An antigen retrieval protocol was required for BrdU (2N HCl, 37°C, 30 min) prior to blocking. The corresponding fluorescent secondary antibodies were applied the next day at a concentration of 1:300 for 1 hour at room temperature. The preparations were coated with Prolong Gold Mounting Media. Images were taken on a light microscope at 5x magnification.

2. Experimental groups.

First Experimental Group (see FIGS. 1A-2B): 2-month-old or 18-month-old C57B1/6 mice were injected with either a control IgG antibody by ip injection or compound 1 subcutaneously using an Alzet osmotic pump for 2 or 4 weeks. During the last week of exposure, on the last day before perfusion, mice were tested for their behavior. All mice received 5 consecutive days of ip injections of BrdU at a concentration of 150 mg/kg immediately prior to exposure.

The composition of the drug. Clone 54447 control rat IgG2A (MAB006, R & D Systems) was administered at a dose of 50 μg/kg in sterile saline. Compound 1 was prepared in 40% HP-p-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). Solutions were prepared fresh weekly and stored at 4°C.

impact groups.

Treatment group 1. Young control mice: C57BL/6 young mice (n=18) aged 1-2 months received 5 injections of control IgG by intraperitoneal (ip) injection, one injection every 3 days for 14 days.

Treatment Group 2 Old Control Mice: Old C57BL/6 mice (n=18) aged 18 months received 5 injections of control IgG by ip injection, one injection every 3 days for 14 days.

Treatment Group 3 Compound 1 (dose 1) in aged mice: aged C57BL/6 mice (n=16) at 18 months of age received an infusion of ˜50 mg/mL Compound 1 using an Alzet model 2001 minipump (1 µL/ h), within two weeks with one replacement.

Treatment group 4 Compound 1 (dose 2) in aged mice: aged C57BL/6 mice (n=16) at 18 months of age received an infusion of ˜50 mg/mL Compound 1 using an Alzet mini-pump model 2002 (0.5 µl/h), within two weeks

Treatment group 5 Compound 1 (dose 2) in aged mice: aged C57BL/6 mice (n=16) at 18 months of age received an infusion of ~50 mg/mL Compound 1 using an Alzet mini-pump model 2002 (0.5 µl/h) for four weeks with one change.

Four-week subcutaneous administration of compound 1 to 18-month-old mice increased the number of doublecortin-positive cells in the hippocampus, which is indicative of neurogenesis (see Fig. 1A). A higher dose of compound 1 for 2 weeks tended to increase the number of BrdU-positive cells in the hippocampus, which is a marker of cell proliferation (see Fig. 1B). Low or high Compound 1 infusion over 2 or 4 weeks resulted in improved Y-maze scores, a memory test (see Figure 2 showing percentage of time normalized to total interaction time and number of visits - similar to 83 041892 These effects were also observed when assessing the total time spent). Comparisons were made with control groups (exposure groups 1 and 2) administered with IgG antibody without compound, and dosing and behavior analysis were performed in parallel.

Thus, administration of compound 1 increased the number of Dcx and BrdU positive cells, indicating that compound 1 increased neurogenesis and cell survival, respectively. Compound 1 was able to improve memory (cognitive function) as evidenced by improved Y-maze completion rates.

Second experimental group (see Fig. 3-6): C57B1/6 mice of three months or 16.5 months of age were injected subcutaneously with either a control vehicle or compound 1 using an Alzet osmotic pump for 4 weeks. During the last week of exposure, on the last day before perfusion, mice were tested for their behavior. All mice received 5 consecutive days of ip injections of BrdU at a concentration of 150 mg/kg immediately prior to exposure.

The composition of the drug.

Compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Solutions were prepared fresh weekly and stored at 4°C.

impact groups.

Treatment Group 1: Young Control Mice: Young C57BL/6 mice (n=19) at 3 months of age were infused with vehicle using an Alzet Mini-Pump Model 2002 (0.5 µl/h) for four weeks with one change .

Treatment Group 2: Old Control Mice: Old C57BL/6 mice (n=19) at 16 months of age were infused with vehicle using an Alzet Mini-Pump Model 2002 (0.5 µl/h) for four weeks with one change .

Treatment Group 3: Compound 1 (dose 2) in aged mice: aged C57BL/6 mice (n=19) at 16 months of age received an infusion of ˜50 mg/mL Compound 1 using an Alzet mini-pump model 2002 (0.5 µl/h) for four weeks with one change.

Four weeks of subcutaneous administration of Compound 1 to 16.5 month old mice improved cognition in the Y-maze test for memory (see FIG. 3). 4-week administration of compound 1 also tended to improve performance on the Barnes maze, a hippocampal-dependent spatial memory test (see FIG. 4). Trends in memory improvement were also observed when analyzing the average retention time per day for 4 trials, as well as the difference between the retention times in trials 13 and 16. Four weeks of administration of compound 1 also significantly increased the number of BrdU-positive cells in the hippocampus, which is an indicator of neurogenesis (see Fig. 5). Thus, compound 1 is able to both improve cell survival and improve memory (cognitive function), as evidenced by the results obtained using tests with the passage of the Y-like maze and the Barnes maze.

Compound levels in cerebrospinal fluid in mice.

Cerebrospinal fluid (CSF) from groups of 2-month-old young and 16.5-month-old mice was collected and Compound 1 levels were determined by mass spectroscopy. FIG. 6 shows the levels of a compound of the invention found in the CSF of both the young and aged mice group (both below 10 nM). These CSF levels do not approach the Ki for the compound in mice (124 nM as determined by cell line receptor binding) and therefore do not cross the blood-brain barrier (BBB) at significant concentrations. For comparison, the levels of a compound of this invention that were measured in the plasma of young (2-month-old) and old (18-month-old mice) perfused for 2 and 4 weeks, respectively, at a rate of 0.5 μl/h at a concentration of 50 mg/ml solution were significantly higher (352±31 and 355±43 nM, respectively; values are mean±SOS), which further indicates that the compound of this invention cannot cross the BBB in significant amounts.

These data demonstrate that Compound 1 does not act directly in the CNS and therefore acts peripherally. In addition, the concentration of the compound that crosses the BBB is insufficient to be effective. Furthermore, there is no difference in BBB penetration between young and old mice, indicating that the effects Compound 1 exhibits on cognition and neurodegeneration are not due to differences in BBB penetration between the two groups.

Distribution levels of the compound in tissues.

Compound 1 tissue distribution in mice was determined after oral administration to male pigmented C57BL/6JOlaHsd mice (Harlan Labs, BV), wherein compound 1 was labeled with [ ¹⁴ C]-radioactive label (labeled compound). The labeled compound was administered at a dose of 10 mg/kg of body weight, which corresponds to 17 µmol/kg. One animal was sacrificed 1, 24, and 168 hours after administration. Radioactivity concentrations in blood, plasma and in the eye were measured using liquid scintillation detection (LSC). Tissue and organ concentrations were determined by whole body autoradiography (QWBA). Whole body sectioning of animals was performed according to known procedures (see S. Ullberg et al., Autoradiography in Pharmacology in: Int. Encyclopedia of Pharmacology,

J. Cohen (Ed.), 1(78):221-39 (1971)), using a Reichert-Jung CRYO MACROCUT or

CRYO MACROCUT LEICA CM3600 ³ .

The following sections were made at different levels throughout the body of the drenched animal, with whole body sections collected at 5-7 levels for quantification of radioactivity: adrenal glands; blood; Bone marrow; brain; eye (lens); epididymis; fat (white and brown); garder's gland; heart; kidneys; liver; lung; muscles; pituitary; pancreas; prostate gland, spinal cord; spleen, salivary gland; leather; testis; thyroid; thymus; uveal tract. Two sections of each selected level were taken from each animal, and these sections were lyophilized in a microtome at -20 to -25°C for a minimum of 48 hours.

In FIG. 7 is a value chart showing the area under the curve (AUC) for all three time points and quantifying the effect on each tissue of the labeled POI following compound administration. In FIG. 7 demonstrates that Compound 1 does not cross the blood-brain barrier (BBB) at significant levels.

Again, these results demonstrate that since Compound 1 cannot penetrate the BBB at detectable levels, it acts in a peripheral manner. Thus, the effects of Compound 1 do not directly affect the central nervous system, and it overcomes obstacles that have caused many drug candidates to be ineffective in the treatment of CNS diseases.

Pharmacokinetic profiles for PO dosing.

Compound 1 concentrations were measured in the plasma of male 2-month-old C57B1/6 mice at 20 min, 2, 8 and 12 h after oral gavage at 2 doses: 30 and 150 mg/kg. It was found that the dose of 30 mg/kg was sufficient to achieve a concentration of compound 1 greater than 100 nm within 8 h (Fig. 8).

Third Experimental Group (see FIGS. 9-11): Two-month-old C57B1/6 mice were administered either vehicle control or Compound 1 by oral gavage twice daily for 18 days. During the last week of exposure, on the last day before perfusion, mice were tested for their behavior. All mice received 5 consecutive days of ip injections of BrdU at a concentration of 150 mg/kg immediately prior to exposure.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Solutions were prepared fresh weekly and stored at 4°C.

impact groups.

Exposure Group 1a, Vehicle Exposure: Young C57BL/6 mice (n=15) aged 7 weeks received oral (po) twice daily (2 p/day) vehicle solution for 18 days with only one injection at the last day; only 35 injections.

Treatment group 1b, compound 1 exposure: 7-week-old C57BL/6 young mice (n=15) received compound 1 orally (po) twice a day (2 r/day) at a dose of 30 mg/kg for 18 days with only one injection on the last day; only 35 injections.

Exposure group 2a, vehicle exposure with rmCCL11: C57BL/6 young mice (n=15) at 7 weeks of age received oral (po) twice daily (2 r/day) vehicle solution for 18 days with only one injection on the last day; only 35 injections. Mice simultaneously received peripheral injections (i.p.) of rmCCL11 starting on day 1 of exposure, every 3 days; only 5 injections.

Treatment group 2b, exposure to compound 1 with rmCCL11: young C57BL/6 mice (n=15) aged 7 weeks received compound 1 orally (po) twice a day (2 r/day) at a dose of 30 mg/kg per day. within 18 days, with only one injection on the last day; only 35 injections. Mice received concurrent peripheral (ip) injections of rmCCL11 starting on day 1 of exposure every 3 days for a total of 5 injections.

Administration of recombinant murine CCL11 (rmE) significantly worsened anxiety scores in the open field test, but 2 weeks of compound 1 twice daily oral exposure reduced anxiety (see FIG. 9). rmCCL11 worsened memory in the Y-maze test; however, mice that received Compound 1 were no longer significantly different from control mice (see FIG. 10). rmCCL11 also impaired memory in the Barnes maze test, and compound 1 treatment significantly improved memory scores (see FIG. 11). Thus, rmE exacerbated both anxiety in the open field test and memory, as evidenced by the results obtained in the Y-maze and Barnes maze tests. However, the introduction of compound 1 was able to weaken these effects.

Fourth experimental group (see Fig. 12): 23-month-old C57BL/6 mice were administered either vehicle control or Compound 1 via oral gavage twice daily for

- 85 041892 days. After 11 days of exposure, the mice underwent a Y-maze test.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Collifor at a concentration of 10% was added to each solution every week and stored at 4°C.

impact groups.

Treatment Group 1, Vehicle Exposure: Old C57BL/6 mice (n=8) aged 23 months received vehicle solution twice daily (2 p/day) via oral gavage (po) for 19 days.

Exposure Group 2, Compound 1 Exposure: Old C57BL/6 mice (n=11) aged 23 months received Compound 1 at 30 mg/kg twice daily (2 r/day) via oral gavage (po) at within 19 days.

Exposure to compound 1 significantly improved memory performance in the Y-like maze test. Compound 1 treated mice showed intact memory in new offshoots by number of visits (FIG. 12A). Compound 1 exposure also significantly increased the distance traveled by mice during the test (FIG. 12B).

Fifth experimental group (see FIGS. 13-17): 23-month-old C57BL/6 mice were injected subcutaneously with either vehicle control or Compound 1 twice daily for 21 days. Three weeks later, the mice were subjected to a behavioral test and sacrificed the day after the last behavioral test.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Collifor at a concentration of 10% was added to each solution every week and stored at 4°C.

impact groups.

Exposure Group 1b, Vehicle Exposure: Old C57BL/6 mice (n=9) aged 23 months received vehicle solution twice daily (2 p/day) subcutaneously (s.c.) for 21 days.

Exposure Group 4 Compound 1 Exposure: Old C57BL/6 mice (n=17) aged 23 months received Compound 1 at 30 mg/kg twice daily (2 r/day) subcutaneously (s.c.) for 21 day.

Exposure to compound 1 significantly improved memory performance in the test with the passage of the Y-like maze and the Barnes maze. Mice treated with Compound 1 showed intact memory in the new arms both in terms of the number of visits (FIGS. 13A, 13B) and the length of time spent in the new arm (FIGS. 13C, 13D). Compound 1 also significantly increased the speed of the mice during the test (FIG. 13E). Mice treated with Compound 1 performed significantly better on the Barnes Maze in terms of spatial memory (FIG. 14A) and also showed higher speed during the test (FIG. 14B). Locomotor activity also improved in the open field test, during which there were strong trends for improvement in both distance and speed (FIGS. 15A and 15B, respectively).

Inflammatory cytokine levels were measured using the Luminex assay in mouse plasma (FIG. 16). There were strong downward trends in several inflammatory markers including TNFa, IL6, IL1 beta, IL5 and IL17. Activated microglia were also quantified by IHC staining in the mouse hippocampus (FIG. 17). The use of compound 1 was characterized by a strong tendency to reduce microgliosis.

Sixth experimental group (see Fig. 18): 23-month-old C57BL/6 mice were injected subcutaneously with either vehicle control or Compound 1 twice daily for 30 days and then sacrificed on the day of the last injection.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Collifor at a concentration of 10% was added to each solution every week and stored at 4°C.

impact groups.

Exposure Group 1a, Vehicle Exposure: Old C57BL/6 mice (n=9) aged 23 months received vehicle solution twice daily (2 p/day) subcutaneously (s.c.) for 30 days.

Exposure group 3, exposure to compound 1: old C57BL/6 mice (n=18) aged 23 months received compound 1 at a dose of 30 mg/kg twice a day (2 r / day) subcutaneously (sc) for 30 days.

Compound 1 showed a strong trend towards a decrease in blood eosinophils as measured by FACS in a subset of animals (n=2.5) (FIG. 18).

The seventh experimental group (see Fig. 19): 3-month-old hairless mice received oxazolone (Ox) every other day and control saline or compound 1 at a dose of 30 mg/kg for 2 weeks 2 r/day p/o.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Collifor at a concentration of 10% was added to each solution every week and stored at 4°C.

- 86 041892

impact groups.

Treatment Group 1, Vehicle Exposure: 3-month-old hairless mice (n=3) received vehicle solution twice daily (2 p/day) via oral gavage (po) for 2 weeks.

Treatment group 2, vehicle exposure and oxazolone exposure: 3-month-old hairless mice (n=6) received vehicle solution twice daily (2 r/day) via oral gavage (po) for 2 weeks.

Treatment group 3, compound 1 exposure and oxazolone exposure: 3-month-old hairless mice (n=6) received compound 1 at a dose of 30 mg/kg, twice a day (2 r/day) via oral gavage (po) in within 2 weeks.

Compound 1 reduced the oxazolone-induced increase in the content of eosinophils in the blood according to the general blood test (CBC). N=3, 6, 8. *p<0.05, **p<0.01. Compound 1 drastically reduced blood eosinophils in the oxazolone eosinophilia model (FIG. 19). The above data demonstrate that inhibition of CCR3 may be sufficient to reduce eosinophil levels and function, especially in pathological conditions, demonstrating a second mechanism (in addition to reducing brain inflammation) by which Compound 1 may be effective in treating neuronal loss and associated these motor and cognitive deficits.

Eighth experimental group (see Fig. 20-22): 24-month-old C57 mice received for 4 weeks a continuous infusion of compound 1 or vehicle using an Alzet osmotic pump, which was implanted for continuous delivery of these two substances.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Collifor at a concentration of 10% was added to each solution every week and stored at 4°C.

impact groups.

Treatment Group 1 Old Control Mice: Old C57BL/6 mice (n=15) at 23 months of age were infused with vehicle using an Alzet Mini-Pump Model 2002 (0.5 µl/h) for four weeks with one change .

Treatment group 2 Compound 1 (dose 2) in aged mice: aged C57BL/6 mice (n=15) at 23 months of age received an infusion of ˜50 mg/mL Compound 1 using an Alzet model 2002 mini-pump (0.5 µl /h) for four weeks with one replacement.

Mice were tested on a rotating drum for motor coordination. Success or failure was recorded in the last trial, with success being determined by holding on the drum to fall >90 s. The best results were observed in mice treated with compound 1, compared with mice treated with the vehicle, according to the binomial criterion. N=15 each, *p<0.05. A greater percentage of mice treated with Compound 1, 47%, were able to hold onto the spinning drum for longer than 90 s, a threshold where only 20% of mice treated with vehicle control could hold onto the spinning drum after 3 consecutive trials (Fig. 20). These results suggest that Compound 1 affects motor function in eotaxin elevation models.

Mice were tested in a T-maze for cognitive function (FIG. 21). Recorded the number of successful or unsuccessful attempts to refuse to enter the correct branch. The best results were observed in mice treated with compound 1, compared with mice treated with the vehicle, according to the binomial criterion. *p<0.05.

Fecal excretion was measured by weighing the dry weight of the fecal pellets overnight (FIG. 22). Gastric dysfunction is a well-known symptom of Parkinson's disease. Water and food intake were measured over the same time period. Mice treated with Compound 1 excreted significantly less feces compared to mice treated with vehicle control. They also had significantly higher water intake during the night compared to control mice. *p<0.05. These results indicate that gastric insufficiency can be reversed with Compound 1 treatment.

Ninth experimental group (see Fig. 23): three-month-old C57 mice were injected with a single dose of lipopolysaccharide (LPS) 10 mg/kg intraperitoneally to induce inflammation and were administered compound 1 for 18 days.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Collifor at a concentration of 10% was added to each solution every week and stored at 4°C.

impact groups.

Treatment Group 1, Vehicle Exposure: Young C57BL/6 mice (n=15) aged 3 months received a single injection of LPS and vehicle solution twice daily (2 r/day) via oral gavage for 18 days.

Exposure Group 2, Compound 1 Exposure: Young C57BL/6 mice (n=15) aged 3 months received a single injection of LPS and Compound 1 30 mg/kg solution twice daily (2 r/day)

- 87 041892 by oral tube for 18 days.

Brain sections were immunostained to detect CD68+ activated microglia.

Mice treated with Compound 1 showed reduced CD68+ immunoreactivity (decrease in activated microglia) in contrast to mice treated with vehicle (saline saline) (FIG. 23). N=9, 10, 8. *p<0.05 by one-way ANOVA.

These data indicate a powerful anti-neuroinflammatory effect of compound 1, which has therapeutic potential to reduce neuroinflammation-induced neuronal toxicity in diseases manifested by neurodegeneration, cognitive or motor impairments.

Tenth Experimental Group (see FIGS. 24-29): Three-month-old C57 mice were dosed daily with 0.5 mg/kg ip lipopolysaccharide (LPS) to induce inflammation and were treated with Compound 1 for up to 4 weeks.

Composition: compound 1 was prepared in 40% HP-in-cyclodextrin and adjusted to pH 6.5 with NaOH (1 M). The carrier solution was made up and adjusted for pH in a similar manner. Collifor at a concentration of 10% was added to each solution every week and stored at 4°C.

impact groups.

Exposure group 1, vehicle exposure: 3-month-old C57 mice (n=10) were injected daily with intravenous LPS for 7 weeks, and the vehicle solution was administered twice a day (2 r/day) via oral gavage (po) over a period of up to 4 weeks.

Exposure group 2, vehicle exposure and oxazolone exposure: 3-month-old C57 mice (n=10) were injected daily with intravenous LPS for 7 weeks and the vehicle solution twice a day (2 r / day) through an oral tube (p / o) for a period of up to 4 weeks.

Treatment group 3, exposure to compound 1 and exposure to oxazolone: 3-month-old C57 mice (n=9) were injected daily with intravenous LPS for 7 weeks and compound 1, 30 mg/kg twice a day (2 r/day) through an oral tube (p / o), for a period of up to 4 weeks.

In FIG. 24A shows the dosing schedule for the tenth experimental group. The section of the circuit highlighted by a square represents the time points at which the analysis was performed in FIG. 24V. Anxiety was analyzed by open field test after 1 week of Compound 1 administration (FIG. 24B). The introduction of LPS significantly increased anxiety in the open field test, and compound 1 significantly reduced increased anxiety, * p<0.05.

In FIG. 25A shows the dosing schedule for the tenth experimental group. The section of the circuit highlighted by a square represents the time points at which the analysis was performed in FIG. 25V. Cognitive functions were analyzed using a Y-maze after 3 weeks of administration of compound 1 (Fig. 25B). Mice treated with LPS showed no significant preference for the new offshoot. However, Compound 1 treated mice showed a significant preference for the new offshoot, similar to vehicle treated mice, *p<0.05, **p<0.01.

In FIG. 26A shows the dosing schedule for the tenth experimental group. The section of the circuit highlighted by a square represents the time points at which the analysis was performed in FIG. 26B. mRNA levels of the inflammatory cytokine IL-1beta were measured by quantitative PCR 4 weeks after compound 1 administration (FIG. 26B). Mice treated with LPS tended to increase levels of IL-1 beta, and mice treated with Compound 1 showed a significant decrease in IL-1 beta expression, *p<0.05.

In FIG. 27A shows the dosing schedule for the tenth experimental group. The section of the circuit highlighted by a square represents the time points at which the analysis was performed in FIG. 27V. Brain sections were immunostained to detect CD68+ activated microglia. Mice treated with Compound 1 showed drastically reduced CD68+ immunoreactivity (decrease in activated microglia) in contrast to mice treated with LPS alone (FIG. 27B).

In FIG. 28A shows the dosing schedule for the tenth experimental group. The section of the circuit highlighted by a square represents the time points at which the analysis was performed in FIG. 28V. Brain sections were immunostained to detect Iba1-positive microglia. Mice treated with Compound 1 showed drastically reduced Iba1+ immunoreactivity (decrease in total microglia) in contrast to mice treated with LPS alone (FIG. 28B).

In FIG. 29A shows the dosing schedule for the tenth experimental group. The section of the circuit highlighted by a square represents the time points at which the analysis was performed in FIG. 29V. Brain sections were immunostained to detect GFAP-positive astroglia. Mice treated with Compound 1 showed dramatically reduced GFAP+ immunoreactivity (decrease in total astrocyte count) in contrast to mice treated with LPS alone (FIG. 29B).

These data indicate a powerful anti-neuroinflammatory effect of compound 1, which has therapeutic potential to reduce neuroinflammation-induced neuronal toxicity in diseases manifested by neurodegeneration, cognitive or motor impairments.

- 88 041892

3. Mouse MPTP model of Parkinson's disease.

An MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model is used to determine the level of reduction in MPTP-induced deficiency in parkinsonism. MPTP is a prodrug of MPP+ that can cause persistent symptoms of Parkinson's disease. MPP+ works by destroying dopaminergic neurons in the substantia nigra region of the brain.

Eight-week-old male C57BI/6J mice received either vehicle (saline saline) or 20 mg/kg MPTP twice daily (2 r/day) at 3-hour intervals for two consecutive days, on days 1 and 2. On day 3, mice received either vehicle or Compound 1 30 mg/kg twice daily by oral gavage and continued to receive Compound 1, 2 p/day po until day 12 (study plot, FIG. 30A). On day 10, mice were tested for motor function on a rotating drum, and on day 11, mice were tested in the Motorater test for kinematic gait analysis for motor coordination (Tse Systems, Inc., Chesterfield, MO). Mice were sacrificed on day 12. Thirty (30) mg/kg is a sufficient dose to achieve >100 nM Compound 1 concentration within 8 h (FIG. 8) and the IC ₅₀ in the CCR3 receptor internalization biomarker assay is <100 nM; this dosing regimen has been successfully used in studies in aged mice. Number (n) of 14 animals was used for each group. These numbers are based on previous experience where an effect of >20% was observed at a p<0.05 significance level. All results were analyzed by one-way ANOVA to determine

1) statistical difference between the control group and the MPTP group treated with the vehicle; And

2) statistical difference between MPTP groups treated with vehicle and compound 1.

In FIG. 30B summarizes the behavioral, biochemical, and histological evaluation criteria in this study.

4. Synnuclein transgenic mouse model of Parkinson's disease.

The synuclein transgenic mouse model was used to determine the effects of chronic CCR3 inhibition by Compound 1 and its ability to slow, halt or reverse the progression of Parkinson's disease-like symptoms. Thus, this model, which overexpresses human α-synuclein, tests whether Compound 1 prevents α-synuclein-induced behavioral and pathological disorders. To select the optimal model for testing, plasma levels of eotaxin were measured as a biomarker in multiple synuclein mouse models at different ages. The models included A53T, DxJ9M and line 61. In the plasma of 6-month-old synuclein transgenic mice of line 61, eotaxin levels were determined by ELISA as a biomarker. In mice of strain 61 (QPS Neuro, Grambach, Austria) at 6 months of age, a transgene-induced increase in eotaxin levels was observed (Fig. 31), indicating that plasma levels of eotaxin may serve as a suitable clinical biomarker for selecting treatment groups.

Non-transgenic control mice received vehicle and transgenic mice received vehicle or Compound 1 in their drinking water for 6 weeks. Meanwhile, non-transgenic control mice could receive vehicle 2 r/day po, and transgenic mice received compound 1, 2 r/day po. Number (n)=15 animals per group gives statistical significance at p<0.05 with an effect size of 20% based on previous experiments. Within a week, 7 mice were subjected to testing for behavioral disorders and sacrificed at the end of testing at the age of 6 months. All results were analyzed by one-way ANOVA to determine

1) statistical difference between the non-transgenic group and the transgenic group treated with the vehicle; And

2) statistical difference between transgenic groups treated with vehicle and compound 1.

In FIG. 32 summarizes the behavioral, biochemical and histological evaluation criteria.

d. Human examples 1.

Eotaxin levels and aging human eotaxin-1 levels were determined using a commercially available affinity-based assay (SOMAscan, SomaLogic, Inc., Boulder, Colorado). Plasma samples were collected from 18, 30, 45, 55 and 66 year old donors for SomaLogic testing using the SOMAscan aptamer affinity assay which, among other things, analyzed relative levels of human eotaxin-1. Eotaxin-1 levels were determined and plotted according to age group (FIG. 33). Relative concentrations of eotaxin-1 increased with age, indicating that the eotaxin-1 pathway, including its primary receptor, CCR3, is a target for the treatment of aging-associated diseases such as neurodegenerative diseases and cognitive decline. 2.

Human biomarker assays.

Whole blood from humans treated with Compound 1 was incubated with human recombinant eotaxin-1 to induce reshaping of eosinophils (FIG. 34A) or internalization of the CCR3 receptor (FIG. 34B). Both assays demonstrated a strong concentration-dependent effect of Compound 1 on the performance of the respective functional biomarkers.

- 89 041892

Taken together, results from ESC assays and receptor internalization

CCR3 confirm that Compound 1 acts as an inhibitor of the human eotaxin-1 pathway. In particular, Compound 1 can act as a potent inhibitor of CCR3 by binding to this receptor.

The invention described herein is also defined by the following provisions.

A method of treating a neurodegenerative disease in a subject diagnosed with a neurodegenerative disease, comprising administering a therapeutically effective amount of a compound of formula 1

where A represents CH2, O or NC _1-6 -alkyl;

R ¹ is selected from

NHR ^{1 1} , NMeR ^{1 1} ;

NHR ^{1 2} , NMeR ^{1 2} ;

NHCH2-R ^{1 3} ;

NH-C _3-6 -cycloalkyl, where optionally one carbon atom is replaced by a nitrogen atom, and the specified ring is optionally substituted by one or two residues selected from the group consisting of C ₁ - ₆ alkyl, O-C _1-6 -alkyl, NHSO _2- phenyl, NHCONH-phenyl, halogen, CN, SO ₂ -C _1-6 -alkyl, COO-C _1-6 -alkyl;

C _{9 or 10} -bicyclic ring, where one or two carbon atoms are replaced by nitrogen atoms and the specified ring system is connected through the nitrogen atom to the main structure of formula 1, while the specified ring system is optionally substituted by one or two residues selected from the group consisting of C _1-6 alkyl, COO-C _1-6 alkyl, C _1-6 haloalkyl, OC _1-6 alkyl, NO2, halogen, CN, NHSO2C _1-6 alkyl, methoxyphenyl;

a group selected from NHCH(pyridinyl)CH ₂ COO-C _1-6 alkyl, NHCH(CH ₂ O-C _1-6 alkyl)benzimidazolyl optionally substituted with halogen or CN; or

1-aminocyclopentyl optionally substituted with methyloxadiazole;

R ^{1 1} is phenyl optionally substituted with one or two residues selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkylene -OH, C2-6-alkenylene-OH, C2-6-alkynylene-OH, CH2CON(C1-6-alkyl)2, CH2NHCOH-C3-6-cycloalkyl, CN, CO-pyridinyl, CONR ^{1 1} ^ ^{1 1 2} , COO-C1-6-alkyl, N (SO ₂ -C _1-6 -alkyl) (CH ₂ CON (C _1-4 -alkyl) ₂ ), OC _1-6 -alkyl, O-pyridinyl, SO ₂ -C _1-6 -alkyl, SO ₂ -C _1-6 -alkylene-OH, SO ₂ -C _3-6 -cycloalkyl, SO ₂ -piperidinyl, SO2NHC _1-6 -alkyl, SO ₂ N (C _{1 -6} -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl, or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl, NHC _1-6 -alkyl and =O;

R ^{1 1 1} is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 haloalkyl, CH ₂ CON(C _1-6 alkyl) ₂ , CH ₂ CO-azetidinyl, C _1-6 -alkylene-C _3-6 -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C _1-6 -alkylene-OH or thiadiazolyl, optionally substituted with C _1-6 -alkyl;

R ^{1 1 2} is H, C _1-6 alkyl, SO ₂ C _1-6 alkyl; or

R ^{1 1 1} and R ^{1 1 2} together form a four-, five- or six-membered carbocyclic ring, optionally containing one N or O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group, consisting of C _1-6 -alkyl, C _1-4 -alkylene-OH, OH, =0; or

R ^{1 1} is phenyl, where two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing one or two N, S or SO2 independently of each other, which replace a carbon atom in the ring, and the specified ring is optional substituted with C _1-4 -alkyl or =0;

R ^{1 2} is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, CH ₂ COO-C _1-6 -alkyl, CONR ¹ . ² . ¹ R ¹ . ² . ² , COR ^{1 2 3} , COO-C _1-6 -alkyl, CONH2, OC _1-6 -alkyl, halogen, CN, SO ₂ N(C _1-6 -alkyl) ₂ or heteroaryl optionally substituted with one or two residues selected from the group consisting of C _1-6 alkyl;

heteroaryl optionally substituted with a five- or six-membered carbocyclic non-aromatic ring independently containing two N, O, S or SO2 replacing a carbon atom in the ring;

aromatic or non-aromatic C ₉ or ₁₀ -bicyclic ring, where one or two carbon atoms are replaced by N, O or S, each of which is optionally substituted by one or two residues selected from the group consisting of N(C ₁ . ₆ -alkyl) ₂ , CONH-C ₁ . ₆ -alkyl, =O;

a heterocyclic non-aromatic ring optionally substituted with pyridinyl;

4,5-dihydronaphtho[2,1-d]thiazole, optionally substituted with NHCO-C _1-6 -alkyl,

R ¹ ' ² ' ¹ represents H, C ₁ . ₆ -alkyl, C ₁ . ₆ -alkylene-C ₃ . ₆ -cycloalkyl, C _1-4 -alkylene-phenyl, C ₁ . ₄ -alkylenefuranyl, C ₃ . ₆ -cycloalkyl, C _1-4 -alkylene-O-C _1-4 -alkyl, C ₁ . _{a 6} -haloalkyl or five- or six-membered carbocyclic non-aromatic ring optionally containing independently one or two N, O, S or SO2 replacing a carbon atom in the ring, optionally substituted with 4-cyclopropylmethylpiperazinyl;

R ¹ ' ² ' ² represents H, C ₁ . ₆ -alkyl;

R ¹ ' ² ' ³ represents a five - or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S or SO2 independently of each other, which replace a carbon atom in the ring;

R ^1'3 is selected from phenyl, heteroaryl or indolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C ₁ . ₆ -alkyl, C ₃ - ₆ -cycloalkyl, OC ₁ . ₆ -alkyl, OC ₁ . ₆ -haloalkyl, phenyl, heteroaryl;

R ² is selected from the group consisting of C ₁ . ₆ -alkylene-phenyl, C ₁ . ₆ -alkylene-naphthyl and C ₁ . ₆ -alkyleneheteroaryl, each of which is optionally substituted with one, two or three residues selected from the group consisting of C ₁ . ₆ -alkyl, C ₁ . ₆ -haloalkyl, OC ₁ . ₆ -alkyl, OC ₁ . ₆ -haloalkyl, halogen;

R ³ is H, C ₁ . ₆ -alkyl;

R ⁴ is H, C ₁ . ₆ -alkyl; or

R ³ and R ⁴ together form a CH2-CH2 group;

for the treatment of a neurodegenerative disease in a subject'

The method wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, progressive supranuclear palsy'. compound of formula 1

A represents CH ₂ , O or NC ₁ _ ₄ -alkyl;

R ¹ is selected from

NHR ^{1 1} , NMeR ¹ '¹;

NHR ¹ ' ² , NMeR ¹ '²;

NHCH2-R ^1'3 ;

NH- _C3 . ₆ -cycloalkyl, where optionally one carbon atom is replaced by a nitrogen atom, and the specified ring is optionally substituted by one or two residues selected from the group consisting of C ₁ . ₆ -alkyl, OC ₁ . ₆ -alkyl, NHSO ₂ -phenyl, NHCONH-phenyl, halogen, CN, SO ₂ -C ₁ . ₆ -alkyl, COO-C1.6-alkyl;

C ₉ or 10-bicyclic ring, where one or two carbon atoms are replaced by nitrogen atoms and the specified ring system is connected through the nitrogen atom to the main structure of formula 1, while the specified ring system is optionally substituted by one or two residues selected from the group consisting of C ₁ . ₆ -alkyl, COO-C ₁ . ₆ -alkyl, C ₁ . ₆ -haloalkyl, OC ₁ . ₆ -alkyl, NO2, halogen, CN, NHSO2C ₁ . ₆ -alkyl, m-methoxyphenyl;

a group selected from NHCH(pyridinyl)CH ₂ COO-C ₁ . ₆ -alkyl, NHCH(CH ₂ O-C ₁ . ₆ alkyl)benzimidazolyl, optionally substituted with a Cl atom; or

1-aminocyclopentyl optionally substituted with methyloxadiazolyl;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of C1.6-alkyl, C1.6-haloalkyl, CH2CON(C1.6-alkyl)2, CH2NHCOH-C3-6-picloalkyl, CN , CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COO-C1. ₆ -alkyl, OC ₁ . ₆ -alkyl, SO ₂ -C ₁ . ₆ -alkyl, SO ₂ -C ₁ . ₆ -alkylene-OH, SO ₂ -C ₃ . ₆ -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C ₁ . ₆ -alkyl, SO ₂ N(C ₁ . ₆ -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl, or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C ₁ . ₆ -alkyl, NHC ₁ . ₆ -alkyl, =O;

R ¹ ' ¹ ' ¹ represents H, C ₁ . ₆ -alkyl, C _3-6 -cycloalkyl, C ₁ . ₆ -haloalkyl, CH ₂ CON(C ₁ . ₆ -alkyl) ₂ , CH ₂ CO-azetidinyl, C ₁ . ₆ -alkylene-C ₃ . ₆ -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C ₁ . ₆ -alkylene-OH or thiadiazolyl optionally substituted with C ₁ . ₆ -alkyl;

R ¹ ' ¹ ' ² represents H, C ₁ . ₆ -alkyl, SO ₂ C ₁ . ₆ -alkyl; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH;

R ^1'2 is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of C ₁ . ₆ -alkyl, C ₃ - ₆ -cycloalkyl, CH ₂ COO-C ₁ . ₆ -alkyl, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COO-C ₁ . ₆ -alkyl, CONH2, OC ₁ . ₆ -alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl or heteroaryl optionally substituted with one or two residues selected from the group consisting of C ₁ . ₆ -alkyl;

- 91 041892 benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of N(C ₁ .6alkyl) ₂ , CONH-C _1-6 -alkyl, =0;

piperidinyl optionally substituted with pyridinyl;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCO-C _1-6 alkyl;

R ¹ ' ² ' ¹ represents H, C _1-6 -alkyl;

R ¹ ' ² ' ² represents H, C _1-6 -alkyl;

R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C _1-6 -alkyl, C _3-6 -cycloalkyl, O- C _1- b-alkyl, O-C _1- b-haloalkyl;

R ² is selected from

CH2-phenyl or CH2-naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of C _1-6 alkyl, C _1-6 haloalkyl, 0-C _1-6 alkyl, 0-C _{1 -6} -haloalkyl, halogen; or

CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen;

R ³ is H, C _1-4 alkyl;

R ⁴ is H, C _1-4 alkyl; or

R ³ and R ⁴ together form a CH2-CH2 group,

The method in which in the compound of formula 1

A is CH2, O or NMe;

R ¹ is selected from

NHR ^1'1 , NMeR ^1'1 ;

NHR ^1'2 , NMeR ^1'2 ;

NHCH ₂ -R ¹ '³;

NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, NHSO ₂ -phenyl, NHCONH-phenyl, halogen;

NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO ₂ -C _1-4 -alkyl, COO-C _1-4 -alkyl;

piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO ₂ -C _1-4 alkyl, m-methoxyphenyl;

dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl optionally substituted with one or two residues selected from the group consisting of C _1-4 alkyl, COO-C _1-4 alkyl, C _1-4 haloalkyl, O-C _1-4 -alkyl, NO2, halogen;

a group selected from NHCH(pyridinyl)CH ₂ COO-C _1-4 alkyl, NHCH(CH ₂ O-C _1-4 alkyl)benzimidazolyl optionally substituted with C1 atom; or

1-aminocyclopentyl optionally substituted with methyloxadiazolyl;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of C1-4alkyl, C1-4haloalkyl, CH2CON(C1-4alkyl)2, CH2NHCONH-C3-6picloalkyl, CN , CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COO-C1-4-alkyl, O-C _1-4 -alkyl, SO ₂ -C _1-4 -alkyl, SO ₂ -C _1-4 -alkylene -OH, SO ₂ -C _3-6 -picloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C _1-4 -alkyl, SO ₂ N (C _1-4 -alkyl) ₂ , halogen, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, NHC _{1 -4} -alkyl, =O;

R ¹ ' ¹ ' ¹ is H, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-4 haloalkyl, CH ₂ CONC _1-4 alkyl) ₂ , CH ₂ CO-azetidinyl, C _{1 -4} -alkylene-C _3-6 -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C _1-4 -alkylene-OH or thiadiazolyl, optionally substituted with C _1-4 -alkyl;

R ¹ ' ¹ ' ² represents H, C _1-4 -alkyl, SO ₂ C _1-4 -alkyl; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH;

R ¹ ' ² is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of

C _1-4 -alkyl, C _3-6 -cycloalkyl, CH ₂ COO-C _1-4 -alkyl, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COO-C _1-4 -alkyl, CONH ₂ , O-C _1-4 -alkyl, halogen, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C _1-4 - alkyl;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of N(C _1-4 -alkyl) ₂ , CONH-C _1-4 -alkyl, =0;

- 92 041892 piperidinyl optionally substituted with pyridinyl;

4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCO-C ₁ . ₄ -alkyl;

R ¹ ' ² ' ¹ represents H, C1-4-alkyl; R ¹ ' ² ' ² represents H, C1-4-alkyl;

R ^1.3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of Ci-4-alkyl, C ₃ _ ₆ -cycloalkyl, O-Ci-4 -alkyl, OC ₁ . ₄ -haloalkyl;

R ² is selected from

CH ₂ -phenyl or CH ₂ -naphthyl, which are both optionally substituted with one or two residues selected from the group consisting of C _1-4 -alkyl, C _1-4 -haloalkyl, O-C _1-4 -haloalkyl, halogen; or

CH2-thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH2-CH2 group.

A method characterized in that in formula 1 A is CH ₂ , O or NMe;

R ¹ is selected from

NHR ¹ ' ¹ , NMeR ¹ '¹;

NHR ¹ ' ² , NMeR ¹ '²;

NHCH2-R ¹ '³;

NH-piperidinyl optionally substituted with pyridinyl;

NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO ₂ -phenyl, NHCONH-phenyl, F;

NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO ₂ Me, COO-t-Bu;

piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO ₂ -n-Bu, m-methoxyphenyl;

dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF ₃ , OMe, NO ₂ , F, Br;

a group selected from NHCH(pyridinyl)CH ₂ COOMe, NHCH(CH ₂ OMe)benzimidazolyl optionally substituted with a Cl atom; or

1-aminocyclopentyl optionally substituted with methyloxadiazolyl;

R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CH2NHCONH-pyclohexyl, CN, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COOMe, COOEt, OMe, SO2Me, SO ₂ CH ₂ CH ₂ OH, SO ₂ Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO ₂ NHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH2-pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O;

R ¹ ' ¹ ' ¹ is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH ₂ -i-Pr, CH ₂ -t-Bu, CH(CH ₃ )CH ₂ CH ₃ , CH ₂ CHF ₂ , CH ₂ CONMe ₂ , CH ₂ CO-azetidinyl, CH ₂ -cyclopropyl, CH ₂ -cyclobutyl, CH _{2 -pyranyl, CH 2} -tetrahydrofuranyl, CH 2 -furanyl, CH 2 CH 2 OH, or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² represents H, Me, Et, SO ₂ Me, SO ₂ Et; or

R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH;

R ^1'2 is selected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH ₂ COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O;

4,5-dihydronaphtho[2,1-d]thiazole, optionally substituted with an NHCOMe group,

R ^1'2'1 represents H, Me;

R ^1'2'2 represents H, Me;

R ^1'3 is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl, or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF2;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br;

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH2-CH2 group. The method in which in formula 1 A represents CH2, O or NMe;

R ¹ is selected from

NHR ¹ '¹;

NHR ¹ '²;

R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Bu, CF3, CH2CONMe2, CH2NHCONH-pyclohexyl, CN, CONR ¹ ' ¹ ' ¹ R ^{1 1} ' ² , COOMe, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO ₂ -cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanil, pyrazolyl, triazolyl, tetrazolyl , oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O;

R ^{1 1} ' ¹ is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH ₂ -i-Pr, CH ₂ -t-Bu, CH(CH ₃ )CH ₂ CH ₃ , CH ₂ CHF ₂ , CH ₂ CONMe ₂ , CH ₂ CO-azetidinyl, CH ₂ -cyclopropyl, CH ₂ -cyclobutyl, CH 2 -pyranyl, CH ₂ -tetrahydrofuranyl, CH 2 -furanyl, CH 2 CH 2 OH, or thiadiazolyl optionally substituted with Me;

R ¹ ' ¹ ' ² is H, Me, Et, SO ₂ Me, SO2 Et; or

R ^{1 1 1} and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH ₂ OH;

R ¹ ' ² is selected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH ₂ COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, COmorpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group;

benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O;

4,5-dihydronaphtho[2,1-d]thiazole, optionally substituted with an NHCOMe group,

R ¹ ' ² ' ¹ represents H, Me; R ¹ ' ² ' ² represents H, Me;

R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et;

R ³ is H;

R ⁴ is H'

The way in which in formula 1

A is CH2, O or NMe;

R ¹ is selected from

- 94 041892

- 95 041892

- 96 041892

- 97 041892

- 98 041892

- 99 041892

- 100 041892

- 101 041892

R ² is selected from

R ³ is H;

R ⁴ is H; or

R ³ and R ⁴ together form a CH ₂ -CH ₂ group.

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

- 102 041892

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

The way in which that the compound of formula 1 administered is

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

- 103 041892

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

The method in which the administered compound of formula 1 is

where R ¹ represents C _1-6 -alkyl, C _1-6 -haloalkyl, OC _1-6 -haloalkyl, halogen;

m is 1, 2 or 3;

R ^2a and R ^2b are each independently selected from H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 αkynyl, C _3-6 cycloalkyl, COO-C _1-6 alkyl, OC _{1 -6} -alkyl, CONR ^2b '1R ^2b ' ² , halogen;

R ^2b '1 is H, C _1-6 alkyl, C _0-4 alkyl-C _3-6 cycloalkyl, C _1-6 haloalkyl;

R ^2b ' ² represents H, C _1-6 -αkyl; or

R ^2b '1 and R ^2b ' ² together represent a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom;

R ³ is H, C _1-6 alkyl;

X is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyl tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate ;

j is 0, 0.5, 1, 1.5, or 2;

with a co-crystal forming compound selected from the group consisting of orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L-(+)-ascorbic acid, saccharin, piperazine, 3-hydroxy-2- naphthoic acid, mucinic (galactaric) acid, pamoic (embonic) acid, stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine.

A process wherein said compound is a co-crystal of the formula

* (HX)j ft ^d where R ^2a is H, C _1-6 -alkyl, C _1-6 -alkenyl, C _1-6 alkynyl, C _3-6 -cycloalkyl, O-C _1-6 -alkyl , CONR^R ² '²;

R ^2a '1 represents H, C _1-6 alkyl, C _1-6 haloalkyl;

R ^2a ' ² represents H, C _1-6 -alkyl;

R ^2b is H, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _3-6 cycloalkyl, COO-C _1-6 alkyl, O-C _1-6 - alkyl, CONR ^{2b 1} R ^{2b 2} , halogen;

R ^2b '1 represents H, C1-6-alkyl, C0-4-alkyl-C3-6-cycloalkyl, C1-6-haloalkyl; R ^2b '1 is H, C1-6 alkyl; or

R ^2b '1 and R ^2b ' ² together represent a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom.

A process wherein said compound is a co-crystal of the formula

R ¹ is C _1-6 alkyl, C _1-6 haloalkyl, O-C _1-6 haloalkyl, halogen;

m is 1 or 2;

R ^2a is H, C _1-4 alkyl;

R ^2b is H, CONR ^{2b 1} R ^{2b 2} ;

R ^2b '1 is C _1-4 alkyl, C _0-4 alkyl-C _3-6 cycloalkyl, C _1-4 haloalkyl;

R ^2b ' ² represents H, C _1-4 -alkyl; or

R ^2b.1 and R ^2b ' ² together represent a C _3-6 -alkylene group forming a heterocyclic ring with a nitrogen atom, where optionally one carbon atom of the ring is replaced by an oxygen atom;

R ³ is H, C _1-6 alkyl;

X is an anion selected from the group consisting of chloride or dibenzoyl tartrate;

j is equal to 1 or 2.

A process wherein said compound is a co-crystal of the formula

R ^2a is H, C _1-4 alkyl; R ^2b is H, CONR ^{2b 1} R ^{2b 2} ;

R ^2b '1 represents C _1-4 -alkyl;

R ^2b ' ² is C _1-4 alkyl.

- 105 041892

A process wherein said compound is a co-crystal of the formula

R ^2a is H, C _1-4 alkyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^2b '1 is C _0-4 alkyl-C _3-6 picloalkyl;

R ^2b ' ² is H, C _1-4 alkyl.

The process in which said compound is a co-crystal of the formula o^/\

R ^2a is H, C _1-4 alkyl;

R ^2b is H, CONR ^2b '1R ^2b '²;

R ^2b '1 is C _1-4 haloalkyl;

R ^2b ' ² is H, C _1-4 alkyl.

A process wherein said compound is a co-crystal of the formula wherein R ^2b '1 and R ^2b ' ² together represent a C _3-6 alkylene group forming a heterocyclic ring with the nitrogen atom, with one carbon atom in the ring optionally replaced by an oxygen atom .

The method in which said compound is a co-crystal of the formula below,

DNKh);

where j is 0 and the co-crystal forming compound is selected from the group consisting of L-(+)ascorbic acid, mucic acid, pamoic acid, nicotinic acid, succinamide, nicotinamide, isonicotinamide, L-lysine and L-proline.

The method in which said compound is a crystalline salt of the formula below,

*di6enzoyl tartrate

The method in which said compound is a crystalline salt of the formula below,

'2HC1

The method in which said crystalline salt is characterized by having the four highest

- 106041892 peaks in the X-ray powder diffraction pattern at 3.72, 13.60, 16.89 and 19.34° 2Θ (±0.05° 2θ) when measured using CuKa radiation.

A method wherein said crystalline salt is characterized by having the four highest peaks in the X-ray powder diffraction pattern at 16.02, 16.86, 19.45 and 19.71° 2θ (±0.05° 2θ) as measured using CuKa radiation.

A method wherein said compound contains at least one co-crystal of a compound of the formula and a pharmaceutically acceptable carrier.

A method in which a compound of formula 1 is administered in the form of individual optical isomers, a mixture of individual enantiomers, a racemate, or in the form of enantiomerically pure compounds.

A method wherein said compound is a pharmaceutical composition containing one or more compounds of the formula below as an active ingredient,

where R ¹ represents H, C _1-6 -alkyl, C _0-4 -αkyl-C _3-6 -cycloalkyl, C _1-6 -halogenalkyl;

R ² is H, C _1-6 -alkyl;

X is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate;

j is 1 or 2, a first diluent, a second diluent, a binder, a disintegrant, and a lubricant.

The way in which

R ¹ is H, methyl;

R ² is H, methyl;

X is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate;

j is equal to 1 or 2.

The way in which

X is chloride; and j is 2.

A method wherein the pharmaceutical composition further comprises an additional disintegrant.

The method, in which the pharmaceutical composition further comprises an additional sliding agent.

The method wherein the pharmaceutical composition diluent further comprises powdered cellulose, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.

A process wherein the lubricant of the pharmaceutical composition is talc, polyethylene glycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.

A method in which the binder of the pharmaceutical composition is copovidone (copolymers of vinylpyrrolidone with other vinyl derivatives), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (povidone).

A method wherein the disintegrant in the pharmaceutical composition of this item is corn starch.

A process wherein the optional lubricant in the pharmaceutical composition is colloidal silicon dioxide.

The method, in which the pharmaceutical composition additionally contains, %: active ingredient - 10-90; thinner - 15-70; thinner - 25-30; binder - 0-30; baking powder - 1-12; and lubricant - 0.1-3.

The method, in which the pharmaceutical composition additionally contains, %: active ingredient - 30-70; thinner - 120-75; thinner - 25-30; binder - 2-30; buffer agent - 0.5-20; baking powder - 1-12; and lubricant - 0.1-3.

The method wherein the additional disintegrant of the pharmaceutical composition is crospovidone.

A method in which the pharmaceutical composition is presented in the dosage form of a capsule, tablet or film-coated tablet.

- 107 041892

A method in which the pharmaceutical composition additionally contains 2-4% film coating.

A method in which the film coating contains a film-forming agent, a plasticizer, a lubricant, and optionally one or more pigments.

A method in which the film coating contains polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), talc, titanium dioxide and iron oxide.

It should be understood that this invention is not limited to the specific aspects described, as they may vary. It should also be understood that the terminology used in this context is intended to describe only specific aspects and is not intended to be limiting, hence the invention is limited only by the appended claims.

When specifying a range of values, it should be understood that this invention includes every intermediate value between the upper and lower limits of the specified range, to the nearest tenth of the lower limit, unless the context clearly requires otherwise, as well as any other specified or intermediate value in this range. The upper and lower limits of these smaller ranges can be independently included in the smaller ranges and are also included in this invention, except for any specifically excluded limit in the specified range. If the claimed range includes one or both of the limits, then ranges excluding one or both of the included limits are also included in this invention.

Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as is generally understood by a person skilled in the art to which this invention pertains. While any methods and materials such as those described herein, or their equivalents, may also be used in the practice or testing of this invention, typical illustrative methods and materials are described herein.

All publications and patents cited in this document are incorporated herein by reference as if each individual publication or patent were specifically and individually indicated as being incorporated by reference, and are incorporated herein by reference to disclose and describe methods and/or materials in connection with which these publications are cited. The citation of any publication is intended to describe it prior to the filing date and should not be construed as an admission that the present invention is not entitled to predate such publication by virtue of prior invention. In addition, publication dates shown may differ from actual publication dates, which may require independent verification.

It should be noted that in this context and in the appended claims, singular forms include reference to plural forms, unless the context clearly dictates otherwise. Additionally, it should be noted that the claims may be drafted to exclude any optional element. Thus, said statement is intended as a preliminary basis for the use of such exclusive terminology as exclusively, only, etc., in relation to the enumeration of the elements of the claims, or for the application of a negative limitation.

Those skilled in the art will appreciate upon reading this disclosure that each of the independent aspects described and illustrated herein has separate components and features that can be readily isolated or combined with features of any of several other aspects, without departing from the scope. and essence of this invention. Any method cited may be carried out in the order of the steps listed, or in any other order that is logically possible.

While the invention described above has been described in detail for purposes of clarity of understanding by way of illustration and example, it will be readily understood by those skilled in the art in light of the spirit of the present invention that certain changes and modifications may be made to the present invention without departing from the spirit or scope. the appended claims.

Accordingly, the foregoing description is only intended to illustrate the principles of the present invention. It should be understood that those skilled in the art can ascertain various permutations which, while not specifically described or depicted herein, embody the principles of the present invention and are within its spirit and scope. In addition, all examples and conventions used herein are principally intended to facilitate the reader's understanding of the principles of this invention and the concepts introduced by the inventors in the development of the art, and should be construed without limitation to such specific examples and conditions given. In addition, in this context, all statements citing the principles, aspects and aspects of the present invention, as well as specific examples thereof, include both their structural and their functional equivalents.

Further, such equivalents are contemplated to include currently known equivalents as well as equivalents to be developed in the future, i.e. any designed elements that perform the same function, regardless of the structure. Thus, the volume of this

- 108 -

Claims (8)

The invention is not limited to the illustrative aspects presented and described in this document. On the contrary, the scope and spirit of this invention is defined by the appended claims. CLAIM 1. A method of treating aging-associated neuronal loss, memory impairment, or loss of motor coordination in a subject diagnosed with aging-associated neuronal loss, memory impairment, or loss of motor coordination, comprising administering a therapeutically effective amount of a compound of formula 1, a pharmaceutically acceptable salt thereof, or optical isomer, and the compound of formula 1 has the following structure: where A represents CH2, O or NC ₁ . ₆ -alkyl; R ¹ is selected from NHR ^{1 1} , NMeR ^{1 1} ; NHR ^{1 2} , NMeR ^{1 2} ; NHCH2-R ^{1 3} ; NH-Cz. ₆ -cycloalkyl, where optionally one carbon atom is replaced by a nitrogen atom, and the specified ring is optionally substituted by one or two residues selected from the group consisting of C1. ₆ -alkyl, O-C ₁ . ₆ -alkyl, NHSO ₂ -phenyl, NHCONH-phenyl, halogen, CN, SO ₂ -C ₁ . ₆ -alkyl, COO-C1.6-alkyl; C _{9 or 10} -bicyclic ring, where one or two carbon atoms are replaced by nitrogen atoms and the specified ring system is connected through the nitrogen atom to the main structure of formula 1, while the specified ring system is optionally substituted by one or two residues selected from the group consisting of C1 . ₆ -alkyl, COO-C ₁ . ₆ -alkyl, C ₁ . ₆ -haloalkyl, O-C ₁ . ₆ -alkyl, NO2, halogen, CN, NHSO2C1. ₆ -alkyl, methoxyphenyl; a group selected from NHCH(pyridinyl)CH ₂ COO-C ₁ . ₆ -alkyl, NHCH(CH2O-C ₁ . ₆ alkyl)benzimidazolyl optionally substituted with halogen or CN; piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO ₂ -C ₁ .4-alkyl or m-methoxyphenyl; or 1-aminocyclopentyl optionally substituted with methyloxadiazole; R ^{1 1} is phenyl optionally substituted with one or two residues selected from the group consisting of C1.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.6 haloalkyl, C1.6 alkylene -OH, C2.6-alkenylene-OH, C2.6-alkynylene-OH, CH2CON(C1.6-alkyl)2, CH2NHCONH-C3.6-cycloalkyl, CO-pyridinyl, CONR ^{1 1} ^ ^{1 1 2} , COO-C1. ₆ -alkyl, N (SO ₂ -C ₁ . ₆ -alkyl) (CH ₂ CON (C ₁ .4-alkyl) ₂ ), O-C ₁ . ₆ -alkyl, O-pyridinyl, SO ₂ -C ₁ . ₆ -alkyl, SO ₂ -C ₁ . ₆ -alkylene-OH, SO ₂ -C ₃ . ₆ -cycloalkyl, SO ₂ -piperidinyl, SO2NHC1. ₆ -alkyl, SO ₂ N(C ₁ . ₆ -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl, or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C1. ₆ -alkyl, NHC ₁ . ₆ -alkyl and =O; R ¹ · ¹ · ¹ represents H, C1. ₆ -alkyl, C ₃ . ₆ -cycloalkyl, C ₁ . ₆ -haloalkyl, CH ₂ CON(C ₁ . ₆ -alkyl) ₂ , CH ₂ CO-azetidinyl, C ₁ . ₆ -alkylene-C ₃ . ₆ -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C1. _6- alkylene-OH or thiadiazolyl optionally substituted with C1. ₆ -alkyl; R ¹ · ¹ · ² is H, C1. ₆ -alkyl, SO ₂ C ₁ . ₆ -alkyl; or R ^{1 1 1} and R ^{1 1 2} together form a four-, five- or six-membered carbocyclic ring, optionally containing one N or O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group, consisting of C1. ₆ -alkyl, C1. _4- alkylene-OH, OH, =O; or R ¹ · ¹ is phenyl, where two adjacent residues together form a five- or six-membered carbocyclic aromatic or non-aromatic ring, optionally containing one or two N, S or SO ₂ independently of each other, which replace a carbon atom in the ring, and the specified ring optionally substituted with C1. ₄ -alkyl or =0; R ^{1 2} is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of C1. ₆ -alkyl, C ₂ . ₆ -alkenyl, C ₂ . ₆ -alkynyl, C ₃ . ₆ -cycloalkyl, CH ₂ COO-C ₁ . ₆ -alkyl, CONR ^{1 2 1} R ^{1 2 2} , COR ^{1 2 3} , C00-C1. ₆ -alkyl, CONH ₂ , 0-C1. ₆ -alkyl, halogen, CN, SO ₂ N(C ₁ . ₆ -alkyl) ₂ or heteroaryl optionally substituted with one or two residues selected from the group consisting of C1. ₆ -alkyl; - 109 041892 heteroaryl optionally substituted with a five- or six-membered carbocyclic non-aromatic ring independently containing two N, O, S or SO2 replacing a carbon atom in the ring; aromatic or non-aromatic C9 _{or 10} -bicyclic ring, where one or two carbon atoms are replaced by N, O or S, each of which is optionally substituted by one or two residues selected from the group consisting of N(C ₁ . ₆ -alkyl) ₂ , CONH-C ₁ . ₆ -alkylα, =O; a heterocyclic non-aromatic ring optionally substituted with pyridinyl; 4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCO-C ₁ . ₆ -alkyl; R ¹ ' ² ' ¹ represents H, C _1-b -alkyl, C ₁ _ _b -alkylene-C ₃ _ _b -cycloalkyl, C ₁ - ₄ -alkylene-phenyl, C ₁ - ₄ -alkylene-furanyl, C ₃ .b-cycloalkyl, C ₁ _ ₄ -alkylene-O-C ₁ _ ₄ -alkyl, C _1-b -haloalkyl or a five- or six-membered carbocyclic non-aromatic ring, optionally containing independently one or two N, O, S or SO2 which replaces a carbon atom in the ring, optionally substituted with 4-cyclopropylmethylpiperazinyl; R ¹ ' ² ' ² represents H, C _1-b -alkyl; R ¹ ' ² ' ³ represents a five - or six-membered carbocyclic non-aromatic ring, optionally containing one or two N, O, S or SO ₂ independently of each other, which replace a carbon atom in the ring; R ^1'3 is selected from phenyl or heteroaryl, each of which is optionally substituted with one or two residues selected from the group consisting of C1. _b -alkyl, C ₃ _ _b -cycloalkyl, O-C ₁ _ _b -alkyl, O-C ^-haloalkyl, phenyl, heteroaryl; R ² is selected from the group consisting of C ₁ - _b -alkylene-phenyl, C ₁ - _b -alkylene-naphthyl and C ₁ - _b -alkyleneheteroaryl, each of which is optionally substituted with one, two or three residues selected from the group consisting from C1. _b -alkyl, C _1-b -haloalkyl, O-C ₁ - _b -alkyl, O-C ₁ - _b -haloalkyl, halogen; R ³ is H, C1. _b -alkyl; R ⁴ is H, C1. _b -alkyl; or R ³ and R ⁴ together form a CH2-CH2 group where the heteroaryl group is a five or six membered aromatic ring or a five to ten membered bicyclic aromatic ring which may contain one, two or three heteroatoms selected from oxygen, sulfur and nitrogen, where the heterocyclic non-aromatic ring is a five-, six-, or seven-membered non-aromatic ring or a five-to-ten-membered bicyclic non-aromatic ring which may contain one, two, or three heteroatoms selected from oxygen, sulfur, and nitrogen, and wherein administration of a therapeutically effective amount of a compound of formula 1 is peripherally, so that the compound does not cross the blood-brain barrier in significant concentrations. 2. The method according to claim 1, characterized in that in the compound of formula 1 A is CH2, O or NC ₁ . ₄ -alkyl; R ¹ is selected from NHR ¹ ' ¹ , NMeR ¹ '¹; NHR ¹ ' ² , NMeR ¹ '²; NHCH2-R ¹ '³; NH- _C3 . _b -cycloalkyl, where optionally one carbon atom is replaced by a nitrogen atom, and the specified ring is optionally substituted by one or two residues selected from the group consisting of C _1-b -alkyl, O-C _{1 -b} -alkyl, NHSO ₂ -phenyl, NHCONH-phenyl, halogen, CN, SO ₂ -C ₁ . _b -alkyl, COO-C1-6 alkyl; C9 and _l and ₁₀ -bicyclic ring, where one or two carbon atoms are replaced by nitrogen atoms and the specified ring system is connected through the nitrogen atom to the main structure of formula 1, while the specified ring system is optionally substituted by one or two residues selected from the group consisting of C1. _b -alkyl, COO-C ₁ _ _b -alkyl, C1. _b -haloalkyl, O-C ₁ _ _b -alkyl, NO ₂ , halogen, CN, NHSO ₂ C1. _b -alkyl, m-methoxyphenyl; a group selected from NHCH(pyridinyl)CH ₂ COO-C ₁ . _b -alkyl, NHCH(CH ₂ OC ₁ . _b alkyl)benzimidazolyl, optionally substituted with a Cl atom; or 1-aminocyclopentyl optionally substituted with methyloxadiazolyl; R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of C1.b-alkyl, C1-b-haloalkyl, CH2CON(C1.b-alkyl)2, CH2NHCONH-C3.b-cycloalkyl, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COO-C1- _b -alkyl, O-C ₁ - _b -alkyl, SO ₂ -C ₁ . _b -alkyl, SO ₂ -C ₁ . _b -alkylene-OH, SO ₂ -C ₃ . _b -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C ₁ . _b -alkyl, SO ₂ N(C ₁ . _b -alkyl) ₂ , halogen, CN, CO-morpholinyl, CH ₂ -pyridinyl or a heterocyclic ring optionally substituted with one or two residues selected from the group consisting of C _1-b -alkyl, NHC ₁ . _b -alkyl, =O; R ¹ ' ¹ ' ¹ represents H, C1. _b -alkyl, C ₃ _ _b -cycloalkyl, C1. _b -haloalkyl, CH ₂ CON (C ₁ . _b -alkyl) ₂ , CH ₂ CO-azetidinyl, C ₁ _ _b -alkylene-C ₃ _ _b -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ - furanil, - 110 041892 C1-b-alkylene-OH or thiadiazolyl optionally substituted with C1- _b -alkyl; R ¹ ' ¹ ' ² is H, C1- _b -alkyl, SO ₂ C _1-6 -alkyl; or R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH ₂ OH; R ^1'2 is selected from heteroaryl optionally substituted with one or two residues selected from the group consisting of C1- _b -alkyl, C3 _-b -cycloalkyl, CH ₂ COO-C1- _b -alkyl, CONR ¹² 1R ¹²² , COO -C1- _b -alkyl, CONH ₂ , O-C1 _-b -alkyl, halogen, CN, CO-pyrrolidinyl, CO-morpholinyl, or heteroaryl optionally substituted with one or two residues selected from the group consisting of C1- _b -alkyl ; benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of N(C ₁ .6-alkyl) ₂ , CONH-C ₁ . _b -alkyl, =O; piperidinyl optionally substituted with pyridinyl; 4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCO-C ₁ _ ₆ alkyl; R ¹²¹ is H, C1- _b -alkyl; R ^{12 2} is H, C1- _b -alkyl; R ¹³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl, or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C1- _b -alkyl, C3 _-b -cycloalkyl, O-C1- _b -alkyl, O- _C1-6 -haloalkyl; R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of C1- _b -alkyl, C1- _b -haloalkyl, O-C1. _b -alkyl, O- _{C1_b} -haloalkyl, halogen; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen; R ³ is H, _C1-4 alkyl; R ⁴ is H, _C1-4 alkyl; or R ³ and R ⁴ together form a CH2-CH2 group. 3. The method according to claim 1, characterized in that in the compound of formula 1 A represents CH ₂ , O or NMe; R ¹ is selected from NHR ^1'1 , NMeR ^1'1 ; NHR ^1'2 , NMeR ^1'2 ; NHCH ₂ -R ¹ - ³ ; NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of _C1-4 -alkyl, NHSO ₂ -phenyl, NHCONH-phenyl, halogen; NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO ₂ -C ₁ . ₄ -alkyl, COO-C1_ ₄ -alkyl; piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO ₂ -C ₁ . ₄ -alkyl, m-methoxyphenyl; dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl optionally substituted with one or two residues selected from the group consisting of _C1-4 alkyl, COO- _{C1_4} alkyl, _C1-4 haloalkyl, O- _{C1_4} alkyl, NO ₂ , halogen; a group selected from NHCH(pyridinyl)CH ₂ COO-C ₁ . ₄ -alkyl, NHCH(CH ₂ OC ₁ . ₄ alkyl)benzoimidazolyl optionally substituted with a C1 atom; or 1-aminocyclopentyl optionally substituted with methyloxadiazolyl; R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of C1-4-alkyl, C1-4-haloalkyl, CH2CON(C1_4-alkyl)2, CH2NHCONH-C3.b-cycloalkyl, CN, CONR ¹⁴⁴ R ^{14 2} , COO-C1_4-alkyl, O-C1_ ₄ -alkyl, SO ₂ -C ₁ . ₄ -alkyl, SO ₂ -C ₁ . ₄ -alkylene-OH, SO ₂ -C ₃ . _b -cycloalkyl, SO ₂ -piperidinyl, SO ₂ NH-C ₁ . ₄ -alkyl, SO ₂ N(C ₁ . ₄ -alkyl) ₂ , halogen, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of _C1-4 -alkyl, NHC ₁ . ₄ -alkyl, =O; R ¹ ' ¹ ' ¹ is H, C1- _b -alkyl, C _3-b -cycloalkyl, _C1-4 -haloalkyl, CH ₂ CON(C ₁ . ₄ -alkyl) ₂ , CH ₂ CO-azetidinyl, C1. ₄ -alkylene-C ₃ . _b -cycloalkyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, C1-4-alkylene-OH or thiadiazolyl optionally substituted with C1-4-alkyl; R ¹ ' ¹ ' ² is H, _C1-4 alkyl, SO ₂ C ₁ . ₄ -alkyl; or R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH ₂ OH; - 111 041892 R ¹² is selected from pyridinyl, pyridazinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl, optionally substituted with one or two residues selected from the group consisting of C1.4-alkyl, C3.6-cycloalkyl, CH2COO-C1.4-alkyl , CONR ¹² 'R ¹²² , COO-C1. ₄ -αkylα, cOnH ₂ , OC ₁ . ₄ -alkyl, halo, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C ₁ . ₄ -alkyl; benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of N(C _{1 .4} alkyl) ₂ , CONH-C ₁ . ₄ -alkyl, =O; piperidinyl optionally substituted with pyridinyl; 4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCO-C ₁ . ₄ -alkyl, R ¹ ' ² ' ¹ represents H, C ₁ . ₄ -alkyl; R ¹ ' ² ' ² represents H, C ₁ . ₄ -alkyl; R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of C ₁ . ₄ -alkyl, C ₃ _ ₆ -cycloalkyl, OC ₁ . ₄ -alkyl, OC ₁ . ₄ -haloalkyl; R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of C ₁ . ₄ -αkyl, C ₁ . ₄ -haloalkyl, OC ₁ . ₄ -haloalkyl, halogen; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of halogen; R ³ is H; R ⁴ is H; or R ³ and R ⁴ together form a CH2-CH2 group, 4, The method according to claim 4, characterized in that in the compound of formula 1 A is CH2, O or NMe; R ¹ is selected from NHR ^1'1 , NMeR ^1'1 ; NHR ¹ ' ² , NMeR ¹ '²; NHCH2-R ¹ '³; NH-piperidinyl optionally substituted with pyridinyl; NH-cyclohexyl optionally substituted with one or two residues selected from the group consisting of t-Bu, NHSO ₂ -phenyl, NHCONH-phenyl, F; NH-pyrrolidinyl optionally substituted with one or two residues selected from the group consisting of SO ₂ Me, COO-t-Bu; piperidinyl optionally substituted with one or two residues selected from the group consisting of NHSO ₂ -n-Bu, m-methoxyphenyl; dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl optionally substituted with one or two residues selected from the group consisting of Me, COOMe, CF ₃ , OMe, NO2, F, Br; a group selected from NHCH(pyridinyl)CH ₂ COOMe, NHCH(CH ₂ OMe)benzimidazolyl optionally substituted with a Cl atom; or 1-aminocyclopentyl optionally substituted with methyloxadiazolyl; R ^1'1 is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, t-Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, CONR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , COOMe, COOEt, OMe, SO2Me, SO ₂ CH ₂ CH ₂ OH, SO ₂ Et, SO _{2 -cyclopropyl, SO 2 -piperidinyl} , SO ₂ NHEt, SO ₂ NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O; R ¹ ' ¹ ' ¹ is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH ₂ -i-Pr, CH ₂ -t-Bu, CH(CH ₃ )CH ₂ CH ₃ , CH2CHF2, CH ₂ CONMe ₂ , CH ₂ CO-azetidinyl, CH ₂ -cyclopropyl, CH ₂ -cyclobutyl, CH ₂ -pyranyl, CH ₂ -tetrahydrofuranyl, CH ₂ -furanyl, CH 2 CH 2 OH or thiadiazolyl optionally substituted with a Me group; R ¹ ' ¹ ' ² represents H, Me, Et, SO ₂ Me, SO ₂ Et; or R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH; R ¹ ' ² is selected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH ₂ COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, COOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, CO- 112 041892 morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group; benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each of which is optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O; 4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCOMe; R ¹ ' ² ' ¹ represents H, Me; R ¹ ' ² ' ² represents H, Me; R ¹ ' ³ is selected from phenyl, pyrazolyl, isoxazolyl, pyrimidinyl, indolyl or oxadiazolyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, cyclopentyl, OMe, OCHF2; R ² is selected from CH ₂ -phenyl or CH ₂ -naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; or CH ₂ -thiophenyl optionally substituted with one or two residues selected from the group consisting of Cl, Br; R ³ is H; R ⁴ is H; or R ³ and R ⁴ together form a CH2-CH2 group, 5, The method according to pD, characterized in that in the compound of formula 1 A is CH2, O or NMe; R ¹ is selected from NHR ^1'1 ; NHR ^1'2 ; R ¹ ' ¹ is phenyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Bu, CF3, CH2CONMe2, CH2NHCONH-cyclohexyl, CN, COnR ¹ ' ¹ ' ¹ R ¹ ' ¹ ' ² , CoOme, COOEt, OMe, SO2Me, SO2CH2CH2OH, SO2Et, SO2-cyclopropyl, SO ₂ -piperidinyl, SO2NHEt, SO2NMeEt, F, Cl, CO-morpholinyl, CH ₂ -pyridinyl or imidazolidinyl, piperidinyl, oxazinanil, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, each of which is optionally substituted with one or two residues selected from the group consisting of Me, NHMe, =O; R ¹ ' ¹ ' ¹ is H, Me, Et, t-Bu, i-Pr, cyclopropyl, CH2-i-Pr, CH ₂ -t-Bu, CH(CH ₃ )CH2CH ₃ , CH2CHF2, CH ₂ CONMe ₂ , CH2CO-azetidinyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2-pyranyl, CH2-tetrahydrofuranyl, CH2-furanyl, CH2CH2OH, or thiadiazolyl optionally substituted with Me; R ¹ ' ¹ ' ² is H, Me, Et, SO2Me, SO2Et; or R ¹ ' ¹ ' ¹ and R ¹ ' ¹ ' ² together form a four-, five- or six-membered carbocyclic ring, optionally containing one O atom replacing a carbon atom in the ring, optionally substituted with one or two residues selected from the group consisting of CH2OH; R ¹ ' ² is selected from pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, thiadiazolyl optionally substituted with one or two residues selected from the group consisting of Me, Et, Pr, Bu, cyclopropyl, CH ₂ COOEt, CONR ¹ ' ² ' ¹ R ¹ ' ² ' ² , COOMe, cOOEt, CONH2, OMe, Cl, Br, CO-pyrrolidinyl, CO-morpholinyl or pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, each of which is optionally substituted with a Me group; benzothiazolyl, indazolyl, dihydroindolyl, indanyl, tetrahydroquinolinyl, each optionally substituted with one or two residues selected from the group consisting of NMe2, CONHMe, =O; 4,5-dihydronaphtho[2,1-d]thiazole optionally substituted with NHCOMe; R ¹ ' ² ' ¹ represents H, Me; R ¹ ' ² ' ² represents H, Me; R ² is selected from CH2-phenyl or CH2-naphthyl, both of which are optionally substituted with one or two residues selected from the group consisting of CH ₃ , CF ₃ , OCF ₃ , F, Cl, Br, Et; R ³ is H; R ⁴ is H' 6' Method according to PD, characterized in that in the compound of formula 1 A represents CH ₂ , O or NMe; - 113 041892 R ¹ is selected from Z ^CH 3 N - 114 041892 - 115 041892 - 116 041892 - 117 041892 - 118 041892 - 119 041892 where X1 represents the point of attachment of R ¹ to the formula 1; R ² is selected from where X ₂ represents the point of attachment of R ² to the formula 1; R ³ is H; R ⁴ is H; or R ³ and R ⁴ together form a CH ₂ -CH ₂ group. - 120 041892 7. The method according to claim 1, characterized in that said compound is a co-crystal of formula 2, wherein the compound of formula 2 has the following structure: where R ¹ represents C ₁ . ₆ -alkyl, C _1-6 -haloalkyl, OC _1-6 -haloalkyl, halogen; m is 1, 2 or 3; R ^2a and R ^2b are each independently selected from H, C ₁ . ₆ -alkyl, C ₁ . ₆ -alkenyl, C _1-6 alkynyl, C ₃ . ₆ -cycloalkyl, COO-C _1-6 -alkyl, OC _1-6 -alkyl, CONR ^2b .1R ^2b .2, halogen; R ^2b.1 is H, C _1-6 alkyl, C _0-4 alkyl-C _3-6 cycloalkyl, C _1-6 haloalkyl; R ^2k2 is H, C _1-6 alkyl; R ³ is H or Me; X is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, fumarate, tartrate, dibenzoyl tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate ; j is 0, 0.5, 1, 1.5, or 2; with a co-crystal forming compound selected from the group consisting of orotic acid, hippuric acid, L-pyroglutamic acid, D-pyroglutamic acid, nicotinic acid, L-(+)-ascorbic acid, saccharin, piperazine, 3-hydroxy-2- naphthoic acid, mucinic (galactaric) acid, pamoic (embonic) acid, stearic acid, cholic acid, deoxycholic acid, nicotinamide, isonicotinamide, succinamide, uracil, L-lysine, L-proline, D-valine, L-arginine, glycine. 8. The method of claim 1, wherein said compound is a crystalline salt of the formula below, wherein said crystalline salt has the four highest peaks in the X-ray powder diffraction pattern at 16.02, 16.86, 19.45 and 19.71° 2Θ (±0.05° 2θ) when measured using CuKa radiation. 9. The method of claim 7 comprising administering a pharmaceutical composition comprising at least one co-crystal of a compound of formula 2 and a pharmaceutically acceptable carrier. 10. The method according to claim 1, characterized in that the compound of formula 1 is administered in the form of individual optical isomers, a mixture of individual enantiomers, a racemate or in the form of enantiomerically pure compounds. 11. The method according to claim 1, including the introduction of a pharmaceutical composition containing as an active ingredient one or more compounds of formula 3 or a co-crystal, and the compound of formula 3 has the following structure: where R ¹ represents H, C ₁ . ₆ -alkyl, C ₀ . ₄ -alkyl-C ₃ . ₆ -cycloalkyl, C ₁ . ₆ -haloalkyl; R ² is H, C ₁ _ ₆ alkyl; X is an anion selected from the group consisting of chloride or 1/2 dibenzoyl tartrate; j is equal to 1 or 2, and the pharmaceutical composition additionally contains one or more of the first dilution - 121 -