WO2014012593A1

WO2014012593A1 - Alkyl substituted 3-hydroxypyridines for the treatment of depression

Info

Publication number: WO2014012593A1
Application number: PCT/EP2012/064214
Authority: WO
Inventors: Igor Anatolievich Pomytkin
Original assignee: HandelsOrt AG
Priority date: 2012-07-19
Filing date: 2012-07-19
Publication date: 2014-01-23
Also published as: EA020371B1; EA201300141A1

Abstract

The present invention relates to the use of compounds of formula (I) wherein R¹ is selected from the group consisting of C_1-8alkyl; R² is selected from the group consisting of C_1-8alkyl; R³ is selected from the group consisting of H and C_1-8alkyl; and R⁴ is selected from the group consisting of C_1-8alkyl; or a pharmaceutically acceptable salt thereof for the treatment of depression, preferably anxious depression.

Description

ALKYL SUBSTITUTED 3-HYDROXYPYRIDINES FOR THE

TREATMENT OF DEPRESSION

Field of the Invention

[0001] The present invention relates to the use of alkyl substituted hydroxypyridines for the treatment of depression.

Background of the invention

[0002] Depression is a common mental disorder that is characterized by a lasting sad mood and/or loss of interest or pleasure in most activities, feelings of guilt or low self- worth, disturbed sleep or appetite, low energy, and poor concentration. At its worst, depression can lead to suicide. Depression occurs in persons of all genders, ages, and backgrounds. By estimation of the World Health Organization, depression affects 121 million people worldwide. Antidepressant medications are effective for 60-80 % of those affected. Common side effects of antidepressants are nausea, weight gain, sexual dysfunction, insomnia, memory impairment and anxiety. Antidepressants can be addictive, and can cause withdrawal symptoms in patients. Thus, there is a great need in reducing the side effects of antidepressants. [0003] Depression and anxiety are two different conditions. However, when both disorders overlap, it may result in mixed depression anxiety, also called anxious depression, which often has more severe symptoms compared to when depression and anxiety occur independently. Anxious depression is associated with greater symptom severity, suicidality, and unemployment, less education, worse functioning, and poor prognosis. Anxious depression has poorer acute outcomes than non-anxious depression following antidepressant treatment. Fava M et al., Am J Psychiatry 165:342-351, 2008. Thus, there is a great need in safe and effective drugs for the treatment of anxious depression.

[0004] RU Patents No. 2168992, 2168993, 2185826, and 2190404 disclose the treatment of arthritis, ischemia, metabolic syndrome, and atherosclerosis with 2- ethyl-6 -methyl- 3 -hydroxypyridine . [0005] Patent application WO 2007/017713 Al discloses 2,4,6-trimethyl-3- hydroxypyridine as a substance having antioxidant, anti-ischemic, and geroprotective action in ophthalmology. [0006] Patent application WO 2009/078746 Al discloses alkyl-substituted 3- hydroxypyridines as compounds useful for the treatment of age-related disorders arising from dysfunctional insulin receptor signaling.

[0007] However, nothing is published or disclosed in the art related to the use of alkyl substituted 3-hydroxypyridines for the treatment of depression.

[0008] Surprisingly, it has been found that 3-hydroxypyridines has antidepressant activity and that this activity strongly depends on alkyl substitution of the pyridine ring. Alkyl substitution of 3-hydroxypyridine at the 4-position is critical for the presence of antidepressant activity. Moreover, alkyl substituted 3- hydroxypyridines have been found to exert antidepressant and antianxiety activity that is useful for the treatment of anxious depression.

[0009] Subject matter of the present invention is to provide a method for the treatment of depression comprising a step of administering to a mammal in need thereof an effective amount of an alkyl substituted 3-hydroxypyridine or a pharmaceutically acceptable salts thereof.

Detailed Description of the Invention

[0010] The present invention provides a method of treating depression comprising a step of administering to a mammal in need thereof an effective amount of a compound of formula (I) formula (I)

wherein

R is selected from the group consisting of Ci-galkyl

R is selected from the group consisting of Ci^alkyl

R is selected from the group consisting of H and Ci^alkyl

R⁴ is selected from the group consisting of Ci-galkyl

or a pharmaceutically acceptable salt thereof.

[0011] As used herein, the term "depression" refers to a mental disorder typically characterized by a lasting sad mood and/or loss of interest or pleasure in most activities. Examples of depressive disorders which may preferably be treated with an effective amount of a named compound or pharmaceutically acceptable salt thereof include, but are not limited to: major depressive disorder also known as major depression, unipolar disorder, or clinical depression; major depressive episode; atypical depression; depression (mood); melancholic depression; psychotic depression; postpartum depression; and depression co-morbid with anxiety (mixed depression anxiety disorder).

[0012] Preferably, the depression to be treated with a compound of formula (I) of the present invention is anxious depression.

[0013] As used herein, the term "anxious depression" refers to depression as defined above with high levels of anxiety symptoms that include, but are not limited to, panic, worry, and fear in situations or at events where no obvious reasons for such emotions are present.

[0014] As used herein, the term "treating" refers to the management and care of a mammal for the purpose of (a) preventing depression from occurring in a subject which may be predisposed to such disorder but has not yet been diagnosed as having it; (b) inhibiting depression, i.e., arresting its development; or (c) relieving depression, i.e., causing regression of the disorder. [0015] As used herein, the term "Ci-galkyl" refers to a straight or branched alkyl radical chain of 1 to 8 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl, hexyl, and octyl and the simple aliphatic isomers thereof.

[0016] As used herein, the term «pharmaceutically acceptable salt" refers to nontoxic salts. The pharmaceutically acceptable salts of the invention are prepared by a reaction of a compound of formula (I) with a pharmaceutically acceptable acid by methods well-known from the art. Such salts include, but are not limited to, hydrochloride, hydrobromide, succinate, fumarate, malate, and acetate salt. Preferably, the pharmaceutically acceptable salt of the invention is selected from the group consisting of hydrochloride salt, succinate salt, fumarate salt, L-malate salt, ketoglutarate salt, and citrate salt. [0017] Preferably, the pharmaceutically acceptable salt is the salt of a compound of formula (I) with succinic acid having the formula HOOCCH₂CH₂COOH (CAS RN 110-15-6).

[0018] Preferably, the compound of formula (I) is selected from the group consisting of 2-ethyl-4,6-dimethyl-3-hydroxypyridine; 2-ethyl-4,5,6-trimethyl-3- hydroxypyridine; 2-isopropyl-4,6-dimethyl-3-hydroxypyridine; 2-isopropyl-4,5,6- trimethyl-3-hydroxypyridine; 2-ethyl-4,6-dimethyl-5-butyl-3-hydroxypyridine; 2,6-diethyl-4-methyl-3-hydroxypyridine; and 2-ethyl-4,6-dimethyl-5-octyl-3- hydroxypyridine.

[0019] As used herein, the term "an effective amount" refers to the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof that is required for treating depression described herein. The attending physician can readily determine an effective amount by the use of conventional clinical diagnostic methods. In determining an effective amount of a compound of formula (I), a number of factors are considered by the attending physician, including, but not limited to, the type of compound of formula (I) to be administered, the coadministration of other agents; the species of mammal, its size, age, and general health; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and other relevant circumstances.

[0020] Preferably, the effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the use in the method of the present invention is 0.1 to 100 mg/kg body weight per day. More preferably, the effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 1 to 25 mg/kg body weight per day.

[0021] A compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a mammal by a variety of routes, which routes include, but are not limited to, oral, oromucosal, sublingual, buccal, intranasal, topical, parenteral, intraocular, intramuscular, subcutaneous, intravenous, and intraperitoneal administration.

[0022] A compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a mammal in a variety of dosage forms. Such dosage forms include, but are not limited to, tablets, capsules, powders, solutions, water solutions, aerosols, elixirs, syrups, and injections. [0023] Preferably, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for a period of one day or longer. More preferably, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily for a period of four weeks or longer.

[0024] In some preferred embodiments of the invention, compounds of formula (I) can be prepared by methods well-known from the art. Bosshard P et al., Adv. Heterocvcl. Chem. 7, 377, 1966. WO 2009/078746 Al. Alkyl-substituted 3- hydroxypyridines may be prepared by reacting ammonia with alkyl-substituted 2- acylfuranes of formula (II)

fomiula (II)

wherein R 1 is selected from the group consisting of Ci-galkyl; R 2 is selected from the group consisting of Ci-galkyl; R is selected from the group consisting of H and Ci-galkyl; and R⁴ is selected from the group consisting of Ci-galkyl.

[0025] Further, the present invention provides use of a compound of formula (I)

fomiuta (I)

wherein R 1 is selected from the group consisting of Ci-galkyl; R 2 is selected from the group consisting of C^alkyl; R is selected from the group consisting of H and Ci-₈alkyl; and R⁴ is selected from the group consisting of Ci^alkyl or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical composition for treating depression in a mammal in need thereof.

[0026] The pharmaceutical composition of the invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with compatible pharmaceutically acceptable carrier materials, or diluents, well known in the art. The carriers may be any inert material, organic or inorganic, suitable for administration, such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such compositions may also contain other pharmaceutically active agents, and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, binders, disintegrants, lubricants, glidants, antiadherents, propellants, and the like. The content of compound of formula (I) or a pharmaceutically acceptable salt thereof in the composition is in the range from 0.1 to 99 , preferably 0.5 to 10 % by weight of the composition.

[0027] The pharmaceutical compositions of the invention are prepared by methods well-known from the art in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa., Eighteenth edition (1990).

[0028] Preferably, the mammal in the present invention is a human.

[0029] The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way. Example 1.

[0030] This example demonstrates the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof.

An ammonia saturated solution in absolute ethanol (50 ml), obtained at -20°C, is placed into an autoclave, then an alkyl- substituted 2-acylfurane (0.36 moles) is added thereto. The reaction mixture is heated to 170°C for 15 hours, with stirring. After cooling, ethanol is evaporated off under reduced pressure to obtain an oily residue which is taken up into a 2N sodium hydroxide solution (400 ml). After stirring and thoroughly triturating, the alkali solution is extracted with chloroform (100 ml x 4) to recover the unreacted alkyl-substituted 2-acylfurane. The alkali liquors are neutralized with concentrated hydrochloric acid to separate the alkyl- substituted 3-hydroxypyridine. Liquors are extracted with chloroform (200 ml x 8), and the organic extracts are washed with some water, dried with Na₂S0₄, filtered and evaporated to give more product. The two solid fractions are combined and repeatedly treated with anhydrous ether (250 ml x 6) to separate the present chloride. From the ether solution, during concentration, the alkyl- substituted 3-hydroxypyridine progressively crystallizes. The following compounds of formula (I) have been prepared: 2-ethyl-4,6-dimethyl-3- hydroxypyridine, MS (m/z): 152 (M+l); 2-ethyl-4,5,6-trimethyl-3- hydroxypyridine, MS (m/z): 166 (M+l); 2-isopropyl-4,5,6-trimethyl-3- hydroxypyridine, MS (m/z): 180 (M+l); 2-isopropyl-4,6-dimethyl-3- hydroxypyridine, MS (m/z): 166 (M+l); 2-ethyl-4,6-dimethyl-5-butyl-3- hydroxypyridine, MS (m/z): 208 (M+l); 2,6-diethyl-4-methyl-3-hydroxypyridine, MS (m/z): 166 (M+l); and 2-ethyl-4,6-dimethyl-5-octyl-3-hydroxypyridine, MS (m/z): 264 (M+l). For the preparation of succinate salts of compounds of formula (I), saturated solution of succinic acid (0.1 mole) in anhydrous ethanol is added to the solution of an alkyl-substituted 3-hydroxypyridine (0.1 mole) in anhydrous ethanol. Ethanol is evaporated and the product is recrystallized from isopropanol- acetone to purity to obtain the corresponding succinate salt.

Example 2.

[0031] This example demonstrates that substitution of 3-hydroxypyridines at 4- position with alkyl group is critical for the presence of antidepressant activity. Three-months-old male C57B16J mice were treated with 2-ethyl-4,6-dimethyl-3- hydroxypyridine, succinic acid salt (1: 1) (25 mg/kg/day, i.p., n=25); 2-ethyl-6- methyl-3-hydroxypyridine, succinic acid salt (1: 1) (25 mg/kg/day, i.p., n=25); saline (i.p., n=25, stress control); or saline (i.p., n=10, non-stress control) during 7 days prior to chronic stress and 10 days of a chronic stress period. Control mice (saline i.p., n=10) were not stressed. Stressed groups were submitted to a 10-day chronic stress that was previously shown to induce anhedonia, behavioral despair and other deficits typical for a depression-like state. Strekalova et al., Neuropsvchopharmacology 2004, 29:2007-2017.

Sucrose preference test. In this test, mice were given for 8 h free choice between two bottles, one with 1 -sucrose solution and another with tap water. The beginning of the test period started with the onset of the dark (active) phase of the animals' activity cycle. To prevent possible effects of side-preference in drinking behavior, the position of the bottles in the cage is switched mid-way through testing, i.e., after 4 h. No food was given nor was water deprived before the test. Other conditions of the test were as described elsewhere. The sucrose preference test was applied at baseline prior to stress and after chronic stress induction. The sucrose preference test is a state-of-the-art method to assess depression-like symptoms. Data are presented in Table 1 as mean + SEM of

Differs significantly of stressed control (P < 0.05).

Table 1 shows that 3-hydroxypyridine substituted with alkyl in 4-position has antidepressant activity, while non-substituted 3-hydroxypyridine, administered at the same dose, has no such activity.

Forced swim test. The forced swim test has been modified to prevent behavioral artifacts caused by stress-induced hyperlocomotion. Mice were placed into a transparent pool (20 cm x 35 cm x 15 cm) lit with red light and filled with warm water (30°C, height 9.5 cm) for 2 min. Floating behavior was defined as the absence of directed movements of animals' head and body and was measured by visual observation that was validated previously by automated scoring with a special observation software. Latency to begin floating was scored as time between introduction of a mouse into the pool and the very first moment of complete immobility of the entire animal body for a duration of >3 seconds, irrespective of the duration of the first floating episode. The forced swim test is a state-of-the-art method to assess depression-like symptoms. The total time spent floating was scored for the entire duration of the test. Data are presented in Table 2 as mean + SEM of latency of floating behavior in chronically stressed mice.

Table 2

*Differs significantly of stressed control (P < 0.05); Differs significantly of 2- ethyl-6-methyl-3-hydroxypyridine, succinate (1: 1) (P < 0.05).

Table 2 shows that 3-hydroxypyridine substituted with alkyl at 4-position has antidepressant activity, while non- substituted 3-hydroxypyridine has even depression enhancing activity, when administered at the same dose.

Social interaction test. C57BL/6J mice were placed individually as a resident in an observation cage (30 cm x 60 cm x 30 cm) for 30 min. Thereafter, a male CD1 mouse was introduced as an intruder to the same cage and left with the resident mouse for 4 min. Behavior was analyzed online. Mice displayed dominant or subdominant social behavior. Initiation of attacks towards the partner and fighting back in response to attacks were categorized as dominant behavior. Lack of these behaviors accompanied by specific "submissive" postures was regarded as subdominant behavior. Latency to the first attack and number of attacks, as well as tail rattling, mounting and following behaviors were scored. Above-listed parameters were assessed during baseline test. After stress induction, the number of dominant behavior events was determined in the same test paradigm. Data are presented in Table 3 as mean + SEM of the number of dominant behavior events in chronically stressed mice.

Table 3

Differs significantly of stressed control (P < 0.05); Differs significantly of 2- ethyl-6-methyl-3-hydroxypyridine, succinate (1: 1) (P < 0.05).

Table 3 shows that chronically stressed mice treated with 3-hydroxypyridine substituted with alkyl-group at 4-position demonstrate dominant-like behavior as compared to mice treated with non- substituted 3-hydroxypyridine given at the same dose.

Thus, these results suggest that the substitution of 3-hydroxypyridine with an alkyl group at 4-position provides the molecule with antidepressant activity, which activity is absent in non-substituted 3-hydroxypyridine analogues.

Example 3.

[0032] This example demonstrates that compounds of the present invention are effective for the treatment of anxiety.

The effect of treatment of anxiety with compounds of the invention was assessed in rodents using the light/dark transition test. Stressed C57B1/6J mice from Example 2 were tested in a dark/light box. Animals were scored during 5 min for the time spent in the light box. Statistical analysis was done using ANOVA and Mann-Whitney test as a post-hoc analysis. Data are presented in Table 4 as mean + SEM.

Table 4

Group Time in lit box, s

Control, non-stressed 58 + 4* Control, stressed 37 + 4

2-ethyl-4,6-dimethyl-3-hydroxypyridine, succinate (1: 1) 55 + 6* 2-ethyl-6-methyl-3-hydroxypyridine, succinate (1: 1) 44 + 4

^Differs significantly of stressed control (P < 0.05).

Table 4 shows that a compound of the present invention has antianxiety activity along with antidepressant activity shown above.

Example 4.

[0033] This example demonstrates that compounds of the present invention have antidepressant activity.

To this end, young male CD1 mice, singly housed, were used in the forced swim test. Mice were treated orally with saline (control), the reference compound 2- ethyl-6-methyl-3-hydroxypyridine succinate salt (1: 1) 25 mg/kg, or compounds of formula (I) succinate salts (1: 1) 25 mg/kg for 7 days once-a-day and tested on the 8th day. The forced swim test was done in a glass cylinder of 17 cm diameter, filled with 13 cm of water at ambient temperature (7 cm to the edge of the cylinder). Animals were scored during 6 min. The latency to the first floating episode was accepted as a measure of forced swim behavior. Statistical analysis was done using AN OVA and Mann-Whitney test as a post-hoc analysis. Data are presented in Table 5 as mean + SEM latency of the first floating episode.

Table 5

Group Latency to floating, s

Control 25 + 8

Reference (2-ethyl-6-methyl-3-hydroxypyridine) 14 + 5*

2-ethyl-4,6-dimethyl-3-hydroxypyridine 63 + 11*

2-ethyl-4,5,6-trimethyl-3-hydroxypyridine 66 + 7*

2-isopropyl-4,5,6-trimethyl-3-hydroxypyridine 92 + 12*

2-isopropyl-4,6-dimethyl-3-hydroxypyridine 101 : b 10*

2-ethyl-4, 6-dimethyl- 5 -butyl- 3 -hydroxypyridine 72 : b 7*

2,6-diethyl-4-methyl-3-hydroxypyridine 69 : b 8*

2-ethyl-4,6-dimethyl-5-octyl-3-hydroxypyridine 87 ± 11*

2,4,6-trimethyl-3-hydroxypyridine 41 : b 6*

*Differs significantly of control (P < 0.05).

Table 5 shows that alkyl-substituted 3-hydroxypyridines of formula (I) have antidepressant activity. Example 5.

[0034] This example demonstrates the preparation of tablets comprising a compound of formula (I).

The following ingredients are combined in the following proportions:

Ingredient Percentage

2-ethyl-4,6-dimethyl-3- hydroxypyridine, succinate (1: 1) 75

Starch 11.5

Calcium carbonate 13

Magnesium stearate 0.1

Povidone K-25 0.4 The ingredients are mixed and compressed into tablets.

Claims

Patent Claims

L A method of treating depression comprising a step of administering to a mammal in need thereof an effective amount of a compound of formula (I)

formula (I)

wherein

R¹ is selected from the group consisting of Ci^alkyl

R is selected from the group consisting of Ci-galkyl

R is selected from the group consisting of H and Ci-galkyl

R⁴ is selected from the group consisting of Ci^alkyl

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the depression is anxious depression.

3. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of 2-ethyl-4,6-dimethyl-3-hydroxypyridine; 2-ethyl-4,5,6- trimethyl-3-hydroxypyridine; 2-isopropyl-4,6-dimethyl-3-hydroxypyridine; 2- isopropyl-4,5,6-trimethyl-3-hydroxypyridine; 2-ethyl-4,6-dimethyl-5-butyl-3- hydroxypyridine; 2,6-diethyl-4-methyl-3-hydroxypyridine; and 2-ethyl-4,6- dimethyl-5-octyl-3-hydroxypyridine or succinate salts thereof.

4. The method of claim 1, wherein the pharmaceutically acceptable salt thereof the salt of a compound of formula (I) with succinic acid.

5. The method of claim 1, wherein the mammal is a human.

6. Use of a compound of formula (I)

formula (I)

wherein

R¹ is selected from the group consisting of Ci^alkyl

R is selected from the group consisting of Ci-galkyl

R is selected from the group consisting of H and Ci-galkyl

R⁴ is selected from the group consisting of Ci^alkyl

or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical composition for treating depression in a mammal in need thereof.

7. The use of claim 6, wherein the depression is anxious depression.

8. The use of claim 6, wherein the compound of formula (I) is selected from the group consisting of 2-ethyl-4,6-dimethyl-3-hydroxypyridine; 2-ethyl-4,5,6- trimethyl-3-hydroxypyridine; 2-isopropyl-4,6-dimethyl-3-hydroxypyridine; 2- isopropyl-4,5,6-trimethyl-3-hydroxypyridine; 2-ethyl-4,6-dimethyl-5-butyl-3- hydroxypyridine; 2,6-diethyl-4-methyl-3-hydroxypyridine; and 2-ethyl-4,6- dimethyl-5-octyl-3-hydroxypyridine or succinate salts thereof.

9. The use of claim 6, wherein the pharmaceutically acceptable salt thereof salt of a compound of formula (I) with succinic acid.

10. The use of claim 6, wherein the mammal is a human.