Patent Grant
11358939
This present application claims the benefit of International Application No. PCT/RU2018/000907, entitled, “1,4-BENZODIAZEPIN-2-ONE DERIVATIVES AND USE THEREOF”, filed Dec. 29, 2018, which claims priority to Russian Application No. 201714001, entitled, “1,4-BENZODIAZEPIN-2-ONE DERIVATIVES AND USE THEREOF”, filed Nov. 24, 2017. The contents of International Application No. PCT/RU2018/000907 and Russian Application No. 201714001 are incorporated herein by reference.
The invention relates to organic chemistry, pharmacology and medicine, in particular, to compounds of benzodiazepine series, which can be used for pain treatment (analgesic), weight regulation, treatment of medical disorders, obsessive disorders, panic attacks and other central nervous system disorders.
1,4-benzodiazepine derivatives are widely used in medicine, since they have hypnotic, sedative, anxiolytic, myorelaxant and anticonvulsive action. Over 50 pharmaceutical substances based on 1,4-benzodiazepines are included in different drugs used to prevent and treat different central nervous system disorders as anxiolytic medications (tranquilizers) and as hypnotic and anticonvulsant drugs.
Over the last 20 years great progress was made in the chemistry and pharmacology of 1,4-benzodiazepines: many new compounds—ligands of benzodiazepine sites of GABAA receptors were synthesized, some of which, in addition to anxiolytic properties, also have analgesic, anorexigenic, antidepressant, antihypoxic, nootropic and other properties.
In particular, it was discovered that 1,4-benzodiazepine derivatives, that have amide residues in the third position, exert considerable analgesic activity and high affinity to the receptors of bradykinin—a potent natural pain inducer [1,2].
It's also known that some 3-substituted-1,2-dihydro-3H-1,4-benzodiazepin-2-ones have not only analgesic activity, but also anorexigenic, antidepressant, antihypoxic, nootropic and other types of activity. Pharmacological properties of these compounds are mediated by their binding with the receptors of benzodiazepine, cholecystokinin and bradykinin [3, 4, 5, 6, 7].
Thus, synthesis of new 1,4-benzodiazepine derivatives is a promising approach for creating new drugs for solving relevant medical problems: pain alleviation, weight regulation and treatment of different disorders of central nervous system.
Chronic pain of different causes and the accompanying depression, anxiety and insomnia pose a serious medical and social problem. Modern analgesic drugs are either not effective enough (in case of non-steroidal anti-inflammatory drugs) or have dangerous adverse effects, especially prominent in narcotic analgesic drugs.
Over 1 billion people worldwide suffer from excessive weight and obesity [8], which poses a serious medical problem, since it increases the risk of diabetes, cardiovascular and other diseases. On the other hand, advertising of thinness, lack of appetite, severe body mass loss in diseases such as tuberculosis, cancer, AIDS, leads to an increase in the number of people with anorexia [9]. This increases the interest in the problem of weight regulation and eating behavior.
An important task of modern pharmacology is the search for drugs increasing human life expectancy and survival in conditions of severe hypoxia. The existing antihypoxic and nootropic drugs do not fully satisfy the requirements of practical medicine.
Treatment of depression remains a highly relevant problem. The incidence of depressive disorders in the population is growing, including masked depressions with somatovegetative component. According to the WHO data, worldwide over 110 million people (3-6% of the population) have clinically significant manifestations of depression.
The closest compound to the disclosed compounds, 1,4-benzodiazepin-2-one derivatives, in chemical structure and pharmacology, a prototype of the invention, is methyl-2-(7-bromo-3-etoxy-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl) acetate, which demonstrates analgesic activity in acetic acid-induced writing test with ED50=0.47±0.15 mg/kg [10]:
Analogs of the disclosed compounds, 1,4-benzodiazepin-2-one derivatives, in certain types of pharmacological activity are: sodium diclofenac, demonstrating analgesic activity in acetic acid-induced writing test with ED50=10.0±1.8 mg/kg; the hormone leptin, which reduces appetite and body mass but doesn't have antihypoxic and antidepressant activity; antidepressant amitriptyline which has potent antidepressant effect, but doesn't have antihypoxic action and doesn't affect the appetite.
The goal of the present invention is to widen the range of pharmacologically active benzodiazepine compounds by using 3-substituted-1,2-dihydro-3H-1,4-benzodiazepin-2-ones of general formula I:
as potential medical drugs, having analgesic activity, regulating appetite and body weight, having antihypoxic, nootropic, antidepressant and anxiolytic properties.
The goal is solved by the synthesis of 3-substituted-1,2-dihydro-3H-1,4-benzodiazepin-2-ones of general formula I, including its variants:
a) 1-substituted 3-alcoxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones of general formula Ia;
b) 1-substituted 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones of general formula Ib.
Table 1 lists the synthesized 1-substituted 3-alcoxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones (Ia).
1 g (3.367 mmol) of 3-hydroxy-7-nitro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one is put into a 100 ml flask, 50 ml of anhydrous chloroform is added, then 1.0 ml (13.78 mmol) of thionyl chloride is added, the mixture is boiled for 40 min, the precipitate is dissolved, then 5 ml of anhydrous 1-propanol is added. The mixture is boiled for 1 hours, rinsed with water (5×5 ml), chloroform is evaporated at a rotary evaporator. The precipitate is crystallized from xylol. Yield=79%, (0.9 g); melting point=220-222° C.
1 g (3.367 mmol) of 7-nitro-5-phenyl-3-propoxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one is put into a 100 ml flask, 40 ml of dioxane is added, then 20 ml of saturated potassium carbonate solution is added, 10 mg of tetrabutylammonium iodide is added, then 1.5 ml (15.78 mmol) of methylbromoacetate is added. The reaction mixture is stirred at room temperature for 2-3 hours. Dioxane is separated at a separation funnel and evaporated at a rotary evaporator. The precipitate is crystallized from xylol. Yield=65.0%, (0.9 g); melting point=214-215° C., needle-like white to off white crystals. Compounds 1-47, 49-82 in Table 1 are produced in a similar way).
Table 2 lists 1-substituted 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones of general formula Ib.
1 g (3.367 mmol) of 3-hydroxy-7-nitro-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one is put into a 100 ml flask, 50 ml of anhydrous chloroform is added, then 1.0 ml (13.78 mmol) of thionyl chloride is added, the mixture is boiled for 40 min, the precipitate is dissolved, then 0.93 g (6.73 mmol) of 2-nitroaniline is added. The mixture is boiled for 1 hours, rinsed with water (5×5 ml), chloroform is evaporated at a rotary evaporator. The precipitate is crystallized from ethanol. Yield=64%, (0.9 g); melting point=225-227° C.
1 g (3.367 mmol) of 7-nitro-5-phenyl-(2-nitrophenyl)amino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one ( 275 in Table 2) is put into a 100 ml flask, 40 ml of dioxane is added, then 20 ml of saturated potassium carbonate solution is added, 10 mg of tetrabutylammonium iodide is added, then 1.5 ml (15.78 mmol) of methylbromoacetate is added. The reaction mixture is stirred at room temperature for 2-3 hours. Dioxane is separated at a separation funnel and evaporated at a rotary evaporator. The precipitate is crystallized from xylol. Yield=65.0%, (0.9 g); melting point=218-220° C., yellow crystals. Compounds
83-274, 276, 277, 279-400 in Table 2 are produced in a similar way).
Affinity of the compounds to central benzodiazepine receptors (CBR) was studied using radioreceptor method of competitive displacement of radioligant [3H]-flumazenil (Ro 15-1788) from its specific binding sites at the receptor. Ligand displacement were performed in 1×10−6 mol/L concentration.
Data on the affinity of 3-alcoxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones (Ia) to central and peripheral benzodiazepine receptors is presented in Table 3.
Assessment of analgesic activity was performed in a model of peripheral pain based on chemical pain induced by intraperitoneal administration of acetic acid, leading to involuntary contractions of abdominal muscles, termed “writhes”, accompanied by hind leg extension and spine arching. The writhes were induced by 0.75% solution of acetic acid, which was administered intraperitoneally 40 min after intraperitoneal administration of test compounds in 0.001-5 mg/kg dose range. The animals were observed for 20 min and the number of writhes in each animal was counted. Analgesic activity was assessed by the ability of the compounds to reduce the number of writhes in test group compared to control group, and indicated as percentage using the following formula:
AA=(Wc−Wt/Wc)×100%,
where AA—analgesic activity in %;
Wc—average number of writhes in control group;
Wt—average number of writhes in test group
Test compounds were studied in comparison with the reference drug sodium diclofenac in 10 mg/kg dose [11]. ED50 was calculated using Prozorovsky method [12].
As the data in Table 4 shows, all studied derivatives of 3-alcoxy-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones (Ia) exert potent analgesic action, inhibiting writhes in animals in 1 mg/kg dose by 45-88% compared to control. For certain derivatives of Ia ( 21, 22, 44, 45, 48 in Table 4) effective dose ED50 was determined, which was: 0.29±0.025; 0.08±0.02; 0.07±0.02; 0.047±0.014; 0.058±0.015, respectively. ED50 values of reference drugs were: 1.50±0.26 mg/kg for indomethacin, 10.0±1.8 mg/kg for sodium diclofenac. Thus, the disclosed compounds of formula Ia have more potent analgesic activity than the reference drugs, since they have a much lower (by 1-2 orders of magnitude) ED50 value.
The derivatives of 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones (Ib) also have potent analgesic activity, inhibiting writhes in animals in 1 mg/kg dose by over 50% (data on their analgesic activity is presented in Table 5).
Studies of pharmacological activity of 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones, namely, their action of appetite, assessment of antihypoxic and antidepressant activity was performed in white male rats with body mass 150-180 g and male mice with body mass 18-22 g. The animals were kept on a standard laboratory diet and natural lighting. Animals of control group were given a water-Tween suspension. Test compounds were administered in a suspension with Tween-80 Reference drugs were the hormone leptin, in 0.0002 mg/kg dose, and a well-known antidepressant amitriptyline (solution for injections in 1 ml vials. Test compounds and the water-Tween suspension were administered in a dose of 0.2 ml/100 g of rat body mass.
The action of the compounds on rat appetite was studied using «norexia» method. For 2 weeks in an experimental equipment the rats were conditioned to consume liquid food. Then a water-Tween suspension of test articles was administered intraperitoneally to conditioned animals one day before the experiment. After 40 minutes the animals were allowed access to liquid food and the amount of consumed food (in ml) of every rat was registered every 30 minutes for 3 hours. The next day after 2 hours of deprivation the rats in control group were administered a water-Tween suspension intraperitoneally, while the test group was administered the test articles. After 40 minutes the animals were allowed access to liquid food and the amount of consumed food (in ml) of every rat was registered every 30 minutes for 3 hours. Then all food consumption values for each rat were summed and compared to control values. The control group has consumed on average 7 ml of liquid food per 30 minutes. The effect was calculated in percentage compared to control [13].
Effect of 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones (Ib) on food consumption by rats, assessed using «Anorexia» method, is presented in Table 6.
Among test articles compounds 194, 248 and 356 (Table 6) have anorexigenic action, as evidenced by the reduction in appetite and food consumption by the studied rats by 47%, 41% and 39%, respectively, compared to control (Table 6).
The hormone leptin has reduced appetite and food consumption by 63% compared to control. It should be noted that compound 358 (Table 6) had a hyperphagic effect, i.e. increased the appetite.
Screening of antihypoxic activity was performed using the model of acute confined space hypoxia (CSH). CSH was modeled by placing mice into isolated sealed chambers (V=200 ml). Each group included 10 animals. The observation lasted until the death of the animals. Antihypoxic effect was assessed by the survival duration (in min) compared to control, which was taken as 100%, and according to the calculation of antihypoxic protection ratio (Rpr):Rpr=Tt/Tc, where Tt—average animal survival time in the test group; Tc—average animal survival time in the control group [11].
The advantage of the test compound over the reference drug, the hormone leptin, is the presence of potent antihypoxic and antidepressant activity, in addition to high anorexigenic activity. It was shown, that the derivatives of 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones in 10 mg/kg dose have antihypoxic action in a model of acute confined space hypoxia in mice. The highest efficacy was observed in compounds 250 and 357, the action of which increased mice survival time during acute confined space hypoxia by 70% and 40.5%, respectively, compared to control. The reference drug, hormone leptin, had no antihypoxic properties [14].
Antidepressant activity was studied using «Porsolt forced swimming test» [15], which models stress in mice by forcing them to swim in a narrow translucent cylinder, filled by ⅓ volume with water at 23-25° C. temperature. Antidepressant action is assessed by the reduction in immobility time, when the animals have minimal amount of paddling, in seconds or percentage compared to control. The animal behavior was registered for 4 minutes after acclimatization for 2 minutes.
Study of action of 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones of formula Ib on mice immobility time in forced swimming test has shown that all test compounds in 1 mg/kg dose have antidepressant effects. Compounds 159 and
194 have the most potent antidepressant action, reducing immobility time in mice by 32% and 40%, respectively, compared to control, being as effective as the reference drug amitriptyline in 1 mg/kg dose (40%). The hormone leptin in 0.0002 mg/kg dose reduces immobility time by only 14% compared to control, i.e. it has a weak antidepressant effect.
The performed studies have shown that among 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones of formula 1b there are compounds having potent anorexigenic activity and interesting for further research as potential medical drugs, regulating eating behavior and reducing appetite and body mass. The advantage of the disclosed compounds over the reference drugs is the additional presence of potent antihypoxic and antidepressant activity compared to the reference drugs amitriptyline and the hormone leptin.
Anxiolytic activity was assessed in a model of conflict situation based on the conflict of two reflexes (drinking and defensive) when drinking water from a water fountain. Anxiolytic activity was assessed by the number of drinking actions despite electric shock [16].
General movement activity was assessed in an open field test. While the animals were in the open field (3 min), the number of rearings (vertical movement activity), transitions between squares (horizontal movement activity) and the number of explored holes (exploratory activity) were registered. The sum of these values is general movement activity [17].
Diazepam drug was used as the reference drug. All test compounds and the reference drug diazepam were administered in a suspension with Tween-80 in 5 mg/kg dose 30 min before the start of experiments.
Anxiolytic properties and action on general movement activity of 1-methoxy-carbonylmethyl-3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones (Ib) is presented in Table 7.
Table 7 shows that compounds 173, 227 and
281 had potent anxiolytic properties, while compounds
89, 317, 327, 363 and
399 don't have sedative properties, their general movement activity values didn't statistically differ from animals of the control group.
Thus, many of the synthesized compounds—derivatives of 1,4-benzodiazepin-2-one of general formula I, including compounds of formula Ia and compounds of formula Ib, have potent analgesic action. The disclosed compounds may be used as non-opioid analgesics for treating pain of different causes and intensity. At the same time, among 3-arylamino-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-ones of formula Ib, unlike the compounds of formula Ia, compounds with high anorexigenic activity were discovered, manifested in the reduction in appetite and body mass in rats under effect of the test compounds in low doses 0.1-0.05 mg/kg using “Anorexia” method compared to control and the reference drug—satiation hormone leptin (0.0002 mg/kg).
In addition to anorexigenic activity, the disclosed compounds of formula Ib have antihypoxic, antidepressant and anxiolytic properties, which makes them different from the reference drugs—satiation hormone leptin and amitriptyline. Therefore compounds of formula Ib, in addition to their use as analgesics, can also be used to regulate weight (gain or loss) as anorexigenic or orexigenic drugs, treat mental disorders as antidepressant and anxiolytic drugs, and also to prevent and treat disorders of CNS functioning as antihypoxic and nootropic drugs.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201714001 | Nov 2017 | RU | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/RU2018/000907 | 12/29/2018 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2019/103658 | 3/31/2019 | WO | A |
| Number | Date | Country |
|---|---|---|
| 102273 | Jun 2013 | UA |
| 2004106310 | Dec 2004 | WO |
| 201 9103658 | May 2019 | WO |
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| Number | Date | Country | |
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| 20200361878 A1 | Nov 2020 | US |
