Alpha 2-adrenoceptor subtype C (alpha-2C) antagonists for the treatment of sleep apnea
阅读说明：本技术 用于治疗睡眠呼吸中止的α2-肾上腺素受体亚型C(α-2C)拮抗剂 (Alpha 2-adrenoceptor subtype C (alpha-2C) antagonists for the treatment of sleep apnea ) 是由 M·德尔贝克 M·哈恩 于 2019-09-19 设计创作，主要内容包括：本发明涉及α2-肾上腺素受体亚型C(α-2C)拮抗剂,特别是式(I)的芳基哌嗪,其用于治疗及/或预防与睡眠有关的呼吸疾病,优选阻塞性和中枢性睡眠呼吸中止和打鼾的方法中。(The present invention relates to alpha 2-adrenoceptor subtype C (alpha-2C) antagonists, in particular arylpiperazines of formula (I), for use in a method of treatment and/or prevention of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.)
1. Compounds of formula (I) and their salts, solvates, and solvates of the salts,
wherein
X is O, S or CH2；
Z is- [ CH ]2]n-；
A. B, D and E are independently C or N, provided that at least three of A, B, D and E are C;
R1is H, halogen, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-、(R5)2N-(C1-C6) Alkyl, (R)5)2N-(C＝O)-、SH-(C1-C6) Alkyl, hydroxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, hydroxy (C)1-C6) alkyl-S (Op) - (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) alkyl-S (Op) - (C)1-C6) Alkyl or furyl;
R2is H, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy or hydroxy (C)1-C6) An alkyl group;
R3is H, halogen, (C)1-C6) Alkyl or phenyl;
R4is halogen, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, CN or (R)5)2N-；
R5Independently at each occurrence, is H, (C)1-C6) Alkyl or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
m is 0, 1 or 2;
n is 1 or 2; and is
p is 1 or 2;
for use in a method of treatment and/or prevention of sleep-related respiratory disorders.
2. The compound according to claim 1, wherein the compound is selected from the group consisting of: methyl 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) piperazin-1-yl) benzoate, methyl (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) piperazin-1-yl) phenyl) methanol, 1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) piperazin-1-yl) benzonitrile, and mixtures thereof, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-yl) phenyl) methylamine, 1- (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-yl) phenyl) -N-methylmethanamine, 1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (2- (ethoxymethyl) phenyl) piperazine, 2- (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-ylphenyl) propan-2-ol, 1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine, (S) - (2- (4- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) -piperazin-1-yl) pyridin-3-yl) methanol HC1, (S) -1- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazinehI, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (3- ((2-fluoroethoxy) methyl) pyridin-2-yl) piperazine, 1- (2, 3-difluorophenyl) -4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazine, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) methanol, (S) - (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, (R) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, and, (S) - (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-yl) phenyl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine, (1- ((2, 3-dihydrobenzo [ b ] [1, 4] oxathiacyclohexadien-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, 1- (chroman-2-ylmethyl) -4- (2- (methoxymethyl) phenyl) piperazine, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-yl) -6-fluorophenyl) methanol, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-yl) -3-fluorophenyl) methanol, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-yl) -5-fluorophenyl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (2-propylphenyl) piperazino Oxazines, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (2- (trifluoromethoxy) phenyl) piperazine, (S) -1- (biphenyl-3-yl) -4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazine, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (2- (furan-2-yl) phenyl) piperazine, (S) -ethyl-2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) piperazin-1-yl) benzoate, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) -4-o-tolylpiperazine, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) -4-m-tolylpiperazine, (S) - (3- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) piperazin-1-yl) -4-methylphenyl) methanol, (S) - (3- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) piperazin-1-yl) phenyl) methanol, (S) -2- (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) piperazin-1-yl) phenyl) ethanol, methyl 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) -1, 4-dioxep-1-yl) benzoate, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) -1, 4-dioxepan-1-yl) phenyl) methanol, 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) -1, 4-dioxepan-1-yl) nicotinic acid carbonitrile, 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) -1, 4-dioxepan-1-yl) nicotinamide, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) -1, 4-dioxepan-1-yl) pyridin-3-yl) methanol or (S) - (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) -1, 4-dioxepan-1-yl) pyridin-3-yl) methanol.
3. The compound according to claim 1, wherein the compound is selected from (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, (R) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) piperazin-1-yl) -6-fluorophenyl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) -4- (2- (furan-2-yl) phenyl) piperazine, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxin-2-yl) methyl) -4-o-tolylpiperazine, methyl 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -1, 4-diazepan-1-yl) benzoate, methyl (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxinyl-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine.
4. The compound according to claim 1, wherein the compound is selected from (S) -1- ((2, 3-dihydrobenzo [ b)][1，4]Dioxinyl-2-yl) methyl-4- (3- (methoxymethyl) pyridin-2-yl) piperazine or (S) -1- ((2, 3-dihydrobenzo [ b)][1，4]Dioxanyl-2-yl) methyl) -4- (3- ([ 2 ], [ solution of a salt of a carboxylic acid11C]-methoxymethyl) pyridin-2-yl) piperazine.
5. Use of a compound according to claims 1 to 4, wherein the sleep-related respiratory disorders are obstructive and central apneas and snoring.
6. A combination of one or more compounds of formula (I) with one or more further active compounds for use according to any one of claims 1 to 5.
7. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 4 in association with one or more inert non-toxic pharmaceutically suitable excipients for use according to any one of claims 1 to 4.
8. A pharmaceutical composition comprising a combination according to claim 6 in combination with one or more inert non-toxic pharmaceutically suitable excipients for use according to any one of claims 1 to 5.
9. Method of treatment and/or prevention of sleep-related respiratory diseases by systemic and/or local administration of a therapeutically effective amount of a compound of formula (I) according to at least one of claims 1 to 4 or a pharmaceutical composition comprising at least one compound of formula (I) according to any of claims 1 to 4 in combination with inert, non-toxic, pharmaceutically acceptable additives.
10. The method according to claim 9, wherein the medicament further comprises at least one additional active compound selected from the group consisting of: muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids.
11. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 4 in association with one or more further active ingredients selected from: muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids.
Technical Field
The present invention relates to alpha 2-adrenoceptor subtype C (alpha-2C) antagonists, in particular arylpiperazines of formula (I), for use in a method of treatment and/or prevention of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
Background
Obstructive Sleep Apnea (OSA) is a sleep-related respiratory disorder characterized by recurrent episodes of upper airway obstruction. Upon inhalation, the interaction between the two opposing forces ensures patency of the upper airway. The expansion of the upper airway muscles counteracts the negative pressure within the lumen, causing the lumen to contract. The active contraction of the diaphragm and other auxiliary respiratory muscles creates a negative pressure in the respiratory tract, constituting the driving force for breathing. The stability of the upper respiratory tract is essentially dependent on the coordination and contraction properties of the upper respiratory tract dilator muscles.
Since some upper airway dilator muscles are less active, it is believed that the upper airway collapse of OSA occurs at the beginning of sleep, with the result that the physiologically weak (vulnerable) airway cannot be kept open. However, certain upper airway dilator muscles, including the genioglossus muscle (which is the most important of the upper airway dilator muscles and is innervated by the hypoglossal nerve), can respond to respiratory stimuli to enhance activity during sleep, potentially offsetting some of these changes at the onset of sleep. It has been observed that OSA patients have intervals without apnea during which the activity of the genioglossus muscle is increased by only 25-40% compared to sleep stages with frequent obstructive apneas (Jordan AS, White DP, Lo YL et al, air way muscle activity and long volume reducing stable respiration in structural sleep apple 2009, 32 (3): 361-8). Norepinephrine is one of the most potent neuromodulators of hypoglossal motor neuron activity (Horner r. l. neuromodulation of hypoglucosal motoneurons duringsleep. respir. Physiol Neurobiol 2008, 164 (1-2): 179-196). It is believed that reduced noradrenergic drive results in an excitatory sleep-dependent decrease in the hypoglossal motoneurons, which in turn results in reduced activity of the upper airway dilator muscles, and in particular of the tongue muscles.
Alpha 2C adrenergic receptors modulate norepinephrine release from central norepinephrine neurons, which are autoreceptors involved in presynaptic feedback inhibition of norepinephrine (Hein L et al, Two functional disorders alpha 2-acquired receptors regulated systemic chemotherapy Nature 1999, 402 (6758): 181-184). The increased mobility of motor neurons of the hypoglossal nerve by antagonism of the α 2c adrenoceptor stabilizes the upper respiratory tract and protects them from collapse and obstruction. In addition, snoring can be inhibited by a mechanism that stabilizes the upper respiratory tract.
For simple snoring only, the upper airway is not obstructed. As the upper airway narrows, the flow rate of inhaled and exhaled air increases. This, together with the relaxed muscles, causes the soft tissues of the mouth and throat to flutter in the air stream. This slight vibration produces the typical snoring sound.
Obstructive snoring (upper airway resistance syndrome, severe snoring, hypopnea syndrome) is caused by repeated partial obstruction of the upper airway during sleep. This results in an increase in airway resistance, and thus in an increase in work of breathing at significant fluctuations in intrathoracic pressure. The development of negative pressure within the thoracic cavity during inspiration may reach values due to complete airway obstruction in OSA. The pathophysiological effects on heart, blood circulation and sleep quality are the same as for obstructive sleep apnea. Its pathogenesis may also be the same as OSA. Obstructive snoring is often a precursor to OSA (Holland J.H., et al, Upper Air Resistance Syndrome (UARS) -based snoring. HNO 2000, 48 (8): 628-634).
Central Sleep Apnea (CSA) is caused by brain dysfunction or impaired respiratory regulation. CSA is characterized by a lack of driving force for breathing during sleep, resulting in the occurrence of inadequate or absent sexual ventilation and repeated periods of poor gas exchange. There are several manifestations of CSA. These include high altitude induced periodic breathing, idiopathic csa (icsa), narcotic-induced central apnea, obesity-hypoventilation syndrome (OHS), and Cheyne-Stokes respiration (CSB). Although the precise precipitation mechanisms involved in various types of CSAs may vary greatly, ventilatory drive of unstable sleep devices is a major potential feature (Eckert D.J., et al, Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131 (2): 595-607).
US 2018/0235934 a1 describes the use of agents for promoting hypoglossal motor neuron excitability in the treatment of diseases such as obstructive sleep apnea. As an agent for promoting the excitability of sublingual motor neurons, a disinhibition agent and/or an excitant agent for central adrenal neurons is described. In some embodiments, the central noradrenergic neuron de-inhibitor is an α 2-adrenoceptor antagonist, such as a yohimbine (yohimbine) or α 2-adrenoceptor subtype a (α -2A) antagonist or an α 2-adrenoceptor subtype C (α -2C) antagonist. The alpha 2-adrenoceptor antagonist is selected from the group consisting of atipamazole (Atipamezole), MK-912, RS-79948, RX 821002, [3H ] 2-methoxy-idazoxan (idazoxan) and JP-1302.
The α 2C adrenergic receptors belong to the G protein-coupled receptor family. In addition to the presence of different α 1-adrenoceptors, there are three different α 2-adrenoceptor subtypes (α 2A, α 2B and α 2C). They are involved in the mediation of several different physiological actions in different tissues when stimulated by endogenous catecholamines (epinephrine, norepinephrine), which originate either from the synapse or via the blood. Alpha2 adrenoceptors play important physiological roles, mainly in the cardiovascular system and the central nervous system. The α 2A and α 2C adrenoreceptors are the major autoreceptors involved in presynaptic feedback inhibition of norepinephrine in the central nervous system. Norepinephrine is more potent and avidity at the α 2C-adrenoceptor than at the α 2A-adrenoceptor. Alpha 2C-adrenoceptors inhibit the release of noradrenaline at low endogenous concentrations of noradrenaline, whereas alpha 2A-adrenoceptors inhibit the release of noradrenaline at high endogenous concentrations of noradrenaline (Uys M.M. et al. Therapeutic Potential of selective Targeting the alpha 2C-Adrenoceptor in Cognination, Depression, and Schizophrania-New Developments and Future Perfects. Frondiers in Psychiatry 2017, Aug 14; 8: 144. doi: 10.3389/fpsyt.2017.00144. extraction 2017).
Aryl piperazines as alpha 2-adrenoreceptor subtype C (alpha 2C) antagonists and methods of their preparation and use as medicaments are known from WO 2010/058060 a1, which discloses that the compounds are useful in the treatment of diseases such as diseases caused by stress conduction (propathed), parkinson's disease, depression, schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive compulsive disorder, Tourette's syndrome, blepharospasm or other focal dystonias, temporal lobe epilepsy, drug-induced psychosis, Huntington's disease, disorders caused by fluctuations in sex hormone levels, panic disorder, alzheimer's disease or mild cognitive impairment. There is no disclosure of the use of these compounds in the treatment of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
The current gold standard treatment for OSA patients is Continuous Positive Airway Pressure (CPAP). The positive pressure of the airflow generated by the turbine pump splint opens the upper airway, reversing all possible causes of throat collapse, thus preventing hypopnea, apnea, and hypopnea. Unfortunately, CPAP is not tolerated chronically by up to 50% of all OSA patients (M.Kohler, D.Smith, V.Tippett et al, Thorax 201065 (9): 829-32: Predictors of long-term compliance with connected positive air pressure). Thus, there remains a need to find effective therapeutic agents for the treatment and/or prevention of sleep-related respiratory disorders, such as obstructive sleep apnea. Accordingly, it is an object of the present invention to provide an effective therapeutic agent for the treatment and/or prevention of sleep-related respiratory disorders, such as obstructive sleep apnea, central sleep apnea, and snoring.
Surprisingly, it has now been found that the arylpiperazines of formula (I) according to the invention inhibit upper airway collapse and are therefore suitable for the preparation of a medicament for the treatment and/or prevention of sleep related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
The present invention relates to compounds of formula (I) and salts, solvates, and solvates of said salts:
wherein
X is O, S or CH2；
Z is- [ CH ]2]n-；
A. B, D and E are independently C or N, provided that at least three of A, B, D and E are C;
R1is H, halogen, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-、(R5)2N-(C1-C6) Alkyl, (R)5)2N-(C＝O)-、SH-(C1-C6) Alkyl, hydroxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) alkyl-S- (C)1-C6) Alkyl, hydroxy (C)1-C6) alkyl-S (Op) - (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) alkyl-S (Op) - (C)1-C6) Alkyl or furyl;
R2is H, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy or hydroxy (C)1-C6) An alkyl group;
R3is H, halogen, (C)1-C6) Alkyl or phenyl;
R4is halogen, hydroxy, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, CN or (R)5)2N-；
R5Independently at each occurrence, is H, (C)1-C6) Alkyl or (C)1-C6) Alkoxy (C)1-C6) An alkyl group;
m is 0, 1 or 2;
n is 1 or 2; and is
p is 1 or 2;
for use in a method for the treatment and/or prevention of sleep-related respiratory ailments, preferably obstructive and central sleep apnea and snoring.
In a possible subgroup of the compounds of formula I, X is O.
In another possible subgroup of the compounds of formula I, A, B, D and E are C.
In another possible subgroup of the compounds of formula I, a is N; and B, D and E are C.
In another possible subgroup of the compounds of formula I, n is 1.
In another possible subgroup of the compounds of formula I, n is 2.
In another possible subgroup of the compounds of formula I,
x is O, S or CH2；
Z is- [ CH ]2]n-；
A is C or N;
B. d and E are C;
R1is H, halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl or phenyl;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 1 or 2.
In another embodiment of the present invention, the substrate is,
x is O;
z is- [ CH ]2]n-；
A is C or N;
B. d and E are C;
R1is halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl or phenyl;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 1 or 2.
In another embodiment of the present invention, the substrate is,
x is O;
z is- [ CH ]2]n-；
A. B, D and E is C;
R1is (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy radicalRadical (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H or halogen;
R3is H;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 1 or 2.
In another embodiment of the present invention, the substrate is,
x is O;
z is- [ CH ]2]n-；
A is N;
B. d and E are C;
R1is halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H or halogen;
R3is H;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 1 or 2.
In another embodiment of the present invention, the substrate is,
x is O;
z is- [ CH ]2]n-；
A is N;
B. d and E are C;
R1is halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl or phenyl;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 1.
In another embodiment of the present invention, the substrate is,
x is O;
z is- [ CH ]2]n-；
A is N;
B. d and E are C;
R1is halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl or phenyl;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 2.
In another embodiment of the present invention, the substrate is,
x is O;
z is- [ CH ]2]n-；
A. B, D and E is C;
R1is halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl or phenyl;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 1.
In another embodiment of the present invention, the substrate is,
x is O;
z is- [ CH ]2]n-；
A. B, D and E is C;
R1is halogen, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, hydroxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy- (C ═ O) -, CN, (R)5)2N-(C1-C6) Alkyl, (R)5)2N- (C ═ O) -or furanyl;
R2is H, halogen, (C)1-C6) Alkyl or hydroxy (C)1-C6) An alkyl group;
R3is H, (C)1-C6) Alkyl or phenyl;
R5independently at each occurrence is H or (C)1-C6) An alkyl group;
m is 0; and is
n is 2.
In a preferred embodiment, the present invention relates to a compound of formula (I) selected from: methyl 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) benzoate, methyl (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) phenyl) methanol, 1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, 2- (4- ((2, 3-dihydrobenzo [ b ] [ l, 4] dioxol-2-yl) methyl) piperazin-1-yl) benzonitrile, and mixtures thereof, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) phenyl) methylamine, 1- (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) phenyl) -N-methylmethanamine, 1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (ethoxymethyl) phenyl) piperazine, 2- (2- (4- ((2, 3-dihydrobenzo [ b ] [ l, 4] dioxol-2-yl) methyl) piperazin-1-ylphenyl) propan-2-ol, 1- ((2, 3-dihydrobenzo [ b ] [ l, 4] dioxol-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine, (S) - (2- (4- ((7-fluoro-2, 3-dihydrobenzo [ b ] [ l, 4] dioxol-2-yl) methyl) -piperazin-1-yl) pyridin-3-yl) methanol HC1, (S) -1- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazinehI, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (3- ((2-fluoroethoxy) methyl) pyridin-2-yl) piperazine, 1- (2, 3-difluorophenyl) -4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxalen-2-yl) methyl) piperazine, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) methanol, (S) - (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) pyridin-3-yl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, (R) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, and, (S) - (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) phenyl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine, (l- ((2, 3-dihydrobenzo [ b ] [1, 4] oxathiacyclohexadien-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, 1- (chroman-2-ylmethyl) -4- (2- (methoxymethyl) phenyl) piperazine, and mixtures thereof, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) piperazin-1-yl) -6-fluorophenyl) methanol, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) piperazin-1-yl) -3-fluorophenyl) methanol, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) piperazin-1-yl) -5-fluorophenyl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxan-2-yl) methyl) -4- (2-propylphenyl) piperap Oxazines, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (trifluoromethoxy) phenyl) piperazine, (S) -1- (biphenyl-3-yl) -4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazine, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (furan-2-yl) phenyl) piperazine, (S) -ethyl-2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) piperazin-1-yl) benzoate, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) -4-o-tolylpiperazine, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) -4-m-tolylpiperazine, (S) - (3- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxino-2-yl) methyl) piperazin-1-yl) -4-methylphenyl) methanol, (S) - (3- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) phenyl) methanol, (S) -2- (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-1-yl) phenyl) ethanol, methyl 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -1, 4-dioxep (diazepan) -1-yl) benzoate, methyl 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -1, 4-dioxepan-1-yl) phenyl) methanol, 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -1, 4-dioxepan-1-yl) nicotinic acid carbonitrile, 2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -1, 4-dioxepan-1-yl) nicotinamide, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -1, 4-dioxepan-1-yl) pyridin-3-yl) methanol or (S) - (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -1, 4-dioxepan-1-yl) pyridin-3-yl) methanol, and their salts, solvates, and solvates of said salts; for use in a method for the treatment and/or prevention of sleep-related respiratory ailments, preferably obstructive and central sleep apnea and snoring.
In a more preferred embodiment, the present invention relates to a compound of formula (I) selected from: (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, (R) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (methoxymethyl) phenyl) piperazine, (2- (4- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) piperazin-l-yl) -6-fluorophenyl) methanol, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (2- (furazan) 2-yl) phenyl) piperazine, (S) -1- ((2, 3-dihydrobenzo [ b ] [ l, 4] dioxol-2-yl) methyl) -4-o-tolylpiperazine, methyl 2- (4- ((2, 3-dihydrobenzo [ b ] [ l, 4] dioxol-2-yl) methyl) -1, 4-diazepan-1-yl) benzoate, (S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxanen-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine, and their salts, solvates, and solvates of said salts; for use in a method for the treatment and/or prevention of sleep-related respiratory ailments, preferably obstructive and central sleep apnea and snoring.
In a most preferred embodiment of the invention, the compound of formula (I) is (S) -1- ((2, 3-dihydrobenzo [ b ]][1，4]Dioxohexen-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine or (S) -1- ((2, 3-dihydrobenzo [ b)][1，4]Dioxycyclohexen-2-yl) methyl) -4- (3- ([ 2 ], [ solution ]11C]-methoxymethyl) pyridin-2-yl) piperazine.
The terms used herein have the meanings described below. The term "at least one" as used in the following meanings means one or more, for example one.
The term "hydroxy", as used herein by itself or as part of another group, refers to an-OH group.
Term "(C)1-C6) Alkyl ", as used herein by itself or as part of another group, refers to a straight or branched chain saturated hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. (C)1-C6) Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.
Term "(C)1-C6) Alkoxy ", as used herein by itself or as part of another group, refers to (C) as defined herein1-C6) The alkyl group is attached to the parent molecular moiety through an oxygen atom. (C)1-C6) Representative examples of alkoxy groupsIncluding, but not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2-dimethylpropoxy, 3-methylbutoxy, and n-hexyloxy.
The term "halo" or "halogen," as used herein by itself or as part of another group, refers to fluoro, chloro, bromo, or iodo.
The term "hydroxy (C)1-C6) Alkyl ", as used herein by itself or as part of another group, means that at least one hydroxyl group, as defined herein, passes through (C), as defined herein1-C6) The alkyl group is attached to the parent molecular moiety. Hydroxy (C)1-C6) Representative examples of alkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-dihydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, and 1-hydroxy-1-methylpropyl.
Term "(C)1-C6) Alkoxy (C)1-C6) Alkyl ", as used herein by itself or as part of another group, refers to at least one (C) as defined herein1-C6) Alkoxy is defined by (C)1-C6) The alkyl group is attached to the parent molecular moiety. When there are more than one (C)1-C6) When it is an alkoxy group, (C)1-C6) The alkoxy groups may be the same or different.
(C1-C6) Alkoxy (C)1-C6) Representative examples of alkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-dimethoxyethyl, 1-methyl-2-propoxyethyl, 1-methoxy-1-methylethyl, and 4-methoxybutyl.
The term "hydroxy (C)1-C6) Alkoxy ", as used herein by itself or as part of another group, means that at least one hydroxy group, as defined herein, passes through (C), as defined herein1-C6) The alkoxy group is attached to the parent molecular moiety. Hydroxy (C)1-C6) Representative examples of alkoxy groups include, but are not limited to, hydroxymethoxy, dihydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 3-hydroxypropoxy, 2-hydroxybutyl, and 2-hydroxy-1-methylethoxy.
Term "(C)1-C6) Alkoxy (C)1-C6) Alkoxy ", as used herein by itself or as part of another group, refers to at least one (C) as defined herein1-C6) Alkoxy is defined by (C)1-C6) The alkyl group is attached to the parent molecular moiety. (C)1-C6) The alkoxy groups may be the same or different. (C)1-C6) Alkoxy (C)1-C6) Representative examples of alkyl groups include, but are not limited to, methoxymethoxy, propoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-butoxyethoxy, 2-dimethoxyethoxy, 1-methyl-2-propoxyethoxy, 2-methoxypropoxy, and 4-methoxybutoxy.
The term "halo (C)1-C6) Alkoxy ", as used herein by itself or as part of another group, means that at least one halogen as defined herein passes through (C) as defined herein1-C6) The alkoxy group is attached to the parent molecular moiety. When multiple halogens are present, the halogens may be the same or different. Halo (C)1-C6) Representative examples of alkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, trifluoromethoxy, 2-bromoethoxy, 2, 2, 2-trichloroethoxy, 3-bromopropoxy, 2-chloropropoxy, and 4-chlorobutoxy.
The expression "compound of the invention" as used herein refers to a compound of formula I.
Pharmaceutically acceptable salts, such as acid addition salts comprising organic and inorganic acids, are known in the pharmaceutical art. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chloride, bromide, sulfate, nitrate, phosphate, sulfonate, methanesulfonate, formate, tartrate, maleate, citrate, benzoate, salicylate, ascorbate, acetate, and oxalate.
According to the invention, hydrates or solvates are specified as those forms of the compounds of formula (I) which are molecular compounds or complexes formed by hydration with water or coordination with solvent molecules in the solid or liquid state. Examples of hydrates are sesquihydrate, monohydrate, dihydrate or trihydrate. Also, hydrates or solvates of salts of the compounds of the invention are suitable.
Pharmaceutically acceptable esters, if appropriate, can be prepared by known methods using pharmaceutically acceptable acids which are conventional in the pharmaceutical art and retain their pharmacological effect in free form. Non-limiting examples of such esters include esters of aliphatic alcohols or esters of aromatic alcohols. Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and benzyl esters.
The present invention includes within its scope all possible geometric isomers of the compounds, such as z and E isomers (cis and trans isomers), as well as all possible optical isomers of the compounds, such as diastereomers and enantiomers. Furthermore, the present invention includes within its scope individual isomers as well as any mixtures thereof, such as racemic mixtures. The individual isomers may be obtained using starting materials having the corresponding isomeric forms, or may be separated after preparation of the final compound according to conventional separation methods. In order to separate optical isomers, such as enantiomers, from their mixtures, conventional resolution methods, such as fractional crystallization, may be used.
WO-a 2010/058060 discloses broadly compounds of formula (I), their preparation and their use as α 2C antagonists for the treatment of diseases or conditions of the peripheral or central nervous system, and in particular, these compounds are specifically an explicit part of the present specification and are therefore incorporated herein by reference.
The term "effective amount" as used herein refers to an amount of a compound of formula (I) which is effective in the treatment and/or prevention of sleep related respiratory disorders, preferably obstructive and central apnea and snoring.
The present invention relates to (alpha-2C) antagonists, in particular arylpiperazines of formula (I), for use in a method of treatment and/or prevention of sleep related respiratory disorders, preferably obstructive and central apnea and snoring.
The invention also relates to the use of compounds of formula (I) for producing medicaments for the treatment and/or prophylaxis of sleep-related respiratory diseases, preferably obstructive and central apneas and snoring.
Another subject of the invention is the use of one or more compounds of formula (I) in combination with one or more other active compounds in a method for the treatment and/or prophylaxis of sleep-related respiratory complaints, preferably obstructive and central apneas and snoring.
Another subject of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) in association with one or more inert non-toxic pharmaceutically suitable excipients for use in a method for the treatment and/or prevention of sleep-related respiratory diseases, preferably obstructive and central apneas and snoring.
The invention also relates to a pharmaceutical composition comprising a combination of one or more other active compounds in combination with one or more inert, non-toxic pharmaceutically suitable excipients for use in a method for the treatment and/or prevention of sleep-related respiratory diseases, preferably obstructive and central apneas and snoring.
The invention also relates to a method for the treatment and/or prevention of sleep-related respiratory diseases by systemic and/or topical administration of a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) in combination with inert, non-toxic, pharmaceutically suitable additives.
Another subject of the invention is the combination of one or more compounds of formula (I) with one or more other active compounds for use in a method for the treatment and/or prophylaxis of sleep-related respiratory disorders, preferably obstructive and central apneas, and snoring.
According to the invention, the arylpiperazines of formula (1) can be used alone or, if desired, in combination with one or more other pharmaceutically active substances, provided that the combination does not lead to undesired and unacceptable side effects. Preferred examples of combinations suitable for this purpose for treating sleep-related respiratory ailments, preferably obstructive and central sleep apnea, and snoring, include:
respiratory stimulants such as, and preferably theophylline (theophylline), doxaproram (doxapram), nikkacetamide (nikkamide), or caffeine (caffeine);
psychostimulants such as, and preferably, modafinil (modafinil) or armofinib (armodafinil);
amphetamines and amphetamine derivatives, such as and preferably amphetamine, methamphetamine (methamphetamine) or methylphenidate (methylphenidate);
serotonin reuptake inhibitors, such as, and preferably, fluoxetine (fluooxetine), paroxetine (parooxetine), citalopram (citalopram), escitalopram (escitalopram), sertraline (sertraline), fluvoxamine (fluvoxamine) or trazodone (trazodone);
serotonin precursors, such as and preferably L-tryptophan;
a selective serotonin norepinephrine reuptake inhibitor, such as and preferably venlafaxine (venlafaxine) or duloxetine (duloxetine);
noradrenergic and specific serotonergic antidepressants, such as and preferably mirtazapine (mirtazapine);
a selective norepinephrine reuptake inhibitor, such as and preferably reboxetine (reboxetine) or atomoxetine (atomoxetine);
tricyclic antidepressants, such as, and preferably, amitriptyline (amitriptyline), protriptyline (protriptyline), doxepin (doxepin), trimipramine (trimipramine), imipramine (imipramine), clomipramine (clomipramine) or desipramine (desipramine);
muscarinic receptor antagonists such as, and preferably oxybutynin (oxybutynin);
GABA agonists such as, and preferably, baclofen (baclofen);
glucocorticoids, such as, and preferably, fluticasone (fluticasone), budesonide (budesonide), beclomethasone (beclometasone), mometasone (mometasone), tixocortol (tixocortol) or triamcinolone (triamcinolone);
a cannabinoid receptor agonist;
carbonic anhydrase inhibitors such as, and preferably, acetazolamide (acetazolamide), methazolamide (methazolamide), or diclofenamide (diclofenamide);
opioids and benzodiazepine (benzodiazepine) receptor antagonists, such as and preferably flumazenil (flumazenil), naloxone (naloxone) or naltrexone (naltrexone);
cholinesterase inhibitors, such as, and preferably, neostigmine (neostigmine), pyridostigmine (pyristigmine), physostigmine donepezil (phystigmine donepezil), galantamine (galantamine) or rivastigmine (rivastigmine);
appetite suppressants such as, and preferably, sibutramine (sibutramine), topiramate (opiramate), phentermine (phentermine), lipase inhibitors (lipase inhibitors) or cannabinoid receptor antagonists;
mineralocorticoid receptor antagonists.
A preferred subject of the present invention is the combination of one or more compounds of formula (I) with one or more further active compounds selected from muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids for use in a method for the treatment and/or prophylaxis of sleep-related respiratory diseases, preferably obstructive and central apnea, and snoring.
In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a muscarinic receptor antagonist (e.g. and preferably oxybutynin).
In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, such as, and preferably, spironolactone, eplerenone or fenmonene.
In a preferred embodiment of the invention, the compound of the invention is administered in combination with a diuretic such as, and preferably, furosemide (furosemide), bumetanide (bumetamide), torasemide (torsemide), bendroflumethiazide (bendroflumethiazide), chlorothiazide (chlorothiazide), hydrochlorothiazide (hydrochlorothiazide), hydroflumethiazide (hydroflumethiazide), methylchlorothiazide (methylthiothiazide), polythiazide (polythiazide), trichlormethiazide (trichlorethazide), chlorothiazide (chlorothalidone), indapamide (indapamide), metolazone (methazone), quinethazone (quinazone), acetazolamide (acetazolamide), dichlorofenamide (dichlorphenamide), acetofenamide (methazolamide), acetofenamide (acetofenamide), acetofenamide (hydramide (acetofenamide (mannitol), triamcinolone (sorbitol (or triamcinolone (sorbitol).
In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a corticosteroid such as, and preferably, prednisone (prednisone), prednisolone (prednisone), methylprednisolone (methylprednisone), triamcinolone (triamcinolone), dexamethasone (dexamethasone), betamethasone (betamethasone), beclomethasone (beclomethasone), flunisolide (flunisolide), budesonide (budesonide) or fluticasone (fluticasone).
The arylpiperazines of formula (I) of the invention may also be used in combination with one or more medical-technical devices or aids, if desired, provided that they do not cause unwanted and unacceptable side effects. Medical devices and accessories suitable for such combined applications, such as and preferably:
positive airway pressure devices such as, and preferably, CPAP (continuous positive airway pressure) devices, BiPAP (bi-level positive airway pressure) devices and IPPV (intermittent positive airway pressure) devices;
neurostimulators of neurotropism;
intraoral aids such as and preferably protruding braces (brases);
nasal disposable valves;
nasal stents.
The arylpiperazines of formula (I) of the invention may act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by the oral, parenteral, pulmonary, intrapulmonary (inhalational), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or auditory canal routes, or as implants or stents.
Another subject of the invention is a pharmaceutical composition comprising a compound of formula (I) for systemic and/or topical administration, by the following route: oral, parenteral, pulmonary, intrapulmonary (inhalational), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival, or auditory canal routes, or as an implant or stent. The preferred route of administration is oral.
For these routes of administration, the methods of the invention may be administered in a suitable form of administration.
For oral administration, the administration forms are those which work according to the prior art, which can release the compounds of the invention rapidly and/or in a modified manner, and which contain the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with a gastric juice-resistant or delayed-dissolving or insoluble coating which controls the release of the compounds of the invention), tablets which disintegrate rapidly in the oral cavity or films/wafers, films/lyophilizates or capsules (for example hard or soft gelatin capsules), dragees, granules, pills, powders, emulsions, suspensions, aerosols or solutions.
Parenteral administration may omit an absorption step (e.g., by intravenous, intraarterial, intracardiac, intraspinal, or intralumbar administration) or include an absorption step (e.g., by intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal administration). Administration forms suitable for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
For other routes of administration, suitable are, for example, inhalable pharmaceutical forms (including powder inhalers and nebulizers), nasal drops, solutions or sprays, tablets for lingual, sublingual or buccal administration, tablets, films/wafers or capsules, suppositories, oral or ocular preparations, vaginal capsules, aqueous suspensions (emulsions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), creams (milks), pastes, foams, dusting powders, implants or stents.
Oral or parenteral administration is preferred, especially oral and intravenous administration.
The compounds of the invention may be converted into the administration forms described. This can be carried out in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable additives. These additives include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, e.g. ascorbic acid), dyes (e.g. inorganic pigments, e.g. iron oxides) and flavouring and/or odour correctors.
In general, this has been found to be advantageous, for effective results in the case of parenteral administration, in amounts of from about 0.001 to 10mg/kg body weight, preferably from about 0.01 to 1mg/kg body weight. In the case of oral administration, the dose is about 0.01 to 100mg/kg of body weight, preferably about 0.01 to 20mg/kg of body weight, very particularly preferably 0.1 to 15mg/kg of body weight.
However, it may sometimes be necessary to deviate from the stated amounts, i.e. depending on the body weight, the route of administration, the individual response to the active compound, the nature of the preparation and the time or time interval of administration. Thus, in some cases it may be sufficient to process with less than the minimum amount mentioned above, while in other cases the upper limit specified must be exceeded. In case of administration in relatively larger amounts, it is suggested that it may be divided into several individual doses during the day.
The following examples illustrate the invention. The present invention is not limited to these examples.
Examples
A. Experimental methods
The advantageous pharmacological properties of the compounds of the invention can be determined by the following methods.
The therapeutic potential of the compounds of formula (I) of the present invention for sleep apnea has been pre-clinically evaluated in a porcine model of Obstructive Sleep Apnea (OSA).
The use of negative pressure may lead to collapse and thus obstruction of the upper respiratory tract of anaesthetised, spontaneously breathing pigs (Wirth K.J. et al Sleep 36(5) (2013), page 699-.
German Changbai pigs (German Landrace pigs) were used in this model. The pigs were anesthetized and the trachea was dissected. Two pipe fittings are inserted into the air pipe, one is inserted into the head part of the air pipe, and the other is inserted into the tail part of the air pipe. The head cannula is connected to tubing leading to the negative pressure device and the distal tracheal cannula using a connector. The distal tracheal tube was additionally connected to a tube with an open end to atmosphere via a connector for free breathing of the trachea, thereby bypassing the upper airway. By appropriately opening and clamping these tubes, breathing can be switched from nasal breathing to breathing through the tail tracheal tube, thereby bypassing the upper airway, and the (isolated) upper airway can be connected to a negative pressure device, thereby causing airflow in the inspiratory direction.
At some point in time, the swine were breathed by passing through the tail cannula and applying-50, -100 and-150 cm head of water (cm H) to the upper respiratory tract2O) to test the collapsibility of the upper respiratory tract. This causes the upper airway to collapse, which manifests as airflow disruption and pressure drops in the ductwork. The test is performed at certain intervals before the test substance is administered, and after the test substance is administered. A suitably effective test substance may prevent airway collapse during the inspiratory phase.
In this OSA pig model, systemic administration of an α 2-adrenoreceptor subtype C (α -2C) antagonist of formula (I) ((S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine in a single bolus intravenous injection of 1.5mg/kg followed by intravenous infusion of 0.475mg/kg/h for 4h at all negative pressures of-50, -100 and-150 cm for up to 5 hours inhibited collapse of the upper breath.
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FIG. 1: α 2-adrenoceptor subtype C (α -2C) antagonist of formula (I) ((S) -1- ((2, 3-dihydrobenzo [ b ] [1, 4] dioxol-2-yl) methyl) -4- (3- (methoxymethyl) pyridin-2-yl) piperazine was administered at time point 0min in a single bolus intravenous injection of 1.5mg/kg followed by intravenous infusion for 4h at 0.475mg/kg/h, giving the effect on the upper respiratory tract' S collapsibility at different negative pressure levels.
From the above data it can be concluded that antagonists of the alpha2-adrenergic receptor subtype C (alpha-2C) of formula (I) are useful in the treatment of sleep-related respiratory disorders, preferably obstructive and central sleep apnea and snoring.
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