Non-sedative a-2-agonist 1-(2,3-dimethyl-phenyl)-ethyl-1,3-dihydro-imidasole-2-thione
SUBSTANCE: present invention pertains to α-2A/α-1A selective agonist, which is a compound with formula , as well as to a pharmaceutical composition, which contains a pharmaceutical carrier and a therapeutic effective quantity of α-2A/α-1A selective agonist, which contains a compound with structure 1.
EFFECT: obtaining selective agonist which can be used for preventing or alleviating neurological conditions without an accompanying sedative effect during extraneous administration.
6 cl, 2 tbl, 2 ex, 2 dwg
According to 35 USC §119 (e) of this patent application has the advantage of conditional priority patent application 60/502, 562, registered September 12, 2003, which, thus, here is the link.
The scope of the invention
In General, the invention relates to molecular medicine and more to α-2 the adrenergic agonists that are highly selective with respect to α-2A adrenergic receptor compared to α-1A adrenergic receptor.
The diversity of States can be at least partially due to the sympathetic nervous system, including the diversity of conditions associated with stress. Simpaticeskii reinforced condition include, without limitation, sensory hypersensitivity, such as sensory hypersensitivity caused by fibromyalgia or headache, such as migraine; diseases of the gastrointestinal tract, such as irritable bowel syndrome and dyspepsia; dermatological diseases such as psoriasis; cardiovascular disorders; tachycardia; diseases of peripheral narrowing of the blood vessels, including Raynaud's syndrome and scleroderma; panic attack; metabolic disorders such as type II diabetes, insulin resistance and obesity; disorder of muscle contraction, including the contraction of skeletal disorders is ysz, violations of the reduction of smooth muscles, muscle spasticity and violations of muscle contraction due to tension-type headache; behavioral disorders such as overeating and drug dependency, but not limited to, and sexual dysfunction.
Despite the fact that α-2 adrenergic agonists are promising in the treatment of symptoms simpaticeskii reinforced States, the use of these α-2 adrenergic agonists may be unsuitable due to concomitant sedative effects. For this reason, limited effective treatment α-2 adrenergic agonist other conditions, including neurological conditions, eye conditions and chronic pain. Thus, there is a need for new effective, does not have a sedative effect α-2 adrenergic agonists for use in therapy. The present invention satisfies this need, and also has a number of interrelated advantages.
Summary of the invention
In the present invention proposed α-2A/α-1A selective agonist, which is the following connection:
or its pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture. In addition, in the present invention proposed by the pharmaceutical is a mini-composition, which contains a pharmaceutical carrier and a therapeutically effective amount α-2A/α-1A selective agonist, which is the following connection:
(structure 1) or its pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture.
Brief description of drawings
Figure 1 shows the connection 1 ((+)-(S)-4-[1-(2,3-dimetilfenil)ethyl]-1,3-dihydroimidazole-2-tion) of (+)-(S)-4-[1-(2,3-dimetilfenil)ethyl]-1H-imidazole.
Figure 2 shows that compound 1 is superior to brimonidine in its ability to weaken sulprostone-induced tactile hypersensitivity in the absence of sedation. Antihypercholesterolemic to the dose and sedative effects of four α-2 agonists compared to models sulprostone-induced tactile hypersensitivity and motor activity. The upper-left region: intraperitoneal administration of brimonidine. The upper right area: intraperitoneal administration of dexmedetomidine. The bottom left pane: oral administration of compound 1. The bottom right pane: intraperitoneal injection of compound 2. The calculated average value of the total sensitivity index and the standard deviation for this value (see solid line and shaded symbols, left axis). Locomotor activity of the animals with the drug expressed in percent, and the percentage of sedative effect is calculated as 100% minus the percentage of motor activity (see the dotted line where there's no shading and symbols, right axis).
Detailed description of the invention
Adrenergic receptors mediate physiological responses to catecholamines, noradrenaline and adrenaline, and are members of the superfamily linking G-protein receptors with seven transmembrane domains. These receptors, which in pharmaceuticals are divided into types α-1, α-2 β-adrenergic receptors are involved in various physiological functions, including functions of the cardiovascular and Central nervous systems. α-Adrenergic receptors mediate the stimulating and inhibitory functions: α-1 adrenergic receptors are typical excitatory postsynaptic receptors, which primarily mediate responses in effector nerve outgrowth, whereas α-2 adrenergic receptors are located both postsynaptic and presynaptic, where they inhibit the release of neurotransmitters. Currently agonists α-2 adrenergic receptors are used clinically in the treatment of high blood pressure, glaucoma, muscle spasticity syndrome of impaired attention, when discontinuation of narcotic drugs, as well as optional General anesthesia and in the treatment of pain, caused cancer.
At the moment, α-2 adrenergic receptors are classified into three subtypes based on their pharmacological and molecular features: α-2A/D (α-2A in man and α-2D in rat); α2 and α-2C (Bylund et al., Pharmacol. Rev. 46: 121-136 (1994) and Hein and Kobilka, Neuropharmacol. 34: 357-366 (1995)). α2 and α-2 In subtypes can manage arterial contraction in some vascular beds, and α2 and α-2C subtypes transfer reaction inhibition of the release of noradrenaline from sympathetic nerve endings on the basis of feedback. α-2A subtype also serves as a mediator of many of the main effects α-2 adrenergic agonists (Calzada and Artinano, Pharmacol. Res. 44: 195-208 (2001); Hein et al., Ann. NY Acad. Science 881: 265-271 (1999); Ruffolo (Ed.), α-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology S. Karger Publisher′s Inc. Farmington, CT (1991)).
As here disclosed, some α-2 agonists were analyzed on a α-2A/α-1A functional selectivity, using cellular assays in vitro. Example 1 shows receipt α-2 adrenergic agonist ((+)-(S)-4-[1-(2,3-dimetilfenil)ethyl]-1,3-dihydroimidazole-2-tion) of (+)-(S)-4-[1-(2,3-dimetilfenil)ethyl]-1H-imidazole (also see figure 1). As shown in table 1, this α-2 adrenergic agonist, is indicated as compound 1 showed high selectivity towards α-2A/α-1A, which is confirmed by mediano the appropriate level α -1A activity observed in this connection in a functional cellular assay (also see example II). On the contrary, dexmedetomidine was less than α-2A/α-1A selective than brimonidine (see table 1). These results show that compound 1 is highly selective for activation α-2A receptor compared to α-1A receptor.
|α-1A relative effectiveness and value α-1A/α-2A efficiencies of some α-2 agonists|
|Connection||α-1A relative effectiveness*||ratio α-1A/α-2A efficiencies|
|* Efficiency relative to the full agonist, phenylephrine|
|ON = inactive|
In addition, as disclosed in example II, α-2A/α-1A functional selectivity, shown in in vitro cellular analysis, is associated inversely with in vivo sedative activity at terapeuticas the first dose. As shown in figure 2, α-2 agonist, which was the most selective for α-2A/α-1A function in vitro also showed the greatest interval between therapeutic dose facilitating sulprostone-induced tactile hypersensitivity, and the dose leading to a significant sedative effect. In particular, compound 1, administered orally at a dose of 1 mg/kg, caused a 50% reduction in sensitization (solid line, left axis) with less than 30% of the sedative effect (where there's no shading diamonds, right axis) at doses hundred or even a thousand times greater than therapeutically effective dose of 1 mcg/kg (see figure 2, bottom left pane). This separation between therapeutically effective dose and sedative dose was greater than that observed for any other investigational α-2 agonist. These results indicate that α-2A/α-1A adrenergic receptor selectivity α-2 agonists, which are defined using a functional cell in vitro, inversely associated with sedative activity at therapeutic doses of systemic or peripheral injection in vivo. In addition, these results show that especially useful α-2 agonists, with a wide interval between therapeutically effective dose and sedative dose, show α-2A/α-1A functional selectivity ADR is energicheskomu receptor.
Based on these discoveries, the present invention offers α-2A/α-1A selective agonist, which includes the following connection:
(structure 1) or its pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture. Selective agonist of the invention may, for example, to show α-1A efficacy less than brimonidine, or to have a ratio of α-1A/α-2A efficiencies greater than brimonidina. In one embodiment α-2A/α-1A selective agonist of this invention includes the compound represented by formula 1.
"α-2A/α-1A selective agonist" according to the invention can partly be described as, first, with more than 25% efficiency compared to brimonidina for one or more α-2 adrenergic receptors, including α-2A adrenergic receptor, and, secondly, with α-1A efficacy less than brimonidine, in other words, the ratio of α-1A/α-2A efficiencies more compared with brimonidine. In certain embodiments of this invention α-2A/α-1A selective agonist has α-1A/α-2A EU50the ratio at least twice α-1A/α-2A EU50the ratio for brimonidine, or α-1A/α-2A EU50soothes the tion, which, at least five, ten, twenty, thirty, forty, fifty, sixty, seventy, eighty, ninety, or a hundred times more than α-1A/α-2A EU50the ratio for brimonidine. It is clear that in addition to the activity α-2A agonist, α-2A/α-1A selective agonist of the invention may, optionally, have agonist activity or antagonist of one or more adrenergic or other receptors, provided that selective agonist satisfies the above criterion α-2A/α-1A selectivity.
Efficiency, also known as internal activity, is a measure of the maximum activation of the receptor, achieved by the agent. To determine α-2A/α-1A selectivity efficiency, it is preferable to determine, using any functional analysis, which does not increase significantly the response of the receptor. Efficiency can be represented as a ratio or percentage of the maximum effect of the agent is to maximize the effect of standard agonists for each receptor subtype. Usually as standard agonist for α-2A, α-2V α-2C receptors use brimonidine (UK 14304)when determining the relative efficiency α-2 receptor of the present invention as a standard also used brymon the Dean. Phenylephrine is an accepted standard agonist for α-1A, α1V α-1D receptors, and was used here as a standard for determining the relative efficiency α-1 receptor.
Functional definition α-2A/α-1A selective agonist of the invention α-1A efficiency, or the ratio of α-1A/α-2A efficiencies, or both values were compared with those values for brimonidine. The term "brimonidine" is used here to refer to compounds having the following formula:
or its pharmaceutically acceptable derivative. Brimonidine represents, without limitation, 5-bromo-6-(2-imidazolin-2-ylamino)cinoxacin D-tartrate (1:1), Alphagan™ and UK 14304. Brimonidine and its pharmaceutically acceptable derivatives can be purchased from industrial sources or to receive routine methods, for example as described in U.S. patent No. 6323204.
Any of many analyses is suitable to determine α-2A/α-1A functional selectivity. Not limited to the examples, efficiency, activity or EU50we α-2A receptor can be determined by analyzing the inhibition of adenylate cyclase activity. In addition, inhibition of adenylate cyclase activity can be analyzed, without limitation, the PC 12 cells stably ex is desiroush α -2A receptor, for example α-2A receptor of human rights. Moreover, not limited to the examples, efficiency, activity or EU50for α-1A receptor can be determined by analyzing intracellular calcium. Intracellular calcium, without limitation, can be analyzed in cells NECK, stably expressing α-1A receptor, for example a bullish α-1A receptor.
Thus, it is clear that α-2A/α-1A functional selectivity can be described using any routine functional analysis, such as cellular in vitro tests that measure the response of the proximal agent to the excitation of the receptor. Suitable tests, without limitation, include in vitro, for example analyses of cyclic AMP (adenosine monophosphate), or analyses enable GTPγS (γ-thioguanosine) to determine proximal to the activation α-2 receptor function (Shimizu et A1., J.Neurochem. 16: 1609-1619 (1969); Jasper et al., Biochem. Pharmacol. 55: 1035-1043 (1998); analyses of intracellular calcium, such as FLIPR assays and determination of changes of calcium using fluo-3 to determine the proximal-to-activate α-1 receptor function (Sullivan et al., Methods Mol. Biol. 114: 125-133 (1999); Kao et al., J. Biol. Chem. 264: 8179-8184 (1989)). Later in example II analyses revealed α-2A selectivity, based on the suppression of Forskolin-induced accumulation of cyclic amp in PC12 cells stably e is preservesig α -2A receptor, and the increase in intracellular calcium in cells NECK, stably expressing α-1A receptor. Additional useful assays include, without limitation, analyses of intitolata, for example analyses of coincidence scintillation (Brandish et al., Anal. Biochem. 313: 311-318 (2003); definition β-arrestin sequestration GPCR (receptors associated with G-proteins), such as the analysis of resonant energy transfer bioluminescence (Bertrand et al., J. Receptor Signal Transduc. Res. 22: 533-541 (2002)and analyses citcumstances microphysiometry (Neve et al., J. Biol. Chem. 267: 25748-25753 (1992)). These and additional tests for proximal function α-2 α-1 receptor are standard and well known from the prior art.
For another non-limiting of the invention example, the definition of the GTPγS represents the analysis is useful for detecting α-2A/α-1A functional selectivity α-2 adrenergic receptors transmit enable guanosine 5′-O-(gamma-thio)triphosphate ([35S]GTPγS) G-proteins in the selected membrane catalyzed by receptor metabolism [35S]GTPγS for GDF (guanozintrifosfata). Essentially, the analysis based on the inclusion of [35S]GTPγS, you can spend as previously described in Jasper al. 1998. Briefly, confluent cells treated with the agent, which should protection is th gather with cups cell culture tissue in phosphate buffer saline solution before centrifugation at 300 rpm for 5 minutes at 4°C. the precipitated cells after centrifugation resuspended cold lyse buffer (5 mm Tris/HCl, 5 mm etc, 5 mm EGTC (etilenvinilatsetata acid), 0.1 mm PMSF (phenylmethylsulfonyl, pH 7.5)using a Cage mill Polytron (setting #6, five seconds) and centrifuged at 34000×g for 15 minutes at 4°before resuspending in cold lyse buffer and re-centrifuged as described above. After the second stage of leaching aliquot of sample membrane preparation is placed in membrane buffer (50 mm Tris/HCl, 1 mm etc, 5 mm MgCl2, 0.1 mm PMSF, pH 7.4) and frozen at -70°s to use in the analysis of binding.
The inclusion of the GTPγS analyze, using [35S]GTPγS when the specific activity 1250 Curie/mmol. Frozen membrane aliquot of sample is thawed and diluted in incubation buffer (50 mm Tris/HCl, 5 mm MgCl2, 100 mm NaCl, 1 mm add, 1 mm DTT (dithiothreitol), 1 mm propranolol, 2 mm GDF, pH 7.4) and incubated with radioligand at a final concentration of 0.3 nm at 25°C for 60 minutes. After incubation the samples filtered through glass fiber filters (Whatman GF/B, treated with 0.5% bovine serum ALB is min) in 96-well reservoir cells and rapidly washed four times with four milliliters of ice-cold wash buffer (50 mm Tris/HCl, 5 mm MgCl2, 100 mm NaCl, pH 7.5). After drying in a drying apparatus, the filters are transferred into test tubes scintillation containing five milliliters of scintillation mixture Beckman′s Ready Proteins®for counting. Then for α-2A receptor define EU50and the maximum effect (effectiveness).
It is clear that suitable tests are usually carried out using cells that naturally Express high levels of only one subtype α-adrenergic receptor, or using transfection cells that Express significant levels only subtype recombinant α-adrenergic receptor. As not limiting the invention of example, adrenergic receptor may be a receptor of a person or its homolog, with similar pharmacology. As here disclosed, α-2A/α-1A selectivity preferably determine the receptor-proximal analyses, ie, those in which the response of the receptor does not increase or increases only marginally, or such, which is detected by the fast signal. From the point of view of the foregoing, a qualified expert in this field will prefer to use tests other than analysis Technologies Receptor Selection and Amplification (RSAT) and similar analisa is, which are not clearly differentiated partial or complete agonism.
Pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture of compound 1 can be obtained by traditional methods. α-2A/α-1A selective agonist having the structure 1, is simply a characteristic of a number of salts, esters, amides, etc. this connection that a qualified expert in the field can be easily obtained revealed here by the way when using the well known methods of chemical synthesis, including methods, similar to those shown here (see example I).
A qualified person skilled in the art understands that in addition to the synthesis scheme shown in example I, you can use a number of methods for obtaining, for example, systems with imidazole cycle connection 1. Such syntheses are well known from the prior art, as described, for example, Grimmett, "Imidazole and Benzimidazole Synthesis", Ross Academic Press (1997). In addition, can also be suitable for obtaining selective agonist compounds 1 alternative imidazol-2-thiones from imidazoles. As not limiting the invention example, the cyclic system imidazole-2-thione can be obtained from the imidazole ring, selectively protecting the nitrogen atom N1 trailvoy group, then deprotonate strong OS is a Finance, such as n-BuLi or LDA (diisopropylamide lithium), with the formation of the anion in the position C2. Then the anion can react with sulfur with the formation of the desired imidazole-2-thione. As a further non-limiting of the invention of example, imidazole cycle can react with phenylcarbamates with the formation of 2-imidazolone, which can be turned into tion, using, for example, the reagent Lawesson. These and similar ways of getting the connection 1 and the other α-2A/α-1A selective agonist of the invention are well known from the prior art.
Here α-2A/α-1A selective agonist can be useful, for example, to prevent or facilitate simpaticeskii reinforced condition without concomitant sedation upon peripheral administration. Any of a series simpaticeskii enhanced state it is possible to prevent or reduce without concomitant sedation under the action α-2A/α-1A selective agonist of this invention, including, without limitation, sensory hypersensitivity, such as caused by fibromyalgia or headache, such as migraine headaches, diseases of the gastrointestinal tract, such as irritable bowel syndrome and dyspepsia; dermatological diseases such as psoriasis; cardiovascular disorders; tachycardia is; diseases of peripheral narrowing of the blood vessels, including Raynaud's syndrome and scleroderma; panic attacks; metabolic disorders such as type II diabetes, insulin resistance and obesity; disorder of muscle contraction, including disorders of contraction of skeletal muscle disorders contraction of smooth muscles, muscle spasticity and violations of muscle contraction due to tension-type headache; conduct disorder, for example, but not limited to, overeating and drug addiction, and sexual dysfunction.
Here α-2A/α-1A selective agonist can also be useful, for example, to prevent or relieve chronic pain without concomitant sedation upon peripheral administration. Chronic pain is a term which means pain is different from acute pain, and includes, without limitation, neuropathic pain, inner pain, inflammatory pain, headache, muscle pain and repercussions pain. It is clear that chronic pain lasts relatively long, for example several years, and may be constant or periodic. Chronic pain differs from acute pain, which occurs in the moment, as a rule, the higher the threshold, the pain is usually caused by injury such as a cut, blow, burn the Lee chemical irritation, for example, you experience when exposed to capsaicin, the active component of Cayenne pepper.
Any of a variety of types of chronic pain can prevent or reduce without concomitant sedation under the action α-2A/α-1A selective agonist of this invention, including but not limited to, neuropathic pain, such as neuropathic pain due to diabetic neuropathy or post herpetic neuralgia; chronic pain due to cancer; postoperative pain; allodynia, for example, pain caused by fibromyalgia, chronic pain, due to complex regional pain syndrome (crbs); chronic internal pain, for example, caused by irritable bowel syndrome or dysmenorrhea; chronic headache, such as migraine, avascular headache, "histamine" headache or daily headache tension; chronic muscle pain, such as, but not limited to it, the pain caused by spasm of the back.
Here α-2A/α-1A selective agonist can be useful, for example, to prevent or alleviate neurological condition without concomitant sedation upon peripheral administration. This neurological condition, without ogran the treatment, can be acute or chronic neurological condition. As neogranichinymi the invention examples, can lead to acute neurological condition that can prevent or reduce without concomitant sedation under the action α-2A/α-1A selective agonist of this invention, include stroke, traumatic brain and spinal cord and seizures. Moreover, a chronic neurological condition that can prevent or reduce without concomitant sedation under the action α-2A/α-1A selective agonist of this invention include, but are not limited to the above examples, neurodegenerative diseases such as Alzheimer's disease; Parkinson's disease; Huntington's disease; amyotrophic lateral sclerosis and multiple sclerosis, dementia and neuropathy caused by HIV; eye diseases such as glaucoma, diabetic neuropathy and age-related macular degeneration, schizophrenia, drug addiction, the withdrawal syndrome and drug dependency, depression and anxiety.
Term neurological condition includes all acute and chronic disorders that affect, at least in part, the neurons. Thus, the term neurological condition includes, without limitation, hypoxia-ischemia (stroke); damage to golovnogo and spinal cord; epilepsy; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Parkinson's disease; Huntington's disease; amyotrophic lateral sclerosis and multiple sclerosis; ocular neuropathy such as glaucoma, secondarymenu degeneration of the retina, such as photoreceptor degeneration, and macular degeneration; disorders of photoreceptor degeneration, such as pigmentary degeneration of the retina; dementia due to HIV (complex dementia and acquired immune deficiency syndrome) and neuropathy caused by HIV; metabolic, mitochondrial and infectious mental abnormalities, such as, but not limited to, encephalitis; neuropathic pain syndromes, such as causalgia or painful peripheral neuropathy; oligometastases atrophy; mitochondrial abnormalities and other biochemical disorders such as MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, insulinopenia episodes), MERRF syndrome (myoclonus epilepsy with broken red fibers), Leber's disease, a disease Wernicke, rett syndrome, homocystinuria, hyperhomocysteinemia, hyperprolinemia, necklacesa hyperglycinemia, hydroxipropionic aminoaciduria, failure sulfadoxine, combined systems disease, lead encephalopathy; liver ence alopecia, Tourette syndrome; drug abuse and drug dependence; withdrawal of a medicinal product, such as discontinuation of alcohol or sedatives; syndromes of depression or anxiety (see, for example, Lipton and Rosenberg, New Enql. J. Med. 330:613 (1994)).
Here α-2A/α-1A selective agonist, in addition, it may be useful, for example, to prevent or relieve ocular condition without concomitant sedation upon peripheral administration. Eye conditions that can prevent or reduce without concomitant sedation under the action α-2A/α-1A selective agonist of the invention include, without limitation, glaucoma, macular degeneration and retinal degeneration, such as diabetic retinopathy.
Any of a variety of eye conditions can prevent or reduce without concomitant sedation after peripheral injection α-2A/α-1A selective agonist of this invention. Such conditions include, but are not limited to only them, diabetic retinopathy; macular edema, for example, due to diabetes; the state of degeneration of the retina, such as glaucoma, macular degeneration such as age-related macular degeneration (ARMD) and pigmentary degeneration of the retina; retinal degeneration; the inflammatory Rastro is of the retina; the state of occlusion of retinal vessels, such as occlusion retinal vein or branch vessel, or occlusion of the Central retinal artery; retinopathy early development; retinopathy due to blood diseases such as sickle cell anemia; increased intraocular pressure; ocular itching; violation after retinal detachment; damage or hemorrhage due to vitrectomy, retinal surgery and other surgery; other retinal damage, including therapeutic damage, such as resulting from laser treatment of the retina, for example, panretinal photocoagulation for diabetic retinopathy or retinal phototherapy. In addition, an eye condition that can prevent or reduce without concomitant sedation with the peripheral introduction α-2A/α-1A selective agonist of this invention include, without limitation, genetic and acquired optic neuropathy, such as optic neuropathy, characterized primarily by loss of Central vision, for example, hereditary optic atrophy (LHON), autosomal dominant optic atrophy (illness ciera) and other neuropathies of the optic nerve, for example, including mitochondrial defects, aberrant dynamin-related proteins or not poistenie apoptosis; optic neuritis, for example, due to multiple sclerosis, occlusion of the retinal vein, or phototherapy or laser therapy. See, for example, Carelli et al., Neurochem. Intl. 40: 573-584 (2002), and Olichon et al., J. Biol. Chem. 278: 7743-7746 (2003). It is clear that these and other visual abnormalities, especially deviations neurosensory retina, it is possible to prevent or reduce without concomitant sedation, using selective agonists according to the invention.
In addition to the prevention or relief simpaticeskii enhanced conditions, neurological conditions, eye conditions and chronic pain, α-2A/α-1A selective agonist can be useful to prevent or alleviate other disorders without concomitant sedation. This disorder can be, for example, attention deficit disorder (add/ADHD, attention deficit disorder with hyperactivity disorder)is a disorder characterized primarily by inattention, pathologically increased twicemonthly and impulsivity, beginning before the age of seven. Symptoms may include, without limitation, the manifestation of impatience and restless movement, difficulty staying in a sitting position, light otvlekaemost, difficulty waiting position changes, difficulty in holding answer, the failure followed the instructions, excessive talkativeness and other destructive behavior (Anderson, previously, 1994). Moreover, ADHD/add are stored in puberty for many individuals, despite the fact that were originally installed in children (see, for example. Block, Pediatr. Clin. North Am. 45:1053-1083 (1998), and Pary et al., Ann. Clin. Psychiatry 14:105-111 (2002)). A qualified specialist in this field it is clear that the method according to the invention may be useful for preventing and mitigating ADHD/add in children and adults with as mild and severe forms of the disorder.
α-2A/α-1A selective agonist can also be useful for preventing or reducing nasal congestion; diarrhea; disorders of urination, such as the overactive bladder and overactive bladder; congestive heart failure or psychosis, such as manic disorder. Moreover, α-2A/α-1A selective agonist may be useful for preventing or reducing one or more symptoms associated with anesthesia, such as nausea, vomiting, tremor, or anxiety; to improve memory and development processes, without concomitant sedation.
As here disclosed, α-2A/α-1A selective agonist of this invention is partly characterized by the ability to prevent or reduce any variety simpaticeskii enhanced status is th, neurological conditions, eye conditions and types of chronic pain without concomitant sedation. Used herein, the term "facilitate" means the weakening of at least about 50% of at least one symptom of a separate state or type of chronic pain during the treatment.
As is well known from the prior art, the term sedative effect implies a decrease in motor activity. Used here is a relatively selective agonist phrase "without concomitant sedation" means that when the peripheral introduction selective agonist causes less than 30% of the emergence of sedation at a dose ten times higher than the dose selective agonist required for 50% attenuation of one or more symptoms of a separate state or types of chronic pain during the treatment. For example, as shown in figure 2 (lower left pane), compound 1 was administered orally at the dose of 1 μg/kg to cause 50% reduction in the rate of sensitization (solid line, left axis) with less than 30% of the sedative effect (where there's no shading diamond, right axis) at doses of 100 and even 1000 times greater than therapeutically effective dose of 1 mcg/kg Thus, α-2A/α-1A selective agonist represented by the formula of the compound 1, has an effective therapeutic activity "without accompanying the CE is exploring the effect. On the contrary, many α-2 agonists, such as dexmedetomidine, fully show sedative effect at doses 10 times higher than the dose required for 50% reduction in the rate of sensitization.
As not limiting the invention examples, dose α-2A/α-1A selective agonist required to create approximately 30% sedative effect (decrease in motor activity), may be, at least in 25, 50, 100, 250, 500, 1000, 2500, 5000 or 10,000 times greater than the dose required for 50% attenuation of one or more symptoms of a separate state or types of chronic pain during the treatment. Methods for determination as to the amount of attenuation of symptom, and the degree of sedation is described here and, in addition, well known from the prior art.
In addition, according to the present invention created a pharmaceutical composition which comprises a pharmaceutical carrier and a therapeutically effective amount α-2A/α-1A selective agonist, which includes the following connection:
(structure 1) or its pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture. In the pharmaceutical compositions of this invention are selective agonist may, for example, to have α-1A efficacy less than brimonidina, risotteria α -1A/α-2A efficiencies greater than brimonidina. In one embodiment α-2A/α-1A selective agonist of this invention, included in the pharmaceutical composition of this invention contains a compound represented by structure 1.
Thus, according to the invention features a pharmaceutical composition comprising an effective amount of a pharmaceutical carrier and a therapeutically effective amount α-2A/α-1A selective agonist of this invention. Such pharmaceutical composition can be useful to prevent or facilitate, for example, any of the above simpaticeskii reinforced, neurological or ocular conditions or types of chronic pain without concomitant sedation. The pharmaceutical composition of the invention includes α-2A/α-1A selective agonist and, in addition, includes a pharmaceutically acceptable carrier, which is any carrier, excipient or diluent, generally do not have a long period or harmful residual effects of the introduction of patsientov. Excipient, usually mixed with active 2A/α-1A selective agonist, or give him the opportunity to dilute or surround selective agonist. The carrier may be solid, semi-solid or liquid agent, which deistvie is as excipients or binders for active selective agonist. Examples of solid carriers suitable for pharmaceutical compositions of this invention include, without limitation, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, saccharin sodium, polyalkylene glycols, talc, cellulose, glucose, sucrose, and magnesium carbonate. Part suppositories can, for example, to enter propylene glycol as a carrier. In addition, examples of pharmaceutically acceptable carriers include, without limitation, water, such as distilled or deionized water; saline solution; the aqueous dextrose, glycerol, ethanol and the like, it is Clear that the active components in the pharmaceutical composition can be dissolved or in suspension in the desired carrier or solvent.
The pharmaceutical composition can optionally include one or more agents such as, without limitation, emulsifying agents, surfactants, sweeteners or flavoring agents, toning agents, preservatives, buffers, or antioxidants. Tonic substances usable in the pharmaceutical compositions of this invention include, but are not limited to, salts of, for example, sodium acetate, sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonic substances. Preservatives suitable in pharmaceutical com is Aziziyah of this invention, include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, finalstate acetate and finalstate nitrate. You can use various buffers and means regulating the pH to obtain pharmaceutical compositions, including, but not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. Similarly, the antioxidants useful in the pharmaceutical compositions is well known from the prior art and include, for example, sodium metabisulfite, sodium thiosulfate, acetylcysteine, bottled hydroxyanisol and bottled hydroxytrol. It is clear that these and other substances known from the prior art pharmacology, can be included in the pharmaceutical composition of this invention. See, for example, Remington′s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA 16th Edition, 1980. In addition, it is clear that the pharmaceutical composition containing α-2A/α-1A selective agonist can choose to enter in combination with one or more other therapeutic agents, in the same or different pharmaceutical compositions and the same or other methods of introduction.
α-2A/α-1A selective agonist enter patsientov perifericheskie in therapeutically effective amounts. Such therapeutically effective amount is usually the minimum is at school dose, necessary to achieve the required prevent or alleviate one or more symptoms, for example, simpaticeskii reinforced condition, neurological condition, eye condition or chronic pain, for example, such an amount of about you need to loosen to acceptable levels of physical discomfort caused simpaticeskii power condition, neurological condition, eye condition, or chronic pain. This dose can be an amount that reduces at least one symptom of the condition or type of pain is at least about 50% and, as a rule, is 0.1-1000 mg/day and may be, for example, 0.1 to 500 mg/day, 0.5 to 500 mg/day, 0.5 to 100 mg/day, 0.5 to 50 mg/day, 0.5 to 20 mg/day, 0.5 to 10 mg/day or 0.5-5 mg/day, with the actual prescribed quantity that should be entered considering the significant terms, including the severity and type of simpaticeskii reinforced condition, neurological condition, eye condition or chronic pain; age and weight of the patient; General physical condition of the patient; a pharmaceutical composition and method of administration. As will be discussed hereinafter, the pharmaceutical composition can also be used in the form of suppositories or composition sustained release, for example, without limitation, skin patch composition for coating on or under the skin, or composition for intramuscular injection.
In one embodiment the pharmaceutical composition of this invention is an ophthalmic composition. Ophthalmic composition contains acceptable ophthalmic carrier, which is any carrier, basically do not have a long period or harmful residual effects on the eyes when its introduction. Examples of acceptable ophthalmic carriers include, without limitation, water, such as distilled or deionized water; saline and other aqueous environment. Ophthalmic compositions can include, for example, soluble α-2A/α-1A selective agonist or α-2A/α-1A selective agonist in the form of a suspension in an appropriate medium.
Also useful local ophthalmic composition. Such compositions are, without limitation, eye drops, eye ointments, eye gels and eye creams. Such pharmaceutical compositions it is convenient to use, and they now release selective agonist. In the following table 2 shows the components is not limiting the invention, a typical local ophthalmic composition.
|Component||Content (% weight/volume)|
|Connection 1||from about 0,0001|
|up to approximately 0.1|
|The pH regulator||sufficient for pH 4.5 and 7.5|
|Purified water||How much you want to 100%|
If required, the ophthalmic composition of this invention can include a preservative. This preservative may be, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, finalstate acetate and finalstate nitrate. Binders suitable for local ophthalmic compositions include, but are not limited to, polyvinyl alcohol, povidone, hypromellose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Also, if you want, you can include in ophthalmic composition of this invention tonic substance. This tonic can be, without limitation, a salt, such as sodium chloride, potassium chloride, mannitol or glycerol, or other pharmaceutically acceptable or acceptable the eye toning substance.
To obtain antalgicheskoy compositions according to this invention, it is possible to use various buffers and means regulating the pH, provided that the resulting product will be acceptable for ophthalmology. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers. It is clear that to achieve the desired pH of the composition can be used acids and bases. Acceptable ophthalmic antioxidants suitable for obtaining ophthalmic compositions include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, bottled hydroxyanisol and bottled hydroxytrol.
α-2A/α-1A selective agonist of the invention or a pharmaceutical composition containing such selective agonist, enter patsientov perifericheskie. Used herein, the term "input perifericheskie" or "peripheral" introduction of a relatively α-2A/α-1A selective agonist means the introduction of the patient α-2A/α-1A selective agonist, bypassing the Central nervous system. Thus, peripheral injection is carried out by any method other than direct injection into the spinal column or brain.
Therapeutically effective amount α-2A/α-1A selective agonist can enter the patient is at perifericheskie in any way, depending on, for example, on the type of condition or chronic pain, which should prevent or reduce, the pharmaceutical composition, and the history, risk factors and symptoms of the patient. Appropriate ways of peripheral injection include both systemic and local administration. As not limiting the invention examples, a therapeutically effective amount α-2A/α-1A selective agonist can be administered orally; parenterally; a pump under the skin; a skin patch; intravenous, intra-articular, subcutaneous or intramuscular injection, topical drops, creams, gels or ointments; implanted or injected composition of extended release; or Minnesota under the skin or other implanted device.
A qualified specialist in this field it is clear that peripheral administration can be local or systemic. Local introduction leads to a significantly greater release α-2A/α-1A selective agonist at and near the site of local injection than in areas located far from the site of injection. Essentially, the system introduction leads to the release of α-2A/α-1A selective agonist, at least throughout a peripheral system of the patient.
Methods peripheral injection, suitable for delivery α-2α -1A selective agonist or pharmaceutical compositions of this invention are, without limitation, oral administration, local injection, intravenous or other injections and implanted pumps or other devices or compositions prolonged release. α-2A/α-1A selective agonist or a pharmaceutical composition of this invention can be entered perifericheskie, without limitation, orally in any acceptable form, such as tablets, pills, capsules, powder, solution, suspension, emulsion and the like; in aerosol form; in the form of suppositories; intravenous, intraperitoneal, intramuscular, subcutaneous or parenteral injection; transdermal diffusion or electrophoresis; locally in any acceptable form, such as in the form of drops, creams, gels or ointments; and Minnesota or other implanted device or prolonged release composition. α-2A/α-1A selective agonist, optionally to form, in the form of dosage forms suitable for single administration, or dosage form extended release for continuous controlled administration.
Chronic introduction α-2A/α-1A selective agonist or pharmaceutical compositions according to the invention can for example be used to prevent or facilitate the surveillance of chronic pain or other chronic conditions, for example, without limitation, a chronic neurological condition. Methods for repeated or continuous peripheral injection include, without limitation, repeated oral or local introduction and introduction by subcutaneous Minnesota. As not limiting the invention, examples, α-2A/α-1A selective agonist or a pharmaceutical composition of this invention can be entered perifericheskie and constantly continuous intravenous through an implanted infusion Minnesota or using the composition of slow release.
It is clear that the slow release formulations may be useful for preventing or alleviating chronic pain or other chronic conditions, such as, without limitation, a chronic neurological condition. Moreover, it is clear that the frequency and duration of dosing such a slow release composition should depend on preventing or extent of the required relief and half-life α-2A/α-1A selective agonist, and that, as mentioned above, a variety of routes of administration suitable for slow release formulations.
α-2A/α-1A selective agonist or ophthalmic composition according to the invention it is possible to enter the patient perifericheskie prevented for the I or facilitate eye condition in any way, dependent, in part, on the characteristics of the selective agonist, which should be entered, and from history, risk factors and symptoms of the patient. Peripheral routes of administration suitable for the prevention and relief of eye condition, include both systemic and local administration. In certain embodiments of the ophthalmic composition containing α-2A/α-1A selective agonist, injected locally, for example, in the form of eye drops or local injection, or is released from the eye or eye implant.
Systemic and local routes of administration useful in the prevention or relief of eye condition with the introduction of α-2A/α-1A selective agonist or ophthalmic compositions of this invention are, without limitation, oral enteral nutrition; intravenous injection; intraperitoneal injection; intramuscular injection; subcutaneous injection; transdermal diffusion and electrophoresis; local eye drops and ointments; eye and intraocular injections, including subconjunctival injection; apparatus prolonged release, for example locally implanted devices sustained release, ocular and eye implants, including biodegradable and tank-posted by implants.
In one waples the Institute of ophthalmic composition, containing α-2A/α-1A selective agonist, injected locally into the eye. α-2A/α-1A selective agonist can be entered, for example, as part of the ophthalmic solution, such as eye drops. In another embodiment of the ophthalmic composition containing α-2A/α-1A selective agonist of this invention, is injected directly into the eye. In still another embodiment of the ophthalmic composition containing α-2A/α-1A selective agonist of this invention, is released from the eye or eye implant, for example, biodegradable or tank-placed implant.
As mentioned above, the ophthalmic composition containing α-2A/α-1A selective agonist can be entered locally through the eye or eye implant, which, without limitation, may be biodegradable or tank is placed. Used herein, the term "implant" refers to any substance that extends slightly from the introduction after implantation. The implant can be biodegradable not biodegradable or consist of biodegradable and non biodegradable materials; not biodegradable implant may optionally include a removable tank. Implants suitable for the prevention and relief of ocular condition, luchot, for example, pieces, particles, fibers, platelets, microcapsules and the like, and can have any shape and size that is compatible with the selected injection, which, without limitation, may be the rear chamber of the eye, anterior chamber of the eye, vessels plate and subconjunctival eyes. It is clear that suitable implant usually releases implantirovannoi ophthalmic composition in a therapeutically effective dose is in the eye of the patient for a long period of time. Various ocular implants and prolonged release formulations suitable for ocular release, well known from the prior art, as described, for example, in U.S. patent No. 5869079 and 5443505.
The following examples are intended length of illustrating the present invention without limiting it.
Getting connection 1
This example describes how to obtain 2A/α-1A selective agonist, compound 1.
A. Obtaining compound 1. ((+)-(S)-4-[1-(2,3-dimetilfenil)ethyl]-1,3-dihydroimidazole-2-thione)
A mixture of (+)-(S)-4-[1-(2,3-dimetilfenil)ethyl]-1H-imidazole (dexmedetomidine; 2.00 g, 10.0 mmol), obtained as described in Cordi al., Synth. Comm. 26: 1585 (1996), in THF (45 ml) and water (40 ml) was treated with NaHCO3(of 8.4 g, 100 mmol) and familiarisation (3,7 ml, a 27.4 mmol). On the Le stirring for four hours at room temperature the mixture was diluted with water (30 ml) and ether (75 ml). The organic layer was separated and the aqueous layer was twice extracted with 50 ml of ether. The organic layers were dried over MgSO4and filtered. The residue was concentrated under vacuum, diluted Meon (54 ml), and the residue was reacted with NEt3(6.5 ml) at room temperature for 16 hours. The solvent was removed under vacuum and diluted with 30% of CH2Cl2: hexane. Again the solvent was removed, and formed the dry residue. After another suspension in 30% of CH2Cl2: hexane, the residue was collected on a filter, washed with a mixture of CH2Cl2hexane and dried under vacuum to obtain compound 1 ((+)-(S)-4-[1-(2,3-dimetilfenil)ethyl]-1,3-dihydroimidazole-2-thione) mass of 1.23 g (53%). Above is shown schematically the connection 1.
Product features the following. Optical rotation: [α]D 20=+14° (1.25 in Meon).1H-NMR: (300 MHz, DMSO): d 11,8 (s, 1H), and 11.6 (s, 1H), 7.03 is-7,01 (m, 2H), 6,95-6,91 (m, 1H), 6,50 (s, 1H), 4,15 (q, J=6,9 Hz, 1H, in), 2.25 (s, 3H), of 2.20 (s, 3H), 1,38 (d, J=6.9 Hz, 3H).
B. Method of obtaining compound 2 (5-(1H-imidazol-4-ylmethyl)-cyclohex-1-Edelmetalle)
8-(2-Benzyloxyethyl)-1,4-dioxaspiro[4.5]decane (intermediate R1; 1,02 g, 3,70 mmol) was received, as described by Ciufolini al., J. Amer. Chem. Soc. 113:8016 (1991). This compound was dissolved in a mixture of acetone (100 ml) and water (5 ml)was subjected to reaction with TsOH (140 mg, of 0.74 mmol) at 45°in ECENA 5 hours. After standard water treatment substance was purified chromatography on SiO2obtaining 4-(2-benzyloxyethyl)cyclohexanone in the form of a colorless oil (97%).
A solution of LDA (33 ml, 1.5 M in Et2O) in THF (50 ml) at -78°was treated with 4-(2-benzyloxyethyl)cyclohexanone (9.5 g, with 40.2 mmol). The mixture was heated to 0°C for 30 minutes before re-cooling to -78°and With the addition of HMPA (hexamethylphosphoramide, 7 ml). Added medicinepharmacy (4,1 ml, 85 mmol)and the mixture was stirred for 15 minutes before water cooling and processing. The product was purified chromatography on SiO2with 10% EtOAc : hexane. Allocated methyl ester 5-(2-benzyloxyethyl)-2-oxocyclohexanecarboxylic acid, 5.8 g (49%), which was restored with an equivalent amount of NaBH4in the Meon at -10°C. Alcohol (above intermediate R2) was purified chromatography on SiO2with 30-50% EtOAc : hexane (yield approximately 90%).
A solution of methyl ester 5-(2-benzyloxyethyl)-2-hydroxycyclohexanecarboxylate acid (intermediate R2; 0,72 g, 2.48 mmol) in pyridine (10 ml) was treated with SOCl2(0,73 ml, 12.4 mmol) at -20°C. Gave the mixture to react for 15 minutes and then was heated to 55°C for 16 hours. The solvents were removed under vacuum and the residue was dissolved in ether at 0°C. the Solution was cooled with water and washed with 1 M HCl, 5% NaOH and sole is the first solution. The organic layer was dried over MgSO4was filtered and separated solvent. The mixture was dissolved in benzene and water was removed by azeotropic distillation under vacuum. The residue was dissolved in benzene (15 ml) was added DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 0,76 ml, 5 mmol). The mixture was reacted for 30 minutes at room temperature. After treatment chromatography on SiO2with 20% EtOAc : hexane allocated 0.56 g (82%) of methyl ester 5-(2-benzyloxyethyl)cyclohex-1-inkarbaeva acid (intermediate R3).
Intermediate R3 was dissolved in THF (100 ml) was added to a solution of DIBAL (hydride diisobutylaluminum, 70 ml, 1 M in hexane) in THF (160 ml) at -35°C for 35 minutes. The mixture was cooled with a solution of Rochelle salt and extracted with ether. The residue was purified chromatography on SiO2with 30% EtOAc : hexane to obtain [5-(2-benzyloxyethyl)cyclohex-1-enyl]methanol by weight of 4.6 g (80%). A solution of alcohol (4.0 g, to 18.7 mmol) in DMF (60 ml) was treated with triethylamine (3 ml), and then TBSC1 (tert-butyldimethylsilyloxy, 3.0 g, 22,4 mol) for 20 minutes at room temperature. The residue was allocated water treatment and purified chromatographically to obtain 3.6 g (63%) [5-(2-benzyloxyethyl)cyclohex-1 animetake]-tert-butyldimethylsilyl (intermediate R4).
Alcohol with benzyl protection (intermediate R4) (2.0 g, 5,55 mmol) in THF (20 ml) was cooled to -70°and in this flask Conde who was saravali NH 3(about 20 ml). Added small pieces of sodium and the mixture was stirred at -70°C for 15 minutes. The mixture was heated to -30°C for 20 minutes, cooled NH4Cl and extracted. The residue was purified chromatography on SiO2with 25% EtOAc : hexane (99%). The alcohol was oxidized under standard reaction Swarna. The alcohol 2-[3-(tert-butyldimethylsilyloxy)cyclohex-3-enyl]ethanol (1.3 g, 4.8 mmol) was added to a solution of oxalicacid (3.55 ml, 7.1 mmol) in CH2Cl2(30 ml) with DMSO (0.63 ml, 8.9 mmol) at -78°C. After 40 minutes were added NEt3(of 2.51 ml) and the mixture was heated to room temperature. After a standard water-treatment and purification were isolated [3-(tert-butyldimethylsilyloxy)cyclohex-3-enyl]acetaldehyde (intermediate R5) (about 95%).
The following receipt was performed according to the method of Horne al., Heterocycles 39: 139 (1994). A solution of the aldehyde (intermediate R5, 0.34 g, 1.3 mmol) in EtOH (5 ml) was treated with toiletrieschoice (TosMIC; Aldrich; 0.25 g; 1.3 mmol) and NaCN (about 15 mg, catalyst) and stirred at room temperature for 20 minutes. The solvent was removed in vacuo; the residue was dissolved in ˜7 M NH3in Meon and carried in a resealable tube was then heated to 100°C for 15 hours. The mixture was concentrated and was purified chromatography on SiO2with 5% Meon (feast upon. the mass / NH3) : CH2Cl2. A solution of the product in THF p is remedial with TBAF (tetrabutylammonium fluoride, 1.5 EQ.) at room temperature after water treatment. Dirty product chromatographically (5-7% NH3/Meon in CH2Cl2) and was designated as compound 2.
The characteristics of the connection 2 is the following.1H-NMR: (300 MHz, DMSO-d6): d 7,52 (s, 1H), 6,72 (s, 1H), 5,54 (brs, 1H), of 3.73 (s, 2H), 2,46 (d, J=6 Hz, 2H), of 1.5-2.1 (m, 6H), from 1.0 to 1.55 (m, 1H).
Feature α-2 agonist with greater α-2A/α-1A functional selectivity than brimonidine
This example shows that α-2A/α-1A selectivity in receptor proximal functional tests correlate with activity that does not have a sedative effect in vivo.
A. In vitro functional analyses
Proximal functional activity in α1A α-2A adrenergic receptors compared with those for brimonidine, dexmedetomidine, connection 1 and connection 2. Brimonidine were obtained from Sigma; dexmedetomidine received, as described earlier in Cordi al. in 1996, and compounds 1 and 2 were synthesized as described above in example I. Pharmacological profiles α-adrenergic receptor was analyzed in samples with the following cell lines, stably expressing α2 and α-1A receptors.
To determine α-1A activity of the compounds functionally tested for the ability to enhance the increase of intracellular calcium in NECK to edah, stably expressing a bullish α-1A receptor. α-1A relative efficiency was determined relative to the full agonist, phenylephrine, as described below. As shown in the above table 1, α-1A relative effectiveness of dexmedetomidine and connection 2 is greater than brimonidine, while α-1A relative effectiveness of compound 1 was so small that it was nediagnostirovannoe in this sample.
Also, these compounds were functionally tested at the proximal α-2A function, analyzing the suppression of Forskolin-induced accumulation of cyclic amp in PC12 cells stably expressing α-2A receptor of human rights. Intracellular camp levels were determined using enzyme immunoassay camp Biotrak described next. EU50for α-2A suppression of camp was expressed as a ratio with α-1A EU50to obtain the ratio of α-1A/α-2A efficiencies. As shown above in table 1, α-2 adrenergic agonist, is indicated as compound 1, was highly α-2A/α-1A selective, as evidenced by undiagnosed level α-1A activity observed in this connection. On the contrary, dexmedetomidine, for example, was less than α-2A/α-1A selective than brimonidine. These results show that compound 1 is highly selective for activation #x003B1; -2A receptor compared to α-1A receptor.
Stable cell lines expressing adrenergic receptor, set as follows. cDNA (complementary DNA) bullish α-1A receptor, α-1 receptor hamster, α2 and α-2C receptors man was subclinically blunt end into the NheI-EcoRI sites in the retroviral vector pCL BABE Puro. Design-based retroviral vector was verified by sequencing double-stranded DNA. Pseudotyped retroviral particles with high titers generated by cotransfection HEK293GP, cell line NECK, stably expressing Gag-Pol Maloney leukemia virus, with an appropriate retroviral vector and pMD.G expressing vector for G-protein of vesicular stomatitis virus, VSV-G. After sixteen hours after transfection modified medium (DMEM (modified by way of Dulbecco Wednesday Needle), 10% FCS (serum fetal cow)); after 48 hours were given environment with a high titer (˜1×106pfu/ml). The supernatant was filtered through a 0.4 μm filter.
Added different amounts of supernatant α-2A receptor person to simple PC12 cells, which were then cultured for 48 hours. The transformed cell population was re-seeded at low density and cultured in a medium containing 100 µg/ml puromycin. Untransformed cells UB is Wali three days, and a separate center grew within two months. The center collected, expanded and analyzed for receptor density radioligand binding with brimonidine. Functional activity α-2 receptor intensified suppression of Forskolin-induced accumulation of camp.
Added different amounts of supernatant bullish α-1A receptor simple PC12 cells, which were then cultured for 48 hours. The transformed cell population was re-seeded at low density and cultured in medium containing 0.25 μg/ml puromycin. Significant cell necrosis was clearly occurred within three days, a separate centre appeared two weeks. Then, the center has collected and expanded, the subclones functionally analyzed for the expression of α-1A receptor, measuring the phenylephrine-induced accumulation of intracellular Ca+2as described below. Receptor density was measured in the analysis of radioligand binding of prazosin.
The responses of intracellular CA+2measured in cells NECK, stably expressing a bullish α-1A adrenergic receptor. One day before use from 40,000 to 50,000 cells were placed in one well of a 96-of linkovich tablets coated with poly-D-lysine, in 0.2 ml of DMEM containing 10% thermoinactivation serum fetal cow, 1% antibiotic fungicide and 0.25 is/ml puromycin. Cells are washed twice with HBSS (balanced salt solution Hanks)containing 10 mm HEPES, 2.0 mm CaCl2and 2.5 mm probenecid, and then cultivated at 37°C for 60 minutes with 4 M Fluo-4 (molecular probes; Eugene, Oregone). Extracellular dye was twice washed with tablets before placing tablets in fluorimetry for microplate reader (FLIPR; Molecular Devices; Sunnyvale, California). Connections that were required to analyze, was dissolved in HBSS and placed in 96-locovei the microplate; compounds were tested in the concentration range from 0.64 to 10000 nm. Data responses Sa+2received in random units of fluorescence.
Percentage α-1A efficiency (%) was determined by comparing the maximum effect of each agonist with maximum effect standard full agonist phenylephrine. Values represented the mean value and SEM of 3 to 15 independent experiments. Single selective agonists for α-2 receptors relative to α-1 receptors was calculated from the ratio of their values EU50to activate α1A α-2A receptors.
Measurement of intracellular camp was carried out as follows. PC12 cells stably expressing α-2A adrenergic receptor human, were placed on 96-well tablet coated with poly-D-lysine at a density of 30,000 cells per well in 100 μl DMEM containing 10% horse is th serum 5% thermoinactivation serum fetal cow, 1% antibiotic fungicide and 100 µg/ml puromycin. Cells were cultured overnight at 37°C and 5% CO2. Cells were dosed out by adding an equal volume of medium containing IBMX (to a final concentration of 1 mm), Forskolin (to final concentration of 10 M) and the diluent of the relevant medicinal product (to a final concentration of 10-5 M to 10-12 M). After 10 minutes of cultivation medium was aspirated and the cells were dissolved in 200 ál lyse buffer (Amersham Biosciences; Piscataway, New Jersey). The tablets were stored at -20°to analyze up to 24 hours. Intracellular camp was determined using enzyme immunoassay camp Biotrak (Amersham Biosciences)according to the manufacturer's instructions. With tablets took the readings on the device to read the tablets at 450 nm.
The curves of dependence "dose-effect" for in vitro was obtained using KaleidaGraph (Synergy Software; Reading, PA) with a minimum square deviation from the equation, effect = the maximum effect + ((minimum effect maximum effect) / (1 + (concentration of ligand / EC50)). Percentage α-1A efficiency was determined by comparing the maximum effect connection with the effect of a standard full agonist phenylephrine.
B. In vivo efficacy and sedative effects
In addition to the above cleoc the th analyses, analyzed various α-2 agonists on the ability to facilitate sulprostone-induced tactile hypersensitivity and sedative activity at different doses. Tactile hypersensitivity 5-6 mice per group were evaluated every five minutes between 15 and 50 minutes after intraperitoneal administration. Animals with the solvent usually had a rate of about 4. In addition, locomotor activity 5-6 mice per group was measured within five minutes after 30 minutes after intraperitoneal administration. Locomotor activity relative to animals with the drug was expressed as a percentage; the percentage sedative effect was calculated as 100% minus the percentage of motor activity.
As shown in figure 2 (top left pane), brimonidine shows approximately 60% of the sedative effect dose 10 times higher than the dose of 100 µg/kg, which gives a 50% reduction in sensitization of sulprostone. Moreover, dexmedetomidine shown in the upper right area of figure 2, was completely sedated at a dose 10 times higher than the dose needed to obtain 50% reduction in the rate of sensitization. On the contrary, compound 1, administered orally at a dose of 1 mg/kg caused a 50% reduction in the rate of sensitization (solid line, left axis) with less than 30% of the sedative effect (where there's no shading diamond, right hand axis) and the doses of 100 and even 1000 times more what dose of 1 mcg/kg (see figure 2, bottom left pane). Similar results were observed after intraperitoneal administration of compound 1. Intraperitoneal administration of compound 2 also caused more than 50% reduction in the rate of sensitization at 10 ág/kg (solid line, left axis) with less than 30% of the sedative effect at doses 10 times more. Thus, compound 1, which has an extremely low (undiagnosed) α-1A relative efficiency, reduces tactile hypersensitivity without concomitant sedation upon peripheral administration. Similarly, compound 2, which has the value α-1A/α-2A efficiencies of more than brimonidine also facilitates tactile hypersensitivity without concomitant sedation upon peripheral administration.
The in vivo experiments were performed as follows. Sulprostone (Cayman Chemical; Ann Arbor; Michigan) was dissolved in dimethyl sulfoxide (DMSO), brimonidine, phenylephrine and clonidine were obtained from Sigma (St. Louis, MO) and was dissolved in saline. Spinal injections of the drug was carried out as follows. Introduced spinal mice (20-30 g), as described by Hylden and Wilcox, Eur. J. Pharmacol. 67: 313-316 (1980). Briefly, sterile 1/2-inch 30-gauge needle attached to microspace, inserted between the L5 and L6 vertebrae. The mouse holding the and pelvic belt with one hand, until the syringe was held in the other hand at an angle of approximately 20° above the spine. The needle was inserted into the fabric with one hand L6 thorn ridge in the groove between thorn and transverse processes. The angle of the needle was reduced to approximately 10° and the needle slowly moved forward into the intervertebral space until then, until he felt the push and explicit serpentine movement of the tail. The connection was slowly introduced into the subarachnoid space in a volume of 5 ál. Each compound was tested at multiple doses. For all subsequent experiments used the minimum effective dose.
Sensitivity to light touch was measured by noting the response of mice to light stroking their sides with a small brush, which usually does not cause pain. Mice were evaluated according to the following scale once every five minutes between 15 and 50 minutes after injection: an indicator of "2" was assigned to animals, showing energetic reaction to escape together with squeak and bites the brush; the indicator of "1" was assigned to animals, showing a light squeak with attempted escape and the index of "0" was given if the animal showed no reaction to light stroking with a brush. The scores were summed up to obtain the total score of the index from 0 to 16, as described by Minami al., Pain 57: 217-223 (1994). Statistical calculations meant is I for in vivo studies conducted, using student test based on the double sampling.
In summary, these results show that α-2A/α-1A functional selectivity adrenergic receptor α-2 agonists in functional cellular assays in vitro is associated with the absence of sedative activity at therapeutic dose after a system or peripheral injection. In addition, these results show that compound 1, which shows better than the selectivity of brimonidine, α-2A/α-1A in vitro functional selectivity adrenergic receptor, is especially useful α-2 agonist due to the absence of sedative effects in vivo at therapeutic doses.
All journal articles, links and patent citations given above in parentheses or otherwise, as before stated, and no combined here with regard to their integrity.
Although the invention described in the above examples, it should be clear that it is possible to make various modifications without deviating from the invention. Thus, the invention is limited only by the claims.
1. α-2A/α-1A selective agonist, representing the following connection:
or its pharmaceutically acceptable salt or isomer.
2. α2A/α -1A selective agonist according to claim 1, where the specified selective agonist has α-1A efficacy less than brimonidina aspect ratio α-1A/α-2A efficiencies greater than brimonidina.
3. α-2A/α-1A selective agonist according to claim 1, which represents the following connection:
4. Pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount α-2A/α-1A selective agonist, which is the following connection:
or its pharmaceutically acceptable salt or isomer.
5. The pharmaceutical composition according to claim 4, where the specified selective agonist has α-1A efficacy less than brimonidina aspect ratio α-1A/α-2A efficiencies greater than brimonidina.
6. The pharmaceutical composition according to claim 4, where the specified selective agonist represents the following connection:
SUBSTANCE: invention relates to the compound of formula I: , where R1, R2 and R3 are equal or different and represent hydrogen, halogen, alkyl, aloxy, hydroxyl, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group, R4 represents hydrogen, alkyl or alkylaryl group; X represents CH2, oxygen atom and sulphur atom; n represents 2 or 3, and individual (R)- and (S)-enantiomers or the mixture of enantiomers and its pharmaceutically acceptable salts; where alkyl termine denotes straight and branched hydrocarbon chains, containing fro one to six atoms of carbon, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups, termine aryl denotes phenyl or naphtyl group, optionally substituted alkyloxy group, halogen or nitro group, termine halogen denotes fluorine, chlorine, bromine or iodine. The compounds have valuable pharmaceutical properties and perspectives for the treatment of cardiovascular disorder, such as hypertension and chronic heart failure. The method of production of individual (R)- and (S)-enantiomers or the mixture of enantiomers and pharmaceutically acceptable salts of the compound of formula I, pharmaceutical composition having inhibitor dophamine-β-hydrolaze potency, containing therapeutic effective volume of the compound of formula I, different variants of formula I compound application and intermediate compounds are described.
EFFECT: production of new compounds, imidazole derivatives having useful biological properties.
21 cl, 2 tbl, 46 ex
FIELD: organic chemistry, medicine, pharmacology.
SUBSTANCE: invention relates to compounds of the formula: , wherein variable value Y in ring is not obligatory and represents heteroatom chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms under condition that N atom is trivalent and O or S atoms are bivalent; k means a whole number from 0 to 1; n means a whole number 0, 1 or 2; p means a whole number 0, 1 or 2; X means O or S atom; dotted lines represent a bond or its absence under condition that ring comprises only a single double bond and two adjoining lines are not a bond; R1, R2, R3 and R represent independently hydrogen atom (H), phenyl wherein indicated phenyl group is substituted optionally with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy-, (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl; 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms wherein indicated heteroaryl groups are substituted optionally and independently with one, two or three substitutes represented by (C1-C6)-alkyl, -SO3H, -N3, halogen atom, -CN, -NO2, -NH2, (C1-C6)-alkoxy- (C1-C6)-thioalkoxy-, (C1-C6)-alkylamino-, (C1-C6)-dialkylamino-group, (C2-C6)-alkynyl, (C2-C6)-alkenyl, or indicated groups R1, R2, R3 and R4 represent independently alkyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 5 carbon atoms, -CH2CN, -CH2SR5, -CH2NR6R6, -COR5, -CH2OR5, -OR6, -SR6, -NR6R6, alkenyl comprising from 1 to 4 carbon atoms, alkynyl comprising from 1 to 4 carbon atoms, cycloalkyl comprising from 3 to 6 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom, -CF3 or -CN, oxygen atom bound by a double bond with ring carbon under condition that adjoining dotted line inside of ring means absence of a bond; R5 means H, -OR7, alkyl comprising from 1 to 4 carbon atoms, -CF3, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R5 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, and 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atoms, bromine atom, iodine atom or -CF3; R6 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3, either R6 represents 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms, either 5- or 6-membered heteroaryl comprising from 1 to 3 heteroatoms chosen from O, S and N atoms substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R7 means H, alkyl comprising from 1 to 4 carbon atoms, allyl, cycloalkyl comprising from 3 to 6 carbon atoms, phenyl, phenyl substituted with one or two alkyl groups comprising from 1 to 4 carbon atoms, fluorine atom, chlorine atom, bromine atom, iodine atom or -CF3; R1 and R2 or R2 and R3, or R3 and R4 can form in common a ring with corresponding carbon atoms to which they are bound; fragments represented by substitutes R1 and R2 or R2 and R3, or R3 and R4 have the following formulae (i): , (ii): , (iii): , (iv): or (v): - wherein m means a whole number from 0 to 3; R8 represents independently H, alkyl comprising from 1 to 6 carbon atoms, alkenyl comprising from 2 to 6 carbon atoms, alkynyl comprising from 2 to 6 carbon atoms, -SO3H, -N3, -CN, - NO2, F, Cl, Br, J atoms, -CF3, -COR9, -CH2OR9, -OR10, -SR10, (C1-C)-alkylamino- or (C1-C6)-dialkylamino-group wherein R9 means H, alkyl comprising from 1 to 6 carbon atoms, or -OR10 wherein R10 represents independently H or alkyl comprising from 1 to 6 carbon atoms. Also, invention relates to compounds of the formula: and , and to a method for activation of alpha2B- or alpha2C-adrenergic receptors. Invention provides synthesis of novel biologically active compound possessing activity as agonists of alpha-2B and alpha-2C-adrenergic receptors.
EFFECT: valuable medicinal properties of compounds.
34 cl, 5 tbl, 33 ex
FIELD: organic chemistry, biochemistry, medicine.
SUBSTANCE: invention describes compound of the general formula (3): wherein R15 represents a heterocyclic group chosen from 3-7-membered saturated or 4,7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom, or 7-14-membered polycyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R16 represents a cycloalkyl group comprising 3-7 carbon atoms, monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms, or heterocyclic group chosen from 3-7-membered saturated or 4-7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R17 represents a monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms or heterocyclic group chosen from 4-7-membered saturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R18 represents hydrogen atom or (C1-C)-alkyl group; X represents -S-, -SO- or -SO2; or N-oxide or S-oxide of this compound; their salt; or solvate of above described compound. Proposed compounds possess the inhibitory activity against producing/secretion of β-amyloid protein and can be used in treatment of such diseases as Alzheimer's disease, Down's disease and other diseases associated with amyloid deposition.
EFFECT: valuable medicinal properties of inhibitors.
7 cl, 1 tbl, 410 ex
R1means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; CandH2A-phenyl, where a = 0, which is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, J, CF3, metoxygroup; CdH2d(C3-7-cycloalkyl, where d = 0; R2and R3independently from each other denote hydrogen, F, Cl, J, C=N; COR6where R6denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, OR30where R30- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; OR7where R7denotes hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; phenyl; or R2and R3, independently of one another, denote CqH2q-phenyl, where q=0; or R2and R3independently from each other mean-SOnR22where n stands for zero, R22- alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; R4and R5independently of one another denote hydrogen, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, F, Cl, Br, J, CF3and their physiologically acceptable salts; and to medicines, inhibiting Na+dependent Cl-/HCO-3- exchange rate is
< / BR>where R1is hydrogen or heteroaromatic, R2is a group selected from CH2-O-aralkyl, CH2OCO-alkyl, CH2ОСОNН2CH2ОСОРh, CH2LLC-alkyl; R3- C3-alkyl; R4- dichlorophenyl, including interaction of the compounds of formula I
< / BR>where R1, R2and R3such as defined above, with a compound of formula II: R4-S-Hal, where R4like is definitely above and Hal represents halogen, in the presence of a base
< / BR>in which R1' has the abovementioned meaning and M represents a hydrogen atom or the radical R2' which has the values specified above for R2in which the possible reactive functions can be protected by a protective group, is subjected to reaction with the compound of the formula (VIII) defined above, to obtain a product of formula (X):
< / BR>in which R1' M and R4' have the above values, the obtained compound of formula (X), if M implies R2' defined above, is subjected to a halogenation reaction, to obtain the product of formula (XI):
< / BR>in which R1', R2', R4' and Hal have the above values, which is subjected to the reaction of the exchange of the halogen-metal, then the reaction with the compound of the formula (XII):
< / BR>in which R9' matter referred to in paragraph 1 for R9where possible reaction ф�g/rupat4/200110/01/2174513-36t.gif" ALIGN="ABSMIDDLE">< / BR>in which R1', R2', R4' and R9' have the above meanings and, if necessary, or interact product of formula (I2) with the compound of the formula (XV):
in which R6' matter referred to in paragraph 1 for R6in which the possible reactive functions can be protected by a protective group, to obtain a product of formula (I3):
< / BR>in which R1', R2', R4', R6' and R9' have the above meanings, or the product of formula (I2) is subjected to a saponification reaction with the product of formula (I4):
< / BR>in which R1', R2', R4' and R9' have the above meanings, is subjected to reaction with COCl2to obtain a product of formula (I5):
< / BR>in which R1', R2', R4' and R9' have the above meanings, or the product of formula (X), provided that M denotes a hydrogen atom, is subjected to a halogenation reaction to obtain a product of formula (XIV):
< / BR>in which R1', R4'Hal and R3" have the above values, the compound obtained is subjected to the reaction of the exchange of the halogen-metal, then the processing of the compound of formula (IVa') (IVb'), (IVc'), (IVd') or (IVe') defined above, to obtain a product of formula (I7):
< / BR>in which R1', R4', R2and R3" have the above meanings; then the above products of formula I2, I3, I4, I5, I6, I7that are a product of the formula I, allocate or subjected, if necessary, one or more reactions of transformation to other products of the formula I, in any order:
a) esterification of the acid function,
(b) saponification functions of ester to acid functions,
C) transforming functions of ester function acyl,
d) transforming Sinopoli in an acid function,
e) conversion of the acid function to an alcohol function,
g) transforming functions alkoxy function hydroxyl or hydroxyl function in the function alkoxy,
h) oxidation of the alcohol function to the aldehyde, acid or keto-function
i) the conversion of the formyl radical in the radical carbarnoyl,
j) turning radical carbarnoyl in the nitrile radical,
k) converting the nitrile radical in tetrazolyl,
l) oxidation of ancilliary or aristocraty to the corresponding sulfoxide or sulfone,
m) the transformation function sulfide, sulfoxide or sulfone function corresponding sulfoximine,
n) the transformation function oxo function of thioxo,
a) transforming radical
< / BR>in radical
< / BR>p) conversion of the acid function in function
< / BR>q) is the transformation function of beta-keto-sulfoxide in the function of alpha-ketotioefir,
r) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,
s) removal of protective groups, which can protect the reaction functions,
t) salt formation using mineral or organic cisisomer, enantiomers and diastereoisomers
FIELD: medicine; gastroenterology.
SUBSTANCE: treatment of chronic viral hepatitis type C is provided by oral introduction of Reaferon-EC-Lipint dosed 1 million ME twice a day within 10 days, thereafter introduced in the same dosage once a day within 6 months. Furthermore in addition Ronkoleukine is introduced orally in dosage 500 thousand ME twice a week within 3 months.
EFFECT: effective treatment in patients suffering from cytopenic, autoimmune syndrome combined with immunodeficiency with contraindications to injection interferons.
FIELD: medicine; otorhinolaryngology.
SUBSTANCE: preparation pyobacteriophage polyvalent purified liquid is injected in maxillary sinus in amount 5-10 ml twice a day, every 12 hours within 6 days. Besides, from the first day of treatment, the preparation is introduced intranasal dosed 3 ml twice a day within 21 days.
EFFECT: long remission of disease resulted from restored adequate immune response and absence of depressed condition of cellular representation of nasal and sinus mucous membrane, stable synthesis of secretory immunoglobulin class A, normalised indicators of phagocytosis completeness, maximal pathogen elimination from nasal and sinus mucous membranes.
2 tbl, 1 ex
FIELD: medicine; dermatology.
SUBSTANCE: in addition to Griseofulvin, Pioployphage is introduced orally in dosage 30-50 ml or on 1-2 tablets twice a day within 14 days.
EFFECT: antibacterial action, nonspecific phagocytosis stimulation, intensified immune response on infestant antigen, escaping complications associated with secondary pyogenic infection.
4 tbl, 2 ex
SUBSTANCE: treated skin conditions and diseases include but not limited acne vulgaris, acne rosacea, seborrheic dermatitis, eczema (atopic dermatitis), psoriasis, sunlight induced skin ageing and ketarosis solaris. Discovered therapeutic compositions are produced from Porifera types, specifically sponges, and more particularly, fresh-water sponges. One of discovered implementation versions is produced from Spogilla type and made with pharmaceutically acceptable excipients.
EFFECT: safe, effective local medical compositions of multiple actions.
18 cl, 9 ex, 5 tbl, 3 dwg
FIELD: medicine; sexual pathology.
SUBSTANCE: Sildenafil citrate dosed 12.5 mg or Tadalafil dosed 5 mg is introduced 1 hour prior to expected coitus and combined with Vicalin dosed 1 tablet. Method allows for lowered dosage of specified phosphodiesterase inhibitors type 5 in 2-4 times.
EFFECT: effective treatment without by-effects.
FIELD: medicine; neurology.
SUBSTANCE: treatment of clinical presentations of lumbar osteochondrosis is ensured as follows. Autoblood 2-4 ml is sampled from spongy tissues of lumbar vertebral body in a syringe prefilled with medicinal solution, including 1% lidocaine solution and dexamethasone 1-2 mg. After that, produced solution is intraosseous injected into autoblood sampling point.
EFFECT: higher efficiency of intraosseous blockade ensured by local stimulation of reparative regeneration of osseous tissue and osteoperforation induced muscular revasculisation at segmental level.
FIELD: medicine; pulmonology.
SUBSTANCE: treatment of bronchial asthma, either intermittent or mixed of mild severity level is ensured with introduction of anti-inflammatory preparations being labrocyte stabilisers, combined with introduction of immunomodulators Polyoxidonium and Galavit. Herewith specified immunomodulators are introduced sequentially according to the certain schedule.
EFFECT: higher efficiency of treatment due to normalisation of immune system function and structural restoration of bronchi mucous membrane.
FIELD: medicine; sexual pathology.
SUBSTANCE: prevention of cardiovascular by-effects induced by introduction of phosphodiesterase type 5 inhibitors for treatment of erectile dysfunction in men is ensured with introduction of one preparation from the specified group: Sildenafil citrate dosed 25-100 mg, or Vardenafil hydrochloride dosed 5-20 mg, or Tadalafil dosed 20 mg, combined with introduction of De-Nol dosed 1 tablet.
EFFECT: improved microcirculation due to higher synthesis of endogenous prostaglandins and prevented cardiovascular by-effects induced by introduction of specified preparations, improved erection in present category of patients.
FIELD: medicine; sexual pathology.
SUBSTANCE: phosphodiesterase inhibitor type 5 that is Sildenafil citrate in unit-dose 12.5 mg is introduced. It is combined with antidepressant Maprolitine (Ludiomil) in unit-dose 5.0 mg daily, once a day. Course of treatment is 30 days.
EFFECT: effective treatment with preparations in smaller doses without by-effects.
FIELD: medicine; pharmacology.
SUBSTANCE: composition contains lidocaine concentrated approximately 5 to 12.5 wt % as medical product and bioadhesive carrier including swelling, but water-insoluble cross-linked polymer of polycarboxilic acid, providing prolonged release of the agent. Furthermore, the invention refers to method of reduction or simplification of uterus rhythm disturbance including introduction of declared composition to the patient requiring treatment.
EFFECT: reduction or simplification of uterus rhythm disturbance due to normalisation of abnormal or undesirable uterus contraction.
11 cl, 33 ex
FIELD: medicine; stomatology.
SUBSTANCE: on a vestibular surface of gum mucosa in the field of the damaged site or if the lesion is generalised - that in the field of roots of 4 or 5 teeth of a corresponding jaw fix size of amplitude of the electromagnetic fluctuations induced in a tissue by external natural electromagnetic fields (EMF) as a result of its bioelectric activity. According to amplitude, form initial parametres of a low-frequency impulsive complex of modulated electromagnetic field (CM EMF). Form the field with parametres: frequency of modulation in a range from 0.3 to 0.8 Hz, frequency of following of impulses in a range from 3 to 30 Hz, with width of a spectrum of harmonious components in a range from 500 Hz to 1 kHz, size of an induction of a magnetic field from 8 to 12 mT. Apply by means of applications a medical product on a surface of a gum mucosa from the oral and vestibular sides and a normal saline solution on a surface of teeth. As a medical product, use a composition prepared on a basis organosilicone glycerogel and containing chlorhexidine, metronidazole, pefloxacin at a following parity of masses, %: chlorhexidine - from 0.001 to 0.2; metronidazole - from 1.0 to 1.5; pefloxacin - from 1.0 to 1.5; organosilicone glycerogel - the rest. Influence CM EMF simultaneously on the parodontium tissues and on a spine column. In the course of influence constantly supervise size of amplitude of electromagnetic fluctuations and change size of CM EMF by a feedback principle.
EFFECT: deep penetration of a medical product into area of locomotive structures of teeth and creation of depot of a pharmacological preparation of the necessary concentration, the expressed local antiinflammatory, antiedematous and antibacterial effect at patients with chronic generalised periodontosis of various severity level, chronic granulating periodontitis, chronic periodontitis, including an exacerbation stage.