Novel salt form of dopamine agonist

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt form of 5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]piridine-2-amine (I): , and specifically to 5-[2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridine-2-amine di-(1S)-camphorsulphonate (di-S-camsylate), to a pharmaceutical composition having effect on dopamine D3 receptor, as well use of the given compound in preparing a medicinal agent for treating sexual dysfunction and neuropsychiatric disorders and a method of obtaining the said compound and an intermediate compound.

EFFECT: novel salt form of a dopamine agonist which has advantages, specifically is not hygroscopic, has a crystalline form and has high melting point is obtained and described.

11 cl, 9 ex, 2 tbl, 6 dwg

 

This invention relates to a new salt form of a dopamine agonist 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine (I):

More specifically, this invention relates to 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-(1S)-camphorsulfonate (di-S-camsylate) and to methods for, to intermediate compounds used in the preparation of this salt, to compositions containing this salt, and the applications of this salt.

As described in the international patent application WO 2004/052372 it was shown that the compound of formula (I) is a selective D3 agonist, is useful for treatment and/or prevention of sexual dysfunction, such as female sexual dysfunction (ISD), specifically female sexual arousal disorder (GRPW), and male sexual dysfunction, particularly male erectile dysfunction (MED). It is implied that male sexual dysfunction, as it is here referred to, includes ejaculation disorder such as premature ejaculation, anorgasmia (inability to achieve orgasm) or disorders of desire, such as hypoactive sexual desire disorder (GSRG; lack of interest in sex). It is implied that female sexual dysfunction, as it is here referred to, includes hypoactive with czwalinae upset desire, disorder sexual arousal disorders, orgasm and pain sexual dysfunction. This compound is also useful in the treatment of neuropsychiatric disorders and neurodegenerative disorders.

The form of the free base 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine has a low melting point and is also blurring due to the absorption of moisture. These properties make this connection unwanted selected for inclusion in a pharmaceutical composition.

Interestingly, it was found that 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate has the advantage of possessing the required properties, making it possible for its preparation in the form of medicines. Namely, it is not blurred due to the absorption of moisture, has a high melting point, is not hygroscopic and has a crystalline form.

In addition, 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-8-camsylate monohydrate has the following additional useful properties that make it even more relevant to the conditions used in the manufacture of a pharmaceutical product on an industrial scale, that is:

It does not lose water through 3.5 hours at a relative humidity (RH) of 0% and at 30°C. Tipi is but would be expected, the pharmaceutical hydrate loses water within a few hours of exposure to S 0%. In addition, by heating a sample of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate in the current S 0% actual moisture loss was observed at 85°C. This is considerably higher temperature than the temperature which would normally be expected for the hydrated salt. This kinetic stability is desirable to ensure a successful grinding this connection before cooking in the medication.

Many hydrates are unstable in hard vacuum drying conditions required for the selection of pharmaceutical drug product. However, 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-5-camsylate monohydrate would be stable in this process, because when exposed to low partial pressure at 40°C. the hydrate is preserved reduce the pressure to 10 mbar (1 kPa).

The present invention includes the following embodiments:

a) 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate:

b) the Compound according to a) in the form of a monohydrate.

C) the Compound according to b), with the main characteristic peaks in the picture x-ray diffraction on powder 6,3, 12,7, 15,1,, 16.3 and 25.6 degrees 28.

g) Connection with the public hearing a), b) or C)having an enantiomeric excess of at least 80%.

d) the Compound according to g), with enantiomeric excess of at least 95%.

(e) a Pharmaceutical composition comprising 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and a pharmaceutically acceptable diluent or carrier.

g) the Pharmaceutical composition according to (e), 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-5-Camelot is in the form of a monohydrate.

C) the Way to obtain 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-3-camsylate monohydrate, including interaction of the compounds of formula (X)

with (1S)-10-camphorsulfonic acid in a suitable solvent.

and) the Method according to h), where the solvent is acetone/water.

th) the Method according to and, where the amount of water used is in the range from 0.7 l to 1 l of water per kg of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine.

K) the Method according to and, where the amount of water used is in the range from 0.8 l 0.9 l of water per kg of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine.

l) Compound of formula (VII)

and its pharmaceutically acceptable salt and solvate.

The connection according to the invention can exist, depending on the atmospheric conditions (temperature and humidity), in opposition to Laterano and solvated forms. The term "MES" is used herein to describe a molecular complex containing the compound according to the invention and one or more than one molecule pharmaceutically acceptable solvent, such as ethanol. The term "hydrate" is used when the specified solvent is water. Accordingly, the present invention further includes a pharmaceutically acceptable solvate of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate.

Currently accepted classification system of organic hydrates is a system that determines hydrates with isolated site, channel hydrates and hydrates, the coordinated metal ion - see Polymorphism in Pharmaceutical Solids K.R. Morris (Ed. H.G.Brittain, Marcel Dekker, 1995). Hydrates with isolated site are hydrates, in which water molecules are isolated from direct contact with each other by the organic molecules between them. In channel hydrate water molecules lie in the channels of the crystal lattice, where they are adjacent to other water molecules. In the hydrates, the coordinated metal ion, water molecules are bound with a metal ion.

When the solvent or water are firmly linked, this complex will have a well-defined with what ageometry, regardless of humidity. However, when the solvent or water are loosely coupled, as in channel solvate and hygroscopic compounds, the content of water/solvent will depend on the humidity and drying conditions. In such cases, non-stoichiometric quantity will be the norm.

Also included in the scope of the present invention are multi-component complexes (other than salts and solvate), where the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (inclusion complexes medicine-host) and societally. The latter is usually defined as crystalline complexes of neutral molecular components, which are connected to each other through non-covalent interactions, but they could also be complex neutral molecules with salt. Secretary can be obtained by crystallization from the melt, by recrystallization from solvents or by physical rubbing of the components with each other - see Chem Commun, 17, 1889-1896, .Almarsson, M.J.Zaworotko (2004). As for a General overview of multicomponent complexes, see J Pharm Sci, 64 (8), 1269-1288, Haleblian (August 1975).

This invention also includes all polymorphs and crystal forms of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-who of Aminata and 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate.

The present invention includes all pharmaceutically acceptable labeled isotopes of the compounds 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its monohydrate, where one or more than one atom are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number, which are prevalent in nature.

Examples of isotopes suitable for inclusion in the connection according to the invention include isotopes of hydrogen, such as2H and3N, carbon, such as11C,13C and14With nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, and sulfur, such as35S.

Certain labeled isotopes of the compounds according to the invention, for example compounds containing a radioactive isotope, are useful in studies of the distribution in the tissues of the medicinal product and/or substrate. Radioactive isotopes tritium,3N, and carbon-14, that is,14With, are particularly useful for this purpose in mind ease their integration and simple detection methods.

The substitution of heavier isotopes such as deuterium, i.e2N, can provide certain therapeutic advantages resulting from greater metabolic stability, for example increased half-life i vivo or reduced requirements for dosage, and, therefore, may be preferable in some cases.

Substitution with isotopes emitting positrons, such as11C,18F,15O and13N, may be useful in studies of positron emission tomography (PET) to study the lessons of the receptor substrate.

Labeled isotopes of the compounds 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate you can usually get traditional techniques known to experts in the field, or by methods similar to the methods described in the accompanying experimental section, using a suitable labeled isotopes reagent instead of unlabeled reagent used earlier.

Pharmaceutically acceptable solvate according to this invention includes a solvate, where the solvent of crystallization may be substituted with isotopes, for example, D2Oh, d6-acetone, d6-DIVISO.

5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate can be obtained according to the following scheme. Specialists in this field can know other synthesis methods, which can be equally feasible.

2-Amino-5-bromopyridine allow you to interact with (1) 2,5-hexandione and p-toluensulfonate acid under the reaction conditions Dean-stark (Dean-Stark) in a suitable dissolve the barely (such as heptane) to give the protected bromopyridine (II). Bromopyridin (II) is then treated (2) n-butyllithium in a suitable solvent (such as tertiary-butyl methyl ether at low temperature. Then add a solution of amide (III) obtaining chloretone (IV). This ketone is then converted into the epoxide (V) through (3) restore a suitable regenerating agent (such as sodium borohydride) in a suitable solvent (such as tetrahydrofuran) followed by treatment with a suitable base (such as sodium hydroxide). The epoxide (V), subject to (4) nucleophilic attack (S)-(+)-2-amino-1-propanol (VI) in a suitable solvent (such as tetrahydrofuran) at a high temperature to obtain an amine (VII). The amine (VII) is then converted into the compound (VIII) through (5) reductive alkylation with Propionaldehyde in the presence of a suitable reducing agent (such as triacetoxyborohydride sodium). The compound (VIII) into a compound (IX) through (6) remove the protection hydroxylamine in a suitable solvent (such as ethanol) at an elevated temperature. The compound (X) is generated by (7) cyclization of the compound (IX) in acidic conditions. Finally, 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate (XI) is generated by (8) interaction of the compound (X) with (1S)-10-camphorsulfonic acid in a suitable solvent (such as acetone/water) posleduuschei crystallization of salts.

5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its polymorphs and pharmaceutically acceptable solvate are useful as selective D3 agonist in the treatment of painful conditions.

Accordingly, in the first another embodiment according to the present invention proposed the use of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-8-camsylate and its polymorphs and pharmaceutically acceptable solvate in medicine.

5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its polymorphs and pharmaceutically acceptable solvate may be particularly suitable for the treatment of female sexual dysfunction, male erectile dysfunction, pain, neurodegeneration, depression and psychiatric disorders.

Accordingly, in the second another embodiment according to the present invention proposed the use of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-3-camsylate and its polymorphs and pharmaceutically acceptable solvate in the manufacture of medicinal products for the treatment and/or prevention of sexual dysfunction; and suitable condition include female sexual dysfunction (ISD), specifically female sexual arousal disorder (GRPW), and male sexual dysfunction, particularly male erectile dysfunction (MED). Assume that muisc what I sexual dysfunction, as it is here referred to, includes ejaculation disorder such as premature ejaculation, anorgasmia (inability to achieve orgasm) or disorders of desire, such as hypoactive sexual desire disorder (GSRG; lack of interest in sex). It is implied that female sexual dysfunction, as it is here referred to, includes hypoactive sexual desire disorder, sexual arousal disorder, disorders of orgasm and painful sexual disorders.

In the third another embodiment according to the present invention proposed the use of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its polymorphs and pharmaceutically acceptable solvate in getting medicines for the treatment of male erectile dysfunction.

In the fourth another embodiment according to the present invention proposed the use of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its polymorphs and pharmaceutically acceptable solvate in getting medicines for the treatment of female sexual dysfunction, specifically female sexual arousal disorder and hypoactive sexual desire disorder.

Salt of the present invention may also be useful in the treatment of pain, specifically chronic notice the positive pain, but not limited to it.

Physiological pain is an important protective mechanism designed to prevent danger from potentially harmful stimuli from the external environment. This system operates through a specific set of primary sensory neurons and is activated by noxious stimuli through peripheral transformative mechanisms (see for review Millan, 1999, Prog. Neurobiol., 57, 1-164). These sensory fibers are known as nociceptors and represent axons is typical of small diameter with slow conduction velocities. The nociceptors encode the intensity, duration and quality of the harmful stimulus and, owing to their topographically organized projection to the spinal cord, the location of the stimulus. The nociceptors are on nociceptive nerve fibers, of which there are two main types: A-Delta fibers (moulinsiana) and fiber (demyelination). The activity generated by the input of the nociceptor, after complex processing in the dorsal horn is transferred, either directly or through the transmission of nuclei in the brain stem, in ventrobasal the thalamus and then to the cortex, where it generates the sensation of pain.

The pain usually can be classified as acute or chronic. Acute pain begins suddenly and is short (usually lasting for twelve weeks or less). It is usually associated with exactly what the cause, such as specific damage, and is often sharp and strong. It is a type of pain that can occur after certain damage resulting from surgery, dental treatment, sprain or dislocation. Acute pain usually does not cause any permanent psychological reactions. In contrast, chronic pain is a long pain, usually persisting for more than three months and cause significant psychological and emotional problems. Common examples of chronic pain is neuropathic pain (for example, painful diabetic neuropathy, post herpetic neuralgia), their carpal canal syndrome, back pain, headache, pain caused by cancer, arthritic pain and chronic surgical pain.

When there is significant damage to the body tissues by disease or injury, the characteristics of the activation of nociceptor change and sensitization on the periphery, locally around damage and Central nervous system, where the end of the nociceptors. These effects lead to increased pain. In acute pain, these mechanisms can be useful in stimulating protective behavioral responses that can better ensure the progress of the recovery processes. Norms is determined as being the prediction would be that, that sensitivity would return to normal as soon as the damage would be repaired. However, many chronic pain hypersensitivity lasts much longer healing process and is often caused by damage to the nervous system. This damage often leads to abnormalities in sensory nerve fibers associated with incorrect adaptation and impaired activity (Woolf&Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when the discomfort and abnormal sensitivity are characteristic symptoms of the patient. Patients tend to be quite heterogeneous and can have different pain symptoms. Such symptoms include: 1) spontaneous pain, which may be dull, burning, or shooting; 2) exaggerated pain response to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994; in Textbook of Pain, 13-44). Despite the fact that patients suffering from various forms of acute and chronic pain can have similar symptoms, the underlying mechanisms may be different and, therefore, may require different treatment strategies. Pain, therefore, also can be divided into a number of different subtypes according to different pathophysiology, including nociceptive, Pospolita the ing and neuropathic pain.

Nociceptive pain induced by tissue injury or intense stimuli that have the potential to cause damage. Pain afferent fibers are activated by conversion incentives by nociceptors at the site of injury and activate neurons in the spinal cord at the level of graduation. It is then transmitted up the spinal pathways to the brain where it is perceived pain (Meyer et al., 1994; in Textbook of Pain, 13-44). Activation of nociceptors activates two types of afferent nerve fibers. Moulinsiana A-Delta fibers carry out quickly and are responsible for sensations of sharp and shooting pain, whereas demyelination With the fibers pass with a slower speed and tell stupid or nousou pain. Nociceptive pain from moderate to strong is a prominent feature of pain resulting from injury to the Central nervous system, sprains/dislocations, burns, myocardial infarction and acute pancreatitis, postoperative pain (pain after any type of surgery), post-traumatic pain, renal colic, pain in cancer and back pain. Pain in cancer the disease can be chronic pain, such as pain associated with the tumor (for example, pain in bones, headache, facial pain or visceral pain)or pain associated with cancer therapy (for example, POSTH Biotherapeutics syndrome, the syndrome of chronic surgical pain or postradiotherapy syndrome). Pain in cancer can also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain can be caused by herniated discs or ruptured intervertebral disks or abnormalities of the lumbar facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain can pass in a natural way, but in some patients, where it lasts more than 12 weeks, it becomes a chronic condition, which can be especially debilitating.

Neuropathic pain is currently defined as pain initiated or caused by primary lesion or dysfunction in the nervous system. The nerve damage can be caused by injury and disease, and, thus, the term "neuropathic pain" covers many disorders of different etiology. They include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, neuropathy in HIV, phantom pain, syndrome carpal, Central post-stroke pain and pain associated with chronic alcoholismo is, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and lack of vitamins. Neuropathic pain is pathological because it has no protective role. It's often much later than the disappearance of the original cause, often continuing for many years, significantly reducing the patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Symptoms of neuropathic pain is difficult to treat, as they are often heterogeneous even among patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf and IVIannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be lengthy, paroxysmal or abnormal induced pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).

The inflammatory process is a complex cascade of biochemical and cellular events that are activated in response to tissue damage or presence of foreign substances, which leads to swelling and pain (Levine and by Taiwo on, 1994, in Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the most common chronic inflammatory diseases in developed countries, and the roar of foigny arthritis is a common cause of disability. The exact etiology of rheumatoid arthritis is unknown, but current hypotheses suggest that important can be both genetic and microbiological factors (Grennan & Jayson, 1994, in Textbook of Pain, 397-407). Estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative disease of the joints, most of them over 60 years, and it is expected that this number will increase to 40 million, with increasing age of the population, making it a public health problem on a huge scale (Houge & Mersfelder, 2002, Ann Pharmacother, 36, 679-686; McCarthy et al., 1994, in Textbook of Pain, 387-395). The majority of patients with osteoarthritis require medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function, and it is known that it is the leading cause of disability in old age. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the joints of the spine and sacroiliac joints. It varies from periodic episodes of back pain that occur throughout life, to serious chronic disease that affects the spine, peripheral joints and other organs of the body.

Another type of inflammatory pain, visceral pain, which includes pain, svjazanno is with inflammatory bowel disease (IBD). Visceral pain is the pain associated with internal organs, which covers the abdominal organs. These bodies include the genitals, spleen and part of the digestive system. The pain associated with internal organs, can be divided into visceral pain digestive disorders and visceral pain that is not associated with the digestive system. Common gastrointestinal (LCD) disorders that cause pain include functional bowel disorder (PRK) and inflammatory bowel disease (IBD). These LCD disorders include a wide range of painful conditions, which are currently controlled by only a moderate degree, including in regard to PRK, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) syndrome and functional abdominal pain, and in regard to inflammatory bowel diseases, Crohn's disease, REIT and ulcerative colitis, which are all regularly give visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis, and pain in the pelvic region.

It should be noted that some types of pain have multiple etiologies and, thus, may be classified in more than one area, such as back pain and pain in cancer have both nociceptive and neuro is eticheski components.

Other types of pain include:

pain originating from musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, seronegative (primatine) arthropathies, sustavnoi rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;

- heart and vascular pain, including pain caused by angina, myocardial infarction, mitral stenosis, pericarditis, phenomenon, Raynaud's disease, scleredema and skeletal muscle ischemia;

- headache, such as migraine (including migraine with aura and migraine without aura), histamine headache, headache voltage, mixed headache and headache associated with vascular disorders; and

- rotaliana pain, including dental pain, ear pain syndrome burning mouth and temporomandibular myofascial pain.

Therefore, in another fifth preferred embodiment according to the present invention can also be offered the use of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its polymorphs and pharmaceutically acceptable solvate in the preparation of drugs for treating or preventing pain. In addition, according to the present invention can also be offered the use of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its polymorphs and pharmaceutically pickup is acceptable solvate of the preparation of drugs for treating or preventing chronic nociceptive pain.

In another sixth preferred embodiment according to the present invention can also be offered the use of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate and its polymorphs and pharmaceutically acceptable solvate in the preparation of medicines for the treatment of neuropsychiatric disorders or neurodegenerative disorders, and appropriate conditions may include hypertension, neurodegeneration, psychiatric disorders, depression (e.g., depression in cancer patients, depression in patients with Parkinson's disease, depression after myocardial infarction, symptomatic subsyndromal depression, depression in infertile women, major depression, depression in children, caused by abuse, postpartum depression and irritable elderly person), single episodic or recurrent great depressive disorders, estimatesa disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early awakening in the morning or psychomotor retardation; atypical depression (or reactive depression)including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder pediatricheskoe depression; bipolar disorder or manic depression, for example bipolar I disorder, bipolar II disorder and cyclothymic disorder; conduct disorder; a disorder associated with aggressive behavior, trichotillomania, kleptomania, attention deficit disorder with hyperactivity (ADHD); behavioral disturbances associated with mental retardation, autism, borderline personality disorder; a disorder associated with avoidant personality; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, such as specific phobias towards animals, anxiety in public places, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, disorder, generalized anxiety, emotional lability, pathological crying; schizophrenia and other psychotic disorders, for example schizophreniform disorders, schizoaffective disorders, disorders associated with delirium, brief psychotic disorder, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety, concerns about annoy with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; disorders nastoenie associated with schizophrenia; eating disorders (e.g. anorexia nervosa and neurogenic bulimia nervosa), obesity, disorders of motor activity, such as akinesia, dyskinesia, including family paroxysmal dyskinesia, spasticity, Tourette's syndrome, Scott syndrome, paralysis (palsys) and akineticalkie rigid syndrome; extrapyramidal disorders of motor activity, such as disorders of motor activity induced by drugs, such as parkinsonism induced by neuroleptics, neuroleptic malignant syndrome, acute dystonia induced by a neuroleptic, acute akathisia induced by neuroleptics, late dyskinesia induced by neuroleptics, and postural tremor induced drug; chemical dependencies and addictions (e.g., dependencies on, or addictions to alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol)and behavioral addictions such as an addiction to gambling; and ocular disorders, such as the glaucoma and ischemic retinopathy; tired leg syndrome, Huntington's disease, multiple sclerosis, moderate deterioration of cognitive abilities, down syndrome, stroke, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, cerebral amyloid angiopathy, delirium, dementia, age-related decline in cognitive abilities (ARCD), amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (BP), Huntington's disease (BG), Alzheimer's disease, senile dementia, dementia type, memory disorders, loss of Executive function, vascular dementia, dementia of mixed vascular and degenerative origin, dementia associated with the disease Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with corticobasal degeneration, multi-infarct dementia, dementia in alcoholics or other dementia-related drugs, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington disease, a disease of the Peak, the disease of Creutzfeldt-Jakob disease, dementia associated with HIV or AIDS, Alzheimer's disease with calves Levi diffuse type, fronto-temporal dementia with parkinsonism (FTDP), head injury, spinal cord injury, demyelinating diseases the project for the nervous system, peripheral neuropathy, pain, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, multiple sclerosis, dyskinesia associated with therapy with dopamine agonists, mental retardation, learning disorders, including reading disorder, disorder of mathematical abilities or disorder of written expression; age-related decline in cognitive abilities, the amnestic rasstroistva, parkinsonism induced by neuroleptics, late dyskinesia and acute and chronic neurodegenerative disorders; premenstrual syndrome, fibromyalgia syndrome, stress incontinence, endocrine rasstroistva (e.g., hyperprolactinaemia), vasospasm (particularly in the vascular system of the brain), cerebellar ataxia, disorders of the gastrointestinal tract (including changes in contractility and secretion), histamine headache, migraine, pain, chronic paroxysmal hemicrania, headache (associated with vascular disorders), sleep disorder (cataplexy) and shock.

In another embodiment of the present invention further includes a use listed above, where 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate is in the form of a monohydrate.

Activity against receptor dopamine D3 which can be determined, using the methods described in WO 2004/052372, which is incorporated in this description by reference. Using this analysis of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-3-camsylate monohydrate has functional activity in relation to the D3 receptor, expressed as EC, 21 nm and 476-fold selectivity for D3 compared to D2. Selectivity is calculated as the value IS D2 divided by the value AS D3.

Appropriate tests to determine the use of the compounds according to this invention in different pain conditions described below.

Neuropathic pain

The potency of the compound in the treatment of neuropathic pain can be measured according to the following Protocol analysis.

Animals: Male rats Sprague Dawley place groups. All animals contain in terms of 12-hour cycle of light/dark (light include at 07 h 00 min) without restrictions on feed and water. All experiments were performed blind observations in the treatment and according to the Act on home and office animals (scientific procedures) 1986 (Home Office Animals (Scientific Procedures) Act 1986).

Rat model of chronic damage to the tug (CCl) neuropathic pain

CCl sciatic nerve was performed as previously described (Bennett and Xie (Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain: 33:87-107, 1988). Animals were anestesiologi a mixture of 2%is of isofluorane/About 2. Right rear thigh was shaved and treated with 1%iodine. Then the animals were transferred to homoeothermic blanket at the time of the procedure and maintained anesthesia during surgery through the nose fairing. The skin is cut along the line of the femur. The common sciatic nerve was exposed at mid-thigh by blunt dissection through the biceps muscle of the thigh. Proximally relative to trifurcate sciatic nerve was released about 7 mm of nerve inserting forceps under the nerve and gently removed the nerve of the thigh. Using tongs, under the nerve stretched the ligature and tied a simple knot until you feel slight resistance, and then tied a double knot. This procedure was repeated up until around the nerve was not freely tied 4 ligatures (4-0 silk) at a distance of approximately 1 mm from each other. The incision was sutured in layers and was treated with local wound with antibiotics.

Diabetic neuropathy in rats induced by streptozocin (STZ)

Diabetes was induced by single intraperitoneally injection streptozocin (50 mg/kg), freshly dissolved in 0.9%sterile saline. Injection streptozocin within 3 weeks induces a reproducible mechanical allodynia, continuing for at least 7 weeks (Chen SR, Pan and HL. Hypersensitivity of Spinothalamic Tract eurons Associated With Diabetic Neuropathic Pain in Rats. J Neurophysiol 87: 2726-2733, 2002).

Evaluation of static and dynamic-allodynia

Static allodynia

Before evaluating allodynia animals were habituated to the test cage with a wire bottom. Static allodynia was assessed by applying hairs von Frey (von Frey) (Stoelting, Wood Dale, Illinois, USA) in ascending order of strength(0,6, 1, 1,4, 2, 4, 6, 8, 10, 15 and 26 grams) to the surface of the soles of the hind feet. Each hair von Frey was applied to the paw up to 6 seconds or until the reaction of otdergivanija. Once installed the responses otdergivanija on the verge von Frey, paw was tested a second time, starting with the hair, previous to that, which caused OTDELENIE, and consistently with the rest of the hairs in descending order of strength, while OTDELENIE did not stop. The biggest force 26 g raised a paw, and had caused the reaction, being, thus, the cut-off point. Each animal was tested in this way both hind paws. The least amount of force required to cause the reaction was recorded as the threshold otdergivanija feet (PWT) in grams. Was determined that the static allodynia was present, if the animals reacted to the stimulus of 4 g or less than 4 g, which is harmless in normal rats (Field MJ, Bramwell S, Hughes J, Singh L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primarysensory neurones? Pain, 1999:83:303-11).

Dynamic allodynia

Dynamic allodynia was assessed by light stroking cotton swab over the surface of the soles of the hind feet. Cared about performing this procedure, the fully accustomed rats, not active, in order to avoid registration of General motor activity. Did at least two measurements at each time point, the average of which was a timeout otdergivanija feet (PWL). If within 15 seconds, the reaction was not shown, the procedure was finished and the animals were attributed to this time of otdergivanija. The reaction pain otdergivanija was often accompanied by repeated otdergivanija or licking of the paws. Believed that dynamic allodynia was present, if the animals reacted to the stimulus of a cotton swab to 8 seconds of stroking (Field et al, 1999).

Nociceptive pain

The potency of the compound in the treatment of nociceptive pain can be measured according to the following protocols.

Electric stove

Experimental methods: Male rats Sprague Dawley placed on an electric stove (Ugo Basile, Italy)maintained at a temperature of 55±5°C. Measure the time between the location of the animal on the electric stove and the emergence of licking the front or hind legs, shivering or off a given surface. Will be held measurement source is level, and the animals will be re-evaluated after drug administration. The time cutoff for expectations regarding electric tile set for 20 seconds to prevent tissue damage.

Ovariohysterectomy (OH)

Experimental methods: Female rats Sprague Dawley placed in the anesthetic chamber and anaesthetize with a mixture of 2%of isofluorane/About2. During surgery anesthesia support via nose cone. OVX performed through a median incision (2 cm long) on the white line, when the animal is on the blanket. Put the ligature silk 5-0 on the ligament of the ovary and cervix, using the methodology of a single clip. Then remove the ovaries and the uterus. The abdominal wall is sutured using 4 simple interrupted sutures, and the skin sutured using 4 clamps for wounds. Immediately after surgery the animals are placed in individual Plexiglas chambers. As soon as the animals recovering from anesthesia, fixed abdominal body position for 30 minutes, the time intervals at different points in time. Calculate the positions of the body are hunched position, contraction of the abdominal muscles associated with movements of the hind limbs inside, pulling the body and flattening the lower part of the belly on the floor. Each of these types of behavior to be rated as one Polo is giving body.

Brennan

Experimental methods: Male rats Sprague Dawley placed in the anesthetic chamber and anaesthetize with a mixture of 2%of isofluorane/About2. During surgery anesthesia is supported through a nose cone. Plantar side of right hind paws sterilized 50%ethanol. Through the skin and fascia of the plantar side of the feet make a longitudinal incision 1 cm long blade number 11, starting 0.5 cm from the proximal edge of the heel and continuing in the direction of the fingers. Plantar muscle UPS, using tweezers, and along incised so that the beginning of a muscle and attaching remained intact. After hemostasis at low pressure the skin sutured with two simple stitches woven silk.

Model of OA induced moneyeducation (MIA)

Male 6-week-old rats, Sprague-Dawley (SD, Japan SLC or Charles River Japan) anaesthetize pentobarbital. The injection vypivaut and sterilized with 70%ethanol. 25 μl of the solution MIA or saline solution is injected into the right knee joint using a needle 29G. After 7, 14, 19, and 20 days after injection MIA trained rats to measure the weight of the load (VL) without putting their stress. After 21 days after injection MIA measure NR on each of the two rear legs, and the lack of NR is calculated as of 10.2. Determine the lack of NR as "przeznaczenie". When considering PR is znaczenia and predprijatija experimental group distribute evenly. After administration of test compounds or media was measured HV on each of the two rear legs.

Model of pain in cancer

In these experiments used adult male mice SN/HeN (Ninon SLC, Shizuoka, Japan). Data of mice were placed according to the guidelines of the National Institute of health in vivarium, which maintained a temperature of 22°C with 12-hour cycle of alternating light-dark, and gave them food and water without restrictions. Used Protocol injection of sarcoma cells was described. After induction of General anesthesia by inhalation izoflurana (2%) in the skin, lying above the knee cap, made a superficial cut using scissors Mora. Then cut the ligament of the patella, exposing Medelci the distal part of the femur. In the bone marrow cavity at the level of mimimally excavation inserted the needle 30 rooms to create the original center of the aisle. After creating the original center was used needle 29th rooms to create the final passage in the bone. Then did a 0.5-mm notch using semicircular boron in the handpiece pneumatic high-speed drill to ensure that it serves for the mechanical delay of the tooth rubber seals. Then were injected with 20 µl of α-minimum basic medium (Sigma; simulation of injection) or 20 μl of medium containing 1×1052472 osteolytic RAA is UMNO cells (American Type Culture Collection, Rockville, Maryland; injection sarcoma), using the needle 29th rooms and syringe 0.25 cm3. To prevent leakage of cells from the bone injection site was closed binder for prosthodontic materials, followed by abundant rinsing with filtered water. Wound closure was achieved using automatic clamps for RAS (Becton Dickinson, San Jose, California). Clamps for wounds was removed on the 5th day so that they do not interfere with the behaviour test.

Evaluation of static and dynamic-allodynia

Static allodynia

The technique is the same as described above for neuropathic pain.

Dynamic allodynia

The technique is the same as described above for neuropathic pain.

OTDELENIE paws in response to infrared radiation

Experimental method: thermal OTDELENIE paws were evaluated using rat plantar test (Ugo Basile, Italy), following the modified method of Hargreaves et al., 1988. Rats were habituated to the installation, consisting of three separate boxes of organic glass raised the glass table. A movable source of infrared radiation disposed under the table, focused on the hind foot, and recorded timeout otdergivanija paws. There is an automatic cut-off point of 22.5 seconds to prevent tissue damage. Timeout otdergivanija paw is recorded 2-3 times for both hind paws of each animal, the average value which represents the initial level for the left and right hind paws. The setup is calibrated so that it shows timeout otdergivanija paws approximately 10 seconds.

Weight capacity

Experimental methods: Animals explore hypersensitivity test weight load using a device incapacitance tester" (Linton Instruments, Diss, Norfolk, U.K.). Rats were positioned so that their front legs were on the slope of organic glass, and measured the load distribution on the rear legs by means of force sensors under each hind paw. Each animal is placed in the instrument and record the weight load exerted hind legs. The difference in the weight load are calculated by subtracting the weight of the load on the ipsilateral (injured nerve) the paw of the weight load on the contralateral (normal) paw, and this is the source data.

Inflammatory pain

The potency of the compound in the treatment of inflammatory pain can be measured according to the following testing Protocol.

The lack of weight in rats, induced by CFA

Male SD rats 7 weeks of age do not feed during the night. In the pad of the right hind paws of rats injected with CFA (300 μg of Mycobacterium tuberculosis H37 RA (Difco Laboratories) in 100 μl of liquid vaseline (Wako)). Two days after the conduct of the CFA measure changes in the distribution of the weight load of the rear legs between the left (ipsilateral) and right (contralateral) limb as an index of pain with the use of device Linton Incapacitance tester (Linton Instrumentation, UK). The test compound, suspended in 0.1% MS (Wako), administered orally in a volume of 1 ml per 100 g body weight. Each animal is placed in the installation, and the weight load exerted hind legs, Imarat before and after 1, 2 and 4 hours after administration of the drug.

Mechanical hyperalgesia in rats induced by carageenan

Male SD rats 4 weeks of age do not feed during the night. Hyperalgesia induce vnutripolostnoe injection lambda Karenina (0.1 ml of 1%wt./about. solution in physiological solution, Zushikagaku). Test compound (1 ml of 0.1%methyl cellulose/100 g body weight) give oral after 5.5 hours after injection Karenina. The threshold otdergivanija feet (grams) measure analgesiometer (Ugo Basile) in 3.5, and 4.5, 6.5 and 7.5 hours after injection Karenina (L.O. Randall &Selitto I.J., Arch. Int. Pharmacodyn. 111, 409-419, 1957).

Thermal hyperalgesia in rats induced by carageenan

Thermal hyperalgesia was assessed using the rat plantar test (Ugo Basile, Comerio, Italy), according to the method, the modified Hargreaves et al. (1988). Rats were habituated to the installation, consisting of three separate boxes of organic glass on the glass table. A movable source of infrared radiation disposed under the table and focused on the desired paw. Timeout otdergivanija paws was recorded three times for each rear l is p each animal, the average value which represents the initial level for the left and right hind paws. The setup was calibrated so that in normal rats, it showed a timeout otdergivanija paws approximately 10 seconds. To prevent damage to the tissue of the plantar area was cut-off point 22.5 seconds. Lambda carageenan were injected with vnutripolostno (100 μl, 20 mg/ml) in the right hind paw and record baseline timeout otdergivanija paws produced via the 2 h after injection.

Visceral pain

The potency of the compound in the treatment of visceral pain can be measured according to the following test protocols.

Several models are available for determining whether a compound is effective in the treatment of disorders of internal organs. These models include a model of LPS (Eutamene H et al, J Pharmacol Exp Ther 2000 295 (1): 162-7), the model of TNBS (L. Diop et al, Gastroenterology 1999, 116, 4(2): A986), the model of IBD (Clemett D, Markham A, Drugs 2000 Apr; 59(4):929-56), a model of a pain in the pancreas (Isia AM, Hosp Med 2000 Jun; 61(6):386-9) and the model of visceral pain, not related to the digestive system (M Boucher et al, J Urol 2000 Jul; 164(1):203-8).

Chronic visceral allodynia in rats induced by TNBS

In this experimental model stretching of the colon in awake rats pre-injection trinitrobenzenesulfonic acid (TNBS) in proximal the ing part of the colon was reduced threshold of visceral pain.

Materials and methods: Using male rats Sprague-Dawley. Animals are placed on a 3 cell under conditions controlled environment (20±1°C, humidity 50±5%, with lighting from 8:00 to 20:00). At day 0 under anesthesia (ketamine 80 mg/kg, administered intraperitoneally; acepromazine 12 mg/kg, administered intraperitoneally) in the proximal wall of the colon (1 cm from the caecum) carry out the injection of TNBS (50 mg/kg in 30%ethanol) or saline (1.5 ml/kg) for control rats. After surgery the animals are individually placed in polypropylene cages and kept in conditions controlled environment (20±1°C, humidity 50±5%, with lighting from 8:00 to 20:00) for 7 days. On the 7th day after administration of TNBS in the anus introducing a balloon catheter (with a length of 5-6 cm) and hold it in the correct position (the tip of the balloon catheter is located at a distance of 5 cm from the anal verge) by gluing catheter with tape to the base of the tail. Oral administration of the tested compounds is conducted for 1 hour to cycle stretching of the colon: a balloon catheter is gradually pumped up by steps of 5 mm Hg (0,667 kPa) 0 to 75 mm Hg (0 to 10 kPa), and each step of inflating lasts 30 seconds Each cycle of elongation of the colon is controlled by the standard barostat. Threshold (mm Hg) corresponds to a pressure that gives the first abdomi the material reduction, and then the cycle stretch break. The threshold for the colon was determined after four cycles stretching from the same animal.

Rectal hypersensitivity in rats induced by LPS

It was shown that intraperitoneally injection of bacterial lipopolysaccharide (LPS) induces in awake rats rectal hyperalgesia.

Materials and methods: Animals surgically prepared for electromyography: rats anaesthetize intraperitoneally injection of acepromazine (0.6 mg/kg) and ketamine (120 mg/kg). Three groups of three electrodes implanted in the external oblique abdominal muscles just above the inguinal ligament. The output electrodes on the back side of the neck and protects the glass tube attached to the skin. Animals are individually placed in polypropylene cages and kept in a room with controlled temperature (21°C). Feed (pellets UAR, Epinay, France) and water give without restrictions.

Electromyographic recordings begin in five days after surgery. The electrical activity of the abdominal striated muscle burn facility for electroencephalography (VIII Mini Alvar, Paris, France), using a short time constant (0.03 in) to remove low-frequency signals (less than 3 Hz) and the speed of movement of the paper tape 3.6 cm/min. Group of teeth recorded as the index of abdominal contractions.

Methods strain: Rats placed in plastic tunnels (6 cm diameter × 25 cm length), where they can't move to escape or be deployed in order to prevent damage to the balloon catheter. Animals are trained to do this procedure for four days prior to rectal distension in order to minimize the stress response during experiments. A balloon catheter used for stretching, is an arterial catheter for embolectomy (Fogarty, Edwards Laboratories Inc.). Rectal stretching is conducted by inserting a balloon catheter (2 mm in diameter × 2 cm) into the rectum at a distance of 1 cm from the anus, and the catheter is fixed at the base of the tail. It gradually filled with cool water in steps of 0.4 ml from 0 to 1.2 ml, each step of inflating takes 5 minutes To determine possible leakage amount of water introduced into the balloon catheter, check by complete removal of the syringe at the end of the period of extension.

The connection according to the invention can be entered separately or in combination with one or more than one drug. Usually it will be introduced in the form of a composition in Association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound from which bretania. The choice of excipient largely will depend on such factors as the specific route of administration, the effect of excipient on solubility and stability, and from the nature of the dosage form.

Suitable auxiliary active agents that can be used in combination with the compound of the present invention, include:

1) naturally occurring or synthetic prostaglandins or their esters. Suitable prostaglandins for use in this invention include such compounds as alprostadil, prostaglandin E1, prostaglandin E0, 13,14-dihydroprogesterone E1, prostaglandin E2proctinal, natural, synthetic and semi-synthetic prostaglandins and their derivatives, including those compounds which are described in WO-00033825 and/or US 6037346, issued March 14, 2000, which are all included in this description by reference, PGE0, PGE1, PGA1, PGB1, PGF1α, 19-hydroxy PGA1, 19-hydroxy PGB1, PGE2, PGB2, 19-hydroxy-PCA3, 19-hydroxy-PGB2, PGE3α, carboprost tromethamine, dinoprost tromethamine, dinoprostone, limaprost, gemeprost, metropost, sulprostone, tiaprost and moxicillin;

2) connection-antagonists, α-adrenergic receptors, also known as α-adrenoceptor or α-receptors or α-block is ora. Suitable compounds for use in this invention include antagonists, α-adrenergic receptors as described in PCT application WO 99/30697, published June 14, 1998, the description of which is related to α-adrenergic receptors, are included in this description by reference and include, selective blockers α1-adrenoceptors or α2-adrenoceptors and non-selective blockers of adrenoceptors, and appropriate blockers α1-adrenoceptors include phentolamine, fentolamina mesilate, trazodone, alfuzosin, indoramin, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efaroxan, yohimbine, rauwolfia alkaloids, Recordati 15/2739, SNAP 1069, SNAP 5089, RS17053, SL 89.0591, doxazosin, terazosin, abenaqui and prazosin; blockers α2antagonists of US 6037346 [March 14, 2000], dibenamine, tolazoline, trimazosin and dibenamine; α-adrenergic receptors, as described in U.S. patents: 4188390; 4026894; 3511836; 4315007; 3527761; 3997666; 2503059; 4703063; 3381009; 4252721 and 2599000, each of which are included in this description by reference; blockers α2-adrenoceptors include clonidine, papaverine, papaverine hydrochloride, possibly in the presence of kharitonenkov agent, such as pirkanen;

3) connection-NO donors (NO-agonists). Suitable connections-NO donors for use in this invention include organic is the cue nitrates, such as mono-, di - or trinitrate, or esters of organic nitrates, including glyceryltrinitrate (also known as nitroglycerin), isosorbide 5-Mononitrate of the isosorbide dinitrate treatment, pentaerythritol TETRANITRATE, erythrityl TETRANITRATE, sodium nitroprusside (SNP), 3-morpholinosydnonimine molsidomine, S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amylnitrate, linsidomine, linsidomine hydrochloride, (SIN-1) S-nitroso-N-cysteine, diazene diolate (NONOa), 1,5-pentanedinitrile, L-arginin, ginseng, fruit of sispi, molsidomin, Re-2047, nitrotoluene moxisylyte derivatives such as NMI-678-11 and NMI-937 as described in published PCT application WO 0012075;

4) substances that open potassium channels, or modulators of potassium channels. Suitable substances, opening potassium channels modulators of potassium channels for use in this invention include nicorandil, cromakalim, levcromakalim, imaclim, pinacidil, clutched, Minoxidil, charybtotoxin, gliburid, 4-aminopyridine, BaCl2;

5) vasodilators. Suitable drugs for use in this invention include nimodipin, pinacidil, cyclandelate, isoxsuprine, chlorpromazin, Rec 15/2739, trazodone;

6) agonist thromboxane A2;

7) CNS-active agents;

8) ergot alkaloids; suitable ergot alkaloids, are disclosed in PA is anti USA 6037346, issued March 14, 2000, and include acetylamino, brotherhood, bromargyrite, Lonergan, deligates, dealersin, ergonovine maleate, ergotamine tartrate, etiology, lergotrile, lysergide, mesulergine, metergoline, metergoline, nicergoline, pergolid, prepierced, procercoid and terguride;

9) compounds which modulate the action of natriuretic factors, specifically trialing natriuretic factor (also known as trially natriuretic peptide), natriuretic factors of type b and C, such as inhibitors of neutral endopeptidase;

10) compounds which inhibit angiotensin-converting enzyme, such as enapril and combined inhibitors of angiotensin-converting enzyme and neutral endopeptidase, such as omapatrilat;

11) receptor antagonists angiotensin such as losartan;

12) substrates for NO-synthase, such as L-arginine;

13) calcium channel blockers such as amlodipine;

14) antagonists endothelioma receptors and inhibitors of endothelin-converting enzyme;

15) agents that lower cholesterol, such as statins (e.g. atorvastatin/Lipitor-trademark) and fibrates;

16) antiplatelet and antithrombotic agents, such as tPA, uPA, warfarin, hirudin and other thrombin inhibitors, heparin, inhibitors of factor that activates tro is blastin;

17) insulin sensitizers, such as rezulin and hypoglycemic agents such as glipizide;

18) acetylcholinesterase inhibitors, such as donezepil;

19) steroid and non-steroid anti-inflammatory agents;

20) receptor modulators estrogen and/or estrogen agonists and/or estrogen antagonists, preferably raloxifene or lasofoxifene, (-)-CIS-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol and its pharmaceutically acceptable salts, which are described in detail in WO 96/21656;

21) inhibitor PDE (phosphodiesterase), more specifically an inhibitor of PDE 2, 3, 4, 5, 7, or 8, preferably the inhibitor of PDE2 or PDE5, and most preferably the PDE5 inhibitor (see below), and these inhibitors preferably have an IC50 against the respective enzyme of less than 100 nm (provided that inhibitors of PDE3 and 4 impose only topically or by injection into the penis);

22) vasoactive intestinal protein (VIP), VIP mimetic, analogue VIP, more particularly one, which is mediated by one or more than one subtype of receptor VIP VPAC1, VPAC or RACER (pituitary peptide that activates adenylate cyclase), one or more than one agonist of the receptor VIP or a VIP analogue (eg Ro-125-1553) or a VIP fragment, one or more than one antagonist α-adrenoceptor with a combination of VIP (for example, Invicorp, Aviptadil);

23) AG is NIST or modulator of receptor melanocortin (specifically the subtype MS or MS), or enhancer of melanocortin, such as Melanotan II, PT-14, PT-141 or compounds claimed in WO-09964002, WO-00074679, WO-09955679, WO-00105401, WO-00058361, WO-00114879, WO-00113112, WO-09954358;

24) agonist, antagonist or modulator of serotonin receptor, more particularly agonists, antagonists or modulators of receptors NTA (including VML 670), NTA, NTC, NT and/or NT, including those described in WO-09902159, WO-00002550 and/or WO-00028993;

25) the agent, the replacement testosterone (including dehydropiandrosterone), testosterone (Tostrelle), dihydrotestosterone or testosterone implant;

26) estrogen, estrogen? and medroxyprogesterone or medroxyprogesterone acetate (MPA) (i.e. as a combination), or the agent of hormone replacement therapy estrogen or methyltestosterone (for example, HRT, especially Premarin, Cenestin, Astrogemini, Equine, Estrus, Estrofem, Elleste Solo, Estring, Estraderm TTS, Estraderm matrix, Dermestril, Premphase, Prempro, Prempak, Premik, Estratest, Estratest HS, Tibolone);

27) a modulator of transporters of noradrenaline, dopamine and/or serotonin, such as bupropion, GW-320659;

28) agonist and/or modulators of purinergic receptor;

29) receptor antagonist neirokinina (NK)including antagonists described in WO-09964008;

30) agonist, antagonist or modulator of opioid receptor, preferably agonists of the receptor ORL-1;

31) agonist, antagonist or modulator Retz is Perov oxytocin, preferably selective agonist or modulator of oxytocin;

32) modulators of cannabinoid receptors;

33) inhibitor SEP (SEPi), for example SEPi with HK50less than 100 nm, more preferably less than 50 nm.

Preferably inhibitors SEP according to the present invention have more than 30-fold, more preferably more than 50-fold selectivity for SEP compared with neutral endopeptidase NEP EC 3.4.24.11 and angiotensin-converting enzyme (ACE). Preferably SEPi also has more than 100-fold selectivity in comparison with endothelin-converting enzyme (ECE);

34) antagonist or modulator of the receptor NPY (specifically subtypes Y1 and Y5);

35) antagonist or modulator globulin, sex hormone binding, which inhibits the binding of estrogens and/or androgens;

36) an inhibitor of arginase II;

37) agonist, antagonist or modulator of vasopressin receptors, preferably selective to the V1a receptor;

38) a PDE5 inhibitor. Suitable PDE5 inhibitors include:

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he (sildenafil), specifically sildenafil citrate;

(6R,12aR)-2,3,6,7,12,12A-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil);

2-[2-ethoxy-5-(4-ethylpiperazin-1-yl-1-sulfonyl)-phenyl]-5-IU the Il-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one (vardenafil); 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he; 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinol)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he; 5-[2 ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridine-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-he; 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidine-2-ylmethyl)pyrimidine-5-carboxamide (TA-1790); 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-α]pyrimidine-5-yl)-N-[2-(1-methylpyrrolidine-2-yl)ethyl]-4-propoxybenzaldehyde (DA 8159) and their pharmaceutically acceptable salts;

39) selective agonist of the dopamine receptor D4, such as 2-[(4-pyridine-2-reparation-1-yl)methyl]-1H-benzimidazole (EVT);

40) one or more than one selective inhibitor of serotonin reuptake (SSRIs), such as priligy generic, paroxetine, 3-[(dimethylamino)methyl]-4-[4-(methylsulfanyl)phenoxy]benzosulfimide (Example 28, WO 0172687), 3-[(dimethylamino)methyl]-4-[3-methyl-4-(methylsulfanyl)phenoxy]benzosulfimide (Example 12, WO 0218333), N-methyl-N-({3-[3-methyl-4-(methylsulfanyl)phenoxy]-4-pyridinyl}methyl)amine (Example 38, PCT application number PCT/1 V/01032);

41) one or more than one NEP inhibitor, preferably where this NEP is EC 3.4.24.11, and more preferably, where the specified NEP inhibitor is select the hydrated inhibitor EC 3.4.24.11, more preferably, a selective NEP inhibitor is a selective inhibitor for EC 3.4.24.11, which has IR50less than 100 nm (e.g compatriot, sampatrilat), suitable connections - NEP inhibitors are described in EP-A-1097719; values UK50in relation to NEP and ACE can be identified using the methods described in published patent application EP 1097719-A1, paragraphs [0368] to [0376];

42) agonists receptor melanocortin (for example, Melanotan II and RT) and selective agonists MS and MS (for example, THIQ);

43) inhibitors of the transport of monoamines, such as inhibitors of reuptake of noradrenaline (norepinephrine) (NRIs), including selective NRIs, such as reboxetine, either in its racemic (R,R/S,S)or optically pure (S,S) enantiomeric form, such as (S,S)-reboxetine).

Through here cross reference compounds contained in the patents and patent applications, which can be used according to the invention, the authors of this invention have in mind therapeutically active compound, as defined in the claims (specifically in paragraph 1) and in the specific examples (all of which are included in this description by reference). Patents and patent applications referred to above, incorporated into this description by reference.

If they combined the Oia active agents, then they can be administered simultaneously, separately or sequentially.

Pharmaceutical compositions suitable for delivery of the compounds of the present invention, and methods for their preparation will be obvious to the person skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington''s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), which is incorporated in this description by reference.

The connection according to the invention can be administered orally. Oral administration may include ingestion, so that the connection enters the gastrointestinal tract, and/or transbukkalno, lingual or sublingual introduction, through which the connection enters the bloodstream directly from the mouth.

Compositions suitable for oral administration include solid, semi-solid and liquid systems, such as tablets, soft or hard capsules containing drugs in the form of multi - or nanoparticles, liquid, semi-solid or solid matrix, or powder; tablets (including lozenges, fluid-filled); chewing gum; gels; quickly dispersible dosage form; films; ovule; sprays and intraoral/stick to mucous membranes patches.

Liquid compositions include suspensions, solutions, syrups and elixirs. Such compositions can be used as n is the fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), and they usually contain a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more than one emulsifier and/or suspendisse agent. Liquid compositions can also be obtained by dissolving solid substances, for example, from Sasha.

The compound of the present invention can also be used in the instant, rapidly decaying dosage forms, such as dosage forms described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 Liang and Chen (2001), which is incorporated in this description by reference.

As for the dosage forms as tablets, depending on the dose of the drug may be from 0.5% by mass to 80% by weight of the dosage form, more typically from 1% by mass to 60% by weight of the dosage form. In addition to drug tablets usually contain baking powder. Examples of disintegrating agents include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium-croscarmellose, crosspovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropylcellulose, substituted lower alkyl, starch, pregelatinized starch, and sodium alginate. Typically, the baking powder will be part of the best from 1 mass% to 25 mass%, preferably from 5% by mass to 20% by weight of the dosage form.

Binders are usually used to make tablets drug cohesive properties. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hypromellose. Tablets may also contain diluents, such as lactose (monohydrate monohydrate, spray dried, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and hydrogen phosphate dihydrate calcium.

Tablets also may contain surfactants such as sodium lauryl sulfate and Polysorbate 80, and moving materials, such as silicon dioxide and talc. Surface-active agents, when they are present, can be from 0.2% by mass to 5% by weight of the tablet, and sliding substances can range from 0.2 mass% to 1% by weight of the tablet.

Tablets also usually contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium fumarate and mixtures of magnesium stearate with sodium lauryl. Lubricants typically comprise from 0.25% by weight to 10% by the Assos, preferably from 0.5% by mass to 3% by weight of the tablet.

Other possible ingredients include antioxidants, dyes, corrigentov, preservatives and substances that corrects the taste.

Exemplary tablets contain up to about 80% of the medicinal product, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight of diluent, from about 2% by weight to about 10% by weight of baking powder and from about 0.25 per cent by weight to about 10% by weight of the lubricant.

Mixture for tablets can be pressed directly or with the aid of the cylinder to form tablets. Mixture for tablets or part mixtures, alternatively, can be pelletized wet, dry granulation or pelletizing by melting, by solidification of the melt or to squeeze out prior to pelletizing. The final product may contain one or more than one layer and may be covered or uncovered; it can even be encapsulated.

Getting the tablets discussed in Pharmaceutical Dosage Forms: Tablets, Vol.1, H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980), which is incorporated in this description by reference.

Fit for the consumption of oral films for human use or for veterinary use are usually flexible water soluble Il is swellable in water dosage forms in the form of thin films, which can be instant or stick to mucous membranes and usually contain a compound according to the invention, the polymer constituting the film, binder, solvent, humectant, plasticizer, stabilizer or emulsifier agent, viscosity modifier, and a solvent. Some components of this drug can perform more than one function.

The connection according to the invention can be water soluble or insoluble. Water-soluble compound typically contains from 0.5 mass% to 80 mass%, more typically from 20% by mass to 50% by weight of dissolved substances. Less soluble compounds can constitute a large proportion of the composition, typically up to 88% by weight of dissolved substances. Alternatively, the connection according to the invention can be in the form of beads of many particles.

The polymer constituting the film, you can choose from natural polysaccharides, proteins or synthetic hydrocolloids, and typically it is present in the range of from 0.01 to 99% by weight, more typically in the range of from 30 to 80 mass%.

Other possible ingredients include antioxidants, dyes, corrigentov and flavor enhancers and flavor, preservatives, agents for stimulating salivation, cooling agents, co-solvents (including oil), softeners, fillers, antifoaming agents, surface is surface-active substances and agents, correcting the taste.

The film according to this invention is usually obtained by evaporative drying of thin water films deposited on legkouswaivaemye substrate or paper. This can be done in a drying oven or tunnel kiln, usually in a combined device for coating/drying, or freeze-drying or vacuum.

Solid compositions for oral administration can be prepared for immediate and/or modified release. Composition with modified release include songs with slow, long, pulsed, controlled, targeted and programmed release.

A suitable composition with modified release for the purposes of this invention are described in U.S. patent No. 6106864. Details of other appropriate technologies release, such as high energy dispersions and osmotic and coated particles can be found in Pharmaceutical Technology On-line, 25(2), 1-14, Verma et al (2001), which is incorporated in this description by reference. The use of chewing gum to achieve a controlled release described in WO 00/35298, which is incorporated in this description by reference.

The connection according to the invention can also be entered directly into the blood stream, into muscle, or into the wall of the body. Suitable methods of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, vnutrigrudne, intracranial, intramuscular, intra-articular and subcutaneous administration. Suitable devices for parenteral administration include needle (including microhylinae) injectors, needleless injectors and equipment for infusion.

Parenteral compositions are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but for some applications they can be prepared in the form of the drug in a more suitable way as a sterile non-aqueous solution or as a dried form to be used in combination with a suitable carrier, such as sterile pyrogen-free water.

Receiving parenteral compositions in sterile conditions, for example by lyophilization, can be easily done using standard pharmaceutical techniques well known to specialists in this field.

The solubility of the compounds according to the invention, used in receiving parenteral solutions may be increased by the use of suitable methods of preparation, such as activating agents, the behavior is destructive solubility.

Compositions for parenteral administration can be prepared in the form of drugs with immediate and/or modified release. Composition with modified release include songs with slow, long, pulsed, controlled, targeted and programmed release. Thus, the connection according to the invention can be prepared in the form of the drug as a suspension or as a solid, semi-solid substance or thixotropic liquid for administration in the form of implanted depot providing modified release of the active compounds. Examples of such compositions include a covered drug stents and semi-solid substances and the suspension containing microspheres of poly(dl-lactic-coglycolide) acid (PGLA), loaded drug.

The connection according to the invention can also be entered topically, (intra)dermal or transdermal skin or mucous membrane. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. You can also use liposomes. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol and propylenglycol the ü. The composition can be incorporated amplifiers permeability - see, for example, J. Pharm. Sci., 88 (10), 955-958, Finnin and Morgan (October 1999), which is incorporated in this description by reference.

Other ways local injection include shipping elecrophoresis, iontophoresis, phonophoresis, sonophoresis and microholes or needleless (such as PowderjectTM, BiojectTMand so on) injection.

Compositions for local injection can be prepared in the form of drugs with immediate and/or modified release. Composition with modified release include songs with slow, long, pulsed, controlled, targeted and programmed release.

The connection according to the invention can also be entered intranasally or by inhalation, typically in the form of a dry powder (either one, in the form of a mixture, for example in a dry blend with lactose, or in the form of particles of mixed components, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to obtain fine droplets) or a nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetraf aratan or 1,1,1,2,3,3,3-Heptafluoropropane, or in the form of nasal drops. As for intranasal use, the powder may contain bioadhesive agent such as chitosan or a cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) according to the invention, containing, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilization, or extending release of the active agent, the propellant(s) as solvent and possibly surface-active substance, such as sarbatorile, oleic acid or oligobrachia acid.

Before using the drug in the form of a dry powder or suspension of the medicinal product micronizer to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable grinding method, such as grinding in a spiral jet mill, jet mill, fluidized bed, the supercritical processing fluid to obtain nanoparticles, homogenization under high pressure or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator can be prepared in the form of a drug that contains powder, see the camping compounds according to the invention, a suitable powder base such as lactose or starch, and modifier efficiency, such as I-leucine, mannitol, or magnesium stearate. Lactose may be anhydrous or may be in the form of a monohydrate, preferably in the last form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable composition is in the form of a solution for use in a spray bottle using electrohydrodynamics to obtain small droplets may contain from 1 μg to 20 mg of the compounds according to the invention in one click, and volume when triggered, may vary from 1 μl to 100 μl. A typical composition may contain the compound according to the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

In the compositions according to the invention, which are intended for inhalation/intranasal, may be added suitable corrigentov, such as menthol and levomenthol, or sweeteners, such as saccharin and sodium saccharin.

Compositions for inhalation/intranasal can be prepared in the form of drugs with immediate and/or modified release using, for example, the R, PGLA. Composition with modified release include songs with slow, long, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols unit dosage to be installed using a valve that delivers a measured amount. Unit according to this invention is usually set to introduce a metered dose or "zilch", containing the compound according to the invention.

The connection according to this invention it is possible to enter rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppozitornyj basis, but how appropriate it is possible to use various alternatives.

Compositions for rectal/vaginal injection can be prepared in the form of drugs with immediate and/or modified release. Composition with modified release include songs with slow, long, pulsed, controlled, targeted and programmed release.

The connection according to this invention can also be entered directly in the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH adjusted sterile saline. Other songs that fit the La eye and ear introduction, include ointments, gels, biodegradable (for example, suction gel sponges, collagen) and nonbiodegradable (e.g., silicone) implants, wafers, lenses and systems of particles or vesicles, such as Nozomi or liposomes. The composition may include a polymer, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymer, such as hypromellose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymer, for example Galanova gum, together with a preservative, such as benzalkonium chloride. Such compositions can also be delivered by iontophoresis. Composition for eye/ear injection can be prepared in the form of drugs with immediate and/or modified release. Composition with modified release include songs with slow, long, pulsed, controlled, targeted and programmed release.

The connection according to the invention may be combined with soluble macromolecular substances, such as cyclodextrin and suitable derivatives or polymers containing polyethylene glycol, to improve its solubility, dissolution rate, correct taste, improve the bioavailability and/or stability for use in any of the above methods in which edenia.

Detected, for example, that the complexes of the drug-cyclodextrin are generally useful for most dosage forms and routes of administration. Can be used as inclusion complexes, and complexes, non-inclusion complexes. Alternatively, the direct formation of the complex with the drug cyclodextrin can be used as an auxiliary additive, that is, a carrier, a diluent or a solubilizer. Most often used for these purposes are alpha-, beta - and gamma-cyclodextrins, examples of which can be found in international patent application no WO 91/11172, WO 94/02518 and WO 98/55148, which are included in this description by reference.

Since it may be desirable introduction the combination of active compounds, for example, for treating a particular disease or condition within the scope of the present invention is that two or more than two pharmaceutical compositions, at least one of which contains a compound according to this invention, can be combined in the form of a kit suitable for joint introduction of these compositions.

Thus, a set of this invention contains two or more than two separate pharmaceutical compositions, at least one of which contains Obedinenie according to the invention, and means for the separate storage of such compositions, such as a container, divided bottle, or divided foil pack. An example of such a set is the usual blister pack, used for packing tablets, capsules and the like.

Set according to the invention is particularly suitable for the introduction of different dosage forms, such as oral and parenteral administration of separate compositions with different dosage intervals, or for the titration of individual compositions relative to each other. To promote adherence and regimen, this set typically contains instructions for insertion and can be equipped with so-called memo.

Description of graphic materials

1

Isothermal gravimetric analysis 5-[(2R,5S)-5-methyl-4-propylmercaptan-2-yl]pyridine-2-amine di-S-camsylate monohydrate in 40, 45, 80 and 85°C. the Material is kept at the selected temperature with a stream of nitrogen having a relative humidity of 0%. Salt of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate dehydratases at 85°C at a relative humidity of 0%. Many hydrates would be lost at 30°C/relative humidity is 0%.

2

Sorption of water 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate at 30°C. the Adsorption at a relative humidity of 90% is 0,316% (the AC./wt.) by weight in the dry state. This value refers to the unbound water and, in addition, to the water included in the crystal lattice.

3

Comparison of water sorption 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate, free base, di-D-tartrate and hydrobromide salt at 30°C.

4

Simulated picture of the x-ray diffraction on the powder for 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate.

5

The actual picture of the x-ray diffraction on the powder for 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate.

6

thermogram of DSC (differential scanning calorimetry) for 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate.

Experimental section

Differential scanning calorimetry (DSC): Differential scanning calorimetry was performed using the installation Perkin Elmer Diamond DSC, aluminum cups with holes and lids. Approximately 3 mg of sample was heated at 20°C per minute in the range from 30 to 250°C by blowing nitrogen gas.

Thermogravimetric analysis (TGA): Used plant model 2950, manufactured by TA Instruments. Approximately 8 mg of the sample was kept at a temperature analysis in an open Cup under the stream of nitrogen with a relative wet the STU 0% for at least 30 minutes The results are an indication of the kinetic stability of the hydrate over a period of time when the sample was exposed to.

Dynamic vapor sorption (DSP): Used automatic analyzer sorption models DVS-1, manufactured by Surface measurement Systems Ltd. UK. Solid (10-20 mg) were subjected to controlled environment relative humidity (% relative humidity) and record the change in mass over time. Humidity speed changed from relative humidity 0 to 90 and back to 0% with intervals of 15%relative humidity. In this way at each value of moisture you can reach speeds of sorption of 0.0005%/min prior to exposure to the following humidity values. When the sample is blurring due to moisture absorption, equilibrium sorption is achieved not always.

Digrazia x-rays on the powder Pattern x-ray diffraction on powder were obtained using a diffractometer x-ray powder Bruker-AXS Ltd. D5000, equipped with automatic device for changing samples, theta theta a goniometer, automatic slots for the divergence of the beam, a secondary monochromator and a scintillation counter. The sample analyzed in the form of a layer of powder on the holder for the sample in the form of a silicon wafer. The sample was rotated during irradiation of copper To al the and 1x-rays (wavelength =1,5406 angstroms) x-ray tube operating at 40 kV/40 mA. This analysis was performed with the goniometer running in continuous mode set to 5 seconds at a step of 0.02° for the interval in two theta from 2° to 55°.

The peaks obtained for 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate, compared with peaks from the calculated pattern from the structure of the single crystal.

Angles 2-theta, and relative intensity of the simulated diffraction pattern for the powder was calculated from the structure of the single crystal, using the module "Reflex Powder Diffraction" Accelrys Materials StudioTM[version 2.2]. Suitable simulation parameters in each case consisted of:

Wavelength =1,540562 E (si α),

The polarization factor =0,5,

Pseudomotor Vogt (U-Value=0.01, V=-0,001, W=0,002).

As will be clear to the specialist, the relative intensity of different peaks in the tables below may vary due to a number of factors, such as, for example, the effects of orientation of crystals in the x-ray beam or purity of the analyzed material, or the level of crystallinity of the sample. The position of the peaks can also shift due to changes in the height of the sample, but the position of peaks essentially remain the same as defined in the following tables.

The specialist will also realize that change is possible with the use of different wavelengths will result in different shifts according to the Bragg equation - nλ=2d sin θ.

Such additional picture of the x-ray diffraction on the powder generated by use of alternative wavelengths are considered to be alternative representations of paintings by x-ray diffraction on the powder of crystalline compounds of the present invention, and, as such, they are within the scope of the present invention.

The connection according to this invention can be synthesized according to the procedures below. When obtaining carried out at different scales, given appropriate ways to perform synthesis of a large and small scale. Uses the following abbreviations and definitions:

TWOtertiary-butyl methyl ether
DCMDichloromethane
IPAIsopropyl alcohol
m/zthe peak of the mass spectrum
HClHydrochloric acid
NaOHSodium hydroxide
MSMass spectrum
mMu is tiplet
qQuartet
sThe singlet
tTriplet
brWide
kgPounds
lLiter
ggrams
CDCl3deuterated chloroform
ppmparts per million million-1.

NMR spectra were obtained using a spectrometer Varian Inova 300 MHz, dissolving the sample in a suitable solvent.

Mass spectra were obtained using LC-MS (liquid chromatography - mass spectrometry), consisting of a system of HPLC (high performance liquid chromatography) Thermo-Finnigan Surveyor in combination with a mass spectrometer with an ion trap Thermo Finnigan LCQ.

5-Bromo-2-(2,5-dimethylpyrrole-1-yl)pyridine

2-Amino-5-bromopyridin (6.0 kg, 34,7 mol), 2,5-hexandione (4,35 kg, 38,2 mol) and p-toluensulfonate acid (12 g) was dissolved in heptane (36 l) and boiled under reflux overnight under conditions of Dean-stark Dean Stark). The equipment was installed for the distillation, and heptane (18 l) was removed by distillation. This mixture was cooled to 20°C for 60 minutes. Added seed crystals and grained mixture at 20°C for 2 hours and then at 5°C during the night. The product was collected by filtration, washed with heptane (2×6 l) and dried at 45°C under vacuum overnight. Yield =80% (7,0 kg) δn(CDCl3300 MHz) 2.20 (6N, s), 5.95 (2H, s), 7.15 (1H, d), 7.95 (1H, d), 8.70 (1H, s) mn-1. MS m/z 253 (MH+the isotope VG).

2-Chloro-1-[6-(2,5-dimethylpyrrole-1-yl)pyridine-3-yl]alanon

A solution of 5-bromo-2-(2,5-dimethylpyrrole-1-yl)pyridine (1.00 kg, 3,98 mol) in TWO (7.5 l) was cooled to -70°C. was Added dropwise n-utility (2.5 n in hexane; 1,73 l, 4,32 mol) over 1 hour, maintaining the temperature of -74°-69°C. and Then stirred the mixture at a temperature of -74°-69°C for an additional 15 minutes. Then was added dropwise a solution of 2-chloro-N-methoxy-N-methylacetamide (0.65 kg, 4,72 mol) in TWO (3.0 litre) for 100 minutes, maintaining the temperature of -73°C to -67°C. the Resulting mixture was then stirred at temperatures from -73°C to -67°C for an additional 100 minutes. Then added dropwise within 45 minutes 2 n HCl (5.0 l), allowing the temperature to rise during the addition of from -70°C to 17°C. was Added to the resulting suspension, TWO (4.0 l) and water (2.0 l) and stirred Yes what percent of the mixture before giving the phases to separate. The organic layer was washed with water (2.0 l), aqueous NaHCO3(0,13 kg 2.0 l of water) and water (2.0 l) before concentrating under vacuum. Was added to the residue IPA (1.50 l) and the mixture was heated to the temperature of reflux distilled. Then gave the mixture to cool to room temperature and stirred it overnight before cooling to 8-12°C for 1 hour. The product was collected by filtration, washed with IPA (2×0.1 l) and dried at 45°C under vacuum overnight. The yield of 78.8% (0,78 kg), δn(CDCl3, 300 MHz) 2.20 (6N, s), 4.70 (2H, s), 5.95 (2H, s), 7.35 (1H, d), 8.40 (1H, dd), 9.15 (1H, d) mn-1. MS m/z 249 (MN+)

2-(2,5-Dimethylpyrrole-1-yl)-5-oxiranylmethyl

To a suspension of sodium borohydride (0.17 kg, 4,36 mol) in 1,4-dioxane (of 6.49 l) was added dropwise water (1.08 kg) at 16°C and the resulting solution was stirred at room temperature. Added over 1 hour a solution of 2-chloro-1-[6-(2,5-dimethylpyrrole-1-yl)pyridine-3-yl]ethanone (1,08 kg, 4.35 mol) in tetrahydrofuran (2,16 l) and the resulting solution was stirred at room temperature for 45 minutes. When I spent the entire 2-chloro-1-[6-(2,5-dimethylpyrrole-1-yl)pyridine-3-yl]Etalon, the reaction mixture was cooled to 19°C and treated with concentrated HCl (36% wt./wt.) (1.08 l) for 40 minutes. This mixture was cooled to 11°C and was added NaOH (32% wt./wt.) (1,64 l) for 45 minutes, keeping the temperature less than the 25°C. Then gave the mixture to granulomatosa at room temperature over night. When all harpertown intermediate connection was spent, was added DCM (5.0 l) and water (5.0 l) and stirred the mixture before giving the phases to separate. The aqueous phase was extracted with DCM (2,50 l) and the combined organic phases were washed with water (2×1.0 l) and then concentrated under vacuum. Exit 98% (0,92 kg) δn(CDCl3, 300 MHz) 2.10 (6N, s), 2.90 (1H, dd), 3.25 (1H, dd), 4.00 (1H, dd), 5.90 (2H, s), 7.20 (1H, d), 7.70 (1H, dd), 8.40 (1H, d) mn-1MS m/z 215 (MN+).

(2S)-2-[{(RS)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine-3-yl]-2-hydroxyethyl}propylamino]propane-1-ol

A mixture of 2-(2,5-dimethylpyrrole-1-yl)-5-oxiranylmethyl (0.65 kg, totaling 3.04 mol), (S)-(+)-2-amino-1-propanol (0.30 kg, 3.95 mol) in toluene (6,50 l) was heated to the temperature of reflux distilled during the night. The reaction mixture was cooled to room temperature, was added DCM (6.5 liters) and water (1,30 l) and gave the phases to separate. Was added to the organic layer triacetoxyborohydride sodium (0.96 kg, 4,56 mol) followed by the addition dropwise of Propionaldehyde (0,48 l, of 6.68 mol) and glacial acetic acid (0.17 l, totaling 3.04 mol), keeping the temperature below 30°C. the Reaction mixture was stirred at room temperature for 1 hour before quenching with water (1.20 l) and an aqueous solution of potassium carbonate (1.00 kg in 3,23 kg of water) and gave phases will share the camping. The aqueous phase was extracted with DCM (1.20 l) and the combined organic phases were washed with water (0,60 l), water (0.30 liter) and concentrated in vacuum. Yield 89% (0.89 kg, this substance was isolated with a purity of approximately 70%) δn(CDCl3, 300 MHz) 0.8-1.0 (6N, m), 1.50-1.70 (2H, m), 2.10 (6N, s), 2.50-3.15 (5H, m), 3.50 (2H, dd), 4.80 (1H, dd), 5.90 (2H, s), 7.20 (1H, m), 7.80-7.90 (1H, m), 8.60 (1H, m) million-1. MS m/z 332 (MN+). Intermediate amine compound was characterized as δn(CDCl3, 300 MHz) 1.10 (3H, t), 2.10 (6N, s), 2.7-3.2 (3H, m), 3.45 (1H, m), 3.70 (H, dd), 4.85 (1H, m), 5.90 (2H, s), 7.20 (1H, d), 7.90 (1H, dd), 8.60 (1H, d) mn-1. MS m/z 290 (MH+).

(2S)-2-[{(RS)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine-3-yl]-2-hydroxyethyl}amino]propan-1-ol

Water (15,0 l) was added to a suspension of sodium borohydride (4,11 kg, 109 mol) in tetrahydrofuran (140 l) at 15°C and the resulting solution was stirred at 15°C. was Added over 40 minutes a solution of 2-chloro-1-[6-(2,5-dimethylpyrrole-1-yl)pyridine-3-yl]ethanone (30.0 kg, 120,6 mol) in tetrahydrofuran (100 l) and water (15 l), keeping the temperature below 30°C. the Resulting solution was stirred for 60 minutes at 15°C. When he spent the entire 2-chloro-1-[6-(2,5-dimethylpyrrole-1-yl)pyridine-3-yl]Etalon, the reaction mixture was treated with concentrated HCl (27% wt./wt., 47 kg) for 80 minutes, keeping the temperature below 30°C. the Mixture was cooled to 15°C and was added NaOH (34% wt./wt., 79 kg) within 60 mi the ut, maintaining the temperature below 30°C. This mixture was then granulated at 20°C during the night. When I spent all harpertown intermediate connecting, separating the aqueous phase. Added DCM (150 l) and water (140 l) and stirred the mixture before giving the phases to separate. The organic phase is washed with water (2×30 l). Was added over 20 minutes (S)-(+)-2-amino-1-propanol (17,2 kg, 229 mol) and tetrahydrofuran (15 l). Installed equipment for distillation and DCM was replaced with tetrahydrofuran to obtain a final volume of 160 liters. The reaction mixture was left at the temperature of reflux distilled at night. After cooling to room temperature was added DCM (150 l) and the mixture was washed with water (3×30 l). Installed equipment for distillation and tetrahydrofuran, and DCM was replaced with acetonitrile to obtain a final volume of 84 liters. Were added within 60 minutes ααα-triptorelin (300 l), the mixture was cooled to 5°C for 8 hours and was granulated at 5°C for 6 hours. The product was collected by filtration, washed ααα-CryptoStream (2×30 l) and dried at 45°C under vacuum overnight. Yield = 65% (22.7 kg) δn(CDCl3, 300 MHz) 1.10 (3H, t), 2.10 (6N, s), 2.7-3.2 (3H, m), 3.45 (1H, m), 3.70 (H, dd), 4.85 (1H, m), 5.90 (2H, s), 7.20 (1H, d), 7.90 (1H, dd), 8.60 (1H, d) mn-1MC m/z 290 (MH+). Intermediate epoxy compound described as δn(CDCl3, 300 MHz) 2.10 (6N, s), 2.90 (1H, dd), 3.25 (1H, dd), 4.00 (1H, d), 5.90 (2H, s), 7.20 (1H, d), 7.70 (1H, dd), 8.40 (1H, d) mn-1MC m/z 215 (MN+).

(2S)-2-[{(RS)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine-3-yl]-2-hydroxyethyl} propylamino]propane-1-ol

Propionic aldehyde (5,02 kg, 86,4 mol) for 10 minutes was added to a solution of (2S)-2-[{(RS)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine-3-yl]-2-hydroxyethyl}amino]propan-1-ol (22,7 kg, 78,6 mol) in DCM (123 l) at 20°C. the Resulting solution was stirred at 20°C for 2 hours and then gave it to him to settle before adding it to a suspension of triacetoxyborohydride sodium (25,8 kg, 122 mol) in DCM (123 l) for 90 minutes, keeping the temperature below 30°C. the Reaction mixture was stirred at 20°C for 1 hour before quenching with an aqueous solution of potassium carbonate (36,4 kg 136 l of water) and gave the phases to separate. The organic phase is washed with water (2×23 l). Installed equipment for distillation and removed DCM (190 l) by distillation to obtain a final volume of 45 liters. This mixture was cooled to 20°C. the Output is 100% (51,1 kg, 50,9% wt./wt. in DCM). δn(CDCl3, 300 MHz) 0.8-1.0 (6N, m), 1.50-1.70 (2H, m), 2.10 (6N, s), 2.50-3.15 (5H, m), 3.50 (2H, dd), 4.80 (1H, dd), 5.90 (2H, s), 7.20 (1H, m), 7.80-7.90 (1 H, m), 8.60 (1 H, m) million-1. MS m/z 332 (MH+).

(2S)-2-[{(RS)-2-[6-aminopyridine-3-yl)-2-hydroxyethyl}(propyl)amino]propan-1-ol

(2S)-2-[{(RS)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine-3-yl]-2-hydroxyethyl}propylamino]propane-1-the l (0.90 kg, a 2.71 mol), hydroxylamine hydrochloride (0,56 kg, 8,05 mol), ethanol (5,20 l) and water (0.45 l) were combined and heated to the temperature of reflux distilled during the night. The reaction mixture was cooled to room temperature and concentrated in vacuum. Was added water (1.50 l) and cooled suspension of up to 5°C. the Resulting suspension was added in portions to a mixture of concentrated HCl (36% wt./wt., 0.25 l) and water (3,10 l). Added DCM (1,00 l) and gave the phases to separate. The aqueous phase washed with DCM (2×0,40 l) before merging with DCM (1,60 l) and alkalinization of 10 n NaOH (1,45 l). After separation of the phases the aqueous phase was extracted with DCM (1,60 l) and the combined organic phase was washed with NaOH 1.4 n (0,70 l), NaOH 0,9 n (0,55 l), water (0,50 l), water (0.25 l) and concentrated in vacuum. Yield 87% (0,55 kg).

United (2S)-2-[{(R,S)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine-3-yl]-2-hydroxyethyl}propylamino]propane-1-ol (51,1 kg, 50,9% wt./wt. in DCM, 78.5 per mol), hydroxylamine hydrochloride (16,4 kg, 236 mol), sodium bicarbonate (3,30 kg, 39,3 mol) and ethanol (136 l). Installed equipment for distillation and replaced DCM ethanol to obtain a final volume of 130 litres. The reaction mixture was cooled to room temperature and kept overnight at this temperature. The reaction mixture was heated to the temperature of reflux distilled and was stirred for 10.5 hours at the temperature of reflux distilled before cooling to room temperature. The mustache is enableval equipment for vacuum distillation and ethanol was replaced with water to obtain a final volume of 120 liters. This mixture was cooled to room temperature and granulated during the night. The side product was isolated by filtration and washed with water (13 l). The filtrate was acidified with HCl (22% wt./wt., 13.2 kg) and washed with DCM (3×26 l) before merging with DCM (78 l), water (39 l) and alkalinization of NaOH (40% wt./wt., 38,7 kg). After separation of the phases the aqueous phase was extracted with DCM (52 l) and the combined organic phase was washed with NaOH (4,4% wt./wt., 14,6 kg) and water (2×9 l). Yield 93% (196,3 kg, 9.5% wt./wt. in DCM).

δn(CDCl3, 300 MHz), 0.85 (3H, t), 0.95 (3H, m), 1.40-1.60 (2H, m), 2.40-2.80 (4H, m), 2.95-3.10 (1H, m), 3.40 (1H, d), 3.45 (1H, d), 4.45 (2H, br), 4.55 (1H, m), 6.50 (1H, d), 7.45 (1H, d), 8.00 (1H, s) mn-1. MS m/z 254 (MH+).

5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine (Compound a) and

5-[(2S,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine (Compound B)

A solution of (2S)-2-[{(2RS)-2-[6-aminopyridine-3-yl)-2-hydroxyethyl}(propyl)amino]propan-1-ol (0.50 kg, 1.97 mol) in DCM (1.0 l) was added in portions to concentrated sulfuric acid (98% wt./mass.) (1,10 l), keeping the temperature below 25°C. This mixture was stirred at room temperature for 1 hour and then cooled to a temperature of from 5°s to 10°C. was Added dropwise water (2.0 l) and gave the phases to separate. The aqueous phase washed with DCM (0.5 l) and then was added dropwise to a solution of NaOH (1,71 kg) in water (11,0 l). Added DCM (1.5 l) and gave the phases to separate. Water the second phase was extracted with DCM (0.5 l) and the combined organic phase was washed with water (0.5 l), water (2×0.25 l) and concentrated in vacuum. Yield 82% (0.38 kg).

(2S)-2-[{(2RS)-2-[6-aminopyridine-3-yl)-2-hydroxyethyl}(propyl)amino] propan-1-ol in DCM (9,04% wt./wt., 340,6 kg, 122 mol) was added over 3.5 hours to concentrated sulfuric acid (98% wt./wt., 119,4 kg, 1217 mol), keeping the temperature below 30°C. This mixture was stirred at room temperature for 1 hour and then cooled to 5°C. was Added water (145 l) for 2 hours, keeping the temperature below 30°C, and gave the phases to separate. To the aqueous phase for 2 hours was added DCM (92 l) and aqueous ammonia (35% wt./wt., 130 kg, 2678 mol), keeping the temperature below 30°C. After separation of the phases the aqueous phase was extracted with DCM (31 l) and the combined organic phase was washed with water (2×16 l). Installed equipment for distillation and DCM was replaced with acetone to obtain a final volume of 120 liters. The yield of 92.5% (123,3 kg 21,5% wt./wt. in acetone).

δn(CDCl3, 300 MHz), 0.85 (3H, 2t), 1.00 (3H×0.45, d, diastereoisomer A), 1.10 (3H×0.55, d, diastereoisomer B) 1.40-1.60 (2H, m), 2.20-2.90 (5H, m), 3.30-3.90 (2H, m), 4.20 (2H, br), 4.20-4.30 (1H, m), 6.50 (1H, m), 7.45 (1H, m), 8.05 (1H, m) million-1. MS m/z 236 (MN+).

The ratio of diastereoisomers and diastereoisomer B determine the 1 H-NMR after measurement of the ratio of the signals δn1.00 million-1and δn1.10 million-1.

5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine, di((1S)-10-campers lifenet)monohydrate

To a solution of 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine and 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine (2,62 kg, 11.1 mol) in acetone (31,4 l) solution was added (1S)-10-camphorsulfonic acid (5,11 kg 22,0 mol) in water (2,29 l) and acetone (5,24 l). This solution was stirred at 20°C for 15 minutes, was added seed crystals and grained mixture at 20°C during the night. The product was collected by filtration, washed with acetone (2×2.6 liters) and dried at 40°C under vacuum overnight. Exit 34% (2,71 kg).

To a solution of 5-[(2S,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine and 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine (143,7 kg 21,5% wt./wt. in acetone, 131 mol) in acetone (343 l) solution was added (1S)-10-camphorsulfonic acid (63,3 kg, 256 mol) in water (24 l). This solution was stirred at 20°C for 15 minutes, was added seed crystals and grained mixture at 20°C during the night. The product was collected by filtration, washed with acetone (62 l) and dried at 45°C under vacuum overnight. The output of 37.8% (35,6 kg).

δn(CDCl3, 300 MHz) 0.7 (6N, s), 0.9 (3H, t), 1.05 (6H, s), 1.2-1.35 (7H, m), 1.5-1.75 (2H, m), 1.8 (2H, d), 1.8-1.9 (2H, m), 1.95 (2H, m), 2.25 (2H, m), 2.40 (2H, d), 2.55-2.7 (2H, m), 2.90 (2H, d), 2.95-3.35 (5H, m), 3.65 (1H, m), 4.10 (1H, m), 4.7 (1H, m), 7.0 (1H, d), 7.95 (2H, m), 8.15 (2H, br), 9.8 (2H, br) million-1. MS m/z 236 (MH+).

The characteristic peaks of the x-ray diffraction on powder israsena pattern for 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate

The main characteristic peaks;

Angle 2-Theta (Degrees)Intensity (%)Angle 2-Theta (Degrees)Intensity (%)
6,327,317,69,9
10,975,918,015,9
12,318,318,815,4
a 12.710,719,329,6
14,015,021,713,5
14.4V10,2of 21.925,9
15,1100,022,432,2
16,368,823,235,0
16,4 28,023,520,4
16,622,125,69,4
the 17.331,627,98,5

The characteristic peaks of the x-ray diffraction on the powder for 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate

Angle 2-Theta (Degrees)Intensity (%)Angle 2-Theta (Degrees)Intensity (%)
6,390,625,6100,0
10,96,127,215,8
a 12.798,328,57,6
14,023,132,36,1
15,158,434,7 the 9.7
16,323,638,78,8
the 17.312,439,710,5
19,17,139,86,0
19,824,541,17,1
21,75,846,910,5
23,210,247,06,0

1. 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate:

or its monohydrate.

2. Monohydrate according to claim 1, having a main characteristic peaks in the picture x-ray diffraction on the powder generated using copper K-alpha1x-rays (wavelength equal 1,54056 Å)comprising 6,3, 12,7, 15,1,, 16.3 and 25.6 degrees 2θ.

3. Pharmaceutical composition having activity against receptor dopamine D3 containing 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate Il is its monohydrate and a pharmaceutically acceptable diluent or carrier.

4. The pharmaceutical composition according to claim 3, where 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate is in the form of a monohydrate.

5. The compound according to any one of claims 1 and 2 for use in medicine.

6. The use of compounds according to any one of claims 1 and 2 in the preparation of drugs for the treatment of sexual dysfunction.

7. The use according to claim 6, where sexual dysfunction is a male erectile dysfunction or female sexual dysfunction.

8. The use of compounds according to any one of claims 1 and 2 in preparation of medicines for the treatment of neuropsychiatric disorders or neurodegenerative disorders.

9. The way to obtain 5-[(2R,5S)-5-methyl-4-propylparaben-2-yl]pyridine-2-amine di-S-camsylate monohydrate, including interaction of the compounds of formula (X)

with (1S)-10-camphorsulfonic acid in a suitable solvent.

10. The method according to claim 9, where the solvent is acetone/water.

11. The compound of formula (VII)

and its pharmaceutically acceptable salt and solvate.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenylalanine derivatives and their pharmaceutically acceptable salts. In formula (1) R11 is a hydroxyl group, an alkoxyl group having 1-6 carbon atoms, which can be substituted with a methoxy group, cycloalkoxyl group having 3-6 carbon atoms, or a benzyloxy group; R12 and R13 each independently represents a hydrogen atom, alkyl group having 1-6 carbon atoms, cycloalkyl group having 3-6 carbon atoms, acetyl group or methyloxycarbonyl group, or N(R12)R13 is a 1-pyrrolidinyl group, 1-piperidinyl group, 4-morpholinyl group; R14 is a methyl group; R1' is a hydrogen atom, fluorine atom; X1 is -CH(R1a)-, -CH(R1a)CH(R1b)-, -CH(R1a)CH(R1b)CH(R1c)-, -N(R1a)CH(R1b)CH(R1c)-, -OCH(R1a)CH(R1b)-, -OCH(R1a)CH(R1b)CH(R1c)- or 1,3-pyrrolidinylene, where R1a, R1b, each independently represents a hydrogen atom or a methyl group, and R1c is a hydrogen atom; Y11 and Y12 represent any of the combinations (CI, Cl), (CI, Me), (CI, F). Invention also relates to phenylalanine derivatives of formulae (2)-(14), given in the formula of invention.

EFFECT: obtaining a pharmaceutical composition having antagonistic effect on α4-integrin, containing a phenylalanine derivative as an active ingredient, a α4-integrin antagonist and a therapeutic agent.

65 cl, 51 tbl, 244 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

Mif inhibitors // 2383541

FIELD: chemistry.

SUBSTANCE: there is described compound of formula 1

where R1 represents unsubstituted or substituted (C3-C8)cycloalkyl(C1-C4)alkyl, phenyl(C1-C4)alkyl, (C3-C8)cycloalkyl, phenyl, naphthyl, phenyl condensed with 18-(crown)-6, where substitutes include phenyl, halogen, hydroxy, aminosulfonyloxy, (C1-C4)alkoxy, tri(C1-C6)alkylsilyloxy, halogen(C1-C4)alkyl or halogen(C1-C4)alkoxy, R2 represents hydrogen, hydroxyl, aminosulfonyloxy, (C1-C4)alkoxy, tri(C1-C6)alkylsilyloxy or halogen(C1-C4)alkoxy. Also described is use of the compound for making a medicinal agent and a pharmaceutical composition.

EFFECT: disclosed compounds have macrophage migration inhibitory factor activity (MIF).

8 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

where R1 is hydrogen, alkyl, cycloalkyl, hydroxy group, hydroxyalkyl, alkoxy group, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, alkylsulfonyl, alkylsulfanyl, alkylcarbonylalkyl, alkylcarbonyloxyalkyl, aminocarbonylalkyl, heterocyclylcarbonylalkyl, alkoxycarbonylalkyl, alkoxyalkylaminocarbonylalkyl, cycloalkylalkoxyalkyl, arylalkyloxyalkyl, aryloxyalkyl, haloidalkyl, haloidalkoxy group or haloidalkoxyalkyl, R2 is hydrogen, alkyl, cycloalkylalkoxyalkyl, alkoxyalkyl, arylalkoxyalkyl, haloidalkoxyalkyl, pyrrolidyl, morpholinyl, thiomorpholinyl, arylalkyl, arylalkoxy group, aryloxy group or heterocyclylalkyl, R3 is hydrogen or alkyl, R4 is hydrogen, alkyl or haloid, R5 is phenyl, naphthyl, piperidyl or 1,2,3,4-tetrahydroisoquinolinyl optionally substituted with one or more substitutes independently selected from alkyl, cycloalkyl, haloid, alkoxy group, nitro group, trifluoromethyl, trifluoromethoxy group, trifluoromethylcarbonyl group, aryl, aryloxy group, alkoxycarbonylalkoxy group and alkylsulfonyl, R6 is hydrogen or alkyl, and their pharmaceutically acceptable salts and esters, under the condition that N-(6-(1,1-dimethylethyl)-2-pyridinyl)-4-methylbenzenesulfamide is excluded, and in cases when R1 is hydrogen or methyl, R2 is not hydrogen or methyl, as well as a pharceutical composition based on these compounds.

EFFECT: novel chemical compounds which can be used in treating and preventing diabetes, obesity and eating disorders are obtained and described.

15 cl, 192 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula ; or their pharmaceutically acceptable salts, where A is phenyl, X is CH2- or C=O; Y is O; k equals 1; m equals 0; R2 and R3 each independently represents hydrogen or alkyl, R4 is a group of formula or . Disclosed compounds have selective affinity to 5-HT6 and 5-HT2A receptors. Also described is a pharmaceutical composition containing said compounds and use of the said compounds in making a medicinal agent for treating diseased conditions of the central nervous system.

EFFECT: more effective treatment.

49 cl, 1 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a combined product containing compounds of formula (I): where: R1 and R2 represent CF3; R3 and R4 represent fluoro; R5 and R6 represent hydrogen; R7 presents Cl, X represents CR8, where R8 represents Cl; and R9 represents NH2; or its veterinary acceptable salt, and b) doramectin. The invention also relates to an antiparasitic veterinary composition based on the said combined product.

EFFECT: obtaining a combined product which can be used in veterinary for treating parasitic infections in mammals.

4 cl, 1 dwg, 1 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

FIELD: chemistry.

SUBSTANCE: benzamide derivatives are presented by the formula [1] or its salt, where Z is -O-, -NR5-, -S-, -SO-; 1 is 0 or 1; m is 0 or 1; R1 is hydrogen atom, C1-6-alkyl group, R2 is hydrogen atom, hydroxylic group, C1-6- alkyl group, carboxyl group, C1-6-alkoxycarbonyl group or -CONR10R11, or R2 and R1 together form =O; R3 is hydrogen atom or C1-6-alkyl group; R4 is hydrogen atom or halogen atom; V is direct bond or -(CR21R22)n-; P1 and P2 rings are the same or different, and each is aromatic or saturated carbocyclic group, or 5-10-member saturated or unsaturated heterocyclic group containing 1-3 heteroatoms selected out of N, O, S.

EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a free base (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)- ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine in crystalline form, having a powder X-ray diffraction pattern with peaks at diffraction angles (2θ) 15.7±0.1, 17.3±0.1 and 19.7±0.1. The invention also relates to a pharmaceutical composition, to methods of treating cancer in mammals, as well as to a method of treating abnormal cell growth in mammals in need of such treatment.

EFFECT: obtaining an novel biologically active compound having the said inhibitory activity.

12 cl, 1 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) and their pharmaceutically acceptable salts as chemokine receptor CCR3 activity modulators, a pharmaceutical composition based on the said compounds, to synthesis method and use thereof. Said compounds can be used for treating and preventing diseases mediated by chemokine receptor CCR3 activity, such as inflammatory and allergic diseases etc. In general formula , R1 represents phenyl, [1,2,4]triazolo[4,3-a]pyridinyl, thiazolo [5,4-b]pyridinyl, benzothiazolyl, benzoxazolyl, pyridinyl, where each of the said phenyl or heterocycles can be substituted with one, two or three radicals R2; R2 each independently represents (C1-C6)halogenalkyl, halogen, COOR3; CONR3R4; R3 represents H or (C1-C6)alkyl; R4 represents H or (C1-C6)alkyl, R5 represents (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl; R6 each independently represents (C1-C6)alkoxy, (C1-C6)halogenalkyl, halogen, OR3, CN, CONR3R4; A represents C(CH3)2-CH2-CH2-, CH2-CH2-CH2- or B represents phenyl; D-E represents CH-CH2- or C=CH-, X-W-V represents N-C=CR7 or C=C-NR7; R7 represents H or (C1-C6)alkyl; Y represents NR4, O, S(O)n; i, j, m each equals 1, n equals 0 or 2.

EFFECT: increased effectiveness of using said compounds.

13 cl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) which are protein tyrosine kinase 1B(PTP-1B) inhibitors and can be used in medicinal preparations for treating and preventing diseases related to high concentration of glucose in blood, for example diabetes and obesity. In formula (I) X is a X-1 group or X-2: , where R1 and R2 are each independently selected from a group consisting of hydrogen, lower alkyl, alkoxy-lower alkyl and hydroxyl-lower alkyl, under the condition that, R1 and R2 both represent hydrogen; R3, R4, R6 and R7 are each independently selected from a group consisting of hydrogen, lower alkyl; lower alkyl substituted with halogen or hydroxy; lower alkoxy; lower alkoxy substituted with halogen, hydroxy or lower alkoxy; hydroxyl, halogen, lower alkylthio, lower alkylsufanyl, lower alkylsufanyl, aminosufonyl, cyano, nitro, carbamoyl, lower mono- or dialkylcarbamoyl, lower alkanoyl, benzoyl, phenyl, phenyl substituted with halogen, phenyloxy, lower mono- or dialkylamino, hydroxy-substituted lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, heterocycloalkyl, hydroxy-substituted heterocycloalkyl, heterocyclyloxy, heterocyclylcarbonyl; where each heterocycloalkyl in the said values represents a 5-6-membr ring containing 1-2 heteroatoms selected from nitrogen and oxygen, and which can be substituted with lower alkyl or phenyl-lower alkyl; carboxyl, lower alkoxycarbonyl and a substitute of formula: ; R8 is selected from a group consisting of hydrogen, lower alkylthio, halogen, alkoxy-lower alkoxy, lower alkoxy, halogen-lower alkyl, hydroxy-lower alkyl; represents a 5-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of hydrogen, sulphur and nitrogen; R8 and R9 each independently represents hydrogen or lower alkyl.

EFFECT: novel compounds have useful biological properties.

31 cl, 7 dwg, 152 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a combined product containing compounds of formula (I): where: R1 and R2 represent CF3; R3 and R4 represent fluoro; R5 and R6 represent hydrogen; R7 presents Cl, X represents CR8, where R8 represents Cl; and R9 represents NH2; or its veterinary acceptable salt, and b) doramectin. The invention also relates to an antiparasitic veterinary composition based on the said combined product.

EFFECT: obtaining a combined product which can be used in veterinary for treating parasitic infections in mammals.

4 cl, 1 dwg, 1 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of formula (I) or to salts thereof: , where R1 is a hydrogen atom, amino group, R11-NH-, where R11 is a C1-6alkyl group, hydroxy-C1-6alkyl group, C1-6alkoxycarbonyl-C1-6alkyl group, R12-(CO)-NH-, where R12 is a C1-6alkyl group or C1-6alkoxy-C1-6alkyl group, C1-6alkyl group, hydroxy-C1-6-alkyl group, C1-6alkoxy group or C1-6alkoxy-C1-6alkyl group; R2 is a hydrogen atom, C1-6alkyl group, amino group or di-C1-6alkylamino group; one of X and Y represents a nitrogen atom, while the other represents a nitrogen or oxygen atom; ring A is a 5- or 6-member heteroaryl ring or benzene ring which can have 1 or 2 halogen atoms; Z is a single bond, methylene group, ethylene group, oxygen atom, sulphur atom, -CH2O-, -OCH2-, -NH-, -CH2NH-, -NHCH2-, -CH2S- or -SCH2-; R3 is hydrogen or a halogen atom, or C1-6alkyl group, C3-8cycloalkyl group, C6-10aryl group, 5- or 6-member heteroaryl group, where these groups can have 1 or 2 substitutes selected from a group of α substitutes: and [group of α substitutes] group of α substitutes is a group consisting of a halogen atom, cyano group, C1-6alkyl group, C1-6alkoxy group, C1-6alkoxycarbonyl group, C3-8cycloalkyl group, C1-6alkenyl group and C1-6alkynyl group; R4 is a hydrogen atom or halogen atom; except compounds in which all of R1, R2 and R4 represent a hydrogen atom while Z represents a single bond or R3 is a hydrogen atom; as well as a pharmaceutical composition and a medicinal agent with antifungal activity, based on these compounds, to an antifungal agent and use of formula I compounds for preparing an antifungal agent.

EFFECT: novel compounds with excellent antifungal effect are obtained and described.

36 cl, 228 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of benzene sulphonamide of formula (I), tautomeric and stereoisomeric forms and physiologically acceptable salts thereof: where X is O, S; R1 is H, halogen; R2 is H, halogen; halogen; R3 is NO2, CN; R4 is: ,

where R71 is H; R72 is H; Z1 is -[CH2]P-, where p = 2.

EFFECT: compounds have antagonistic activity towards CCR3, which enables for their use in making medicinal agents.

13 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention belongs to medicine and pharmaceutics, notably to making remedy for dismenorrea treatment. Remedy includes chaga mushroom, killwort, milfoil, tormentil roots, elecampane roots, licorice roots, common Saint-John's wort - all equally.

EFFECT: remedy shows higher therapeutic effect without side reactions.

4 ex

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