Crystal form

FIELD: chemistry.

SUBSTANCE: (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide in essentially crystal form has powder radiograph, expressed in angle values 20, and obtained by means of difractometer, including peaks, located in the following positions expressed in angles 2θ: 9.1-9.2 (±0.1), 16.0-16.1(±0.1), 18.0-18.2 (±0.1) and 18.3-18.4 (±0.1) degrees, and term "essentially crystal form" means that said form is mainly free from amorphous form of (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide, and by term "mainly free from" content of amorphous form less than 50% is meant.

EFFECT: increased activity.

15 cl, 2 dwg, 5 tbl, 2 ex

 

The present invention relates to crystalline derivative oxopyrrolidin compounds and their use in medicine. In particular, the invention relates to essentially crystalline form of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda, the pharmaceutical compositions based on it, the means of its production and its use in medicine, in particular the application to improve the clinical condition for which you want inhibitor of Factor XA.

Factor Xa is representative of the enzymes belonging to the class of trypsin-like serine proteases. He is a key enzyme in the cascade of blood coagulation. One-to-one binding of Factors Xa and Va calcium ions and phospholipid converts prothrombin into thrombin. Thrombin plays a Central role in the mechanism of blood clotting, making a soluble plasma protein, fibrinogen into insoluble fibrin. Insoluble fibrin matrix is required for the stabilization of the primary hemostatic plug. Many common diseases are associated with abnormal hemostasis. From the point of view of the coronary arterial vascular system, the abnormal formation of blood clot due to the gap formed atherosclerotic plaque is the main cause of acute myocardial infarction and nestabil the th angina. As the treatment of occlusion of the coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) is often accompanied by a sharp re-thrombotic occlusion of the affected vessel that requires immediate intervention. As for the venous vascular system, a high percentage of patients undergoing extensive surgery in the lower extremities or abdomen, suffering a blood clot in the venous vascular system, which can lead to decreased blood flow in the affected limb and susceptibility to embolism of blood vessels of the lungs. Disseminated intravascular coagulation usually occurs in both vascular systems during septic shock, certain viral infections and cancer and is characterized by rapid consumption of coagulation factors and systemic coagulation which leads to the formation of life-threatening thrombi occurring throughout the vascular system, followed by the involvement of many organs.

In addition to its direct role in the formation of enriched fibrin of blood clots, thrombin, as reported, has a strong bioregulatory effects on several cellular components within the vascular system and blood (Shuman, M.A., Ann. NY Acad. Sci., 405:349(1986)).

Inhibitor of Factor Xa can be and is used for the treatment of acute vascular diseases, such as acute coronary syndromes (for example, primary and secondary prevention of myocardial infarction and treatment prothrombotic consequences associated with myocardial infarction or heart failure), thromboembolism, acute occlusion of the vessel associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty, transient ischemic disorders, embolism of the lungs, deep venous thrombosis, peripheral arterial occlusion, prevention of the narrowing of the lumen of the vessel (restenosis), and the prevention of thromboembolic complications associated with atrial fibrillation, e.g. stroke. Factor Xa inhibitors can also be used for prevention of thrombosis and complications in patients with hereditary predisposition to arterial thrombosis or venous thrombosis, and patients who have associated with disease predisposition to thrombosis (e.g. type 2 diabetes). Thrombin, as reported, contributing to the proliferation of lung fibroblasts, therefore, Factor Xa inhibitors can be used for the treatment of certain pulmonary fibrotic diseases. Inhibitors of Factor XA can also be used for the treatment of tumor metastasis by inhibiting the coagulation of blood, resulting in preventing the deposition of fibrin, lightweight and is completed with the formation of metastasis. Inhibitor of Factor XA can also be useful as anti-inflammatory agents through inhibition mediated FXa activation of protease-activated receptors (PAR 1-4). Inhibitor of Factor XA can also be useful as protivoateroskleroticheskim means by suppressing the activation of platelets. Thrombin can cause retraction of Narita, and therefore inhibitors of Factor Xa can be potentially used in the treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Inhibitors of Factor XA can also be useful as anti-coagulants funds in the process of receiving, storage, fractionation, or the use of whole blood. As reported, they are used in combination with thrombolytic agents, thereby allowing you to use a lower dose of thrombolytic tools.

(E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole is an inhibitor of FXa, disclosed in patent publications W002/100886 and W002/100830 included in the present description by reference, in a substantially amorphous form. (E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole has the structure shown below:

The essence and the gain

The inventors have found that (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole can be obtained in essentially crystalline form. In line with this, in the first aspect of the invention features (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form.

Other aspects of the invention are:

pharmaceutical composition comprising (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form together with a pharmaceutical carrier and/or excipient;

- (E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form for use in therapy;

- the use of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form to obtain drugs for the treatment of a patient suffering from a condition susceptible to improvement by using the inhibitor of Factor XA;

- the method of treatment of a patient suffering from a condition which can be improved by using an inhibitor of Factor XA, comprising introducing a therapeutically effect the main amount of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form.

Detailed description of the invention

Essentially crystalline form of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda can be obtained by crystallization under certain conditions in the form of needle and/or blankaartia particles, a length of up to 250 microns, as described below. Therefore, in another aspect, the invention features essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in the form of needle crystals. In another aspect of the invention it is also proposed essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in the form blankaartia crystals. In another aspect of the invention it is also proposed essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in the form of a mixture of needle-shaped crystals and blankaartia crystals. Preferably the crystals have a length of up to 250 microns. However, it should be borne in mind that under certain conditions it is possible to obtain crystals of alternative types. Accordingly, it should be borne in mind that all these alternative types of crystals are within the scope of the present invention.

Used in the estuaries and the ü the term "acicular" means needle-like prism. This form is also known as "spiny". Preferably needle-shaped crystals have a size of up to 250 microns in length.

Used herein, the term "blankaartia (lath-shaped)implies V - or spade-like crystal, in other words, splyusnutoy acicular shape. Preferably blankaartia crystals have a size of up to 250 microns in length.

Essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole has an initial melting point 163-165°C. Thus, in this aspect of the invention provides the (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form, having an initial melting point, as measured using DSC (DSC) (±0,5°C): 160°C or more, preferably in the range of 161-167°C, more preferably in the range 163-165°C.

For sample essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda obtained, as described below, were obtained powder diffraction pattern of x-rays, shown in figure 1 and Figure 2. The diffraction pattern of x-rays (hereinafter referred to as the "x-ray") is the specific who for some crystalline forms. Essentially crystalline form shows the diraction pattern with a unique set of diffraction peaks, which can be expressed in angles 2 theta (°), d is the interplanar distances (Å) and/or relative intensities of the peaks.

The diffraction angles 2θ and the corresponding values of interplanar distances (d) are responsible for the provision of various peaks on the radiograph. The values of the interplanar distance d calculated by thethe observed angles 2θ and the wavelength CuKα1,using the Bragg equation. There may be minor variations in the observed values of the angles 2θ and interplanar distances d, depending on the specific model used diffractometer and methods preparation of the analyzed sample. More significant variations are expected in the value of the relative intensity of the peaks. Identification of the exact shape of the crystal connections should be based primarily on the observed angles 2θ or interplanar distances (d), while the relative intensity of the peaks are less important. For identification of essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda characteristic peak angle 2θ is when 18,3±0,1 degrees, or interplanar distance d 4,8#x000B1; 0,1 Å. In one aspect of the invention the characteristic peak angle 2θ is when 18,39 degrees, or interplanar distance d 4,2 Å.

Although a specialist in the art can identify essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole on the basis of the characteristic peak angle 2θ 18,3±0,1, for example 18,39, C, and in some cases to identify essentially crystalline ((E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda it is desirable to use peaks at several angles 2θ or corresponding multiple of interplanar distances d.Essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole can also be identified by the presence of several characteristic peaks corresponding to corners 2θincluding two, three or all four corners 2θ, which are quite typical for this particular crystalline form. These peaks are located in the following positions, expressed in 2 cornersθ (±0.1 degrees): 9,1-9,2, 16,0-16,1, 18,0-18,2, 18,3-18,4 degrees. In one embodiment, to identify essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-kaatil]-2-oxopyrrolidin-3-yl}Tinsulanonda use, at least one of the above angles 2θ.

In one particular aspect of the invention, the peaks correspond tothe following positions, expressed in 2 cornersθ (±0.1 degree): 9,21, 13,79, 16,11, 18,11, 18,39 degrees. For identification of essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda use at least one, preferably two, more preferably 3, even more preferably 4, most preferably 5 of the above-mentioned angles 2θ.

In another specific aspect of the invention, the peaks are located in the following positions, expressed in 2 cornersθ (±0.1 degree): 9,1, of 16.0 and 18.0, 18.3 degrees. For identification of essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda use at least one, preferably two, more preferably 3, most preferably 4 of the above angles 2θ.

Some margin of error is present in each of these angle values 2θ and interplanar distances d, described above. The error in the determination of interplanar distances d decreases with increasing diffraction angle scanning or decrease in the interplanar distance d. The error limit for the above angles 2θ with the hat approximately ± 0.1 degrees, preferably ±0.05 degrees for each of the values specified above peaks. The error limit for the values of interplanar distance d is approximately ±0.1 angstroms, preferably ±0.05 angstroms.

Since there is a certain margin of error in the determined value of the angles 2θ and the interplanar spacings d, the preferred method of comparison of powder x-ray to identify a specific crystalline form involves application of powder x-ray sample of unknown form in the powder x-ray sample of known forms. For example, a specialist in the art may impose a powder x-ray photograph of unidentified forms of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda obtained using the methods described here, in figure 1 or Figure 2 and it is easy to determine whether the unidentified x-ray form is essentially the same as the powder x-ray essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda. If the powder x-ray will be essentially the same as in figure 1 or Figure 2, a previously unknown form can be easily and accurately identify canfora essentially crystalline (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda.

Although the main way to identify a particular crystalline form is to determine the angles 2θ or interplanar distances d, it is also desirable to make comparisons of the relative intensities of the peaks. As noted above, the relative intensities of peaks may vary depending on the model of the diffractometer and methods preparation of the analyzed sample. Intensity peaks correlate with the intensity of the strongest peak. Unit intensity on the graph of the diffraction spectrum is represented as the number of pulses/sec. the Absolute number of pulses = number of pulses/time x time of pulse = number of pulses/sec x 10 C.

Used herein, the term "essentially crystalline form" means that she (crystalline form), mostly free from amorphous forms of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda. The term "essentially free from" means the content of amorphous forms less than 50%, preferably the content of amorphous form less than 20%, more preferably the content of amorphous forms less than 10%, more preferably the content of amorphous forms less than 5%, even more preferably, the content of amorphous forms less than 2%, most preferably the content of the amorphous form is anise, than 1%.

Used herein, the term "essentially amorphous form" means the amorphous form of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda, which may contain up to 10% of crystalline form of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda, but preferably contains less than 5% crystalline form, more preferably less than 3% of the crystalline form, even more preferably less than 2% of the crystalline form, most preferably less than 1% crystalline form.

(E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole contains a chiral (asymmetric) centers, denoted by*in the formula (I). Individual stereoisomers (enantiomers and diastereoisomers) and their mixtures are included in the scope of the present invention. Preferably, the stereochemical configuration at the 3-position 2-oxopyrrolidin ring represents (S)-configuration. Preferably, the 1-position oxoethylidene group is of the stereochemical configuration (S).

The present invention also provides a method of obtaining (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form, is this method involves the crystallization of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda from the organic solution, optionally in the presence of water. As a rule, (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole dissolved in an organic solvent, for example an aromatic hydrocarbon (e.g. toluene), cycloalkane (for example, cyclohexane), complex ether (e.g. ethyl acetate), alcohol (e.g. ethanol, methanol or propane-2-OLE) or a ketone (e.g. acetone), preferably a ketone (e.g. acetone) or cycloalkane (for example, cyclohexane), more preferably cyclohexane, preferably at elevated temperature, for example, 50-70°C, and optional add water as protoveratrines. Crystallization was carried out by lowering the temperature of the solution, preferably to a temperature in the range from room temperature to 0°C, more preferably 0-5°C. In a preferred aspect of the invention, crystals of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda allocate filtering.

Described here are methods of obtaining essentially crystalline substances constitute another aspect of the present invention.

(E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole is an inhibitor of Factor XA and, as such, is used in the treatment of CL is technical conditions which can be improved by the introduction of an inhibitor of Factor XA. Such conditions include acute vascular diseases such as acute coronary syndromes (for example, primary and secondary prevention of myocardial infarction and unstable angina and treatment prothrombotic consequences associated with myocardial infarction or heart failure), thromboembolism, acute occlusion of the vessel associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic disorders, embolism of the lungs, deep venous thrombosis, peripheral arterial occlusion, prevention of the narrowing of the lumen of the vessel (restenosis) and prevention of cases of thromboembolic complications associated with atrial fibrillation, e.g. stroke; treatment of ischemic stroke; to prevent thrombosis and complications in patients genetically predisposed to arterial thrombosis or venous thrombosis, and patients who have associated with disease predisposition to thrombosis (e.g. type 2 diabetes); treatment of pulmonary fibrosis; treatment of tumor metastasis; treatment of inflammation; atherosclerosis; neurodegenerative disease such as Parkinson's and Alzheimer's disease; syndrome Kasabach Merritt; haemolytic uraemic syndrome; endothelial dysfunction; as anticoagulation means for extracorporeal blood, for example, in dialysis, blood filtration, bypass and storage of blood productand to cover invasive devices, such as prostheses, artificial valves and catheters to reduce the risk of blood clots.

Accordingly, one aspect of the present invention provides the (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form for use in therapy, in particular for applications in order to improve the clinical condition in a mammal, including humans, for which you want inhibitor of Factor XA.

In another aspect the invention provides a method of treatment and/or prophylaxis of a mammal, including man, suffering from a condition that can be improved with the help of an inhibitor of Factor XA, and this method comprises the administration to the patient an effective amount of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form.

In another aspect the present invention provides the use of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form to obtain a drug is for the treatment and/or prevention of a condition, which can be improved with the help of an inhibitor of Factor XA.

Preferably a condition that can be improved with the help of an inhibitor of Factor XA, choose from the treatment of acute vascular diseases such as coronary thrombosis (e.g., myocardial infarction and unstable angina, thromboembolism, acute occlusion of the vessel associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty, transient ischemic disorders, embolism blood vessels of the lungs, deep vein thrombosis, peripheral arterial occlusion, prevention of the narrowing of the lumen of the vessel (restenosis), and the prevention of thromboembolic complications associated with atrial fibrillation, e.g. stroke.

More preferably a condition that can be improved through inhibitor of Factor XA, choose from coronary thrombosis (e.g., myocardial infarction and unstable angina), embolism blood vessels of the lungs, deep vein thrombosis and prevention of thromboembolic complications associated with atrial fibrillation, e.g. stroke.

It should be borne in mind that reference to treatment includes the treatment of acute illness or the prevention and alleviation of established symptoms.

Although it is possible that, for use in therapy (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-and is-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form can be entered as the source of the chemical product, preferably, it is present in the form of active component in the form of pharmaceutical compositions.

The following aspect of the invention provides a pharmaceutical composition comprising (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form in a mixture with a pharmaceutically acceptable carrier and/or excipient. The carrier and/or excipient must be "acceptable" in the sense that it must be compatible with the other components of the composition and is not harmful to the recipient.

Accordingly, the present invention provides a pharmaceutical composition comprising (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form together with a pharmaceutically acceptable carrier and/or excipient. The carrier and/or excipient must be "acceptable" in the sense that it must be compatible with the other components of the composition and is not harmful to the recipient.

In another aspect the invention provides a pharmaceutical composition comprising as an active ingredient (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form together with a pharmaceutically acceptable nose is Telem and/or excipient for use in therapy, and in particular for the treatment of human or animal suffering from a condition that can be improved with the help of an inhibitor of Factor XA.

Further according to the present invention provides a method of obtaining a pharmaceutical composition, and the method comprises mixing (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form with a pharmaceutically acceptable carrier and/or excipient.

(E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form may be in the composition for oral, buccal, parenteral, local, rectal or transdermal injection or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).

For oral administration the pharmaceutical compositions may take the form of, for example, tablets or capsules, obtained in the usual way with pharmaceutically acceptable excipients such as binders (for example, klasterizovannykh corn starch, polyvinylpyrrolidone or hypromellose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or dioxidine); the disintegrators (e.g., potato starch or matrikamantra) or moisturizing agent (e.g. sodium lauryl sulphate). The tablets may be coated by methods known in this field. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented in the form of dry powders for dilution with water or other suitable fillers before use. Such liquid preparations can be obtained in the usual way with pharmaceutically acceptable additives such as suspendresume means (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying means (e.g., lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agent, if appropriate.

Preparations for oral administration can be suitably made in the form of forms with controlled release of active compounds, using pharmaceutically acceptable carrier and/or fillers, for example the EP the hypromellose.

For buccal injection composition can take the form of tablets or candy corresponding composition.

Compounds according to this invention can be in the form of a composition for parenteral administration by injection, for example by bolus injection or continuous infusion. Preparations for injection can be presented in dosage form, for example in ampoules or containers with multiple doses, with added preservative. Songs can have such forms as suspensions, solutions or emulsions in oily or aqueous fillers, and may contain tools such as suspendida, stabilizing and/or dispersing the funds. Alternatively, the active ingredient may be in powder form for reconstitution before use with a suitable filler, such as sterile, pyrogen-free water.

Compounds according to this invention can be in the form of a composition for local administration by insufflation and inhalation. Examples of agents for local injection include sprays and aerosols for use in inhalers and insufflator.

Powders for external use can be formed using any powder base, such as lactose, talc or starch. Composition for spraying can be formed in aqueous solutions is whether suspensions or in the form of aerosols, spray from pressurized packs, such as inhalers with adjustable dose, using a suitable propellant.

Compounds according to this invention can also be formed in rectal compositions such as suppositories or retention enemas, containing conventional bases for suppositories, such as cocoa butter or other glycerides.

In addition to the preparations described previously, the compounds may be formed as the product of prolonged action. These drugs for long periods can be administered by implantation (for example subcutaneously, transdermally or intramuscularly) or by intramuscular injection. Thus, the compounds of this invention can be in the form of a composition with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The proposed dose (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form according to this invention for administration to man (weighing about 70 kg) is from 0.1 mg to 1 g, preferably 1 mg to 500 mg of the active component in the standard dose, which is expressed in the mass of a free OS is Finance. The standard dose can be administered, for example, from 1 to 4 times a day. The dosage is usually dependent on route of administration. Keep in mind that you may need to make regular changes to the dosage depending on the age and weight of the patient, and the severity of the condition to be treated. The dose may also depend on the route of administration. Selection of the exact dose and route of administration, ultimately, is usually done at the discretion of the attending physician of the hospital or veterinarian.

(E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form can also be used in combination with other therapeutic agents. Thus, in another aspect the invention provides a combination containing (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form, together with another therapeutic agent.

When (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form is used in combination with a second therapeutic agent active against the same morbid state the dose of each compound may differ from that dose, which is used when only one joint is. The appropriate dose can be easily picked up by specialists in this field. It should be borne in mind that the number of compounds in this invention required for use in treatment can vary depending on the nature of the condition to be treated, and the age and condition of the patient and, ultimately, it is usually at the discretion of the attending physician of the hospital or veterinarian. (E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form can be used in combination with other antithrombotic agents (such as thrombin inhibitors, receptor antagonists of thromboxane, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, thrombolytic agents such as tissue plasminogen activator and streptokinase, non-steroidal anti-inflammatory drugs such as aspirin, etc), antihypertensive agents (such as inhibitors of angiotensin-converting enzyme, receptor antagonists angiotensin-II inhibitors, ACE/NEP β-blockers, calcium channel blockers, PDE inhibitors, blockers, aldosterone), antiateroskleroticescoe/dyslipidemias means (such as inhibitors of HMG-CoA reductase) and antiarrhythmic agents.

The above combination could the t to be appropriately represented for use in the form of pharmaceutical compositions and, accordingly, pharmaceutical compositions containing defined above in combination with pharmaceutically acceptable carrier or excipient, are an additional aspect of the invention. Individual components of such combinations can be entered either sequentially or simultaneously in separate or combined pharmaceutical compositions in any suitable way.

The sequential introduction you can enter either the inhibitor of Factor XA, or the second therapeutic agent. With the simultaneous introduction of combination can be entered either in the same or in different pharmaceutical compositions.

When combined in the same drug should be borne in mind that the two compounds must be stable and compatible with each other and other components of the drug. When forming separately they can be presented in any suitable solvent, conveniently thus, as is known for such compounds in a given field of technology.

Further the present invention is illustrated in the accompanying examples, which should not be construed as limiting in any way the scope of the invention.

All publications, including but not limited to, patents and patent applications cited herein, incorporated by reference as if each individual is Naya publication was specifically and individually indicated as incorporated in full by reference.

Examples

Reduction

API Active pharmaceutical component.

DCM Dichloromethane.

DMF N,N-Dimethylformamide.

HOBT 1-Hydroxybenzotriazole.

GC Gas chromatography.

LOD Loss during drying.

PAR the Ratio of peak areas (Peak Area Ratio).

The intermediate connection 1

tert-Butyl N-[(benzyloxy)carbonyl]-L-methionyl-L-alaninate

Z-Protected L-methionine (10 g) dissolved in DMF (200 ml) and add 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8,13 g) followed by addition of HOBT (5,72 g) and triethylamine (19.7 ml). The mixture is stirred for 1 h, then addtert-butyl ester of L-alanine (7.7 g) and stirring is continued for 18 hours the Mixture is concentrated under reduced pressure and partitioned between diethyl ether and water. The separated organic phase is washed with chloroethanol acid (1M), saturated sodium bicarbonate solution and saturated salt solution, dried (over magnesium sulfate) and concentrated under reduced pressure, gettingspecified in the header connection(11.9 g) as an orange oil, which crystallized upon standing.

Mass spectrum: Found: MH+411.

Intermediate compound 2

tert-Butyl(2S)-2-((3S)-3{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)PR is Pinout

A solution of intermediate compound1(11.9 g) in acetone (75 ml) is treated with methyliodide (18 ml) and stirred at room temperature for 72 hours Then the reaction mixture was concentrated under reduced pressure, obtaining an orange solid, which was dissolved in acetonitrile (200 ml). Add resin Dowex (OH-form) (19,42 g) and the mixture stirred for 18 h at room temperature. The mixture is filtered and the resin washed with ethyl acetate. The filtrate is concentrated under reduced pressure, obtaining a yellow oil, which was purified by Biotage chromatography™ (elwira with a mixture of cyclohexane:ethyl acetate 3:2), receivingspecified in the header connection(of 2.92 g) as a colourless oil.

Mass spectrum: Found: MH+363.

Intermediate compound 3

(2S)-2-((3S)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid

The intermediate connection2(0.5 g) was dissolved in DCM (7 ml) and add triperoxonane acid (4,7 ml). The mixture is stirred at room temperature for 1.5 h and then concentrated under reduced pressure, gettingspecified in the header connection(0,423 g) as a colourless oil, which, after azeotropic distillation with toluene crystallizes.

Mass spectrum: Found: MH+307.

Intermediate compound 4

Benzyl (3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-kaatil]-2-oxopyrrolidin-3-ylcarbamate

The intermediate connection3(84.5 g) dissolved in DMF (2 l) and add tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (161 g), with posleduyushim the addition of N,N-diisopropylethylamine (92 ml) and research (46 ml). The mixture is stirred under nitrogen atmosphere for 2.5 h and add saturated aqueous ammonium chloride. The mixture is stirred for 15 min, then partitioned between water and ethyl acetate. The separated organic layer is washed with lithium chloride (10% wt.), then saturated sodium bicarbonate and saturated salt solution. The organic layer is dried (over sodium sulfate) and concentrated under reduced pressure, gettingspecified in the headerconnection(65 g) as a yellow solid.

Mass spectrum: Found: MH+376.

The intermediate compound 5

(3S)-3-Amino-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]pyrrolidin-2-he

A mixture of intermediate compound4(20 g), 10% palladium on carbon (2 g) and ethanol (1.3 l) was stirred in hydrogen atmosphere for 16 hours, the Reaction mixture was filtered through Celite™ and the filtrate is concentrated under reduced pressure, gettingspecified in the header connection(12.3 g) as a pale white oil.

1H NMR (D4MeOH): δ of 5.05 (1H, DD), 3,59 (9H, m), 3,37 (2H, m), 2,42 (1H, m)of 1.75 (1H, m)of 1.30 (3H, d) ppm

The intermediate compound 6

(S)-3-Amino-1-[(S)-1-m is Teal-2-morpholine-4-yl-2-oxoethyl]pyrrolidin-2-he hydrochloride

To a suspension of intermediate compounds4(5 g, 0,013 mol, 1 equivalent) in ethanol (75 ml) and chloroethanol acid (2.2 ml, 0,026 mol, 2 equivalents) is added 20% palladium hydroxide on carbon, wetted with 50% water (100 mg, 2% wt.). The suspension is stirred at room temperature for approximately 15-20 lb/in2within about 3 hours. The mixture is filtered through celite. The precipitate is washed with acetonitrile (2x30 ml). The filtrate contained (S)-3-amino-1-[(S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]pyrrolidin-2-he hydrochloride (output reached 100%).

Example 1

(E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}tinsulanond (method 1)

To a solution of intermediate compound5(14.9 g) in anhydrous acetonitrile (750 ml) is added (E)-2-(5-chlortan-2-yl)tinsulanond (16.5 g) in acetonitrile (250 ml) and pyridine (11 ml) and the mixture is stirred at room temperature for 72 h Add a saturated solution of ammonium chloride and the resulting mixture was stirred at room temperature for 30 minutes the Mixture is concentrated under reduced pressure and the residue partitioned between chloroform and a mixture of 1:1 chloroethanol acid (2M) and water. The organic layer was washed with a mixture of 1:1 saturated sodium bicarbonate and water, and saturated salt solution. The organic layer is separated, dried (over sulfate is Agnes) and concentrated under reduced pressure, gettingspecified in the header connection(19.3 g) as a white solid (essentially amorphous form).

Mass spectrum: Found: MH+ 448.

HPLC (HPLC) Rt2,99 minutes

1H NMR (CDCl3): δ of 7.48 (1H, d), was 7.08 (1H, d), of 6.90 (1H, d), 6,55 (1H, d), 5,12 (1H, SD), is 5.06(1H, K), of 3.96 (1H, m), 3,70-3,48 (9H, m)to 3.35 (1H, m), 2,62 (1H, m), is 2.05 (1H, m)of 1.34 (3H, d) ppm

Crystallization of the product of example 1

The product of example1(33,3 g) dissolved in acetone (350 ml) at 55°C under stirring in nitrogen atmosphere. Water (780 ml) is added dropwise and portions for 3.5 hours, during this addition the solution begins to thicken. Heating is stopped and the solution allowed to reach room temperature for 2 hours the Mixture was incubated for another 18 h at room temperature in the absence of light. The resulting suspension is filtered, washed with cold water (200 ml) and then dried in vacuum 30°C for 24 h, gettingspecified in the header connectionin the form of a white essentially crystalline solid.

Received essentially crystalline substance used as a seed to initiate crystallization in the re-crystallization process (described above), in which a seed crystal added after removal of the heat to getspecified in the header connection(29,2 g) as a white essentially crystalline solid which CSOs substances.

Melting point (according to DSC (differential scanning calorimetry)): the beginning of the melting point 163-165°C.

Essentially crystalline solid substance exists mainly in the form of needle and blankaartia particles, the length up to 250 microns, which form a loose agglomerate.

Powder x-ray crystal compounds shown in figure 1, receive, using the settings shown in table 1. Table 2 shows the list of data of the characteristic peaks.

Table 1(a)
Characteristics of the instrument for recording the x ray powder patterns (XRPD) and the measurement conditions
ManufacturerPhilips Analytical X-Ray B.V. Netherlands
Type of diffractometerPW3040
SeriesDY667
The anode tubeCu
λα11,54056
λα21,54439
Attitude α2/α10,50000
Divergentional slitProg. Div. Slit
Reception slitProg. Rec. Slit
Used monochromatorYES
The voltage generator40 kV
The current in the tube50 mA
Range of angle (°2θ)2,0000-45,0000
The size of the scanning step (°2θ)0,020
Scan typeContinuous
Step scan1,00 seconds

Table 1 (b)
Characteristics of the device for determining the beginning of the melting method DSK and measurement conditions
DeviceManufacturer/Model:TA Instruments DSC2920
Serial No.M2920-234
MethodPre-treatment sampleNo
The purge gas/

the flow velocity
Nitrogen/20 ml min-1
Type moulds for sampleFiller aluminum
The heating rate10°C min-1
Temperature range heatingFrom ambient temperature to 300°C

The beginning of melting for sosestagiarios.com substances 163-165° C.

Microscopy

The particles are described as acicular or blankaartia crystals along the length of up to 400 microns.

Table 2
The data peaks in the powder x-ray (XRPD) for (E)-2-(5-chlortan-2-yl)-N-{[(3S)-1-[(S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form (Example 1); characterized by powder x-ray that includes, but is not limited to, the peaks are presented in table 2
Angle (°2θ)d K-alpha (Å)Relative intensity (%)
4,6518,980,9
8,6710,190,69
of 9.219,59of 17.5
of 9.559,261,1
10,828,173,2
12,417,133,4
12,71of 6.961,0
13,796.42 perthe 11.6
14,386,163,2
15,19of 5.830,7
16,115,5013,2
16,645,32Ls 16.805,276,7
17,275,132,5
18,114,8916,8
18,394,82100,0
18,904,692,7
19,574,532,3
20,25of 4.383,7
vs. 20.624,303,1
21,144,204,0
21,954,052,6
22,373,979,6

Example 2

(E)-2-(5-Chlorothieno-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}tinsulanond (method 2)

The stoichiometry of starting compounds and the reagents and volumes (vol.) used solvents was calculated based on the number of hydrochloride (S)-3-amino-1-[(S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]pyrrolidin-2-it, which output from the intermediate connection5reached 100%.

Charged to the reactor hydrochloride (S)-3-Amino-1-[(S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]pyrrolidin-2-she (1.0 EQ.), The intermediate connection6in ethanol and pyridine (3 volume) and then the content was concentrated in vacuo at a temperature below 40°C to about 3 volumes. Add 10 volumes of ACE is onitrile, then the solution was concentrated in vacuo at a temperature below 40°C to about 3 volumes. Adding and concentration of acetonitrile repeat (4 cycle) up until an acceptable level of ethanol will not be below 0.1% wt./wt. (the analysis for ethanol by GC method). Samples for GC is taken between the 4th and 5th cycles after adding about 10. acetonitrile.

Volumes of a solution of the hydrochloride of (S)-3-amino-1-[(S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]pyrrolidin-2-it is brought to about 13 volumes of acetonitrile (roughly pyridine, 3 vol.; acetonitrile, 10 vol.) when the ambient temperature. Charged to the reactor in one portion of (E)-2-(5-chlorothiophene-2-yl)tinsulanond (1.0 to 1.4 EQ.) in the form of solids. The mixture was stirred at ambient temperature until completion of the reaction, controlling the course of its HPLC. (Note: the reaction was considered complete when, according to HPLC analysis the relation(E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole:(E)-2-(5-chlorothiophene-2-yl)tinsulanond (plus acid of (E)-2-(5-chlorothiophene-2-yl)Tinsulanonda) accounted for more than 86:14 PAR.) The reaction mixture was added butyl acetate (15 vol.). The solvents are removed by distillation in vacuo at a temperature below 70°C to achieve approximately 12-13 about. Add water (10 vol.) and stirred at about 70°C for 30-60 min to ensure dissolution of all oily substances. The mixture remains on for about 30 min and separated. The organic phase is washed with water (5 vol.) when 60-70°C. the combined aqueous phase is extracted with butyl acetate (15 vol.) at around 60°C. the combined organic phases are filtered at 50-60°C (end API) and then concentrated to about 10 rpm. in vacuum at a temperature of <80°C. During the concentration of precipitated solid. The suspension is cooled to ambient temperature. Add cyclohexane (about 10. filtered) and the suspension was incubated for 4-24 hours the Solid is filtered off and washed with cyclohexane (10 vol. filtered). The product is dried at 60-70°C in vacuum to constant weight or LOD <0.5% for 125°C for 5 min, not quite getting white solid. The observed range of output: 60-70%.

Crystallization of the product of example 2

(E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole(29,25 g) is suspended in n-propanol (225 ml, 7.5 volumes). The suspension is heated to 75°C. Then the solution is filtered hot. Add cyclohexane (225 ml, 7.5 volumes) and the mixture is heated to the temperature of reflux distilled (74°C). Then the solution is cooled to about 65°C and add seed (0.2% wt./wt. in cyclohexane). The resulting suspension is incubated at 65°C within 30 minutes of polemical crystallization. The contents cooled to 0-5°C (cooling rate of 0.5°C/min). The suspension is stirred at 0-5°C for 1 hour and filtered under vacuum. Then the precipitate is washed with cyclohexane (150 ml, 5.0 volumes) and set in a vacuum drying Cabinet (60°C/25 MND) for drying to constant weight. Weight(E)-2-(5-chlortan-2-yl-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanondawas 24.7 g (85%). The observed range of output, %: 85-90% light yellow solid.

Table 3
Characteristics of the instrument for recording XRPD and measurement conditions
ManufacturerPhilips Analytical
Type of diffractometerX'pert Pro MPD Diffractometer
Detector typeX Celerator RTMS(Real Time Multi Strip)
The anode tubeCu
λα1(E)1,54056
λα2(E)1,54439
Attitude α2/α10,50000
Optics of the primary beamFixed slits (0,5° aperture), the Soller slit 0.04 radian, a restriction of up to 10 mm
Optics diffraction beamFixed slits (mo is ul X Celerator), slit Soller 0.04 radian
The generator voltage (kV)40
The current in the tube (mA)40
Range of angle (°2θ)a 2.0 to 40.0
The size of the scanning step(°2θ)0,017
Scan typeContinuous
Step scan(seconds)80
Sample rotation (rpm)25

Table 4
The data peaks in the powder x-ray (XRPD) for (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form (Example 2); characterized by powder x-ray that includes, but not limited to, the peaks are presented in table 4
Angle (°2θ)d K-alpha 1 (Å)Relative intensity (%)
4,519,521
8,610,322
9,1the 9.738
9,49,428
10,78,353
12,3 7,234
12,67,016
13,76,517
16,05,566
16,65,386
16,75,377
17,25,227
18,0a 4.981
18,34,8100
19,54,619
20,24,431
20,54,318
of 21.94,119
22,34,027
22,9a 3.919
23,1the 3.820
23,5the 3.822

1. (E)-2-(5-Chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}atenolole in essentially crystalline form has a powder x-ray are expressed in the values of the angles 2θ and obtained using a diffractometer, and this x ray powder includes peaks that are in the following positions, expressed in 2 cornersθ: from 9.1 to 9.2 (±0,1), 16,0-16,1(±0,1), 18,0-18,2 (±0,1) and 18.3-18,4 (±0,1)&x000B0; and where the term "essentially crystalline form" means that this form is mostly free from amorphous forms of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda, and the term "essentially free from" means the content of amorphous forms less than 50%.

2. Essentially crystalline form according to claim 1 in the form of needle crystals.

3. Essentially crystalline form according to claim 1 in the form blankaartia crystals.

4. Essentially crystalline form according to claim 1 in the form of a mixture of needle-shaped crystals and blankaartia crystals.

5. Essentially crystalline form according to any one of claims 1 to 4, in which the melting point is higher than 160°C.

6. Essentially crystalline form according to claim 1, having a powder x-ray are expressed in the values of the angles 2θand obtained using a diffractometer, and this x ray powder includes peaks that are in the following positions, expressed in 2 cornersθ: of 9.21±0,05, 13,79±0,05, 16,11±0,05, 18,11±0.05 and 18,39±0,05°.

7. Essentially crystalline form according to claim 1, having a powder x-ray are expressed in the values of the angles 26 and received by means of the diffractometer, and this x ray powder includes peaks that are in the following positions, expressed in 2 cornersθ: 9,1±0,1,16,0±01,18,0± 0,1 and 18.3±0,1°.

8. Essentially crystalline form according to claim 1, the data of x-rays which are presented in table 2.

9. Essentially crystalline form according to claim 1, the data of x-rays which are presented in table 4.

10. Essentially crystalline form according to claim 1, radiograph which is presented in figure 1.

11. Essentially crystalline form according to claim 1, radiograph which is presented in figure 2.

12. The method of obtaining (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form according to any one of claims 1 to 11, comprising the crystallization of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda from the organic solution, optionally in the presence of water.

13. The method according to item 12, where the organic solution is selected from aromatic hydrocarbon, cycloalkane, of ester, alcohol or ketone, or mixtures thereof.

14. Pharmaceutical composition in solid form, which has active inhibitor of factor XA, comprising a therapeutically effective amount of (E)-2-(5-chlortan-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form according to any one of claims 1 to 11, together with a pharmaceutical carrier and/or excipient.

15. The use of (E)-2-(5-chlortan-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholine-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}Tinsulanonda in essentially crystalline form according to any one of claims 1 to 11 to obtain drugs for the treatment of the patient, suffering from a condition which can be improved by using an inhibitor of Factor XA.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new compounds presented by the following formula (I), or to the pharmaceutically acceptable salts: , where R1 and R2 represent substitutes, adjoining with each other and with two carbonic atoms, to each of which they are adjoined forming the group presented by the following formula: 1) , or

2) , , , , , , , , or

3) or

4) , , or

where hydrogen atom in each cyclic group can be substituted bi 1-4 substitutes selected fro the following group of substitutes B1, R3 represents hydrogen atom or methyl group; and R6 represents substitute selected from the following group of A1 substitutes, the group of A1 substitutes: (1) hydrogen atom, (2) C1-C6 alkoxy group; substitute B1 group: (1) hydrogen atom, (2) hydroxyl group, (3) oxo group, (4) C1-C6 alkanoyl group, (5) C3-C8 cycloalkyl group, (6) C1-C6 alkyl group (where C1-C6 alkyl group can be substituted by C1-C6 alkoxy group), (7) C1-C6 alkoxy group, (8) C1-C6 alkoxyimino group, (9) C5-C6 cycloalkyl group, derived by two C1-C3 alkyl groups joined to the same carbonic atom with hydrogen atom and the carbons. The invention is also relates to the pharmaceutical composition.

EFFECT: production of the new biologically active compounds and pharmaceutical compositions on their basis having inhibitor potency towards to serotonine1A receptor.

34 cl, 73 ex, 12 tbl, 4 dwg

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to compounds with formula (I), their pharmaceutical salts or N-oxide used as an inhibitor to replication and/or proliferation of HCV, to the method of inhibiting replication or proliferation of hepatitis C virion using formula (I) compounds, as well as to pharmaceutical compositions based on them. The compounds can be used for treating or preventing infections, caused by hepatitis C virus. In general formula (I) cycle B is an aromatic or non-aromatic ring, which contains two heteroatoms, where X and Y, each is independently chosen from C, CH, N or O, under the condition that, both X and Y are not O and that, both X and Y are not N; U and T represent C; Z represents -CH-; A represents N or -CR2-; B represents -CR3-; D represents N or -CR4-; E represents N or -CR5-; G represents N or -CR6-; J represents N or -CR14-; K represents -CR8-; L represents N or -CR9-; M represents N or -CR10-; R2 and R6, each is independently chosen from a group, consisting of hydrogen, halogen, C1-C6alkyl, substituted C1-C6alkyl, C1-C6alkoxy, C1-C6substituted alkoxy, C1-C6alkoxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, -O-carbamoil, substituted -O-carbamoil, halogen C1-C6alkyl, diC1-C6alkylamino, substituted diC1-C6alkylamino and sylye ethers, where cycloheteroalkyl is a 3-7-member ring, containing 1-2 heteroatoms, chosen from N and O, under the condition that, one of R2 and R6 is not hydrogen; R3 and R5, each is independently chosen from a group, consisting of hydrogen, halogen; R4 represents hydrogen; R7 represents - NR11C(O)R12; R8, R9, R10 and R14, each is independently represents hydrogen; R11 represents hydrogen, C1-C6alkyl; and R12 is chosen from a group, consisting of halogen C1-C6alkyl; where each substituted group is substituted with one or more groups, chosen from -Q, -R40, -OR40, -C(O)R40, -C(O)OR40, where each Q independently represents halogen, R40 and R41 are independently chosen from a group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, under the condition that: (i) at least one of A, D, E, G, J, L or M represents N; (ii) not more than one of A, D, E or G represents N; and (iii) not more than one of J, L or M represents N.

EFFECT: obtaining pyridyl-substituted heterocycles for treating and preventing infections, caused by hepatitis C virus.

33 cl, 85 dwg, 101 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new derivatives of imide indolylmaleic acid with the formula I , where Ra denotes H; C1-4alkyl or C1-4alkyl, with substituted OH, NH2, NH(C1-4 alkyl) or H(C1-4alkyl)2; Rb denotes H or C1-4alkyl; R denotes a radical of the formula (d) or (e) , where each one from R8 and R11 independently denotes OH; heterocyclic residue; NR16R17, where each from R16 and R17 independently denotes H or C1-4alkyl, or R16 and R17 together with a nitrogen atom; to which they are joined, form a heterocyclic residue; or a radical of the formula -X-RC-Y (α) where X denotes a covalent bond, O, S or NR18, where R18 denotes H or C1-4alkyl; Rc denotes C1-4alkylen or C1-4alkylen, in which one CH2 has been changed with the group CRxRy, whereby one of Rx and Ry denotes H, and the other denotes CH3, each of the Rx and Ry denote CH3 or Rx and Ry together form the group -CH2-CH2-, and Y is joined with the terminal carbon atom and is selected from OH, -NR19R20, where each one of R19 and R20 independently denotes C1-4alkyl; each one of R9, R10, R12, R13 independently denotes H, halogen, C1-4alkyl, OH, NH2, C1-4alkoxy, NH(C1-4alkyl) or N(C1-4alkyl)2 or each E denotes -N= and G denotes -CH= or E denotes -CH= and G denotes -N=, and cycle A is unsubstituted, monosubstituted, where the substitute is selected from a group containing halogen, OH, C1-4alkoxy, C1-4alkyl, NO2, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2 or CN; where the heterocyclic residue is 3-8 member saturated, heterocyclic rings, containing 1-2-heteroatoms, of which one is N, and the other N or O, possibly substituted with one or more carbon atoms in the cycle and/or with a nitrogen atom in the cycle, if it is in the ring; where the substitutes of the carbon atom ring, if they exist, are selected from the group which contains C1-4alkyl, C3-C6cycloalkyl, it is optional to further substitute C1-4alkyl; , where p denotes 1, 2 or 3; and where the substitutes on the nitrogen atom ring if they exist, are selected from a group which contains C1-4alkyl, C3-C6cycloalkyl, C3-C6cycloalkyl C1-4alkyl, phenyl, phenylC1-4alkyl, heterocyclic residue and the residue from the formula β: -R21-Y' (β) R21 - denotes C1-C4alkylen, a Y' denotes OH, NH2, NH(C1-4alkyl) or N(C1-4alkyl)2, where the heterocyclic residue is of importance, as stated above, or its pharmaceutically acceptable salts.

EFFECT: bonds possess an action, which has an inhibitory activity on proteinkinase C and can be used in a pharmaceutical composition for treatment or prophylaxis of acute or chronic rejection of allo or xenotransilants of organs or tissues.

10 cl, 7 tbl, 182 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to 2-thio substituted derivatives of imidazole with formula I , where R1 represents aryl, which can be substituted by a halogen atom or halogen-C1-C6-alkyl; R2 is chosen from a group, containing a) aryl-C1-C4-alkyl, and b) C1-C6-alkyl; R3 is chosen from a group, containing (a) NR4R10, (b) NR7COR10, (c) OR10, (d) NH2; R4 represents H; R3 and R6, which can be the same or different, represent H, halogen, OH, C1-C6-alkoxy, C1-C6-alkyl or halogen-C1-C6-alkyl; R7 represents R4; R10 has one of the following values: (a) A-B, (b)-(e), (f) C1-C6-alkyl, which is substituted with 2 phenyl groups; A represents linear or branched C1-C6-alkylene; B is chosen from a group, containing (a) H, (b)-(e), (f) OC1-C6-alkyl, (g) OH; Hy represents 3-10-member non-aromatic, mono-, bi- or tricyclic carbocycle, which can be or not be condensed with a benzene ring; Ar represents 5- or 6- member aromatic heterocycle, which has 1 heteroatom, chosen from a group, consisting of O, S, and N, and which may not be condensed with a benzene ring, Het represents 5- or 6-member non-aromatic heterocycle, which has 1 heteroatom, which represents O, which may not be condensed with a benzene ring; m is 0,1 or 2; or its optical isomers or physiologically used salts. Compounds with formula I are used when making pharmaceutical compositions with inhibiting effect on release of cytokines.

EFFECT: obtaining of derivatives, which have inhibiting action to release of cytokine action.

13 cl, 4 tbl, 148 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to a new method of obtaining derivatives of N-phenyl-2-pyrimidineamine (2-anilinopyrimidine) with general formula (I), which have a wide spectrum of biological effects and can be used mainly, for treating various types of tumours, leucaemia, cerebral ischemia, vascular stenosis and other diseases. In general formula (I) , R1 represents a pyridyl or its oxide bonded to a carbon atom, which can be substituted with a low alkyl or alkoxy, each of R2 and R3 independently represents hydrogen, branched of unbranched low alkyl, phenyl, unsubstituted of substituted with a haloid, R4 represents hydrogen, unbranched or branched low alkyl, R5 represents hydrogen, low alkyl, possibly substituted with halogen atoms. Other representations of radical are given in the formula of invention. The method involves the following stages: A) reaction of urea, mainly in a basic medium with N,N-dialkyamino-1-(3-pyridyl)-2-propene-1-ono with general formula II: with obtaining of the corresponding dihydropyrimidinone with general formula (III) B) oxidation of compound (III) by proton oxidation, with obtaining of the corresponding hydroxypyrimidine with formula IV , C) activation of the hydroxy group in the obtained compound IV , for example, treatment using sulphohalide R'SC2Hal or anhydride R'(SO2)2O, with obtaining of a compound with general formula V , where R' represents aryl of low alkyl, D) reaction of the obtained compound V with the corresponding aromatic amino compound with formula VI , with obtaining of compound with formula (I) and subsequent possible conversion of the obtained compounds to other compounds with general formula (I).

EFFECT: method allows for excluding use of toxic compounds and simplifies the process.

13 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of quinoline with general formula Ia or Ib their stereoisomers and pharmaceutical salts, where X represents oxygen or sulphur, Z-CH2, Y-NO2, -C(O)OR5, -NR5SO2R5, -SO2R5 (for Ia) and -NO2 or -C(O)OR5 (for Ib). Description is also given of the method of obtaining Ia and Ib compounds, pharmaceutical compositions based on them, and their use when making medicinal preparations.

EFFECT: compounds can be used for treating lesions, related to inhibition of migration of magrophage, for example, during treatment of septic shock or arthritis.

175 cl, 16 tbl, 22 ex, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 2-[1-(1,1-dioxothietanyl-3)-1,2,4-triasolyl-5-thio]acetic acid of formula I , where R=H2N+(CH2CH2OH)2 (Ia); R=H3N+CH2CH2OH (Ib).

EFFECT: increased hemorrheologic activity and possibility to apply for reduction of blood viscosity.

4 cl, 2 tbl, 2 ex

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