Pharmaceutical composition for treatment of allergic diseases, the method antihistamine treatment, the use of a composition for obtaining a medicinal product

 

(57) Abstract:

The invention relates to medicine. The proposed pharmaceutical composition comprising a metabolite of terfenadine for treatment of allergic rhinitis. Composition expands the Arsenal of tools specified destination. 4 C. and 16 h.p. f-crystals, 4 PL.

The present invention relates to new pharmaceutical compositions containing 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] - dimethylbenzenamine and 1-[p-(2-hydroxymethylene-2-yl)-phenyl] -4-[4-(hydroxy-phenyl-benzyl)piperidine-1-yl] butanol, and their optically pure derivatives. These compositions have a strong antihistaminic activity and are suitable for the treatment of allergic rhinitis, asthma and other allergic diseases, drugs, does not cause any side effects associated with the introduction of other-aryl-4-substituted derivatives of piperidinemethanol, such as terfenadine, including cardiac arrhythmia, drowsiness, nausea, fatigue, weakness, and headache, and not only them. In addition, such compositions in combination with non-steroidal anti-inflammatory drugs or other non-narcotic analgesics suitable for the treatment of cough, colds, symptoms and ned the e combination can not necessarily, include one or more other active ingredients, including decongestants means of a person's cough or antitussives or expectorants.

Moreover, such new pharmaceutical compositions containing 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,,- dimethylbenzenamine and 1-[p-(2-hydroxymethylene-2-yl)phenyl]-4-[4-( -hydroxy-phenylbenzyl)-1-piperidine-1-yl]butanol, and their optically pure derivatives suitable for the treatment of motion sickness, dizziness, diabetic retinopathy, complications due to diabetes, small vessels and other such conditions that may be correlated with the activity of these derivatives as antagonists vitaminnogo receptor N-1, without causing at the same time, the side effects associated with the introduction of other-aryl-4-substituted derivatives of piperidinemethanol, such as terfenadine.

Also disclosed methods of treatment of the above conditions in person to avoid side effects that are associated with the introduction of other-aryl-4-substituted derivatives of piperidinemethanol, such as terfenadine, by introducing the above-mentioned pharmaceutical compositions containing 4-[1-hydro is-4-[4-( -hydroxy-phenylbenzyl)piperidine-1-yl] -butanol or their optically pure isomers, mentioned the man.

Active compounds in these compositions and methods are metabolic derivatives of terfenadine. From a chemical point of view, these derivatives represent methyl-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)-butyl] -,- dimethylbenzene, 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid and 1-[p-(2-hydroxymethylene-2-yl)phenyl] -4-[4-( -hydroxy-phenylbenzyl)piperidine-1-yl] butanol and optical isomers of compounds. These compounds are described Garteig et al., Argeneimittel-Frschung / Drug Research, 32: 1185-1190 (1982). From a chemical point of view, the optical isomers of these compounds are methyl-R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylphenylacetic, methyl-S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylphenylacetic, R-(+)-4-[1-hydroxy-4- (4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid, S-(-)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid, R-(+)-1-[p-(2-hydroxymethyl-2-prop-2-yl)phenyl]-4-[4-( -hydroxy-phenylbenzyl)piperidine-1-yl] butanol and S-(-)-1-[p-(2-hydroxymethylene-2-yl)phenyl]-4-[4-( -hydroxy-phenylbenzyl)piperidine-1-yl]bcee compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to ensure the absolute configuration of the molecule about its chiral center (centers). Prefixes or (+) and (-) are used to indicate the direction of rotation of the connection plane-polarized light, and (-) or means that the connection is levogyrate. The connection to the prefix (+) or is Pervouralsk. When this chemical compound structure, called stereoisomers are identical, except that they are mirror images of one another. A specific stereoisomer may also be called an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.

The stereochemical purity can have a value in the pharmaceutical field, when 12 of the 20 most commonly prescribed drugs exhibit chirality. A striking example is the L-form - adrenergic blocking tools - propranolol known that he is 100 times more potent than the D-enantiomer.

Moreover, optical purity mo inert. For example, indicates that the D-enantiomer of thalidomide is a safe and effective sedative agent, when prescribed for combating nausea in pregnancy, while the corresponding L-enantiomer is considered a strong teratogen.

The enantiomers of 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid are described in Zamani et al, Chirality, 3: 467-470 (1991). In this work indicated that (R)-enantiomer of the input oral racemic terfenadine mainly oxidized in the body of rats with the formation of carboxylic acid metabolite enriched (R)-enantiomer. The enantiomers of 4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid also describes Chan et al, J. Chromatog, 571: 291-297 (1991). In this work indicates that terfenadine in human body does not undergo any stereoselective isomeric interconversion.

Terfenadine is an antagonist of the protein N-1 vitaminnogo receptor. Proteins histaminic receptors are found in tissues in two well-recognized forms - in the form of receptors N-1 and N-2. Receptors N-1 are receptors that mediate antagonistic reactions to normal GS and in bronchial smooth muscle of the Guinea pig. Terfenadine inhibits the action of histamine on the isolated ileum of the Guinea pig histamine suppresses caused blisters on the skin of rhesus monkeys and protects Guinea pigs from a lethal outcome caused by histamine.

After the reaction, the mediator which is H-2-receptor, histamine stimulates gastric acid secretion in Guinea-pig and chronotropic effect in the isolated atrium of the Guinea pig. Terfenadine no effect on gastric acid secretion induced by histamine, and does not change the chronotropic action of histamine on the auricle. Thus, terfenadine has no obvious effect on histaminic H-2-receptor. Cm. Cheng et al., Drug Development Research, 2; 181-196 (1982).

Terfenadine is well absorbed, but in the course of metabolism he fully converted. Cm. Okerholm et al., Biopharmaceuties and Drug Distribution, 2: 185-190 (1981). Identified two main metabolite, and it is assumed that one of the metabolites of 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzanthracene acid can detect antigistaminny activity in vitro, but the actual data is not published. Cm. Garteig et al. , Argneimittel-Forschung/Drug Research, 32: 1185-1190 (1982).

Based n the economic rhinitis. Clinical testing the efficacy of terfenadine showed that he was somewhat less effective than chlorpheniramine - another antagonist N-1, Cm. Connell, Pharmacetherapy, 5: 201-208 (1985).

It was also assumed that terfenadine is suitable for the treatment of asthma. Terfenadine suppresses the increase of the airway resistance caused by LTD4(leukotriene D4) in Guinea pigs. Cm. Akagi et al., Oyo yakuri, 35: 361-371 (1988).

Terfenadine may also be useful in the treatment of motion sickness and vertigo. I found that some antihistamines are effective for prophylaxis and treatment of motion sickness. Cm. Wood, Drugs, 17: 471 - 479 (1979). Also it is confirmed that some antihistamines are suitable for the treatment of vestibular disorders such as Meniere's disease, and other types of dizziness. Cm. Cohen et al, Archives of Neurology, 27: 129 - 135 (1972).

In addition, terfenadine may be useful in the treatment of diabetic retinopathy: having fine vessels and other disorders associated with diabetes (diabetes mellitus). When tested on rats in which diabetes induced by streptozocin, treatment with antihistamines prevents activation of retinal histaminic receptors, which participate in the development of diabeticescomu diabetes, disclosed in U.S. patent N 5019591.

It is also assumed that terfenadine in combination with non-steroidal anti-inflammatory drugs or other non-narcotic analgesics will be useful in the treatment of cough, colds, prostatomegaly and/or flu symptoms and the discomfort, pain, headache, fever and General associated with such disorders, ailments. The use of pharmaceutical compositions containing terfenadine and non-narcotic analgesics or non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen and ibuprofen, are described in U.S. patent N 4783465 and 4829064. Such compositions for the treatment of the above symptoms does not necessarily can include one or more other active ingredients, including decongestants tools (such as pseudoephedrine), suppress cough or antitussives such as dextromethorphan) or expectorants (such as guaifenesin).

Many antihistamines cause of action, similar to some extent with the side effects. Such side effects include, but are not limited to, sedation, gastrointestinal upset, dry mouth and constipation or diarrhea. About the playing technique, gastrointestinal upset, dry mouth and constipation or diarrhea.

However, it was found that the introduction of terfenadine man cause other side effects. Such side effects include, but are not organicists them, cardiac arrhythmia, including ventricular tachyarrhythmia, Torsade de pointes and ventricular fibrillation. Recently, practitioners in the clinics of the increasing number of cases of cardiac arrhythmia in a joint introduction of terfenadine with other drugs, such as ketoconazole and erythromycin, or overdose of terfenadine. Cm. Brian P. Monahan et al., in JAMA, 5th Dec 1990, Vol. 264, N 21, PP. 2788-2790, and the work of Sandra Knowles in Canadian Journal of Hospital Phasmacy-Vol. 45, No. 1, Ist Feb 1992, p. 33.

Thus, it would be particularly desirable to find a compound with the advantages of terfenadine, but which would not have the aforementioned disadvantages.

Presently discovered that methyl-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)-butyl] -,- dimethylbenzene, 4-[1-hydroxy-4-(4-hydrazinophenyl-1-piperidinyl)butyl] -,-dimethylbenzoquinone acid and 1-[p-(2-hydroxymethylene-2-yl)phenyl]-4-[4-( -hydroxy-phenylbenzyl)piperidine-1-yl]butanol and their optically pure isomers (hereinafter called the estuaries and the ina") are effective antihistamines. Also found that pharmaceutical compositions containing the metabolic derivatives of terfenadine or their optically pure isomers are suitable for the treatment of allergic diseases and other such conditions as may be assigned to tracks with antihistamine activity, and the number of such States include, but are not limited to, allergic rhinitis, solar urticaria and symptomatic dermographism.

In addition, it is found that the metabolic derivatives of terfenadine and their pure optical isomers are suitable for the treatment of motion sickness and vertigo, and treatment of disorders such as retinopathy: having fine vessels and disorders associated with diabetes. The present invention also includes methods of treatment of the above conditions in humans, and thus it is possible to avoid the side effects that accompany terfenadine, including, but not limited to, cardiac arrhythmias, sedation, gastrointestinal upset, dry mouth and constipation or diarrhoea, by introducing metabolic derivatives of terfenadine or their optically pure isomers mentioned the man.

Also found that metabolic pastime or other non-narcotic analgesics suitable for the treatment of cough, colds, prostatomegaly and/or flu symptoms and the discomfort, pain, headache, fever and General malaise associated with such conditions. Applied pharmaceutical composition of the present invention containing (1) metabolic derivatives of terfenadine or their optically pure isomers and (2) non-narcotic analgesics or non-steroidal anti-inflammatory drugs such as aspirin, acetaminophen or ibuprofen, can optionally contain one or more other active compounds, including decongestants tools (such as pseudoephedrine), suppress cough or antitussives such as dextromethorphan), or expectorants (such as guaifenesin).

The present invention includes a method of treating humans suffering from or susceptible to allergic disease, and thus it is possible to avoid interfering side effects associated with the introduction of terfenadine, and the above-mentioned method includes the introduction mentioned the person suffering from or susceptible to allergic disease, a certain amount of one or more compounds selected from the group consisting of metabolic derivatives of those the x salts, moreover, the above quantity is sufficient for the treatment of allergic mentioned diseases, but insufficient to cause adverse effects associated with terfenadine.

Accordingly, in the first aspect, the present invention provides a pharmaceutical composition comprising a compound of the formula I

(I)

in which Z represents COOH, COOCH3or CH2OH or its pharmaceutically acceptable salt, for use with antihistamine treatment that does not cause any appreciable cardiac arrhythmia, and this treatment includes an introduction to the patient a therapeutically effective amount of the compounds of formula I. the compounds of formula I include metabolic derivatives of terfenadine and their optically pure isomers, which are mentioned above.

Until the present invention, the experts in this field of technology believed that the compounds of formula I induce a cardiac arrhythmia known as Torsade de pointes (reported by Brian P. Monahan et al., in JAMA 5 th Dec 1990. Vol 264, N 21, pp. 2788-2790, and Sandra Knowles in The Canadian Journal of Hospital Pharmcy, Vol. 45, No. 1, ISt Feb 1992, p.33), as it is believed that such a potentially lethal arrhythmia is a "group effect" reseating antihista the rd. Accordingly, the fact that the composition of the present invention does not cause any such cardiac arrhythmia, is a new and very useful and unexpected technical effect, which gives the opportunity to enter the composition of the invention for individuals who are sensitive to cardiac arrhythmia, and potentially higher doses than the dose reseating antihistamines, such as terfenadine, which are used at the present time.

Antihistamine treatment may be a method of treatment of humans suffering from or susceptible to allergic violation; motion sickness; dizziness; retinopathy or other disease of the small vessels associated with diabetes; coughs, colds, colds or duly verified symptoms; or malaise, pain, fever or General malaise associated with such conditions. In embodiments implementing the invention may be any one, any combination or all of the aforementioned methods of treatment.

Preferably, the invention relates to the treatment of allergic diseases, which, preferably, is an asthma or allergic rhinitis.

In preferred embodiments of the invention Alceste 20-200 mg per day. When the composition of the invention is intended for use in the treatment of asthma or retinopathy or other diseases of the small blood vessels associated with diabetes, a sufficient amount of the composition according to the invention must be such a number that provides the patient the compounds of formula I in an amount of 0.01 to 500 mg per day, preferably in an amount of 0.1 - 200 mg per day.

In preferred variants of the invention, the composition according to the invention also includes pharmaceutically acceptable carrier or excipient.

In particular, when antihistamine treatment is a method of treating a person from coughs, colds, prostatomegaly or flu symptoms or discomfort, pain, fever or General malaise associated with such conditions, the composition may also contain therapeutically effective amount of a nonsteroidal anti-inflammatory agent or non-narcotic analgetic, such as acetylsalicylic acid, acetaminophen, ibuprofen, Ketoprofen, or naproxen, or pharmaceutically acceptable salt of such funds. On the other hand, or in addition, the composition according to the present invention may also include therapeutic is acceptable salt.

In a preferred embodiment of the invention the composition according to the invention comprises from 20 to 200 mg of the compounds of formula I and from 25 to 600 mg anti-inflammatory drugs or analgetika. When the composition according to the invention contains a therapeutically effective amount of an antitumor means, it preferably contains from 20 to 200 mg of the compounds of formula I and from 5 to 150 mg decongestant tools.

In preferred embodiments, the implementation of the present invention the compounds of formula I is in the form of only one optical isomer, and the composition essentially contains no other isomers of such compounds. In this embodiment of the invention the compounds of formula I, preferably selected from the group consisting of methyl-R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl) butyl] -,- dimethylbenzylamine, R-(+)-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid and R-(+)-1-[p-(2-hydroxymethylene-2-yl)phenyl]-4-[4-(-hydroxy-phenylbenzyl)piperidine-1-yl]butanol, and their pharmaceutically acceptable salts, and the composition essentially contains no S-stereoisomer of the selected connection; or the compounds of formula I are selected from the group consisting of 4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid and S-(-)-1-[p-(2-hydroxymethylene-2-yl)phenyl]-4- (-hydroxy-phenylbenzyl)piperidine-1-yl] butanol and their pharmaceutically acceptable salts, and the composition essentially contains no R-stereoisomer of the selected connection.

The compounds of formula I preferably contains 90% or more of the selected R - or S-stereoisomer.

In the most preferred embodiment of the invention Z in the formula I represents COOH and a compound of formula I is terminalinmarsat.

In another aspect, the present invention relates to a method providing patient antihistamine treatment that does not cause any appreciable cardiac arrhythmia, and which consists in the introduction to the patient a therapeutically effective amount of a pharmaceutical composition, which corresponds to the first aspect of the invention, preferably, one of the preferred variants of its implementation. Preferably, the method of the invention is a method of treatment of humans suffering from or susceptible to allergic disease; motion sickness; dizziness; retinopathy; or other disease of the small vessels associated with diabetes; coughs, colds, colds or duly verified symptoms; or malaise, pain, fever or General malaise associated is sensitive to allergic disease, and, preferably, when the allergic disease is an asthma or allergic rhinitis.

In its third aspect the present invention relates to the use of a composition of the first aspect of the invention, or any preferred variants of its implementation, in the manufacture of a medicinal product for use with antihistamine treatment that does not cause any appreciable cardiac arrhythmia, and is in the introduction to the patient a therapeutically effective amount of the compounds of formula I. Preferably, when such use is for the production of a medicinal product for use in the treatment of a human suffering from or susceptible to allergic disease; motion sickness; dizziness; retinopathy or other disease of the small vessels associated with diabetes; cough, cold, colds or duly verified symptoms; or malaise, pain, fever or General malaise associated with such conditions. Preferably, when the above-mentioned method is a method of treatment of a human suffering from or susceptible to allergic disease, which, preferably, predstavlyaet treatment and symptoms of various conditions and disorders, related to allergic diseases, diabetes and other conditions; however, this drug although gives hope for efficiency, has an unwanted effect. The use of metabolic derivatives of terfenadine or essentially pure optical isomers results in clearer dose-dependent detection efficiency, reduces side effects and improves therapeutic index. Therefore, it is advisable to apply a metabolic derivative of terfenadine or its optically pure isomer than terfenadine.

The term "side effects" ("undesirable effects") includes, but is not limited to, cardiac arrhythmias, sedation, gastrointestinal upset, dry mouth, constipation and diarrhea. The term "cardiac arrhythmia" includes, but is not limited to, ventricular tachyarrhythmia, Torsade de pointes and ventricular fibrillation.

The term "essentially not containing S-stereoisomer" as used, means that the metabolic derivative of terfenadine, is present in the composition contains at least 90 wt.% R-isomer metabolic derivative of terfenadine and 10 wt.% or less S-derivative. In predpochtiteljno derivative of terfenadine in the composition contains at least 90 wt.% R-isomer metabolic derivative of terfenadine and 1% or less S-isomer. In another preferred embodiment of the invention, the term "essentially not containing S - stereoisomer" as used here, means that the metabolic derivative of terfenadine in the composition contains greater than 99 wt.% R-isomer metabolic derivative of terfenadine and less than 1 wt.% S-derivative. The terms "essentially optically pure R-isomers metabolic derivatives of terfenadine" and "optically pure R-isomers metabolic derivatives of terfenadine" are also covered by the above definitions.

The term "essentially not containing R-stereoisomer" as used here, means that the composition contains at least 90 wt.% S-isomers metabolic derivatives of terfenadine and 10 wt.% or less than R-derivatives. In a preferred embodiment of the invention, the term "essentially not containing R - stereoisomer" means that the composition contains at least 99 weight. % S-isomers metabolic derivatives of terfenadine and 1% or less R-isomers. In another preferred embodiment of the invention, the term "essentially not containing R - stereoisomer" as used here, means that the composition contains more than 99 wt.% S-isomers metabolicheskikh derivatives of terfenadine in the composition. The terms "essentially optically pure S-isomers metabolic derivatives of terfenadine" and "optically pure S-isomers metabolic derivatives of terfenadine" are also covered by the above definitions.

The phrase "therapeutically effective amount" means such amount of one or more compounds of the invention, which provides a favorable therapeutic effect with antihistamine treatment, including treatment or assistance in allergic diseases, asthma, retinopathy or other diseases of the small blood vessels associated with diabetes, motion sickness, dizziness, or coughs, colds, prostatomegaly and/or flu symptoms and the discomfort, pain, fever and General malaise associated with these conditions. Examples of allergic diseases include, but are not limited to, allergic rhinitis, solar urticaria and symptomatic dermographism. The symptoms associated with these allergic diseases, cough, cold, prostatomegaly and/or flu-like symptoms include, but are not limited to, sneezing, rhinorrhea, lacrimation and painful skin sensitivity. The term "asthma" defines a disease characterized by the increases which indicate stercorosus breath, cough and shortness of breath. The term "dizziness" as used here, means dizziness associated with motion, height, body position change, but is not limited to this. The term "diabetic retinopathy or retinopathy associated with diabetes mellitus" refers to a disease caused by the increased permeability of the capillaries in the eyes, which leads to hemorrhage and edema of the eyes and may cause blindness. The term "disease of small blood vessels associated with diabetes" includes, but is not limited to, diabetic retinopathy, and peripheral vascular disease.

The separation of optically pure isomers of metabolic derivatives of terfenadine can be done by splitting of racemic mixtures of enantiomers metabolic derivatives of terfenadine with conventional means, such as optically active digestive acid. In addition, the optically pure isomers metabolic derivatives of terfenadine can be obtained from racemic mixtures by enzymatic biocatalytic cleavage. See, for example, the U.S. patents NN 5057427 and 5077217 described in the present invention as references.

The value of routine the military therapy or long-term treatment of the disease will vary depending on the severity of the condition, which are treated, and how the introduction. The dose, and perhaps the frequency of the dose will also vary according to age, body weight and individual response of the patient. In General, the interval of the total daily dose for these States ranges from 0.01 to 50 mg, which is entered as a single dose or divided doses, orally, topically, transdermal or locally using the aerosol. For example, the preferred interval daily dose by oral administration should be from 1 to 500 mg, with a preferred spacing of the daily dose by oral administration should be from 20 to 200 mg. in Addition, it is recommended that children, patients over 65 years of age and patients with weakened kidneys or liver, to give first a small dose, then titrated (adjusted) on the basis of individual reactions (reactions), or content in the blood. It may be necessary in some cases to apply a dose outside this range that will be obvious to specialists. Note, moreover, that the doctor at the clinic or doctor will be clear when and how to interrupt, adjust, or terminate, the treatment depending on the individual reactions of the patient.

accurate, to cause the aforementioned side effects", "quantity sufficient to facilitate in these asthma, but not enough to cause the aforementioned undesirable actions", "quantity sufficient to facilitate referred to motion sickness, but not enough to cause the aforementioned side effects" and "sufficient quantity to facilitate mentioned retinopathy and other diseases of small vessels associated with diabetes, but not enough to cause the aforementioned side effects are covered by the above dosages and mode of their reception. In addition, the phrase "pharmaceutical composition for use in the treatment of a person coughs, colds, prostatomegaly and/or flu symptoms and the discomfort, pain, fever and General malaise associated with these conditions, and the said composition comprises (i) a therapeutically effective amount of at least one metabolic derivative of terfenadine or its optically pure isomer, (ii) a therapeutically effective amount of at least one non-steroidal anti-inflammatory agent or non-narcotic analgetic" and the phrase "pharmaceutical composition for use ate pain, fever and General malaise associated with these conditions, and said composition includes (i) a therapeutically effective amount of at least one metabolic derivative of terfenadine or its optically pure isomer, (ii) a therapeutically effective amount of anti money", as the expression "therapeutically effective amount of at least one derivative - aryl-4-substituted derivative piperidinemethanol", also covered by the above described dosage and schemes of their application.

Any suitable route of administration may be used to provide the patient an effective dose of a composition according to the invention. For example, can be used for oral, rectal, parenteral, transdermal, subcutaneous, intramuscular and the like forms of administration. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, pads and the like.

The pharmaceutical compositions of the present invention contain as the active ingredient metabolic derivative of terfenadine or its optically pure isomer or pharmaceutically acceptable salts, and may also include the pharmacist is acceptable salt" includes salts, derived from pharmaceutically acceptable non-toxic acids or bases including inorganic acids or bases, or organic acids or bases. Examples of such inorganic acids are hydrochloric acid, Hydrobromic, Modesto-hydrogen, sulfuric and phosphoric acid. Appropriate organic acids may be selected, for example, among the aliphatic, aromatic, carboxylic and organic sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, glucoronosyl, maleic, Turaeva, glutamic, benzoic, antanimena, salicylic, phenylacetic, almond,albanova (AMOVA), methansulfonate, econsultancy, Pantothenic, benzolsulfonat, stearic, sulfanilic, alginic, and galacturonic acid. Examples of such inorganic bases are metal salts, including aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Suitable organic bases may be chosen, for example, from N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), lysine and procaine.

The composition of the present invention includes compositerule, diluents, granulating tools, lubricants, binders, dezintegriruetsja tools, etc. in the case of solid preparations (such as powders, capsules and tablets) for oral administration, and solid preparations for oral administration are preferable to liquid preparations for oral administration. The most preferred solid preparations for oral administration are tablets.

Due to the simplicity of their administration tablets and capsules represent the most convenient form of a standard dose of a drug for oral administration, and in this case, use solid pharmaceutical carriers. If desired, tablets may be coated with standard techniques, with water or without water.

In addition to conventional dosage forms mentioned above, the compounds of the present invention can also be entered by means of adjustable selection and/or devices for delivery, such as the devices described in U.S. patents NN 3845770, 3916899, 3536809, 3598123 and 4008719.

The pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as kapoe amount of the active ingredient, in the form of powder or granules, or in the form of a solution or suspension in an aqueous liquid, non-aqueous liquid, emulsion, oil-in-water or emulsion water-in-oil. Such compositions can be prepared by any method known in pharmacy, but all methods include the stage of bringing in connection active ingredient with the carrier which consists of one or more necessary ingredients. Generally, the composition is prepared by thorough mixing to a homogeneous condition of the active ingredient with liquid carriers, or finely powdered solid carriers, or with both, and then, if necessary, shaping the product into the desired shape.

For example, tablets can be obtained by extrusion or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in free presuposes form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made in a suitable machine by molding the mixture is scored from 10 to 150 mg of active ingredient, and each wafer or capsule contains from 10 to 150 mg of active ingredient, i.e., a metabolic derivative of terfenadine. Most preferably, when the tablet, wafer or capsule contain one of these three doses of 30, 60 or 90 mg of the active ingredient.

Further, the invention is defined by the examples describing in detail the receipt of compounds and compositions of the present invention and their use. Specialists will be clear that in practice can be implemented numerous modifications as materials and methods that are within the scope of the present invention.

Examples

Example 1

A. Obtaining methyl-R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-,- dimethylbenzenamine

Connect 4-( -hydroxy-phenylbenzyl)piperidine (4.3 g) with methyl-n-(4-chloro-1-oxobutyl)-,-dimethylbenzenamine (4.5 g), potassium bicarbonate (2.9 g), potassium iodide (approximately 50 mg) and isobutyl ketone (50 ml), and heated under reflux for 48 hours. Add a further quantity of 4-(-hydroxy-phenylbenzyl)piperidine (1.1 g) and heating continued for another 48 hours. After cooling the mixture to room temperature, water is added the display with ethyl acetate. An ethyl acetate solution is washed with saturated aqueous sodium bicarbonate and with brine and dried over sodium sulfate. The ethyl acetate is removed on a rotary evaporator, and the residue is treated with 25% ethyl acetate in hexane. The resulting precipitate is filtered off and dried in the air, get methyl-4-[oxo-4-(4-hydroxydiphenylmethyl-1-piperidinyl)-butyl] -,-dimethylphenylacetic. This intermediate residue (2.4 g) are combined with tetrahydrofuran (10 ml) and (+)-- chlorine-deisopentanisation (4.5 g) and stirred for 48 hours. To the reaction solution was added methanol (10 ml) and sodium bicarbonate (1.5 g) and the mixture is stirred for 12 hours. The mixture is diluted with ethyl acetate (200 ml), washed with saturated aqueous bicarbonate sodium, methyl get-R-4[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylphenylacetic.

B. R-(+)-4-[1-Hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl[ -,- dimethylbenzoxazole acid [R-(+)-terminalinmarsat]

Connect methyl-R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] dimethylanthracene (1.2 g) with potassium hydroxide (0.4 g) and ethanol (5 ml) and the mixture heated under reflux for 7 hours. The ethanol is removed on the river is receiving solids, which is recrystallized from a mixture of methanol with ethyl acetate (1: 1), and obtain R-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzoxazole acid (R-terminalinmarsat) (so pl. 213 - 215oC).

C. Obtaining methyl-S-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzenamine

Mix 4-( -hydroxy-phenylbenzyl)piperidine (4.3 g) with methyl-n-(4-chloro-1-oxobutyl)-,-dimethylbenzenamine (4.5 g), potassium bicarbonate (2.9 g), potassium iodide (approximately 50 mg) and isobutyl ketone (50 ml) and heated under reflux for 48 hours. Add a further quantity of 4-(-hydroxy-phenylbenzyl)piperidine (1.1 g) and heating continued for another 48 hours. After cooling the mixture to room temperature, add water and bring the pH to approximately 12 by add aqueous sodium hydroxide solution. The mixture is extracted with ethyl acetate. An ethyl acetate solution is washed with saturated aqueous sodium bicarbonate with the saline solution and dried over sodium sulfate. The ethyl acetate is removed on a rotary evaporator and the residue is treated with 25% ethyl acetate in hexane. The resulting precipitate is filtered off and dried in visualizating compound (2.4 g) is mixed with tetrahydrofuran (10 ml) and ( - ) - chlorodiisopinocampheylborane (4.5 g) and stirred for 48 hours. To the reaction solution was added methanol (10 ml) and sodium bicarbonate (1.5 g) and the mixture is stirred for 12 hours. The mixture is diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate, get methyl-S-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)-butyl] -,-dimethylphenylacetic. If the above-mentioned precipitate intermediate compounds enter into interaction with racemic - chlorodiisopinocampheylborane, then they'll get a racemic mixture of methyl-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-,-dimethylphenylacetate.

DS-(-)-4-[1-Hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl] -,- dimethylbenzanthracene acid

[S-(-)-terminalinmarsat]

Mix methyl-S-4-[1-hydroxy-4-(4-hydroxydiphenylmethyl-1-piperidinyl)butyl]-,-dimethylanthracene (1.2 g) with potassium hydroxide (0.4 g) and ethanol (5 ml) and the mixture heated under reflux for 7 hours. The ethanol is removed on a rotary evaporator and the residue is dissolved in water (2 ml). The aqueous solution acidified with glacial acetic acid to obtain a solid, which is recrystallized from a mixture of methanol with ethyl acetate (1: 1), and receive S-(-)-4-[1- hydroxy-4-(4-hydroxydiphenylmethyl-1-p is the Example 2

The activity of compounds of the invention against vitaminnogo 1receptors evaluated using the definition of the binding of [3H]pyrilamine that described by Chang et al., J. Neurochem, 32; 1653 - 1663 (1979). Briefly, the test is carried out as follows. Membranes of cerebellar cow incubated with3H]-pyrilamine and variable concentrations of the test compounds. The reaction is carried out in 50 mm nutrifaster buffer (pH 7.5) at 25oC for 30 minutes. The reaction is finished rapid filtration under vacuum through a filter made of fiberglass. Determine the radioactivity trapped by the filters, and compared to control values in order to make sure the interaction of test compounds with H1-a receptor. Get the following results (see tab. 1).

Example 3

Single ventricular myocytes obtained from selected hearts cats conventional techniques. Plochodrazni individual cells stored in HEPES-buffer and fix them in a bunch-patches" ("patch clamped"), using a pipette, calibrated on the intake volume. To write current waveforms use the amp Patch-Clamp L/M-PEC 7 and the recording electrodes filled with a solution of potassium aspartate. The voltage pulses piles (Clamp) and information con and each experimental concentrations of the following drugs: racemic terfenadine, the racemic terminalinmarsat and quinidine (as the compound selected for comparison). The results are shown below (see tab. 2).

These results show that terminalinmarsat, surprisingly, not prone to cause cardiac arrhythmia at the dose levels at which there is a clear risk of this side effect caused by terfenadine.

The active ingredient, which can be a instead of (S) terfenadinecyclosporine (R)terminalinmarsat or the racemic terminalinmarsat, sieved and mixed with fillers. The mixture is poured into suitable size hard gelatin capsules consisting of two parts, using appropriate mechanisms. You can cook other doses, changing charging weight, and if necessary, changing the size of the capsule to the right.

Example 5

Oral formulation tablets (see tab. 4).

The active ingredient, which can be a instead of (R)-terfenadinecyclosporine (S)-terminalinmarsat or the racemic terminalinmarsat, sieved and blended with the lactose until a uniform mixture. Add appropriate amount of water and powder granularit. After wyszukiwanie form. Tablets with different efficiency can be obtained by varying the ratio of the active ingredient and filler (filler) or mass for extrusion.

1. Pharmaceutical composition comprising a metabolite of terfenadine formula

< / BR>
or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, for the treatment of allergic rhinitis, does not cause cardiac arrhythmia, characterized in that it contains 15 to 90 wt.% metabolite of terfenadine in the form of R-(+)-stereoisomer, essentially free from S-(-)-isomer, and 85 - 10 wt.% pharmaceutically acceptable carrier or excipient.

2. The pharmaceutical composition under item 1, characterized in that it additionally contains about 25 to 600 mg nonsteroidal anti-inflammatory agent or non-narcotic analgesic.

3. The pharmaceutical composition according to p. 2, characterized in that it contains about 50 to 300 mg anti-inflammatory agent or analgesic.

4. The pharmaceutical composition under item 1, characterized in that it further comprises about 5 to 150 mg protivozastojnog or decongestants tools.

5. The pharmaceutical composition according to p. 4, characterized in that ccomposite, including metabolite of terfenadine formula

< / BR>
or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, for the treatment of allergic rhinitis, does not cause cardiac arrhythmia, characterized in that it contains 15 to 90 wt.% metabolite of terfenadine in the form of S-(-)-stereoisomer, essentially free of R-(+)-isomer, and 85 - 10 wt.% pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition according to p. 6, characterized in that it additionally contains about 25 to 600 mg nonsteroidal anti-inflammatory agent or non-narcotic analgesic.

8. The pharmaceutical composition according to p. 7, characterized in that it contains about 50 to 300 mg anti-inflammatory agent or analgesic.

9. The pharmaceutical composition according to p. 6, characterized in that it further comprises about 5 to 150 mg protivozastojnog or decongestants tools.

10. The pharmaceutical composition according to p. 9, characterized in that it contains about 10 to 75 mg protivozastojnog or decongestants tools.

11. Pharmaceutical composition comprising a compound of the formula I

< / BR>
or its pharmaceutically acceptable Sol is technoi arrhythmia, characterized in that it contains 15 to 90 wt.% metabolite of terfenadine formula I and 85 - 10 wt.% pharmaceutically acceptable carrier or excipient.

12. The pharmaceutical composition according to p. 11, characterized in that it additionally contains about 25 to 600 mg nonsteroidal anti-inflammatory agent or non-narcotic analgesic.

13. The pharmaceutical composition according to p. 12, characterized in that it contains about 50 to 300 mg anti-inflammatory agent or analgesic.

14. The pharmaceutical composition according to p. 11, characterized in that it further comprises about 5 to 150 mg protivozastojnog or decongestants tools.

15. The pharmaceutical composition according to p. 14, characterized in that it contains about 10 to 75 mg protivozastojnog or decongestants tools.

16. Pharmaceutical composition in the form of an oral solid preparation, comprising 60 mg of the compounds of formula

< / BR>
or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, for the treatment of allergic rhinitis, does not cause cardiac arrhythmia.

17. The pharmaceutical composition according to p. 16, characterized in that it further comprises a LASS="ptx2">

18. The pharmaceutical composition according to p. 16, characterized in that it contains about 25 to 600 mg anti-inflammatory agent or analgesic.

19. The pharmaceutical composition according to any one of paragraphs.16 to 18, characterized in that it further contains an effective amount protivozastojnog or decongestants tools.

20. The pharmaceutical composition according to p. 19, characterized in that it contains about 5 to 150 mg protivozastojnog or decongestants funds.

 

Same patents:

The invention relates to the field of medicine and is suitable for the treatment of seasonal and perennial allergic rhinitis, conjunctivitis, hay fever, urticaria, including chronic idiopathic urticaria, angioedema, psevdoallergicakie reactions caused by the release of histamine, itching dermatoses, allergic reactions to insect bites and itching of various etiology

The invention relates to cyclopentapeptide formula (I):

cyclo (A-B-C-E-F-(D)-Ala)

in which A, B, C, E and F, independently of one another, may be the same or different and represent a residue of a natural amino acid except cysteine (Cys) and tryptophan (Trp), and accordingly can be an alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), glutamine (Gln), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), Proline (Pro), serine (Ser), tryptophan (Thr), tyrosine (Tyr) or valine (Val), as well as their physiologically compatible salts

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2

The invention relates to medicine, in particular to pharmacology concerns anti-allergic and anti-inflammatory agents of the formula I, with low toxicity

-cyclodextrin with antihistaminic activity" target="_blank">

The invention relates to medicine, in particular to pharmacology, comes to tablets diazoline prepared on the basis of the inclusion complex of the substance with-cyclodextrin with antihistaminic activity

The invention relates to new derivatives of railbirding formula I, where X and Y independently of one another denote N or CH; ring a is an unsubstituted or substituted benzene ring, or their salts

The invention relates to an external preparation for topical application, in particular to the outer local drug use, containing as activitiesthese substance 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or its pharmaceutically acceptable acid salt additive
The invention relates to medicine, namely to Allergology, and for the treatment of hay fever in children

The invention relates to new derivatives of naphthalene or dihydronaphthalene formula I, where R1means-HE or-O(C1-C4-alkyl), R2- C1-C6-alkyl or C5-C7-cycloalkyl, X represents-CH(OH)-, or-CH2-, M represents-CH2-CH2- or-CH=CH-, n is 2 or 3, R3denotes 1-piperidinyl or 1-pyrrolidinyl, or their pharmaceutically acceptable salts

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

The invention relates to novel di - and trivalent small selectin inhibitors of formula II, where X is selected from the group comprising-CN, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)m-CO2H, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H), (CH2)mCO2H,

-OH; Y = -(CH2)f; R1, R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2; R3selected from the group including hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkyl-carboxylic acid; f = 1 - 6; n = 0 to 2; b = 0 - 2; m = 1 to 3; Z represents lower alkyl, phenyl, or their pharmaceutically acceptable salts, esters, Amida

The invention relates to new niftystories compounds of formula I, where R1and R2- H, -OH, -O(C1-C4alkyl), -OCOC6H5, -OCO(C1-C6alkyl), -OSO2(C4-C6alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, 1 hexamethyleneimino; intermediate compounds, which are suitable for easing symptoms of postmenopausal syndrome, including osteoporosis, hyperlipemia and estrogenzawisimy cancer, and inhibition of uterine fibroids, endometriosis and proliferation of aortic smooth muscle cells

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, carboxypropyl, (C1- C4-alkoxy)carbonyl GRU

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions for oral administration in the form of a solid dispersion

The invention relates to therapeutic tools, specifically setidentityproviderid N-substituted nitrogenous heterocyclic compounds and methods of producing such compounds, intermediate products used in obtaining, compositions containing such compounds and the use of such heterocycles

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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