Method of inhibiting conditions associated with bradykinin

 

(57) Abstract:

The invention relates to medicine, in particular for therapy and for the treatment of pathological conditions in which it participates, including an excess of bradykinin. For this purpose it is proposed to use a group of 2-phenyl-3-koivistoinen as antagonists of the bradykinin receptor. The method provides the inhibition of pathological conditions involving bradykinin. 2 C.p. f-crystals.

Bradykinin is a nonapeptide having the amino acid sequence of

Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg,

which is hereinafter referred to as SEQ ID NO:1, belonging to the family of kinins, which also includes kallidin or lysyl-bradykinin, which has the amino acid sequence of

Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg,

which poured forth as SEQ ID NO:2, and methionyl-lysyl-bradykinin, which has the amino acid sequence of

Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg,

which is hereinafter referred to as SEQ ID NO:3. These kinini stand out from the plasma predecessors (kininogens) under the influence of plasma and tissue kallikreins to regulate important physiological functions [For a review of therapeutic prospects of bradykinin receptor antagonis, jeludochno-intestinal function and tone of smooth muscle in vascular and other tissues. Bradykinin is one of the key mediators of reactions to trauma and damage. Abnormally elevated secretion of bradykinin in response to harmful substances, tissue damage or lack of circulating kinases can induce various pathological conditions from rheumatoid arthritis to asthma.

The bradykinin receptor exist in the nervous system, epithelium, smooth muscle and fibroblasts. Each type of tissue bradykinin is trigger specific reactions, including allocation of neurotransmitter, muscle contraction, fluid secretion by the epithelium and the stimulation of cell growth. The initial interaction for biological response occurs at the site of the bradykinin receptor on the cell.

Bradykinin can activate neurons and cause the secretion of neurotransmitter. He can activate phospholipase C and a2, resulting in the formation of a number of biologically active intermediates.

The bradykinin receptor is G protein-coupled receptors that activate phospholipase C or phospholipase a2and increase the synthesis of Vlada family of membrane proteins, which become activated only after the binding of guanosine triphosphate. Activated G proteins in turn activate amplificating enzyme on the inner surface of the membrane; then the enzyme converts molecules of the precursor in the secondary messengers.

The bradykinin receptor is classified as1and IN2based on the relative potencies of agonists (kinins) and antagonists (analogues cenina) at various pharmacological drugs. R. J. Vavrek and J. M. Stewart, Peptides, 6: 161-164 (1985). IN1receptors are generated de novo in vascular smooth muscle during incubation of isolated tissues and induced antigen arthritis. J. Bouthiller, et al., British Journal of Pharmacology, 92: 257-264 (1987).

There is still a continuous need for dipeptidyl the receptor antagonists of bradykinin. Known pharmacological agents containing fragments of molecules guanidine. See, for example, the U.S. patents 5059624 and 5028613. These two issued patents describe a number of pyrroloquinoline alkaloids, isolated and purified from some marine sponges. U.S. patent 5288725, issued February 22, 1994, describes a series of compounds pyrroloquinoline-guanidine which are useful as antagonists of the receptor bradykinin is s useful as antagonists of the bradykinin receptor, possessing analgesic properties. U.S. patent 5216165, issued June 1, 1993, describes a series of N-substituted aminoquinolines, useful as analgesics agents, due to their properties as receptor antagonists of bradykinin.

Continues to exist a need for an effective and safe compounds that are useful as antagonists of the bradykinin receptor. The present invention presents a new series of such antagonists that can be entered in various ways, including oral and parenteral administration.

This invention provides a method of inhibiting a physiological disorder associated with an excess of bradykinin, which includes the introduction of a person in need, a therapeutically effective amount of the compounds of formula 1

< / BR>
in which R1and R3independently represent hydrogen, -CH3-C(=O)-(C1-C6alkyl) or-C(=O)-AG, where AG is optionally substituted phenyl;

R2selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino; and its pharmaceutically acceptable salts and solvate.

The present invention relates to the discovery that a select group of 2-phenyl-3-araille what itCOM of bradykinin.

Therapeutic and prophylactic treatments provided by the present invention, carried out in practice, the introduction of a person in need, the dose of the compounds of formula 1 or its pharmaceutically acceptable salt or MES, which is effective for inhibiting physiological condition associated with an excess of bradykinin or its symptoms.

The term "inhibit" includes its generally accepted meaning, which includes preventing, prevention, limitation and slow, stop or reverse the development of gravity or the final symptom. Thus, the present method includes both medical therapeutic and/or prophylactic administration, respectively.

Raloxifene is the preferred compound of this invention and represents the cleaners containing hydrochloride salt of the compound of formula 1, where R1and R3is hydrogen, and R2- 1-piperidinyl.

Typically, the formulation of the medicinal product is at least one compound of formula 1 with the usual excipients, diluents or carriers, which are pressed into tablets or cooked as elixirs or solutions suitable for convenient oral vident included in dosage forms with delayed allocation, and so p.

The compounds used in the methods of the present invention, can be obtained in accordance with established procedures, such as described in U.S. patent 4133814, 4418068 and 4380635 listed here for information. Basically, the process starts with benzo[b]thiophene, 6-hydroxyl group and 2-(4-hydroxyphenyl). The original connection protects, acelerou and remove protection, to obtain the compounds of formula 1. Examples for such compounds are given in U.S. patents discussed above. The term "optionally substituted phenyl" includes phenyl and phenyl mono - or di-substituted C1-C6the alkyl. WITH1-C4alkoxy, hydroxy, nitro, chlorine, fluorine or three(chlorine or fluorine)stands.

The compounds used in the methods of the present invention form pharmaceutically acceptable additive salts with a wide variety of organic and inorganic acids and bases and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to obtain such salts include hydrochloric, brimstowad is, is received from organic acids such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate and hydroxyalkanoate acids, aromatic acids, aliphatic and aromatic sulfonic acids. So, for such pharmaceutically acceptable salts include the acetate, phenyl acetate, triptorelin, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, acetoxybenzoic, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, Butin-1,4-diet, hexyne-1,4-diet, capret, kaprilat, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymet, malonate, mandelate, mesilate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, secondary acid phosphate, monopotassium phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacina, succinate, suberate, sulfate, bisulfate, persulfate, sulfite, bisulfite, sulfonate, benzene sulfonate, p-bromophenyl-sulfonate, chlorobenzene-sulfonate, aconsultant, 2-hydroxyethanesulfonic, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfonate, killcullen additive salts with the acid is usually produced by reaction of the compound of formula 1 with an equimolar or excess amount of acid. Reagents mainly unite in a common solvent, such as simple diethyl ether or benzene. The salt normally precipitates out of solution within about one hour to 10 days, her evolve by filtration or distillation of the solvent in the usual way.

The base is usually used for the formation of salts include ammonium hydroxide and the hydroxides and carbonates of alkali and alkaline earth metals, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. The Foundation is particularly useful for obtaining additive salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, Ethylenediamine and cyclohexylamine.

Pharmaceutically acceptable salt, typically, have improved solubility compared to the compound from which they are derived, so they are better suited to cooking liquid and emulsion products.

Pharmaceuticals (finished form) are obtained by known procedures. For example, the compounds are mixed with conventional excipients, diluents and carriers and give them the form of tablets, capsules, suspensions, powders, etc., Examples of excipients, diluents and carriers, which are the s as starch, sugar, mannitol and silica-containing derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants, such as glycerol; dezintegriruetsja substances such as calcium carbonate and sodium bicarbonate; means for slowing down the dissolution such as paraffin; accelerators resorbtive, such as Quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite, and lubricants, such as talc, calcium stearate and magnesium and solid popeater-glycols.

Connection in the form of finished dosage can also be prepared as elixirs or solutions for conventional oral administration or as solutions intended for parenteral administration, for example, intramuscular, subcutaneous or intravenous route. In addition, the connection is very convenient for the preparation of drugs in dosage forms with delayed allocation, etc., Drugs can be designed to allocate the active ingredient only or predominantly in a given part of the gastrointestinal tract, possibly over a certain period of the EU ETS or waxes.

It is often desirable or necessary to introduce the pharmaceutical composition to the brain either directly or indirectly. The technique of direct injection usually involves placing a troop medicine catheter into the ventricular system of the host to bypass the blood-brain barrier. One such implantable emitting systems used for the transfer of biological factors to specific anatomical regions of the body, is described in U.S. patent 5011472, issued April 30, 1991, which is reproduced here for information.

The individual dosage of the compounds of formula 1, is required for the inhibition of the physiological condition associated with an excess of bradykinin or its symptoms, in accordance with the present invention will depend on the severity of the condition, the route of administration and like factors and should be determined by the attending physician. Basically, adopted and effective daily amount from about 0.1 to about 1000 mg/day, and more typically from about 50 to about 200 mg/day. Such dosages are introduced to a subject in need this one to three times daily or more often as required for effective treatment or prevention of disease (diseases) or symptom (symptoms).

Drugs

(finished form)

The following drugs "Active ingredient" means a compound of formula 1.

The drug 1: Gelatin capsules

Hard gelatin capsules get, using the following:

The ingredient Quantity (mg/capsule)

The active ingredient is 0.1-1000

Starch, NF 0-650

Bulk powder starch - 0-650

Silicone fluid 350 cSt - 0-15

The ingredients are mixed, passed through a sieve of 45 mesh U.S. and fill them hard gelatin capsules.

Examples of specific drugs raloxifene capsules, which have been prepared include the following:

Drug 2: Capsule raloxifene

The ingredient Quantity (mg/capsule)

The active ingredient is 1

Starch, NF - 112

Bulk powder starch - 225,3

Silicone fluid 350 cSt - 1,7

Drug 3: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Active ingredient - 5

Starch, NF - 108

Bulk powder starch - 225,3

Silicone fluid 350 cSt - 1,7

Prepare, Nf - 103

Bulk powder starch - 225,3

Silicone fluid 350 cSt - 1,7

Preparation 5: Capsule raloxifene

The ingredient Quantity (mg/capsule)

Active ingredient - 50

Starch, NF - 150

Bulk powder starch - 397

Silicone fluid 350 cSt - 3,0

The above specific drugs can be changed in accordance with acceptable variations.

The drug comes in pill form and receive, using the following ingredients:

Preparation 6: Tablets

The ingredient Quantity (mg/tablet)

The active ingredient is 0.1-1000

Cellulose, microcrystalline - 0-650

Silicon dioxide, colloidal 0-650

Stearic acid - 0-15

The components are mixed and pressed into tablets.

Alternatively, tablets, each containing 0.1 to 1000 mg of active ingredient, was prepared as follows:

Preparation 7: Pills

The ingredient Quantity (mg/tablet)

The active ingredient is 0.1-1000

Starch - 45

Cellulose, microcrystalline - 35

Polyvinylpyrrolidone (as 10% solution in water) - 4

Sodium carboxymethyl cellulose is 4.5

Magnesium stearate and 0.5

Talc - 1

The active ingredient is received're asked powders, which is then passed through a 14 mesh sieve USA. Thus obtained granules are dried at 50-60oWith and pass through a sieve 18 mesh US. Sodium carboxymethyl cellulose, starch, magnesium stearate and talc, previously passed through a sieve of 60 U.S., then added to the granules which, after mixing is pressed on the tablet press machine to obtain tablets.

Suspensions, each of which contains 0.1 to 1000 mg of the active ingredient in 5 ml dose, receive the following way:

Preparation 8: Suspension

The ingredient Quantity (mg/5 ml)

The active ingredient is 0.1-1000 mg

Sodium carboxymethyl cellulose 50 mg

The syrup 1.25 mg

A solution of benzoic acid 0.10 ml

Flavor - q. V.

Dye - q. V.

Purified water to 5 ml

The active ingredient is passed through a sieve of 45 mesh U.S. and mix with the sodium salt of carboxymethyl cellulose and syrup to achieving a smooth paste. A solution of benzoic acid, flavouring and colouring agent is diluted with a certain amount of water with stirring. Then add water in sufficient quantity to obtain the desired volume.

The biological activity of the compounds of the present invention, Ocenia with known sites of the receptor of bradykinin. Tests suitable for evaluation of receptor antagonists of bradykinin, are well known. Cm. for example, the U.S. patents 5162497, issued November 10, 1992; 5212182, issued may 18, 1993 ; 5216165, issued June 1, 1993, and 5288725, issued February 22, 1994, which are given here for information. Cm. also, Ransom, et al., Biochemical Pharmacology, 43:1823 (1992).

Analysis of the binding of bradykinin in Guinea pigs

Guinea pigs humanely kill and remove the intestines. These intestines thoroughly washed with 0.9% saline solution, dried with absorbent material and weighed. Tissue homogenize at least four volumes of 50 mm Tris buffer, pH of 7.7 and centrifuged at 15000 g for about thirty minutes.

Precipitation then washed three times consecutive suspendirovanie in 50 mm Tris, pH of 7.7, followed by centrifugation. The final sediments re-suspended in sufficient volume of 50 mm Tris, 7,7, to obtain a concentration of 1 g wet weight tissue in 4 ml of buffer. These samples should be stored frozen at -80oC.

For analysis of binding 190-195 ál analytical buffer (50 mm Tris, pH 7.4, 1 mm 1,10-phenanthroline and 10 μl of inhibitor Plummer) is mixed with 200 μl of tissue homogenate and 5-10 μl of the test sample,the second binding determined in the presence of 1 μm unlabeled bradykinin.

This cocktail for analysis add 100 ál (1 PM)3H-labeled bradykinin. The reaction mixture for analysis of binding and then incubated for 90 minutes at room temperature and then filtered through glass fiber filters GF/B, which are pre-soaked, at least for one hour in 0.3% polyethylenimine. The filters are washed with cold 50 mm Tris, pH of 7.7 (33 ml), and then produce a count in scintillation counter.

Many of the compounds obtained above, show significant activity as antagonists of the bradykinin receptor. Since the compounds of formula 1 are effective antagonists of the bradykinin receptor, these compounds are useful in the treatment of a large variety of clinical conditions which are characterized by the presence of an excess of bradykinin. Thus, the invention is for the treatment or prevention of physiological disorders associated with an excess of bradykinin, this method provides an introduction to the mammal in need of such treatment, an effective amount of the compounds of formula 1 or its pharmaceutically acceptable salt, MES or prodrugs. The term "physiological disorder associated with an excess of bredice is rubbing on the presence of an effective amount of bradykinin in the localization.

These physiological disorders may include violations such as rhinitis, asthma, irritable bowel syndrome, ulcerative colitis, pain or the perception of the damaging effects of inflammation, periodontitis, rheumatoid arthritis, and osteomyelitis. It is also known that bradykinin play an important role in the homeostasis of blood circulation, and therefore antagonists of the bradykinin receptor can be useful for regulating blood pressure and for the treatment or prophylaxis of hypertension or hypotension. Antagonists of the bradykinin receptor useful in the treatment or prevention of bacterial endotoxin-toxic shock, which is a consequence of the interaction of endotoxin produced by the walls of the bacterial cells, with the cells of the reticuloendothelial system.

1. Method of inhibiting a physiological condition associated with an excess of bradykinin, by influencing effective for this amount of compounds having formula 1

< / BR>
in which R1and R3are independently hydrogen, -CH3WITH(=O)-(C1-C6alkyl) or-C(=O)-Ar, where Ar is optionally substituted phenyl;

R2selected from the group consisting of pyrrolidino, hexamethyleneimino m the specified connection is its cleaners containing hydrochloride salt.

3. The method according to p. 1, in which the specified connection represents the connection formulas

< / BR>
or cleaners containing hydrochloride salt.

 

Same patents:

The invention relates to medicine, namely to infectious diseases, in particular to the treatment of hemorrhagic fever with renal syndrome (HFRS)

The invention relates to new derivatives of 2-renominate General formula (I), where R1and R2represent hydrogen, C1-C6-alkyl, deformity, trifluoromethyl, C3-C6-cycloalkyl, saturated 5-membered heterocycle containing one oxygen atom, indanyl, 6,7-dihydro-5H-cyclopentadienyl or1-C6-alkyl, substituted phenyl, indayla or3-C6-cycloalkyl, R3is hydrogen, R4represents hydrogen, halogen, C1-C6-alkyl, trifluoromethyl, or R4represents a radical of the formula-O-R7where R7is hydrogen, R5represents hydrogen or R4and R5taken together may form a bivalent radical of formula-CH2-CH2-O-CH2-CH2-, R6represents hydrogen or C1-C6-alkyl, -a-b - represents a bivalent radical of the formula- (CR10= CR11or СНR10-СНR11where each R10and R11independently represents hydrogen or C1-C6-alkyl, L represents hydrogen, C1-C6-alkyl, C1-C6-allyloxycarbonyl,1-C6-alkyl, substituted by one or two penilai

The invention relates to medicine, in particular to the field of pharmacology, medicinal substances used for the prevention and treatment of diseases, the mechanisms of pathogenesis are the primary biochemical links are release from the depot of histamine and/or hyperactivation of free radical process

The invention relates to medicine, in particular for experimental Oncology, and for the treatment of malignant tumors

The invention relates to medicine, namely to obtain drugs used for the treatment of primary and secondary immunodeficiencies
The invention relates to medicine, in particular to Allergology, to methods for treating allergies

The invention relates to a new compound - derived 4-oxo-1,4-dihydropyrimidin formula I, having antihypoxic, cerebroprotective and immunotropic activity, and may find application in medicine

The invention relates to medicine and relates to drugs to prevent transplant rejection, monoclonal antibodies to the CD3 antigen of T-lymphocytes person, hybridoma producing these antibodies, and treatment of patients with reaction acute transplant rejection after kidney transplantation
The invention relates to medicine, in particular to immunology
The invention relates to medicine, in particular to Oncology, and concerns the application of the antidepressant amitriptyline as a means of having antiallergic action, for the correction of allergic status in patients with lung cancer
The invention relates to medicine, namely to internal medicine and psychosomatic medicine, and for the treatment of essential arterial hypertension

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

The invention relates to medicine, in particular to obstetrics

The invention relates to medicine

The invention relates to medicine, namely to psychotherapy and neurology
The invention relates to medicine, in particular to obstetrics and gynecology, and can be used for labor induction and termination of pregnancy for various indications

The invention relates to medicine, namely to neurology and psychiatry

The invention relates to new, containing diazepambuy group of compounds with biological activity, and more particularly to a derivative of diazepinone, their racemic forms, their isomeric configurations defined by the carbon in position 3 diazepinone-4-about the kernel and their pharmacologically acceptable salts, intermediate compounds and pharmaceutical compositions inhibiting phosphodiesterase IV activity
The invention relates to agriculture, in particular sheep to sheep breeding method embryo transfer securities genotype

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt
Up!