The quinoline derivative and pharmaceutical composition on the basis of their active leukotriene antagonist

 

(57) Abstract:

The quinoline derivatives of the formula I, in which R1it is a 6-F or 6,7-F2or their pharmaceutically acceptable salt, active leukotriene antagonist. 2 S. and 4 C.p. f-crystals.

Leukotrienes are a group of hormones local actions generated in living systems from arachidonic acid. The main leukotrienes are leukotriene B4(LTB4), LTC4, LTD4and LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to obtain epoxy compounds, known as leukotriene A4(LTA4), which is converted to other leukotrienes in the later stages of fermentation. Other features of the biosynthesis of leukotrienes, as well as the mechanism of their exchange can be found in the publication Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevir, Amsterdam (1989). The action of leukotrienes in living systems and their participation in various pathological processes are also described in this book Rokach'a.

The invention represents some chinaencourage compounds as compounds with activity, antagonistic action of leukotrienes. For example, in EP 3180 is supplied invention compounds correspond to the formula I':

< / BR>
which is described in EP 480717, April 15, 1992.

Brief description of the invention

The present invention relates to fluorinated hydroxyechinenone acids having activity as leukotriene antagonists, processes for their preparation and methods, as well as pharmaceutical compositions, suitable for use with mammals (particularly humans).

Because of their activity as leukotriene antagonists, the present invention compounds can be used as anti-asthmatic, anti-allergic, anti-inflammatory agents and as agents that have the ability to protect cells. They can also be used in the treatment of angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, reactions of rejection of allogenic transplant.

Detailed description of the invention

Submitted by invention compounds correspond to the formula I,

< / BR>
in which R1it is a 6-F or 6,7-Fe or their pharmaceutically acceptable salts.

Legend:

The following abbreviations (abbreviations) have the following meanings:

Ac is acetyl,

DMF - dimethylformamide,

Et is ethyl,

Salt

Present invention the pharmaceutical compositions include a compound of formula I as the active ingredient or its pharmaceutically acceptable salt and can contain other pharmaceutically acceptable excipients and optionally other therapeutic ingredients.

The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases, including organic and inorganic bases. Salt-derived inorganic bases include salts of aluminum, ammonium, calcium, copper, iron, gelezinis salts, and salts of lithium, magnesium, manganese, manganese salt, salts of potassium, sodium, zinc, etc.

Especially preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Salt-derived pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines including naturally existing in nature, cyclic amines and basic ionoobmennyh resins, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like.

If the present invention the compound is basic, salts may be obtained from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Among such salts include acetic, benzolsulfonat, benzoic, camphorsulfonic, glutamic, Hydrobromic, hydrochloric, citric, econsultancy, fumaric, gluconic, glutamic, setinova, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, Panova, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluensulfonate and the like. Particularly preferred are citric, Hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

It is clear that when discussing treatment methods presented below, reference to a compound of formula I include, and pharmaceutically acceptable salts.

Use

The ability of compounds of the formula I to be antagonists to the action of leukotrienes makes them suitable for preventing, stopping and returning to the source is some action on leukotrienes suggests, what compounds and containing pharmaceutical compositions can be used to treat, prevent, and return to the initial state the symptoms of some diseases in mammals, especially humans, namely:

1) lung diseases, including diseases such as asthma, chronic bronchitis, diseases associated with airway obstruction;

2) allergic and allergenic disorders, such as allergic rhinitis, contact dermatitis, allergic conjunctivitis and the like;

3) inflammatory diseases, such as arthritis or inflammation of the intestine;

4) pain;

5) skin diseases such as psoriasis, diffuse neurodermitis etc.;

6) cardiovascular diseases such as angina, myocardial ischemia, hypertension, platelet aggregation and the like;

7) renal insufflation (blowing) in ischemic events caused by immunological or chemical (cyclosporin) reasons;

8) migraine or histamine headaches;

9) ocular changes, such as uveitis;

10) hepatitis due to chemical, immunological or infectious stimuli;

11) trauma or shock, such as burns, EN the drop side effects related to introduction to therapeutic uses of cytokines, such as interleukin 11 and tumor necrosis;

14) chronic lung diseases such as cystic fibrosis, chronic bronchitis and other respiratory diseases, and

15) cholecystitis.

Submitted by invention compounds can also be used for treatment or prevention in mammals, especially in humans, diseases such as gastritis, accompanied by the appearance of erosion, erosive esophagitis (inflammation of the esophagus), diarrhea, spasms of cerebral vessels, premature birth, spontaneous abortion, dysmenorrhea, ischemia caused by harmful substances defeat or necrosis of hepatic, pancreatic, renal, or myocardial tissue damage, parenchymal liver damage caused hepatoxicity substances such as CCl4and D-galactosamine, ischemic renal failure, diseases associated with dysfunction of the pancreas, disorders of the pancreas and stomach, associated with the secretion of bile and salts, cell changes associated with stressful events and injuries caused by glycerol renal failure. Connections to the characteristics of lugati as in animal experiments, and in studies on human volunteers, locking the increased resistance of the mucous membrane of the gastrointestinal tract on the harmful effects of strong stimuli, such as shallsee action of aspirin or indomethacin.

In addition to reduce the effect of non-steroidal anti-inflammatory drugs on the gastrointestinal tract, animal experiments show that these compounds, characterized by the ability to have a protective effect on cells, can prevent pathological changes caused by oral introduction of strong acids, strong bases, ethanol, hypertonic saline, etc.

To measure the ability to protect cells can be used two methods of analysis: (A) analysis of the pathological changes caused by ethanol, and (B) analysis of the ulcer induced by indomethacin, described in EP 140684.

Dose

The value of prophylactic and therapeutic doses of compound I depends, of course, on the severity of the disease of the patient, specific compounds of formula I and the method of drug administration. In addition, it depends on the age, body weight and individual reactions of the patient in each case.

Basically the size of the daily dose) ranges from about 0.001 to about 100 ml per kg of body weight of the mammal, preferably 0.1 to 10 mg / kg, particularly preferably 0.1 to 1 mg / kg as a single or divided dose forms. On the other hand, in some cases it may be necessary to use dosages outside these limits.

In cases where the necessary formulations for intravenous administration, suitable dosage range for anti-asthmatic, anti-inflammatory or anti-allergic use is from about 0.001 mg to about 25 mg (preferably from about 0.001 to about 1 mg) of the compounds of formula I per kg of body weight per day, and for the purposes of protection of cells, respectively, from about 0.1 mg to about 100 mg (preferably from about 1 mg to 100 mg, and particularly preferably from about 1 mg to about 10 mg) of the compounds of formula I per kg of body weight per day.

When recommended formulations for oral administration, the acceptable dose range for anti-asthmatic, anti-allergic or anti-inflammatory use is from 0.01 mg to about 100 mg of the compounds of formula I per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for the protection of cells from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg, and particularly preferably is I use ophthalmic compositions for injection into the eye, containing 0.001 to 1% by weight of the solution or suspension of the compounds of formula I in an acceptable ophthalmic forms.

The exact amount of the compounds of formula I, which can be used as a tool for protection of cells, among other things, depends on whether it is administered for the treatment of diseased cells or to avoid possible damage in the future, from the nature of the affected cells (e.g., ulcerative changes in the gastrointestinal tract, leading to nephrotic necrosis) and on the nature of etymological factors of the disease.

For example, the use of the compounds of formula I in order to protect cells in the future involves co-administration of compounds of formula I together with non-steroidal anti-inflammatory agent, which otherwise could cause such lesions (eg, indomethacin). In this case, the compound of formula I is administered 30 minutes before and 30 minutes after administration of nonsteroidal anti-inflammatory drugs. Preferably, the introduction of to produce up to or simultaneously with it (for example, in the combined dose form).

Pharmaceutical compositions

For the introduction of a mammal and especially a human an effective dose of the present invention is, local, through the eyes, lungs, nose, and so on Dose forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc.

Present invention the pharmaceutical compositions contain a compound of formula I as the active ingredient or pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable excipient and optionally with other ingredients with therapeutic effect. The term "pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.

The compositions include compositions acceptable for oral, rectal, local, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (through the nose or cheek) applications, as well as insertion through the nose, although most acceptable methods of use in some of these cases will depend on the nature or severity of the disease and the patient's condition, which is to be treated and on the nature of the Hells, well-known specialists-pharmacists.

For use in inhalations present invention compounds usually applied in the form of an aerosol inhalers or tanks providing a dispersion of the drug. Compounds can also be prepared in the form of powders, brewed according to a special technology, or powder compositions which can be inhaled by the method of insufflation using inhalers. The preferred system for inhalation is an aerosol metered dose that can be prepared in the form of a suspension or solution of compound I in a suitable propellant, for example, fluorinated hydrocarbons or hydrocarbons.

Acceptable formulations of compound I for local applications include devices for transdermal administration, aerosols, creams, ointments, lotions, lotions, sprayable powders and similar forms.

For the practical application of the compounds of formula I can be combined as the active ingredient at careful hashing with a pharmaceutically acceptable carrier according to conventional pharmaceutical techniques. With carriers and fillers you can get a great reasnoable forms (including intravenous).

For the preparation of compositions for oral dose forms can recommend any pharmaceutical environment, such as, for example, water, glycols, oils (vegetable), alcohols, corrigentov, preservatives, podsvechivaya tools, etc. if we are talking about liquid formulations for administration by mouth, such as, for example, suspensions, elixirs and solutions; or carriers (fillers), such as starches, sugars, microcrystalline cellulose, diluents, means of granulation, lubricants, binding agents, means providing a decomposition, and the like in the case when it comes to solid compositions for oral administration such as, for example, powders, capsules and tablets, with the solid compositions for oral administration preferred over liquid.

Due to the simplicity and ease the introduction of tablets and capsules represent the most promising dose form, in the preparation of which it is recommended to use conventional pharmaceutical carriers. Optionally, the tablets can be coated using "water" or "anhydrous" methods.

In addition to the usual dose forms described above, the compounds of formula I can be administered using the means to 3536809, 3598123, 3630200 and 4008719, description of them is given here as links.

Present invention, the compositions for oral administration can consist of separate units, such as capsules Sasha or tablet containing a predetermined amount of the active ingredient, powders or granules or as a solution or suspension in an aqueous liquid, non-aqueous liquid, emulsion oil in water or a liquid emulsion of water in oil.

Such compositions can be obtained in accordance with known pharmaceutical methods, but all methods include the stage of connection of the active ingredient with extenders, representing one or more necessary ingredients. In General, the compositions are obtained by uniform internal mixing the active ingredient with liquid carriers and finally distributed in the solid filler or produce both, and then, if necessary, give the mass of a desired shape.

For example, tablets can be obtained by extrusion or molding, optionally with one or more additional ingredients. For pressing tablets, you can use special teletrauma machine, introducing the active ingredient in the form Svobodny, inert diluents, surfactants and dispersing agents.

Molded tablets can be obtained in a special molding machine, moistening the mixture of powdered compounds inert liquid diluent. Preferably, each tablet contains from about 2.5 mg to about 500 mg of the active ingredient, and each sachet or respectively each capsule is from about 2.5 to about 500 mg of the active ingredient.

Below are examples of the present pharmaceutical dose forms for compounds of formula I:

Suspension for injection (intramuscularly) - mg/ml:

The compound of formula I - 10

Methylcellulose - 5,0

Tween 80 and 0.5

Benzyl alcohol - 9,0

Benzylaniline - 1,0

Water for injection for a total volume of 1 ml

Tablet mg/tablet

The compound of formula I - 25

Microcrystalline cellulose 415

Povidon - 14,0

Pre gelatinizing starch - 43,5

Magnesium stearate - 2,5 - 500

Capsule mg/capsule

The compound of formula I - 25

Powdered lactose - 573,5

Magnesium stearate - 1,5 - 600

Aerosols - spray

The compound of formula I - 24

Lecithin, NF liquid concentrate - 1,2
In addition to the compounds of formula I, the present invention pharmaceutical compositions can also contain other active ingredients, such as cyclo-oxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSPs), analgesics peripheral range, such as for example, zomepirac diflunisal etc.

The weight ratio of the compounds of formula I and a secondary active ingredient may be varied and will depend upon the effective dose of each ingredient. Usually use an effective dose of each. For example, if the compound of formula I is combined with non-steroidal anti-inflammatory agent, the ratio of the compound (weight) of formula I and non-steroidal anti-inflammatory drugs will range from 1000:1 to about 1: 1000, preferably from about 200:1 to about 1:200.

The compound of formula I and other active ingredients are usually combined in the above ratio, but in each case must be used effective dose of each active ingredient.

Non-steroidal anti-inflammatory drugs can be divided into five groups:

(1) derivatives of propionic acid,

(2) derivatives of acetic acid is or their pharmaceutically acceptable salts.

Derivatives of propionic acid, which can be used include: alminoprofen, benoxaprofen, bulochnikov acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, Ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen. Structurally related derivatives of propionic acid, which has similar analgesic (pain relieving) and anti-inflammatory properties are also intended to be included in this group.

Thus, "propionic acid derivatives" here in the specified value are medicines mixed non-narcotic analgesic and nonsteroidal anti-inflammatory actions, which include free-CH(CH3)COOH or-CH2CH2COOH (which in turn may not necessarily exist in the form of a pharmaceutically acceptable salt group, e.g.- CH(CH3)COO-Na+or-CH2CH2COO-Na+), usually connected directly or via a carbonyl group with a cyclic system, preferably with the system of the aromatic ring.

Derivatives vinegar is dstanley a non-steroidal anti-inflammatory agent, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, enclosing acid, fentiazac, furofenac, ibufenac, isoxepac, exping, sulindac, tiopinac, tolmetin, zidometacin, zomepirac. Structurally related derivatives of acetic acid having similar analgesic and anti-inflammatory properties, may also be included in this group.

Thus, derivatives of acetic acid" here in the specified value are medicines mixed non-narcotic analgesic and non-steroidal anti-inflammatory action with free-CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g.- CH2COO-Na+), usually connected directly with a cyclic system, preferably an aromatic system or heteroaromatic ring.

Derivatives fenaminovoj acid suitable for use in these purposes include: flufenamic acid, meclofenamic, methenamine, nefelinovoe and tolfenamic acid. Structurally related derivatives fenaminovoj acid having similar is x2">

Thus, the "derivative fenaminovoj acid" here in the specified value are medicinal substances mixed non-narcotic analgesic and non-steroidal anti-inflammatory action, containing the basic structure:

< / BR>
which may have a variety of substituents and in which the free -- COOH group can be in the form of a pharmaceutically acceptable salt group, e.g.- COO-Na+.

Derivatives "biphenylcarbonic acid", which can be used include diflunisal and flufenisal. Structurally related derivatives biphenylcarbonic acid having similar analgesic and anti-inflammatory properties, may also be included in this group.

Thus, the "derivative biphenylcarbonic acid" here in the specified value are medicines mixed non-narcotic analgesic and non-steroidal anti-inflammatory action, containing the basic structure

< / BR>
which can have a number of substituents and in which the free -- COOH group can be in the form of a pharmaceutically acceptable salt group, e.g.,- COO-Na+

Thus, oxicam" here in the specified value are medicines mixed anarquismo analgesic and restarting anti-inflammatory action of a General formula

< / BR>
in which R represents aryl or heteroaryl cyclic structure.

In the present invention can also be used: amanacare, alminoprofen, nitrazepan, entretenir, auranofin, bendazac lisinac, benzydamine, barosin, properly, buttala, cinmetacin, coprokazan, classimat, dasadmin, debacle, delimitation, detomidine, dexindoprofen, diacerin, di-filamin, divinename, emorfazone, angenlina acid, analika, epirizole, Etisalat, etodolac, etofenamate, fanatical mesilate, vinklarek, fendosal, penfluridol, penprase, floctafenine, flunixin, flunoxaprofen, fluprofen, papertole, posposil, perclorate, glucometry, quamatel, ibuproxam, isophtalic, sonicrim, ibuprofen, isoclinal, lefetamine HCl, Leflunomide, lo is Eton, Nintendo, nimesulide, herpanacine, oxiplatin, hexapedal, personsal citrate, timeproven, peltatin, pirprofen, pyrazoles, pirfenidone, proglumetacin maleate, proquazone, pyridoxine, sudoxicam, tolmetin, talniflumate, tenoxicam, titledbutton, talvin B, tiaramide HCl, diflunisal, timelady, solpadol, tryptamide and openmath.

Can also be used in the following non-steroidal anti-inflammatory drugs designated by company code numbers (see e.g. Pharmacoprojects), namely:

480156, AA861, AD1590, AFP802, AFP860, A177B, AP504, AU8001, BPPC, BW540C, CHIN01N 127, CN100, EB3821, EL 508, FI044, GV3658, ITF182, KCNTE16090, KME4, LA2851, MR714, MP897, MY309, ON03144, PR823, PV108, PV102, R830, RS2131, SCR152, SH440, SIR133, SPA 510, SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1-indocaribbean acid), TVX2706, U60257, UR2301 WY41770.

Finally, suitable for the purpose, the compounds include salicylates, especially acetylsalicylic acid and phenylbutazone, and their pharmaceutically acceptable salts.

In addition to indometacin, preferred non-steroidal anti-inflammatory drugs considered acetylsalicylic acid, diclofenac, fenbufen, fenoprofen, flubiprofen, ibuprofen, Ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac, tolmetin.

Pharmaceutical is new, described, for example, in EP 138481 (April 24, 1985), EP 1156394 (August 8, 1984), EP 136893 (April 10, 1985) and EP 140709 (may 8, 1985), and are presented here in the form of links.

The compounds of formula I can also be used in combination with leukotriene antagonists, as described, for example, in EP 106565 (April 25, 1984) and EP 104885 (April 4, 1984), shown here as links and other known compounds of this type are described in the Annex to the EP Nos 56172 (July 21, 1982) and 61800 (June 10, 1982) and the specification for U.S. Pat. UK N 2058785 (April 15, 1981), represented here by reference.

Containing the compounds of formula I, pharmaceutical compositions can contain as the second active ingredient antagonists of prostaglandin, such as described for example in EP 11067 (may 28, 1980) or antagonists of thromboxane presented in U.S. Pat. USA 4 237160. They may also contain inhibitors of histidin decarboxylase, such as formutilities described in U.S. Pat. USA 4325961.

Prospective can be also the connection of the compounds of the formula I with an antagonist of H1or H2-receptors, for example, acetazolam, aminothiadiazole described in EP 40696 (December 2, 1981), as well as substances type Benadryl, cimetidine, famotidine, framarin, histadyl, the e compositions can also contain an inhibitor of K+/H+ATP-ases, for example, omeprazole, described in U.S. Pat. USA 4255431 and the like.

Other pharmaceutical compositions comprising the compounds of formula I in combination with serotonin antagonists, such as medicarpin, serotonin antagonists, as described, for example, in Nature, volume 316, pages 126-131, 1985 and the like. Each of the links relating to such use, is provided in the form of a link.

Other promising pharmaceutical compositions include compounds of formula I in combination with antiholinergicakimi, for example, ipratropium bromide, bronchodilators means, such as beta agonist salbutamol, metaproterenol, terbutaline, fenoterol and similar substances, and Antiasthmatic drug theophylline, choline by theophyllinate and enprofylline, calcium antagonists nifedipine, diltiazem, nitrendipine, verapamil, nimodipine, felodipina and so on, as well as corticosteroids, hydrocortisone, methylprednisolone, Bettona, dexamethasone, beclomethasone, and the like.

The table illustrates the present invention the connection.

Methods of synthesis.

Submitted by invention compounds can be obtained is
The compound of the formula I can be tested using the following methods of analysis for the determination of their activity as leukotriene antagonists and their ability to inhibit leukotriene biosynthesis in mammals.

Study linking LTD4-receptor on the membrane of the lung of the Guinea pig trachea of the Guinea pig and in vivo studies in Guinea pigs under General anesthesia.

A detailed description of these three tests are presented in the publication by T. R. Jones and al., Can. J. Physiol. Pharmacol. 67, 17-28 (1989).

Using the following methods of analysis of the compounds of formula I, can be used to determine their activity against inhibition of leukotriene biosynthesis in mammals. The analyses are described in detail in EP 480717, April 15, 1992.

Determining the ability of inhibiting 5-lipogenesis LTB4-determination of polymorphonuclear neutrophils in humans.

The compounds of formula I can be tested using the following methods of analysis for the determination of their activity as leukotriene antagonists and inhibitors of leukotriene biosynthesis. Analysis methods described in EP 480717, April 15, 1992.

Analysis on rats suffering from asthma.

The dynamics of light in the C, suffering from allergies.

Further object of the invention is illustrated by the following examples, the description of which is not limited. All the temperature data are given in degrees Celsius.

Example 1.

Sodium 1-((R)-(3)(2))6,7-debtor-2-chinoline(-ethynyl/phenyl)-3-(2-(2-hydroxy-2-propyl(phenyl)-propyl)thio methyl)cyclopropaneacetic

Stage 1: 6,7-debtor-2-methylinosine

CROTONALDEHYDE (226,34 g, 3,23 mol) in 100 ml of 2-butanol is added dropwise to boiling under reflux to a solution of 3,4-diferencia (417,27 g, 3,23 mole) of n-chloranil (794,65 g, 3,23 mole) and conc. hydrochloric acid (808 ml) 5.4 l 2-butanol. 2 hour heating 2.7 l of solvent is distilled under vacuum at a temperature of about 60o.

Then to the reaction mixture add 2 l of toluene, followed by removal of 2.5-3 solvent until then, until it forms a pasty solid. Add tetrahydrofuran (2 l), and heat the mixture for 30 minutes, after which produce cooling to 0oC. the Solid product is collected and washed with tetrahydrofuran, cleaning by thin layer chromatography. Then the solid product is dissolved in the equivalent amount of K2CO3(ethyl acetate) and OTDELA the atom of magnesium, and the solvent is distilled off. The product is crystallized in a minimum amount of ethyl acetate to obtain 328,08 g (57%) specified in the connection header.

1H NMR (CDCOCD3): 8,19 (1H, d), of 7.75 (2H, m), and 7.4 (1H, d), of 2.64 (3H, s).

Stage 2: 3-(2)6,7-debtor-2-chinoline (ethynyl) benzaldehyde

In accordance with the methods described in example 24, step 1 Pat. USA 4851409, but when using diftormetilirovaniya from stage 1 are specified in the header of the connection.

1H NMR (CDCOCO3): 10,12 (1H, s), and 8.4 (1H, d), 8,29 (1H, s), 8,1 - a 7.85 (6H, m), 7,7 - of 7.55 (2H, m).

Stage 3: 1-(3-/2-)6,7-debtor-2-chinoline(ethynyl)-phenyl-2-propen-1-ol.

In accordance with the methods described in example 80, step 1 EP 480717, but using 3-(2-)6,7-debtor-2-chinoline (ethynyl)benzaldehyde with stage 2 receive specified in the header of the connection.

1H NMR (CD3COCO3): 8,32 (1H, d), 7,92 one - 7.8 (4H, m), of 7.75 (1H, Shir.(C) and 7.6 (1H, m), 7.5 to to 7.25 (3H, m), equal to 6.05 (1H, DDD), lower than the 5.37 (1H, DDD), a 5.25 (1H, m), 5,1 (1H, DDD), br4.61 (1H, d).

Stage 4: Ethyl 2-(3-)3-(2-)6,7-debtor-2-chinoline(-ethynyl(phenyl)-3-oxopropyl)benzoate.

In accordance with the methods described in example 146, step 1 EP 480717, but when using difterinogo alcohol from step 3 get the,33 (2H, square), 3,5 - 3,3 (4H, m) of 1.32 (3H, t).

Stage 5: Ethyl 2-(3)(-)3-(2-)6,7-debtor-2-chinoline(ethynyl)phenyl-3-hydroxypropyl/benzoate.

In accordance with the methods described in example 146, step 2 EP 480,717, but when using divorcethe with stage 4 receive specified in the header of the connection.

1H NMR (CD3COCO3): 8,31 (1H, d), 7,92 to 7.75 (6H, m), 7,6 - of 7.25 (7H, m), 4,78 (1H, m), 4,47 (1H, d), a 4.3 (2H, square), a 3.2 - 2,95 (2H, m), is 2.05 (2H, m) of 1.32 (3H, t).

Stage 6: 2-(2)3-(S)-(3-)2-/6,7-debtor-2-chinoline(ethynyl(phenyl)-3-hydroxypropyl(phenyl)-2-propanol

A mixture of anhydrous CeCl3(40,5 g, 164 mmole) in tetrahydrofuran (500 ml) is refluxed overnight using a trap Dina stark, filled with activated 3 a molecular sieve. To a suspension CeCl3is added dropwise within 30 minutes at 0oC methylaniline (263 ml, 3.0 M in tetrahydrofuran, 790 mmol). After 2-hour stirring at 0oC the mixture is cooled to -5oC and added dropwise a solution of hydroxyether (71,8 g, 152 mmole) in toluene (600 ml) with stage 5.

The reaction mixture is stirred for another hour, before adding 2M (HOAc) (600 ml) and toluene (600 ml). The organic layer was washed with saturated aqueous NaHCO3and salt is toluene) get 63,48 g (91%) specified in the connection header.

1H NMR (CD3COCD3): 8,4 (1H, d), 8.0 to about 7.8 (5H, m), the 7.65 (1H, m), and 7.5 (3H, m), 7,35 to 7.1 (4H, m), 4,88 (1H, m), 4,58 (1H, d), 4,19 (1H, s), up 3.22 (2H, m), of 2.15 (2H, m) 1,70 (3H, s), by 1.68 (3H, s).

Stage 7: Cyclic sulfite 1,1-cyclopropanemethanol

To a solution of complex compounds BH3:THF (1 mol tetrahydrofuran, 262 ml) is added diethyl 1,1-cyclopropanedicarboxylic (25 g, 134 mmole) at 25oC in nitrogen atmosphere. The solution is refluxed for 6 hours, cooled to room temperature and carefully added MeOH (30 ml). The solution is stirred for 1 hour, then concentrated to obtain an oily product.

The crude diol was dissolved in CH2Cl2(234 ml) and (15.9 g, 134 mmole) and added dropwise within 15 minutes at 25oC SOCl, (15.9 g, 134 mmole). After stirring for 15 minutes, the mixture was washed with aqueous NaHCO3. The organic extract is dried over sodium sulfate, filtered and concentrated to obtain quantitatively specified in the connection header in the form of a solid white color.

Stage 8: 1-(hydroxymethyl)cyclopropanecarbonitrile

To a solution of the cyclic sulfite of the product from step 7 (14,7 g, 99 mmol) in dimethylformamide (83 ml) add NaCH (is washed with a solution saturated NaHCO3-solution (55 ml), H2O (4 x 55 ml), saturated NaCl solution and dried over sodium sulfate. The solution is concentrated with the receipt of 7.1 g (65%) specified in the connection header.

Stage 9: 1-(acetyltributyl)cyclopropanecarbonitrile

To a solution of alcohol from step 8 (42 g, 378 mmol) in dry CH2Cl (450 ml) at -30oC is added dropwise EF3N (103,7 ml, 741 mmol) at -30oC, and then CH3SO2Cl (43,3 ml, 562 mmol). The mixture is heated to 25oC, washed with NaHCO3, dried over sodium sulfate and concentrated in vacuo to obtain the corresponding nelfinavir. Then mesilate dissolved in dimethylformamide (450 ml) and cooled to 0oC. Add thioacetate potassium (55,4 g, 485 mmol) and stirred the mixture at 25oC for 18 hours. Add ethyl acetate (1.5 l), the solution washed with NaHCO3, dried over sodium sulfate and concentrated in vacuo to obtain 45 g (70%) specified in the connection header.

Step 10: Methyl 1-(thiomethyl)cyclopropaneacetic

To a solution of the nitrile from step 9 (45 g, 266 mmol) in MeOH (1,36 l) add water (84 ml) and concentrated sulfuric acid (168 ml). The mixture is refluxed for 20 hours, cooled to 25oC, add water (1 l) and estragole concentration of the organic solution obtain 36 g (93%) specified in the connection header.

Stage 11: Methyl 1-(((R)-(3-)2-)6,7-debtor-2-chinoline(ethynyl)-phenyl)-3(2-)2-hydroxy-2-propyl phenyl)propyl(thio)methyl)cyclopropaneacetic

Diol from step 6 (1.0 g, 2.1 mmole) was dissolved in tetrahydrofuran (1 ml) and dimethylformamide (1 ml) and cooled to -40oC. Add diisopropylethylamine (383 μl, 2.2 mmole), and then methanesulfonanilide (170 μl, 2.2 mmol). The mixture is stirred for 2 hours with slow warming to -30oC. To the turbid reaction mixture are added thiol (370 mg, 2.3 mmole) from step 10, and then injected dropwise a solution of tert.-butoxide potassium in tetrahydrofuran (2,52 ml, 1.75 M, 4.4 mmole).

The reaction mixture is stirred at -30oC for 3.5 hours before you can redeem the 25% aqueous solution of NH4The OAc. After extraction with ethyl acetate (3x), washing the organic layer with brine and evaporation of the solvent receive the residue, after purification using flash chromatography (5%-10% ethyl acetate in toluene) to give 658 mg (53% specified in the connection header).

1H NMR (CD3COD3): 8,21 (1H, d), from 7.9 to 7.7 (5H, m), EUR 7.57 (1H, m), and 7.4 (3H, m), 7,25 - 7,05 (4H, m), 4,07 (1H, t), 3,95 (1H, s) to 3.58 (3H, s), 3,2 (1H, DDD), with 2.93 (1H, DDD), 2,58 (2H, s) to 2.41 (2H, DD), of 2.25 (2H, m), was 1.58 (6H, s), 0.55 to 0.35 in (4H, m).

Stage 12: Sodium 1-(((1R)-(3-)2-)6,7-dejstvie to the method of hydrolysis of example 146, stage 11 EP 480717, but when using difterinogo ester from step 1, get the acid specified in the connection header.

1H NMR (CD3COD3): 8,32 (1H, d), 7.95 is - to 7.77 (5H, m), 7,65 - 7,38 (5H, m), a 7.2 to 7.0 (3H, m), 4,07 (1H, t), 3,18 (1H, DDD), 2,9 (1H, DDD), 2,8 (1H, Shir. (C) to 2.6 (2H, s), 2,42 (2H, s), 2,2 (2H, m) of 1.53 (6H, s), 0.55 to 0.35 in (4H, m).

In accordance with the method of example 146, step 12 EP 480,717 for the above-mentioned acid get specified header connection.

1H NMR (CD3COD3): 8,2 (1H, d), a 7.85 - in 7.7 (5H, m), 7,52 - of 7.25 (5H, m), 7,1 - a 7.0 (3H, m), Android 4.04 (1H, t), and 3.2 (1H, m), 3,8 - 2,5 (4H, m), 2,3 - 2,05 (4H, m), and 1.54 (3H, s), 150 (3H, s) to 0.45 (2H, m) 0,25 (2H, m).

Mass spectrum FAB: MH+at 610, (M+23)+at 632. Estimates microanalysis for C35H34NO3SF2Na 3H2O:

C 63,99, H 5,97, N 2,07.

Found: C 64,52, H 5,95, N 2,07.

Example 2

Sodium 1-(((R)-(3)(2-)6-fluoro-2-chinoline)ethynyl)-phenyl)-3-(2-(2-hydroxy-2-propyl(phenyl)propyl (thio)methyl)cyclopropaneacetic

In accordance with the method of example 1 step 2, but using as starting compound 6-fluoro-2-methyl-quinoline (see C. M. Leir, J. Org. Chem, T. 42, pages 911 - 913, 1977) receive specified in the header of the connection.

Acid:

1H NMR (CD3COD3): 8,15 (1H, d), 8,02 (1H), 0,55 - 0,35 (4H, m).

Sodium salt

1H NMR (CD3COD3): 8,35 (1H, d), of 8.09 (1H, DD), 8,0 - to 7.35 (10H, m) and 7.1 (3H, m), 4.09 to (1H, t), and 3.2 (2H, m), 2,85 - to 2.55 (3H, m), 2,35 - 2,0 (4H, m), of 1.52 (3H, s), for 1.49 (3H, s) to 0.45 (2H, m) 0,25 (2H, m).

Estimates microanalysis for C35H35FNNaO3S H2O: C 68,93, H 6,13, N, 2,30.

Found: C 68,42, H Of 5.99, N To 2.29.

Mass spectrum (FAB): MH+at 592 (M + 23)+at 614 (30%).

1. The quinoline derivatives of the formula I

< / BR>
in which R' represents a 6-F or 6,7-F2,

or their pharmaceutically acceptable salt.

2. The sodium salt of the compound under item 1.

3. The pharmaceutical composition active leukotriene antagonist containing an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a compound of formula I under item 1 or 2, or its pharmaceutically acceptable salt in an effective amount.

4. The pharmaceutical composition according to p. 3, characterized in that it further contains an effective amount of a second active ingredient antagonist N1-receptor.

5. The pharmaceutical composition according to p. 4, characterized in that the second active IASA fact, that the weight ratio of the compounds under item 1 and the second active ingredient ranges from 1000 : 1 to 1 : 1000.

 

Same patents:

The invention relates to new chemical compounds having valuable properties, in particular derivatives of dihydropyridines of General formula (I)

< / BR>
where R1aryl with 6-10 carbon atoms, unsubstituted or once-three times substituted by identical or different substituents from the group comprising halogen atom, a nitro-group, cyano, trifluoromethyl, cryptometer and triptoreline,

or substituted unbranched or branched alkyl with 1-8 carbon atoms, which is not substituted or substituted aryl with 6-10 carbon atoms, or substituted unbranched or branched alkoxygroup or alkoxycarbonyl with 1-8 carbon atoms, carboxypropyl, an amino group or a group of the formula-NR4R5in which

R4and R5the same or different and mean a hydrogen atom, an unbranched or branched alkyl with 1-8 carbon atoms, phenyl or benzyl,

or thienyl,

R2a hydrogen atom or cycloalkyl with 5-8 carbon atoms or an unbranched or branched alkyl, alkenyl, alkadienes, or quinil with 1-10 carbon atoms, unsubstituted or once or twice substituted od the cyano and nitro-group, or unbranched or branched alkylthiol, alkoxygroup, alkoxycarbonyl, acyl or alloctype with 1-8 carbon atoms, or cycloalkyl with 3-8 carbon atoms, fenoxaprop or phenyl, the latter is not substituted or once or twice substituted by identical or different substituents from the group comprising halogen atom, an unbranched or branched alkyl and alkoxygroup with 1-6 carbon atoms, or substituted by the group-NR4R5in which R4and R5have the above values,

R3a hydrogen atom or an unbranched or branched alkyl with 1-8 carbon atoms,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerable salts

The invention relates to organic synthesis and relates to new quinoline derivatives and method of production thereof

The invention relates to pharmaceutical compositions having high stability, and more exactly, to pharmaceutical compositions containing the inhibitors of HMG-CoA reductase, the stability of which depends on the pH of the medium, especially (E)-3,5-dihydroxy-7-[4', 4"- forfinal-2'-cyclopropylamino-3'-yl] -6-heptanoyl acid, or its salt or ester
The invention relates to the field of veterinary medicine

The invention relates to compounds of formula I:

< / BR>
where X represents CH2, CO, CS or SO2,

Y is selected from:

direct connection (i.e

The invention relates to bicyclic compounds having a core formed of two condensed six-membered cycles, such as isoquinoline, izoliranim, tetrahydronaphthalene, dihydronaphthalene or tetralone, replaced both acidic and basic functional groups, which are useful in the inhibition of aggregation of erythrocytes

The invention relates to medicine, namely, pulmonology, and is used to correct psevdoallergicakie reactions in patients with chronic obstructive lung disease

The invention relates to medicine, namely, neurology

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides antibacterial drug in the form of enveloped tablet with its nucleus containing ofloxacin as active substance and auxiliary ingredients: silica powder, calcium stearate, collidone, sodium carboxymethylcellulose, milk sugar, talc, and microcrystalline cellulose. Envelop of tablet contains collidone, hydroxypropylcellulose, talc, and titanium dioxide. Manufacture of tablet comprises mixing ofloxacin, silica powder, milk sugar, and microcrystalline cellulose; moistening resulting mixture with collidone solution; wet granulation; drying; dry granulation; and powdering of granules with mixture of calcium stearate and sodium carboxymethylcellulose. Afterward, granules are enveloped.

EFFECT: increased storage stability.

2 cl

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.

EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides composite therapeutical agent exhibiting antituberculous effect and made in the form of solid dosage form containing as active principle combination of lomefloxacin, isoniazid, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides high-activity antituberculous formulation made in the form of solid dosage form containing as active principle combination of lomefloxacin, protionamide, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries.

EFFECT: increased assortment of antituberculous drugs.

4 cl, 1 tbl, 4 ex

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