Containing diol derivatives of quinoline, the method of production thereof, pharmaceutical drugs based on them and a way of inhibiting

 

(57) Abstract:

Containing the diode quinoline derivatives of General formula I,

< / BR>
where R1denotes hydrogen or halogen, preferably fluorine or chlorine, and m is 0,1 or 2. The above compound is produced by interaction of the amine of formula II

< / BR>
with the compound of the formula III

< / BR>
The compounds of formula I possess antagonistic activity and can therefore be used as a pharmaceutical in human medicine. The present invention relates also to a method of inhibiting specific reduction of smooth muscles. 4 C. and 4 h.p. f-crystals, 3 tables.

The invention relates to previously unknown compounds, useful in medical and veterinary practice, to their pharmaceutically acceptable salts and biopremier derivatives, to methods for obtaining data of new compounds, to pharmaceutical compositions containing these new compounds, to a single dosage forms of these compositions and to methods of treating patients using these compositions, and dosage forms.

Leukotrienes, which are formed via the 5-lipoxygenase way in the process of exchange of arachidonic salt involved in the development of various pathophysiologically and degranulation of neutrophils (E. J. Goetzl, D. G. Payan and D. W. Godman, J. Clin. Immunol. 4 (1984) 79). Thus the development of compounds which are antagonists of the action of leukotriene, is of considerable interest.

The international patent application N PCT/DK 93/00254 (Publication N WO 94/03431) describes a number of finalisation N-phenylsilane of azaserine with leukotrieneantagonists activity.

The authors were surprised to find that the new discodermia compounds corresponding to General formula I, are powerful antagonists, especially in the presence of human serum albumin, and have high bioavailability and prolonged activity in vivo.

These compounds have a General formula I

< / BR>
R is hydrogen or halogen, preferably fluorine or chlorine and m is 0,1 or 2

These compounds have several centers of asymmetry and thus can form a large number of stereoisomers. The present invention includes all possible stereoisomers and racemic and stereochemical mixture.

Presents salts of compounds of formula I may be derived from pharmaceutically acceptable inorganic and organic acids such as chlorostoma, p-toluensulfonate, methanesulfonate, formic acid, acetic acid, propionic acid, citric acid, tartaric acid and maleic acid.

Inhibitors of 5-lipogenesis and leukotriene antagonists may be of interest as a means to treat asthma, allergies, rheumatoid arthritis, spondylitis, badagry, atherosclerosis, proliferative and inflammatory skin diseases such as psoriasis and atopic dermatitis, chronic inflammatory intestinal diseases, and other inflammatory conditions, vascular spasm associated with angina, pulmonary hypertension, fibrosis of the gallbladder, syndrome age-related respiratory disorders, ischemic and reperfusion disorders, migraine and others (R. A. Lewis. K. F. Austen and R. J. Soberman, New Eng. J. Med. 323 (1990) 645.) The discovery of specific inhibitors of 5-lipoxygenase and antagonists leukotriene thus is a new approach that opens wide possibilities in the treatment of various clinical disorders.

The leukotriene antagonists may be detected by observation of the reduction occurring in the slice preparation from the ileum of the Guinea pig, suspended in physiological buffer, when added on the units making LTD4to the drug ileum were added the compounds of the present invention, showed a significant inhibition of specific reduction caused LTD4. Inhibition occurred at a concentration not lower than 0.1 to 1 nm. On the other hand, the reduction caused by histamine at a concentration of 10-7M, was not suppressed by these compounds even at micromolar concentrations.

It is very important to investigate the mechanism of receptor binding of leukotriene antagonists in inhibiting contractions of smooth muscles. The study of receptor binding can be performed on lung membranes of the Guinea pig in direct konkurrenten test between leukotriene antagonists and [3H] LTD4in linking LTD4- receptors. (I. Ahnfelt-Ronne, D. go directly Kaergaard and C.-Nielsen, European J. Pharmacol. 155 (1988) 117. S. Mong. H.-L. Wu, M. O. Scott, M. A. Lewis, M. A. Clarke, B. M. Weichman, C. M. Kinzig J. G. Gleason and S. T. Crooke, J. Pharmacol. Exp. Ther. 234 (1985) 316). The magnitude pIC50is defined as the negative logarithm of the molar concentration of antagonist, inhibiting [3H]LTD4binding by 50%. Values plC50for compounds of the present invention is equal to or higher than the same values for the control connection SR3040 (International Patent Appl. N PCT/DK/00254 (Publ. The N LTD4induced bronchospasm in under anesthesia Guinea pigs. (I. Abnfelt-Ronne, D. go directly Kaergaard and C.-Nielsen, European J. Pharmacol. 155 (1988) 177). Intravenous connection was introduced for 10 minutes, and through the mouth for 24, 48 and 72 hours prior to bronchospasm. The value of the ED50represents the dose which inhibits leukotriene-induced bronchospasm by 50%. The value of the ED50was calculated in the analysis of 2-3 smaller doses. The results are shown in table. 2.

The activity of the compounds of the present invention is superior to the same values for SR3040.

The present invention also relates to methods of producing these compounds.

In one variant embodiment, the amine of formula II

< / BR>
in which R and m have the above meaning, is reacted with a compound of formula III

< / BR>
in which X can form a "well-removed group, X can thus be, for example, a halogen atom, such as chlorine, bromine or iodine, or alkyl or arylsulfonate, but to obtain the compounds of formula I can be used and other leaving groups, such as alkylsulfonate, chlorosulfonylisocyanate, alkylsulfanyl group, mono - or dialkylphosphate group, or a group of nitrate.

Reaktsii used and other solvents. The reaction is preferably carried out at room temperature, but in some cases, depending on the nature of the reagent of formula I and III, it may be convenient to cool the reaction mixture below room temperature or heated above room temperature up to the boiling point of the used solvent. The resulting crude reaction products of the formula I are collected by filtration, or, after dilution in water, stand out from the reaction mixture using a suitable solvent, such as diethyl ether, ethyl acetate, dichloromethane or chloroform. The reaction products are purified, for example, by recrystallization or chromatography.

In another embodiment, the amine of formula II is reacted with the compound of the formula IV

< / BR>
The reaction is carried out in a suitable inert organic solvent, such as methanol, ethanol, dimethylformamide or HEXAMETHYL phosphoric triamide, or in water, or in mixtures thereof. The reaction is carried out at or near room temperature, or above it, up to the boiling point of the used solvent. However, in some cases, depending on the nature of the used compounds of formula IV, it is possible to cool the reaction mixture to below room temperature. what it is possible intended for use in pharmaceutical compositions which can be used in the treatment of the above diseases.

The amount of the compounds of formula I (hereinafter referred to as active ingredient), necessary to obtain a therapeutic effect will, of course, vary depending on the particular compound, the route of administration and whether the mammal being treated. Acceptable dose of a compound of formula I for the systemic treatment from 0.1 to 20 mg per kilogram of body weight, the most preferred dose of from 0.2 to 10 mg/kg of body weight, administered once or several times a day.

For spray-drugs suitable anti-asthmatic dose of the compounds of formula (I) ranges from 1 μg to 5 mg per kilogram of body weight, the most preferred dose of from 1 μg to 1 mg/kg of body weight of the mammal, for example, from 1 μg to 0.5 mg/kg

Although you can assign the active ingredient itself, as a chemical, it is preferable to present it as a pharmaceutical preparation. Typically, the active ingredient may be from 0.1% to 100% by weight of the preparation. Useful if dosage form of the preparation contains from 0.07 mg to 1 g of the active ingredient. The local application the preferred concentration of active ingredient with the aqueous or buccal use, may contain from 0.1 to 20% V/V, for example about 2%/active ingredient.

The term "dosage form" refers to a unit, i.e. a single dose which may be accepted by the patient and which is convenient from the point of view of packing and drinking, staying physically and chemically stable unit dose containing the active material as such or a mixture with a solid or liquid pharmaceutical diluent or carrier.

The drug of the present invention, intended for both veterinary and medical purposes, contains the active ingredient in combination with pharmaceutically-acceptable carriers and optionally other therapeutic ingredients. The carrier must be "appropriate" in the sense that it must be compatible with other ingredients of the drug and not to be harmful to the recipient.

The product includes forms suitable for oral administration, ophthalmic, rectal, parenteral (including subcutaneous, intramuscular and intravenous), intradermal, intraarticular, local, nasal or buccal administration.

The drug can be presented in the form of dosage form and prepared by any of horary consists of one or more additional ingredients. In General, the drugs are prepared by homogeneous and careful connection of the active ingredient with liquid carriers or finely powdered solid carrier, or both, by the way, and then, if necessary, the drug is given the desired shape.

The preparations of the present invention, intended for oral administration may be presented as discrete units such as capsules, pills, tablets or pellets, each of which contains a certain amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous or nonaqueous liquids, or in the form of an emulsion of oil-in-water or water-in-oil. The active ingredient may also be assigned in the form of a bolus, medicinal porridge or paste.

The drug is intended for rectal use, can be in the form of a suppository, connecting the active ingredient and a carrier, or in the form of enemas.

The drug is intended for parenteral use that contains sterile oil or aqueous solution of the active ingredient, is isotonic with respect to blood recipient.

Drugs suitable for intra-articular or ocular application, could the s, for example in the form of an aqueous microcrystalline suspension. Liposomal drugs or biodegradable polymer systems can also be used to prepare the active ingredient for both intra-articular and for ophthalmic use.

Drugs intended for local or ocular application, will include liquid or semi-liquid preparations such as emulsions oil-in-water or water-in-oil, ointments or pastes; solutions or suspensions such as drops.

Drugs intended for insertion in the nasal or buccal cavity, include powder for inhalation or spray, such as aerosols or sprays.

Other drugs intended for nasal applications include fine powder, which is made by way of inhalation, i.e. by rapid inhalation through the nose of the container with powder, brought close to the nose.

The preparations of this invention, in addition to the above, can include one or more additional ingredients.

The composition may further contain other therapeutically active substances which are commonly used in the treatment of these pathological conditions, such as glucocorticoids, Academy of Sciences of Santini, b-adrenergic agents, salicylates, indomethacin, flufenamic, naproxen, timelady, gold salts, penicillamine, serum cholesterol-reducing agents, retinoids, zinc salts, and salicylazosulfapyridine (Salazopyrin).

The invention may be further described in the following examples.

Example 1

(+)-2R, 3R-E-3-N-[3-2-(quinoline-2-yl)ethynyl]-phenylamino-3-phenyl-1,2 - propandiol

The mixture of E-3-[2-(quinoline-2-yl)ethynyl] aniline (0.5 g, 2 mmol) (cf EP 0206751 A Merk Frosst Canada Inc) and (2R,3R-(+)-3-phenyl-glycidol (Aldrich) (0.3 g 2 mmol) in ethanol (10 ml) is refluxed for 8 days. After cooling, the resulting precipitate is collected by filtration and washed with ethanol and ether. Receive the above-mentioned compound (specified in the header) with a melting point 164-166oC and [a]D20= +60.9o(c = 1,0, CH3OH)

Example 2-8

Using the procedure described in example 1 and using the appropriate starting materials, to obtain compounds shown in table. 3.

< / BR>
Example 9

Tablet

(+)-2R, 3R-E-3-N-[3-2-(6,7-diperkenalkan-2-yl)ethynyl] phenylamino-3-phenyl-1,2-propandiol

(active substance) - 100 mg

Lactose 75 mg

Starch - 12 mg

Methyl cellulose 2 mg

Sodium carbox what about the homogeneous state in a suitable mixer and moistened with 5% aqueous solution of methyl cellulose 15 SDR. Mixing continued until the formation of granules. If necessary, the wet granules are passed through a suitable sieve and dried to a water content less than 1% in a suitable manner, for example in a fluidized bed or in a drying oven. The dry granulate is passed through 1 mm sieve and mixed to a homogeneous state with natrocarbonatite. Magnesium stearate is added and mixing continues for a short period of time.

Tablets weighing 200 mg get from the granulate by means of a suitable teletrauma machine.

1. Diol derivatives of quinoline of the formula I

< / BR>
in which R1is hydrogen or halogen, preferably fluorine or chlorine, and m = 0, 1, or 2; and its stereoisomers.

2. The compound of formula I under item 1, where R1represents preferably fluorine or chlorine.

3. Connection PP.1 and 2, composed of a mixture of stereoisomers.

4. Connection on p. 1, which is selected from the group consisting of

(+)-2R, 3R-E-3-N-[3-2-(6,7-diperkenalkan-2-yl)ethynyl] -phenylamino-3-phenyl-1,2-propandiol,

(+)-2R, 3R-E-3-N-[3-2-(quinoline-2-yl)ethynyl] -phenylamino-3-phenyl-1,2-propandiol,

(-)-2S, 3S-E-3-N-[3-(2-quinoline-2-yl)ethynyl] -phenylamino-3-phenyl-1,2-propandiol,

(+)-2R, 3R-E-3-N-[3-2-(7-chloroquinoline-2-yl)atenol,

(+)-2R, 3R-E-3-N-[3-2-(7-perkenalan-2-yl)ethynyl] -phenylamino-3-phenyl-1,2-propandiol,

(-)-2S, 3S-E-3-N-[3-2-(7-perkenalan-2-yl)ethynyl] -phenylamino-3-phenyl-1,2-propandiol,

(-)-2S, 3S-E-3-N-[3-2-(6,7-diperkenalkan-2-yl)ethynyl] -phenylamino-3-phenyl-1,2-propandiol,

and their enantiomeric forms.

5. Connection on p. 1 for medicines used in certain medical conditions, including asthma, allergies, rheumatoid arthritis, spondylarthritis, gout, atherosclerosis, proliferative and inflammatory skin disorders, chronic inflammatory intestinal diseases and other inflammatory diseases, vascular spasm associated with angina, pulmonary hypertension, fibrosis of the bladder syndrome age-related respiratory disorders, ischemic and reperfusion disorders, migraine.

6. Pharmaceutical drug that has antagonistically activity against leukotriene containing the active substance and the necessary auxiliary additives, characterized in that it as the active substance contains a compound according to PP.1 to 4 in an effective amount.

7. Method of inhibiting specific reduction of smooth muscles induced leuko necessary together with one or more other therapeutically active ingredients.

8. The method of obtaining compounds of formula I on p. 1, characterized in that the amine of formula II

< / BR>
in which R1and m have the above meanings, is reacted with the compound of the formula III.

(

 

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 unknown compounds useful in the treatment of humans and animals, their pharmaceutically acceptable salts, to their bioapatite derivatives, methods of producing these new compounds, pharmaceutical compositions containing the new compounds, to dosage units of the compositions and to methods of treating patients using these compositions and unit dosages

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

The invention relates to pharmaceutical industry and relates to radiotherapy radiodiagnostic reagents and peptides
The invention relates to the field of pharmacology, and relates to means for correcting energy metabolism

The invention relates to medicine

The invention relates to medicine, in particular to a method of treating a condition of fear or treating and/or preventing a panic state
The invention relates to the medical industry, medicine and veterinary medicine and relates to a composition for tableting and method of making tablets

The invention relates to medicine

The invention relates to the object characterized in the claims, t

The invention relates to the field of medicine and for the treatment of a dysbacteriosis, secondary immunodeficiencies when allergic
The invention relates to medicine and relates to antibacterial, antioxidant, detoxifying, immunomodulatory and anticarcinogenic drug
Up!