Derivatives piano-quinoline synthesis method and pharmaceutical composition

 

(57) Abstract:

The invention relates to pharmaceutical compounds, their preparation and use. Derivatives piano-quinoline General formula I, where R1is phenyl, optionally substituted by nitro, a halogen atom, a C1- C4-alkoxy, trifluoromethyl; R2- nitrile group; R3- NR8R9where R8and R9- N or C1- C4-alkyl; ring R is a pyridine ring fused with benzopyranones core in three forms structures and century of the Compounds of formula I possess antiproliferation effect on cell division and can be used in the treatment of diseases in which excessive growth of cells or secretion of enzymes is an important aspect of the pathology. 3 S. and 3 C.p. f-crystals, 1 table.

This invention relates to pharmaceutical compounds, their preparation and use.

In previously known works reveals some piano-quinoline, for example, 4H-pyrano [3,2-h] quinoline - Z. H. Khalil et al., Bull Chem. Soc. Jpn., 64, 668 - 670 (1991), A. G. A. Elagamey et al., Collection Czechoslovak Chem. Commun. , 53(7), 1534-8 (1988), F. M. A. El-Jaweel et al., Pharmazie, 45(9), 671-3 (1990) and K. D. Paul et al. Cancer Res., 52(14), 3892 - 3900 (1992).

Found that compounds of the following General formula prednaznachalas a phenyl or heteroaryl, choose from among tanila, pyridyl, benzothiazyl, chinoline, benzofuranyl or benzimidazolyl, and the above-mentioned phenyl or heteroaryl group possibly substituted, or a substituent R1is furanyl, possibly substituted C1- C4-alkyl;

Deputy R2represents a nitrile group, a carboxyl group, -COOR4where R4represents an ester group, -CONR5R6where R5and R6each represents a hydrogen atom or a C1- C4-alkyl, or R7SO2where R7represents a C1- C4-alkyl or possibly substituted phenyl;

Deputy R3represents NR8R9, -NHCOR8, N(COR8)2, -N=CHOR8where the substituents R8and R9each represents a hydrogen atom, or a C1- C4-alkyl, or-NHSO2R10where R10represents a C1- C4-alkyl or possibly substituted phenyl; or

< / BR>
where X represents a C1- C4-alkylen; and group

< / BR>
represents a pyridine ring condensed with benzopyranones core;

and their salts.

Compounds of the present and the tion for the treatment of immune diseases in which a significant role is played by the excessive growth of cells or excessive release of the enzyme.

Compounds of the above formula (I) are new, with the exception of compounds in which the group

< / BR>
represents a

< / BR>
and

(I) the substituent R1represents phenyl or phenyl substituted in the para-position of one atom of chlorine, hydroxy - or methoxy-group, the substituent R2represents a nitrile group, and the substituent R3represents-NH2.

(II) the substituent R1represents phenyl or phenyl substituted in para-position by one chlorine atom or methoxy group, a substituent R2represents-COOC2H5and the substituent R3represents-NH2or

(III) the substituent R1represents phenyl, the substituent R2represents-NHCOCH3and the substituent R3represents-NHCOCH3or N= CHOC2H5.

Specific examples of the compounds of the present invention, which are excluded from this new group is 2-amino-4-phenyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile.

It should be understood that the compounds of the present invention mo < / BR>
< / BR>
Preferred compounds are compounds represented by structures II, III and IV, and especially by structures II and IV. The new compounds of structure II include some compounds defined above.

In the above formula I C1- C4is an alkyl group represents, for example, methyl, ethyl, propyl and butyl, preferably methyl or ethyl.

Substituted phenyl group substituted by one or more substituents, preferably one or two substituents selected from among, for example, halogen atom, triptorelin group, C1- C4-alkoxygroup, hydroxy-group, nitro, C1- C4-alkyl, C1- C4-allylthiourea, hydroxy-C1- C4-alkyl, hydroxy-C1- C4-alkoxygroup, triptoreline groups, carboxyl groups, - COOR11where substituent R11represents an ester group, groups,- CONR12R13or NR12R13where each substituent R12or R13represents a hydrogen atom or a C1- C4-alkyl. If the Deputy is a group - COOR11the substituent R11can represent, for example, ethyl or ethyl. Substituted naftalina or heteroaryl groups can be substituted in a similar way. In addition, the substituted phenyl may be a phenyl group, in which neighboring atoms substituted by a slice-O(CH2)mO-, where m takes on the values 1, 2, or 3.

If the substituent R1is heteroaryl, then preferably it is a 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-benzothiazyl, 3-benzothiazol, 2-chinoline, 3-chinoline, 2-benzofuranyl, 3-benzofuranyl, 2-benzimidazolyl, 2-furanyl or 3-furanyl. Naftalina group attached 1 - or 2-position. Such groups can be substituted at any available position, but should be preferably unsubstituted.

Preferably the substituent R1represents a possibly substituted phenyl, preferably phenyl, containing a single Deputy, in particular, a nitrogroup, triptorelin group, C1- C4-alkoxygroup, for example, a methoxy group, or a group-COOR11where substituent R11represents a C1- C4-alkyl, for example methyl. A preferred group of compounds is the group in which the substituent R1represents phenyl, substituted Alannah above as examples of substituents in the phenyl group.

The group R2represents a nitrile group. If the substituent R2is a-COOR4the substituent R4can be any ester group, for example, aryl-CH2group such as benzyl group, and preferably is C1- C4-alkyl, in particular the stands or ethyl.

Deputy R3preferably represents-NR8R9in particular, -NH2.

Preferred are compounds in which the substituent R1represents a possibly substituted phenyl, the substituent R2- nitrile, and the substituent R3- NH2group.

A preferred group of compounds of the above formula II is a group in which the substituent R1represents phenyl, substituted by a single substituent in the meta-position, the substituent R2represents a nitrile, and the substituent R3- NH2group.

Another preferred group of compounds of the above formula II is a group in which the substituent R1represents phenyl substituted by a nitro-group, triptorelin group, a methoxy group or a group-CO2Me, replace the AMB, what if, for example, the substituent R2represents COOH, there is a possibility of formation of salts. They can be obtained from any well-known reasons. Examples of basic salts are salts derived from ammonium hydroxide and the hydroxides of alkali and alkaline earth metals, carbonates and bicarbonates and salts derived from aliphatic and aromatic amines, aliphatic diamines and hydroxyethylamino. The grounds, which are particularly useful in obtaining such salts are ammonium hydroxide, potassium carbonate, sodium bicarbonate, lithium hydroxide, calcium hydroxide, methylamine, diethylamine, Ethylenediamine, cyclohexylamine and ethanolamine. Preferably the formation of potassium, sodium and lithium salts.

You must understand that the pyridine ring also provides the possibility of obtaining the acid additive salts. Acid additive salts can be obtained from the appropriate acids such as inorganic acids, e.g. hydrochloric, Hydrobromic, nitric, sulphuric or phosphoric acid, or organic acids such as organic carboxylic acids, for example glycolic, maleic, fumaric, malic, tartaric, citric, salcinovic, toluene-persulfonic or naphthalene-2-sulfonic acid.

In addition to pharmaceutically acceptable salts in the present invention includes and other salts. They can be used as intermediates in the purification of the compounds of the present invention or the other, for example, pharmaceutically acceptable acid additive salts, or can be used in the identification, description of properties, or when cleaning.

It should be understood that the compounds of the present invention contain an asymmetric carbon atom, which leads to the appearance of enantiomers. Compounds are usually prepared in the form of racemates and are usually used in this form, but can be selected and individual enantiomers using ordinary methods, if necessary. Such racemates and individual enantiomers form part of the present invention.

The present invention also provides a method for obtaining compounds of the above formula I, which includes:

(1) the interaction of the compounds of formula

< / BR>
with the compound of the formula

< / BR>
with the formation of the compounds of formula I in which the substituent R3represents NH2group, or

(2) a group-NR8R9, -NHCOR8, -N(COR8)2, -N=CHOR8, -NHSO2R10,

< / BR>
In accordance with method I, the reaction is carried out preferably at a temperature of from 0 to 100oC and in the presence of an organic solvent, such as ethanol. The compounds of formula VI are known or can be easily obtained by known methods.

Reagents of formula VII can be obtained by reaction of the appropriate nitrile of the formula

R2CH2CN

with an aldehyde of the formula

R1CHO

preferably at a temperature of from 20 to 100oC in the presence of an organic base as a catalyst, such as piperdine, and in the presence of an organic solvent, such as ethanol. Nitrile and aldehyde reactants are either known compounds or can be obtained by methods known in this field.

As for the method (2), then free the enamine can be obtained by the reaction of (1) with subsequent conversion into compounds in which the substituent R3takes other values. For example, the free amino group can be proaccelerin reagent of formula R8X or R9X, where X Deputy is Sobolinaya using Alliluyeva reagent of formula R8COX or (R8CO)2O with the formation of compounds in which the substituent R3is a-NHCOR8or-N(COR8)2. Compounds in which the substituent R3represents-N=CHOR8can be obtained by reaction with a suitable trialkylaluminium, and compounds in which the substituent R3represents-NHSO2R10the reaction with sulphonylchloride formula R10SO2X.

As indicated above, the compounds have pharmaceutical activity. They have antiproliferation effect on cell division and consequently, they can be used in the treatment of diseases in which excessive growth of cells or secretion of enzymes is an important aspect of the pathology.

For example, the compounds of the present invention inhibit natural growth T fibroblasts at a concentration of IC50below 10 Microm.

In addition, the compounds of the present invention have been shown to modify the immune response by inhibiting the proliferation of T-cells caused by concanavalin A, in the tests described Lacombre P. et al., FEBS, 3048, 191, 227 - 230.

Compounds of the present invention also inhibit retractation in bovine retinal capillary endothelial cells.

Also in the tests described K. Deshmukh - Phadke, M. Lawrence & S. Nanda (Biochem. , Biophys. Res. Commun., 1978, 85, 490 - 496), an inhibition of the environment caused by macrophages due to the release of neutral protease in chondrocytes.

Such properties indicate that the compounds have the potential to treat a wide range of diseases, such as rheumatoid arthritis, atherosclerosis, cirrhosis, fibrosis and malignant tumors and for the treatment of auto-immune diseases such as systemic lupus erythematosus, and to prevent transplant rejection. They can also be used to treat osteoarthritis and diabetic complications.

In addition, the compounds of the present invention, has been shown to inhibit the proliferation of vascular soft cells. This was shown when using cultural soft cells derived from rabbit aorta, and proliferation was determined by measuring DNA synthesis. Cells received explanandum by the method described in J. of Cell Bio., 50, 172 (1971). The cells were made in 96-cellular microtiter tablets for five days. Cultures mingled and growth stopped. Cells then were transferred to Dulbecco's Modified Medium (DMEM) is a, 1 µs/ml3H-thymidine, 20 ng/mg trombotsitnoy growth factor and various concentrations of compounds. The original solution of the compounds were prepared in dimethyl sulfoxide and then diluted to the required concentrations (0.01 - 10 µl/ml) in the above-described environment for testing. The cells were then cultured at 37oC for 24 h in an atmosphere of 5% CO2/95% air. After 24 h the cells were fixed with methanol. The inclusion of3H-thymidine into DNA was determined by scintillation account, which is described in Exp. Cell Res. 181, 475 - 482 (1989), Bonin et al.

The inhibition of proliferation of smooth muscle cells by compounds of the present invention is shown in the determination of their effect on exponentially growing cells. The cells of the soft muscle of rabbit aorta were obsenely 12-aerated tissue culture plates in DMEM containing 10% fetal bovine serum, 2 mm glutamine, 100 units/ml penicillin and 100 μg/ml streptomycin. After 24 hours was recorded, the medium was replaced with DMEM containing 2% plasma-depleted platelet, 2 mm L-glutamine, 100 units/ml penicillin, 100 μg/ml streptomycin, 40 ng/mg trombotsitnoy growth factor and various concentrations of compounds. The cells were given the opportunity to grow within a few days. Cells were treated tripti is certain in the above-described tests, shows that the compounds of the present invention can be used in the treatment of restenosis, which is characterized by migration and proliferation of smooth muscle cells in response to damage.

Thus, the present invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent in combination with the compound of the formula (I) or its pharmaceutically acceptable salt.

The compounds can be applied in various ways, for example, orally or rectally, locally or parentale, for example, by injection, usually applied in the form of pharmaceutical compositions. Such compositions form part of the present invention and are prepared by methods which are well known in the pharmaceutical industry, and typically contain at least one active ingredient in combination with pharmaceutically acceptable carrier or diluent. In the preparation of compositions of the present invention the active ingredient is usually mixed with a carrier, or diluted by a carrier, and/or concluded with a carrier, which may for example be in the form of a capsule, pouch, paper or other container. When the carrier serves as a diluent, it may be the active ingredient. Consequently, the composition may be in the form of tablets, pellets, wafers, elixirs, suspensions, solid or in liquid medium, ointments containing for example up to 10% (wt. the active compound, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions, and sterile packaged powders.

Examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, gum Arabic, calcium phosphate, alginates, tragakant, gelatin, syrup, methyl cellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Compositions for injection can be retseptoriani thus, in order to provide fast, permanent or prolonged release of active ingredient after administration to the patient, which is well known in this field.

If the composition obtained in the form of single dosing form, it is preferable that each unit form contains from 5 mg to 500 mg, for example from 10 to 200 mg, the Term "single dosing form" refers to physically discrete units that are acceptable as a single dose for the treatment of humans or animals, each unit contains a predetermined quantity of active material, which frames the media.

The active compounds are effective within a wide range of doses and, for example, the daily dose will typically fall in the range from 0.5 to 300 mg/kg, or in the range from 5 to 100 mg/kg should be understood, However, that the assigned number will be determined by a physician considering various factors, including the condition to be treated, the choice of assigned connections and the choice of method of its application, and therefore the above intervals doses should not limit the scope of the invention.

The invention is illustrated by the following examples.

Example 1

Suspension of malononitrile (7,52 g) and 3,4-dimethoxybenzaldehyde (18,95 g) in ethanol (100 ml) was boiled under stirring. The orange solution was no longer to heat and added piperidine (0.5 ml). After the rapid decay of the reaction the reaction mass was again heated to boiling and boil 35 minutes By this time, there is a large number of bright-yellow solid product. The mixture was cooled in an ice bath for 10 min and the yellow solid product was filtered, washed with ethanol and ether and dried in vacuum at 70oC, was obtained 3,4-dimethoxybenzenesulfonamide, so pl. 37oC.

A similar technique obtained sleduushii, so pl. 102oC.

3-carbomethoxybiphenyl, so pl. 125oC.

3-triftoratsetilatsetonom, so pl. 81oC.

3,4-dichlorobenzaldehyde, so pl. 154oC.

Example 2

To a suspension of 5-hydroxyisoquinoline (2,90 g) and 3,4-dimethoxybenzaldehyde (4,28 g) in ethanol (11 ml) was added dropwise piperidine (1.70 g). The resulting suspension was boiled for 1 h, was obtained red solution. The solution is then cooled to room temperature, it was formed brown precipitate. The precipitate was filtered, washed with ethanol and ether and dried in vacuum at 60oC, was obtained 2-amino-4-(3,4-acid)- 4H-pyrano(2,3-f)isoquinoline-3-carbonitrile in the form of a brown solid product, so pl. 225 - 228oC.

According to the same method the following compounds:

2-amino-4-(3,4-dichlorophenyl)-4H-pyrano[2,3-f] isoquinoline - 3-carbonitril, so pl. 215 - 218oC.

2-amino-4-(3-methoxyphenyl)-4H-pyrano[2,3-f]isoquinoline - 3-carbonitril, so pl. 223 - 224oC.

2-amino-4-(3-nitrophenyl)-4H-pyrano[2,3-f] isoquinoline - 3-carbonitril, so pl. 239 - 243oC.

2-amino-4-(3-triptoreline)-4H-pyrano[2,3-f]isoquinoline - 3-carbonitril, so pl. 117 - 118oC.


A suspension of 8-hydroxyquinoline solution (2,90 g) and 3,4-dimethoxybenzaldehyde (4,28 g) in ethanol (15 ml) was treated with piperidine (1.70 g) and stirred at room temperature for one hours the mixture is Then boiled for 90 minutes the Obtained red solution was left to cool to room temperature overnight. Precipitated orange solid product was filtered, washed with ethanol, ether and dried in vacuum at 60oC, was obtained 2-amino-4-(3,4-acid)-4H - pyrano[3,2-h]quinoline-3-carbonitrile, so pl. 118 - 120oC.

According to the same method the following compounds:

2-amino-4-(3,4-dichlorophenyl)-4H-pyrano[3,2-h] quinoline - 3-carbonitrile, so pl. 218 - 222oC.

2-amino-4-(3-methoxyphenyl)-4H-pyrano[3,2-h] quinoline - 3-carbonitrile, so pl. 190 - 192oC.

2-amino-4-(3-nitrophenyl)-4H-pyrano[3,2-h] quinoline - 3-carbonitrile, so pl. 198 - 200oC.

2-amino-4-(3-triptoreline)-4H-pyrano[3,2-h] quinoline - 3-carbonitrile, so pl. 228 - 231oC.

Methyl 3-(2-amino-3-cyano-4H-pyrano[3,2-h] quinoline-4-yl)benzoate, T. pl. 208 - 210oC.

Example 4

A suspension of 5-hydroxyquinoline solution (703 mg) and 3-triftoratsetilatsetonom (1.07 g) in ethanol (5 ml) was treated with piperidine (410 g). Paul who was chromatographically on Florisil, using as eluent dichloromethane, received 188 mg of 2-amino-4- (3-triptoreline)-4H-pyrano[2,3-f] quinoline-3-carbonitrile in the form of a cream solid color, so pl. 167 - 168oC.

According to the same method the following compounds:

2-amino-4-(3,4-dichlorophenyl)-4H-pyrano[2,3-f] quinoline-3 - carbonitrile, so pl. 223 - 228oC.

2-amino-4-(3-methoxyphenyl)-4H-pyrano[2,3-f] quinoline-3 - carbonitrile, so pl. 218 - 222oC.

2-amino-4-(3-nitrophenyl)-4H-pyrano[2,3-f] quinoline-3 - carbonitrile, so pl. 200 - 202oC.

2-amino-4-(3,4-acid)-4H-pyrano[2,3-f] quinoline-3 - carbonitrile, so pl. 160 - 163oC.

Methyl 3-(2-amino-3-cyano-4H-pyrano[2,3-f] quinoline-4-yl)benzoate, T. pl. 203 - 206oC.

Example 5

Soft gelatin capsules

Each gelatin capsule contains:

The active ingredient, 150 mg

Peanut butter - 150 mg

After mixing the components, the mixture is filled soft gelatin capsules using suitable equipment.

Example 6

Hard gelatin capsules

Each capsule contains:

Active ingredient: 50 mg

Polyethylene glycol 4000 250 mg

Polyethylene glycol 4000 was melted and mixed with the active is SS="ptx2">

Example 7

Tablet

Each tablet containing 10 mg of active ingredient is prepared from the following components:

Active ingredient 10 mg

Starch - 160 mg

Microcrystalline cellulose 100 mg

Polyvinylpyrrolidone (10% solution in water) - 13 mg

Sodium salt of carboxymethyl amylum - 14 mg

Magnesium stearate 3 mg

The total number of 300 mg

The active ingredient, starch and cellulose are thoroughly mixed. The solution of polyvinylpyrrolidone is mixed with the obtained powder and pass through a sieve. Thus obtained granules are dried and again passed through a sieve. To the pellet add sodium salt of carboxymethyl amylum and magnesium stearate and after mixing the granules are pressed into teletrauma machine into tablets each weighing 300 mg

Example 8

As the primary in vitro evaluation of the activity of the compounds of the present invention used the response of concanavalin A spleen cells of rats. The literature describes a large number of methods for determining the response of concanavalin A. Used a method similar to the method described in FEBS 3048 191, 227-230 (Lacombe P. et al.). We used 2 of 105cell culture the cell, and concanavalin A was used for allali 0,25 MX labeled with tritium thymidine. All compounds of the present invention described in the examples, inhibited the growth of cells and had these tests IC50less than 5 microns. Test data are given in the table.

1. Derivatives piano-quinoline General formula I

< / BR>
where substituent R1represents phenyl, optionally substituted by nitro, a halogen atom, a C1- C4-alkoxy, trifluoromethyl;

R2- nitrile group; R3- NR8R9where R8and R9- each H or C1- C4-alkyl;

group

< / BR>
represents a pyridine ring condensed with benzopyranones core in three forms of the following structures:

< / BR>
with the exception of compounds in which the group

< / BR>
represents a

< / BR>
and R1represents phenyl or phenyl substituted in the para-position by one chlorine atom or a methoxy group, R3represents NH2,

or their salts.

2. The compound of formula I under item 1 of the formula II

< / BR>
where R1, R2and R3have the specified values.

3. The compound of formula I under item 1, characterized in that it has the structure

< / BR>
where R1, R2and R3have the specified values.

2represents a nitrile, and the substituent R3represents - NH2.

5. Pharmaceutical composition having anti-proliferative activity, comprising an active substance and a pharmaceutically acceptable diluent or carrier, wherein the active substances it contains a compound of formula I under item 1 or its salt in an effective amount.

6. A method of obtaining a connection on p. 1, characterized in that the compound of formula VI

< / BR>
where the group P has the value

subjected to interaction with the compound of the formula VII

< / BR>
R1and R2has the specified values,

and the resulting compound of formula I, where R3- NH2group, if necessary, transferred to the compound of formula I, where R3- NR8R9-group.

 

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< / BR>
(I) where a lower alkylene;

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A< / BR>
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< / BR>
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< / BR>
and their pharmaceutically acceptable salts,

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