Derivatives of pyrrolidinone, the retrieval method, intermediate compounds for their production, pharmaceutical composition and method thereof

 

(57) Abstract:

Derivatives of pyrrolidinone formula I, where L is a radical of the formula-O - Alk - NHp- C (=O) - R1, Alk - C1-6-alcander; p = 0 or 1; R1is hydroxy, alkoxy or-NR2R3; R2Is h or alkyl; R3- C3-7-cycloalkyl or piperidinyl, possibly substituted by alkyl, vinylmation or3-7-cycloalkylation; R2and R3may together form a piperazinil, or piperidinyl, or their pharmaceutically acceptable salt additive, or their stereochemical isomeric forms, are potent inhibitors of phosphodiesterase type III (cardiotoniceski-sensitive PDE III). 5 s and 5 C.p. f-crystals, 3 PL.

EP-0406968 describes derivatives of imidazoquinolines with positive myotropic and Lusitania properties.

GB-2190676 and EP-0426180 reveal a number of imidazoquinolines as inhibitors of C-AMP phosphodiesterase. US-5196428 describes imidazoquinolines, showing the effect of inhibiting

ADP-induced aggregation of blood platelets in platelet-rich plasma.

Perkin and Robinson (J. Chem. Soc., 103, 1973, (1913) describe obtaining 1,3-dihydro-2H-pyrrolo [2,3-b]quinoline-2-it. However, according T innovage connection but even flat quinoline derivatives.

Vogel with TCS. (Helv. Chim. Acta, 52(7), 1929 (1969) and US-3, 974, 165 describe getting some partially hydrogenated derivatives pyrrolo [2,3-b]quinoline-2-it.

Compounds of the present invention differ from the known compounds of particular substitution pyrroloquinoline fragment and its favorable myotropic and lusitropic properties.

The present invention relates to new derivatives of 1,3-dihydro-2H-pyrrolo [2,3-b]quinoline-2-it, having the formula

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their pharmaceutically acceptable additive salts and their stereochemical isomeric forms,

where, L is a radical of the formula-O-Alk-NHp-CO-R1where Alk-C1-6-alcander; p is 0 or 1 and R1is hydroxy, C1-4-alkoxy or-NR2R3where R2is hydrogen or C1-4-alkyl and R3-C3-7-cycloalkyl or piperidinyl, which may be substituted C1-4-alkyl, vinylmation or C3-7-cycloalkylation; R2and R3can also together form a piperazinil, optionally substituted C3-7-cycloalkyl, C3-7-cycloalkylation, C1-6-alkyl optionally substituted by one or two hydroxy groups, 2,2-dimethyl-1,3-DIOXOLANYL, be the sludge or phenyl, optionally substituted C1-4-alkoxyl or halogen; or R2and R3together form piperidinyl, optionally substituted imidazolylalkyl.

In the above definitions, halogen is fluorine, chlorine, bromine and iodine; the term "C1-4-alkyl" denotes normal and branched saturated hydrocarbon radicals, having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl; "C1-6-alkyl" denotes a C1-4-alkyl and the higher homologues, such as, for example, pentyl, hexyl and the like.

"C3-7-cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopentyl; "C1-6-alcander" means normal and branched bivalent radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,1-ethandiyl, 1,1-propanediyl, 1,2-propanediyl and the like.

Pharmaceutically acceptable salt additive mentioned above, comprise therapeutically active non-toxic additive form salts, which are capable of forming compounds of formula (I). These salt forms may be p is such as inorganic acids, for example, halogenation (chloromethane, Hydrobromic, etc.,), sulphuric, nitric, phosphoric acid and the like, or organic, such as, for example, acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, atindimubona, perpendicularly, butandikislota, (Z)-2-butandikislota, (E)-2-butandikislota, 2-hydroxybutyrophenone, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultation, benzosulfimide, 4-methyl-benzosulfimide, cyclohexanecarboxylate, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and the like acids. On the contrary, the salt form can be converted into a form of free bases by treatment with alkali.

The compounds of formula I containing an acidic proton may also be converted into a therapeutically active non-toxic additive metal salts or ammonium by treatment with appropriate organic or inorganic bases. Suitable basic salt forms comprise, for example, ammonium salts, salts of alkali and alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium and the like, salts of organic bases, Nuprin and the like.

The term "additive salt also comprises the hydrates and additive forms part of the solvent that the compounds of formula I can form. Examples of such forms are hydrates, alcoholate, for example, ethanolate and the like.

Stereochemical pure isomeric forms of the compounds of formula I can be obtained using known techniques. The diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques, for example, the distribution chromatography, liquid chromatography, and the like, the enantiomers can be separated from each other by the following well-known methods of separation, for example, selective crystallization of their diastereomeric salts of chiral acids. Stereochemical pure isomeric forms may be separated from the corresponding pure stereochemical forms of the original substances with stereospecificity proceeding reactions. As another alternative, the enantiomers can be separated by liquid chromatography using a chiral stationary phase. Stereochemical isomeric forms of the compounds of formula I, obviously, should be included in the subject matter.

Credit tautomeric forms should be included in the subject matter.

Particular compounds of formula I are those compounds where L is a radical of the formula-O-Alk-NHp-CO-R1where Alk-C1-6-alcander; p is 0 or 1 and R1is hydroxy, C1-4-alkoxy or-NR2R3; where R2is hydrogen or C1-4-alkyl and R3- C3-7-cycloalkyl or piperidinyl, which may be substituted C1-4the alkyl or vinylmation; R2and R3can also be joined together, forming piperazinil optionally substituted C3-7-cycloalkyl, C3-7-cycloalkylation, C1-6-alkyl, benzyl, diphenyl C1-4-alkyl, pyridinyl, pyrimidinyl or phenyl, optionally substituted C1-4-alkoxyl or halogen; or R2and R3together form piperidinyl, optionally substituted imidazolylalkyl.

Preferred compounds of formula I are those where R1is-NR2R3.

More preferred compounds of preferred compounds are those where R2and R3joined together, forming piperidinyl, substituted C3-7-cycloalkylation.

Even more preferred compounds are those more preferred compounds are those where R1cyclohexylmethyl)-4-[4[(2,3-dihydro-2-oxo-1H-pyrrolo -[2,3-b] quinoline-6-yl)oxy] -1-oxo-butyl]piperazine and 1-(cyclohexylmethyl)-4-[5-[(2,3-dihydro-2-oxo-1H-pyrrolo- [2,3-b]quinoline-6-yl)oxy]-1-oxobutyl]piperazine, their pharmaceutically acceptable additive salts and their stereochemical isomeric form.

The compounds of formula I can be obtained by reacting the intermediate compounds of formula II in the presence of a suitable dehydrating reagents in an inert solvent.

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The above reaction can be suitably carried out using, for example, 4,5-sodium dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile and similar compounds as a dehydrating reagent in tetrahydrofuran, 1,4-dioxane or mixtures of these solvents. On the other hand, the above-mentioned reaction can be performed in the presence of a suitable catalyst, e.g. platinum or palladium on charcoal, in a suitable solvent, for example toluene, diiso-propylbenzene, xylene, cumene and the like, possibly with the admixture of catalyst poisons, for example, thiophene, and possibly in the presence of acceptor hydrogen, for example, 2,5-dimethyl-2,4-hexadiene, cyclohexene and the like. If you are using the catalyst as described above, the reaction conversion of II to I is preferably carried out at elevated temperature and/or pressure.

The compounds of formula I can also be obtained shackles of bis(triphenylphosphine)-palladium (II, tetrakis(triphenylphosphine)palladium (O), palladium on charcoal and the like in a suitable solvent, for example, methylbenzol, acetic acid, propanoic acid, 2-methylpropanoic acid, 2,2-dimethylpropanoate acid and the like.

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The compounds of formula (I) can be obtained by O-alkylation of the corresponding 6-hydroxypyrrolidine compounds or their protected derivatives, using well known methods.

The compounds of formula (I) can also be converted into each other using well-known methods of transformation of functional groups, for example, (TRANS)esterification, (TRANS) amidation and similar methods.

For example, the compound of formula (I), where R1the hydroxyl can be obtained by hydrolysis of the corresponding compounds where R1- C1-4-alkoxy, following the well-known methods, for example, in the presence of base or acid.

Further, the compound of formula (I), where R1-NR2R3can be obtained by reaction of the corresponding carboxylic acid with other2R3in the presence of a suitable reagent capable of forming amides, for example, diphenyl-phosphorylated. If ispolzuem(ethane)amine, optionally, in the presence of catalytic amounts of N,N-dimethyl-4-pyridylamine in an inert solvent, for example N,N-dimethylformamide, 1-methylpyrrolidine-2-Ohe and the like. The last procedure conducted at elevated temperatures (preferably 180 to 200oC) can lead to reactions of the type rearrangement Curtis, as described in J. Med. Chem. 1993, 36, 22, 3252, thus giving the compound (1), where p=1.

The specified carboxylic acid can also be converted into its appropriate reactive functional derivative, such as, for example, allalone or anhydride to the reaction with the amine other2R3. These reactive functional derivative can be obtained, following the well-known methods, for example, by reacting carboxylic acid with a halogenation reagent such as, for example, thionyl chloride, and the like. The acid anhydride can be obtained by the reaction of derivatives of acylhomoserine with salts of carboxylic acids. Functional derivatives described above are distinguished by the fact that R1- halogen or C1-4allyloxycarbonyl.

The compounds of formula (I), where R2and R3form piperazinilnom group can be procentiem, for example, the hydrogenation. The compounds of formula (I), where2and3form piperazinilnom group can then be N-alkylated, following the well-known methods N-alkylation, for example, reductive N-alkylation. The compounds of formula (1), where R2R2form piperazinilnom group, a substituted 2,3-dihydroxypropyl, can be obtained by the reaction of pieperazinove derived, substituted 2,2-dimethyl-1,3-DIOXOLANYL in the presence of acid.

In all previous and subsequent transformations of the products of the reactions can be isolated from the reaction mixture and, if necessary, further purified according to known methods.

Intermediates of formula II can be obtained by cyclization of the intermediate products of the formula III under catalytic hydrogenation in the presence of a suitable catalyst, e.g. palladium on charcoal in an inert solvent, for example, 2-methoxyethanol, acetic acid and the like.

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Intermediate products of the formula II can also be obtained by cyclization of intermediates of formula IV with a catalytic hydrogenation in the presence of a suitable catalyst, e.g. palladium on aktivnye products of formula III can be obtained by catalytic hydrogenation of the intermediates of formula IV in the presence of a suitable catalyst, for example, platinum on charcoal in an inert solvent, for example, 2-methoxyethanol and the like, preferably in the presence of catalytic poisons, such as thiophene.

Intermediates of formula IV can be obtained by reaction of intermediates of formula V phosphides of formula VI in an inert solvent, e.g. ethanol and the like.

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The compounds of formula I, their pharmaceutically acceptable salt additive and stereochemical isomeric forms, as well as intermediate products of the formula II, pharmaceutically acceptable salt additive and stereochemical isomeric forms are potent inhibitors of phosphodiesterase type III (cardiotoniceski-sensitive PDE III) warm-blooded animals, particularly humans. Inhibition of PDE III leads to the selection cAMP in cardiac muscle, which, in turn, increases the amount of Co+2in the shell striated muscle fibers and probably also increases the secretion and re-absorption of Ca2+sarcoplasmic reticular tissue, and probably also increases the sensitivity of contractile proteins to the Ca2+. The result is increased reducing power of the heart (polojitelnaia observation, what positive isotropically and lusitropic effects usually do not coincide with a simultaneous increase in other hemodynamic parameters such as heart rate and blood pressure. A concomitant increase in heart rate and/or blood pressure, in fact, would lead to an additional burden on the heart would stop beneficial positive cardiac inotropy and lusitropic. In vivo studies with the data of the formula (I) showed moderate dilation of blood vessels and, consequently, a decrease in blood pressure. The heart rate was usually increased only at high doses. In General, these compounds of formula (I) significantly increase cardiac output due to positive heart inotropy and lusitropic without appreciable influence on the pulse and/or blood pressure.

Accordingly, the compounds of formula (I) and (II) are considered as a valuable therapeutic agent for the treatment of warm-blooded animals, especially humans, from congestive heart failure. Congestive heart failure - abnormal physiological state determined by the inability of the heart to pump the required amount of blood to the peripheral organs with subsequent mismatch of metabolicheskogo, chronic hypertension, difficulty action of the heart valves and other heart disorders, leading to congestive heart failure.

Some of these compounds have high solubility in comparison with the known compounds.

Due to their positive inotropism and lusotropicalism properties, these compounds can be administered in different pharmaceutical forms for administration into the body. To prepare the pharmaceutical compositions of the present invention an effective amount of the compounds in the form of a base or addition salt of the acid as the active principle is mixed with micronized pharmaceutically acceptable carrier, which may have a wide variety of forms depending on the desired for the injection form of the drug. It is desirable to prepare these pharmaceutical compositions in unit dosage forms suitable mainly for administration orally, rectally, through the skin or for parentally injection. For example, for formulation of oral dosage forms can be used in the pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like, conventional media, such as starches, sugars, kaolin, lubricant, binder and loosening agents and the like, the usual powders, pills, capsules, and tablets. Because of the ease of administration, tablets and capsules seem to be the most promising oral dosage forms that use solid pharmaceutical carriers. For parentally compositions media is usually a sterile water is the main component of the carrier, while other ingredients may be introduced, for example, to improve solubility. Injectable solutions, for example, can be prepared with a carrier that represents saline solution, glucose solution or a mixture. When the thus prepared suspension for injection, you can use the appropriate liquid carriers, suspendresume agents and similar substances. In the compositions suitable for administration through the skin, the carrier can be an agent that enhances the penetration and/or wetting agent in combination with suitable additives of any nature in smaller quantities, which do not cause significant adverse effects to the skin. These additives can facilitate introduction through the skin and/or may be useful in the preparation of the desired composition is an ointment. Additive salts of compounds of formula (I) due to their increased water solubility compared to the respective basic form, obviously, more suitable for the preparation of aqueous compositions.

It is especially advantageous to produce these pharmaceutical compositions in dosage forms to simplify and unify doses. Dosage forms called physically discrete units, which is the lowest dosage that contains a predetermined amount of the active agent calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including tablets with notches in the shell), capsules, pills, powder packets, records, input solutions or suspensions and the like and their types.

Regarding the usefulness of these compounds in the treatment of congestive heart failure it is clear that the present invention provides a method of treating warm-blooded animals from congestive heart failure, the method includes the systematic introduction of pharmaceutically effective amounts of compounds of formula (I) or (II) or and the Kim carrier. In the General case it is established that an effective daily amount varies from 0.01 to 4 mg/kg weight, more preferably from 0.04 to 2 mg/kg of body weight.

Specified daily amount may be reduced or increased depending on the patient's condition and/or depend on physician prescribing the compounds of the present invention. Border daily quantities specified above, therefore, are only guidelines and in no way limit the scope of the invention.

The following examples illustrate the present invention but do not limit its application (see table 1).

Experimental part

A. Obtaining an intermediate product

Example 1

a) a Mixture of ethyl-5-(3-formyl-4-nitrophenoxy)pentanoate (of 0.60 mol) and the internal salt hydroxide (4,5-dihydro-2-hydroxy-5-oxo-1H-pyrrol-3-yl)triphenylphosphane (or 0.57 mol) in ethanol (1500 ml) is stirred and refluxed for 1 hour. Remove the solvent. The residue is stirred with methylbenzol. Filter the resulting precipitate, washed with methylbenzol, 2,2'-oxybisethane and dried. Get 137,3 g (61%) of (E)-ethyl-5-[3-[2,5-dioxo-3-pyrrolidinyl-inden)methyl]-4-nitrophenoxy] -pentanoate; So ioxo-3-pyrrolidinone)methyl] -4-nitrophenoxy] -butanoate (P. 2);

(E)-3-[2-(nitrophenyl)methylene]-2,5-pyrrolidinyl; So pl. 174,1oC (P. 3)

ethyl-(E)-[3-[2,5-dioxo-3-pyrrolidinone)methyl]-4-nitrophenoxy]-acetate; So pl. 147,8oC (P. 9); and

methyl-(E)-6-[3-[2,5-dioxo-3-pyrrolidinone)methyl] -4-nitrophenoxy]-hexanoate; (P. 10);

b) a Mixture of intermediate (1) (0,179 mol) in 2-methoxyethanol (600 ml) and 4% solution of thiophene (4 ml) hydronaut at 50oC in the presence of platinum on charcoal (5%) (8 g) as a catalyst. After absorption of theoretical amount of hydrogen, the catalyst is filtered off. After standing overnight the precipitate is filtered off, washed with ethyl acetate and dried in vacuum. Receive and 42.7 g of the product. The filtrate is evaporated and the residue is stirred with ethyl acetate. The precipitate is filtered off, washed with ethyl acetate, 2,2'-oxybisethane and dried in vacuum. Receive the second portion of the product (13.8 g) which is recrystallized from methoxyethanol; output of 8.3, the Total yield of 51 g (82.2 per cent)

ethyl-(E)-5-[4-amino-3-[(2,5-dioxo-3-pyrrolidinone)methyl] phenoxy] -pentanoate; So pl. 183,5oC (P. 4).

Similarly get:

ethyl-4-[4-amino-3-[(2,5-dioxo-3-pyrrolidinone)methyl] phenoxy] butanoate; So pl. 176,5oC (P. 12); and

ethyl-(E)-[4-amino-3-[(2,5-dioxo-3-pyrrolidinone)methyl]phenoxy] acetate (P. 13).

c) (P. 5) (0.06 mol) in acetic acid (250 ml) hydronaut at 50oC in the presence of palladium on charcoal (10%) (4 g) as a catalyst. After absorption of theoretical amount of hydrogen, the catalyst is filtered off and washed with acetic acid. The filtrate is evaporated and the residue is boiled with ethanol. The precipitate is filtered off, washed with ethanol, 2,2'-oxybisethane and dried in vacuum. Obtain 15.2 g (80%) of ethyl 4-[(2,3,3 a, 4-tetrahydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]-butanoate (P. 6).

Example 2

b) a Mixture of (P. 1) (0.07 mol) in ethanol (150 ml) hydronaut with palladium on charcoal (10%) (2 g) as a catalyst at 50oC at normal pressure. After absorption of theoretical amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated. This fraction was stirred in boiling ethyl acetate, filtered off, washed with ethyl acetate and 2,2'-oxybisethane and dried in vacuum. Obtain 1.0 g (45%) of ethyl 5-[(2,3,3 a, 4-tetrahydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]- pentanoate; So pl. 179,1oC (P. 7).

Similarly get:

ethyl 4-[(2,3,3 a,4-tetrahydro-2-oxo-1H-Pierre is [2,3-b] quinoline-6-yl)oxy]- hexanoate; So pl. 199,3oC (P. 15); and

ethyl [(2,3,3 a,4-tetrahydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]- acetate (P. 16).

Example 3

Solution (P. 3) (0,0215 mol) in acetic acid (150 ml) hydronaut under atmospheric conditions with palladium on charcoal (10%) (2 g) as a catalyst. After absorption of theoretical amount of hydrogen, the catalyst is filtered off and the reaction mass is stirred for 4 hours under reflux (removal of H2). The catalyst is filtered off and the filtrate is evaporated. The precipitate was washed with 2-propanol (40 ml), then dried. Get 2,53 g (64%) of 1,3-dihydro-2H-pyrrolo [2,3-b]quinoline-2-it; So pl. 261,1oC (P. 8).

B. obtain the final compounds

Example 4.

a) a Solution of (P. 6) (0,0064 mol) in tetrahydrofuran (80 ml) was stirred at 7 0oC (oil bath). Portions add 4,5-sodium dichloro-1,4-cyclohexadiene-1,2-dicarbonitrile (2.16 g) and the mixture is stirred for 5 minutes. Add the second batch of 4,5-sodium dichloro-1,4-cyclohexadiene-1,2-dicarbonitrile (0,00158 mol) and stirred the mixture for another 10 minutes. The solvent is evaporated. The residue is stirred with a mixture of CH2Cl2/CH3OH 90/10 and washed with water. The insoluble residue is removed by filtration and the filtrate evaporated. Sediment clean number is inaut, the solvent is evaporated. The residue was stirred in boiling ethanol (30 ml). The precipitate is filtered off, washed with ethanol and 2,2'-oxybisethane and dried in vacuum. Get 0,76 g (38,1%) ethyl 4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] quinoline-6-yl)oxy] butanoate; So pl. 181,4oC (Conn. 1).

Similarly get:

ethyl 5-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]pentanoate; So pl. 180,9oC (Conn. 2).

b) Solution (Conn. 1) (0,0130 mol) in a mixture of 1 n sodium hydroxide (0.040 mol) and ethanol (40 ml) was stirred at room temperature until completion of the reaction. Then add 1 N. HCl (40 ml) and the resulting mixture was concentrated under reduced pressure. The residue is stirred in water and the precipitate is filtered off, washed with water and dried (vacuum, 70oC). This fraction was stirred in boiling ethanol, filtered off, washed with ethanol and 2,2'-oxybisethane and dried in vacuum at 60 - 70oC. Get 3,22 g(86,5%) 4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]butane acid; So pl. 260oC (Conn. 3).

Similarly get:

5-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] quinoline-6-yl)oxy]pentane; So pl. 260oC (Conn. 4);

6-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] quinoline-6-yl)OED. 19);

Example 5

The mixture (P. 6) (0.06 mol), 2,5-dimethyl-2,4-hexadiene (40 g) in methylbenzene (400 ml) day heated at 195oC (closed vessel) in the presence of platinum on charcoal (10%) (3 g) as a catalyst and a 4% solution of thiophene (2 ml). The mixture is cooled, filtered through dicalite and washed with methylbenzol. The precipitate is stirred in a mixture of dichloromethane and acetic acid (50/50) and filtered through dicalite. The filtrate is evaporated and the residue was stirred in boiling ethanol, filtered off, washed and dried in vacuum. Obtain 14.5 g (77%) of ethyl 4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]butanoate; So pl. 181,4oC (Conn. 1).

Similarly get:

ethyl-5-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] quinoline-6-yl)oxy]pentanoate (Conn. 2).

ethyl-6-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] quinoline-6-yl)oxy]hexanoate (Conn. 20).

ethyl-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] quinoline-6-yl)oxy] acetate; (Conn. 21).

Example 6

Diphenyl-phosphorylated (0,0085 mol) is added to the mixture (Conn. 3) (0,0059 mol), 1-(cyclohexylmethyl)piperazine (0,0072 mol), N,N-diethylethanamine (0,0124 mol) and N,N-dimethyl-4-pyridine (catalytic amount) in N, N-dimethyl-formamide (30 ml), stirring at room temperance the mixture washed with water. The organic layer is dried, filtered and the solvent is distilled off. The residue is stirred in boiling methanol (20 ml). The precipitate is filtered off, washed with methanol and 2,2'-oxybisethane and dried. Fraction (1.5 g) is dissolved in methanol/methanol (NH3)/trichlormethane 5/ 5/ 90 and passed through a column of silica gel. The desired fractions are combined and remove the solvent. The residue is stirred in boiling methanol (20 ml), filtered off, washed with methanol and 2,2'-oxybisethane and dried in vacuum at 60oC. Gain of 1.36 g (51,2%) 1-(cyclohexylmethyl)-4-[4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b] quinoline-6-yl)oxy]-1-oxobutyl]piperazine; So pl. 227,2oC (Conn. 5).

Similarly get:

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and 4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]-N-(1-methyl-4-piperidinyl)butanamide; So pl. 212,4oC (Conn. 8)

b) (Conn. 6) (0,0033 mol) is stirred in boiling ethanol (20 ml). This mixture is acidified with HCl in 2-propanol. The mixture is cooled. The precipitate is filtered off, washed with ethanol, 2,2'-oxybisethane and dried in vacuum. Obtain 1.40 g (84.7 per cent) of the hydrochloride of 1-(cyclohexylmethyl)-4-[5-(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]piperazine; So pl. 271,8oC (Conn. 15).

Similarly get:

etano perazine; So pl. 204,8oC (Conn. 16).

Example 7

Thionyl chloride (0,00803 mol) is added dropwise to the suspension (Conn. 3).

(0,0073 mol) in N,N-dimethyl-formamide (25 ml) and the Mixture is stirred for 5 minutes. Then one portion add N-methyl-cyclohexylamine (0,0438 mol), the reaction mixture was stirred at room temperature. The solvent is evaporated. The residue was dissolved in CH2Cl2/CH3OH 90/10 and washed with water. The separated organic layer is dried (MgSO4), filtered and evaporated the solvent. The residue purified column chromatography on silica gel (eluent: CHCl3/CH3OH/ tetrahydrofuran 90/5/5). Eluent of the desired fractions are evaporated and the residue (0.4 g) is recrystallized from ethanol. The precipitate is filtered off, washed with a small amount of ethanol, 2,2'-oxybisethane and dried in vacuum at 60oC. Get 0,150 g (5,3%) polyhydrate N-cyclohexyl-4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]-N-butanamide; So pl. amount of 203.9oC (Conn. 17).

Example 8

a) a Mixture of (Conn. 10) (0,0078 mol) in 2-methoxyethanol (250 ml) gidrirovannah at 50oC in the presence of palladium on charcoal with a palladium content of 10% (1 g) as a catalyst. After the absorption of 1 equivalent of hydrogen Catalonia with ethyl acetate and dried in vacuum. Obtain 2.4 g(87%) 1-[4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]-1-oxobutyl]- piperazine. (Conn. 35).

b) a Mixture of (Conn. 35( (0,0067 mol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (0,0091 mol) in 2-methoxyethanol (150 ml) hydronaut at 50oC in the presence of palladium on charcoal containing palladium 10% (2 g) as a catalyst. After the absorption of 1 equivalent of hydrogen the catalyst is filtered off and the filtrate is evaporated. The residue purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH 94/6). Pure fractions are combined, the solvent is evaporated. The residue was stirred in boiling ethanol. The precipitate is filtered off, washed with ethanol and DIPE, then dried in vacuum. Get 0,62 g(16,6%) 1-[[3-(cyclopentyloxy)-4-methoxyphenyl] methyl]-4-[4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy]-1-oxobutyl]piperazine. So pl. 194,1oC (Conn. 36).

Example 9

The mixture (Conn. 32) (0,0085 mol) in acetic acid (95 ml) is stirred for 10 hours at 60oC. the Solvent is distilled off. The residue is stirred in water and the mixture is alkalinized with an aqueous solution of ammonia. The aqueous layer was separated and extracted with CH2Cl2/CH3OH 90/10. The separated organic layer is dried (MgSOB>2Cl2/CH3OH/NH390/10). The fractions of pure substances combine, the solvent is evaporated. The residue is stirred in DIPE, filtered off, washed and dried in vacuum. Get 1,05 g (28,2%) hemihydrate ()-4-[(2,3-dihydro-2-oxo-1H-pyrrolo [2,3-b]quinoline-6-yl)oxy] -1-oxobutyl]- - -hydroxy-1-piperazineethanol; So pl. RUR 219.7oC (Conn. 37).

C. Pharmacological examples

Positive isotropically and lusitropic effect of these compounds was evaluated through a system of in vitro experiments to determine the effect of inhibition of phosphodiesterase type III, and in the in vivo experiment on nanostation dogs by monitoring cardiac and hemodynamic effects of intravenous medicinal balls of these compounds.

Example 10: the Inhibition of phosphodiesterase type III (PDE III)

The phosphodiesterase activity was measured in the incubation medium (200 l) containing 40 mm Tris, 5 mm MgCl2, 3.75 mm 2-mercaptoethanol, [3H]cAMP and [3H]cGMP (310 mCi/mmol) at a pH of 7.1. For each experiment was measured dependence of the hydrolysis of the cyclic nucleotide concentration and time. From these data was chosen as the protein concentration at which there is a linear dependence of activity phosphodi the population of the substrate and stopped after 10 minutes after placing the tubes in a water bath at 100oC for 40 sec. After the tubes were cooled to room temperature, was added alkaline phosphatase 0.25 g/ml), and the mixture is left for 20 minutes at 37oC. the Mixture sequentially pass through onemillimeter column of DEAE-Sephadex A-25 and washed twice in 3 ml of 20 mm Tris-HCl at a pH of 7.4. The reaction products, labeled3H, were quantitatively determined in the eluate liquid scintillation counting.

The effect of inhibition of these compounds on the phosphodiesterase type III (PDE III) heart of a dog was measured at various concentrations of compounds. Values 1C50were calculated graphically from the received data. Table 2 shows the achieved values for these compounds on PDE III heart of a dog (see the end of the description).

Example 11

Positive inotrope and lusitropic, blood pressure and heart rate in dogs.

The test compound was dissolved in an aqueous glucose solution with a concentration of 1 mg/ml. the Experiments were carried out on three Beagle dogs (Beagle) of different gender and age with body weight from 11 to 18 kg (mean 13 kg). Animals intravenously was anestesiologi a mixture of 0.015 mg/kg of scopolamine and 0.05 mg/kg lofentanil. Animals introduced endotracheal cuff. Throbbing petalum flow Siemens Elema. In the control period, the concentration of CO2breath (ET CO2) defined capnography Gould Godart, was maintained at the level of 5% (vol.) adjustment of inhaled volume (respiratory rate of 20 cycles/min). Continuous intravenous administration of 0.5 mg/kg / hour etomidate was started immediately. Body temperature was monitored by a thermistor located in the pulmonary artery. To prevent blood coagulation was introduced intravenously heparin (1000 units/kg).

Electrocardiogram (ECG) was removed from the conductors on the limbs (standard conductor 2). Blood pressure in left stomach (LVP) and the upward pressure in the aorta (AOP) was measured by catheterization through the femoral artery highly sensitive catheter pressure gauges (Honeywell). The other femoral vein was kemuliaan for the introduction of saline at room temperature in the right artery and injection of the test compounds. The maximum speed of the rising blood flow in the aorta was measured through the carotid artery electromagnetic catheter sensor, connected to an electromagnetic flowmeter anssen Scientific Instruments. The following variables were calculated "on-line", usually after 1 minute: heart rate (HR), diastolic blood pressure in a positive rate of change isovolumetric LVP (LV dp/dtmaxandminrespectively), the maximum positive first derivative developed by the pressure in the left ventricle (LV dp/dtmax/Pd). The time constant (T) relaxation was measured using exponential analysis, which was estimated asymptote. After the stabilization period, the animals were treated with intravenous balls of the test compounds with an interval of 30 minutes of cumulative doses 0,0005, 0,001, 0,004, 0,016, 0,065, 0,125 and 0.25 mg/kg

Tested compounds have a positive inotropics properties, which shows a significant increase in variables related to cardiac activity (LVdp/dtmax, LVdp/dtmax/Pd). Tested compounds have a positive lusitropic property that follows from a significant reduction in the time constant of relaxation. With the introduction of the tested compounds significantly decreased total peripheral and pulmonary ventricular resistance. This shows that compound also have more General and pulmonary vasodilator properties. The load on the heart is reduced without changing the pulse, but with a concomitant increase in cardiac performance. These positive isotropically, lusic is to continue for more than 30 minutes after the introduction of the balls.

Table 3 shows the changes of hemodynamic parameters measured 5 minutes after intravenous cumulative introduction to Beagle dogs balls some of these compounds. Variable AoPd (diastolic blood pressure in the aorta) shows a decrease in blood pressure (vasodilation), HR (the effect of the compounds on the heart rate), LV dp/dtmax(the maximum positive rate of change isovolumic pressure in the left ventricle) indicate positive isotropically effect.

Calculated dose (intravenous, in mg/kg), which produces the effect of a 30% increase in cardiac contractility, 30% increase in heart rate (HR), 15% reduction in diastolic blood pressure in the aorta (AoPd) and 15% decrease in total ventricular resistance (TSR) relative to the value then 5 minutes after intravenous injection shot dogs (n = 3 for each connection).

D. Examples of compounds

The term "Active principle" (A. N.), used throughout these examples relates to a compound of formula (I) or (II), their pharmaceutically acceptable additive salts or their stereochemical isomeric forms.

Example 12: a Copy for oral darling cooling to 30 40oC there is added 35 l of polyethylene glycol and the mixture well stirred. Then there is added a solution of 1 750 g Na-saccharin in 2.5 l of purified water, then added with stirring 2.5 l essences cocoa and polyethylene glycol to a volume of 50 L. Get the solution to drip oral administration containing 10 mg/ml A. N. the resulting solution is poured into a suitable container.

Example 13: a Solution for oral administration

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are first dissolved 10 g of 2,3-dihydroxypentanoic acid and then 20 g A. N. the resulting solution was combined with the remaining part of the original solution and add 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of Na-saccharin dissolved in 0.5 l of water and add 2 ml of raspberry and gooseberry family essences. The latter solution is combined with the previous one, add water to a volume of 20 liters Receive a solution for oral administration containing 5 mg A. N. in teaspoonful (5 ml). The resulting solution is poured into a suitable container.

Example 14: Capsules

20 G. A. N., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide and 1.5 g of magnesium stearate quickly Pach of which contains 20 mg A. N.

Example 15: Tablets, coated

Preparation of core tablets

A mixture of 100 g of A. N., 570 g lactose and 200 g starch is mixed well, then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon K-90) about 200 ml of water. The wet mixture of powders sieved, dried and again sieved. It added 100 g of crystalline cellulose (Aviceland 15 g hydrogenated vegetable oil (Sterotex). All the components are well mixed and pressed into tablets, receiving 10,000 tablets each containing 10 mg A. N.

The coatings

To a solution of 10 g methyl cellulose (Methcel 60 HGin 75 ml denatured add a solution of 5 g of ethyl cellulose (Ethocel 22 cpsin 150 ml of dichloromethane. Then there is added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of the polyethylene is melted and dissolved in 75 dichloromethane. The last solution is added to the previous and then they added 2.5 g of octadecane magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye (Opaspray K-1-2109) and the mixture is homogenized. Core tablets cover the mixture in a designated apparatus.

P is IMEMO in 0,5 l of boiling water for injection. After cooling to approximately the 50oC there is added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g A. N. the Solution is cooled to room temperature and add water for injection to volume of 1 liter Obtain a solution containing 4 mg/ml A. N. the Solution is sterilized by filtration (U. S. P . HOOP p. 811) and poured into sterile containers.

1. Derivatives of pyrrolidinone formula I

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their pharmaceutically acceptable additive salts or their stereochemical isomeric forms,

where L is a radical of the formula-O-Alk-NHp-C(=D)-R1where Alk - C1-C6-alcander, p = 0 or 1;

R1is hydroxy, C1-4-alkoxy or-NR2R3where R2is hydrogen or C1-4-alkyl, R3- C3-7-cycloalkyl or piperidinyl, which may be substituted C1-4-alkyl, or vinylmation, or C3-7-cycloalkylation;

R2and R3can also be joined together, forming piperazinil, optionally substituted C3-7-cycloalkyl, C3-7-cycloalkylation, C1-6-alkyl optionally substituted by one or two hydroxy groups, 2,2-dimethyl-1,3-DIOXOLANYL, benzyl, halogenerator (cyclopentyloxy)-(methoxy)-vinylmation, diphenyl-Cand R2and R3joined together, forming piperidinyl, optionally substituted imidazolylalkyl.

2. Connection on p. 1, where R1is NR2R3.

3. Connection on p. 2, where R2and R3joined together, forming piperazinil, substituted C3-7-cycloalkylation.

4. Connection on p. 3, where the compound of formula I is 1-(cyclohexylmethyl)-4-[4-[(2,3-dihydro-2-oxo-1H-pyrrolo-[2,3-b]quinoline-6-yl)oxy] -1-oxobutyl]piperazine or 1-(cyclohexylmethyl) -4-[5-[(2,3-dihydro-2-oxo-1H-pyrrolo-[2,3-b] quinoline-6-yl)oxy] -1-oxobutyl] piperazine, their pharmaceutically acceptable additive salt or stereochemical isomeric form.

5. Pharmaceutical composition having inotropism, lusotropicalism, vasodilator, including an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient contains a compound according to any one of paragraphs.1-4 in an effective amount.

6. A method of obtaining a pharmaceutical composition having inotropism, lusotropicalism, vasodilator, wherein therapeutically effective amount of a compound of the formula is from PP.1-4, possessing pharmacological activity.

8. A method of obtaining a compound according to any one of paragraphs.1-4, characterized in that interoperate intermediate product of the formula II with a dehydrating agent in an inert solvent

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and, if required, conversion of the compounds of formula I with each other using the reaction of transformation of functional groups, and further, if required, conversion of the compounds of formula I in salt form by treatment with pharmaceutically acceptable acid or base, or Vice versa, the conversion of the salt form into the free base or free acid by treatment with alkali or acid, and/or getting them stereochemical isomeric forms.

9. Hydrogenated derivatives of pyrrolidinone formula II

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their additive salt or a stereochemical isomeric form,

where L is defined for compounds of formula I under item 1.

10. Phenyl derivatives of dioxopyrimidine formula

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their additive salt or a stereochemical isomeric form,

where L is defined for compounds of formula I on p. 1;

Z - nitro - or amino group.

 

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