CS244683B2 - Production method of spiro-3-hereroazolanes - Google Patents

Description

The invention relates to a process for the production of novel spiro-3-heteroazolidinediones which are useful for the treatment of certain chronic complications of diabetes mellitus, such as diabetic cataract, retinopathy and neuropathy, pharmaceutical compositions containing these compounds, and methods of using said agents.

Various attempts have been made in the past to provide more effective orally administrable antidiabetic agents. These efforts generally consisted in the synthesis of new organic compounds, especially sulfonylureas, and in their ability to substantially reduce blood sugar levels by oral administration. However, little is known about the effects of organic compounds on preventing or alleviating chronic complications of diabetes, such as diabetic cataract, neuropathy and retinopathy. U.S. Pat. No. 3,821,383 discloses aldose reductase inhibitors such as 1,3-dioxo-1H-benzo / c, isoquinolin-2 (3H) -acetic acid and derivatives thereof, which can be used for the treatment of such conditions. U.S. Pat. No. 4,117,230 discloses the use of certain hydantoins as aldose reductase inhibitors for the treatment of complications in diabetes.

These aldose reductase inhibitors act by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for controlling the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals.

In this way, unwanted accumulations of galactitol in the ocular lenses of galactosemic patients and sorbitol in the ocular lenses, peripheral nerves and kidneys of various diabetics are prevented or at least reduced.

Accordingly, such compounds acting as aldose reductase inhibitors are therapeutically valuable in suppressing certain chronic complications of diabetes, including those of an ophthalmic nature, as it is known in the art that the presence of polyols in ophthalmic lenses leads to cataract associated with loss of clarity lenses.

The compounds produced by the process of the invention are spiro-heteroazolidinetriones of the general formula I in which

U is oxygen, sulfur or

having 1 to 4 carbon atoms, n being 0 or 1,

X represents a hydrogen, chlorine, bromine or iodine atom, a (C1-C4) alkyl group, a dimethyl group or a radical (C1-4) 2, wherein m is 1 or 2 and Q represents a phenyl or halophenyl group, if

X is a dimethyl grouping, n is 1,

Y represents a hydrogen atom, a halogen atom, a nitro group, a trifluoromethyl group, a C1 -C4 alkoxy group or a C1 -C4 alkyl group, and Z represents a hydrogen or halogen atom, a nitro group, a trifluoromethyl group, a C1 -C4 alkoxy group or a (C 1 -C 4) alkyl group, with the proviso that when either Y and Z is nitro, the other is hydrogen.

The present invention includes those compounds in which U is oxygen, especially when n is 1. Preferred are those compounds in which X represents a methyl group, Y represents a fluorine atom and Z represents a hydrogen atom.

The present invention further includes another group of compounds wherein U is hydrogen substituted with nitrogen and n is 0. Within this group of substances, preferably X and Z are hydrogen and Y is hydrogen or fluorine.

A further group of compounds within the scope of the invention are those wherein U is a nitrogen atom substituted by a hydrogen or C 1 -C 4 alkyl group, preferably a methyl group having an value of 1. Preferred are those compounds wherein Y and Z are hydrogen atoms in which Y represents a fluorine atom and Z represents a hydrogen atom and a positive rotation enantiomer. Preferably X is also bromine. Preferred are those compounds in which both Y and Z are hydrogen atoms. Further preferably, X is methyl. Preferred compounds are those wherein Y and Z are hydrogen atoms and their positive rotation enantiomers. Further, X may be a dimethyl group, preferably Y is a chlorine atom and Z is a hydrogen atom.

The invention includes both mixtures of optically active isomers and partially or fully resolved optically active isomers of the compounds as defined above.

The pharmaceutical compositions comprise a pharmaceutically acceptable carrier or diluent and a compound of formula I. Preferred are compositions comprising those compounds wherein U is hydrogen substituted with nitrogen, n is 1, X and Z are hydrogen, Y is fluorine, and the compound is positive rotating enantiomer. Also preferred are compositions comprising compounds wherein U is a hydrogen substituted nitrogen atom, n is 1, X is a methyl group, and Y is a fluorine atom, even more preferred compositions comprising an enantiomer of the active compound having a positive optical rotation angle (hereinafter). abbreviated as optical rotation).

A method of treating diabetic patients for diabetes-related complications is characterized by administering to the patient an effective amount of a compound of Formula I. The method preferably comprises the active ingredient wherein n is 1, X and Z are hydrogen, Y is the fluorine atom and the corresponding compound is the positively rotating enantiomer. Also preferred is a method using a compound wherein n is 1, X is a methyl group, Z is a hydrogen atom and Y is a fluorine atom, particularly preferably the positively rotating enantiomer of the compound.

The numbering of the ring system of spiro compounds of formula I in which n is 0 (compounds of formula IA) is given in the following formula:

(XA)

T^Em^andto slou^Cen^andU.S^and The general formulas IA are^ted^y 6'-Ύ-4'- no^bO^-5'^-Z-2'^-X-properties Sp^andro / imi dazolidine-, oxazolidine- or thiazolidine-4,1-indane-2,5,3'-trione derivatives.

The numbering of the ring system of compounds of formula I in which n is 1 (compounds of formula IB) is given in the following formula:

(IB)

To those^anddo it with grunts. obecn^EIts formulas IB are 7 '^-γ-6 '^- or⁵'^-Z-3'^-X-properties Sp^andro^/im^andda zolidine-, oxazolidine- or thiazolidine-4,1'-3'-H-1 '-, 2'-dihydronaphthalen-4'-one-2,5-diones.

Compounds of formula (I) of the following reaction scheme:

(II) may be prepared by the procedure of

--NH (Until X =

(AND)

I (X = Br, Cl or I)

It is an object of the present invention to provide a process for the preparation of compounds of formula I, characterized in that the compound of formula III is treated with a strong Lewis acid.

The starting appropriately substituted 3-benzylpropionic acids are known and can be prepared either by literature procedures or by the method discussed below. Said intermediate acids allow the preparation of differently substituted final products of the general formula I.

A particularly suitable way to prepare 3-benzoylpropionic acids is to condense the benzaldehyde derivatives with acrylonitrile or α-substituted acrylonitrile in the presence of potassium cyanide in dimethylformamide, resulting in the formation of 3-benzoylpropionitrile, which is then hydrolyzed in concentrated mineral acid such as hydrochloric acid corresponding to 3-benzoylpropionic acid.

A representative procedure for carrying out this condensation step is described by H. Stelter and M. Schrecke in Chem. Ber. 107, 210-214 (1974).

The 3-substituted 3-benzoylpropionic acids not previously described in the literature can be prepared by methods closely related to those used to prepare known compounds according to the method described by P.J. McEvoy and G.R. Allen Jr. in J. Org. Chem. 38, 4,044-4,048 (1973).

The 3-benzoylpropionic acids substituted in the 2-position with a substituent other than a hydrogen atom lead to the 3-benzoylpropionic acids used in the synthesis of the final tetrahydronaphthalene derivatives of the formula I. This route is particularly useful due to the easy availability of substituted benzaldehydes and the substituted-acrylonitriles. (X is not hydrogen), such as methacrylonitrile, are commercially available or can be prepared by the general procedure described by RB Miller and BF Smith and Sy. Comm., 413-417 (1973). 2-substituted 3-benzoylpropionic acid can also be prepared by this process.

3-Benzoylpropionic acids can also be prepared from known substituted bromobenzenes. The bromobenzene derivative is converted to a Grignard reagent and then to a cadmium reagent which is reacted with a succinic ester halide to form an ester.

3-Benzoylpropionic acid. This ester can be cleaved to the free acid by basic hydrolysis.

This process is particularly suitable for the preparation of final tetrahydronaphthalenes in which X is a dimethyl moiety. For example, J, N, -dimethylsuccinate can be converted to D-methoxycarbonylisovaleryl chloride (X = dimethyl moiety) by the procedure described in С. C. Price and T ·. Padmanathan in J. Org. Chem. 30, 2064-2677 (1965).

This acid chloride can be reacted with various bromobenzene derivatives to give 3,3-dimethyl-3-substituted-benzoylpropionic acids.

A suitable procedure for the preparation of 3-benzoylpropionic acids is by Friedel-Craftos acylation of the corresponding benzene derivative to directly obtain 3-benzoylpropionic acid (for a general procedure see LF Fieser and E.B. Heishberg, J. Amer. Chem. Soc. 58. 2 314 (1936) J. The nature of the product is determined both by the orientation effect of the Y and Z substituents on the benzene ring and by the nature of the X substituent when it is not hydrogen.When X is a dimethyl moiety, benzoylpropionic acid is formed. Thus, using asymmetric dimethylsuccinic anhydride, 3-benzoyl-2,2-dimethylpropionic acid can be prepared which can be converted to the final tetrahydronaphthalene derivatives in which X is dimethyl according to the above reaction scheme.

A suitable way to increase the versatility of the synthesis of 3-benzoylpropionic acids is to convert the primary 3-benzoylpropionic acid to a substance containing a strong electron-attracting moiety by complexing with aluminum chloride so that the aromatic ring can be halogenated meta-to the carbonyl group. it is in the form of a complex with aluminum chloride.

This method is particularly suitable for the conversion of 3,3-dimethyl-3- (4-substituted-benzoyl) propionic acids to 3,4-disubstituted benzoyl derivatives. These derivatives can then be converted to 6 ', 7'-disubstituted tetrahydronaphthalenes using the above reaction scheme.

A further suitable method for the preparation of 3-benzoylpropionic acids is by reacting an aryl Grignard reagent prepared from an aryl iodide, such as any commercially available iodobenzene derivative, with a silylated β-butyrolactone followed by oxidation.

The 2-benzoylacetic acids and their ester derivatives can be used as starting materials for the preparation of the final dihydroindenes.

ammonium carbonate and alkaline cyanide, preferably sodium cyanide, in aqueous alcohol such as water and ethanol at a pH ranging from about 50 to about 50

The following procedure can be used to produce compounds of formula I wherein U is NH. The corresponding benzene-N-oxo-acids of the formula II which are known or can be prepared by processes analogous to those described for the preparation of known compounds are reacted with an ammonium salt, such as a metal such as sodium or potassium cyanide, solution in water or in water in the range of about 9-10, preferably pH 10 at 100 DEG-eye preferably about ^l * 70 ^ and

M ^{F whose} gains ^and slip generally ^eh of the formula III (U = NH).

The resulting condensation product of formula III is reacted with a strong Lewis ^to YSE ^L another-such as a ^p o ^lyf axis ^f orečnou ^to YSE ^l another ^{at t} e ^pl ot ^e o ^d l ^{00 d 200} ° ≤ preferably eye ^{l 150} DEG-MMN as ^{well as} u ^ sbučeiú ^generally it formula I.

Alternatively, using concentrated sulfuric acid (6 to 9 M, preferably 9 M), and operate ^at rt te ^{pl of B} and 6 represent about ^0-180 ° ≤ ^h above with the eye ou ^{l d 120} ° C. It is possible these ^runs ou ^p Other strong Lewis acids such as mineral acids, aluminum trichloride, ferric chloride and the like.

Compounds of formula I wherein X is hydrogen may be halogenated to 2 ' haloketones in which X is halogen. This halogenation may be carried out with a molecular halogen (bromine, chlorine or iodine) in a suitable solvent such as a lower carboxylic acid having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular acetic acid, using a mineral acid such as hydrobromic acid, such as a hangman ^{Ly and} Toru, p ^{s t} e ^{p h} a lot ^of interference and ^b 0 to ¹⁰⁰ DEG C., Oda ^H above ^25-80 ° C.

Alternatively, a compound of formula I wherein X is hydrogen may be halogenated to product containing for X a halogen so that the compound ^generally it RP ^and RCE I therefrom ^p tearing ^Pooh with ^{running in p} er ^fl uorkar ^b oxime ^and neim contained ^ j uM N ^-t rialk ^yl Book yl ^l and O-trialkylsilyl group such as N-trimethylsilyl-O-trirnetylsilylperfluoracetiminem in a nonreactive halogenated solvent such as chloroform, followed by reaction with the desired molecular halogen, as described above formulas II to the compound of formula III in the scheme for converting the compound of formula

AND.

For the preparation of compounds of formula I in which U is oxygen, the corresponding benzene-J-oxoacids of formula II, which are either known or can be prepared by methods closely related to the processes for preparing known compounds, are reacted in trialkylsilyl cyanide ((? SiCN in which R 'represents a lower alkyl group to give cyano-trialkylsilyloxy derivatives according to the general procedure described in U.S. Patent 4,267,342.

Compounds of formula I wherein U is sulfur can be prepared in an analogous manner to that used to prepare a compound of formula I wherein U is NH. Preferably, cyantrialkylsilyloxy derivatives are prepared which are intermediates for the preparation of compounds of formula I wherein U is oxygen. These cyantrialkylsilyloxy derivatives can be converted to intermediates of formula III wherein U is sulfur by analogous methods.

The intermediates of formula (II) in which U is sulfur may be converted to the final products of formula (I) as described above for the case where U is NH.

Due to the presence of an acidic hydrogen atom in the spiroheterocyclic ring of the compounds of formula (I), these may form salts with pharmaceutically acceptable cations. These salts are prepared by conventional methods. For example, these salts can be prepared by reacting a compound of formula I with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a solution of the compound of formula I in lower alkanol may be mixed with an alkoxide derived from the desired metal and the resulting solution then evaporated to dryness. Suitable pharmaceutically suitable cations include, but are not limited to, alkali metal cations such as potassium and sodium cations, ammonium cations, water-soluble amine addition salts such as lower alkanolammonium salts and other organic amines which are pharmaceutically acceptable as well as alkaline earth metal cations such as calcium and magnesium.

It should be noted that the term pharmaceutically acceptable salts as used herein, which is also used in the present invention, includes both acid addition salts and salts formed with the corresponding cations as described above.

The invention also relates to derivatives which are metabolized in vivo to compounds of formula IA or IB. In particular, they are derivatives in which the acidic NH group at the 1-position in formula IA or IB is converted to an N-R group, wherein R represents a lower alkyl radical containing generally 1 to 4 carbon atoms, preferably a methyl radical. Such compounds may be obtained by alkylating a compound of formula IA or IB with an alkylating agent in the presence of a suitable base. Suitable bases include, for example, alkali metal hydroxides, such as sodium or potassium hydroxide, alkali metal carbonates or alkoxides, such as sodium carbonate or sodium ethoxide, and alkali metal hydrides in a non-protic solvent such as sodium hydride in Ν, Ν-dimethylformamide, a temperature of about 0 to 50 ° C, preferably about 25 ° C.

Suitable alkylating agents are, for example, methyl iodide, dimethyl sulfate and ethyl bromide. Alkylating agents which may be used in the absence of a base include diazoalkanes such as diazomethane.

A particularly suitable process for the preparation of derivatives corresponding to formula IA or IBy in which the acidic NH group at the 1-position is converted to the NR group is to dissolve the compound of formula IA or IB in dry Ν, Ν-diemtylformamide and at about 0 to 50 ° C, preferably about 25 ° C, add 1 equivalent of sodium hydride. The reaction mixture is stirred until the foaming ceases, then 1 mol equivalent of an alkylating agent such as a lower alkyl halide or alkyl sulfate is added dropwise thereto, and the mixture is stirred until the alkylation is complete. Methyl iodide is the preferred alkylating agent, and the reaction takes about 1 hour using the halide and operating at about 25 ° C.

The reaction mixture may be worked up by pouring it into ice water. The alkylated products may be separated from the starting materials preferably using the acidic nature of the starting materials of formulas IA and IB, thereby distinguishing them from the neutral alkylated products.

For example, the compound of Example 28 has a pk of about 8.3 in water, and any unreacted starting material residues can be removed by shaking the crude product between an organic solvent such as ethyl acetate or methylene chloride and a basic aqueous solution.

The alkylated product is soluble in an organic solvent, the material is dissolved in an aqueous base solution.

while the unreacted default

The novel compounds of formula I and their pharmaceutically acceptable salts are useful as inhibitors of the enzyme aldose reductase in the treatment of chronic complications of diabetes such as diabetic cataract, retinopathy and neuropathy. As used herein, it is meant both preventive treatment and curative treatment to alleviate these conditions. The disclosed compounds can be administered to patients in a variety of conventional routes of administration, including oral, parenteral and topical. In general, they will be administered orally or parenterally at dosages ranging from about 0.05 to 25 mg / kg of the patient's body weight per day, preferably from about 0.1 to 10 mg / kg, and of course deviations therefrom, an appropriate dose depending on the condition of the patient being treated. In any case, the doctor will determine which patient.

The novel compounds of the invention can be administered as such or in combination with pharmaceutically acceptable carriers in single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions produced by combining the novel compounds of formula I with pharmaceutically acceptable carriers can then conveniently be administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions may optionally contain other ingredients such as flavoring agents, such as sodium citrate, calcium carbonate and calcium phosphate, together with various disintegrating agents such as starch, alginic acid and various complex silicates, and in conjunction with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia.

Substances such as magnesium stearate type can also be used materials for this purpose are

Sliding sodium lauryl sulfate is also frequently used in the preparation of tablets. and talc. Solid compositions similar to filling soft and hard gelatin capsules. Preferred are, for example, lactose or milk sugar and higher molecular weight polyethylene glycols. In aqueous suspensions or elixirs for oral administration, the principal active ingredient may be combined with various sweetening or flavoring agents, coloring and optionally emulsifying or suspending agents and diluents such as water, ethanol, propylene glycol, glycerin and mixtures thereof.

For parenteral administration, solutions of the novel compounds of formula I in sesame or peanut oil, aqueous propylene glycol, or sterile aqueous solutions thereof may be used. If necessary, these aqueous solutions must be buffered and the liquid diluent first rendered isotonic by adding sodium chloride or glucose. These particular aqueous solutions are separate. suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media used for this purpose can generally be prepared by standard techniques known in the art.

for the preparation of aqueous pharma, but especially for the preparation

The compounds of formula (I) are not only preferably used in the form of pharmaceutical preparations for parenteral administration, as described for pharmaceutical preparations suitable for use as solutions for ophthalmic administration. Such ophthalmic solutions are essential for the treatment of diabetic cataract by topical application, and the treatment of the disease in the aforementioned manner is a preferred aspect of the invention. Thus, in the treatment of diabetic cataracts, the compounds of the invention are applied to the eye of a treated patient in the form of an ophthalmic formulation made according to conventional pharmaceutical practice (see, for example, Remington ' s Pharmaceutical Sciences, 15th Edition, pp. 1,488-1,501). , Bye.)/.

The ophthalmic preparation comprises a compound of Formula I or a pharmaceutically acceptable salt thereof at a concentration of about 0.01 to 1% by weight, preferably about 0.05 to 0.5%, and is in the form of a pharmaceutically acceptable solution, suspension or ointment. It will be understood that certain variations in this concentration will necessarily occur, depending on the compound used, the condition of the patient, and the like, the most appropriate concentration for which patient will be determined by the attending physician. The ophthalmic preparation is preferably in the form of a sterile aqueous solution containing optionally other ingredients such as preservatives, buffers, osmotic pressure adjusting agents, antioxidants and stabilizers, nonionic surfactants or finings agents, viscosity enhancing agents, etc. Suitable preservatives include benzalkonium chloride, benethonium chloride , chlorobutanol, thimerosal and the like.

Suitable buffers are, for example, boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium and potassium carbonate, sodium acetate, sodium hydrogen phosphate and the like, which are used in an amount sufficient to maintain a pH of about 6 to 8, preferably about between 7 and 7.5. Suitable agents for adjusting the osmotic pressure are dextran 40, dextran 70, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride and the like, with an equivalent sodium chloride concentration in the ophthalmic solution of 0.9-0.2%.

Suitable antioxidants and stabilizers are, for example, sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and fining agents are, for example, polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity enhancers include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, natural petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, and the like. in the form of drops or by rinsing the eye with this ophthalmic solution. ,

The effectiveness of the compounds of the invention as agents for the treatment of chronic complications of diabetes can be ascertained by a variety of standard biological or pharmacological tests. Suitable tests include:

1) measuring the ability of test substances to inhibit the enzymatic activity of isolated aldose reductase,

(2) measuring the ability of test substances to reduce or inhibit the accumulation of sorbitol in the sciatic nerve and ophthalmic lenses of rats in whom diabetes has been acutely induced by streptozotocin,

3) measuring the ability of the test substances to reverse the already elevated levels of sorbitol in the sciatic nerve and eye lenses of rats with chronic streptozotocin-induced diabetes,

4) measuring the ability of test compounds to prevent or inhibit galactitol formation in the lens of acutely galactosemic rats;

5) measuring the ability of test compounds to delay cataract formation and reduce ophthalmic lens opacities in chronically galactosemic rats,

6) measuring the ability of test compounds to inhibit sorbitol accumulation and cataract formation in isolated eye lenses of rats incubated with glucose,

7) measuring the ability of test compounds to reduce already elevated sorbitol levels in isolated eye lenses of rats incubated with glucose.

The invention is illustrated by the following non-limiting examples. Proton nuclear magnetic resonance spectra (NMR) were measured at 60 MHz (unless otherwise specified) in solution in perdeuterodimethylsulfoxide (DMSO-dg) and the signal positions are expressed in ppm values over tetramethylsilane. Signal shapes with the following abbreviations:

s = singlet d = doublet t = triplet q = quartet m = multiplet b = wide signal

Example 1

S ^p iro £ ^{imidazolidin-4,} 1 ' ^-indan-3 ' -one] - ^{2, 5-d} ion ^{2, 5-di-oxo-4} phen ^yl - ^{4 people} -im ^id azo N acetic acid ^{and the aryl and} went on to ^BC i ^t e ^p lo ^t e ¹⁵ 0 C en sus ^{p d} U is in 15 mL of polyphosphoric acid. The solids gradually dissolved and after two hours, heated ^{Ri ck} 0 to ¹⁵ ° C, ^{both for} the site reatón tunes oc ^h at ²⁵ ° C and were diluted with ¹⁵ m ^l voty. Poma ^l with solid precipitates which is filtered, washed with water, dried and recrystallized from water. 0.210 g (40% yield) of the title compound is obtained, m.p. 268-270 ° C.

Analysis: for ^{C 11 H} 8 ^N 2 ° 3

calcd, 61.11 % C 3.73% H 12.96 % N found 60.89 % C 3.87% H 12.98 % N Example 1 and d 2

Spiro [imidazolidine-4, l'-3'H-l ', 2'-dihydrofuran dronaftalen ^yl-4'-one] -2,5-dione

2.48 g (10 mmol) of 2,5-dioxo-4-phenyl-4-imidazolidinpropionové acid in 25 ml of ^the oncentrovan ^{é alkyl when} n is ^{y E,} sulfuric ^HRI weighing therefrom ^p tearing liocUnu ¹ to ⁹⁰ ° C and pa ^{to 45} m ^and the nut to ¹²⁰ ° C, whereupon the reaction mixture is poured onto 200 g of ice. The solid product was filtered off and dried 60 hours in ^{width to} va uu p ^r i te rt ^{pl of 100} ° C. ^{September KA 1.85 g of} crude ^p ^ o ^to the genus ^¹H melting ^at about ^144-149 ° C. This material was dissolved in isopropanol, decolorized with activated carbon and recrystallized from isopropanol after isolation. There were obtained 1.11 g (48% yield) of the title compound of ^t e ^ ^pl counting revolutions ^{of 261 s} and ^{of 263} ° C.

Analysis: for ^C 12 ^H 10 ^N 2 ° 3: calculated: 62.60% C 4.38% H 12.17% N Found: 62.34% C 4.51% H 12.16% N

Example 1 a and 3

Spiro [imidazolidine-4,1'-3'-H-1 ', 2'-dihydronaphthalen-4'-one] -2,5-dione

2.48 g (10 mmol.) Of ^{2,5-dioxo-4-phenyl-4} -imi ^d azolidinpropionové acid at ¹ 50 ° C en sus ^{p d} U is ²⁵ ml, after ^lyf osforečné ^alkyl selj.ny.

The solid material dissolved gradually and after 135 minutes the reaction mixture was cooled to 25 ° C. Once P ^{s also} given ⁷⁵ ml of water in the ^y ou ^{No. yl} Eny crude solid for at ^{kt d filt} from estrous, rozjpusd in isopropanol, treated with charcoal and after isolation was crystallized from isopropanol. Give ⁴ 5 ⁰ mg (yield ^17%) of compound ^No. enyne ^y uvetenié title ^pl ^ o te rt • Counting ^{of s 2 2} 6 ^{and 2} 63 ° C.

NMR (DMSO-d 6): 10.98 (bs, 1H), 8.65 (bs, 1H), 8.03 to 7.30 (m, 4H), 3.07 to 2.23 (m, 4H) ) o

ppm.

Example 4.

7'-fluoro-f ^l s ^p iro ^{[imi d} oxazolidine-4, l'- ³ 'H-l', 2'-dihydronaftalen- ^4'-one] - ^2,5 -dione

1.33 g (5 mmol) of 2,5-dioxo-4-m-fluorophenyl-4-imidazolidinpropionové acid was added with 15 m oles ^{lp f f} orečn axis ^E k ^y n ^{y i} sel and ^{1.5 h} of ^di n ^{y Ri á} heated at ¹ 50 ° C. Rea ^CZK the mixture was cooled to ^s 0 ° C, dilute ^{the Di} in ^d ou dark evný ^{p p} ro ^d u ^KT ODF ^il Trituration off and ^p e between the. et ^y acetate ^and a dilute aqueous solution of the sodium hydroxide (pH 8). The ethyl acetate layer was extracted with 10% aqueous sodium hydroxide solution, the combined aqueous layers were decolorized with activated carbon and acidified to pH 3 with concentrated hydrochloric acid. The water was evaporated in vacuo and the resulting white solid triturated with boiling isopropanol to remove sodium chloride. The isopropanol solution was filtered and concentrated in vacuo. This afforded 115 mg of the title compound as a white foam.

NMR (DMSO-d 6): 8.55 (bs, 1H), 8.02 (q, 1H), 7.37 (m, 1H), 7.17 (q, 1H), 3.15-2, 96 (m, 1H), 2.75-2.6 (m, 1H), 2.45-2.3 (m, 2H) ppm.

Example 5

7'-Fluoro-spiro [imidazolidin-4'1'-3'-H-1 ', 2'-dihydronaphthalen-4'-one] -2,5-dione

68.55 g (0.26 mol) of 2,5-dioxo-4-m-fluorophenyl-4-imidazolidinpropionové acid mixture with ^{í í 500} m ^lk oncentrovan ^{Star alkyl when} n is ^y with ⁱ Rove and ^{2.5 h} from ⁱ n ^{y Ri} was heated ^and at 75 and ^{of 77} ° C. Rea ^{at the} CN ^and mixtures of the ad ^I oc ^hl to ²⁵ ° C and ^Yli is the ^l ed. In ^{y P} sr ^and women evný protott the ^{dfilt oestrus,} dissolved in 800 ml of methanol and the solution is decolorized with charcoal. The methanol was evaporated in vacuo, the white solid residue was triturated with 75 ml of methanol and the solid product was filtered off. After rom ^{p y} t ^{i l 30} m in this ^{dy p} evný mater ^{ial 20 h} of ^di n dried cotton ^t e ^{pl at} about ^{the 80} ^ yield 52.07 g (81% yield) of the title compound mp 229-231 ° C.

Analysis: for C 12 H 9 FN 2 O 3 calculated: 58.07% C 3.65% H 11.29% N, found: 57.86% C 3.59% H 11.39% N.

Example 6

7'-methoxy ^y -s ^pi ro ^[i m ⁱ d ⁱ imidazo ^if n ^{-4, 1 '-3' -} H ^-1 ', ^{2' -di- t} and ^L hydronaf en-4'-one] - ^{2 5-d} ion

8.35 g (30 mmol) of 2,5-dioxo-4-m-methoxyphenyl-4-imidazolidinpropionové acid with ^p ol, 60 ml of ^{p lyf} osfore ^No n ^{e l} is ^alkyl in ^Y 1 ho nu ^{di HRI} for weighing to ⁵⁰ ° C. ^R ea ^CZK the mixture ^of with the oc-ADI to 25 ° C, from ^row diluted with ^water ignites ^kl Y ^P evný mater ^ial from ^filt oestrus in ^originally m ^{extensible EXPERIMENT} is decolorized with charcoal and crystallized from water. 2.9 g (37% yield) of the title compound ^ o ^{t h} e ^{p th} lot ^{of ck of 251} and ²⁵⁰ ° C.

Analysis: ^{Gi3 «i2N2} ° ^4: calculated: 60.00% C 4.65% H 10.76% N Found: 59.83% C 4.71% H 10.79% N

Example 7

7'-nitro-spiro-imidazolidine-4,1'-Z'-H-1 ', 2'-dihydronaphthalen-4'-one] -2,5-dione

The title compound was prepared according to the procedure for EXAMPLE 5, substituting 2,5-dioxo-4-m-nitrophenyl-4-imidazolidinepropionic acid for the corresponding m-fluorophenyl compound.

Example 8

7'-chloro-6'-methyl-spiro [imidazolidine-4,1'-3'-H-1 ', 2'-dihydronaphthalen-4'-one] -2,5-dione

10.0 g (34 mmol) of 4- (m-chloro-p-methylphenyl) -2,5-dioxo-4-imidazolidinepropionic acid are mixed with 150 ml of concentrated sulfuric acid and the mixture is heated at 80 ° C for 2 hours. The reaction mixture was cooled to 25 ° C and poured onto ice, the resulting white solid product collected and washed with water and dried. 8.78 g (94% yield) of crude product of melting point 260 DEG-265 DEG C. are obtained. The crude product was recrystallized from isopropanol / water to give 5.80 g of the title compound, m.p. 277-278 ° C.

Analysis: ^ ^1з н ц М 2 ° ^С ^ 3 calculated: 56.03% C 3.98% H 10.05% N Found: 55.63% C 4.01% H 9.96% N

Example 9

6'-Methyl-spiro [imidazolidine-4,1'-3'-H-1 ', 2'-dihydronaphthalen-4'-one] -2,5-dione

2.85 g (10.9 mmol) of 2,5-dioxo-4-p-polyl-4-imidazolidinepropionic acid are treated with 25 ml of concentrated sulfuric acid and the mixture is heated at 95 ° C for 1.5 hours. The reaction mixture is poured onto ice, the resulting solid material is filtered off and washed with water. 1.88 g (71% yield) of crude product, m.p. 206 DEG-214 DEG C. are obtained. 1.76 g of this crude material, after recrystallization from isopropanol, gave 1.12 g of the title compound, m.p. 245-248 ° C.

Analysis: for ^{C 13 H 12 N} 2 ° 3 calculated: 63.93% C 4.95% H 11.47% N, found: 63.56% C 5.15% H 11.24% N.

Example 10

7'-Chloro-spiro [imidazolidine-4,1'-3'-H-l ', ^{2'-dihydronaphthalene-4-one} -onj 2,5-dione

5.42 g (20.0 mmol) of 2,5-dioxo-4- (m-chlorophenyl) -4-imidazolidinepropionic acid are mixed with 40 ml of concentrated sulfuric acid, heated at 90 ° C for 3 hours, then cooled. to 25 ° C and poured onto ice. The resulting solid material was collected and recrystallized from water after drying. 2.61 g of a melting point of 202 DEG-230 DEG C. is obtained, which, according to NMR spectroscopy, is a mixture of the starting propionic acid and the desired product. 2.4 g of this substance are then mixed with 25 ml of concentrated sulfuric acid and the mixture is heated to 120 ° C for 3 hours. The reaction mixture is then cooled to 25 ° C, poured onto ice, the solid formed is filtered off and recrystallized water. 700 mg (14% yield) are obtained. the title compounds, melting at 279-280 ° C.

Analysis: Calculated: C 54.58% C 3.41% H 10.60% Found: C 54.42% 3.60% H 10.42% N.

Example 11

3'-methyl-7'-fluoro-spiro [imidazolidine-4,1'- ³ 'H-l', 2'-dihydronaphthalene-4'-one] -2,5-dione

(2.1 g, 7.5 nunol) of 2,5-dioxo-4-m-fluorophenyl-4-imidazolinisomáselné acid was mixed with 30 ml of concentrated ^{alkyl when} n is ^y and sulfuric mixture 2 ^{'of di} n ^y it ^HRI for weighing at ^115-120 ° C. Reaction ^mixture to poured onto ice and stirred for 30 minutes with activated charcoal. The resulting mixture is filtered through a pad of diatomaceous earth, the filter aid is heated to reflux in 250 ml of methanol, and the mixture is filtered again. The filter residue is extracted again with 250 ml of methanol at reflux and the mixture is filtered again. The combined filtrates were concentrated in vacuo to a gummy residue which was stirred with water for 3 hours. The resulting white solid was filtered and dried to give 0.85 g (yield 43%) of the title compound, mp ^216-2 20 ^o C. The analytical sample was prepared by crystallization from water, melts at 224 DEG 2 ² 5 ^About C.

Analysis for ^C NE ^3: calculated: 59.54% C 4.23% H 10.68% N Found: 59.41% C 4.32% H 10.71% N

NMR spectrum (DMSO-d6, 250 MHz) indicates the presence of a 94: 6 diastereomeric pair, major component: 11.07 (bs, 1H), 8.60 (s, 1H), 8.05 (m, 1H) 7.39 (m, 1H); 7.24 (m, 1H);

3.34 (m, 1H), 2.5 (t, 1H), 2.18 (t, 1H) and 1.15 (d, 3H);

minor component: 8.94 (s, 1H), 3.0 (m, 1H) and 1.18 (d, 3H) ppm.

Separation of diastereomers

Using the general procedure described above, a sample of crude 3'-methyl-7'-fluoro-spiro [imidazolidin-4,1'-3'-H-1 ', 2'-dihydronaphthalen-4'-one] -2 is isolated, Analysis of the NMR spectrum shows that this crude sample contains three components, 5.85 mol%. racemic 4, l '(S) -3' - (S) -3'-methyl-7-fluoro-spiro [imidazolidine-4, l ^- - (2 'H) -3'-H-naphthalen-4'- on] -2,5-dione, 71.70 mol%. corresponding to 4.1 * - (S) -3 '- (R) -epimer and 22.44 mol%. non-cyclized starting carboxylic acids.

The mixture was suspended in 1.5 liters of acetonitrile at reflux and dissolved in the solution by adding 300 ml of methanol. After decolourising with charcoal, the solution was concentrated by distilling off the solvent to a volume of 800 ml, whereby a solid of 13.04 g was formed which was filtered off. The mother liquors were concentrated in vacuo to a solid residue which was dissolved in acetonitrile and the solution was concentrated to a volume of 300 ml by distilling off the solvent. 39.44 g of solid are precipitated from this concentrate, which is filtered off.

An additional 1.17 g of solids precipitated on standing from the mother liquor, which was also filtered off. The residual mother liquor was concentrated in vacuo to a glassy solid residue, to which chloroform was added and the mixture was stirred overnight. A solid product is formed which is filtered off (9.0 g) and the mother liquors are concentrated in vacuo to a wet foam residue of 25 to 30 g.

The foam was applied to a silica gel column (0.062-0.037 mm) eluting with 5% methanol in chloroform. 6.77 g of material consisting of only two components are obtained. NMR analysis shows that this material is now enriched in racemic 4,1 '- (S) -3' (S) -3-methyl-7-fluoro-spiro [imidazolidine-4,1 '- (2H)] -3'-H-naphthalen-4'-2,5-ONJ ^"d ion to ^58.3 mole% range. ^For the next ^I om ^p onenta forms ^a pre c ^{s 4} К ⁷ mol%. The mixture ^{with said composition} is comprised of the corresponding racemic 4, l '- (S) -3' - (R) epimer.

. . Six preps of 250 mg of this 58.3: 41.7 ψ-stereomeric mixture were chromatographed using prepaffrative high pressure liquid chromatography using a hexane gradient of 5 to 20% isopropyl alcohol to isolate the fraction with a shorter retention time.

Combining obdobfých fraction with a shorter retention time was obtained 369 mg of material with a melting point ^{of 196} and ¹⁹⁹ ° C. The ^t of mater ^ial is subjected to analysis in a ^{newly y} with ^the rev ^{l p} ka such ^as new al chromatography which exhibits a major peak with area 97.449% and a retention time of 5.78 minutes and two minor peaks with area of 2.23% (retention time 6.33 minutes) and 0.32% (retention time 6.76 minutes). Using NMR spectroscopy, the material with a retention time of 5.78 minutes was identified as racemic 4, 1 '- (S) -3' - (R) -3'-methyl-7'-fluoro-spiro [imidazolide-4,1] ^Γ- (2'Η) -З'-Н-па аЪэп ^ ^ '- оп] - ^{2, 5} ^^^ ^{what would} l ^C o ^d e various ^p ^ Imer for women in the above described product.

The major epimer of the product described above is racemic 4, 1 '- (S) -3' - (R) -3'-methyl-7'-fluoro-βpiro [imidazolidine-411 '- (2'-H) -3'- H-naphthalene-4'-one'-215-dione which can be isolated in a purity greater than 99 mol%. repeated crystallization from acetonitrile. 4,1 '- (S) ~ -3' - (R) .- epimer of ⁱ with ^k Aný for ^p ou ^fo three of advancements has a ^pl ol ^t U ^{s 230} to ²³² ° C and a retention time of ^{N NU} 6 , 34 minutes.

Example 12 (+) ^ '- fluoro-S ^ ^ din rofimíLdazo ^-4.1 * -3 '^{H-1', 2 'F} -dihydrona talen- ^{4' -} one] - ^2,5-di one

24.62 g (0.099 mol) of (+) -7'-fluoro-spiro [imidazolidine-4,1'- ³ 'H-l'12'-o-dihydronaftalene4'e ^^^ - dione was cut with ^p ust ^s in ⁷⁰⁰ m ^l of acetonknlu.vrou ^ ^p from ^{d p} Etna c ^{hl di} what and ^to this solution was added 42.96 g (0.099 mole 8.) brucine dihydrate. The acetonitrile mixture was filtered to remove traces of insoluble material while still hot, and the filtrate was allowed to cool to 25 ° C. The resulting ^p evný ^P roducts about ^dfil off and the ^y su ^{whose width} is ¹ m ^f is from ^I to ^26.83 g ^ka taj Sol ^{i s} c ^s maiden under ^kl and ^{d at 229} and at ^{from 230} ° C oo ^PTI C ^to a rotation of ^{[a] 2} ° = 0 + ^{3, 7} ° (methanol ^ Mon ^BC e ^k r ^{y s} Raindance Connect the salt from acetone by ^{the IT} R ^{il s} of ^{kA 18.8 g} of Ne ^yčiště Sou ^t and ⁱ C ⁱ under decomposition t oo ^{p and} ck ^s rotation [a = + ³² ° 0 (methanol).

^at 230 °

The purified salt weighing 17.8 g was decomposed by stirring with 500 ml of Zpočátku.se dissolve most salts and then a new solid material, and ^y su ^dimensional. Z ⁱ · com ^and the optical rotation ^{and s} [r ^and J

Based on the X-ray crystal analysis of individual center was 4,1'- ^p řisouzena absolute configuration.

chloroform, filtered with ^{6.32 g l No} ou en ny ^{and d} Uve ene title ^ o te ^{pl of} revolutions counting ^{d 263-264} ° ^ 2 ° + 20 = ^3, 5 ° (methanol).

Example 13

3'-e ^b Rome ⁷ ' ^-fluoro-p s iro _[1 imi ^d azole ^d in-- ⁴ 11'-3'-H-1 ', 2'-dihydrofuran dronaftalen ^yl-4'-one] -2,5 -dion /

1.6 g (6.4 mmol) with ^p-7'efluor iro ^[d imino-oxazolidine 411'- ³ 'H-H ^{y d} l'12'- dronaftalen 4'-ONJ ^^ - dian mixed with 1.13 g (7.1 mmol) bromine and 1 ml concentrated hydrobromic acid ^says metal in an ^{ice-l 15} m ^é ^ oc tyseU b ^{s t E} and the mixture was heated ¹⁰ minutes ^{of manufacture} VA ^{80 PRICE} EMZ-end at this time the bromine color disappears. The reaction mixture was concentrated in vacuo to a white solid residue, which was filtered off and dried. 1.9 g (91%) of the title compound are obtained.

name mp 223-224 ° C.

N, 8.56. Found: C, 43.61; H, 2.61; N, 8.31.

Example 14

7'-methyl-spiro ['imidazolidine- (4,1') - 3'-H-1 ', 2'-dihydronaphthalen-4'-one] -2,5-dione

1.4 g (5.3 mmol.) Of 2,5-dioxo-4-m-tolyl-4-imidazolidinpropionové acid are mixed with 25 ml of ^the oncentrovan Sehne ^s k ^{y y} with ^{i é} ROV and stirred for ³⁰ m ⁱ nu ^t ^ a play at 9 ⁵ ° C. ^Mixtures of the reaction was poured over ice, resulting · solid product was filtered, hot water is decolorized with charcoal and crystallized from water. There were obtained 420 mg (yield 32%) of the title compound, a ^p te Lot ^E t ^ck 20 ⁶ ° C.

Analysis: for ^C 13 ^H 12 ^N 2 ° 3: calculated: 63.93% C 4.95% H 11.47% N Found: 63.57% C 4.91% 11.45% N of manufacture

The activated charcoal was dried and extracted with methanol under reflux. An additional 110 mg (yield 8.5%) of the title compound is obtained, m.p. 202 ° C.

Example 15

5 ', 7'-Dimethyl-spiro [imidazolidin-4'1'-3'-H-1', 2'-dibycdrone-f-ally-4-one] -2,5-dione

1.0 g (3.7 mmol) of 2,5-dioxo-4-j - xlyl ---- midazolidin ^{p p} ro ionic acid are mixed with ^{2 to} 0 ml oncentrovan yseUn ^{E k y} with ⁱ RTR E ^F, with the mixture ^{of 45} m ^and heated nut ^{Ri and} 85 ° C if ^P is cooled to ²⁵ ° C and ^Yli is the ^l ed. The compound act ^{yl H} N ^No reddish precipitate ^{EDA TOWING on} the odMKruje ^{in y} su ^SI, 'dissolved under reflux in 200 ml methanol and decolorized with charcoal. The methanolic solution is concentrated in vacuo, the residue is triturated with 10 ml of water, the resulting solid is filtered off and dried. There were obtained 630 mg (yield 70%) of the title ^compound, a te ^pl ot ^{th of} n ^s and ²⁶⁰ 1 ^{of the 26}

Analysis:. H, 5.45; N, 10.85%. Found:% C, 64.80;% H, 5.48;% N, 10.73.

Example 16

6'-chУor with ^p-iro [iiidazolidin - ' 3 ' H-l ', 2'-dihydronaphthalene-4'-one] -2,5-dione

5.0 g (18 mmol) of 2,5-dioxo- ^p- chlorophenyl-imidazolidinopropionic acid were added. mixed with 90 mL of concentrated ^E k ^{y if y} N sulfuric ^acid, with a mixture ^of 16 ^h of ^di n ^of IVa heated to 115 ° C, ^p and ^k oc ^hl AD ^and on. 25 ° C, ^wherein L ⁱ is the 800 ^GL EDU and ^{2 h} of ^di n ^y is stirred. After addition of the activated carbon, stirring is continued for 1.5 hours, then the aqueous mixture is filtered through diatomaceous earth, the filter cake is washed with 400 ml of water, and then the filtered solid, activated carbon and diatomaceous earth are stirred and refluxed in 500 ml. of methanol. After stirring for 30 minutes, the suspension is filtered again through diatomaceous earth and the clear filtrate is concentrated in vacuo. 1.1 g of material are obtained. according to NMR spectroscopy, a mixture of equal parts of the starting material. material and title compound. This material 1.1 g was suspended in methanol and the suspension filtered to give 0.31 g (yield, 6 *) of said ^E HV ^and invite ^pl of TE OTE Counting ^{2 s} and 58 1 ^{of the 26} ° C . Ana ^ H ^ y ^d ro pattern uktu ^kp was obtained ^{and Pr} ^ eta talováním ^y of water and melts ^{at 26} 5 and ^{from 266} ° C.

Analysis: for ^ΰ 12 ^Η 9 ^Ν 2 ^Ο 3 ^ calculated: found:

54.46% C

54.21% C

3.43% H

3.41% H

10.58% N,

10.40% N.

Ex 17 d (-) -V-fluoro-spiro ^ i ^ ^ dazoHd ^-4, l ^'-3' hI ^{'^} -d ^ ydronafta ^ n ^^ - one] - ^{2, 5-di} he

24.62 g (0.099 mol) (() -7'-fluoro-spiro ^{[imidazolidine-d} in 4,1 '- 3'-H-1', 2'- ^d iyhdronaftalen-4 '-one] -2 The 5-dione was dissolved in 700 ml of acetonitrile while refluxing, and 42.96 g (0.104 mol) of brucine hydrate was added to the solution, and the acetonitrile reaction mixture was filtered from the hot solution while still hot and allowed to cool slowly. cool. the crystalline product was recovered from the acetonitrile mother liquors which were concentrated on the foamed oily residue. This material was triturated with ether ³⁴ 46 ^{g No} reddish ^gray of ^b arven ^{e p} env ^{Star substances} oo ^PTI C ^to a ro ^t c ⁱ = ^{-1 05 4 <O (methanol,} c = 1). This tan solid was dissolved in chloroform, wherein the first solid material at ^{the d} t is triturated with 500 ml hot chloroform followed by filtration and drying gave ^7, 54 ' env ^{gp s} in it for ^{d to} the ^pl of TE about ^the n ^{th s 260} and ^{from 262 o} C.

it dissolves and after a short time a new solid product begins to precipitate. This ^dfil a camper Truji ^if m ^f is from ^I to ^{8.2 ka} env ^{gp e la sition} of te ^pl ol ^of melting point ²⁵⁸ and ^{from 260 Οc to} now obsolete

A portion of this solid was washed with 0.1 N hydrochloric acid and recrystallized from hot methanol after drying. To give (-) - 7'-Fluoro-spiro £ imidazolidin-4 ' 3 ' H-l ', ^{2' -C-dihydroquinazolin} ronaftaben onJ- ^{4'-2, 5-di} one, te rt ^pl counting ^{of d 264} and ^{from 265} ° C and ^{P and} T C ^to a rotation of [α] = -197.9 ° 2 ° (c = 1, methanol).

EXAMPLE 18 (+) -7 ^{'-fluoro-3-yl} rnet ls ^p iro [.imidazolidin-4, 1 ' -3 &apos;H-1',2'-diyhdronaftalen-4-one] -2,5-dione

Following the general procedure of Example 11 was prepared in 97.4 g of crude ^{3'-methyl-7'yl-fluoro-with p} iro [imidazolidine-4, l'-3'-H-1 ', ^2' -dihydronaftalen- 4'-one] -2,5-dione, which by NMR to be ^2, 5-dioxo-4- (m-fluorophenyl) -4-imidazolidinpropionovou resultant acid and two dihydronaphthalen-4-ones. According to high pressure liquid chromatography (gradient elution with 5 to 20% iscopropanol in hexane, flow rate 2 ml / min, Zorbax-Sil column, Dupont Series 8800), the previously eluted sub-dihydronaphthalen-4-one represented 9.44% area (detector operating at 254 nm) peaks corresponding to the resulting dihydronaphthalen-4-ones. 94.0 g of the crude product was suspended in 1.5 liters of acetonitrile at reflux and methanol was added until dissolved. The solution was decolorized with activated charcoal mixed with diatomaceous earth, filtered, and the filtrate was concentrated to 800 ml by distillation of the solvent, at which point the product began to precipitate. The solid material was filtered off and dried. There were obtained 13.04 g of 4- (m-chlorophenyl) -4-sel iInidazolidinpropioncvé ^{alkyl and} n ^y o te ^pl OTE counting ^{d of 251} and ^{247 o} C.

The methanol-acetonitrile mother liquors are concentrated in vacuo, the residue is redissolved in acetonitrile and the solution is concentrated to a volume of 300 ml by distilling off the solvent. After filtering off the resulting solid, 39.44 g of a material having a temperature of ²²⁷ ° C were obtained. After two ^d m ^d ENN ^also sets ^p r ⁱ te rt ^{pl of} 25 ° C, in ^{whose yl} ou the ^STE da ^LSI c ^h te ^pl of ^1.17 revolutions ^of the ^{T 208} to ²¹² ° C, ^to C TERA ^ fiRru ^ is. Matec ^l ouhy ^s concentrated to a glassy foam, which was triturated with chloroform. After stirring overnight, ^9.0 env ^{gp eh} the mater ^ial u j ^{ih the} esters not ^{at 181} DEG to 222 ^{g of} melting solid ^{la sition} in VA ^to excreted uu 'ca melts ^{at 199} detuning and ^{Z 2} 0 ^{1 O} C.

The mother liquors are concentrated in vacuo to a foamy residue which contains the entrapped solvent and weighs 25-30 g.

The foam was applied to a silica gel column (0.062-0.037 mm) eluting with 5% methanol in chloroform. Fractions containing the resulting dihydronaphthalen-4-ones were collected and evaporated in vacuo to give 6.77 g of a material consisting of a mixture of two diastereomers present by 58.3: 41.7 by NMR spectroscopy.

This material was further analyzed by high pressure liquid chromatography. The first eluted peak has an area of 57.18 compared to the later eluted peak having an area of 42.82. This finding is consistent with the conclusions of NMR spectroscopy.

After analysis, the residue after concentration of the fractions (1.5 g) was subjected to preparative high pressure liquid chromatography (on a Zorbax-Sil preparative column, six injections, gradient elution with 5 to 20% isopropanol in hexane, flow rate 40 ml / min, detection at 300 nm). ).

The first eluted fractions corresponding to the major peak 'were pooled and concentrated in vacuo to yield ^f is from ^I ská ³ 69 mg of ^p EVN ^eh o ^p ro ^d u ^t e ^kt uo ot ^{pl of} T ^and the ^196-199 ° C.

Analysis: ^{C H} N i3 ^c 2 ^N 2 F calculated: 59.54% C 4.23 '% H 10.68% N Found: 59.22% C 4.29% H 10.53% N

According to high pressure liquid chromatography, this material is enriched in the faster progressing diastereomer. Of the total peak area, the faster progressing diastereomer occupies 97.49% and the unidentified byproduct, later eluted, 2.23%. Combination of spectral methods and individual crystal X-ray analysis shows that the racemic component constituting 97.49% of the above mixture has a configuration of 4,1'-S, 3'-S.

Example 19 · (+) - 7'-Chloro-3 ', 3'-dimethyl-spiro (imidazolidin-4,1'-1', 2'-dihydronaphthalen-4-one) -2,5-dione

0.62 g (2 mmol) of 2,5-dioxo-3 _of 3-dimethyl-4- (m-chlorophenyl) -4-imidazolidinepropionic acid was mixed with 4 ml of concentrated sulfuric acid and heated at 70 ° C for 4 hours. . The reaction mixture is poured onto ice, the solid material is filtered off and, after washing with water, dried. 412 mg of solid are obtained, which is taken up in hot acetonitrile, the solution is decolorized with activated charcoal mixed with diatomaceous earth and, after filtration, cooled. The white solid was filtered and dried to give 140 mg of the title compound, a ^p te l ^of thee mp 264-266 ° C.

Analysis: for ^C 11 ^H 1 ₃ ^N 3 ° 2F: calculated: 57.44% C 4.48% H 9.57% N Found: 57.26% C 4.51% H 9.63% N.

Example 20 (+) - 3 ', 3-Dimethyl-spiroimidazolidin-4'1'-1', 2'-dihydronaphthalen-4'-in] -2z 5-ol

26.94 g (0.1 mol) 2z5-Dioxo-Зz3 ^{iimet-yl-4-phen yl-4-imiiazrliiiinrrpiriové} acid mixture ^{í í} with ¹ 35 ml of concentrated ^{KY If} n ^y with ⁱ rrvé ^mixture The mixture is heated at 70 ° C for ⁵ hours and then poured onto ice.

The precipitated solid was filtered and dried to give 21.04 g of crude product. 19.35 g of this crude product are dissolved in 150 ml of 1N sodium hydroxide and the solution is decolorized with activated charcoal mixed with diatomaceous earth. The basic solution was adjusted to pH 7 with hydrochloric acid, the resulting solid was filtered off and washed twice with water. This procedure was repeated again and the resulting solid was partitioned between dilute hydrochloric acid (75 mL) and ethyl acetate (400 mL). The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. Yielding ^12.54 gs ^{l and} amine compound act en ny Uve ^{d é} title taj ^s c ^s p ^{s and 2 229 1} 3 ° C. ·

% H, 5.46;% N, 10.85. Found:% C, 64.74;% H, 5.53;% 00.74%.

EXAMPLE 21 (+) - '7'-chloro or- ^{l 3} ' -methyl-spiro [I ^{d i d} azol-4, L-3'-l''- (HyMronaftalen onJ- ^^ ^ S-idwn

10.72 g (36.1 mmol) of 215-dioxo-3-methyl-4- (m-chlorophenyl) ^-4-p imidazolidinpro -se acid ions mixed with 55 ml of concentrated sulfuric acid, the reaction mixture is heated for 5 hours at 70 ₄ ° C and then poured into ice water. The resulting solid was filtered and washed with water and dried. 7.96 g of crude material are obtained. 7.76 g of this raw material rozpsutí in 400 ml boiling acetonitrile, the solution is decolorized with charcoal, filtered and the ^f ilter ^and T stop, ^and ZC-adnout to ²⁵ ° C. Ignites ^the lysed pevný m ^ riyal from ^fil off and dried. There were obtained 4.48 g of the title compound, which partially melted at from 232 to 23 ⁴ ° C and melts at extended ^{to LD at 255} and at ^{from 257} ° C.

Analysis: ^{C H} N i3 ° ^C 3 ^N 2 Calculated: 56.02% C 3.98% H 10.05% N Found: 56.17% C 4.08% H 10.13% N

EXAMPLE 22 (+) - 7'-Fluoro-3'-benzyl-spiro [imidazolidine-4,1'- ³ 'H-l', 2'-diyhdronaftalen-4'-one] -2,5-dione

A solution of 1.02 g (3.16 mmol) of (+) - 7'-fluoro-3'-benzylidene-spiro [imidazolidine-4,1'-1 ', 2'-dihydronaphthalene-4-one-2-one. ^ -iáionu in 100 ml of ethano ^l in the presence of the ^{CMD 100} m ^{g of 5% p} ia and ^ice on carbon 1.5 hours hydrogenated under atmospheric pressure at room temperature. The catalyst was filtered off and the ethanol was evaporated in vacuo. The crude residue was recrystallized from isopropanol to give 794 mg of the title compound as a mixture of diastereomers.

The minor diastereomer can be isolated as follows. The 794 mg mixture obtained above was treated with triethylamine (0.656 ml) in ethanol (60 ml) for 3 days. The resulting mixture was concentrated in vacuo and the solid residue was recrystallized from acetonitrile to give 330 mg of a solid. The mother liquors were concentrated in vacuo and the residue was recrystallized again to give 130 mg of solid material, the mother liquors were concentrated in vacuo and the residue was recrystallized from ethanol. Yielding a solid which after washing with diethyl ether and dried ^p OSK ^y tne 33 mg of ^p odružného dtastareomerů of te ^pl revolutions ^of T ^and the ²²⁵ and ^{from 226} ° C, and ^five C ^to a rotation θθ = ¹²⁰ ° (methanol c = ^1). ·

High resolution mass spectrum:

P ^{ro C} 19 ^H 15 ^{N 2} ° 3 ^F calculated: 338.106 7 found: 338.106 7.

The major diastereomer can be isolated as follows. Using the hydrogenation conditions described above, from 672 mg (2 mmol) of (+) - 7'-fluoro-3'-benzylidene-spiro [imidazolidin-4,1'-1 ', 2'-dihydronaphthalene-4'- of the [eta] &lt; 5 &gt; -2,5-dione yields a crude product consisting essentially of a single diastereomer. Recrystallization from isopropanol gave 460 mg of the main diastereomer, m.p. 238 DEG-240 DEG C. and optical rotation [.alpha.] D @ 20 = -31 DEG (methanol, c = 1).

Example 23

The compounds of formula (I) from the preceding examples were tested for their ability to reduce or inhibit the activity of the aldose reductase enzyme according to the procedure described in U.S. Patent 3,821,383, based on the method described by Hayman et al. in Journal of Biological Chemistry, 240, 877 (1965). If the same compound was prepared by more than one method, the test results were identical with these differently prepared compounds irrespective of the method of manufacture. As a substrate, the enzyme aldoso-reductase obtained from human placenta was used for the tests and was partially purified. Described compounds

-4-9 were tested at concentrations from 10 to 10 M and were found to inhibit enzymatic activity relative to untreated controls.

Preparation

2,5-dioxo-4-m-fluorophenyl-4-imidazolidinepropionic acid

1.57 g (8 mmol) of m-fluorobenzene-6-oxobutanoic acid / Eur. J. Med. Chem., 13, 533 (1978)] were mixed with 7.7 g (80 mmol) of ammonium carbonate, 1.04 g (16 mmol) of potassium cyanide and 60 ml of water, and the mixture was heated at 70 ° C for 20 hours. The reaction mixture was cooled to 25 ° C and acidified to pH 2 with concentrated hydrochloric acid. The resulting yellowish solid was filtered off and dried under vacuum at 100 ° C. 1.8 g (85% yield) of the title compound of melting point 206 DEG-208 DEG C. are obtained.

NMR (DMSO-d6): 11.0 (bs, 1H), 8.86 (bs, 1H), 7.67-6.88 (m, 4H), 2.25 (bs, 4H) ppm.

Preparation В

2,5-dioxo-4-m-methoxyphenyl-4-imidazolidinepropionic acid

M-methoxybenzen-γ-oxobutanoic acid (10.0 g, 48 mmol) was mixed with ammonium carbonate (22.75 g, 235 mmol), potassium cyanide (6.5 g, 100 mmol) in ethanol (100 mL) and water (100 mL) at temperature 65 ° C. After 5 hours at 65 ° C, an additional 22.75 g (235 mmol) of ammonium carbonate was added and heating was continued for 18 hours.

The reaction mixture is concentrated in vacuo, the residue is triturated with water and the acidity of the mixture is adjusted to pH 4 with concentrated hydrochloric acid. The resulting white solid product is filtered off and dried under vacuum at 80 ° C for 20 hours. This gave ip, 6 g (7% yield) of the title compound, m.p. 138 ° C.

*

Analysis: for ^{C 13 H} 14 ^N 2 ° 5

calculated: 56.11% C found: 55.46 Л C 5.07% H 5.02% H 10.07% N 10.02% N Preparation C

2,5-dioxo-4-m-nitrophenyl-4-imidazolidinepropionic acid

The title compound was prepared according to the procedure of Preparation A. In this case, 3-nitrobehzen-γ-oxobutanoic acid was used instead of the corresponding 3-fluorobenzene derivative.

Preparation D

2,5-dioxo-4- (m-chloro-p-methylphenyl) -4-imidazolidinepropionic acid

22.7 g (100 mmol) of p---chlor - ltyZ ^b lnzli-γ-oiobutaiOvé acid / Bull. Chem. Soc. Jap., 52, 2 441-2 442 (1979) / is mixed with 90 g (0.94 mol) of ammonium carbonate and 13.7 g ⁽² 10 mmoles) of potassium cyanide in 300 ml water, and the mixture was heated for 22 hours 65 ° <mixture oc ^ a ^ to ²⁵ ^ VZN ^IKL evný -amlr Y ^{P i} and ^Z is a ^ H ^ ensures and water. The aqueous suspension with concentrated hydrochloric acid was filtered off and washed with water and dried. Yield boat ^and n ^y en UVL ^{5 Star} HV ^and invite ^pl of TE OTE counting ^{196 s} 9 and ^{Z 19} ° C.

C. Rea ^CZK n ^{d d} U is suspended in the ²⁰⁰ - ^from acidified to pH 2, the resulting

27.8 g (94%) slouPříprava E _r 5-Dioxo-4- (m - 'chlorophenyl) -4-imidazolidÍnpropionová acid

10.6 g (50 mmol) of 3-chlorobenzyl-γ-olobumanoic acid are mixed with ammonium and 6.5 g (100 mmol) of potassium cyanide in 100 ml of ⁶⁵ ° C. ^R ea ^CZK it was och ^l and ⁵ l to 100 ml with water. Concentrated pH 0.5, the resulting solid material is carbonate per ^hour iv ^and to a stirred acidified to dry. There were obtained 11.47 g (yield 84%) of crude genus ^kl adu and lauryl ^ ^ rove dbarven ^{even at 196} DEG 2I ⁷ 47.2 g (490 mmol) of water and then 65 hours ⁰ C \ ^l you oučln ^The mixture was filtered, and the aqueous mixture was filtered, and after washing with 300 ml of water, the title compound melted at 0 ° C.

Preparation F

2,5io10-o-4-m-yl-1-i-idadazoliniroro-acid

3.0 g (10-mol) of 3-methylbendei-γ-o-butobutyric acid are mixed with 14.0 g (144-mol) of ammonium carbonate and 2.2 g (34 mmol) of potassium cyanide in 50 ml of water and zaliřM hours at ^65-70 ° C. Rea ^{d at the} CN with the mixture ^of alpha ^hl and ^Di and ^K oncentrovanou tyse Nou ^ ^ c ^^ orovo Vou was acidified to pH 2. The precipitated solid product was filtered, washed with water and dried. ^{September KA} crude ^p ro ^d u ^k t ^{t I} C and ^{I at 173-178} ° C. This crude ^d ro ^p gr ^{t p} extended breath ^{as well as} in boiling water, insoluble orange colored gum was filtered off and the aqueous solution concentrated in vacuo. of te ^ o ^ T, ^and the ¹⁹⁵ to ¹⁹⁸ ° C.

1.34 g (32% yield) of the title compound are obtained,

Anal. Calc &apos; d: 59.54 Found: 59.25

5.38% H

5.30% H

10,68%

10.32%

N,

N.

Preparation

2,5-o-o-m-yl-0-0-O-pyridazo-50-oxo-acidic acid

3.5 g of P, 5-D-thiophthalic acid are less than or equal to 1 g of ammonium and 2.2 g (33.8 mmol). potassium cyanide in 50 ml of water and blended 26 to ⁶⁰ ° C. Rea ^{CZK tup} direction ^E i ee oh ^^ ²⁵ ^ ° ^ ^^ ition of ^b and ^{d s} alljovit ha п-ло1) uUltoiOtnu heated ma ^ ri-N, pH of the filtrate with concentrated hydrochloric acid adjusted to pH 3 5, the precipitated white precipitate was filtered off and dried. 1.0 g (22% yield) of the title compound of Me ^ ^il am counting ^{of s} 3 ^{232-2 4} ° C.

Preparation H

3- (m-fluoro ^b enzoyl) -2 - ltyliroi0onavá acid

To 180 ml dry dimethylformamide was added 6.5 g (0.10 mol) of powdered potassium cyanide ^ it, the suspension is in ^ ^ o nzivn stirred ^and the mine ^{30 t} warmed to ⁸⁰ ° C; and ^p is cooled to 35 ° C over ⁵⁰ minutes under к ^ck u ^d ržování te ^{pl y} rt to 30 ° C ^when k ^p e solution 124'1 ^g (1.0 mol) of m-fluorobenzaldehyde in 50 ml dimethylformamide. After a further 30 minutes while maintaining the temperature of the mixture at room temperature, 67.1 g (1.0 mol) of methacrylonitrile dissolved in 50 ml of dimethylformamide are added over 20 minutes. After reaction at room temperature for 3 hours, the reaction mixture is filtered, poured into 1500 ml of water and the oily organic layer is separated. Saturated sodium chloride solution was added to the aqueous layer, and the aqueous phase was extracted three times with 150 ml of chloroform each. The combined organic layers were washed successively with dilute sulfuric acid, dilute aqueous sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate, and evaporated in vacuo at not more than ³⁵ ° ^C with chloroform. ZIS plated ^{to 199.8 g of} crude oils ^ o ^'to which is ^{added 2 to} 00 ml of concentrated YSE ^if ny c ^h lorovodí ^the memory 3 and the mixture ^{of di} ny it looks .At ¹²⁵ ° C. Rea ^on Hand ^{E í} mixture was cooled to 60 ° C; top ^and layer sel ^{alkyl and} C ^ ny orovodítové the ^DLI is ^d t ^{EZSIM red} warning ejov ^E o ^{l i} t ^y, the layer 'which solidifies during cooling. The red mixture of oil and solid was dissolved in 500 ml of 3N sodium hydroxide and the aqueous layer was extracted four times with 250 ml of diethyl ether each time. After cooling in ice, the aqueous layer was acidified to pH 2 with concentrated hydrochloric acid to precipitate a light pink solid, which was filtered off and dried. There were obtained 84.4 g (40% yield) of 3- (m-fluorobenzoyl) -2-methylpropanamide ^P ion acid, mp 90-91 ° C.

Preparation

2,5-Dioxo-3,3-dimethyl-4- (m-chlorophenyl) -4-imidazolidinepropionic acid

14.4 g (0.06 mol) of 3- (m-chlorobenzoyl) -2,2-dimethyl ^{p p} ro ionic acid are treated with 28.8 g (0.3 mol) ammonium carbonate and 7.81 g (0 12 mole) of potassium cyanide in 150 ml water and stirred for ²⁴ him ^di n ^y for ^HRI weighing 7 to ⁰ ° C 'to ^No. EZ ^her p ^{s d} and ^Oth give ^{5.7 g} thereof uh ^lychee carbonate AMONN ^s him and heated ^{Ri ck} at ⁷⁰ ° C, ^of edge ^c U is still ^of him ^{di 6} 0 n. Rea ^{at the} CN ^í mixture ^{of d} was cooled in ice and treated dropwise with concentrated hydrochloric acid. The resulting reddish brown solid was filtered off, washed with water and dried. 17.34 g of crude product are obtained, which is applied to a silica gel column which is eluted first with 5% methanol in chloroform and then with 10% methanol in chloroform. There were obtained 3.21 g of the title compound 'as ^ylw ut ^{e p e} l env ^ubstances tajDcí for detuning ^{at 198} and ²⁰ 0 ° C.

Preparation J

3- (m-chlorobenzoyl) -2,2-dimethylpropionic acid

Using the procedure described by T. Joyim et al. in Bull. Chem. Soc. Japan, 52 (8), 2 441-2 442 (1979), 3-benzo ^{yl 2'2-dimethyl-y} l ^p ropionová acid chlorination in the presence of excess aluminum chloride is converted to the title compound.

Preparation

2,5-Dioxo-3-methyl-4- (m-chlorophenyl) -4-imidazolidinepropionic acid

10.36 g (0.046 mol) of 3- (m-chlorobenzoyl) -2-methylpropan ^{p p} ro ionic acid was treated with 24.02 g (0.25 mol) of ammonium carbonate and 6.5 g (0.10 mol) of potassium cyanide in 150 ml water, and the mixture ^{23 di} ny it is heated to ⁷⁰ ° C. ^R e and ^{d at the} CN was oc ^{hl d} s at ²⁰ ° C and ^the Yssel ^s with concentrated hydrochloric acid. The resulting gummy solid was collected, dissolved in diethyl ether, and washed with 25 mL of water. The diethyl ether layer was concentrated in vacuo to a white-yellow solid which, after drying in a vacuum oven overnight ^{at instance t} e ^p lo ^{I 7} 0 ^DEG C oskytne · l ^{'28 g of 2, 5-di oxo-3- yl} methyl 1- 4- (m-chlorophenyl) ^-4 - ⁱ m ⁱ n imidazo ^{people p} ro ^pi -ones ^{s ky Li} n ^{Y 'p kt ER} arc ^{IAL some extensible} and is ^{at from 185} and ¹⁸³ ° C, and ^p and ^k la extended ^{to give p} s 198 to 200 ° C.

Preparation L

3- (m-chlorobenzoyl) -2-methylpropionic acid

1.37 g (30 mmol) of sodium cyanide were mixed with 100 ml Ν, Ν-dimethylformamide and the mixture of ^{d p} 1 nitrogen him ^di nu m ^s s ^{s t} at e ot ^{pl of 35} ° C, ^n-p MŽ Rej ^d e at ^ extended clear ^to him ^{out of} the dropwise during 1 hour 34.0 ml (0.3 mol) of 3-chlorobenzaldehyde dissolved in 50 ml of N, N-dimethyl formamide ^YLF. After al ^{width d} is ^d m Noho ^{di newly at t} e m ^{p I} lo ³⁵ ° C ^b 2 ehem it ^di- N solution of 25.0 ml (0.3 mol) methacrylonitrile in 50 ml N, N -dimethylformamide ^ ^ reaction mixture ^of it with ^{16 d} in MIC ^h and ^{at t h} e ^I 2 ^pl of ⁵ ° C, ^P and ^{k to} n ^{i add 200} m ^{1 y} meth lenchlori ^d ua 4.0 g diatomaceous earth filter aid , the mixture is stirred and filtered.

The filtrate is washed successively with 500 ml of 0.22N hydrochloric acid, twice with 200 ml of water each, 200 ml of 2.5% aqueous sodium bicarbonate solution, 200 ml of 1N hydrochloric acid, 200 ml of water and 200 ml of sodium chloride solution, and the methylene chloride layer is dried. anhydrous sodium sulfate and concentrated in vacuo. Yielding 49.65 g crude 3- (m-chlorlbenzoyl) -2-methylpropionitrile in · yellow solid which partially melts ^{at 50} ° C and that ^{some T PL} and is ^{at 79 F} and 81 ° C. ^{15.57 g (0 075} mol.l personal identification ^p roducts ^s was mixed with 25 ml of formic acid, and the mixture was heated for 2.5 hours under reflux. After cooling, 150 ml of water and the aqueous solution was extracted twice with 150 The ethyl acetate extract was then extracted twice with 150 ml of a 20% aqueous sodium hydroxide solution each time, the aqueous extract was acidified with concentrated hydrochloric acid, the precipitated solid was filtered off and dried after washing with water to give 10.86 g of 3- (m- chlorobenzo ^yl) -2 ^{- methylpiperazino} RQ -ones ^{when s} is ^{alkyl when} n ^y o te ^{pl of} revolutions n ^{th s 100-1} 02 ° C.

Claims (5)

Y N LIE 1. A process for the preparation of spiro-4-heteroazolones of the general formula (I) in which U n X Y Z represents oxygen, sulfur or nitrogen substituted by hydrogen or C1-C4alkyl, is 0 or 1, represents hydrogen, chlorine, bromine or iodine, C1-C4alkyl, dimethyl or a residue (CHp _m Q, where m has a value of 1 or 2 and Q represents a phenyl or halophenyl group, provided that if Y dimethyl group, n is 1, represents hydrogen, halogen, nitro, trifluoromethyl, C 1 -C 4 alkoxy or C 1 -C 4 alkyl and represents hydrogen or halogen, nitro, trifluoromethyl, alkoxy having from 1 to 4 carbon atoms or a (C1-C4) alkyl group, with the restriction that if either Y or Z is nitro, the other of these is hydrogen, and their pharmaceutically acceptable salts, that the compound of formula III (III) Г'- NH Wherein the individual general symbols are as defined above, reacted with a strong Lewis acid, and the resulting product is optionally converted to its pharmaceutically acceptable salt. 2. The process of claim 1, wherein the corresponding starting material of formula III is used to form a compound of formula I wherein: U is oxygen, n is 1, X represents a methyl group, Y represents a fluorine atom and Z represents a hydrogen atom. 3. A method according to claim 1, characterized by: The process of claim 1, wherein the corresponding starting materials of the formula III are used to form compounds of the formula I in which: U is hydrogen substituted with hydrogen, n is 0, X, Y and Z are hydrogen or X and Z are hydrogen and Y is fluorine. 4. A process according to claim 1, wherein the corresponding compounds of the formula III are used as starting materials to give compounds of the formula I in which: U represents a nitrogen atom substituted by hydrogen, n is 1, X, Y and Z are hydrogen or X and Z are hydrogen and Y is fluorine. 5. 1. The method of claim 1, that the starting material used is giving compound of formula III, to give compounds common of formula I, v; which AT means a nitrogen atom substituted with a moiety, !!!, n is 1, X let us introduce a bromine atom and Y and Z are hydrogen atoms. 6. . 1. The method of claim 1, that is like default substances odpo- seeing compounds of Formula III to form compounds of Formula I wherein: U represents a nitrogen atom substituted with hydrogen or a methyl group, n is 1, X represents a methyl group, Y represents a fluorine atom and Z is a vodka atom. 23 jící 7. The process of claim 1, wherein the corresponding compound of formula III is used as the starting material to form a compound. of formula (I) in which the nitrogen atom is substituted with hydrogen, has a value of 1, represents a dimethyl group, represents a chlorine atom and represents a hydrogen atom.