JPH0251548B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel spiro-3-heteroazolidinediones that are useful in the treatment of certain chronic complications caused by diabetes, such as diabetic cataracts, retinopathy, and neuropathies.

Up to now, various attempts have been made to obtain more effective oral antidiabetic drugs. These efforts generally involve the synthesis of new organic compounds, particularly sulfonylureas, and the determination of their ability to substantially lower blood sugar levels when administered orally. However, little is known about the effects of organic compounds in preventing or alleviating chronic complications of diabetes, such as diabetic cataracts, neuropathy, and retinopathy. U.S. Pat. No. 3,821,383 describes 1,3-dioxo-1H-benzo(d,e)
Aldose reductase inhibitors such as -isoquinoline-2(3H)-acetic acid and their derivatives are stated to be useful in the treatment of these conditions. US Pat. No. 4,117,230 teaches the use of certain hydantoins as aldose reductase inhibitors for diabetic complications. Aldose reductase inhibitors of this type inhibit aldose reductase, an enzyme primarily involved in controlling the reduction of aldoses (e.g., glycose and galactose) to the corresponding polyols (e.g., sorbitol and galactitol) in humans and other animals. It works by suppressing activity. As a result, galactitol is added to the lens of patients with galactosemia, and to the lens of various diabetic patients.
Undesirable accumulation of sorbitol in the terminal nerve cord and kidneys is prevented or reduced. Compounds of this type are therefore of value as aldose reductase inhibitors for controlling certain chronic diabetic complications, including ocular ones. This is because it is preferred in the art that the presence of polyols in the lens causes cataracts and a concomitant loss of clarity of the lens.

The compound of the present invention has the following formula: [In the formula, U is NH; n is 0 or 1; W is a carbonyl group or a hydroxymethylene group; R is a hydrogen atom; X is a hydrogen atom, a bromine atom, methyl, dimethyl,
or benzyl, provided that when X is dimethyl, n is 1; Y is hydrogen, halogen, methoxy, or methyl; and Z is hydrogen, chloro, or methyl; or Pharmaceutically acceptable salts thereof.

Both mixtures of optically active isomers and partially or fully optically resolved isomers of the claimed compounds are within the scope of the invention.

The numbering system for the spiro compound (A) of the formula where n is 0 is as shown below.

These compounds (A) are 6'-Y-4' or
5'-Z-2'-X-spiro[imidazolidine-, oxazolidine- or thiazolidine-4,1'-indan]2,5-dione derivative.

The numbering system for compound (B) of formula where n is 1 is as follows.

These compounds are 4'-hydroxy-7'-Y-6' or
5'-Z-3'-X-spiro[imidazolidine-, oxazolidine- or thiazolidine-4,1'-
1', 2', 3'-4'-tetrahydronaphthalene]2,
5-dione. When W is a carbonyl group, these compounds are 7'-Y-6' or 5'-Z-
3'-X-spiro [imidazolidine-, oxazolidine- or thiazolidine-4,1'-3'H-1',
2'-dihydronaphthalene-4'-one]2,5-dione.

The compound of formula can be synthesized by two methods (A and B).
(U is NH). Synthesis method A
The starting materials are 1-indanone and 1-tetralone (). 1-Indanone is a well-known compound, and these starting 1-indanones that are not represented in the literature can be prepared by routes comparable to those used to prepare known compounds.

A particularly useful route used to produce 1-indanones is by ring closure of hydrocinnamic acid derivatives. These intermediates are prepared by hydrogenation of cinnamic acid derivatives, which are prepared by condensation of the appropriate benzaldehyde derivative with malonic acid followed by decarboxylation.

A typical method is the method of R. Fuchs and JA Capiute [J.Org.Chem., 31, 1524-6 (1966)]
It is.

The starting benzaldehydes with appropriate substitution patterns are known compounds. Desired 1-indanone () using appropriate benzaldehyde
can be manufactured.

1-tetralones are also well known compounds, and starting materials 1-tetralones not described in the literature can be prepared by routes comparable to those used to prepare known compounds.

A particularly useful route used to prepare 1-tetralones is the method of LF Fieser and AM Seligman [J. Amer. Chem. Soc., 60, 170-], which optionally employs ring closure of 4-phenylbutyric acids. 6
(1938)]. These acids can be produced by Clemenson reduction of 3-benzopropionic acids.
3-Benzoylpropionic acids with appropriate substitution patterns are known and can be prepared by methods described in the literature or by methods discussed below. These acids are precursors for the 1-tetralones used in Synthesis A. Alternatively, synthesis method B can be employed to obtain final products of the formula with different substitution patterns from these same acid intermediates.

A particularly useful route to 3-benzoylpropionic acids is to condense the benzaldehyde derivative with acrylonitrile or α-substituted acrylonitrile in dimethylformamide in the presence of potassium cyanide to form 3-benzoylpropionitrile, which is then concentrated. hydrolysis in an acid (e.g. hydrochloric acid) to the corresponding 3-benzoylpropionic acid.

A typical method for this condensation step is H.
Stelter and M. Schretzke's method [Chem.
Ber., 107 , 210-14 (1974)].

It will be appreciated that 3-benzoylpropionic acid substituted with something other than a hydrogen atom at the 2-position provides 3-benzoylpropionic acids useful in the synthesis of the final product, tetrahydronaphthalene, by Method A.

3-Substituted-3-benzoylpropionic acids are also useful in preparing the final product of formula tetrahydronaphthalene by Synthesis A. 3-Substituted-3-benzoylpropionic acid, which is not described in the literature, can be obtained by the method of FJ Matsukuevoy and GR Allen Giunia [J.Org.Chem., 38 , 4044-48 (1973)].
can be produced by methods similar to those used to produce known compounds.

It will be appreciated that 3-benzoylpropionic acid substituted at the 2-position with something other than a hydrogen atom provides 3-benzoylpropionic acids useful in the synthesis of the final product tetrahydronaphthalene according to Synthesis B. This route is useful because substituted benzaldehydes are readily available, and α-substituted acrylonitriles (X other than hydrogen) such as methacrylonitrile are commercially available or as described by the general method of RB Miller and BF Smith [Syn.
Comm., 413-17 (1973)], it is particularly useful. 2-Substituted-3-benzoylpropionic acids can also be prepared using this route.

3-Benzoylpropionic acids can also be prepared from known substituted bromobenzenes. The bromobenzene derivative is converted into a Grignard reagent and then into a cadmium reagent, which is reacted with a half-acid halide, half-ester of succinic acid to obtain an ester of 3-benzoylpropionic acid. This ester is then dissociated to the free acid by basic hydrolysis.

This method is particularly useful for making the final product tetrahydronaphthalene, where X is dimethyl.
For example, α,α-dimethyl succinate was synthesized by CC Price and T. patudopanatan (T.
Padmanathan) method [J.Crg.Chem., 30, 2064
-67 (1965)], it can be converted into β-carbomethoxyisovaleryl chloride (X is dimethyl).

This acid chloride can be reacted with various bromobenzene derivatives to obtain 3,3-dimethyl-3-substituted benzoylpropionic acid. These derivatives can be used in Synthesis Method A to obtain the final product tetrahydronaphthalenes where X is dimethyl.

A useful method for producing 3-benzoylpropionic acids is to combine benzene derivatives with an LF feeder and
EB Heisberg's General Law [J.Amer.Chem.Soc.,
58, 2314 (1936)] directly to 3-benzoylpropionic acids. The nature of the product will be determined both by the direct action of the substituents Y and Z on the benzene ring and by the nature of X if it is other than a hydrogen atom. When X is dimethyl,
The benzoylpropionic acids produced are those in which the gem-dimethyl moiety is adjacent to a carbonyl group other than the ketone carbonyl group. Therefore, using as-dimethylsuccinic anhydride, 3-benzoyl-
2,2-dimethylpropionic acids can be prepared which can be converted by synthesis method B to the final product tetrahydronaphthalenes in which X is dimethyl.

A useful method for increasing the usefulness of 3-benzoylpropionic acids is to remove the initially formed ketone carbonyl group of 3-benzoylpropionic acids.
It involves converting it into a strong electron-absorbing group by forming a complex with AlCl ₃ , and as a result, the aromatic ring can be halogenated at the meta-position of the carbonyl group complexed with AlCl ₃ .

This method is particularly useful for converting 3,3-dimethyl-3-(4-substituted benzoyl)propionic acid to 3,4-disubstituted benzoyl derivatives. These can be converted to 6',7'-disubstituted tetrahydronaphthalenes by synthesis method B.

Another method useful for preparing 3-benzoylpropionic acids consists of reacting an aryl iodide, such as an aryl Grignard reagent prepared from a commercially available iodobenzene derivative, with silylated γ-butyrolactone, followed by oxidation.

2-Benzoylacetic acids and their ester derivatives are useful as starting materials for obtaining dihydroindene-based end products.

A compound of the formula can be changed to a corresponding compound of the formula. In synthetic method A, the preparation of compounds of formula is known (see also US Pat. No. 4,117,230 (U=NH)). Compounds of formula can be prepared from compounds of formula by the method described by Reinhard Sturgis, Herry R. Harrod Giunia and Paul R. Kerbau (J.Org.Chem., 1982,
47, 4081-5) by reacting chlorosulfonyl isocyanate with a carboxyimine adduct of a compound of the formula and an amine (H ₂ NR).

Compounds of these formulas are prepared with N-dialkylsilyl and O-dialkylsilyl groups at about 0-60°C, preferably about 25°C, in a non-reactive halogenating solvent (e.g. chloroform) which does not interfere with the subsequent halogenation reaction. (for example, N-dimethylsilyl-O-dimethylsilyl perfluoroacetic acid imine) having a phosphor-containing structure (acting as a protecting group for the imide nitrogen).

In situ halogenation is preferably carried out using molecular halogens such as bromine, chlorine or iodine, more preferably bromine. Bromination carried out in situ using, for example, bromine at a temperature in the range of about 25-100°C, preferably about 60°C, provides the 4'-brome derivative.

The 4'-halo derivative is prepared in water having a pH range of about 1 to 7, preferably about 4, at a temperature of about 0 to 60°C.
℃, preferably about 25℃. Obtained alcohol (W is hydroxymethylene)
in acetic acid using any suitable oxidizing agent such as chromium trioxide, from about 0 to 60°C, preferably at about 25°C.
Further oxidation occurs at °C.

A compound of the formula where W is a carbonyl group and X is a hydrogen atom can be brominated to form an α-brome ketone (X is a bromine atom). This bromination is carried out using molecular bromine in a suitable solvent such as a lower carboxylic acid having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (more preferably acetic acid), with a mineral acid catalyst such as bromination. It can be carried out using hydrohydric acid at a temperature of about 0 to 100°C, preferably 25 to 80°C.

Alternatively, a compound of the formula in which X is a bromine atom and W is a carbonyl group can be first prepared in a non-reactive brominating solvent using N-trialkylsilyl as described above for the conversion to and O-trialkylsilyl groups (e.g. N-trimethylsilyl-O-trimethylsilyl perfluoroacetic acid imine), followed by reaction with the desired molecular halogen. Bromination can be performed to make X a bromine atom.

Alternatively, synthesis method B can be used for compounds of formula. The corresponding benzene-γ-oxoacid (which is known or can be prepared by methods analogous to those described for known compounds) in an aqueous solution, such as water or a hydroalcoholic mixture (such as water-ethanol), at a pH of about 9 ~
10, preferably 10, reacted with an ammonium salt (e.g. ammonium carbonate) and an alkali metal cyanide (e.g. sodium or potassium cyanide, preferably sodium cyanide) at a temperature range of about 50-100°C, preferably about 70°C. to obtain a compound of formula.

The resulting condensation reaction product is reacted with a strong Lewis acid such as polyphosphoric acid at a temperature range of 100-200°C, preferably about 150°C. Alternatively, add concentrated sulfuric acid (6-9M, preferably 9M) to about 60-180℃,
Preferably, it can also be used at about 120°C. Other strong Lewis acids such as mineral acids, aluminum trichloride, iron chloride, etc. can also be used.

Compounds of the formula in which W is a carbonyl group can be reduced using any of a variety of commonly used reducing agents, such as lithium aluminum hydride, sodium borohydride, aluminum isopropoxide, and the like. Preferred solvents for lithium aluminum hydride related derivatives are hydroxyl-free solvents such as ether, dioxane or tetrahydrofuran, and preferred temperatures are about -30
~25°C, preferably about 0°C. Preferred solvents for sodium borohydride and related free radicals are lower alcoholic hydroxyl solvents, such as methanol or ethanol, used at a temperature of about 0-60°C, preferably about 25°C. The preferred solvent for reduction with aluminum isopropoxide is isopropyl alcohol;
It is used under slow distillation of by-product acetone at reflux temperature.

Furthermore, the compound of the formula in which W is a carbonyl group and X is a hydrogen atom, prepared according to Synthesis Method B, can of course be converted into an α-bromoketone by the same method as described above.

Because of the acidic hydrogen atom in the spiroheterocycle of compounds of formula, salts can be formed with pharmaceutically acceptable cations in a conventional manner. For example, these salts can be readily prepared by treating a compound of the formula with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alcoholic solution of the compound of formula can be mixed with the alkoxide of the desired metal and the solution then evaporated to dryness. Pharmaceutically acceptable cations suitable for this purpose include alkali metal cations (e.g. potassium and sodium), ammonium or water-soluble amine addition temperatures (such as lower alkanol ammonium), and pharmaceutically acceptable organic amines and alkaline earth cations. These include, but are not limited to, metalloid cations (eg, calcium and magnesium).

The use of the term pharmaceutically acceptable salts in the description and claims of this invention is intended to include both acid addition salts and salts formed with appropriate cations, as described above.

The novel compounds and their pharmaceutically acceptable salts are useful as inhibitors of aldose reductase in the treatment of chronic complications of diabetes, such as diabetic cataracts, retinopathy and neuropathy. Treatment, as used in the claims and description of the present invention, is intended to include both the prevention and alleviation of such conditions. These compounds can be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, parenterally and topically. Generally these compounds will be administered orally or parenterally at a dose of about 0.05 to 25 mg per kg of body weight per day, preferably about 0.1 to 10 mg/Kg of the subject to be treated. However, some variation will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The novel compounds of this invention can be administered alone or in combination with pharmaceutically acceptable carriers in one or more doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, neat aqueous solutions and various organic solvents. The pharmaceutical compositions thus formed by combining the novel compounds of formula and a pharmaceutically acceptable carrier are readily administered in a variety of dosage forms such as tablets, powder troches, syrups, injections, and the like. These pharmaceutical compositions may optionally contain additional ingredients such as flavoring agents, binders,
It can contain excipients and the like. For example, for oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be combined with various disintegrants such as starch, alginic acid and certain silicate complexes,
as well as binders such as polyvinylpyrrolidone,
It can also be used with sucrose, gelatin and gum arabic. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be used to fill soft and hard-filled gelatin capsules. Preferred materials for this include lactose and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredients therein may be combined with various sweetening or flavoring agents, colorants or dyes, and, optionally, emulsifying or suspending agents. ,
and diluents such as water, ethanol, propylene glycol, glycol, and combinations thereof.

For parenteral administration, solutions of the novel compounds of the formula in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution can be employed. Aqueous solutions of this type should be suitably buffered, if necessary, and the liquid diluent should first be made isotonic with a sufficient amount of saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, all sterile aqueous media used are readily obtained by standard techniques well known to those skilled in the art.

The compounds of the formula are not only advantageously used in the preparation of aqueous pharmaceutical compositions for parenteral administration as described above, but also can be used in the preparation of pharmaceutical compositions suitable as ophthalmic solutions. Ophthalmic solutions of this type are of primary interest for treating diabetic cataracts by topical administration, and treating this type of condition in this manner is a preferred use of the invention. For example, for the treatment of diabetic cataracts, compounds of the present invention may be administered to the eye of the subject in need of treatment using conventional formulation practices (e.g., "Remington's Pharmaceutical Science," Vol. 15).
Edition, pp. 1488-1501, Matsuku Publishing Co., Ltd.
Easton, Pennsylvania, Reference). Ophthalmic solutions contain from about 0.01 to about 1% by weight, preferably about 1% by weight, of a compound of formula or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solution, suspension or ointment.
It will contain concentrations of 0.05 to about 0.5%. Some variation in concentration will necessarily occur depending on the particular compound used, the condition of the subject being treated, etc., and the person responsible for treatment will determine the optimal concentration for the individual subject. Ophthalmic preparations are sterile and may optionally contain additional ingredients such as preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, thickening agents, etc. Preferably it will be in the form of an aqueous solution. Suitable preservatives include benzalkonium chloride, benzethonium chloride, chlorbutanol, thimerosal, etc. Suitable buffering agents include boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium carbonate and potassium in amounts sufficient to maintain the pH at about 6 to 8, preferably about 7 to 7.5. potassium sodium acetate,
Contains sodium dihydrogen phosphate. Suitable tonicity agents are Dextran 40, Dextran 70,
Dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, etc., and the sodium chloride equivalent to ophthalmic solution is 0.9
In the range of ±0.2%. Suitable antioxidants and stabilizers include sodium bisulfite, sodium pyrosulfite, sodium thiosulfite, thiourea, and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamers
282 and tyloxapol. Suitable thickening agents include Dextran 40, Dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylenecellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, and the like. Ophthalmic formulations will be administered topically to the eye of the subject in need of treatment in the conventional manner, eg, in the form of drops or by soaking the eye in an ophthalmic solution.

The activity of compounds of the invention as agents for controlling chronic diabetic complications can be determined by a number of standard biological or pharmacological tests. Appropriate tests include:
(1) determine their ability to inhibit the enzymatic activity of isolated aldose reductase; (2) their ability to reduce sorbitol accumulation in the sciatic nerve and lens of acute streptozotocin-treated, i.e., diabetic, rats. (3) measure their ability to restore elevated sorbitol levels in the sciatic nerve and lens of chronic streptozotocin-induced diabetic rats; (4) measure their ability to restore elevated sorbitol levels in acute galactosemic rats; (5) measure their ability to delay cataract formation and reduce the degree of lens opacity in chronic galactosemic rats; (6) measure their ability to inhibit galactose formation in the lens of the , measuring the ability to inhibit sorbitol accumulation and cataract formation in rat lenses incubated with glucose; and (7)
Their ability to lower already elevated sorbitol levels in isolated rat lenses incubated with glucose is determined.

The present invention will be illustrated by the following specific examples, but it will be understood that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance spectra (NMR) are measured at 60 MHz (unless otherwise indicated) on solutions in perdeuterodimethylsulfoxide (DMSO- _d6 ), peak positions are expressed in ppm down from tetramethylsilane. . The shape of the peak is described as follows: s, singlet; d, doublet; t, triplet; q;
quartet; m, multiplet; b, broad.

CAreg.no. is the Chemical Abstracts Registration Number.

Example 1 3'-Hydroxy-spiro[imidazolidine-
4,1'-Indane]2,5-dione Spiro[Imidazolidine-4,1'-Indane]
2,5-dione (CAreg.no.6252-98-8)
(6.06 g, 30 mmol) in 50 ml of chloroform with 7.95 ml (30 mmol) of bis(trimethylsilyl)trifluoroacetamide and 4.8 g (30 mmol) of bromine in 50 ml of chloroform.
mmol) and heated to reflux. Decolorization occurred during the 18 hour reaction. The reaction mixture was cooled to 25°C, and after stirring for 45 minutes, the crystallized solid was collected and 2.45 g of crude 3'-bromo-spiro[imidazolidine-4,1'-indane]2,5-dione ( 29
%) was obtained. 2.18g more from chloroform mother liquor
(yield 26%) was precipitated. Melting point 58-65℃. 2g
(7.1 mmol) of substance (melting point 58-65°C) in 25 ml of water
It was made into a slurry. After stirring for 22 hours, the resulting solid was collected and dried to yield 0.52 g (33% yield) of the title compound. Melting point 260~263
℃.

Elemental analysis: Calculated value (C ₁₁ H ₁₀ N ₂ O ₃ ):
C, 60.55; H, 4.62; N, 12.84 Actual value: C, 60.84: H, 4.74; N, 12.80 Example 2 Spiro[imidazolidine-4,1'-indan
3'one]2,5-dione 3'-hydroxy-spiro[imidazolidine-
4,1′-indane]2,5-dione (1.2 g, 5.5
0.550 mmol) of chromium trioxide in 20 ml of glacial acetic acid
g (5.5 mmol) at 25°C.
As dissolution occurred, the reaction mixture became dark in color and the temperature rose to 39°C. After 10 minutes the reaction mixture was concentrated in vacuo to give a gummy solid. After trituration with water, a white solid was separated. The solid was dissolved in tetrahydrofuran, filtered, and the liquid concentrated in vacuo to yield 0.470 g (39% yield) of the title compound. Melting point 253-256℃.

Elemental analysis (%): Calculated value (C ₁₁ H ₈ N ₂ O ₃ ):
C, 61.11; H, 3.73; N, 12.96 Actual value: C, 60.54: H, 4.02; N, 13.09 Example 3 Spiro[imidazolidine-4,1'-indan-
3'-one]2,5-dione 2,5-dioxo-4-phenyl-imidazolidine acetic acid (CAreg. no. 62985-01-7) was suspended in 15 ml of polyphosphoric acid at 150°C. Gradual dissolution occurred and after 2 hours at 150°C the reaction mixture was cooled to 25°C and diluted with 15ml of water. A solid gradually formed, which was collected, washed with water, dried and recrystallized from water to obtain 0.210 g (40% yield) of the title compound. melting point
268-270℃.

Elemental analysis (%): Calculated value (C ₁₁ H ₈ N ₂ O ₃ ):
C, 61.11; H, 3.73; N, 12.96 Actual value: C, 60.89; H, 3.87; N, 12.98 Example 4 3'-hydroxy-6'-fluoro-spiro [imidazolidine-4,1'-indan] 2,5-dione 6'-fluoro-spiro[imidazolidine-4,
1′-indane]2,5-dione (CAreg.
no.66892-38-4) (1.1 g, 5 mmol) in bis(trimethylsilyl)trifluoroacetamide
2.65 ml (10 mmol), bromine 0.8 g (5 mmol)
and 30 ml of ethylene dichloride and heated under reflux for 2.5 hours. During this time the reaction mixture was decolorized. The reaction mixture was concentrated in vacuo to a tan oil, which was diluted with 10 ml of water. A solid gradually formed over 16 hours at 25°C. This material was taken and dried in vacuo at 100°C to yield the title compound 1.0
g (yield 85%) was obtained. Melting point 209-211°C Example 5 6'-fluoro-spiro[imidazolidine-4,
1'-indan-3'-one]2,5-dione 3'-hydroxy-6'-fluoro-spiro[imidazolidine-4,1'-indan]2,5-dione (1.0 g, 4.2 mmol) Condensed with 0.424 g (4.2 mmol) of chromium trichloride in 25 ml of glacial acetic acid, 100
Heated at ℃ for 1 hour. The reaction was concentrated in vacuo to a dark foam and 25ml of water was added. A solid was formed, which was collected, washed with water, decolorized with activated carbon in methanol-water 1:1 (volume ratio), and recrystallized from methanol-water 1:1 to yield the title compound.
0.305g (yield 31%) was obtained. Melting point: 310℃ (decomposition).

Elemental analysis (%): Calculated value (C ₁₁ H ₇ FN ₂ O ₃ ):
C, 56.42; H, 3.01; N, 11.96 Actual value: C, 55.85: H, 3.22; N, 12.06 Example 6 4'-hydroxy-spiro[imidazolidine-
4,1′-1′,2′,3′,4′-tetrahydronaphthalene]2,5-dione spiro[imidazolidine-4,1′-1′,2′,3′,
4′-Hydronaphthalene]2,5-dione (CA
reg.no.57998-96-6) (4.33 g, 20 mmol) with 10.40 ml (40.4 mmol) of bis(trimethylsilyl)trifluoroacetamide and 3.69 g (23.1 mmol) of bromine in 40 ml of solvent chloroform.
The temperature was reduced to ℃. When this slurry was stirred for 60 hours, decolorization was observed. Pass the reactants;
The liquid was concentrated in vacuo to an oil. 15 ml of water was added to this solid and the resulting gummy solid was ground for 22 hours. The solid was collected and dried to yield 3.3 g (82% yield) of the title compound. Melting point 180-185℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₁₂ N ₂ O ₃ ):
C, 62.06; H, 5.21; N, 12.06 Actual value: C, 62.08; H, 4.78; N, 12.46 Example 7 Spiro[imidazolidine-4,1'-3'H-1',
2'-dihydronaphthalene-4'-one]2,5-
dione 4'-hydroxy-spiro[imidazolidine-
4,1'-1',2',3',4'-tetrahydronaphthalene]2,5-dione (10.0 g, 43.1 mmol) was condensed with 4.34 g (43.4 mmol) of chromium trioxide in 80 ml of glacial acetic acid. and stirred at 25°C for 1 hour. The reaction mixture was concentrated in vacuo and the resulting solid was triturated with water, taken and washed with water. The precipitate was dissolved in isopropanol and decolorized with activated carbon. The solvent was removed in vacuo and the solid was crystallized from isopropanol to yield 4.0 g (40% yield) of the title compound. Melting point 256-258℃ Elemental analysis (%): Calculated value (C ₁₂ H ₁₀ N ₂ O ₃ ):
C, 62.60; H, 4.38; N, 12.17 Actual value: C, 62.84; H, 4.75; N, 12.15 Example 8 Spiro[imidazolidine-4,1'-3'H-1',
2'-dihydronaphthalene-4'-one]2,5-
Dione 2,5-dioxo-4-phenyl-4-imidazolidinepropionic acid (CAreg.no.30741-72-
1) (2.48 g, 10 mmol) was first heated to 90°C for 1 hour, then to 120°C for 45 minutes in 25 ml of concentrated sulfuric acid,
Pour over 200g of ice. The resulting solid was taken and dried in vacuo at 100°C for 60 hours to yield 1.85 g of crude product.
(melting point 144-149°C) was obtained. This material was decolorized from an isopropanol solution with activated charcoal and recrystallized from isopropanol to yield 1.11 g of the title compound (yield 48
%) was obtained. Melting point 261-263℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₁₀ N ₂ O ₃ ):
C, 62.60; H, 4.38; N, 12.17 Actual value: C, 62.34; H, 4.51; N, 12.16 Example 9 Spiro[imidazolidine-4,1'-3'H-1',
2'-dihydronaphthalene-4'-one]2,5-
Dione 2,5-dioxo-4-phenyl-4-imidazolidinepropionic acid (CAreg.no.30741-72-
1) (2.48g, 10mmol) in polyphosphoric acid at 150℃
It was suspended in 25 ml. Gradual dissolution occurred and after 135 minutes the reaction was cooled to 25°C. Water (75ml) was added and the resulting crude solid was separated. This solid material was decolorized with activated charcoal as a solution in isopropanol and recrystallized from isopropanol to give 450 mg (17% yield) of the title compound. Melting point 262-263℃.

NMR (DMSO-d ₆ ): 10.98 (bs, 1H), 8.65 (bs,
1H), 8.03−7.30 (m, 4H) and 3.07−2.23
(m, 4H) ppm Example 10 7'-fluoro-spiro[imidazolidine-4,
1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 2,5-dioxo-4-m-fluorophenyl-4-imidazolidinepropionic acid (1.33 g, 5
mmol) with 15 ml of polyphosphoric acid and heated to 150℃.
The mixture was heated for 1.5 hours. The reaction mixture was cooled to 0°C,
Diluted with water. The dark solid was collected and partitioned between ethyl acetate and dilute aqueous sodium hydroxide solution (PH8). The ethyl acetate layer was extracted with a 10% aqueous sodium hydroxide solution, the aqueous layers were combined, decolorized with activated carbon, and adjusted to pH 3 with concentrated hydrochloric acid. The water was evaporated in vacuo and the resulting white solid was triturated with boiling isopropanol to remove sodium chloride. Filter the isopropanol solution and concentrate in vacuo to give the title compound.
Obtained 115 mg 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) and 2.45
−2.3 (m, 2H) ppm Example 11 7′-fluoro-spiro[imidazolidine-4,
1′-3′H-1′,2′-dihydronaphthalen-4′-one]2,5-dione 2,5-dioxo-4-m-fluorophenyl-4-imidazolidinepropionic acid (68.55 g,
0.26 mol) with 500 ml of concentrated sulfuric acid and heated to 75-77℃.
The mixture was heated for 2.5 hours. The reaction mixture was cooled to 25°C,
Pour onto ice to precipitate the solid, which was separated.
Dissolve this solid in 800 ml of methanol and
Decolorized with −60 activated carbon. When the methanol was removed in vacuo, a solid remained, which was mixed with methanol 75
Triturate and remove with ml. After washing with 30 ml of water, the solid was dried in vacuo at 80° C. for 2 hours to yield 52.07 g (81% yield) of the title compound. Melting point 229-231
℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₉ FN ₂ O ₃ ):
C, 58.07; H, 3.65; N, 11.29 Actual value: C, 57.86; H, 3.59; N, 11.39 Example 12 3'-bromo-spiro[imidazolidine-4,
1'-3'H-1', 2'-dihydronaphthalene-4'-one]2,5-dione spiro[imidazolidine-4,1'-3'H-1',
2'-dihydronaphthalen-4'-one]2,5-dione (2.08 g, 9 mmol) was condensed with 2.4 ml (9 mmol) of bis(trimethylsilyl)trifluoroacetamide and 20 ml of chloroform to give 1
The mixture was heated to reflux for an hour. Bromine (1.5 g, 9.4 mmol) in 10 ml of chloroform was added and reflux was continued for 40 minutes. At this point a white precipitate began to form. After refluxing for an additional 10 minutes, the reaction was cooled to 25°C.
The solid formed is separated and dried to give the title compound.
1.27g (yield 46%) was obtained. Melting point 221-224℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₉ BrN ₂ O ₃ ):
C, 46.63; H, 2.93; N, 9.06 Actual value: C, 46.42; H, 3.10; N, 9.12 Example 13 7'-methoxy-spiro[imidazolidine-4,
1′-3′H-1′,2′-dihydronaphthalen-4′-one]2,5-dione 2,5-dioxo-4-m-methoxyphenyl-4-imidazolidinepropionic acid (8.35 g, 30
mmol) was condensed with 60 ml of polyphosphoric acid at 150°C for 1 hour. The reaction mixture was cooled to 25°C and diluted with water. The resulting solid was collected, decolorized with activated carbon in an aqueous solution, and recrystallized from water to yield the title compound.
2.9 g (yield 37%) was obtained. Melting point 250-251℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₂ N ₂ O ₄ ):
C, 60.00; H, 4.65; N, 10.76 Actual value: C, 59.83; H, 4.71; N, 10.79 Example 14 7'-chloro-6'-methyl-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 4-(m-chloro-p-methylphenyl)-2,
5-Dioxo-4-imidazolidinepropionic acid (10.0 g, 34 mmol) was condensed with 150 ml of concentrated sulfuric acid and heated to 80°C for 2 hours. The reaction mixture was cooled to 25°C and poured onto ice. The resulting white solid was collected, washed with water, and dried to yield 8.78 g of crude product (yield: 94
%) was obtained. Melting point 260-265℃. The crude product was recrystallized from isopropanol-water to give the title compound 5.80
I got g. Melting point 277-278℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₁ N ₂ O ₃ Cl):
C, 56.03; H, 3.98; N, 10.05 Actual value: C, 55.63; H, 4.01; N, 9.96 Example 15 6'-Methyl-spiro[imidazolidine-4,
1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 2,5-dioxy-4-p-tolyl-4-imidazolidinepropionic acid (CAreg.no.30741 −74
-3) (2.85 g, 10.9 mmol) was condensed with 25 ml of concentrated sulfuric acid and heated to 95°C for 1.5 hours. The reaction mixture was poured onto ice, and the solid produced was collected, washed with water, and dried to obtain 1.88 g (yield: 71%) of a crude product.
Melting point 206-214℃. The crude product (1.76g) was recrystallized from isopropanol to give 1.12g of the title compound. Melting point 245-248℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₂ N ₂ O ₃ ):
C, 63.93; H, 4.95; N, 11.47 Actual value: C, 63.56; H, 5.15; N, 11.24 Example 16 7'-chloro-spiro[imidazolidine-4,
1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 2,5-dioxy-4-(m-chlorophenyl)
-4-Imidazolidinepropionic acid (5.42g,
20.0 mmol) was condensed with 40 ml of concentrated sulfuric acid, heated to 90°C for 3 hours, then cooled to 25°C and poured onto ice. The resulting solid was collected, dried and recrystallized from water to yield 2.61 g of material (melting point 202-230°C).
NMR analysis showed this material to be a mixture of starting propionic acid and desired product. Therefore, combine 2.4 g of this substance with 25 ml of concentrated sulfuric acid and heat at 120°C.
The mixture was heated for 3 hours. The reaction was cooled to 25° C., poured onto ice, and the solid formed was collected and recrystallized from water to give 700 mg (14% yield) of the title compound. melting point
279-280℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₉ N ₂ O ₃ Cl):
C, 54.58; H, 3.41; N, 10.60 Actual value: C, 54.42; H, 3.60; N, 10.42 Example 17 3'-Methyl-7'-fluoro-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 2,5-dioxy-4-m-fluorophenyl-4-imidazolineisobutyric acid (2.1 g, 7.5 mmol) was dissolved in concentrated sulfuric acid. The volume was reduced to 30 ml and heated to 115-120°C for 2 hours. The reaction mixture was poured onto ice and the quenched reaction mixture was stirred with activated carbon for 30 minutes. The reaction mixture was filtered through a diatomaceous earth filter, and the excess mass was poured into 250 ml of methanol under reflux and filtered again.
The residue was re-extracted with 250 ml of methanol and filtered.
The combined liquids were concentrated in vacuo to give a gum.
This gum was stirred in water for 3 hours, the white solid formed was collected and dried to give 0.85 g of the title compound.
(yield 43%). Melting point 216-220℃. Analytical samples were prepared by recrystallization from water. melting point
224-225℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₁ FN ₂ O ₃ ):
C, 59.54; H, 4.23; N, 10.68 Observed: C, _59.41 ; :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, ppm; subcomponents: 8.94 (s,
1H), 3.0 (m, 1H) and 1.18 (d, 3H) ppm Separation of diastereomers 3'-Methyl-7'-fluoro-spiro[imidazolidine-4,1'-3'H-1',2 A crude sample of 94.0 g of '-dihydronaphthalen-4'-one]2,5-dione was isolated according to the general procedure described above. According to nuclear magnetic resonance analysis, this crude sample consisted of the following three components. Racemate 4,1'(S)-3'(S)-spiro-
[Imidazolidine-4,1'(2'H)-3'H-naphthalene-4'-one]2,5-dione-3'-methyl-
7′-Fluor 5.85%; related 4,1′(S)-
71.70 mol% 3'(R) epimer and 22.44 mol% unclosed precursor carboxylic acid.

This mixture was suspended in 1.5 mL of acetonitrile under reflux, and 300 ml of methanol was added to obtain a solution. After decolorizing with activated carbon, the solution was concentrated to 800 ml by boiling off the solvent. A solid (13.04g) formed and was removed. By concentrating the mother liquor in vacuo to a solid, redissolving it in acetonitrile and boiling off the solvent.
It was concentrated to 300ml. A solid (39.44g) formed in the concentrate and was removed. When the mother liquor was allowed to stand, an additional 1.17 g of solid precipitated and was separated.
The mother liquor was concentrated in vacuum to give a glassy foam. After adding chloroform and stirring overnight
9.0 g of solid formed and was separated. The mother liquor was concentrated in vacuo to obtain a moist foam (25-30
g).

Add this foam to silica gel (230 to 400 mesh)
The product was loaded on a column and eluted with 5% methanol in chloroform to yield 6.77 g of a material consisting of only two components. Nuclear magnetic resonance spectroscopy reveals that this material is now racemic 4,1'(S)-3'(S)-spiro[imidazolidine-4,1'(2H)-3'H-naphthan-4'-one] ]2,5-dione-3'-methyl-7-
It was shown to be rich in fluorine (approximately 58.3 mol%). The other component consisted of racemic 4,1'(S)-3'(R) epimer corresponding to 41.7 mol%.

Zorbax-Sil preparative high pressure liquid chromatography columns and 5-20
A 58.3:41.7 diastereomer mixture was employed using a % isopropyl alcohol-hexane concentration gradient.
Six 250 mg samples were chromatographed and the peak exhibiting the shorter retention time was isolated. Similar fractions with shorter retention times are combined to determine the melting point.
369 mg of material was obtained at 196-199°C. This material was reanalyzed by high pressure liquid chromatography and showed one main peak with an area percentage of 97.449 and a retention time of 5.78 minutes, and an area percentage of 2.23 and a retention time of 6.33 minutes, an area percentage of 0.32 and a retention time.
Two sub-peaks with a time of 6.76 minutes were shown. Nuclear magnetic resonance spectroscopy shows that this substance with a retention time of 5.78 minutes is racemic rel4,1'(S)-3'(S)-spiro[imidazolidine-4,1'(2'H)-3'H-naphthalene- 4′−
2,5-dione-3'-methyl-7'-fluoro, the minor epimer found in the above product.

The main epilar in the above product is racemic rel4,
1′(S)-3′(R)-spiro[imidazolidine-4,
1'(2'H)-3'H-naphthalene-4'-one]2,5-
The dione-3'-memel-7'-fluoro was isolated with a purity of over 99 mol% by repeated crystallization from acetonitrile. According to this method, these 4,
1'(S)-3'(R) epimer has a melting point of 230-232°C,
and had a retention time of 6.34 minutes.

Example 18 (+)7'-Fluoro-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalene-
4'-one]2,5-dione (±)7'-fluoro-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalene-
4'-one]2,5-dione (24.62g, 0.099mol)
was dissolved in 700 ml of refluxing acetonitrile. To this solution was added 42.96 g (0.0993 mol) of brucine dihydrate. The acetonitrile mixture was heated to remove traces of insoluble material, and the liquid was allowed to cool to 25°C. The produced solid was collected and dried to obtain 26.83 g of salt. Melting point 229-230℃ (decomposition),
[α] ²⁰ _D +30.7° (methanol). This salt was recrystallized from acetonitrile to obtain 18.8 g of purified salt.
Melting point 230°C (decomposition), [α] ²⁰ _D +32.0° (methanol)
.

Purified salt (17.8g) in chloroform 500ml
It was decomposed by stirring with the same amount of water. Initially most of the salt dissolved and then new solids formed.
This new solid was taken and dried to yield 6.32 g of the title compound. Melting point 263-264℃, [α] ²⁰ _D +
203.5° (methanol).

The absolute configuration at center 4,1' was determined to be "S" based on single crystal X-ray analysis.

Example 19 3'-bromo-7'-fluoro-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 7'-fluoro - Spiro [imidazolidine-4,
1′-3′H-1′,2′-dihydronaphthalen-4′-one]2,5-dione (1.6 g, 6.4 mmol) was dissolved in 15 ml of glacial acetic acid with 1.13 g of bromine (7.1 mmol) and concentrated bromine. Combined with 1 ml of hydrogen acid and heated to 80°C for 10 minutes. At this point the bromine color disappeared. The reaction was concentrated in vacuo to yield a white solid, which was collected and dried to yield 1.9 g (91%) of the title compound.
I got it. Melting point 223-224℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₈ N ₂ O ₃ BrF):
C, 44.06; H, 2.47; N, 8.56 Actual value: C, 43.61; H, 2.61; N, 8.31 Example 20 7'-Methyl-spiro[imidazolidine-(4,
1′)-3′H-1′,2′-dihydronaphthalene-4′-
2,5-dione 2,5-dioxo-4-m-tolyl-4-imidazolidinepropionic acid (1.4 g, 5.3 mmol)
was combined with 25 ml of concentrated sulfuric acid and heated to 95°C for 30 minutes. The reaction mixture was poured onto ice, the resulting solid was collected, decolorized in hot water with Dalco G-60 activated carbon (obtained from ICI Americas), and crystallized from water to yield 420 mg of the title compound (32% yield). I got it. melting point
206℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₂ N ₂ O ₃ ):
C, 63.93; H, 4.95; N, 11.47 Found: C, 63.56; H, 4.91; N, 11.45 The used activated carbon was dried and extracted with methanol under reflux to yield 110 mg of the title product. (yield 8.5%). Melting point 202℃.

Example 21 5′,7′-dimethyl-spiro[imidazolidine-
4,1'-3'H-1',2'-dihydronaphthalene-
4'-one]2,5-dione 2,5-dioxy-4-m-xylyl-4-imidazolidinepropionic acid (1.0 g, 3.7 mmol) was combined with 20 ml of concentrated sulfuric acid and heated to 85°C for 45 minutes. , cooled to 25 °C and poured onto ice. The yellow-brown precipitate formed was collected, dried, dissolved in 200 ml of methanol under reflux and decolorized with Darco G60 activated carbon.
methanol solution. Concentrate in vacuo and dissolve the residue in water.
Triturated with 100 ml. The produced solid was collected and dried to obtain 630 mg (yield 70%) of the title compound.
Melting point 260-261℃.

Elemental analysis (%): Calculated value (C ₁₄ H ₁₄ N ₂ O ₃ ):
C, 65.11; H, 5.46; N, 10.85 Actual value: C, 64.80; H, 5.48; N, 10.73 Example 22 6'-chloro-spiro[imidazolidine-4,
1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 2,5-dioxy-4-p-chlorophenyl-
4-Imidazolidinepropionic acid (CAreg.
No. 30741-76-5) (5.0 g, 18 mmol) was condensed with 90 ml of concentrated sulfuric acid and heated to 115° C. for 16 hours. The reaction was cooled to 25°C, poured onto 800g of ice, and stirred for 2 hours. Dalco G-60 activated carbon was added and stirring continued for 1.5 hours. The reaction product was filtered through diatomaceous earth,
The liquid was washed with 400ml of water, and the filtered solid Dalco G-60 activated carbon and diatomaceous earth were washed with methanol.
Stir with 500 ml under reflux. After stirring for 30 minutes, the slurry was filtered again through diatomaceous earth and the clear material was concentrated in vacuo to yield 1.1 g of material.
This was shown by NMR to be a 1:1 mixture of starting material and title compound. Its 1.1g
was suspended in methanol and filtered to give the title compound.
0.31g (6%) was obtained. Melting point 258-261℃. An analytical sample was recrystallized from water to give the title compound. Melting point 265-266℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₉ N ₂ O ₃ Cl):
C, 54.46; H, 3.43; N, 10.58 Actual value: C, 54.21; H, 3.41; N, 10.40 Example 23 7'-fluoro-4'-hydroxy-3'-methyl-
Spiro [imidazolidine-4, 1'-1', 2', 3',
4'-tetrahydronaphthalene]2,5-dione 7'-fluoro-3'-methyl-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalene-4'-one]2 ,5-dione (1.31 g, 5.0 mmol) was suspended in 25 ml of methanol at 0°C, and 378 mg (10.0 mmol) of sodium borohydride was added. Dissolution occurred as the reaction progressed. After gas evolution ceased, the reaction was concentrated in vacuo to obtain a solid. This was dissolved in 15 ml of water, and 6N hydrochloric acid was added until the final pH was 1. A white solid is formed,
Take this, wash it with water, dry it and form the title compound.
1.0 g (yield 76%) was obtained. Melting point 278-281℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₃ N ₂ O ₃ F):
C, 59.09; H, 4.96; N, 10.60 Actual value: C, 58.00; H, 4.93; N, 10.46 Example 24 7'-fluoro-4'-hydroxy-spiro[imidazolidine-4,1'-1',2',3',4'-tetrahydronaphthalene]2,5-dione7'-fluoro-spiro[imidazolidine-4,
1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione (2.0 g, 8.1 mmol) was dissolved in 50 ml of methanol and cooled to 0°C. Sodium borohydride (0.6 g, 16.0 mmol) 15
It was added in small portions over a period of minutes. After stirring at 0° C. for 1 hour, the reaction mixture was poured into 10% hydrochloric acid and methanol was removed under reduced pressure. The resulting solid was collected, dried, and then recrystallized from water to yield 0.7 g (35% yield) of the title compound. Melting point 258-259℃.

Elemental analysis (%): Calculated value (C ₁₂ H ₁₁ N ₂ O ₃ F):
C, 57.59; H, 4.43; N, 11.20 Actual value: C, 57.70; H, 4.41; N, 11.31 Example 25 (-)7'-fluoro-spiro[imidazolidine-4,1'-3'H- 1′,2′-dihydronaphthalene-
4'-one]2,5-dione (±)7'-fluoro-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalene-
4′-one]2,5-dione 24.62g (0.099mol)
was dissolved in 700 ml of acetonitrile under reflux, and 42.96 g (0.104 mol) of brucine hydrate was added to this solution. The acetonitrile solution was heated to remove a small amount of insoluble material and then allowed to cool gradually. The formed crystals were removed from the acetonitrile mother liquor and the mother liquor was concentrated to obtain an oily foam. This material was triturated with ether to give 34.46 g of a tan solid. [α]
²⁵ _D -105.4° (methanol, C=1). This tan solid was dissolved in chloroform. At first the solid dissolved, but within a short time new solid began to form. This was taken to obtain 8.2g. Melting point 258-260
℃. Trituration with 500 ml of hot chloroform followed by filtration and drying yielded 7.54 g of solid. Melting point 260~
262℃. A portion of this solid material was washed with 0.1N hydrochloric acid, dried, and recrystallized from hot methanol to (-)7'-fluoro-spiro[imidazolidine-
4,1'-3'H-1',2'-dihydronaphthalene-4'-
2,5-dione was obtained. Melting point 264-265℃,
[α] ²⁵ _D = -197.9° (methanol, C = 1).

Example 26 (+)7'-fluoro-4'-hydroxy-3'-methyl-spiro[imidazolidine-4,1'-1',
2′,3′,4′-tetrahydronaphthalene]2,5
-dione (±)7'-fluoro-4'-hydroxy-3'-methyl-spiro[imidazolidine-4,1'-1',2',
3′,4′-tetrahydronaphthalene] 99.51 g (0.379 mol) of 2,5-dione was mixed with brucine dihydrate.
Combined with 171.0g (0.398 mol) and 1.4 ethanol
was dissolved under reflux. The ethanol solution was heated to remove a small amount of insoluble material and concentrated in vacuo to give a foam. Remove this foam with acetonitrile.
3.0 and put together under reflux. Some solids formed during this operation. The reaction was allowed to cool to 23°C. The produced solid was collected to obtain 128.96 g of solid. Melting point 222-224°C, [α] ²⁵ _D = -6.4° (methanol, C=1). Similarly, racemic alcohol
24.82 g of brucine salt was isolated from 20.34 g. melting point
224-226℃, [α] ²⁵ _D = -5.8 (methanol, C =
1). These salts were combined (153.78 g) and added to 1.5 g of acetonitrile under reflux. Boil off 200ml of acetonitrile and heat at 23°C for 20 hours.
It was left to cool until . The produced solid was separated and dried to obtain 137.63 g. Melting point 226-227℃, [α] ²⁵ _D =
3.6° (methanol, C=1), this material was suspended in boiling acetonitrile 1, allowed to cool to 23°C, and the resulting solid was collected and dried to yield 128.63g. Melting point: 227-228°C, [α] ²⁵ _D = +5.0° (methanol, C=1). The salt component was separated by suspending in chloroform 1 at 23°C for 1 hour, and then maintaining the reaction product at 23°C for 20 hours. The resulting solid was collected and dried to yield 45.45 g of the title compound. Melting point: 257.5-258.5°C, [α] ²⁵ _D = +120.1° (methanol, C=1).

The absolute configuration of centers 4, 1', 3' and 4' is:
4,1'S, 3'R and 4'S by combining recrystallization X-ray, nuclear magnetic resonance and chemical interconversion
It was determined that

Example 27 (+)7'-Fluoro-3'-methyl-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione ( +) 7′-fluoro-4′-hydroxy-3′-methyl-spiro[imidazolidine-4,1′-1′,2′,
40.45 g (0.153 mol) of 3',4'-tetrahydronaphthalene]2,5-dione were combined with 15.31 g (0.153 mol) of chromium trioxide in 250 ml of glacial acetic acid, and the reaction temperature was maintained at 25°C. After 1.5 hours the reaction was concentrated in vacuo to give a crude solid. water this solid
Grind together with 150ml, remove the generated solid, and add water.
Washed twice with 125 ml each. Dry this substance
Recrystallization from acetonitrile (after decolorization with Dalco G-60 activated carbon) gave 25.05 g of the title compound. Melting point: 250-251°C, [α] ²⁵ _D = +231.1° (methanol, C=1).

Elemental analysis (%): Calculated value (C ₁₃ H ₁₁ N ₂ O ₃ F):
C, 59.54; H, 4.23; N, 10.68 Observed values: C, 59.36; H, 4.38; N, 10.70 The absolute configurations at centers 4, 1' and 3' were determined by single crystal It was determined to be “R”.

Example 28 (−)7′-fluoro-4′-hydroxy-3′-methyl-spiro[imidazolidine-4,1′-1′,
2′,3′,4′-tetrahydronaphthalene-]2,
5-dione Solid of Example 26 [Melting point 226-227°C, [α] ²⁵ _D =+
After removing 137.63 g of 3.6° (CH ₃ OH, C=1), the acetonitrile mother liquor was concentrated in vacuo to give a foam. The foam was stirred with 1 portion of chloroform to form a solid, which was collected and thoroughly washed 5 times with 1 portion of chloroform to yield 48.22 g of the title compound. Melting point 253-254℃ (decomposition),
[α] ²⁵ _D = -114.2° (CH ₃ OH, C = 1).

Example 29 (-)7'-fluoro-4'-methyl-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalen-4-one]2,5-dione (- )7'-Fluoro-4'-hydroxy-3'-methyl-spiro[imidazolidine-4,1'-1',2',
39.6 g (0.15 mol) of 3',4'-tetrahydronaphthalene]2,5-dione were combined with 15.0 g (0.15 mol) of chromium trioxide in 200 ml of glacial acetic acid and stirred at 25°C. Some cooling was required until the initial heat generation ceased. After 2 hours, thin layer chromatography analysis showed that the reaction was essentially complete. The reaction was concentrated in vacuo to give a dark solid. This was triturated with water to obtain a solid. This solid was washed with water until the washings became colorless and then dried to obtain 36.82 g of a crude product. Recrystallization of this product from acetonitrile (after decolorization with activated carbon mixed with diatomaceous earth) gives the title compound at 21.50
g as a white crystalline solid. Melting point 149~
150.5°C (decomposition), [α] ²⁵ _D = -223.4° (CH ₃ OH, C
=1).

Example 30 (±)7'-Fluoro-3'-methyl-spiro[imidazolidine-4,1',3'H-1',2'-dihydronaphthalen-4-one]2,5-dione Crude 3 97.4 g of '-methyl-7'-fluoro-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione described in Example 17 Manufactured according to the general method. By examining nuclear magnetic resonance, this crude product was identified as 2,5-
It was shown to contain dioxo-4-(m-fluorophenyl)-4-imidazolidinepropionic acid and two dihydronaphthalen-4-one products. High pressure liquid chromatography analysis (5-20% isopropanol-hexane concentration gradient,
seg, 10 minutes long, 2 on Zolbax-sil column
ml/min flow rate using a Dupont Series 8800 instrument), the earlier eluting subcomponent dihydronaphthalene had a peak area of 9.44% of the peak attributable to the dihydronaphthalen-4-one product (detector 254 nm). It was shown that 94.0 g of this crude product was suspended in 1.5 g of acetonitrile under reflux. Methanol was added until dissolution occurred. The solution was decolorized using activated carbon mixed with diatomaceous earth, filtered and concentrated by boiling off the solvent to 800 ml. At this point a solid forms,
Separately dry this and 13.04 g of 4-(m-chlorophenyl)-4-imidazolidine propionic acid.
(melting point 247-251°C) was obtained. The acetonitrile-methanol mother liquor was concentrated in vacuo, redissolved in acetonitrile and concentrated by boiling to 300ml.
39.44 g of solid (melting point 222-227°C) was formed and separated. Leave it at 25℃ for 2 days, then add 1.17
g of solid (melting point 208-212°C) was separated. The mother liquor was concentrated in vacuo to give a glassy foam. This foam was stirred with chloroform and after stirring overnight a solid formed and 9.0 g of material was isolated. Melting point: Shrinkage 199-201°C (decomposition) at 181°C. The mother liquor was concentrated in vacuo to give a foam. This is about 25~
30g and contained trapped solvent.

The foam was loaded onto a column of silica gel (230-400 mesh) and eluted with 5% methanol in chloroform. Dihydronaphthalene-4
The fractions containing the -one product were collected and concentrated in vacuo to yield 6.77 g of material. Its composition, determined by nuclear magnetic resonance analysis, was a 58.3:41.7 mole % mixture of two diastereomers. This substance was analyzed by high pressure liquid chromatography, and compared to the later eluted peak with a peak area of 42.82, the earlier eluted peak had a peak area of 57.18, which was consistent with nuclear magnetic resonance analysis.

The analyzed enriched fraction (1.5 g) was separated by preparative high-pressure liquid chromatography with 6 injections onto a preparative Zolbax-Sil column (5-20%
Isopropanol-hexane concentration gradient, flow rate 40
ml/min, detector 300nm). The earlier eluting main peak fractions were collected and concentrated in vacuo to yield 369 mg of solid. Melting point 196-199℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₁ N ₂ O ₃ F):
C, 59.54; H, 4.23; N, 10.68 Observed: C, 59.22; H, 4.29; N, 10.53 High pressure liquid chromatography analysis indicated that this material was enriched in early eluting diastereomers. . According to the peak area, the sample composition was 97.49% of the diastereomers that eluted earlier;
The amount was 2.23% of an unidentified by-product that was eluted later.
According to a combination of spectral and single crystal X-ray analysis, the structure of the 97.49% racemic component is
They were rel4, 1′S, and 3′S.

Example 31 (±)7'-chloro-3',3'-dimethyl-spiro[imidazolidine-4,1'-1',2'-dihydronaphthalen-4-one]2,5-dione 2,5 -dioxo-3,3-dimethyl-4-
(m-Chlorphenyl-4-imidazolidinepropionic acid (0.62 g, 2 mmol) was combined with 4 ml of concentrated sulfuric acid and heated to 70°C for 4 hours. The reaction was poured onto ice and the solid formed was collected and washed with water. , dried to obtain 412 mg of solid. This solid was placed in hot acetonitrile and decolorized with activated carbon mixed with diatomaceous earth.
The white solid formed upon cooling was collected and dried to yield 140 mg of the title compound. Melting point 264-266℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₁ O ₃ N ₂ F):
C, 57.44; H, 4.48; N, 9.57 Actual value: C, 57.26; H, 4.51; N, 9.63 Example 32 (±)3',3'-dimethyl-spiro[imidazolidine-4,1'-1 ′,2′-dihydronaphthalene-
4'-one]2,5-dione 2,5-dioxo-3,3-dimethyl-4-phenyl-4-imidazolidinepropionic acid (26.94 g, 0.1 mol) was combined with 135 ml of concentrated sulfuric acid;
Heated to 70°C for 5 hours, then poured onto ice. A solid forms, which is collected and dried to give the crude product.
21.04g was obtained. The crude product (19.35 g) was dissolved in 150 ml of 1N sodium hydroxide and decolorized with activated carbon mixed with diatomaceous earth. This basic solution was adjusted to pH 7 with hydrochloric acid, and the resulting solid was collected and washed twice with water. The process was repeated again and the resulting solid was partitioned between 75 ml of dilute hydrochloric acid and 400 ml of ethyl acetate.
The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield 12.54 g of the title compound.
I got it. Melting point 229-231℃.

Elemental analysis (%): Calculated value (C ₁₄ H ₁₄ O ₃ N ₂ ):
C, 65.10; H, 5.46; N, 10.85 Actual value: C, 64.74; H, 5.53; N, 10.74 Example 33 (±)7'-chloro-3'-methyl-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalen-4'-one]2,5-dione 2,5-dioxo-3-methyl-4-(m-chlorophenyl-4-imidazolidinepropionic acid (10.72 g , 36.1 mmol) were combined with 55 ml of concentrated sulfuric acid and heated to 70° C. for 5 hours.The reaction mixture was poured into ice water and the solid formed was collected, washed with water and dried to give 7.96 g of crude product. Crude product (7.76g)
was dissolved in 400 ml of boiling acetonitrile, decolorized with activated carbon, filtered, and allowed to cool to 25°C. The resulting solid was collected and dried to give the title compound 4.48
I got g. Melting point 232~234℃ (partial melting), 255~
257° (decomposition) Elemental analysis (%): Calculated value (C ₁₃ H ₁₁ O ₃ N ₂ Cl):
C, 56.02; H, 3.98; N, 10.05 Actual value: C, 56.17; H, 4.08; N, 10.13 Example 34 (+)7'-Fluoro-3'-benzyl-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalene-4'-one]2,5-dione(+)7'-fluoro-3'-benzylidene-spiro[imidazolidine-4,1] dissolved in 100 ml of ethanol '-1',2'-dihydronaphthalene-4'-one]2,5-dione (1.02 g, 3.16 mmol)
Hydrogenation was performed using 100 mg of 5% palladium on carbon for 1.5 hours at atmospheric pressure and room temperature. Separate the catalyst
Ethanol was removed in vacuo to obtain the crude product.
This was recrystallized from isopropanol to obtain 794 mg of the title compound as a mixture of diastereomers.

The subcomponent diastereomer could be isolated by the following method. The above mixture (794 mg) was mixed with 0.656 ml of triethylamine in 60 ml of ethanol.
Contact was carried out for 1 day and then concentrated in vacuo to give a solid. Recrystallize this from acetonitrile to 330mg
A solid was obtained. The mother liquor was concentrated in vacuo and the residue was recrystallized again to give 130 mg of solid. The resulting mother liquor was concentrated in vacuo and recrystallized from ethanol to obtain a solid. After washing this with diethyl ether and drying, 33 mg of the subcomponent diastereomer was obtained. Melting point 225-226℃. [α] ²⁵ _D = 120° (methanol,
C=1). High-resolution mass spectrum: Calculated value (per C ₁₉ H ₁₅ N ₂ O ₃ F): 338.1067; Actual value:
338.1067.

The main component diastereomer could be isolated as follows.

(+)7-Fluoro-3-benzylidene-spiro[imidazolidine-4'-1',2'-dihydronaphthalen-4'-one] Using 672 mg (2 mmol) of 2,5-dione, the above hydrogenation The reaction conditions were employed to isolate a crude product consisting primarily of one diastereomer. Recrystallization from isopropanol gave 460 mg of the main diastereomer. melting point
238-240℃. [α] ²⁵ _D = -31° (methanol, C=
1).

Example 35 Compounds of the formulas of Examples 1 to 34 were prepared as described in U.S. Pat.
According to the method described in No. 3821383, the ability to reduce or inhibit the activity of aldose reductase was tested based on the method of Hayman et al. [Journal of Biological Chemistry, 240877 (1965)]. When the same compound was produced by two or more methods, the binding of the test compound was equal regardless of the method of production. The substrate used was partially purified aldose reductase obtained from human placenta. The compounds were tested at levels of 10 ^-4 to ^{10 -9} M and were found to inhibit enzyme activity compared to untreated controls.

Production example A 2,5-dioxo-4-m-fluorophenyl-4-imidazolinepropionic acid m-fluorobenzene-γ-oxobutanoic acid (1.57 g, 8 mmol) [Eur.V.Med.Chem., 13 ,
533 (1978)] to 7.7 g of ammonium carbonate in 60 ml of water.
(80 mmol) was combined with 1.04 g (16 mmol) of potassium cyanide and heated to 70° C. for 20 hours. Cool the reaction mixture to 25 °C and adjust the acidity to PH with concentrated hydrochloric acid.
Adjusted to 2. The resulting pale yellow solid was isolated by filtration and dried in vacuo at 100°C to yield the title compound.
1.8g (85% yield) was obtained. Melting point 206-208℃.

(DMSO−d ₆ ) 11.0 (bs, 1H), 8.86 (bs, 1H),
7.67-6.83 (m, 4H) and 2.25 (bs, 4H) ppm Preparation Example B 2,5-dioxo-4-m-methoxyphenyl-4-imidazolinepropionic acid m-methoxybenzene-γ-oxobutanoic acid (CAreg. No. 38102-67-9) (10.0 g, 48 mmol) was combined with 22.75 g (235 mmol) ammonium carbonate, 6.5 g (100 mmol) potassium cyanide in 100 ml ethanol and 100 ml water at 65°C. 22.75g more after being kept at 65℃ for an hour.
(235 mmol) of sodium carbonate was added and heating continued for 18 hours. Concentrate the reaction mixture in vacuo,
It was triturated with water and the acidity was adjusted to PH4 with concentrated hydrochloric acid. Take the generated white solid and store it in vacuum at 80℃.
10.6 g of the title compound (yield 79%)
I got it. Melting point: 138℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₄ N ₂ O ₅ ):
C, 56.11; H, 5.07; N, 10.07 Actual value: C, 55.46; H, 5.02; N, 10.02 Production example C 2,5-dioxo-4-m-nitrophenyl-
4-Imidazolinepropionic acid The method of Preparation Example A was employed to prepare the title compound. The starting material was 3-nitrobenzene-γ-oxobutanoic acid rather than the 3-fluorobenzene compound.

Production Example D 2,5-dioxo-4-(m-chloro-p-methylphenyl)-4-imidazolidinepropionic acid m-chloro-p-methylbenzene-γ-oxobutanoic acid (22.7 g, 100 mmol) [Bull. Chem.
Soc. Jap., 52 , 2441-42 (1979)] with 90 g (0.94 mol) of ammonium carbonate and 13.7 g (210 mmol) of potassium cyanide in 300 ml of water;
Heated to 65°C for 22 hours. The reaction mixture was cooled to 25°C, and the resulting solid was collected and suspended in 200ml of water.
The aqueous suspension was adjusted to pH 2 with concentrated hydrochloric acid, and the resulting solid was collected and washed with water to yield 27.8 g (94 g) of the title compound.
%) was obtained. Melting point 196-199℃ Production example E 2,5-dioxo-4-(m-chlorophenyl)
-4-Imidazolidinepropionic acid 3-chlorobenzene-γ-oxobutanoic acid (C.
A.reg.no.62903-14-4) (10.6g, 50mmol)
was combined with 47.2 g (490 mmol) ammonium carbonate and 6.5 g (100 mmol) potassium cyanide in 100 ml water and heated to 65° C. for 65 hours. The reaction mixture was cooled to 0°C. Take the formed precipitate,
Stirred in 100ml of water. Aqueous PH by adding concentrated hydrochloric acid
Adjust to 0.5, take the generated solid, and add 300ml of water.
Wash and dry the crude title compound 114.7
g (yield 84%) was obtained. Melting point 196-217°C (decomposes and turns purple).

Production example F 2,5-dioxo-4-m-tolyl-4-imidazolidinepropionic acid 3-methylbenzene-γ-oxobutanoic acid (C.
A.reg.no.59618-44-9) (3.0g, 10mmol)
was combined with 14.0 g (144 mmol) ammonium carbonate and 2.2 g (34 mmol) potassium cyanide in 50 ml water and heated to 65-70°C for 22 hours. The reaction mixture was cooled and brought to pH 2 with concentrated hydrochloric acid, resulting in the precipitation of a solid. This solid was weighed, washed with water, and dried to obtain a crude product. Melting point 173-178
℃. The crude product was dissolved in boiling water to remove an insoluble orange gum. The resulting aqueous solution was concentrated in vacuo to yield 1.34 g (32% yield) of the title compound. Melting point 195-198℃.

Elemental analysis (%): Calculated value (C ₁₃ H ₁₄ N ₂ O ₄ ):
C, 59.54; H, 5.38; N, 10.68 Actual value: C, 59.25; H, 5.30; N, 10.32 Production example G 2,5-dioxo-4-m-xylyl-4-imidazolidinepropionic acid 3,5- Dimethylbenzene-γ-oxobutanoic acid (CAreg.no.36440-58-1) (3.5g) was added to 50% of water.
14 g (146 mmol) of ammonium carbonate and 2.2 g (33.8 mmol) of potassium cyanide in ml and heated to 60° C. for 26 hours. reaction mixture
Cool to 25°C and filter the oil. Adjust the pH of the liquid to 3.5 with concentrated hydrochloric acid, remove the white precipitate,
After drying, 1.0 g (22% yield) of the title compound was obtained. Melting point 232-234℃.

Production Example H 3-(m-fluorobenzoyl)-2methylpropionic acid 6.5 g (0.10 mol) of powdered potassium cyanide was added to 180 ml of dry dimethylformamide. The slurry was heated to 80°C for 30 minutes with thorough stirring and then cooled to 35°C. A solution of 124.1 g (1.0 mmol) of m-fluorobenzaldehyde in 50 ml of dimethylformamide was added dropwise over a period of 50 minutes, during which time the reaction temperature was maintained at 30.degree. 67.1 g of methacrylonitrile dissolved in 50 ml of dimethylformamide after a further 30 minutes at ambient temperature
(1.0 mol) was added over 20 minutes. After 3 hours at ambient temperature, the reaction was filtered, poured into 1500 ml of water, and the oily organic layer was separated. A saturated brine solution was added to the aqueous layer, which was then dissolved in chloroform 3x.
Extracted with 150ml. Combine the organic layer parts and add dilute sulfuric acid,
Washed successively with dilute aqueous sodium bicarbonate solution and water. After drying over anhydrous sodium sulfate, the chloroform was removed in vacuo at a temperature not exceeding 35°C, yielding 199.8 g of a crude oil.
Add 200 ml of concentrated hydrochloric acid to this oil to reduce the reaction mass to 125
℃ for 3 hours. The reaction was cooled to 60°C and the supernatant hydrochloric acid was decanted from the heavier red oil. The oil solidified as it cooled. Dissolve the red oil/solid in 500ml of 3N sodium hydroxide;
The aqueous layer was extracted with 4 x 250 ml of diethyl ether. After cooling in an ice bath, the aqueous layer was adjusted to pH 2 with concentrated hydrochloric acid, and a pale pink solid precipitated. Take this and dry it to produce 3-(m-fluorobenzoyl).
84.4 g (yield: 40%) of -2-methylpropionic acid was obtained. Melting point 90-91℃.

Production Example I 2,5-dioxo-3,3-dimethyl-4-
(m-Chlorphenyl)-4-imidazolidinepropionic acid 3-(m-chlorobenzoyl)-2,2-dimethylpropionic acid (14.4 g, 0.06 mol) in 50 ml of water with 28.8 g (0.3 mol) of ammonium carbonate and potassium cyanide. Combine with 7.81g (0.12mol),
Heated to 70°C for 24 hours. A further 5.7 g of ammonium carbonate was added and heating at 70°C was continued for 60 hours.
The reaction mixture was cooled in an ice bath and concentrated hydrochloric acid was added. The resulting tan solid was collected, washed with water, and dried to obtain 17.34 g of crude product. This material was loaded onto a column of silica gel, first with 5% methanol in chloroform and then with 10% methanol in chloroform.
Elution with methanol gave 3.21 g of the title compound as a yellow solid. Melting point 198-200℃ (decomposition).

Production Example J 3-(m-chlorobenzoyl)-2,2-dimethylpropionic acid The method of T. Joyima et al. [Bull.
Chem.Soc.Jap., 52(8)2441-2442 (1979)] to chlorinate 3-benzoyl-2,2-dimethylpropionic acid in the presence of excess ammonium chloride to produce the title compound. changed to

Production example K 2,5-dioxo-3-methyl-4-(m-chlorophenyl)-4-imidazolidinepropionic acid 3-(m-chlorobenzoyl)-2-methylpropionic acid (10.36 g, 0.046 mol) was dissolved in water. together with 24.02 g (0.25 mol) of ammonium carbonate and 6.5 g (0.10 mol) of potassium cyanide in 150 ml;
Heated to 70°C for 23 hours. The reaction mixture was cooled to 20°C and acidified with concentrated hydrochloric acid. A gummy solid forms, which is filtered and dissolved in diethyl ether,
The diethyl ether solution was washed with 25 ml of water. The diethyl ether layer was concentrated in vacuo to a yellow-white solid, which was dried overnight at 70°C in a vacuum oven.
5-Dioxo-3-methyl-4-(m-chlorophenyl)-4-imidazolidinepropionic acid 11.28
I got g. Melting point 183~185℃ (partial melting), 189~
200℃ (decomposition).

Preparation Example L 3-(m-chlorobenzoyl)-2-methylpropionic acid Sodium cyanide (1.47 g, 30 mmol) was combined with 100 ml of N,N-dimethylformamide;
It was then stirred for 1 hour at 30°C under nitrogen to obtain a clear solution. Add N,N-dimethylformamide to this solution.
3-chlorobenzaldehyde dissolved in 50ml 34.0
ml (0.3 mol) was added dropwise over 1 hour. 35
After stirring for a further 1 hour at °C, 25.0 ml of methacrylonitrile in 50 ml of N,N-dimethylformamide
(0.3 mol) was added dropwise over 2 hours and the reaction mixture was stirred at 25° C. for 16 hours. Methylene chloride (200 ml) and 4.0 g of diatomaceous earth were added to suspend the mixture and filter. liquid
0.22N hydrochloric acid 500ml, water 200ml each twice, 2.5% sodium bicarbonate aqueous solution 200ml, 1N hydrochloric acid 200ml, water
200 ml, and 200 ml brine. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated in vacuo to yield crude 3-(m-chlorobenzoyl)-2-methylpropionitrile.
Obtained 49.65 g as a yellow solid. Melting point: Partial melting at 50℃, melting at 79-81℃. 15.57g of this product
(0.075 mol) was combined with 25 ml of concentrated hydrochloric acid and 25 ml of formic acid and heated to reflux for 2.5 hours. After cooling, 150 ml of water was added, and the aqueous solution was extracted twice with 150 ml each of ethyl acetate. The ethyl acetate extract was then extracted twice with 150 ml each of 20% sodium hydroxide in water. The aqueous extract was acidified with concentrated hydrochloric acid to precipitate a solid, which was collected, washed with water, and dried to yield 10.86 g of 3-(m-chlorobenzoyl)-2-methylpropionic acid.
(melting point 100-102°C) was obtained.

Production example M (±)7'-fluoro-3'-benzylidene-spiro[imidazolidine-4,1'-1',2'-dihydronaphthalen-4'-one]2,5-dione (+)7'-Fluoro-spiro[imidazolidine-4,1'-3'H-1',2'-dihydronaphthalene-
4'-one]2,5-dione (1.24 g, 5 mmol) (Example 19) was combined with 531 mg (5 moles) of benzaldehyde, 14 ml of glacial acetic acid and 2.3 ml of concentrated hydrochloric acid. This suspension was stirred for 64 hours to obtain a clear solution. The solution was poured into ice water, and the solid produced was collected, washed with water, and dried. Product 2.48 of Example 19
Repeat the reaction using g and isopropanol-
After recrystallization from water (95:5) (+)7'-fluoro-3'-benzylidene-spiro[imidazolidine-4,1'-1',2'-dihydronaphthalene-4'-
1.62 g of 2,5-dione was obtained. Melting point 290~
292°C, [α] ²⁵ _D = 121° (CH ₃ OH, C = 1).

Elemental analysis (%): Calculated value (C ₁₉ H ₁₂ O ₃ N ₂ ClF):
C, 67.85; H, 3.90; N, 8.33 Actual value: C, 68.07; H, 4.01; N, 8.28 Production example N (±) 7-fluoro-3-methylspiro [3,
4-dihydronaphthalene-1(2H),5'-oxazolidine]2',4'-dione The title compound is named using Chemical Abstracts nomenclature, where U is an oxygen atom, X is a methyl group, and W corresponds to a compound of formula _9b , where is a methylene group, Y is a fluorine atom, and Z is a hydrogen atom.

7-fluoro-1-hydroxy-3-methyl- in 100 ml of dry tetrahydrofuran was placed in a 250 ml flask equipped with a nitrogen inlet, a thermometer, a gas inlet, and a gas outlet leading to an effective trap for trapping phosgene gas. 2.51 g (10.0 mmol) of tetralin carboxyimidic acid ethyl ester and 2.92 ml (21.0 mmol) of triethylamine were charged. The reaction was cooled to 0° C. under nitrogen and phosgene gas was passed through tetrahydrofuran by gas bubbling for 0.5 h. The reaction was warmed to 25 °C, poured onto 500 ml of crushed ice in a well-ventilated hood, and the mixture was dissolved in 300 ml of methylene chloride.
Extracted twice. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo.
2.463 g of a dark brown rubbery solid was obtained. Nuclear magnetic resonance analysis of this solid in deuterochloroform
The product was shown to be a 2:1 mixture of diastereomers. The main diastereomer is
Aromatic multiplet (duplex doublet) from 6.90 to 6.96ppm
showed that. Diastereomer, which is a minor component, is 6.80
An aromatic multiplet (double doublet) was observed at ~6.87 ppm. This diastereomeric mixture was used in Example 36.

A crystalline mixture of diastereomers in a 2:1 ratio was obtained by trituration with ether-petroleum ether.
Melting point 155-163℃. A crystalline mixture containing a 9:1 ratio of diastereomers with an aromatic multiplet between 6.80 and 6.87 ppm to diastereomers with an aromatic multiplet between 6.90 and 6.96 ppm precipitates on addition of petroleum ether from diethyl ether. It was obtained by Melting point 167-171℃.

Production example O (±)7-fluoro-1-hydroxy-3-methyltetralincarboximidic acid ethyl ester This intermediate is 7-fluoro-3-methyl-α-
From tetralone, the method described by Rodney C. Chunneur et al. (J.Med.Chem., 1982, 25, 1451
-54), by converting this ketone into trimethylsilylcyanohydrin and then into the α-hydroxyimidate ester described above.

Claims (1)

[Claims] Linear formula [In the formula, U is NH; n is 0 or 1; W is a carbonyl group or a hydroxymethylene group; R is a hydrogen atom; X is a hydrogen atom, a bromine atom, methyl, dimethyl,
or benzyl, where when X is dimethyl, n is 1; Y is a hydrogen atom, a halogen atom, methoxy or methyl; and Z is a hydrogen atom, chlor or methyl; or Pharmaceutically acceptable salts thereof. 2 n is 0, W is carbonyl group, X, Y and Z
are each a hydrogen atom or X and Z
The compound according to claim 1, wherein each is a hydrogen atom and Y is a fluorine atom. 3 n is 0, W is hydroxymethylene group, X, Y
and Z are each a hydrogen atom or
The compound according to claim 1, wherein and Z are each a hydrogen atom and Y is a fluorine atom. 4 n is 1, W is carbonyl group, X, Y and Z
are each a hydrogen atom, claim 1
Compounds described in Section. 5 n is 1, W is a carbonyl group, X is a hydrogen atom,
The compound according to claim 1, wherein Y is a fluorine atom and Z is a hydrogen atom. 6 n is 1, W is a carbonyl group, X is a bromine atom,
The compound according to claim 1, wherein Y and Z are each hydrogen atoms. 7 n is 1, W is a carbonyl group, X is a methyl group,
The compound according to claim 1, wherein Y is a fluorine atom and Z is a hydrogen atom. 8 n is 1, W is carbonyl group, X is dimethyl,
The compound according to claim 1, wherein Y is a chlorine atom and Z is a hydrogen atom. 9 n is 1, W is hydroxymethylene group, X, Y
and Z are each a hydrogen atom or
The compound according to claim 1, wherein and Z is a hydrogen atom and Y is a fluorine atom. 10. The compound according to claim 1, wherein n is 1, W is a hydroxymethylene group, X is a methyl group, Y is a fluorine atom, and Z is a hydrogen atom.