FI62307B - FOERFARANDE FOER FRAMSTAELLNING AV SPIRO (KROMAN-ELLER -TIOKROMAN-4,4'-IMIDAZOLIDINE) -2 ', 5'-DIONER OCH DYLIKA TIOKROMANERS OXIDATIONSPRODUKTER VILKA AER ANVAENDBARA VID BEHANDLING AV DIABET - Google Patents

Description

RSF ^ l [B] (1i) ANNOUNCEMENT.SU. 9 - l J 1 'utlAggningsskrift oZouv ^ * (51) ICv.lk.3 / lnt.CI.3 C 07 D 491/107. r (Y '| \ \ SUOM I —Fl N LAN D (21) Pwunttltakumu · - PttuntamBkftlnf 7T3o6o (22) Hak «mlipllvt —AmOfcnlngtdai lU.10.77 ^ ^ (23) AlkupUvt — GIMgh« tsd «g lU.10.77 (41) ) Gotten slipped - vests offunttlf 19.0 ^. 78

Futmtti · and the National Board of Registration / 44) NlhtIvtk * lpunon j »kuL | of

Patent- och registerstyreleen Antttkan utltfd och uti.skrifton publteered 31 · 08.82 (32) (33) (31) Requested «vulgarity — Bujird prlorltut 18.10.76 11.02.77 USA (US) 733062, 767803 (71) Pfizer Inc., 235 East U2nd Street, New York, NY, USA (US) (72) Reinhard Sarges,% stic, Connecticut, USA (US) (7U) Oy Kolster Ah (5I +) Method for the development of new spiro (chromania or thiochromane) suitable for the treatment of diabetes for the preparation of oxidation products of β-imidazolidine) β *, 5'-diones and such thiochromanes - Förfarande för framställ-Ning av spiro (chroman-eller-thiochroman-U, b'-imidazolidine) -2 *, 5'-dione The present invention relates to a process for the preparation of novel spiro (chroman or hexochroman-U, V-imidazolidine) -2 ', 5 * -diones and oxidation products of such thiochromanes which are suitable for the treatment of diabetes, the compounds have the formula y0 hn-γ T- where W is 0, S, SO or SOp, and W is 0, and are lower than a alkyl groups or chlorine atoms or X 1 is hydrogen and X 1 is fluorine, hydroxy or lower alkoxy, and when W is S X "'is hydrogen and X 1 is chlorine, fluorine, bromine or lower alkoxy or 2 is. .1 2 X and X are chlorine atoms, and when W is SO or SC> 2 X is hydrogen and X is hydrogen or fluorine and for the preparation of pharmaceutically acceptable base salts of these compounds.

The compounds of the invention are effective against certain additional diseases caused by diabetes (e.g., lens opacities and neurological diseases caused by diabetes).

GB 818 J2h discloses spiro (imidazolidine-k, 1'-indan) -2,5 ′ diones which can be used as anticonvulsants.

DE 1 135 915 discloses spiro (chroman and thiochroman-'-imidazolidine) -2,5-diones which have been reported for use in the treatment of additional diseases of diabetes. The two compounds of this DE publication, spiro (Chroman-k, U'-imidazolidine) -2 *, 5'-dione and 6-chlorospiro (chroman-α} k * -imidazolidine) -2 ', 5'-dione has been used as a reference compound in the pharmacological tests described below.

L. H. Goodson et al., Journal of Organic Chemistry, vol. 25, p. 1920 (1960) have described spiro (imidazolidine-α, 1'-indan) -2,5-diones which have been reported to have anti-cancer activity.

Recently, many researchers in the field of organic pharmaceutical chemistry have sought different ways to find new and better oral antidiabetic drugs. The main focus has been on the synthesis and experimentation of various novel organic compounds, especially sulfonylureas, in order to determine their ability to lower blood glucose (i.e., glucose) when administered orally. In the search for new and increasingly effective therapeutic agents for diabetes, little attention has been paid to other organic compounds that prevent or stop certain additional diseases of diabetes, e.g., myocardial infarction, neurological disease, and retinal disease, however, K. Sestanj et al. U.S. Patent No. 3,821,383 has disclosed that certain aldose reductase inhibitors, such as 1,3-dioxo-1H-benzo [4,17] isoquinoline-2 (3H) -acetic acid, and some of its related derivatives, are useful in this regard, although it is these compounds that are not known to lower the sugar content. All of these aldose reductase inhibitors work by blocking the action of the enzyme aldose reductase, which in the human body primarily regulates the reduction of aldoses (e.g., glucose and galactose) to polyols (e.g., sorbitol and galactitol). In this way, the unwanted accumulation of galactitol in the lens of individuals with galactose hemorrhage and the accumulation of sorbitol in the lens, peripheral nerve body and kidneys of diabetics are prevented or reduced. Thus, these compounds are clearly useful as aldose reductase inhibitors in the treatment of certain additional chronic diseases of diabetes, e.g. eye diseases, as it is already known in the art that polyols in the lens of the eye inevitably lead to lens opacification.

The compounds of formula I prepared according to the invention have surprisingly been found to be very useful as aldose reductase inhibitors when administered to individuals suffering from certain additional diseases of diabetes. In particular, these compounds are effective in treating chronic ophthalmic diseases associated with diabetes in a person suffering from diabetes.

The process according to the invention is characterized in that the compound of formula 10

X2-if II

where, y? and W are as defined above, are reacted with an alkali metal cyanide and ammonium carbonate, and if desired, the resulting thiochroman compound where W is S is oxidized to a compound wherein W is SO or SOg, and if desired, a compound having alkoxy is converted to a compound wherein X R 2 is hydroxy, and if desired, the resulting spirohydantoin is converted to a pharmaceutically acceptable base salt.

Particularly preferred compounds of the invention are 6-fluorospiro (chromane-4,4 · -imidazolidine) -2 ', 5'-dione, 6-chlorospiro (chromane-4,4'-imidazolidine) -2 *, 5 * -dione , 6,7-dichlorospiro (chromane-4,4'-imidazolidine) -2 ', 5'-dione, 6,8-dichlorospiro (chromane-4,4'-thiochroman) -2', 5'- dione and 6 ', 7' - dichlorospiro (imidazolidine-4,4'-thiochroman) -2,5 'dione, as these compounds are potent aldose reductase inhibitors and severely reduce sorbitol levels in the sciatic nerve and lens of diabetics and galactitol levels in the lens of galactose-blooded individuals.

In the process of the invention, a 4-chromanone or thiochroman-4-one of formula (a) wherein W, X 1 and X 1 are as defined above is reacted with an alkali metal cyanide (e.g. sodium cyanide or potassium cyanide) and ammonium carbonate to give the desired spirohydantoin final compound. Normally, this reaction is performed in an inert, polar organic solvent in which both the reactants and reagents are mixed.

Preferred organic solvents in this context are cyclic ethers such as dioxane and tetrahydrofuran, lower alkylene glycols such as ethylene glycol ** 307 trimethylene glycol, water-miscible lower alkanols such as methanol, ethanol and isopropanol, N, N-di- (lower alkyl) aliphatics such as N, N-dimethylformamide, Ν, Ν-diethylformamide and Ν, Ν-dimethylacetamide, etc. In general, the reaction is carried out at a temperature of about 20 ° to about 120 ° C for about two hours to about four days.

Although the amount of reactants and reagents used in the reaction may vary to some extent, for maximum yield, it is preferable to use a slightly excess of alkali metal cyanide reagent compared to the chromanone or thiochromanone compound used as the starting material. Upon completion of the reaction, the desired product can be easily isolated in the usual manner, e.g., by diluting the reaction mixture with water (boiling if necessary) and cooling the resulting aqueous solution to room temperature, and acidifying the mixture to give the spirohydantoin compound as an easily isolated precipitate. 0 f!

Compounds of formula I in which W is -S- or -S- may be

Tl M

0 0 is prepared from the corresponding compounds of the formula I in which W is sulfur by oxidation in a manner known per se. For example, oxidation with sodium periodate results in the formation of oxosulfur compounds and oxidation with peroxyacids such as peracetic acid, perbenzoic acid and m-chloroperoxybenzodiazole to form the corresponding dioxosulfur compounds.

The starting materials required in the process of the invention are for the most part known compounds and are either commercially readily available, such as 6-chloro-U-chromanone, or readily synthesized from conventional chemicals using conventional organic synthetic methods. For example, 6-fluoro-lt-chromanone is obtained by condensing γ- (p-fluorophenoxy) -propionic acid in the presence of polyphosphoric acid and 6, T-dichlorothiochroman-1 * -one is obtained without condensation of - (3, ** - dichlorophenylthio) -propionic acid in the presence of concentrated sulfuric acid. In either case, the organic acid used as starting material is obtained from a commercial compound.

The bases used to prepare pharmaceutically acceptable base salts are those which form non-toxic salts with acidic spirohydantoin compounds of formula I, such as 6-fluorospiro (chromane-U, 1'-imidazolidine) -2 ', 5'-dione. These non-toxic base salts are of such a nature that their cations are said to be almost non-toxic over a wide dosage range. Examples of such cations are sodium, potassium, calcium and magnesium.

These salts are readily prepared by treating a compound of formula I with an aqueous solution of the desired pharmacologically acceptable cation and evaporating the resulting solution to dryness, preferably in vacuo. Alternatively, they can also be prepared by mixing a previous alkanol solution of a compound of formula I and an alkoxide of the desired alkali metal and evaporating the resulting solution to dryness as described above. In either case, stoichiometric quantities of reagents are used in order to obtain a complete reaction and the optimum yield.

As mentioned above, the spirohydantoin compounds of the invention can be used as aldose reductase inhibitors in the treatment of chronic chronic diseases of diabetes because of their ability to statistically significantly reduce lens sorbitol levels in individuals with diabetes. For example, 6-fluoroispiro (chromane-α, U'-imidazolidine) -2 ', 5'-dione has been found to inhibit the formation of sorbitol lipids in diabetic rats when administered orally in a statistically significant manner from 0.75 to 20 mg / ml. kg without any toxic side effect. Similar results are obtained with other compounds prepared according to the invention. The compounds of the invention may be administered either orally or parenterally without adverse pharmacological side effects. Generally, these compounds are administered e.g.

0.1 to about 10 mg / kg body weight / day, although variations will be necessary depending on the weight and condition of the subject being treated and the route of administration chosen.

Pharmacological experiments

The pharmacological efficacy of the compounds of the invention in chronic chronic diseases caused by diabetes is determined using one or more of the following standard biological and / or pharmacological tests: 1) measuring their ability to inhibit the enzymatic activity of isolated aldose reductase; to the sciatic nerve of rats, 3) to measure their ability to alter already elevated sorbitol levels in the sciatic nerve and lens of streptozotocin-treated rats, 1+) to measure their ability to prevent acute accumulation of galactose intolerance in galactose-blooded rats.

The ability of the compounds of the invention and the compounds known from DE (compounds A and B) to reduce or inhibit the activity of the aldose reductase enzyme using the method of S. Hayman et al., Journal of Biological Chemistry, Vol. 20, p. 877 (1965) 7 (K. Sestanj et al., U.S. Patent 3,821,383). In all cases, partially purified aldose reductase enzyme from calf lens was used. The following results were obtained: 6 62307

Inhibition-/? at different concentrates .... l + -m 5-m ... 6-m 7 m

Compound 10 ~ 10 ~ 10 ~ 10-

Example 1 compound 76 6o 18 7

Example 2 Compound 79 87 71 30

Example 3 compound 32

Eg U compound 67 81 76 69

Example 5 compound 8l 77 66 38

Example 6 compound 60 -

Example 7 compound 70 - - -

Example 8 compound 100 92 35 7

Example 9 compound 81 58 52 3

Example 10 compound 59 96 91 81

Example 11 Compound 85 90 78 8l

Example 12 compound 87 80 61 l6

Example 13 compound 85 7l 7l 28

For example, compound IIl 69 31 2

Example 15 Compound 71 81 5I 17

Reference Compound A 73 61 -9 -6

Reference compound B 73 8l 77 61

Reference compound A: spiro (chromane-1,1'-imidazolidine) -2 ', 5'-dione Reference compound B: 6-chlorospiro (chromane-1,1'-imidazolidine) -2', 5'-dione.

The ability of the same compounds to reduce or prevent the accumulation of sorbitol in the sciatic nerve of streptozotocin-treated (= diabetic) rats was tested by the method described in U.S. Patent 3,821,383. Sorbitol accumulation in the sciatic nerve was measured 27 hours after induction of diabetes. The compounds were administered orally in said amounts 1, 8 and 2 hours after streptozotocin administration. Results are expressed as inhibition #s compared to the sorbitol level obtained in an animal that did not receive the test compound. The sorbitol level of the untreated animal normally increased from about 50-100 mmol / g to up to 100 mmol / g of tissue in 27 hours in this experiment.

The following results were obtained: j 62307

Block -%

Compound 0.75 1.5 2.5 5.0 10 mg / kg

Example 1 compound - - - 26 -

Example 2 compound - - 58 - -

Eg compound U - - - 59 -

Example 5 compound 13 i + 5 7b - -

Example 6 compound - 5 - - -

Example 7 compound - 26 - - -

Example 8 compound - - 2 * + - -

Example 9 compound k5 72 -

Example 10 compound - 6k - - -

Example 11 compound 82 - - -

Example 12 compound - 35 - - -

Example 13 compound - - Vf 68 -

Eg IU compound 28 - 12 - -

Reference compound A - - 3 ^ 58 77

Reference Compound B 6k & k - - - 6-fluorospiro (chroman-1 +, 1 '' -imidazolidine) -2 ', 5f-dione (product of Example 9) was able to reduce already elevated sorbitol levels for two weeks in streptozotocin-treated (i.e., chronic) diabetes. rats were tested by oral administration of this compound to animals for seven days. In this study, sorbitol was determined from both the sciatic nerve and the lens. Initially, the animals were administered 65 mg / kg streptozotocin intravenously. The animals were untreated for two weeks. At the end of this time, a control group of eight rats (control group I) was sacrificed to determine baseline sorbitol and two other groups of seven animals were given 2.5 mg / kg twice daily of 6-fluorospiro- (chroman-U, U * -imidazolidine) -2 ', 5, - dione or water alone (control group II). After seven days of freezing, the rats were sacrificed (three hours after dosing) and it was found that when the sorbitol level of the sciatic nerve of the control group (control group II) slightly exceeded baseline and in both the sciatic nerve (68%) and the lens (71%) · The ability of 6-fluorospiro (chroman-1 + '- imidazolidine) -2', 5'-dione to protect or prevent the formation of galactitol in acute galactose-treated rats was determined by administering the compound to animals involved for seven days. In this study, normal male rats were divided into groups of six animals fed 30%. galactose intake and the compound to be administered in three dose levels. One group of animals was given 10 mg / kg of 6-fluorospiro-8 62307 (chroman-1 +, 1 + '- imidazolidine) -2,5'-dione and the other 20 mg / kg. A control group of nine animals received 30% galactose without compound. At the end of the seven-day period, the lenses were removed for the galactitol assay and it was found that when the control group's polyol level rose from barely detectable amounts to well above 30 poli / g, rats fed 72% test compound and galactose showed a clear inhibition of galactitol levels. at a dose of 20 mg / kg and Uo% at a dose of 10 mg / kg).

To determine the effect of 6-fluorospiro (chromane-U, i * '- imidazolidine) -2', 5'-dione on the formation of lens opacities in galactose blood, rats were fed 30 # galactose diets with and without the compound for 29 days, during which time the eyes were examined approximately twice. per week. The experimental animals received the test compound mixed with food at doses of approximately 10 mg / kg and 20 mg / kg. Control animals received galactose diet alone (i.e., no compound). After 8-1U days, it was observed that lens loss had occurred in 90/5 of control animals compared to the lack of turbidity in rats given either 10 mg / kg or 20 mg / kg of 6-fluorospiro (chromane-U, Uf-imidazolidine) as described above. -2 ', 5 * -dione. After seventeen days, it was found that in 100 of the control animals the eyes were clouded, but in only 6 of the animals receiving 10 mg / kg of 6-fluorospiro (chroman-1 *, '- imidazolidine) -2', 5'- dione.

In rats receiving 20 mg / kg of test compound, the corresponding value was 0%. This delay in lens attenuation continued in all treated groups until day 22, when lens attenuation was observed in more than 90 # of animals receiving 10 mg / kg of test compound. But in rats receiving 20 mg / kg of 6-fluorospiro (chroman-N-imidazolidine)? 5, 5'-dione, a clear delay in lens depression was observed for another 29 days, i.e., only $ 37 of the treated group had lens depression.

The efficacy of 6-fluorospiro- (chromane-U, U »-imidazolidine) -2 ', 5 * -dione to delay lens opacification in rats was further specified by the method of Example Uh, which carefully examined the severity of the lens opacity formed. In this study, the the percentage of lens area was measured over a 29-day period and the results obtained served as an index of severity. In this way, it was found that after 17 days, 75 # of the control lenses in question the area was always greater than 10%. On the other hand, values of 6% and 0% were obtained, respectively, in rats receiving 10 mg / kg and 20 mg / kg of 6-fluorospiro) -chromane (U, U'-imidazolidine) -2 *, 5'-dione. Thus, the severity of lens obstruction in the treated groups was always lower than in the control group, including the values at day 29.

9 62307

Example 1 6 * -methoxyispiro (imidazolidine-U, 1 + 1 -t-iochroman) -2.5-dione 6-methoxythiochroman-U-one (2.9 g, 0.015 mol) / Preparation: Chemical Abstracts, Vol. 53.717lc (1959) /, a mixture of potassium cyanide (1.5 g, 0.023 mol) and ammonium carbonate (6.7 g, 0.07 mol) in 20 ml of ethanol was heated in a stainless steel bomb at 110 ° C for 20 hours. The cooled (about 25 ° C) reaction mixture was diluted with 100 mL of water, and the pH of the mixture was adjusted to 2.0 with 6 N hydrochloric acid. The precipitate formed was suction filtered and recrystallized from ethanol to give 1.63 g (1 * 1%) of the title compound, m.p. 170-172 ° C.

Analysis for c 12 H 12 N 2 O 3 S

Calculated: C 5 H 53 H 1 * 5 5 N 10.6 L

Found: C 51 +, 61 + H U, 67 N 10.66.

Example 2 6 * -chlorospiro- (imidates of solidin-1 *, 1 + * -t-iochroman) -2,5-dione.

The procedure of Example 1 was repeated except that 6-chlorothiochroman-1 * -one was used as the starting material. 55, 12397c (196/7 6'-e-toxithiochroman-1 + -one in the above molar ratios to give the title compound in 53% yield, m.p. 2l + 1 + -2l * 6 ° C.

Analysis for C

Found: C 1 * 9.23 H 3.1 + 0 N 10.39.

Example 3 61-Bromospiro- (imidates of solidine-1 *. 1 * * -t iochroman) -2.5-dione.

The procedure of Example 1 was repeated except that 6-bromothiochroman-1-one was used as starting material. Arndt, Chemische Berichte, Vol. 58, pp. 1612 (1925) J

On the position of 6-methoxythiochroman-1 * -one in the above molar ratios. There was thus obtained in 56% yield as the title product, m.p. 231 + ° - 236 ° C.

Analysis for C 12 H 12 BrN 2 S Calculated: C 1 * 2.18 H 2.90 N 8.95

Found: C 1 * 1.98 H 2.92 N 8.95-

Example 1 * 6 *, 7 1-Dichlorospiro (imidazolidine-1 * 1 *, - thiochrome) -2,5-dione.

The procedure of Example 1 was repeated except that 6,7-dichlorothiochroman-1 * -one was used as the starting material instead of 6-methoxythiochroman-1 * -one in the above molar ratios. There was thus obtained in 1 * 9% yield the title compound, m.p. 298-300 ° C.

Analysis for C 11 H 8 Cl 2 N 2 O 2 S Calculated: C 1 + 3.58 H 2.66 N 9.2l +

Found: C 1 * 3.77 H 2.85 N 9.38.

10 62 3 0 7 The starting material was prepared as follows:

To a solution of 12.5 g (0.07 mol) of 3, k-dichlorobenzenethiol (manufactured by Aldrich Chemical Company, Inc., Milwaukee, Wisconsin) in 2N aqueous NaOH (35 mL) and ethanol (5 mL) in ice, an ice-cold solution of 7.6 g (0.07 mol) of β-chloropropionic acid (also manufactured by Aldrich) and 8.6 g (0.07 mol) of sodium carbonate monohydrate dissolved in 50 ml of water were added. The reaction mixture was heated on a water bath for two hours, cooled to room temperature (ca. 25 ° C) and extracted with ethyl acetate to remove impurities. The aqueous phase was poured into 300 ml of ice-cold 3 * hydrochloric acid and the resulting precipitate was filtered off with suction, washed with water, dried to constant weight in air and recrystallized from ethyl acetate-n-hexane to give 11.1 g (65%) of 3- (dichlorophenylthio). -propionic acid, m.p. 70 ° -72 ° C.

Analysis for C 18 H 28 Cl 2 S Calculated: C 3.0 H 3 3.21

Found: C 1 * 3.13 H 3.25.

5.0 g (0.02 mol) of [3- (3,4-dichlorophenylthio) -propionic acid were added to 50 ml of ice-cold concentrated sulfuric acid with constant stirring during the addition. The resulting solution was stirred at 0 ° C for 20 minutes and at room temperature for 20 minutes. The reaction mixture was then poured into 300 ml of ice-water mixture, the resulting precipitate was isolated by suction filtration, washed with water and air-dried to constant weight. Recrystallization from ethanol gave 2.5 g (5I +%) of pure 6,7-dichlorothiochroman-U-one, m.p. 13 ^ ° -136 ° C.

Analysis for C

Found: C 1 + 6.3 ** H 2.1 * 5.

Example 5 6'-Fluorospiro [imidazoline-U. 70, U7335X (1969) on the position of J 6-methoxythiochroman-1 * -one in the above molar ratios. This gave the title compound in 60% yield, m.p. 200-202 ° C.

Analysis for C 18 H 18 FN 2 O 9 S

Calculated: C 52.37 H 3.60 N 11.11

Found: C 52.36 H 3.73 N 11.05.

Example 6 8 * -chlorospiro- (imidazoline -1 * .1 * * -t iochroman) -2,5-dione.

The procedure of Example 1 was repeated except that 8-chlorothiochroman-lt-one was used as the starting material. Chemical Abstracts, Vol. 53, 7161c (1959) for the position of β-methoxythiochroman-1 + -one in the above molar ratios. There was thus obtained 11,630,307 in 66% yield of the title compound, m.p. 265-267 ° C.

Analysis for C 1 H 9 ClN 3 S Calculated: C 1 + 9.16 H 3.38 N 10.1 + 3

Found: C 1 + 9.32 H 3.50 N 10.38.

Example 7 71-Chlorospiro- (imidazolidine-1 + .1 +, -thiochroman) -2,5-dione ·

The procedure of Example 1 was repeated except that the starting material was 7-chlorothiol, self-U-one Chemical Abstracts, vol. 52, 1110 + 1 + b (1958) on the position of J 6-methoxythiochroman-1 + -one in the above molar ratios. This gave the title compound in 67% yield, m.p. 235-237 ° C.

Analysis for C 18 H 18 N 2 O 3 S Calculated: C 1 + 9.16 H 3.38 N 10.1 + 3

Found: C 1 + 9.32 H 3.36 N 10.03.

Example 8 6-Methoxyspiro (chroman-1 + .1 + 1-imidazolidine) -2β-dione 6-methoxy-1 + -chromanone (5.9 g, 0.033 mol) (GB Patent 1,0U 61 + 5) , a mixture of potassium cyanide (2.8 g, 0.01 + 3 mol) and ammonium carbonate (8.26 g, 0.086 mol) in 1 + 0 ml of ethanol was heated in an oil bath at 60 ° C in a stainless steel bomb for 2 + + hours. The reaction mixture was diluted with 300 ml of water, and the mixture was boiled for 15 minutes. After cooling, the mixture was acidified with 6N hydrochloric acid. The resulting precipitate was filtered and recrystallized from ethanol to give 2.6 g (32%) of the title compound, m.p. 170-172 ° C. Analysis for C 12 H 12 N 2 O 2;

Calculated: C 58.06 H 1 +, 87 N 11.29

Found: C 58, Oh H 1 +, 98 N 11.17-

Example 9 6-Fluorospiro (chromane-1 + .1 + 1-imidazolidine) -2 *. 51 -dione.

The procedure of Example 8 was repeated except that 6-fluoro-1 + -chromanone was used as the starting material instead of 6-methoxy-1 + -chromanone in the above molar ratios. This gave the title compound in a yield of $ 36 5.

Analysis for C ^ H ^ FN ^

Calculated: C 55.93 H 3.81+ n n, 86

Found: C 55.51+ H 3.88 N 12.12.

The starting material was prepared as follows:

A mixture of 3.5 g (0.019 mol) of β- (p-fluorophenoxy) -propionic acid Finger et al., Journal of the American Chemical Society, Vol. 8l, pp. 9I + (1959) 7 and 1 + 0 g of polyphosphoric acid, heated on a water bath for 10 minutes. The mixture was poured into 300 ml of ice water and extracted with three portions of ethyl acetate. The combined organic extracts were washed with dilute aqueous sodium carbonate solution and water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was recrystallized from ethanol to give 2.93 g (93%) of pure 6-fluoro-1 + -chromanone, m.p. III + -ll6 ° C.

Analysis C lyOg. 0.25 H 2 O Calculated: C 63.31+ H 1 +, 1 + 3 Found: C 63.2 U H 1 +, 15.

Example 10 6, T-dichlorospiro (chromane-1 + .l +, - imidazolidine) -2t .5 * -άίοηΐ

The procedure of Example 8 was repeated except that 6,7-dichloro-1 + -chromanone (DE-A-1 928 027) was used as the starting material instead of 6-methoxy-1 + -chromanone in the above molar ratios. This gave the title compound, m.p. 263-265 ° C.

Analysis CnHgcl2N2 ° 3 Calculated: C U6.02 H 2.81 N 9.76

Found: C 1 + 5.83 H 2.9 ** N 9.65.

Example 11 6,8-Dichloro-spiro (chromane-1 +. , Journal of Medicinal Chemistry,

Butter. 12, p. 277 (1969) on the position of β-methoxy-1+ -chromanone in the above molar ratios. This gave the title compound in 20% yield, m.p. 23l + -235 ° C. Analysis for C

Calculated: C 1 + 6.02 H 2.81 N 9.76

Found: C 1 + 5.81 H 2.7 * + N 9.69.

Example 12 6'-Fluoro spiro (imidat solidin -1+ .1 + 1 -thiochroman) -2.5 ^ 10 ^ -11-oxide A mixture of 252 mg (0.001 mol) of 6'-fluorospiro [imidazolidine-1 +, 1 + * -thiochroman) -2,5-dione (prepared according to Example 5) in 10 ml of methylene chloride, 50 mg of a 1 + 0 J aqueous solution of tetrabutylammonium hydroxide and 22 l + mg (0.01 mol) of sodium periodate in 5 ml of water were stirred at room temperature (about 25 ° C) for one hour. The resulting precipitate was isolated by suction filtrate, recrystallized from 3 ml of ethanol to give 60 mg (22%) of the title compound, m.p. 289-291 ° C.

Analysis calculated for C 1 F 9.25 H 3.38 N 10.1 + 1 +

Found: C 1 + 9.27 H 3.35 N 10.35-

Example 13 6 * -Fluorospiro (imidazolidine-1 + .1 + * -thiochroman) -2,5-dione-1 *, 1'-dioxide To a suspension of 0.595 g (0.00236 mol) of? -Fluorospiro-imidazolidine- 1 +, 1 + '- thiochroman) -2,5-dione (prepared according to Example 5) in 50 ml of chloroform in a 250 ml three-necked round bottom flask, 1.00 g (0.00579 mol) of m-chloroperoxybenzoic acid were added in small portions over 1 hour 13 62307 . The resulting slurry was stirred at room temperature (ca. 25 ° C) for 36 hours. The mixture was then diluted with 500 mL of ethyl acetate, the yellow organic layer was separated and washed with four 50 mL portions of saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 0.50 g (7.5%) of crude 6 '. fluorospiro (imidazolidine-H, 1 + '- thiochroman) -2,5-dione-1', 1'-dioxide as white crystals. Recrystallization from ethanol-ethyl acetate-n-hexane gave the pure product (m.p. 179-180 ° C, dec.) As a first crop of fine white crystals (0.295 g). Recrystallization twice from ethanol-ethyl acetate gave an analytical sample m.p. 181 + -186 ° C (decomposes).

Analysis C ^ I ^ FN ^ S. 0.5 CH 2 O 2 O 2

Calculated: C 1 + 7.55 H 3.99 N 8.53

Found: C 1 + 7.5 ^ H 3.93 N 8.56.

Example ll +

Spiro (imidazolidine-1 + «1+'-thiochroman) -2,5-dione-1 ', 1'-dioxide. The procedure of Example 13 was repeated except that 0.231+ g (0.001 mol) of spiro (imidazolidine-1 +, 1 + '- thiochroman) -2,5-dione (DE 1 135 915) and 0.1 + 26 g ( 00021 + 7 mol) of m-chloroperoxybenzoic acid was reacted with each other to give 0.20 g (75%) of the title compound. Recrystallization from methanol-ethanol-n-hexane gave an analytical sample (m.p. 280-28 ° C).

Analysis for CH 2 Cl 2

Calculated: C 1 + 9.61 H 3.78 N 10.52

Found: C 1 + 9.82 H 3.85 N 10.19.

Example 15 6,8-Dimethylspiro (chromane-1 + 1 + t-imidazolidine) -2 ', 5'-dione A mixture of 2.75 g (0.01562 mol) of 6,8-dimethyl-1 + -chromanone / Chemical Abstracts, vol. 58, 13900c (1961 +) / *, 3.5 g (0.0538 mol) of potassium cyanide and 10.5 g (0.109 mol) of ammonium carbonate in 60 ml of 50% aqueous ethanol were added to a 125 ml round-bottomed flask and heated at 65 ° C in an oil bath for 1 + 8 hours under nitrogen. The reaction mixture was cooled to room temperature (ca. 25 ° C), filtered and the filtrate was extracted with 50 ml of diethyl ether. The aqueous layer was collected and adjusted to pH 2.0 (with cooling) with 3N hydrochloric acid. The resulting cloudy mixture was extracted three times with 200 ml portions of ethyl acetate, and the combined organic layers were re-extracted three times with 50 ml portions of 1 + aqueous potassium hydroxide solution. The combined basic aqueous layers were acidified with 3N hydrochloric acid to pH 2.0 and saturated with sodium chloride before extraction three times with 200 ml portions of freshly distilled ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered.

il, 62307

The solvent was removed from the filtrate by evaporation in vacuo to give 2.50 g (65%) of 6,8-dimethylspiro (chromane-1'-imidazolidine) -2 *, 5'-dione, m.p. I85-190 ° C (decomposes). Crystallization twice from aqueous ethanol gave an analytically pure sample (m.p. 188-189 ° C).

Analysis for c13H11N2O3

Calculated: C 63.1 * 0 H 5.73 N 11.38

Found: C 63.05 H 5.69 N 11.33.

Example 16 Na salt of 6-fluorospiro (chromane-1 * (1 * 1-imidazolidine) -2 * .51-dione 6-Fluorospiro (chromane-L, L'-imidazolidine) -2 ', 5'-dione was dissolved in an equivalent amount of to water containing sodium hydroxide. Freeze-drying gave the desired alkali metal salt as an amorphous powder which is readily soluble in water.

Potassium and lithium salts and alkali metal salts of all spirohydantoin compounds prepared in Examples 1-15 were also prepared in a similar manner. Example 17 Calcium salt of 6-fluorospiro (chroman-UV-imidazolidine) -2'-5'-dione 6-fluorospiro (chroman-1 * '-imidazolidine) -2', 5 * -dione was dissolved in water containing an equivalent amount of calcium hydroxide. The mixture was lyophilized. In a similar manner, the corresponding magnesium salt and the alkaline earth metal salts of the spirohydanthines prepared in Examples 1-15 were also prepared.

Claims (2)

15 62307 Pat ent t i see suction that: A process for the preparation of novel spiro (chromane or thiochromane-U.U'-imidazolidine) -2 ', 5'-diones and oxidation products of such thiochromanes of the formula HN-f x1 i I.X6 X which are suitable for the treatment of diabetes •. 1.? wherein W is O, S, SO or SO, and when W is 0, X and X are lower alkyl ... ^ 1.2. . . groups or chlorine atoms or X is hydrogen and X is fluorine, hydroxy or lower • 12 · · alkoxy, and when W is SX is hydrogen and X is chlorine, fluorine, bromine or lower 1 2 1 alkoxy or X and X are chlorine atoms, and W is SO or S0? X is hydrogen and X is hydrogen or fluorine, and for the preparation of pharmaceutically acceptable base salts of these compounds, characterized in that the compound of formula X10 is. 12 · wherein X, X and W are as defined above, is reacted with an alkali metal cyanide and ammonium carbonate, and if desired, the resulting thiochroman compound where W is S is oxidized to a compound where W is SO or SO 2, and if desired the compound wherein X is alkoxy is converted to the compound wherein X is hydroxy, and if desired, the resulting spirohydantoin is converted to a pharmaceutically acceptable base salt. Process for the preparation of 6-fluoro-spiro- (chromane-1,1'-imidazolidine) -2 ', 5'-dione according to Claim 1, characterized in that 6-fluoro-U-chromanone of the formula ie 62 307 fyVS is reacted in the presence of alkali metal cyanide and ammonium carbonate. IT 62307 Patent kr av: