HU181912B - Process for preparing new 9-thia-11-oxo-12-aza-prostanoic acids - Google Patents

Abstract

The invention relates to manufacturing processes of the new title compounds. which can be used in medicine as a remedy, which is also an object of the invention "The compounds having the structure wherein Y is -Li2 ~ CH-CH ™ or (CH2) m1, wherein m1 is 1, 3 or 4, have Reactivity in the ovarian prostaglandin test on mice, but strong vasodilatory PJigenschaften with delayed biological effects, but reduced side effects. formula

Description

The present invention relates to a process for the preparation of the novel formula (I)

9-Thia-11-oxo-12-aza-prostanoic acids - wherein

R is carboxy or (1-4C) alkoxycarbonyl,

A is phenylene optionally substituted with halogen, m is 0 or 2,

R ^{1 represents a} hydrogen atom or an isotope or a methyl group,

Z is an optionally unsaturated alkylene group containing 2 or 3 carbon atoms,

R ³ is hydrogen,

R ⁴ is a straight or branched alkyl group containing from 3 to 7 carbon atoms, or

R ³ and R ⁴ taken together with the carbon atom to which they are attached form an alicyclic group containing from 5 to 9 carbon atoms and optionally a hydroxy group, or a heterocyclic group containing from 5 to 7 ring carbon atoms and a heteroatom containing sulfur or oxygen. The novel compounds of formula (I) exhibit, inter alia, excellent renal vasodilators.

Compounds analogous to naturally occurring prostaglandins or compounds of formula I are known, for example, from German Patent Publication No. 2422498, German Patent No. 2 521 517, Belgian Patent 828994, U.S. Pat. U.S. Patent Nos. 883659 and 4022794; and Prostaglandins, 10, 661-666 (1975). However, none of the above-mentioned publications discloses compounds which contain a phenylene group in the side chain bearing the carboxyl group.

Preferably A is a ρ-phenylene, m-phenylene or substituted phenylene group having one or two ring hydrogen atoms replaced by a halogen atom, preferably chlorine.

Preferred values of Z include ethylene, trimethylene, cis-propenylene of formula XXIII, trans-propenylene of formula XXIV, and propynylene.

Preferably R ^{4 is} alkyl, propyl, butyl, amyl, isoamyl, heptyl or 1,1-dimethylpentyl.

R ³ and R ⁴ together to form the alicyclic group Preferred examples are cyclopentyl, cyclooctyl or biciklo15 (3.3.1) nonyl, and the heterocyclic group include a tetrahydropyranyl or tetrahydrothiopyranyl Preferred examples.

Preferably narrower cso20 port of the compounds of formula (I) are the compounds of formula (Ιθ), wherein X is chlorine and r is 0,1 or 2, ^Rl is hydrogen or deuterium or a methyl group, Z is ethylene, trimethylene , cis or trans-propenylene or propynylene, and R ⁴ is a straight or branched alkyl group containing from 3 to 7 carbon atoms. The compounds of formula (I _B) include, for example to the following compounds:

4- [3- {3- (hydroxyoctyl) -4-oxo-2-thiazolidinyl} propyl] benzoic acid,

-1181912

4- [3- {3- (3-hydroxy-decyl) -4-oxo-2-thiazolidinyl} propyl] benzoic acid,

4- [3- {3- (3-Hydroxy-4,4-methyl-octyl) -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid, and

4- [3- {3- (3-Hydroxy-3-methyl-octyl) -4-oxo-2-thiazolidinyl} -5-propyl] -benzoic acid.

A preferred group of compounds of formula (I) are those compounds of formula ( _ID ) wherein X is chlorine, r is 0.1 or 2, Z is ethylene, trimethylene, propenylene or propynylene and 10 W 2 - Refers to a polymethylene group containing 6 carbon atoms.

4- {3- {3- [2- (l-hydroxycyclohexyl) ethyl] -4-oxo-2-thiazolidinyl} propyl-benzoic acid,

4- [3- {3- [2- (1-hydroxycyclopentyl) ethyl] -4-oxo-2-thiazolidinyl} -15

propyl-benzoic acid,

4- [3- {3- [2- (l-hydroxy-cycloheptyl) ethyl-4-oxo-2-thiazolidinyl} propyl-benzoic acid,

4- [3- {3- [2- (1-hydroxy-4,4-dimethyl-dichlohexyl) -ethyl] -4-oxo-2-thiazolidinyl] -propyl} -benzoic acid,

4- [3- {3- {2- [9-hydroxy-9-bicyclo (3.3.1) nomlJ ethyl} -4-oxo-2-propyl-tiazolidinilj acid,

4- [3- {3- [3- (l-hydroxycyclohexyl) propyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid,

4- [3- {3- [3- (1-hydroxycyclohexyl) - (Z) -2-propenyl] -4-oxo-2-25-thiazolidinyl] -propyl} -benzoic acid,

4- {3- [3- [3- (1-Hydroxy-cyclohexyl) - (E) -2-propenyl] -4-oxo-2-. -tiazolidinilj-propyl-benzoic acid,

4- [3- {3- [3- (1-hydroxy-cyclohexyl) -2-propynyl] -4-oxo-2-thiazolidinyl'-propyl} -benzoic acid,

4- [3- {3- [2- (l-hydroxycyclohexyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] -3-chloro-benzoic acid,

4- [3- {3- [2- (1-hydroxy-dichlohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -2-chlorobenzoic acid,

4- [3- {3- [2- (1-hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -35-propyl] -3-methyl-benzoic acid,

4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -1,1,4-tri-oxo-2-thiazolidinyl] -propyl} -benzoic acid, ... [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -5,5-dimethyl-4-oxo-2-thiazolidinyl] -propyl} -benzoic acid;

4- [3- {3- [2- (l-hydroxy-cikloheMl) ethyl] -5,5-dideuterio-4-oxo-2-propyl-benzoic tiazolidinilj.

The compounds of formula (I) to a further preferred narrower group comprises compounds (I _E) of the formula wherein X represents a chlorine atom or a methyl group, 45 r is 0, 1 or 2, m is 0 or 2, ^R1 is hydrogen or methyl; , Z is ethylene, trimethylene, propenylene or propynylene and y is an integer from 4 to 8. The compound of formula (I _E) there may be mentioned 3- [3- {3- [2- (l-hydroxycyclohexyl) ethyl] -4-oxo-2-phenyl tiazolidi- 50} propyl] benzoic acid.

The compounds of formula (I) to a further preferred form the following formulas (I _H) Compounds of formula I wherein R ¹ is hydrogen or methyl; Z is ethylene, trimethylene, propylene or propenylene niléncsoport 55, w and y An integer from 1 to 5, with the proviso that their sum is from 4 to 6, and A is oxygen or sulfur.

The asterisk carbon atom of the thiazolidine ring in each of the compounds of the present invention is asymmetric in size. In compounds having different groups at R ³ and R *, the carbon atom to which they are attached is also asymmetric. Thus, the compounds of the present invention are obtained as racemates when obtained as an asymmetric carbon atom only, or as a mixture of diastereomers when both said carbon atoms are asymmetric. Of course, individual stereoisomers are also included within the scope of the invention. The biological activity of each stereoisomer is similar to that of racemates and diastereomeric mixtures and varies from compound to compound.

Compounds of Formula I are referred to as 9-thia-11-oxo-12-aza-prostanoic acids, indicating that they are derivatives of prostanoic acid of Formula XXV. The carbon skeleton of prostanoic acid is known to be characteristic of natural prostaglandins.

Prostaglandins are known to have a number of characteristic C20 fatty acids. They are found widely but at low concentrations in mammalian tissues, where they are rapidly anabolized and catabolized. They are characterized by their broad therapeutic effect. The most important of these are functional hyperaemia (inflammation of the blood), inflammatory diseases, central nervous system, water and electrolyte circulation, and regulation of cyclic AMP (adenosine monophosphate). As a literature on prostaglandins in chemistry, Pike, J.E. Fortschr. Chem. Org. Naturst., 28, 313 (1970) and Bundy, G.F., in A. Rep. In Med. Chem., 1977, 7, 157; Biochem., 41, 161 (1972), for pharmacology, Weeks, J.R., A. Rev. Pharm., 12, 317 (1972) on the physiological relevance of Horton, E.W., Physiol. Rev., 49, 122 (1969) and for general clinical use, see Hinman, J.E., Postgrad. Med. J., 46, 562 (1970).

It has now been found that, surprisingly, the compounds of Formula I are active only in specific areas of biological activity and have a biological activity spectrum which is not as broad as that of natural prostaglandins or compounds analogous thereto. For example, the compounds of the present invention are completely ineffective in the study of the effects of prostaglandins in the ovary of mice, which measure the increase in the concentration of cyclic adenosine monophosphate in the cell caused by prostaglandins and related compounds.

The compounds of the formula I are thus orally extremely potent renal vasodilators, with extended biological activity and reduced side effects. Thus, the compounds of formula I can be used with excellent results in the treatment of patients with renal impairment. Patients with renal impairment include hypertension, renal dysfunction, congestive heart failure, glomerulonephritis, uremia, and chronic renal failure. The compounds of formula I, by themselves and by their action on the kidney, have the potential to improve renal function, both in themselves and in combination with other renal therapeutic agents. 4- [3- {3- [2- (1-hydroxycyclohexyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid has a particularly high renal vasodilator activity.

Further, the compounds of the formula I are useful as active ingredients in pharmaceutical compositions having an antihypertensive effect upon oral administration. Their antihypertensive effect is otherwise surprisingly great compared to that of structurally related compounds.

The compounds of the formula I also have side effects which make them particularly suitable for the treatment of renal diseases. For example, it is anti-asthmatic, i.e., bronchodilator, immunoregulatory and acidic

-2181912 in tetrahydrofuran was added to give a greenish brown solution. This solution is then stirred at 0 'C for 30 minutes and a solution of 2- (2-bromoethyl) -1,3-dioxolane in tetrahydrofuran (10 ml) is added. The reaction mixture was stirred for 30 minutes and quenched with cold water. The organic layer was separated and the aqueous layer was acidified with 2N hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a solid residue.

The solid residue was dissolved in dimethylformamide (50 mL), and potassium carbonate (69.1 g, 50 mmol) and ethyl iodide (9.36 g, 60 mmol) were added successively. The reaction mixture was stirred at room temperature for 16 hours, then another 1 g of ethyl iodide was added and the mixture was heated in a water bath for 10 minutes. The reaction mixture was allowed to cool to room temperature, quenched with cold water and extracted with diethyl ether. The extract was washed successively with dilute hydrochloric acid and then with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting oily residue is then subjected to fractional distillation. Thus, on the one hand, 2 g of ethyl benzoate (boiling point 55-59 'C at 0.05 mm Hg) are used as a by-product.

5.81 g (22 mmol, 55%) of the desired title compound (b.p. 135-140 ° C at 0.05 mm Hg) are obtained.

NMR (CDC1 _3): δ 1.39 (3H, t, J = 7Hz), 1.76 (2H, n), 2.74 (2H, n), 3.90 (4H, n), 4 , 40 (2H, q, J = 7Hz), 4.89 (1H, t), 7.26 (2H, d, J = 8Hz) and 8.0 (2H, d, J = 8Hz).

the 2. step

Preparation of 4- (4-Oxobutyl) -benzoic acid ethyl ester

At 50-65'C, the a-1. A mixture of 0.9 g (3.4 mmol), water (7 ml), acetic acid (14 ml) and concentrated hydrochloric acid (5 drops) was stirred for 4 hours, diluted with water and extracted with diethyl ether. The ethereal extract was washed twice with water and three times with 5% sodium bicarbonate solution, and the neutralized extract was dried over anhydrous magnesium sulfate and evaporated. The title compound was obtained as a pale yellow oil.

NMR (CDC1 _3): δ1,4 (3H, t, J = 7Hz), 1.7 to 3.0 (6H, n), 4.4 (2H, q, J = 7Hz), 7.25 (2H, d, J = 8Hz), 8.0 (2H, d, J = 8Hz), and 9.8 (1H, m).

Step b) Preparation of 1-Amino-3- (2H-tetrahydropyran-2-yloxy) -octane b-1. step

Preparation of 3-hydroxycaprylonitrile

To a stirred solution of freshly distilled diisopropylamine (4.04 g, 40 mmol) in dry tetrahydrofuran (60 mL) under nitrogen, is carefully added 21 mL of a 1.9 molar solution of n-butyllithium in hexane (40 mmol). The resulting mixture was stirred at room temperature for 15 minutes and then cooled to -78 ° C and a solution of 1.64 g (40 mmol) of anhydrous acetonitrile in 5 ml of anhydrous tetrahydrofuran was added. The resulting cloudy suspension was stirred at the same temperature for 30 minutes and a solution of 4.0 g (40 mmol) of hexane in 5 ml of anhydrous tetrahydrofuran was added to give a clear yellow solution which was kept at -78 ° C for 15 minutes. The cold reaction mixture was then treated with 2N hydrochloric acid (50 mL) and extracted with diethyl ether (100 mL). The extract was washed with water (50 mL) and 5% aqueous sodium bicarbonate (50 mL), dried over magnesium sulfate and concentrated in vacuo. so as a pale yellow oil

5.2 g (92%) of the title compound are obtained. Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 0.97 (3H, t), 2.55 (2H, d), 3.1 (H, s) and 3.93 (H, broad s).

b-second step

Preparation of 3- (2H-Tetrahydropyran-2-yloxy) -capryomitrile

A b-1. 5.2 g (36.8 mmol) of the compound obtained in Step 3a,

A mixture of 3.8 g (45 mmol) of dihydropyran and a catalytic amount of p-toluenesulfonic acid hydrate was stirred at 25 ° C for 16 hours and then diluted with 100 ml of diethyl ether. The resulting solution was washed with 5% aqueous sodium hydroxide solution (25 mL), water (25 mL), dried over magnesium sulfate and filtered. Concentration of the filtrate in vacuo gave the title compound (7.9 g, 95%) as a pale yellow oil.

NMR (CDC1 _3): δ 0.93 (3H, t), 2.54 (2H, q) 4.68 (H, m).

b-third Step 1: Preparation of 1-Amino-3- (2H-tetrahydropyran-2-yloxy) -octane

To a suspension of lithium aluminum hydride (0.76 g, 20 mmol) in anhydrous diethyl ether (90 mL) was added dropwise, under nitrogen, with stirring (b) to (2). from the compound obtained in Step A (4.05 g, 18 mmol) in 10 ml of anhydrous diethyl ether. After the addition was complete, the reaction mixture was heated under reflux for 16 hours with stirring. After cooling to 25 ° C, 1 ml of water was carefully added dropwise followed by 3 ml of 5% aqueous sodium hydroxide solution. A fine suspension is obtained which is cooled to 0-5 ° C and maintained at this temperature for 30 minutes. Filtration and evaporation of the solvent in vacuo gave the title compound (3.95 g, 95%) as a pale yellow oil.

NMR (CDC1 _3): δ 0.88 (3H, t), 2.79 (2H, m) and 4.68 (H, br s).

Step c)

Preparation of 4- {3- [3- (3-Hydroxyoctyl) -4-oxo-2-thiazolidinyl] -propyl] -benzoic acid ethyl ester

At room temperature, 4.82 g (21 mmol) of 1-amino-3-tetrahydro- (2H-pyran-2-yloxy) -octane are added dropwise

-3181912 also show a cardiotonic effect. A further area of use of the compounds of formula I in preventing or preventing transplantation of an organ in an organ transplantation.

The renal vasodilatory activity of the compounds of formula I is measured as follows.

For the test, we use puppy dogs, and the electromagnetic fluid flow meters are attached to one of the renal arteries and to the aorta below. An aortic catheter is used to measure blood pressure (BP) and heart rate (HR). After a 30-minute observation period, during which the kidney blood flow rate (RBF), lower aortic blood flow rate (LAF), blood pressure (BP), and heart rate (HR) were measured, the test substances were administered orally to the animals. we make changes for hours. Each measurement is performed every 2 minutes5. Data are averaged over the control period and 5 hours after drug administration.

See Table I for the mean values.

Among the compounds of Formula I, compounds of Formula II which form a preferred narrow group thereof, wherein A, η, Z, R ¹ , R ³ and R ⁴ are as defined above, are prepared as shown in Scheme A. can be adjusted.

Table I: Effect of Examples 1 and 2 on Renal Blood Flow and Related Cardiovascular Parameters

Compound Number of dogs Monitoring period after drug administration (hour) Medium RBF® ml / min iSE ^ Medium LAF ^b ml / min ± SE Medium BP® mmHgdbSe Medium HR ^d beat / min ± SE Dose p. 0th (Mg / kg) Example 1 4 control ' 150 ± 21 534 ± 100 122 ± 2 91 ± 10 5 of 0-1 201 ± 82 546 ± 136 118 ± 5 103 ± 12 compound 1-2 241 ± 63 560 ± 174 108 ± 6 118 ± 7 2-3 209 ± 33 625 ± 139 116 ± 8 107 ± 6 3-4 183 ± 26 521 ± 152 116 ± 3 92 ± 10 4-5 159 ± 31 510 ± 153 116 ± 3 84 ± 9 Example 2 5 control 140 ± 22 480 ± 90 110 ± 7 89 ± 8 1 of 0-1 179 ± 25 486 ± 65 105 ± 10 122 ± 11 compound 1-2 211 ± 26 517 ± 109 89 ± 9 169 ± 22 2-3 226 ± 25 521 ± 85 97 ± 8 144 ± 15 3-4 233 ± 26 492 ± 89 101 ± 7 131 ± 14 4-5 242 ± 26 477 ± 65 98 ± 5 136 ± 18

'RBF: renal blood flow velocity ^b LAF: lower aortic blood flow velocity ^C BP: arterial blood ^pressure, HR: heart rate' control: 30-minute observation period prior to drug administration f: standard error

Under the secondary alcohol to the conversion first (III) compound - wherein the straight chain alkyl group containing R ⁸ is C 1-4 alkyl - a compound (IV) - wherein R ^3, R ⁴ and Z are as defined above, while THP stands for tetrahydropyranyl - reacted at 0-5 ° C in the presence of sodium sulfate for 0.5-4 hours and then filtered to remove the solid. A compound of formula (V) remaining in the filtrate is then reacted with a thioalcohol compound (VI) using azeotropic distillation of a benzene / toluene mixture to remove water released during the reaction. A compound of formula VII thus obtained is treated with hydrochloric acid in methanol in ethanol at ambient temperature for 1-24 hours to remove the tetrahydropyranyl protecting group, and finally a compound of formula VIII thus obtained is diluted with aqueous sodium, lithium or potassium hydroxide. solution in methanol to give a corresponding compound of formula II.

The compounds of formula (I) are extremely valuable pharmacological properties, particularly in view of the preferred _(S) 4- [3- {3- [2- (l-hydroxycyclohexyl) ethyl] -4-oxo-2-thiazolidinyl } propyl] benzoic acid.

The following examples illustrate the invention.

Example 1

Preparation of 4- {3- [3- (3-Hydroxyoctyl) -4-oxo-2-thiazolidinyl] propyl} benzoic acid

the step

Preparation of 4- (4-Oxobutyl) -benzoic acid ethyl ester according to the procedure described in FIG. step

Preparation of 4- (3- (2- (1,3-Dioxolamyl)] propyl} benzoic acid ethyl ester

With stirring under nitrogen, a solution of 8.08 g (80 mmol) of diisopropylamine in a mixture of 120 ml of anhydrous tetrahydrofuran and 10 ml of hexamethylphosphoric acid amide was treated with 35 ml of a 2.29 molar solution of n-butyllithium in hexane followed by 5.44 g (40 mmol) of p-toluene carboxylic acid in 20 mL

-4181912

Step b)

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid ethyl ester at-C with stirring. To a solution of the product of Step (1) in carbon tetrachloride (1 mL) was added dropwise 4- (4-oxo-butyl) -benzoic acid ethyl ester (4.15 g, 18.8 mmol), and the resulting mixture was stirred for 30 min and then 4 g of anhydrous sodium sulfate is added. Stirring is continued for 2 hours and the precipitate is filtered off and washed with a small amount of benzene. The combined filtrate and washings were diluted with benzene (70 mL) and mercaptoacetic acid (1.84 g, 20 mmol) was added all at once. The resulting mixture was refluxed in a Dean-Stark apparatus for 16 hours, allowed to cool to room temperature, washed successively with dilute hydrochloric acid and 5% sodium bicarbonate, dried over anhydrous magnesium sulfate and filtered. Concentration in vacuo gave an oily residue which was dissolved in a mixture of methanol (50 mL) and concentrated hydrochloric acid (0.2 mL). The resulting solution was stirred at room temperature for 3 hours, then diluted with water and extracted with diethyl ether. The extract was washed with dilute sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting oily residue is applied to a column containing 120 g of silica gel with chloroform. Elution with chloroform: methanol (100: 1, 630 mL) yields a contaminated material, using another 300 mL of the same eluent to elute the pure product. Concentration gave 2.5 g (5.96 mmol, 32%) of the title compound as a pale yellow oil.

NMR (CDC1 _3): δ 1.38 (3H, t), 3.50 (2H, s), 4.40 (2H, q), 4.72 (1H, m), 7.23 (2H , d) and 8.0 (2H, d).

step c)

Preparation of the title compound of the Example

To a solution of 2.48 g (5.91 mmol) of the compound obtained in step b) in a mixture of 25 ml of methanol and 5 ml of water is added 2.5 ml of 5N sodium hydroxide solution (12.5 mmol) and the the mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with water, acidified with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and filtered. Upon cooling of the filtrate, the title compound precipitated as a white precipitate. Filtration afforded the title compound (7.06 g, 2.57 mmol, 42%), m.p. 147-148 ° C after recrystallization from chloroform / diethyl ether.

IR spectrum (KBr): ν 3320, 1700 and 1650 cm ^-1 . Nuclear Magnetic Resonance Spectrum (CDCl3): δ 3.54 (2H, s), 4.70, (1H, m), 7.22 (2H, d) and 8.0 (2H, d).

Analysis calculated for C ₂₁ H ₂₉ NO ₄ S: C, 64.42; H, 7.47; N, 3.58; Found: C, 63.97; H, 7.23; N, 3; -40.

Example 3

Capsule containing 4- [3- {3- [2- (1-hydroxycyclohexyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid as active ingredient

Component Quantity in g 4- [3- {3- [2- (1-hydroxycyclohexyl) ethyl] 4-oxo-2-thiazolidinyl] propyl] benzoic acid 10 g stearic acid ^, 125g

Pluronic F-687.5 g cornstarch 125g

In a suitable vessel, the stearic acid and PluronicF-68 are mixed and then melted at 60-65 ° C using a water bath. The heating is then interrupted and the active ingredient is dispersed in the resulting melt. The corn starch is then added with stirring and the mixture is allowed to cool to room temperature while stirring. The mixture is then granulated and filled into hard gelatin capsules containing a total of 267.5 mg of solids and 10 mg of active ingredient.

Example 4

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid (alternative method)

the step

Preparation of 4- [3- (4-oxo-2-thiazolidinyl) propyl] benzoic acid ethyl ester

Under nitrogen atmosphere, using reflux and a Dean-Stark water separator, 24.89 g (0.113 mmol) of ethyl 4- (4-oxo-butyl) -benzoic acid, 30.93 g (0.339 mol) of mercaptoacetamide, 250 mg of p-toluenesulfonic acid monohydrate and a mixture of benzene (250 ml) was refluxed for 2 hours, then cooled and poured into water (600 ml). The resulting oil was extracted into diethyl ether and the extract was washed well with water and dried over anhydrous magnesium sulfate. The solvent was then removed in vacuo to give the title compound as a yellow precipitate. Trituration with 75 mL of cyclohexane gave 19.7 g of a white precipitate, m.p. Recrystallization of the latter from butyl chloride gives white needles of m.p. 99-100 ° C.

Step b)

Preparation of 4- [3- {3- [2- (1-Cyclohexenyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid ethyl ester

Dissolve 14.67 g (0.05 mol) of the compound obtained in a) in 35 ml of a 1: 1 mixture of benzene and dimethylformamide, and add 1.3 g of this solution dropwise over 30 minutes. 0.055 mol) in a 50 ml suspension of sodium hydride in a 1: 1 by volume mixture of benzene and dimethylformamide. During the addition, the reaction mixture was maintained at 30 ° C with a cold water bath. After the addition was complete, the reaction mixture was 5181912

4- (4-Oxobutyl) -benzoic acid ethyl ester (4.63 g, 21 mmol) was added and the resulting mixture was stirred for 15 min., Anhydrous sodium sulfate (4 g) was added and stirring continued for 1 h. The solid was filtered off and washed with a small amount of benzene. The combined filtrate and wash were diluted with benzene (70 mL) and thioacetic acid (1.93 g, 21 mmol) was added. The resulting solution was then heated under reflux in a Dean-Stark apparatus for 3 hours, allowed to cool to room temperature, washed with dilute hydrochloric acid, 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and evaporated to an oil. getting scraps. The residue was dissolved in methanol (50 mL), and concentrated hydrochloric acid (0.2 mL) was added to the resulting solution, which was then stirred at room temperature for 16 hours. The reaction mixture was diluted with cold water and extracted with diethyl ether. The ether extract was washed with water and washed with 5% aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate, filtration and concentration of the filtrate in vacuo, an oily residue is obtained, which is applied to a chromatographic column containing 300 g of silica gel with chloroform. Elution with chloroform: methanol (100: 1, v / v) gives 1950 ml of impure material, while an additional 450 ml of elution with the same solvent gives pure 25. Concentration of the eluate gave 2.8 g (6.64 mmol, 31%) of the title compound as a pale yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 0.90 (3H, t), 1.40 (3H, t), 3.53 (2H, s), 4.40 (2H, q), 4.70 (1H , m), 7.22 (2H, d) and 8.0 (2H, d).

Step d)

Preparation of the title compound of the Example

With stirring at 0 ° C from the compound obtained in step c)

To a solution of 2.8 g (6.64 mmol) in a mixture of 25 ml of methanol and 5 ml of water is added dropwise 2.5 ml of 5N aqueous sodium hydroxide solution (12.5 mmol) and the reaction mixture is allowed to warm to room temperature, and then stirred for 3 hours. The reaction mixture was then diluted with taste and extracted with diethyl ether. The aqueous phase was separated, acidified with 10 ml of 2N hydrochloric acid and extracted with diethyl ether. This ether extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an oily residue. This is then applied to a chromatographic column containing 75 g of silica gel with doroform. Elution with 25% (v / v) chloroform / acetic acid (410 mL) afforded the contaminated material, while another 420 mL gave the pure product to give, after evaporation, the title compound as a viscous pale yellow oil.

IR (NaCl): ν 1700 and 1665 cm-1 NMR (CDCl ₃ ): δ 0.92 (3H, t), 3.6 (2H, s), 4.72 (1H, m), δ , 30 (2H, d) and 8.08 (2H, d).

Example 2

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid as described in Example -1. step

Preparation of 2- (1-hydroxy-cyclohexyl) -acetomtril

To a solution of diisopropylamine (20.2 g, 0.2 mol) in tetrahydrofuran (280 ml) at 0 ° C under nitrogen was added 5 ml of a 1.6 molar solution of n-butyllithium in n-hexane (0.2 mol) and the resulting mixture was cooled to -78 ° C with a bath of dry ice and isopropanol. A solution of 8.2 g (0.2 mol) of acetonitrile in 10 ml of tetrahydrofuran was added to the mixture, followed by stirring at -78 ° C for 20 minutes and then 19.6 g (0.2 mol) of cyclohexanone and 15 ml of hexamethylenephosphoramide. The reaction mixture was stirred at -78 ° C for an additional 45 minutes and then allowed to warm to room temperature. It is then diluted with 100 ml of diethyl ether, quenched with 200 ml of water and acidified with 140 ml of 3.5N hydrochloric acid. The organic layer was separated, washed with water (200 mL), 5% sodium bicarbonate (100 mL), dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent in vacuo afforded the title compound as a pale yellow oil (23.6 g, 0.17 mol, 85%).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ 1.64 (8H, bs), 2.54 (2H, s) and 2.64 (1H, s).

the 2. step

Preparation of 2- [1- (2H-Tetrahydropyran-2-yloxy) -cyclohexyl] -acetonitrile

While stirring, the a-1. To a mixture of 5.57 g (40 mmol) and 3.78 g (45 mmol) of dihydropyran from 0.16 g of p-toluenesulfonic acid hydrate is added. When the reaction begins (as indicated by the increase in temperature of the reaction mixture), the reaction vessel is rapidly cooled in a cold water bath and stirring is continued for 1.5 hours. The reaction mixture was then diluted with diethyl ether, washed with 5% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. Yield: 8.7 g (39 mmol, 98%) of the title compound as a yellow oil.

NMR (CDC1 _3): δ 2.63 (2H, s), 3.3-4.3 (2H, m) and 4.87 (1H, m).

the 3. Step 1: Preparation of 1-Amino-2- [1- (2H-tetrahydropyran-2-yloxy) -cyclohexyl] -ethane

To a suspension of lithium aluminum hydride (1.292 g, 34 mmol) in diethyl ether (100 mL) was added dropwise a-2. A solution of 8.2 g (39 mmol) in ethyl ether (20 mL) was added and the resulting mixture was refluxed for 16 h. The reaction mixture was cooled to below 5 ° C, and water (1.3 mL), 15% aqueous sodium hydroxide (1.3 mL) and water (3.9 mL) were added sequentially. The resulting mixture is then stirred at room temperature for 30 minutes and the precipitate is filtered off. The filtrate was concentrated in vacuo to give 8.7 g (38.2 mmol, 98%) of the title compound as a pale yellow viscous oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ 2.35 (2H, s, interchangeable with D ₂ O), δ 2.6 - 3.0 (1H, m), 3.2 - 4.2 (3H, m) ) and 4.74 (1H, m).

After stirring for a further 15 min, 10.4 g (0.055 mol) of 1- (2-bromoethyl) cyclohexene are added. The reaction mixture was then 55-60 ° C. After stirring for 3.5 hours, it was cooled and poured into 200 ml of water. The aqueous mixture was extracted with diethyl ether and the extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as an orange viscous oil (20.5 g).

The crude product was then purified by column chromatography (300 g silica gel, eluting with chloroform followed by 2% methanol in chloroform). The pure product fractions were pooled and evaporated to give 2 product fractions. Fraction (A) was a yellow oil (4.5 g) having an R _r of 0.6 with less impurities at an Rf of 0.42 and 0.78 (TLC on silica, 2% v / v methanol). run with chloroform). Fraction (B) is a yellow oil weighing 7.8 g and having an R _r value of 0.6. So the total yield

12.3 g (61%). The product thus obtained is used directly in the next step.

step c)

Preparation of the title compound of the Example

A solution of the compound obtained in step b) (3.6 g, 0.009 mol) in trifluoroacetic acid (16 ml) was allowed to stand at room temperature for 4 hours and then poured into ice-cold water. The oily precipitate was taken up in diethyl ether and the resulting solution was washed with saturated sodium bicarbonate solution until the washings remained basic. The oily product precipitated from the ethereal solution at the moment when excess trifluoroacetic acid was completely removed from the solution. The oily product was redissolved in the organic phase by the addition of chloroform, and the resulting solution was washed with water, dried over anhydrous sodium sulfate and evaporated to give 4.3 g of a brown oil.

This brown oil was then dissolved in a solution of sodium hydroxide (1.2 g, 0.03 mol) in water (10 mL) and methanol (40 mL) and allowed to stand at room temperature for 18 hours. The methanol was then distilled off under reduced pressure and the residue was diluted with water (50 mL) and acidified with concentrated hydrochloric acid. The product precipitates as an oil which then crystallizes rapidly. It is recrystallized twice from a mixture of acetonitrile and water to give a constant melting point. This gave 1.6 g (45%) of the title compound, m.p. 147-148C.

Example 5

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid (alternative method)

the step

Preparation of 4- [3- {3- [2- (1-Cyclohexenyl) ethyl] -4-oxo-2-thiazolidinyl] -propyl] -benzoic acid

4- [3- {3- [2- (1-Cyclohexenyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid ethyl ester, prepared in the same manner as in Example 4 (b), was obtained (4.0 g). A solution of 0.01 mol) in sodium hydroxide (1.2 g) (0.003 mol) in methanol (50 ml) and water (5 ml) was allowed to stand at 25 ° C for 18 hours and then the methanol was distilled off under reduced pressure. The residue was diluted with water (50 mL) and acidified with 2N hydrochloric acid. The title compound then precipitates as an oil which gradually crystallizes. Separate, wash with water and air dry.

Step b)

Preparation of the title compound of the Example

A solution of 3.7 g (0.01 mol) of the compound obtained in step a) in 20 ml of trifluoroacetic acid was allowed to stand at 25 ° C for 4 hours and then excess trifluoroacetic acid was distilled off under reduced pressure. The oily residue was dissolved in a solution of sodium hydroxide (2.0 g, 0.05 mol) in water (40 mL), and the basic solution was acidified with 2N hydrochloric acid. The title compound precipitates. Recrystallization from acetonitrile / water gave the purified title compound, m.p. 147-148C.

Example 6

4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -1,1,4,4-trioxo-2-thiazolidinyl} -propyl] -benzoic acid. production

0.391 g (1.0 mmol) of 4- [3- {3- [2- (1-hydroxycyclohexyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid, 0.362 g (2.1) 100 ml of a mixture of 100% pure 3-chloroperoxybenzoic acid and 5 ml of chloroform are refluxed for 30 minutes and the reaction mixture is concentrated in vacuo. The resulting solid residue was applied to a chromatography column containing 18 g of silica gel with chloroform. Elution with chloroform / acetic acid (25: 1, 150 mL) elutes 3-chlorobenzoic acid and the impure end product. Further continuous elution with said eluent elutes the title compound. Evaporation gave 0.273 g (0.64 mmol, 64%) of a colorless viscous oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 3.75 (2H, s), 4.60 (1H, m), 7.26 (2H, d) and 8.00 (2H, d).

Example 7

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -2-chloro-biphosphonic acid

the step

Preparation of 2-chloro-4- (4-oxobutyl) -benzoic acid ethyl ester

This compound can be prepared by the reaction sequence described in Example 1 (a) except that it is a-1. Step 2 replaces p-toluene carboxylic acid with 2-chloro-4-methyl181912

benzoic acid is used. Thus, in this example, FIGS. 2-Chloro-4- {3- [2- (1,3-dioxolanyl)] propyl} benzoic acid ethyl ester (b.p. 165-170 ° C at 0.1 mm Hg) was used in Step 2 and Step-2. Step 1 to obtain the title compound.

Step b)

Preparation of 3-Chloro-4- [3- (4-oxo-2-thiazolidinyl) propyl] benzoic acid ethyl ester

This compound was prepared as described in Example 4, step a, except that instead of the 4- (4-oxobutyl) -benzoic acid ethyl ester used as starting material there was chemically equivalent amount of 2-chloro-4- (4- oxobutyl) benzoic acid ethyl ester is used. Recrystallization from butyl chloride gave the title compound as white needles, m.p. 81.5-82.5 ° C.

Analysis calculated for C ₁₈ H ₁₈ ClNO ₃ S: Calculated; C, 54.96; H, 5.53; N, 4.27; Found: C, 55.29; H, 5.64; N, 4.31.

step c)

Preparation of 2-Chloro-4- (3- {3- (2- (1-cyclohexenyl) ethyl] -4-oxo-2-thiazolidinyl} propyl) benzoic acid ethyl ester

This compound was prepared as described in Example 4, Step b, except that the starting material was chemically equivalent to ethyl 4- [3- (4-oxo-2-thiazolidinyl) propyl] benzoic acid. ethyl chloro-4- [3- (4-oxo-2-thiazolidinyl) propyl] benzoic acid is used. Column chromatography on silica gel (eluting with 2% methanol in chloroform) affords the title compound as an oil.

Step d)

Preparation of the title compound of the Example

The preparation was carried out in the same manner as in Example 4, step (c), except that the ester obtained in step (c) of the present Example was used instead of the ester used as starting material. The title compound was obtained as an amorphous solid, m.p. 104-108 ° C.

Example 8

Preparation of 3- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl] -propylbenzoic acid a. step

Preparation of 3- (1-Propenyl) -benzoic acid ethyl ester

A mixture of acetaldehyde (5.8 g, 0.132 mol) and ethanol (250 ml) was suspended in (3-methoxycarbonylbenzyl) triphenylphosphonium bromide (54.1 g, 0.11 mol) and added dropwise to the resulting suspension over 30 minutes. a solution of 2.5 g (0.11 mol) of sodium metal in 300 ml of ethanol is added. The reaction mixture was then stirred for an additional 4 hours at room temperature and then concentrated under reduced pressure to about a quarter of its original volume. Water (150 ml) was added to the concentrate and the oily product was extracted into diethyl ether. The extract was dried over magnesium sulfate and evaporated. The residue was treated with 100 ml of petroleum ether, the insoluble triphenylphosphine oxide was filtered off and the filtrate was distilled in vacuo. Yield: 14.0 g (72%) of the title compound of boiling point 85-87 C (0.1 mm Hg). It is noteworthy that ethanol is used as the solvent to give one ethyl ester as a solvent due to transesterification during the reaction.

the 2. step

Preparation of 3- (3-Bromo-1-propethyl) -benzoic acid ethyl ester

While stirring, a. A mixture of 14 g (0.074 mol), 14.9 g (0.084 mol) of N-bromosuccinimide, 150 mg of benzoyl peroxide and 75 ml of carbon tetrachloride was refluxed for 46 hours, cooled and filtering off the precipitate. The filtrate was washed with water, dried over magnesium sulfate and evaporated. Distillation of the residual oil gave 10.2 g (51%) of the title compound, b.p. 129-131 ° C at 0.05 mm Hg.

the 3. step

Preparation of 3- (4-Oxo-1-butenyl) -benzoic acid ethyl ester

To a suspension of 2.4 g (0.1 mol) of sodium hydride in 100 ml of 40 tetrahydrofuran is added dropwise over a period of 30 minutes 12.4 g (0.1 mol) of methyl methylthiomethylsulfoxide and the resulting mixture is added in one portion. a-2 from the compound obtained in Step

26.9 g (0.1 mol) are added. The reaction mixture was then stirred at 30 ° C for 45 hours and then at 45-50 ° C for 2 hours, after which the solvent was distilled off in vacuo. Water was added to the residue and the oily precipitate was taken up in diethyl ether. The resulting solution was dried over sodium sulfate and evaporated. This gives the dimethylmercaptal S-oxide of the title ve50. This material was dissolved in a mixture of tetrahydrofuran (200 mL) and 10% HCl (5 mL) and the resulting solution was refluxed for 2 hours. The solvent was distilled off and the residue was taken up in diethyl ether. The resulting ethereal solution was washed with water, dried over sodium sulfate and concentrated in vacuo to give the title compound as a thin oil, which was used immediately in the next step.

Step b)

Preparation of 3- (3- (3- (2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propenyl] -benzoic acid ethyl ester 65

-8181912

This compound was prepared as described in step b) of the second example, except that instead of the 4- (4-oxobutyl) benzoic acid ethyl ester used as starting material, this compound was prepared in the same manner as in Example 3-3. The ester obtained in Step 1b is used. This gives the title compound as a yellow viscous oil.

step c)

Preparation of 3- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propenyl] -benzoic acid

Step b)

Preparation of the title compound of the Example

The ester obtained in step a) was hydrolyzed exactly as described in Example 2 c) to give the title compound after recrystallization from acetonitrile / water as a crystalline solid, m.p. 132-137 ° C.

Example 10

The title compound was prepared as described in Example 2 (c) except that the ester obtained in Step b of the present Example was subjected to hydrolysis instead of the ester mentioned therein. Chromatography on silica gel (eluting with 2% methanol in chloroform) afforded a yellow viscous oil.

Step d)

Preparation of the title compound of the Example

A solution of 7.8 g (0.02 mol) of the compound obtained in step c) in 125 ml of ethanol is hydrogenated in the presence of 2.5 g of 5% palladium on carbon at 1 atm and 27 ° C. When the theoretically absorbed amount of hydrogen gas (0.02 mol) has been absorbed, the catalyst is filtered off, the filtrate is evaporated and the resulting residue is chromatographed on silica gel, eluting with 4% methanol in chloroform. This gave the title compound as a colorless viscous oil.

Example 9

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -5,5-dimethyl-4-oxo-2-thiazolidinyl} -propyl] -benzoic acid

the step

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclohexyl) -ethyl] -5,5-dimethyl-4-oxo-2-thiazolidinyl} -propyl] -benzoic acid ethyl ester

5.5 g (0.025 mol) of ethyl 4- (4-oxobutyl) benzoate and

A solution of 1- (2-aminoethyl) -cyclohexanol (3.7 g, 0.026 mol) in toluene (40 mL) was heated to reflux for 5 minutes to remove the water formed as an azeotropic mixture. Thereafter, 3.3 g (0.0275 mole) of 2-mercapto-2-methylpropionic acid are added and the mixture is refluxed for 5 hours using a Dean-Stark water separator. The resulting solution was cooled, washed with 2N hydrochloric acid, water, dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed on a silica gel column (165 g) eluting with chloroform containing 2 volumes of methanol. so

4.6 g of the title ester are obtained as a pale yellow viscous oil.

Preparation of 4- [3- {3- [2- (1-Hydroxy-cyclopentyl) -ethyl] -4-oxo-15-thiazolidinyl} -propyl] -benzoic acid

This compound was prepared in the same manner as in Example 2, except that Example 2 is a compound of Example 1. Steps of step 20 use diclohexanone as the starting material in chemically equivalent amounts of cyclopentanone to give the following compounds in the following steps:

the-first Step 2- (1-Hydroxycyclopentyl) acetonitrile a-2. Step 2- [1- (2H-Tetrahydropyran-2-yloxy) -cyclopentyl] -acetonitrile a-3. Step 1: Amino-2- [1- (2H-tetrahydropyran-2-yloxy) -cyclopentyl] -ethane

Step b: Ethyl 4- [3- {3- [2- (1-Hydroxy-cyclopentyl) -ethyl] -4-oxo-230-thiazolidinyl] -propyl} -benzoic acid

Step c): The title compound of the example

The latter is obtained after recrystallization from acetonitrile as a crystalline solid, m.p. 149-150 ° C.

Example 11

Preparation of 4- [3- {3- [2- (1-Hydroxycycloheptyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoate

This compound was also prepared in the same manner as in Example 2, except that Example 2 is a compound of Example 1. Instead of the cyclohexanone used in Step 1b, the starting material used is a chemical equivalent of cycloheptanone. Thus, in the following steps, the following compounds are obtained:

the-first Step 2- (1-Hydroxycycloheptyl) acetonitrile a-2. Step 2- [1- (2H-Tetrahydropyran-2-yloxy) -cycloheptyl] -50-acetonitrile a-3. Step 1: Amino-2- [1- (2H-tetrahydropyran-2-yloxy) -cycloheptyl] -ethane

Step b: Ethyl 4- [3- {3- [2- (1-hydroxycycloheptyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] -benzoic acid

Step c): The title compound of the example

The latter after recrystallization from acetonitrile

It was obtained as a crystalline solid, m.p. 146.5-147.5'C.

Example 12

Preparation of 4- [3- {3- [2- (1-Hydroxy-4,4-dimethyl-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid

-9181912

This compound was prepared in the same manner as in Example 2, except that Example 2 is a compound of Example 1. Instead of the cyclohexanone used in Step 1, the starting material is chemically equivalent 4,4-dimethylcyclohexanone. In the following steps, the following compounds are obtained: a. Step 2- (1-Hydroxy-4,4-dimethyl-cyclohexyl) -acetonitrile a-2. Step 2- [1- (2H-Tetrahydropyran-2-yloxy) -4,4-dimethyl-cyclohexyl] -acetonitrile a-3. Step 1: Amino-2- [1- (2H-tetrahydropyran-2-yloxy) -4,4-dimethylcyclohexyl] -ethane

Step b: 4- [3- {3- [2- (1-Hydroxy-4,4-dimethyl-cyclohexyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid ethyl ester

Step c): The title compound of the example

The latter is obtained after recrystallization from acetonitrile as a crystalline solid, m.p. 142-143 ° C.

Example 13

Preparation of 4- [3- {3- [2- (4-Hydroxy-tetrahydro-4-thiopyranyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid

This compound was prepared in the same manner as in Example 2, except that Example 2 is a compound of Example 1. Instead of the cyclohexanone used in Step 1, the starting material is chemically equivalent 4-oxo-tetrahydro-thiopyran. In the following steps, the following compounds are obtained: a. Step 2- (4-Hydroxy-tetrahydro-4-thiopyranyl) -acetonitrile a-2, Step 2- [4- (2H-Tetrahydro-pyran-2-yloxy) -tetrahydro-4-thiopyranyl] -acetonitrile a-3. Step 1: 1-Amino-2- [4- (2H-tetrahydropyran-2-yloxy) -tetrahydro-4-thiopyranyl] -ethane

Step b: 4- [3- {3- [2- (4-Hydroxy-tetrahydro-4-thiopyranyl) -ethyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid ethyl ester

Step c): The title compound of the example

The latter is obtained after recrystallization from acetonitrile as a crystalline solid, m.p. 157-157.5 ° C.

Example 14

Preparation of 4- [3- {3- [2- (9-Hydroxy-9-bicyclo [3.3.1] nonyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid

This compound can be prepared as described in Example 2, except that Example 2 is a compound of Example 1. Instead of cyclohexanone used in Step 1, 9-oxobicyclo [3.3.1] nonane is chemically equivalent. Thus, the following compounds are obtained in successive steps:

the-first Step 2- (9-Hydroxy-9-bicyclo [3.3.1] nonyl) acetonitrile a-2. Step 2- [9- (2H-Tetrahydropyran-2-yloxy) -9-bicyclo [3.3. lnonylonyl acetonitrile a-3. Step 1: 1-Amino-2- [9- (2H-tetrahydropyran-2-yloxy) -9-bicyclo [3.3. l] nonyl] ethane

Step b: Ethyl 4- [3- {3- [2- (9-hydroxy-9-bicyclo [3.3.1] nonyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] -benzoic acid

Step c): The title compound of the example

The latter after recrystallization from acetonitrile

It is obtained as a crystalline solid, m.p. 176.5-178 ° C.

Example 15

4- [3- {3- [3- (l-Hydroxy-cyclohexyl) -2-propynyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid

the step

4- [3- {3- [3- (l-acetoxy-cyclohexyl) -2-propynyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid ethyl ester

This compound was prepared according to the alkylation method described in Example 4, step b, except that the starting material used was chemically equivalent to 1-acetoxy-1- (3-) instead of 1- (2-bromoethyl) -cyclohexene. bromo-1-propynyl) -cyclohexane is used. Chromatography on silica gel gave the title ester in 85% yield as a yellowish viscous oil.

Step b)

Preparation of the title compound of the Example

The ester obtained in step a) is hydrolyzed in a manner known in Step c) of Example 2 and the resulting crystalline product is purified by recrystallization from a mixture of acetonitrile and butyl chloride. It then had a melting point of 112-115 ° C.

Example 16

Preparation of 4- [3- {3- [3- (1-Hydroxy-cyclohexyl) - (Z) -2-propenyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid Dissolved in ethyl acetate 4.0 ml g (0.01 mol) of 4- [3- {3- [3- (1-hydroxycyclohexyl) -2-propynyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid, and Hydrogenated in the presence of 0 g of 5% palladium on carbon at 1 atm and 25 ° C. The theoretically absorbed amount of hydrogen gas (0.01 mol) is absorbed in 110 minutes. The catalyst is filtered off, the filtrate is evaporated and the residual oil is chromatographed on silica gel (60 g), eluting with chloroform containing 2% (v / v) methanol. The chromatographically purified product crystallizes. Thus, after recrystallization from butyl chloride

1.4 g of the title compound are obtained, m.p. 118-120 'C.

NMR _(CDCl3): δ 5.14 (1H, m, CH ₂ = -Cfí) and

5.60 (1H, d, J = 12Hz, C7-C-OH).

Example 17

Preparation of 4- [3- {3- [3- (1-Hydroxy-cyclohexyl) -propyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid Dissolve 4.0 g (0.01 mol) in ethyl acetate. ) 4- [3- {3- [3- (1-hydroxycyclohexyl) -2-propimyl] -4-oxo-2-thiazolidinyl} -10181912

and the resulting solution was hydrogenated in the presence of 1.0 g of 5% palladium on carbon at 1 atm and 25 ° C. After 0.01 mole of hydrogen gas has been absorbed (this requires 2 hours), the uptake of hydrogen gas will be extremely slow. A further 1.5 g of catalyst was added and the hydrogenation continued for 70 hours, at which time 0.02 moles of hydrogen gas were absorbed. The catalyst is filtered off, the filtrate is evaporated and the residual oil is chromatographed on silica gel, eluting with 2% methanol in chloroform. The chromatographed product crystallizes on trituration with diethyl ether. 1.2 g of the title compound are obtained, m.p. 118-121'C.

Example 18

Preparation of 4- [3- {3- [3- (1-Hydroxy-cyclohexyl) - (E) -2-propenyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid. Step (E) -1- (3-Diethylamino-1-propenyl) -cyclohexanol

A suspension of lithium aluminum tetrahydride (1.13 g, 0.0299 mol) in diethyl ether (25 ml) was cooled to 0 ° C under N 2 with stirring, and 5.0 g (0.0239 mol) was added dropwise over 30 min. a solution of 1- (3-diethylamino-1-propynyl) -cyclohexanol in diethyl ether (5 ml) while maintaining the temperature of the reaction mixture at 0 ° C to 5 ° C using a bath. After the addition was complete, the cooling bath was removed and stirring continued for 3 hours. The reaction mixture was then cooled again with an ice bath, and the unreacted lithium aluminum tetrahydride was quenched by careful addition of 30 mL of saturated ammonium chloride solution. The reaction mixture was then filtered and the filtered semi-solid washed thoroughly with diethyl ether. The filtrate was combined with the washings, washed thoroughly with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. Yield: 3.41 g (yellow oil).

NMR (CDC1 _3): δ 5.73 (2H, m, CH = CH).

the 2. Step (E) -1- (3-Chloro-1-propenyl) -cyclohexanol

For 200 ml of diethyl ether, a. from the compound obtained in Step

23.4 g (0.11 mol) and 1 g of potassium carbonate, respectively, are added dropwise, and 13.1 g (0.12 mol) of ethyl chloroformate in 30 ml of diethyl ether are added dropwise over 30 minutes with stirring. ether. The reaction mixture was stirred at 25 ° C for 18 hours, then washed with 2N hydrochloric acid and water and dried over sodium sulfate. Subsequent vacuum distillation yielded 11.7 g of N, N-diethylcarbamic acid ethyl ester (boiling point 45-50 ° C at 0.25 mmHg) and 7.4 g of boiling point 88-90 ° C (0, 25 mmHg) to give the title compound.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): δ 4.04 (2H, m, CH ₂ Cl) and 5.80 (2H, m, CH = CH)? Step 1. Preparation of (E) -1- (3-Chloro-1-propenyl) -1- (2H-tetrahydropyran-2-yloxy) -cyclohexane

6.1 g (0.035 mol) of (E) -1- (3-chloro-1-propenyl) cyclohexanol,

A solution of dihydropyran (4.6 g, 0.055 mol) and pyridinium tosylate (0.5 g) in dichloromethane (30 ml) was heated at 25 ° C for 3.5 hours and then washed with saturated aqueous sodium bicarbonate and water, dried over sodium sulfate and concentrated under reduced pressure. This gave 9.0 g of the title compound as a yellowish oil which was used in the next step without further purification.

Step b)

Preparation of 4- [3- {3- [3- (1-2H-Tetrahydropyran-2-yloxy-cyclohexyl) - (E) -2-propenyl] -4-oxo-2-thiazolidinyl} -propyl] -benzoic acid ethyl ester

This compound was prepared as described in Example 4, step b, except that the chemically equivalent starting material used in this example was replaced by the compound of Example-3 instead of 1- (2-bromoethyl) -cyclohexene. The compound obtained in Step 1b is used. Chromatography on silica gel gave the title compound as a yellow viscous oil.

step c)

Preparation of the title compound of the Example

A solution of the pyridinium tosylate (4.5 g, 8.7 mmol) and 220 mg (0.87 mmol) in ester obtained in step (b) in ethanol (50 mL) was allowed to stand at 25 ° C for 2.5 h, then added 1. A solution of 2 g (30 mmol) of sodium hydroxide in 12 ml of water. The reaction mixture was allowed to stand at 25 ° C for 20 hours and then the ethanol was evaporated under reduced pressure. The residue was dissolved in water and the resulting aqueous solution was acidified with 2N hydrochloric acid to precipitate the product as a yellow gum. This resin is then chromatographed on 60 g of silica gel, eluting with 2% methanol in chloroform to give 2.4 g of the title compound as a yellow viscous oil.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ 2.74 (2H, broad t, CH ₂ Ph), 3.55 (2H, broad s, COCH ₂ S), 4.70 (1H, broad d, SCHN), δ , 70 (2H, m, CH = CH) and 6.53 (2H, broad s, OH and CO ₂ H).

Example 19

Preparation of 4- [3- {3- [2- (1-hydroxy-cyclohexyl) -ethyl] -5,5-dideuterio-4-oxo-2-thiazolidinyl} -propyl] -benzoic acid '391 mg (1.0 mmol) 4- [3- {3- [2- (1-hydroxycyclohexyl) ethyl] -4-oxo-2-thiazolidinyl} propyl] benzoic acid and 160 mg (4.0 mmol) of sodium hydroxide in 5 ml of deuterium oxide solution was allowed to stand at 25 ° C for 24 hours and then acidified with 2N hydrochloric acid to precipitate a crystalline product. This was collected, washed with water and air dried.

This gave 288 mg of the title compound, mp 146.5-149 'C.

The absence of a 2-proton signal at δ = 3.54 in the NMR spectrum confirms the presence of two deuterium atoms at the 5-position of the thiazolidinone ring.

Claims (4)

Claims. A process for the preparation of 9-thia-11-oxo-12-aza-prostanoic acids of formula (I) wherein R is carboxy or (1-4C) alkoxycarbonyl, A is phenylene optionally substituted with halogen, m is 0 or 2, R 'represents a hydrogen atom or one of its isotopes or a methyl group, Z is an optionally unsaturated alkylene group containing 2 or 3 carbon atoms; R ³ is hydrogen, R * is a straight or branched alkyl group containing from 3 to 7 carbon atoms, or R ³ and R ⁴ together with the carbon atom to which they are attached form an alicyclic group containing from 5 to 9 carbon atoms and optionally a hydroxy group, or a heterocyclic group containing from 5 to 7 ring carbon atoms and a sulfur or oxygen atom as heteroatom, ) with an aldehyde derivative of the general formula wherein A is as defined in the foregoing ring and R ^{8 is a C} 1-4 alkyl group with a primary amine of the formula IV wherein Z, R ³ and R ⁴ are as defined in the foregoing THP represents a 2H-tetrahydropyran-2-yl group, and then ^four imine compounds of formula (V), wherein A, Z, R ³ , R ⁴ , R ⁸ and THP are as defined above, are reacted with with a thioacetic acid derivative of the formula wherein R ¹ is as defined above, a thiazolidinone compound of formula VII is obtained wherein R ¹ , R ³ , R ⁴ and R ⁸ are as defined above, treated with a strong acid, and the resulting compound of formula VIII (wherein R ¹ , R ³ , R ⁴ and R ⁸ are as defined above) is subjected to basic hydrolysis and, if desired, a A compound of formula (I) wherein R is carboxyl is esterified to a compound of formula (I) wherein R is alkoxycarbonyl and / or oxidized to a compound of m = 2. 2. A process according to claim 1, wherein 0.1 mole of strong acid is used per mole of the compound of formula VII. 3. A process for the preparation of a pharmaceutical composition, characterized in that a compound of the formula (I) produced by the process of claim 1, wherein R is carboxy or (1-4C) alkoxycarbonyl, A is phenylene optionally substituted with halogen, m is 0 or 2, R is ^L is hydrogen or one isotope or methyl, Z is an unsaturated alkylene group containing 2 or 3 carbon atoms, R ³ is hydrogen, R ⁴ is a straight or branched alkyl group containing from 3 to 7 carbon atoms, or R ³ and R ⁴ taken together with the carbon atom to which they are attached form an alicyclic group containing from 5 to 9 carbon atoms and optionally a hydroxy group or a heterocyclic group containing from 5 to 7 ring carbon atoms and sulfur or oxygen atoms as heteroatoms; mixed with excipients in a manner known per se to form a pharmaceutical composition. 4 sheets of formula drawing