HU184340B - Process for preparing 4-substituted pgi down 1 derivatives - Google Patents

Abstract

The PGIi derivatives of formula I according to the invention have anti-aggregation properties and have moderate smooth muscle stimulating and cytoprotective effects. -1-

Description

The PGI1 derivatives of the general formula I according to the invention have anti-aggregation properties, moreover have moderate smooth muscle stimulating and good cytoprotective effect.

-1184,340

The present invention relates to a novel 4-substituted PGI _t- derivative of formula I wherein R is hydrogen, an alkali metal cation, an ammonium cation optionally substituted by one or more C 1-6 alkyl groups, or a C 1-4 alkyl group,

R ¹ and R ² are trialkylsilyl containing C 1-4 alkanoyl, tetrahydropyranyl or C 1-4 straight or branched alkyl,

X is hydrogen, chlorine, bromine or iodine or phenylselenyl,

One of X and Z is hydrogen and then the other is Ι-ethoxyethoxy, hydroxy or C 1--C alk alkoxy or halo, or

Y and Z together represent an oxo group.

It is substituted at the new 4-position of formula I

PGIi derivatives are prepared according to the invention by:

a) 4-substituted PGF derivatives of formula I wherein X, H, and Y or Z are hydrogen, wherein R, R ¹ , R ^2, and Z or Y are as defined herein, are prepared using a 4-substituted PGF of formula II Compound _2a , wherein R, R ¹ , R ² , Y and Z are as defined herein, is reacted with mercury (II) acetate or mercury (II) trifluoroacetate in the presence of an acid scavenger, and the resulting mercuric compound is reacted with a complex metal hydride, or

(b) X is other than hydrogen; and

A 4-substituted PGF _2a derivative of the Formula I wherein R, R ¹ , R ² and Z or Y are as defined in the 4-position of formula I wherein Y or Z is hydrogen; , R ¹ , R ² , Y and Z are as defined herein, with an electrophilic reagent of formula XL, wherein X is as defined herein except hydrogen and L is halogen or X is halogen is a succinimido group, and compounds of formula I obtained by process a) or b) wherein Y or Z is hydroxy, wherein R, R ¹ , R ² , X and Z or Y are as defined herein, if desired, or ethyl vinyl ether either by reaction with a C 1-4 alkylating agent, Y or Z containing 1-ethoxyethoxy or a C 1-4 alkoxy group, or an ox reacting with an idylating agent to form a compound of formula I wherein Y and Z are an oxo group

- where R, R ¹ , R ² and X are as defined in the scope of the invention and / or, if desired, from compounds of formula I wherein R is hydrogen - wherein R ¹ , R ² , X, Y and Z are in the scope with a given base to form a salt.

Calcium carbonate is preferably used as the acid scavenger in process a). In process b), elemental bromine, iodine, optionally addition salts thereof with potassium bromide or potassium iodide, phenylselenyl bromide, phenylselenyl chloride, and N-bromosuccinimide are preferred as electrophilic reagents of formula X-L.

The alkylation included in the subsequent conversions,

-ethoxyethylation at the Z or Y hydroxyl groups or their oxidation to the oxo group can be accomplished using reaction conditions and reagents known per se. For example, alkylation with diazoalkanes, 1-ethoxyethylation with ethyl vinyl ether, and oxidation with pyridinium chlorochromate are preferred.

The resulting acids (wherein R is hydrogen) can be converted into salts in a manner known per se, for example by reaction with bases. Suitable bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal alkoxides, ammonia, and ammonium hydroxides substituted with one or more C 1-6 alkyl groups. Salt formation can improve the solubility of molecules in water. In some cases, purification or formulation is easier when the active ingredient is in the form of a salt.

The starting materials of formula II are prepared by oxidation of the appropriately substituted PGF _2a , with selenium dioxide followed by optional substitution at the 4-position of the separated compound containing the 4-hydroxy group.

Further details of the present invention are illustrated by the following non-limiting examples.

Example 7

5-Bromo-4-hydroxy-1,115-di-O-acetyl-PGI i-methyl ester

148.3 mg (0.31 mM) of 4-hydroxy-1,1,15 di-O-acetyl-PGF _2a -methyl ester are dissolved in 6 ml of a 1: 1 mixture of anhydrous tetrahydrofuran and anhydrous chloroform. The solution was cooled to -78 ° C with dry acetone-ice, rinsed with argon and 60.52 mg (0.34 mM) of solid N-bromosuccinimide was added. The acetone-dry ice bath was removed and the reaction temperature was allowed to rise to room temperature and stirred at room temperature for an additional 20 minutes. The reaction mixture was diluted with ether (30 mL), and the organic layer was washed with water (5 mL), dried over magnesium sulfate, filtered and evaporated. The crude title compound was evaporated to yield 160 mg (94.3%). The crude product appears as three spots in a 15: 1 dichloromethane-acetone run at 0.29.0.41 and 0.5 Rf.

The product spots can be separated by column chromatography with dichloromethane-acetone (25: 1), but the crude product can be directly passed on for further reactions.

Analytical data: .......

TLC: silica gel G sheet, 15: 1 dichloromethane-acetone Rf 0.29.0.41 and 0.5 (phosphorus-dibenzoic acid).

NMR (CDCl 3, δ)

5.4-5.6 (m, 2H, olefin protons)

5.1-5.25 (m, 2H, CHOAc)

4.5-4.85 (m, 1H, CHOAc)

4.25 (t, 1H, CHO)

4.05 (t, 1H, CHO)

3.65 (s, 3H, _CH3 O)

3.15 (m, 1H.CHBr)

2.05-2.08 (s + s) 3H + 3H, CH ₃ O 0.9 (t, 3H, CH ₂ CH ₃ )

184,340

Example 2

5-iodo-4-hydroxy-1,115-di-O-acetyl-PGI! methyl ester

The procedure described in Example 1 was followed, except that methylene chloride was used as the reaction medium and 82.50 mg (0.325 mM) of iodine in 3 ml of methylene chloride was added instead of N-bromosuccinimide. This gave 169.5 mg (0.285 mM) (92%) of the title compound. 10

Analytical data:

TLC: silica gel G sheet, 15: 1 dichloromethane-acetone, Rf = 0.53,0.45 and 0.35. (Caller: Phosphformolybdic acid.)

NMR (CDCl 3, δ)

5.41-5.55 (m, 2H, olefin protons)

5.15-5.3 (m, 2H, CHOAc)

4.55-4.90 (m, 1H, CHOAc) 20

4.20 (t, 1H, CHO)

4.15 (t, 1H, CHO)

3.7 (s, 3H, _CH3 0)

Example 3

5-Phenylselenyl-4-hydroxy-1,115-di-O-acetyl-PGI-methyl ester

The procedure described in Example 1 was followed except that 76.69 mg (0.325 mM) of phenylselenyl bromide was added to the reaction mixture instead of N-bromosuccinimide. This gave 177.9 mg (90%) of the title compound. 35

Analytical characteristics:

TLC: silica gel G sheet, 15: 1 dichloromethane-acetone Rf 0.25, 40 0.35 and 0.4.

The sheets may be exposed to UV light or phosphomolybdic acid.

NMR (CDCl ₃ , δ)

7.2-7.6 (m, 5H, aromatic protons) 45

5.4-5.6 (m, 2H, olefin protons)

5.1-5.3 (t, 1H, CHOC)

4.85-5.0 (t, 1H, CHO)

4.3-4.6 (t, 1H, CHO)

3.7 (s, 3H, CH ₃ O) 50

3.2- 3.4 (m, 1H, CHSe)

Example 4

4-Hydroxy-11,15-di-O-acetyl-PGI 1-methyl ester

250 mg (0.53 mM) of 4-hydroxy-11,15-di-O-acetyl-PGFα-methyl ester are dissolved in 5 ml of tetrahydrofuran.

To the solution was added 265, 2 mg (2.65 mM) of calcium 60 carbonate. To the resulting suspension was added mercury (II) acetate (203.9 mg, 0.64 mM) at room temperature. The reaction mixture is stirred for one hour, and then the precipitated X is CH ₃ -COO-Hg, Z is hydrogen, Y is hydroxy,

The tetrahydrofuran is removed from the compound of formula I wherein R ¹ and R ^{2 are} CH ₃ CO and R is methyl by decantation, the residue is suspended in 5 ml of ethanol and cooled to -20 ° C. At this temperature, 120.17 mg (3.18 mM) of sodium borohydride are added to the reaction mixture and stirred for two hours. The reaction mixture was then diluted with ether (50 mL), washed with water, brine, dried over magnesium sulfate, filtered and evaporated. The evaporation! Yield: 207.5 mg (83%). As an epimer mixture, it contains essentially only the title compound. TLC: silica gel G sheet, 15: 1 dichloromethane-acetone Rf 0.43, 0.55,0.61.

Similar results are obtained when 272.9 mg of mercury (II) trifluoroacetate is used instead of 203.9 mg of mercury (II) acetate.

Example 5

5-Bromo-4-hydroxy-1,15-bis (O-tetrahydropyranyl) -PGI _X -methyl ester

The procedure of Example 1 is followed with the difference that instead of 4-hydroxy-1,15-di-O-acetyl-PGF _2a methyl ester 171.6 mg (0.31 mM) of 4-hydroxy-1 l 15-bis (O-tetrahydropyranyl) -PGF ₂₀ , methyl ester was weighed and calcium carbonate (155.1 mg, 1.55 mM) was used as an acid scavenger. 156.12 mg (85%) of the title compound are obtained.

On a silica gel G sheet with a benzene-ethyl acetate 2: 1 run, the title epimer product mixture was 0.45 and 0.50 Rf. The plates are developed with phospho-dibenzoic acid.

Example 6

5-Bromo-4-chloro-11,15-di-O-acetyl-PGI 1 -methyl ester

The procedure described in Example 1 was followed except that 150.97 mg (0.31 mM) of 4-hydroxy-1,115-di-O-acetyl-PGF _{2a was} replaced by 4-chloro-1. 1,15-Di-O-acetyl-PGF _2a -methyl ester was weighed. 157.9 mg (90%) of the title product are obtained.

The product appears on a silica gel G sheet in a 20: 10: 1 mixture of benol-dioxane-acetic acid at 0.5 and 0.55 Rf.

The sheets were developed with phosphformolybdic acid.

Example 7

5-Bromo-4-ethoxy-ethoxy-1,15-di-O-acetyl-PGI 1-methyl ester

270 mg of 5-bromo-4-hydroxy-11,15-di-O-acetyl-PGI, methyl ester are dissolved in 5 ml of anhydrous dichloromethane and 460 µl (355 mg) of ethyl vinyl ether and 1 drop of 10% p-toluenesulfonic acid solution in tetrahydrofuran. The reaction mixture was stirred for 20 minutes at room temperature. The p-toluenesulfonic acid catalyst is then neutralized with 1 drop of triethylamine, and the reaction mixture is diluted with 70 mL of dichloromethane, 2.5% sodium hydroxide,

-3184 340 gene carbonate solution. The organic phase is dried over magnesium sulfate, filtered and evaporated. The crude product was chromatographed with 25: 1 dichloromethane-acetane. Fractions at 0.65 and 0.55 in a 15: 1 dichloromethane-acetone mixture were collected and evaporated on a silica gel analytical sheet. 179.8 mg (58%) of the title product are obtained.

Example 8

5-Bromo-4-oxo-1 1,15-di-O-acetyl-PGI i-methyl ester

Pyridinium chlorochromate (543.1 mg, 2.52 mM) was suspended in anhydrous dichloromethane (5 mL) and glacial sodium acetate (41 mg, 0.5 mM) was added followed by 5-bromo-4-hydroxy (115 mg, 0.21 mM) at room temperature. a solution of 1,15-di-O-acetyl-PGIi-methyl ester in 2 ml of anhydrous dichloromethane. After stirring at room temperature for 7 hours, dichloromethane (5 mL) and ether (10 mL) were added. The organic layer was filtered over Celite 545 (Fischer) and the filtrate was evaporated.

The crude product (150 mg) was chromatographed on a silica gel column in dichloromethane-acetone (30: 1) and the fractions at 0.59 Rf in a 15: 1 dichloromethane-acetone eluent were collected and concentrated to a total of 77 mg. Yield: 68%.

Analytical characteristics:

TLC: silica gel G sheet, 15: 1 dichloromethane-acetone, Rf = 0.59.

NMR (CDCl ₃ ,)

5.4-5.65 (m, 2H, olefin H)

5.05-5.35 (m, 2H, CH

4.1-4.6 (m, 2H, CHO)

3.65 (s, 3H, _CH3 O)

2.9-3.2 (m, 3H, _CH2 CHBr + C0)

2.05 (s, 6H, CH 3 CO).

Example 9

5-Bromo-4-methoxy-1,1,15-di-O-acetyl-PGI 4-methyl ester mg (0.1 mM) 5-bromo-4-hydroxy-1,115-di-O-acetyl-PGI Methyl ester was dissolved in ether (10 mL), cooled to 0 ° C, and silica gel (3 g) was added. 18 mM diazoinethane was bubbled into the slurry for 3 hours under a stream of nitrogen. (Tetrahedron Letter 1979, 4405.)

After stirring for an additional hour, the silica gel was filtered off and the ethereal solution was evaporated. The crude product is chromatographed on a silica gel column with dichloromethane-acetone (30: 1) and the product fractions of the dichloromethane-acetone (15: 1) at 0.83 Rf are collected and evaporated.

36.5 mg (65%) of the title compound are obtained. NMR (CDCl ₃ , 6)

3.2 (s, 3H, CH 3 OCH).

Example 10

5-phenylselenyl-4-hydroxy-1,15-di-O-acetyl-PGI _r

250 mg (0.55 mM) of 4-hydroxy-1,115-di-O-acetylPGF _{2a are} dissolved in 0.5 ml of acetic acid. The solution was cooled to 0 ° C and 80 ₃ 8 pl (0.58 mM), distilled triethylamine were added. After stirring for 5 minutes, add to solution

1.15 ml of a 0.5 mM / Ι solution of phenylselenyl chloride in dichloromethane is added dropwise. After stirring for 1 hour at 0 ° C, the reaction mixture is mixed with 100 ml of ether and washed three times with 10 ml of water. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure.

The residue was evaporated to give 207.8 mg (62%) of the title compound. The product gave three spots by TLC at 0.5, 0.55 and 0.62 Rf. Running was performed with a 20: 10: 1 mixture of benzene-dioxane-acetic acid and a 2: 1 mixture of benzene.

Example 11

5-Bromo-4-hydroxy-1,115-bis (O-dimethyl-tert-butylsilyl) -PGIi-methyl ester

In the same manner as in Example 1, the starting material was replaced by 186.8 mg of 4-hydroxy-11.15 instead of 148.3 mg of 4-hydroxy-11,15-di-O-acetyl-PGF ₂ '-methyl ester. - bis (O-dimethyl-ter-butyl-silyl) -PGF _{2 σ-} methyl ester was used.

Yield: 198.6 mg (91%). Rf = 0.45, 0.6 and 0.7 (30: 1 in dichloromethane-acetone).

Example 12

Sodium salt of 5-phenylselenyl-4-hydroxy-11,15-di-O-acetyl-PGI _x

150 (0.246 mM) of the acid prepared in Example 10 was dissolved in 200 μΐ of methanol and 246 μΐ ΙΜ of aqueous sodium hydroxide solution was added. The reaction mixture was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. This gave 155 mg of the title salt as a white crystalline powder. The Rf values of the product are the same as in Example 10.

Example 13

5-phenylselenyl-4-hydroxy-ll, 15-di-O-acetyl-PGI! sodium salt

All proceed as in Example 12 except that to a solution of 150 mg of the acid prepared in Example 10 and 200 μΐ of methanol was added 246 μΐ of methanolic sodium methoxide solution instead of aqueous sodium hydroxide.

155 mg of the title salt are obtained. Rf values are the same as in Example 10.

-4184 340

Example 14

Ammonium salt of 5-phenylselenyl-4-hydroxy-1,115-di-O-acetyl-PGI1

The methanolic acid solution was prepared as in Example 12, saturated with ammonia at room temperature, and then concentrated under reduced pressure to give the title salt as a evaporation residue. The Rf values are the same as in Example 10.

Example 15

5-Phenylselenyl-4-hydroxy-1 1,15-dl-O-acetyl-PGF-tetrabutylammonium salt

Proceed as in Example 12, except that 246 μθ ΙΜ of methanolic tetrabutylammonium hydroxide solution was added 2θ. The title salt obtained by evaporation of the reaction mixture has the same Rf values as in Example 10.

Claims (7)

Patent claims A process for the preparation of a novel 4-substituted PGI] derivative of the Formula I wherein R is hydrogen, an alkali metal cation or a C ¹⁴ -C 30 alkyl group, R ¹ and R ² are trialkylsilyl containing C 1-4 alkanoyl, tetrahydropyranyl or C 1-4 straight or branched alkyl, X is hydrogen, chlorine, bromine or iodine or phenyl selenyl; One of Y and Z is hydrogen and the other is then 1-ethoxyethoxy, hydroxy or C 1-4 alkoxy or halogen, or Y and Z together form an oxo group, characterized in that (a) PGI] derivatives of the formula I in which X is hydrogen and Y or Z is hydrogen, wherein R, R ¹ , R ² and Z or Y is as hereinbefore defined for the preparation of a 4-substituted PGF _2a derivative of formula II wherein R, R ¹ , R ² , Y and Z are as defined herein, with mercury (II) acetate or mercuric acid. (II) -trifluoroacetate in the presence of an acid scavenger, then reacting the resulting mercuric compound with a complex metal hydride, or (b) X is other than hydrogen; and A 4-substituted PGF _2a derivative of the Formula I wherein Y, or Z is H, substituted in the 4-position, wherein R, R ¹ , R ² and Z or Y are as defined herein, a 4-substituted PGF _2a derivative of Formula II wherein R, R ¹ , R ² , Y and Z are as defined herein for an electrophilic reagent of Formula XL wherein X is as defined in Go, except hydrogen; and Reacting a halogen atom or X a halogen atom to form a succinimido group, then reacting a compound of formula I obtained by process a) or b), wherein Y or Z is hydroxy, wherein R, R ¹ , R ² , X and Z or Y is as defined in the art - optionally reacted with either ethyl vinyl ether or a C 1-4 alkylating agent, Y or Z having í-ethoxyethoxy or C 1-4 alkoxy, or reacting with an oxidizing agent at Y and Z a compound of formula (I) wherein R, R ¹ , R ² and X are as defined herein and / or, if desired, a compound of formula I wherein R is hydrogen, wherein R ¹ , R ² , X, Y and Z represents a salt with the base indicated in the disclosure. (Priority: June 27, 1980) 2. A process for the preparation of new 4-substituted PGI 1 derivatives of the formula I - the azole R ¹ , R ² , X, Y and Z have the same meaning as in claim 1 and R is hydrogen - optionally one or more For the preparation of a C 6 alkyl substituted ammonium salt, characterized in that a new 4-substituted PGI ¹ derivative of the formula I containing H is hydrogen - wherein R ¹ , R ² , X, Y and Z are as defined in claim 1. with ammonia or with ammonium hydroxide optionally substituted with one or more C 1-6 alkyl groups. (Priority: 05.05.1983) 3. Process for the preparation of process b) according to claim 1 for the preparation of compounds of formula I wherein X is bromine, wherein R, R ¹ , R ² , Y and Z are as defined in claim 1, characterized in that the reagent used is N-bromosuccinimide. (Priority: June 27, 1980) B) 4. The process of claim 1 embodiment of compounds of formula where X represents iodine - wherein R, R ^1, R ^2, Y and Z are as defined in Claim 1 - for the preparation, wherein the XL electrophiles of formula elemental iodine is used as reagent. (Priority: June 27, 1980) A process for the preparation of process b) according to claim 1 for the preparation of compounds of formula I wherein X is phenylselenyl wherein R, R ¹ , R ² , Y and Z are as defined in claim 1, characterized in that The electrophilic reagent of formula (II) is phenylselenyl bromide. (Priority: June 27, 1980) 6. A process according to claim 1, wherein the reaction is carried out with mercury (III) acetate in the presence of calcium carbonate and the complex metal hydride is sodium borohydride. (Priority: 27.7.1980) 7. A process for the preparation of compounds of formula I wherein Y, and Z are an oxo group in which Y, Z, R ² and X are as defined in claim 1, characterized in that the subsequent oxidation is carried out by pyridinium with chlorochromate. (Priority: