HU182013B - Process for producing 7-oxo-pgi-two down and analogous compounds - Google Patents

Abstract

The novel biologically active compounds of formula (I) according to the present invention have a number of valuable pharmacology! anti-aggregation and antihypertensive effect. -1-

Description

η is a subject. process for the preparation of the new 7-'U-u-IGI of formula I. ₎ mouth: small - where hydrogen, a pharmaceutically acceptable cation or a C 1-4 alkyl group,

X -011 = 011- or -C = C-,

Y is a methyl group or an oxygen atom,

R1 and R2 are independently hydrogen or C1-C4 alkyl,

C 1 -C 6 alkyl, or Y in the case of oxygen optionally substituted by halogen,

IC represents a 1-alkoxyalkyl group having 1 to 4 carbon atoms or a C 1 -C 4 alkyl group, R ⁶ hydrogen atom, tris-C 1 -C 4 alkylsilyl group or C 1 -C 4 alkyl group or a C 1 -C 4 alkanoyl group.

The novel biologically active compounds of formula I, which can be prepared according to the invention, are considered as stabilized analogs of the highly potent natural substance, PGIg. The first introduction to PGI / prostacyclin is described in Natura. 263, 663 (1976). The substance is considered to be one of the most valuable links in the metabolism of arachldonic acid and is very low in potency. Many valuable pharmacology! Among its effects is the anti-aggregation and antihypertensive effect. Even at nanograms, RGIp prevents platelet aggregation and dissolves already aggregated thrombi. Because of its unique pharmacological action, it can be an extremely valuable pharmacon in the treatment of our century's disease, thrombosis and abnormal hemostasis. To date, numerous reports have been published on the clinical use of the substance.

The biggest problem with using RGI _{2 as a} medicine is the extreme instability of the substance; it undergoes immediate disintegration into 6-oxo-PGF1- in an acidic or neutral medium. PGTp contains a highly reactive enol-ether moiety that reacts immediately with an external or internal proton source. so, PGI _? is not viable in the free acid form, its salts and esters are used in pharmacology! and in clinical trials.

One of the most sensible ways of stabilizing PGI-2 is by reducing the reactivity of the enolether double bond in the edge electron with minimal structural change. In principle, electron withdrawing or conjugating functional groups in the O-position relative to the double bond reduce the reactivity of the enol ethers.

In the compounds of formula I having an oxo group at position 7 of the present invention, the oxo group stabilizes the enol ether structure while preserving the valuable pharmacological effects of PGIg.

The 7-oxo-PGI ₂ derivatives of formula I according to the present invention are prepared by reacting a G-substituted-7-oxo-PGI ₂ derivative of formula II wherein R 1 is hydrogen or a C 1 -C 4 alkyl group. - is a C 1 -C 4 alkyl group

The elements of -2182.013 are removed, and if desired, the protecting groups at Βθ are hydrolyzed in an acidic or basic medium. is removed and / or optionally 1-4 carbon at position Q; thi alkyl is replaced by saponification with a hydrogen atom and, if desired, the hydrogen at the Q is replaced by a salt formation into a pharmacologically acceptable cation.

The starting materials of the formula II can be prepared from the appropriately substituted PGF ₂ -derivatives as disclosed in European Patent Application Publication No. 0031 426.

Compounds of formula I wherein Βθ is hydrogen may be prepared at the substituent R · ³ of C1-4 alpha ^. from compounds of formula II wherein R ⁶ is hydrogen, by elimination of an alcohol of formula R ¹ -OH. Elimination of the alcohol used különböíző bipolar aprotic solvents - by heating - such as a title of 11 fojpmamidban, szulfoxldban dimethylformamide, hexamethylphosphoric acid triamid- ^Λ Ban. The temperature of the reaction mixture can be varied over a wide range, from 70 to 180 θθ. Alcohol release agents such as acid anhydrides, benzene, toluene, etc. may be used to accelerate the elimination. The use of acid anhydrides also produces compounds of formula I wherein Iθ is acyl, which may, if desired, be hydrolyzed by base-catalyzed alcoholysis.

The compounds of formula I formed by the elimination reactions, wherein Q is alkyl of 1 to 4 carbon atoms, are preferably isolated after purification by column chromatography.

Compounds of formula I wherein p6 is a hydroxy protecting group may be prepared from compounds of formula II wherein B5 is C1-C4 alkyl, R6 is hydroxy protecting group by the above-described elimination reaction. Ro is, according to the invention, a tris (C 1 -C 4) alkylsilyl, a (C 1 -C 4) -alkyl containing 1-alkoxyalkyl or (C 1 -C 4) -alkanoyl. Compounds of formula I wherein R 0 is a protecting group can be isolated after column chromatography and, if desired, can be converted to compounds of formula I wherein R 6 is hydrogen. The removal of the trialkylsilyl protecting groups is preferably carried out with tetrabutylammonium fluoride in ether-type solvents, preferably tetrahydrofuran, at a temperature of -20 to 50 ° C, preferably at room temperature. For the removal of acyl protecting groups, an alcoholic base substituted with a weak base, preferably potassium carbonate or alkali metal alcohol, in C1-C4 alcohols, preferably methanol, is suitably in the range of 0-350 DEG C., preferably at room temperature. Compounds of formula II wherein R5 is hydrogen and R0 is a protecting group are prepared by elimination of water elements to give compounds of formula I. The above compounds can be converted to compounds of formula I having a protecting group at position Βθ by boiling in the presence of water-binding agents in aromatic hydrocarbons. After deprotection, compounds of Formula I wherein Q is C1-C4 alkyl, R6 is hydrogen, may be purified by chromatography.

Q is a pharmacologically acceptable cation

Compounds of formula (I) -1882.013 may be obtained from esters of formula (I) containing a C1-C4 alkyl group at the Q position by aqueous alkaline hydrolysis / acidification. As a hydrolyzing agent, can aqueous solutions of hydroxides of alkali and alkaline earth metals be used at 0-100 ° C to lyophilize the salts? after isolation. Carboxylic acids can be liberated from aqueous solutions of salts by careful acidification and can be further converted into aliphatic and aromatic amines in organic solvents.

The 7-oxo-PGI ₂ derivatives of the present invention exhibit the following inhibition of aggregation. -------------------------------......------------- ------------ 1-10-4 Moles of ADP inhibited rabbit platelet rich plasma / PPP / aggregate concentrations of 100-1000 ng / ml.

Plasma isolated from human blood contains 2 x 10 6 moles of ADP and a

Collagen-induced aggregate 2.5-5.0 / ug / ml was inhibited at concentrations of 10-100 ng / ml. Measurements were made using the Born method.

The anesthetized dog's blood pressure is reduced by 10-16% when administered as an intravenous infusion of 1000 ng / kg / minute. This is 0.1-0.05 times the effect of PGI ₂ . ..

Oxo-PGI ₂ and its derivatives of the formula I are stable compounds, their free carboxylic acids can also be isolated, their esters can be kept in solution for a long time without any detectable decomposition. * Further details of the invention are provided without limiting the invention.

Example 1

7-0xo-PGI ₂ methyl ether

-------------- 6-Methoxy-7-oxo-PGI, methyl ester-11,15-bis-tert-butyl-dimethyl ( ₂₀ / 0.31 mmol) -Silyl / ether is dissolved in 5 ml of hexamethylphosphoric triamide. The reaction mixture was stirred at 150-160 ^° C for three hours and then poured into 18 ml. The aqueous layer was extracted with ethyl acetate (3 x 15 mL), and the combined ethyl acetate extracts were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated. The residual product (250 mg) was dissolved in tetrahydrofuran (5 ml) and stirred at room temperature for 3 hours after addition of 2 equivalents of tetrabutylammonium fluoride. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The residual oil was chromatographed on silica gel (10 g) with ethyl acetate. 62 mg (50%) of the title compound are obtained in the form of a colorless oil

R f = 0.44 with ethyl acetate.

^L II NLIB: <£ 5.57 (1H, t, 0-0 = 011 /, 3.76 / 3H, s, -COOCH3 /

Example 2

7-0xo-PGI ₂ methyl ester

-4182.013

Dissolve 200 mg (0.31 mmol) of 6-hydroxy-7-oxo-FGI _{1 ·} -methyl-methyl-11,15-bi-tert-butyldimethylsilyl ether in 30 ml of anhydrous benzene and anhydrous magnesium and boiled in a Soxhlet extractor containing wood for 2 hours. The organic layer was washed with water and then with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated. The crude product is treated with two equivalents of tetrabutylammonium fluoride in tetrahydrofuran and the reaction mixture is worked up as described in Example 1. Chromatography on silica gel (10 g) with ethyl acetate afforded 52 mg (45%) of the title compound as a colorless oil.

Example J 6-Methoxy-7-oxo-FGIn methyl ester of -Oxo-PG 4 -methyl and zester mg (0.215 mmol) was dissolved in 0.8 mL of hexamethylphosphoric triamidyl and the reaction mixture was heated at 140-150 ° C for 2 hours. Stir at C. The reaction mixture was worked up as in Example 1. The residual oil was chromatographed on silica gel (10 g) with ethyl acetate. This gave 40 mg (47%) of the title compound as a colorless oil.

Example 4

7-Oxo-11,15-di-O-ac-ethyl-PGI ₂ -methyl

100 mg of 6-methoxy-7-oxo-11,15-di-O-acetyl -? - ₁ -methyl ester is dissolved in 3 ml of hexamethylphosphoric triamide and stirred in ^x 0.05 ml of acetic acid for 80 hours to 100 ml. 0 ° C. The digestion mixture is further treated as described in Example 1 below. The crude product was chromatographed on silica gel (15 g) with EtOAc / hexane / Iso. This gave 70 mg (72%) of the title compound as a colorless solution.

R f = 0.65 with ethyl acetate-hexane (1: 1). 1 H NMR (in CD017): 5.05-5.53 (5H, m), 4.98 (1H, m), 3.6?

....______________________ _________ / JH, s /, 2.16 and 2.08 / 2x3H, s / ,. 0.97 / 3Η, t / pp ^.

5 · Example

16,16-Dlmethyl-N-oxo-PGIg-methyl ester mg / 0.21 mmol / 6-methoxy-7-oxo-16,16-dimethyl-PGI, methyl ester was dissolved in 1 ml of hexamethylphosphoric acid trlamide and The reaction mixture was stirred at 140-150 ° C for 2 hours. In the following, we proceed as in Example 3. 50 mg (56%) of a colorless oil are obtained.

R t 0.41 hexane-EtOAc gave 2rteiegyével- ~ ⁱ '

1 H NMR (CDCl 3) δ t 5 * 55 / 2H, n /, 5.34 (1H), t /, 4.98 (1H, m /), ^p 4.1-4.3 (2H, m /) 3.67 / 3H, a / ppm.

Example 6

7-0xo-PGl2 * sodium salt

-5182.013 > 0 mg / 0.13 mmol N, O-oxo-PGIg-ethyl ester is dissolved in 0.1 ml of motanol and 1.4 ml of 0.1 N aqueous sodium hydroxide solution is added and the reaction mixture is stirred at room temperature for 24 hours. The solution is lyophilized.

55 mg of the title compound are obtained in the form of a white mass. R: 0.37 is carried out with 20: 10: 1 benzene dioxane-acetic acid.

The solid thus obtained from the reaction mixture has no characteristic melting point or decomposition point. The material is used as an aqueous solution which is uniform in the above chromatographic system.

7 · example.

7-Oxo-PGIg720 mg / 2 mmol / 7-oxo-PGI _? Methyl ester was dissolved in methanol (20 mL) and sodium hydroxide solution (4 mL, 1 N) was added and the reaction mixture was stirred at room temperature for 5 hours. The methanol was removed in vacuo and the residue diluted with water to 30 ml with 5% aqueous sodium hydrogen sulfate solution.

It was acidified to 3 and extracted with ether (3 x 20 mL). The combined organic phase is saturated with water? washed with aqueous sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off.

This gives 625 mg (90%) of an oil which solidifies on standing in a refrigerator.

M.p. 55-60 ° C

_Rf: 0.37, benzene-dioxan-acetic acid 20: 10: 1 mixture of runs ¹ open.

Example 8

7-Oxo-13,14-didehydro-11,15-dl-O-ao e tI-PGIg

410 mg / 1 mmol / 6-methoxy-7-oxo-13,14-didehydro-11,15-di-O-acetyl-PGI, methyl ester was dissolved in 5 ml of hexamethylphosphoric triamide and 0.3 ml of acetic acid. in the presence of anhydride at 80-100 ° C for 2 hours. The reaction mixture is further worked up as in Example 1. The crude product is chromatographed on silica gel (25 g) with exane ethyl acetate (7 x 3). This gave 260 mg (70%) of the title compound as a colorless oil.

R f: 0.52 with 2: 1 hexane-ethyl acetate.

TI NMR / CDC1, /: 5.05 to 5.5 / 4H, m /, 3.7 / 3H, s, COOCH, /, 3.2 to 3.4 ⁹ / 2H, d / 2.1, 1.9 (2x3H, s, -COOH, // 0.98 / 3H, t, -CH3). >

Example 9

7-Oxo-13,14-dldehldro PGIg-methyl ester

342 mg / 0.775 mmol / 7-oxo-13,14-didehydro-11,15-di-0-a-cetyl-PGIg methyl ester was dissolved in 10 mL dry methanol and added 0.38 mL / 0.38 mmol / In methanolic sodium methoxldol data. The reaction mixture was stirred under nitrogen for 4 hours at room temperature. Most of the methanol was distilled off in vacuo, and the residue was dissolved in ether (30 mL), water,

-6182.013 was washed with aqueous sodium chloride solution. After drying over sodium sulfate, the mixture is filtered and the solvent is distilled off. The residue was chromatographed on a silica gel column (30 g) with a 1: 1 mixture of ethyl acetate-hexane (0.5% trlethylamine). This gave 254 mg (87%) of the title compound as a colorless oil.

R _f t 0.35 hexane: ethyl acetate (1: 1), NMR (C 8 D 8): 5.58 (1H, t, 0-5-H), 4.9 (1H, m, C-9). H /,

4.2-4.4 (211, m /, 3.4 / 311, s, ~ COOCH3),

Example 10

7-0x0-13,14-Didehydro-PGI ₂ 45 mg / 0.12 mmol / 7-oxo-13,14-didehydro-PGI ₀ -methyl ester is dissolved in 2 mL of methanol, then added with 1.2 mL of ^ / 0.24 mmol / 0.2 N aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature for 4 hours. Most of the methanol was evaporated in vacuo and the residue was diluted with 2 mL of water and acidified to pH 3 - 1 with 0.2 M aqueous sodium bisulfate. The aqueous layer was extracted with ether (3 x 5 mL), and the combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and the solvent was evaporated. 40 mg (92.5%) of the title compound are obtained in the form of a colorless oil.

R f = 0.46 in benzene-dioxane-acetic acid 20: 10: 1.

Example 11

7-0x0-13,14-didehydro-PGI ₂ -dlcyclohexyl-amyl salt ..,

365 mg / 1 mmol / 7-oxo-13,14-didehydro-PGI _? was dissolved in 30 ml of ether and 181 mg / 1 mmol / dlcyclohexylamine was added with stirring. The reaction mixture was stirred at room temperature for 1 hour and then allowed to stand at 0-5 ° C for 24 hours. From the separated thick oil, the solvent was decanted, digested with 10 ml of ether, the solvent was again decanted and finally dried in a vacuum desiccator. 520 mg (95%) of the title compound are obtained in the form of a waxy solid oil.

The salt obtained above was prepared as an aqueous solution at a concentration of 10 mg / ml and used for pharmacological studies.

R f = 0.46, benzene dioxane-acetic acid 20: 10: 1. IR / KBr /: 3410, 3350, 2980, 1730, 1635, 1560, 1100 cm ^1st

Example 12

7-0x0-17,18,19,20-txanor-16-phenoxy-PGI ₉ -methyl-11,15-bis (1-ethoxy-ethyl) -ether.

640 mg (1 mmol) of 6-methoxy-7-oxo-17,18,19,20-tetranor-16-phenoxy-PGI-methyl ester-11,15-bis (1-ethoxyethyl) ether are dissolved. 6 ml of hexamethylphosphoric triamide and the reaction mixture was heated at 150-160 ° C for three hours. Hereinafter, we proceed as in Example 1, da.

This gave 370 mg (60%) of the title compound as a colorless oil.

-7182.013

Rf: * 0.68 ethyl acetate: hexane, 1: 1 mixture. ¹H NMR (CDClj) δ 5.51 (µl, t, O-C = OH), 3.69 (5H, δ, COOGHj).

lj. example

7 ^"Ο χο ~ 15.14 dlde hidx ο 20-methyl-11-L-PGIp RNE 111 zt er-11,15-bis / dimethyl-tert-butyl 5zilil / ether *

500 mg of 6-hydroxy-7-oxo-13,14-dldehydxo-20-methyl-PGI · methyl ester-11,15-bis / diraet 11-ΐθΓ0 - ΛΓΛζζζ1111111;;; dissolved in 20 ml of benzene and refluxed in a Soxhlet extractor containing anhydrous magnesium sulfate for 2 hours. Further, Example 2 gave 375 mg (74%) of the title compound as a colorless oil.

R _f : 0.73, ethyl acetate: hexyl: 1: 1. ¹H NMR (ODOl¹): 5.35 (1H, t, O-C = CH), 3.75 (5H, α, COOCHj).

The following compounds are also prepared in the same manner as described above: 7-oxo-16-methyl-PG 1, 4-methyl ester, 7-oxo-20-methyl-PGI 9 -methyl ester, 7-oxo-15-methyl-PG 12 -methyl ester. , 7-oxo-15-epi-PG12-methyl ester, 7-oxo-15-epi-16,16-dimethyl-PGI _? methyl ester,

7-oxo-15-epl-16-phenoxyl-17,18,19,

20-tetranor-PGIg ester,

7-oxo-15-e p-20-methyl-PGI _2- methyl ester,

7-oxo-16- (m-chlorophenoxyl) -17,18,19,20-tetranox-PGI ₂ -methyl ester, δ 11 NMR: 5.55 (1H, t), 5.40 / 2H, m /, 5.54 (1H), m /, 4.87 (1H), m /, 4.59 (1H), m /, 3.45 (5H), α, (1.81) and 1.75 (5-5H). , a / ppm.

^E r VR _f B _f =

R _f ^e

R =

R _f =

0.49

0.51

0.55

0.50

0.58

0.63

0.55 (with ethyl acetate); / Ethyl acetate /; / Ethyl acetate /; / Ethyl acetate /;

/ Ethyl acetate /;

/ Ethyl acetate /;

/ Ethyl acetate /;

Q x

R ^x

R ^ ^E 6 R °

Claims (10)

1 / A process for the preparation of a biologically active 7-oxo-PGI ₂ derivative of the Formula I wherein: hydrogen, a pharmacologically acceptable cation, or an alkyl group of 1 to 4 azene atoms, -CH = CH- or -C = C-, methylene or oxygen, and R ^{2 is} independently hydrogen or C 1-4 alkyl, C 1-6 -alkyl, or Y is oxygen. © Cetene having optionally substituted phenyl, hydrogen or C 1-4 -alkyl, hydrogen, tris-1-4-azene alkyl-silyl, 1-4-azene alkyl. Represents a 1-alkoxyalkyl group or a C 1 -C 4 alkanoyl group -8182.013 preparation, characterized in that a general formula II-6, a substituted-7-oxo-PGI. derivative - wherein L, B ^2, b5, b4, r6, χ and i are as defined above, and Q 1-4 azénatomos alkilosoportot, B ^ is hydrogen or a C1-4-alkyl - c tellmináoiós reaction of B ² -OH elements - in which B · ⁵ are as defined above - is removed, _g, and optionally consisting of B ° is appropriate protective groups are removed by hydrolysis with VAA or basic medium SEU and / or, if desired, substitution of the (1-4C) alkyl group of Q for hydrogenation by saponification and, if desired, the substitution of the Q-hydrogen atom for salt formation with a pharmacologically acceptable cation. Conceived method as 2 / to claim 1 ősitás one way, characterized in that a lower B> site of the alkyl '' II a carboxyl group of general formula 6-substituted 7-oxo-PGI. - wherein B *, B ^2, b5, β4,, Βθ, X, Y and Q are as defined in claim 1 in a dipolar solvent, optionally in the presence of a C1-C4 alkanoic acid in the presence of an anhydride or an aromatic solvent, at a temperature of 80-130 ° C. 3 / A process according to claim 2, characterized in that 6-methoxy-7-oxo-PGI 4 derivatives of the general formula II wherein B 5 is a methyl group - wherein B ¹ , B ² , r 3, b 1, Βθ, X, Y and Q are as defined in the characterizing part of claim 1, heating is carried out at 140-150 ° C in hexamethylphosphonic triamide. 4 / The process according to claim 1, wherein a B-is a 6-hydroxy-7-oxo-PGI derivative of the Formula II wherein P 1, B ² , b ³ , b 1, Βθ , X, Y and Q, ^{x are} dehydrated by boiling in the presence of a water scavenger in an aromatic solvent as defined in the typical part of claim 1. 5 / Process according to any one of the preceding claims, characterized in that starting from a 6-substituted-7-oxo-PGI.-derivative of formula II in which B 1, B, B 1, B 4, B *, X, Y and Q are as defined in the characterizing part of claim 1 and Βθ is a hydrogen atom, a tert -butyl group; . ethyldimethylsilyl, 1-ethoxyethyl or acetyl. The process according to any one of the preceding claims, wherein 7 "O} -10 ^J1 Gl2 derivatives of the formula I containing hydrogen at the position Βθ are hydrogen, wherein B1, B2, B3, B4, X1, Y and Q are as defined in claim 1. characterized in that a 7-oxo-PGIp derivative of the general formula I is obtained and has a group other than hydrogen, wherein B ¹ , B ² , R ¹ , p ⁴ , χ, Y and Q are as defined in claim 1. hydrolysis. 7 / A process according to claim 6, characterized in that the t-butyldimethyl- at the position Βθ. The silyl group was removed by treatment with rabutylammonium fluoride in tetrahydrofuran at room temperature. -9182.013 8 / A process of Claim G wherein the C 1-4 aliphatic group of R ⁵ is removed in an alkanol of 1-4 carbon atoms with an alkali metal alkoxide. The process according to any one of the preceding claims, wherein the 7-oxo-PGIg derivatives of formula I wherein Q is hydrogen, or a fax macologically acceptable cation, wherein R ¹ , R ² , R ⁴ , R ⁴ , X and I are A process as claimed in claim 1, characterized in that a 7-oxo-PGI 2 derivative of the formula I obtained having Q is C 1 -C 4 alkyl, wherein R ¹ , R ² , r ³ , R 4f _{p 6 f} χ and Y is by saponification in the basic medium as defined in claim 1, then reacting the resulting free acid with a base which produces a pharmacologically acceptable cation, if desired. Process for the preparation of a compound of formula I as an active ingredient according to any one of the preceding claims, wherein R ^{1 is} . R 2, R 1, R 4, R 6, X, Y and Q for the preparation of a pharmaceutical composition having an anti-aggregation effect as defined in claim 1, characterized in that a 7-oxo-PGI 2 derivative of formula I - wherein R ¹ , R ² , r5, r4, R6t χ, γ and Q are as defined in claim 1, prepared as a pharmaceutical composition using excipients such as fillers, diluents, stabilizing agents and / or formulation agents conventionally used in the preparation of such compositions.