DE2702366A1 - NEW PROSTAGLANDIN ANALOGS AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

HOECHST AKTlETJCiI 'SE) ^. SHAFT

Aktonzcichon: HOE 77 / F 005

Date: 19.1.1977 I) r.La/Kt

KEUE PROSTACLANuJH-ANALOGUE WAD PROCEDURES TO YOUR

HEESTE], LUNG

Addendum to the patent entanm-ldüng Γ 24 07 186.1 (IiOE 74/1 · 'C43) s.ind Prostaqlcndin-Dorivuto Λι-τ al lyemeincTi Pormo] I

809831/0024

-JT-

H H

CH ₀ -CH ₀ -C -C- CH,

- CH ₀ - COOH

(D

in which mean:

R and R "together are oxygen or each is hydrogen or

a hydroxyl group, where

and R "are different.

R ^ is a saturated, straight-chain or branched alkyl radical with 1 to 10 carbon atoms, which in turn can be substituted by an O-alkyl radical with 1 to Alkyl-C-Atomon, through an O-aryl radical, through an O-furyl radical or by a G-benzyl radical, which in turn each by one or more alkyl groups with 1-3 Carbon atoms can be substituted or one saturated cycloalkyl radical with 3 to 7 ring members or an aryl or furyl radical, which in turn by a or more alkyl groups having 1 to 3 carbon atoms can be substituted, and their physiologically acceptable salts with organic and inorganic bases and Ester.

The main patent also relates to a process for the preparation of prostaglandin derivatives of the formula I, which is characterized in that one

809831/0024

a) an acetal of the formula II

, CU / -, 'X ■

, CH- CIU - CH ₀ - CN II

Cm £

in which

X = oxygen or sulfur and Y a -CH-- or a

-C- group or a single bond with a

Grignard compound of the formula III Hal-Mg-CH ₂ -CH ₂ -CH ₂ -CH ₂ -O-CH ₂ III,

in which Hai means chlorine or bromine, to an acetal ketone of formula IV

'CH ₂ X " ^IV

, 0-CH ₂ -C)

in which X and Y have the same meaning as in formula II ,

809831/0024

b) the acetal-ketone of the formula IV obtained in a for Acetfile or thioacetals are usually converted into the aldehyde

ketone of formula V
0

- κ ν

convicted,

c) the aldehyde ketone of the formula V obtained is subjected to an acidic or alkaline-catalyzed aldol condensation, wherein the unsaturated ketone of the formula VI

Π r, —λ

f ^ Tr ^CH 2 " ^CH 2 ~ ^CH 2 ~ °" ^Cn 2 ~ \ / ^VI

arises,

d) the unsaturated ketone of the formula VI obtained under alkaline conditions Reacts conditions with cyanide ions, the cyanetone of the formula VII

VII

: n

is obtained

e) the cyanetone of the formula VII obtained with anhydrous alcoholic acid via the imino ether salt of the formula VII a

-CIU-CK .. O-CH,

C-OR ₁₁

VII a

HH-IlS

809831/0024

270236S

where S is an inorganic acid radical and R is one is a lower alkyl radical with 1-5 carbon atoms, and. Subsequent hydrolysis into the esters of the formula VIII 0

VIII

COOR ₄

wherein R. has the meaning given for formula VII a, convicted,

f) the ester of the formula VIII obtained for splitting off the benzyl ether group in the presence of Hydrogenated catalysts, an ester alcohol of the formula IX

, CH ₂ -CH ₂ -CHp-OrI IX

COOR ₄

wherein R- has the same meaning as in formula VIII will,

g) the resulting ester alcohol of the formula IX to form an aldehyde of formula X

.CH ₂ -CH ₂ -CHO

COOR ₄

in which R- has the same meaning as in formula VIII, is oxidized

809831/0024

Si -

h) the aldehyde obtained of the form] X selectively with ei no Dithiol of the formula Xl

XI

wherein Y. a -CII ₀ - or a -C (CH ^) "group or a single bond, in the presence of acidic catalysts to a thioacelal of the formula XII

S C] I

"'CH ₂ -Cl 1 ₂ -CH_

COORj,

XII

■ S CH,

where R ^ has the same meaning as j.n formula X, converts,

i) the thioacetal of the formula XII obtained by acidic catalyzed ketalization with a glycol of the formula XIII

XlII

where Y- has the same meaning as the radical Y ₁ mentioned for the formula XII, in a ketal thioacetal of the formula XIV

XIV

COOR

wherein Y ₁ and Y "can be the same or different and have the same meaning as in formula X, converted,

809831/0024

Y "

j) the resulting ketal thioacetal of the formula XIV with a complex metal hydride in aprotic solvents to form an aldehyde of the formula XV

CIU-CII --CII

U-CII

ti et

XV

CHO

where Y ₁ and Y_ have the same meaning in the formula XlV, reduced,

k) the obtained aldehyde of formula XV with a phosphonate formula XVI

ClI ₇ O. CH3O-

; Tc) i ₂ -cn,

XVI

wherein R has the same meaning as in formula I, to an unsaturated ketone of the formula XVII

809831/0024

'Kr

XVlI

where Y ₁ and Y_ have the same meaning as in formula XIV and R_ have the same meaning as in formula I,

1) the resulting ketone of the formula XVII with a complex meta] .lhydride to form the epimeric mixture of the alcohols of the formula XVIII

H II ι ν. I. , β. ^x c OH I « H

XVIII

809831/0024

where Y. and Y "and R., the same meaning as in formula] XVI] have, reduced,

m) the alcohol of the formula XVIII obtained as Mixture of epimers or failure to separate the epimers Acid-catalyzed addition of 2,3-dihydropyran in one Tetrahydropyranyl ether of the formula XIX

"CH ^ -CH ^ -CJI

Ί>

XTX

in which Y. and Y_ and R ^ have the same meaning as formula XVII, transferred,

η) the ether of the formula XIX obtained by heating with a C ₁ -C alkyl iodide in a polar aprotic solvent in the presence of an acid-binding agent in an aldehyde ether of the formula XX

CJL,

9 831/0024

- 10 -

wherein Υ_ and R have the same meaning as in formula XVlI have convicted

o) the obtained / \ ldehydather of the form] XX with the ylid from 4-carboxypiopyltriphenylphosphonium bromide in one Solution of sodium hydride in diiviethy] sulfoxide to form a Acid of formula XXI

,. C] I ₀ -CII ₀ -CiI-OH-CIU-CIU-COOII

ei d ti d

κ.

wherein Y "and R have the same meaning as in the formula XVlI have implemented and

p) the tetrahydropyranyl ether protecting group in the one obtained Compound of the formula XXI by gentle, acidic hydrolysis splits off, an alcohol of the formula XXII

C] I ₀ -CH ₀ -Ci] -CII-Clvy

r. ti egg

XXII

- 11 -

809831/0024

'/ 3

-JkT -

in which Y and R .. have the same meaning as in formula XVII, and then the ketal group
in the alcohol of the formula XXlI removed either by gentle acid catalytic hydrolysis or by reketaiization in the presence of a large excess of a ketone, or the cleavage of both protective groups is carried out by gentle acid hydrolysis in one step and optionally the compound of the formula I thus obtained, in which R- and R- together mean oxygen,

to a compound of the formula I in which R. and R “hydrogen or hydroxyl, reduced with a complex metal hydride and the compounds of the formula I

if desired, converted into the physiologically acceptable salts or their esters.

The compounds according to the invention described are characterized by spasmogenic, bronchodilatory, antihypertensive, gastric juice secretion inhibiting, luteolytic and antihypertensive
abortive properties and can therefore be used as drugs.

In a further embodiment of the invention, it has now been found that compounds with stronger and more differentiated A pharmacological effect is obtained if the allylic hydroxyl group on carbon atom 15 of the compounds I is used esterified lower carboxylic acids. The surprising differentiating and effect-enhancing influence of the esterification is particularly pronounced with preparations with antihypertensive effects.

The invention therefore relates to prostaglandin analogs of the general formula XXIII

- 12 -

809831/0024

1 row

.CII = CH R-.

R-CO

- COOH

XXIII

12 3
in which R, R and R have the meaning given for formula I of the main patent application and R is a hydrogen atom or a straight-chain or branched alkyl group with up to 10 carbon atoms,

and their physiologically acceptable salts with organic and inorganic bases as well as their physiologically compatible ones Ester.

For R, those in the Ilauptpatentanmoldung as are preferred preferably mentioned residues. For R, I are preferred: straight-chain or branched alkyl groups with up to 4 carbon atoms.

Preferred salts and esters are those specifically mentioned in the main patent application.

Diis method for the preparation of the invention Connections is characterized by the fact that you have such

1 2

Compounds of the formula I, the radicals of which R and R together denote oxygen, by reaction with suitable ones Acylating agents in compounds of the formula XXIII

1 2
leads, whose radicals R and R together represent oxygen

- 13 -

809831/0024

and these compounds optionally reduced to compounds of the formula XXITI, in which one of the radicals R and R is a hydroxyl group and the other is a hydrogen atom.

The free carboxylic acids and theirs are used as acylating agents reactive derivatives into consideration. When using the Carboxylic acid, the reaction is preferably carried out in this Acid as a solvent at temperatures between 0 ° and 70 °. In some cases it is advantageous to use the reaction solution; to be buffered to avoid subsequent events. (See J. E. Pike, F. H. Lincoln, W. P. Schneider, J. Org. Chem. 34, 3553 (1969)).

The corresponding carboxylic acid halides can also be used for acylation or carboxylic acid anhydrides can be used. The reaction is then preferably carried out in aprotic solvents carried out in the presence of a base at temperatures between 0 ° and 80 °. For the production of the compounds according to the invention the reaction of the alcohols with the corresponding ketenes is also possible. This reaction will also carried out in aprotic solvents at room temperature.

To represent such compounds of the formula XXIIl, in which

1 2
one of the radicals R and R is a hydroxyl group and the other is hydrogen, the 9-keto-1 5-acyloxy-prostadioenoic acid derivatives prepared by the above process are reduced. Particularly suitable reducing agents for this are complex hydrides which are able to reduce a keto group without attacking ester or carboxyl groups. The use of sodium borohydride in methanol / water as a solvent has proven particularly useful here.

The free acids of the formula XXIII can optionally be converted into the corresponding salts or esters by customary processes be convicted.

- 14 -

809831/0024

- yi -

The connections according to experience have valuable pharmakoloqi see properties. You draw particularly well by blood pressure lowering Wi rkunq, the joner dor nichtacyliorton Output compounds is clearly superior. The undesirable for the antihypertensive effect Nobenvi rkunyon on the smoothness J'usku J a door was in these Cases not observed so far. Due to the pharmacologicalon The compounds according to the invention can have effects be used as medicinal products.

They can be in the form of their aqueous solutions or suspensions or also dissolved or suspended in pharniacologically harmless organic solvents such as monohydric or polyhydric alcohols, e.g. Ethyl c -ng] yko.l dimef hyiäthor or also Polyäthcrn like v .. H, Pol yäthy.l onql ykol e or au.c: li i): If other pharmacologically unbecdiuiklichor polymer carriers such as, for example, polyvinyl jvyrrolidon are used.

The usual galenic infusion or 1 η perJ; fi onr solution and tablets, as well as locally applicable zuboj eiingon such as ctcüh-s, emulsions, supjoti t ori, in particular also aerosols can be used as preparations.

Another application of the new compounds is the de: ·] combination with other active ingredients. Next to other suitable substances include:

Diurotics, such as: e.g. furosemide, anti-diabetic drugs such as e.g. Gl y co; Ii a ζ i η, To] but amid, GJi ben el ami d, Phonf ornii η, Buforinin, metformin, circulatory drugs in the broadest sense, e.g. coronary dilators, such as Chromonar or Prenylamine, Antihypertensive substances such as Reserpi η, Ot.-Methyl-Dopa

- 15 -

80983 1/0024

7T

or clonidines or antiarrhythmics, lipid lowering agents, goriatrics and other metabolic drugs, psychotropic drugs, such as Chlord Lazepoxid, Diazepam or Moprobamat so; ie Vitamins, or prostaglandins, or prostaglandin-like ones Compounds as well as prostatlandin antagonists and proslaglandin diosynthesis inhibitors, such as non-steroidal anti-inflammatory drugs.

- 16 -

80903 1/0024

- J6 example 1:

9-Ko Ig- 1 5 ^ -acetoxy-16, 1 6-d i me thy 1-1 8 - ο χα-pro st / ι-4, 13-dlenic acid

200 nicj 9-keto-15'-v'-hydroxy-1 6, 1 6-diniethyl- 1 8-oxa-prosta - 4, 13-dioenoic acid are dissolved in 10 ml of absolute pyridine, mixed with 0.2 ml of acetic anhydride and H hours at 65 ° touched. Then let it cool down, pour the cold solution in a mixture of L'i.s and Natriuinhydrogenphoijphat. The mixture obtained in this way is niohrfacli with ether extraliiet t. The united ether phases become dried and evaporated. The residue is over a silica gel column with cyelohexane / ethyl acetate / glacial acetic acid 80/20/1 old; Mobile phase chroma I-engraved. Mrin receives 110 mg och desired product.

TLC (silica gel, mobile phase cyclohexane / ethyl acetate / cisacetic acid 60/40/1).

Rf ~ - 0.22

NMR (60 MHz, CDCl ₃ )

5.7-4.9 ppm, multiplet 5 II

3.3 ppm, quartet 2 II

3.0 ppni / singlet 2 II

2.5 - 0.6 ppm, other protons with

2.0 ppm, singlet

1.1 ppm, triplet

0.8 and 0.9 ppm, singlets

- 17 -

809ΘΊ I / 0024

Example 2:

9-keto-1 5 ^Cv -acetoxy-16, 1 6-diinet liyl-18-oxa-prostn-4,

acid methyl ester

28 ml of the compound from Example 1 are dissolved in 10 ml of absolute solution and ethereal diazomethane is added dropwise at 0 ° until the solution turns yellow. The mixture is left to stand for a further hour at room temperature, the excess diazomethane is then decomposed by adding a little glacial acetic acid and finally evaporated in vacuo. 2 9 ing of the desired F. κ te rs are obtained.

TLC (silica gel, middle section] cyclohexane / ethyl acetate / glacial acetic acid 60/40/1)
Uf 0, G2

NMR (CIvCl ₃ , GO KUt.)

5.8 - ■ 5.0 ppm, 5 H, multiplet

4.7 ppro, 3H, singlet 3.4 ppm, 2 11, quartet 3.1 ppm, 2 H, Sinyu] ett

2.8 - 0.8 ppm, remaining protons, below

2.1 ppm, Singulelt

., 2 ppm, triplet
1.0 and 0.9 ppm, ßingulel-ts

- 18 -

809831/0024

Claims (5)

hop; 7 γ / κ ο ο :. Claims 1. Compounds of Formula XXI-II , CII ^ CII ^^ - COOH R, XXIII wherein R, R and R correspond to the formula I of the main patent application P 24 07 186.1 mentioned meaning have \ ind R a hydrogen atom or a straight or branched chain Denotes an alkyl group with up to 10 carbon atoms, and their physiologically compatible salts with organic ones and inorganic bases as well as their phsiologinch compatible Ester. 2. Process for the preparation of a compound of the formula XXIII, characterized in that there is a compound 1 2 of formula 1, in which R and R together represent oxygen, according to process steps a) to p) des Claim 3 of the main patent application P 24 07 106. prepares, reacts the compound obtained with an acylating agent and optionally the compound obtained reduced to a compound of formula XXIII, wherein 1 2
one of the radicals R and R is a hydroxyl group and the other is hydrogen, and optionally a free acid of the formula XXIII is converted into a physiologically acceptable salt or a physiologically acceptable ester by a conventional method. - 19 - 809831/0024 ORIGINAL INSPECTED , DOE 77 / f 005 - / 19 - 3. Process for the manufacture of pharmaceuticals, thereby characterized in that a compound of the formula XXIIT mentioned in claim 1, an ester or a physiological Compatible salt of the acid XXTII, optionally with customary 'harmonic carriers and / or stabilizers, brings into a therapeutically suitable application form. 4. Medicines, characterized by a content of one Compound of the formula XXIII mentioned in claim 1 of an ester or a physiologically acceptable salt of Acid XIII or consisting of such a compound. 5. Use of a compound of the formula XXITI mentioned in claim 1 of an ester or a physiologically compatible one XXIII acid salt in medicinal products or as a medicinal product. 809831/0024