DE2804083A1 - PHENYLPENTANIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME - Google Patents

Description

PAT ENTAN VVA LT

Dr. RICHARD KNEISSL Wlden ^ e ^ trae,

D 8COO MUNICH Telephone 29 ei SS. Telex E24432 kne d

3 i. Jan. \ m

! ~ Dr. Rlohnrd Kneissl, Widenmayerstr. 46, D 8000 Munich 22 ~ l

Folder 24 390 Dr.K / rm
ICI case no. PH. 29353

IMPERIAL CHEtHCAL INDUSTRIES LIMITED London / Great Britain

Phenylpentanoic acid derivatives, processes for their preparation and pharmaceutical compositions containing them

description

The invention relates to phenylpentanoic acid derivatives and, more particularly, to phenylpentanoic acid derivatives which have ulcer healing properties own.

According to the invention, phenylpentanoic acid derivatives of the formula:

1 2

proposed, wherein one of the symbols R and R for a phenyl radical which has 1 or 2 substituents selected from halogen atoms, C ^ _ ^ - alkyl, C ^ _ ^ - alkoxy, nitro, amino and CL _, alkanoylamino radicals , stands and the other of the symbols

12 ■ ~ *> U

R and R represent hydrogen; one of the symbols R and R for hydrogen or a C _1; -Alkyl radical and the other of the symbols R "" and R is hydrogen; either R ^ for hydrogen and R for a hydroxy radical or R ⁵

i; 7th

and R "together form a direct bond; and either R represents hydrogen and R represents a hydroxy radical or R and R together form a direct bond; as well as the pharmaceutically acceptable salts thereof.

It should be pointed out that the phenylpentanoic acid derivatives of the formula I contain at least 3 asymmetric carbon atoms and, depending on the nature of the substituents R " ⁵ and R, can contain up to 4 asymmetric carbon atoms. A compound of the formula I can therefore be in racemic forms and optically active Shapes are isolated. This

280-083

Description refers to any racemic and optically active The form of a compound of Formula I which exhibits the useful properties mentioned above. It is generally known, how an optically active form can be obtained by separation or by synthesis from optically active starting materials and vie determines the biological properties of the optical isomers can be, for example by the test given below.

It is further important that this description relates only to those compounds of the formula I which have the specified relative stereochemistry of the carbon atoms, which carry the radical -CR or -CO.R. Finally, it should also be pointed out that the absolute configuration of a compound of Formula I may in fact be the mirror image of that shown in Formula I.

For a more convenient designation, the hydrogen atoms are which are tied to the carbon atoms that make up the radical -OR or -CO.R in Formula 1, and also the Ra-

2 ^

dical R and R ^ in all formulas as in the α configuration labeled standing. The radicals R and R are therefore denoted in the ß-configuration.

A special group before. connections according to the invention

5 7 summarizes those compounds of the formula I in which R and R both stand for hydrogen, so they are phenyl-dihydroxypentanoic acids the formula:

II

f COPY

ACf

12 3 4

wherein R, R, R and R have the meanings given above, as well as the pharmaceutically acceptable salts thereof.

It should be noted that the other compounds according to the invention are derivatives of the two mono-) f-lactones and the only one Di - ^ - lactons are which by a phenyl-dihydroxypentanoic acid of formula II can be formed. Thus, a second special group of the compounds according to the invention comprises the

C f.

Öeni, "j; erx Compounds of the formula I in which R and R together form a direct bond and R 'stands for hydrogen, the are mono-lactones of the formula:

III

A p "Χ Λ

in which R, R, Fr and R have the meanings given above, as well as the pharmaceutically acceptable salts thereof.

A third special group of the compounds according to the invention

"7

gen includes those compounds of formula I in which R and

8 5

R together form a direct bond and R stands for hydrogen stands, so these are mono-lactones of the formula:

IV

80983W0S58

12 3 4

wherein R, R, R and R have the meanings given above, as well as the pharmaceutically acceptable salts thereof.

A fourth special group of compounds according to the invention comprises those compounds of the formula I in which R- ^ and R together and R 'and R together form direct bonds, these are the dilactones of the formula:

12 3 4
wherein R, R, R and R have the meanings given above

1 2
sit, as well as, when R or R is a phenyl radical which carries an amino radical, the pharmaceutically acceptable acid addition salts thereof.

A special value for a substituent that is most substituted

1 2

tuated phenyl radical R. or R can be, for example: if it is a C ^^ - alkyl radical, a methyl or ethyl radical; if it is a C. ^ alkoxy radical, a methoxy or ethoxy radical; if it is a halogen atom, a fluorine, chlorine or bromine atom; and when it is a C ^ __ r alkanoylamino radical, an acetamido or propionamido radical.

1 2

A particularly suitable value for R or R when they stand for a substituted phenyl radical is, for example a 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-acetamidophenyl or 2-aminophenyl radical.

809834 / G558

• ζ. Λ

A special value for R ^ or R, when they _{stand for a C 1} ^ alkyl radical, is, for example, a methyl or ethyl radical.

A special pharmaceutically acceptable salt is, for example: for a compound of the formula I in which one or both of the symbols R ^b and R stand for a hydroxy radical, a Basarr & ddition salt, such as an ammonium salt, an alkali metal or alkaline earth metal salt, for example a sodium, potassium », I-'agnesiua- or calcium salt, or an aluminum salt or a salt with an organic base, such as an aliphatic or cycloaliphatic amine, for example meglumine, diethylamine, triethylamine or morpholine; or for a compound of the formula I in which the substituted phenyl radical 1 is 2

kale R or R carries an amino radical, an acid addition salt with, for example, an organic acid such as acetic acid or with a mineral acid such as hydrogen chloride acid.

It can be seen that various specific and individual groups of phenylpentanoic acid derivatives according to the invention fall within the above general definitions, namely those compounds of formula I wherein one of the radicals R, R, R and R one of the special values given above

j- / " ry rj

te list, R, R, R and R are any of those defined above special values and the rest of the symbols R, R ^, R ^ and R are any of the particulars defined above or have general values, the pharmaceutically acceptable salts also being included here, insofar as this is possible is. However, particular groups of compounds of the invention that are of particular interest include those Compounds of the formulas II, III, IV or V as defined above, in which:

a) R ¹ or R ^{2 represents} a phenyl radical which bears a chlorine atom or a methyl or methoxy radical; or

B0983Ä / 05SS

b) R or R is a phenyl radical containing 1 or 2 nitro

radical bears; or

c) R or R represents a phenyl radical which is an amino or Acetamido radical carries; and or

d) R ³ or R ^ is an ethyl radical;

where the rest of the symbols R, R ² , R? and R have any of the general or specific values defined above; as well as in each group also the pharmaceutically acceptable salts thereof according to the above definition, if this is possible.

Specific compounds of the invention are set forth in the accompanying drawings Examples described.

The compounds according to the invention can be prepared by processes which are known per se for the preparation of analogous compounds. Such processes are exemplified below, where R ¹ , R ² , Bp, R, R ^, R, R ^ and

R have the meanings given, unless otherwise stated:

a) For the preparation of a compound of the formula I in which R,

£ «7 g

R ", R 'and R have the meanings given above,

5 with the restriction that at least one of the symbols R

7th
and R stands for hydrogen, so these are compounds of the formula II, III or IV, a compound of the formula

C μΤ rj Q

mel I, in which R, R, R and R have the meanings given above, with the restriction that at least one of the symbols R ^ and R stands for something other than hydrogen, that is a compound of the formula TU, IV or V, hydrolyzed under basic conditions.

A dilactone starting material of Formula V is preferred. If such a starting material is used, then it depends

the product obtained in each case by the hydrolysis, i.e. the mono-lactone of the formula III or IV or the phenyl-dihydroxyprefcäi'-acid of the formula II according to the above definition from the basic conditions used. In general, under milder basic conditions than is necessary to achieve the corresponding: acid of the formula II for a particular dilactone starting material is a mono-lactone Formula III or IV obtained as defined above. For example, hydrolysis results at a pH of 9 to 10 the corresponding Kono-lactones of the formula III for 1 h or IV, while hydrolysis of a dilactone of the formula V with an excess of pn-sodium hydroxide solution at 20 to 25 ° C the corresponding phenyldihydroxypentanoic acid of the formula II is obtained over 2 to 3 hours.

The reaction can for example be carried out at 0 to 60 C and '\
executed.

are and is, however, preferably at 0 to 30 ^° C., for example

The reaction is expediently carried out in a polar organic solvent, such as aqueous ethanol, methanol, acetonitrile or acetone.

The basic conditions are expediently by an inorganic base, such as z.3. an alkali metal hydroxide such as Sodium or potassium hydroxide. A pH of 9 to 10 is preferred when a mono-lactone of formula III or IV is desired.

If the starting material itself is a mono-lactone of the formula II or IV, basic conditions similar to those described above are used.

The starting materials of formula III, IV or V can be obtained by the other methods described herein, and the dilactones of Formula V can be obtained by the same general procedures as described in GB-PS

809034/0558

1 439 412 are described, of which the correspondingly substituted Phenylacetylene Grignard reagent and ethyl 2,3-dimethoxycarbonylacrylate is assumed.

b) For the preparation of the compounds of formula I, wherein one

1 2

of the symbols R and R a Pheny! radical, the at least one Kitroradikal carries, stands and the other of the symbols R and

ρ
R stands for hydrogen, the corresponding PhenyIver-

1 2

bond of the formula I, wherein one of the symbols R and R is

is a phenyl radical and the other of the symbols R and R ~ is hydrogen, are nitrated.

The nitriding can be carried out using conventional nitriding conditions be carried out, for example with potassium nitrate and sulfuric acid, fuming nitric acid or plucking (II) nitrate and acetic anhydride. The nitration is preferably carried out, for example, at from 0 to 30 ° C., optionally in the presence an inert organic diluent or solvent, for example acetic acid.

c) For the preparation of compounds of the formula I, wherein one

1 2
of the symbols R and R for a phenyl radical which carries at least one amino radical, and the other of the symbols R

ur.d R is hydrogen, the corresponding compound can

1 2

Formation of the formula I, wherein one of the symbols R and R for a phenyl radical that carries at least one nitro radical,

1 2

and the other of the symbols R and R for hydrogen stands, be reduced.

The reduction can be carried out using conventional reducing agents such as sodium dithioni · ^ or by catalytic hydrogenation using a platinum or palladium catalyst system. It is preferably carried out in an inert organic diluent or solvent, such as, for example, ethanol, at from ⁰ to 50 ° C., for example.

809834 / 0S5B

2604083

d) For the preparation of compounds of the formula I in which R ^ and R together and R 'and R together stand for direct bonds, that is to say they are compounds of the general formula V, can be a Compound of the formula:

VI

wherein R is a phenyl radical in either the α or the β configuration stands, where the radical carries 1 or 2 substituents as defined above for R, but where hydrogen is excluded, be subjected to a reductive cyclization.

It should be noted that the compounds of the formula VI either completely or partially in one to the specified Formula VI alternate tutomeric form exist η, namely as keto acids of the formula:

Via

and that the intermediates of the formula VI are expediently isolated and purified as salts of such a keto acid form as for example as their dicyclohexylamine salts.

809834 / Q558

The reductive cyclization can be carried out using, for example, a metal hydride complex such as an alkali metal cyanoborohydride or tri-s-butylborohydride wherein the alkali metal is lithium, sodium or potassium. If a metal hydride complex is used, then the reaction occurs expediently carried out in a temperature range from -70 to 30 ^° C. and in the presence of an organic diluent or solvent, for example tetrahydrofuran. Alternatively, the reductive cyclization can be carried out, for example, using Meerwein-Ponndorf conditions, for example by using a solution of di- isobornyloxyaluminium isopropoxide in toluene, wherein the reaction is suitably carried out in a range of, for example, AO to 100 ⁰ C in this case. the rela-

12th

tive stereochemical arrangement of the substituents R and R in the product of the formula V can be determined to a certain extent by the conditions of the reductive cyclization. For example, if

A compound of the formula VI, in which R is an o-tolyl radical, R ^{J is} a methyl radical and R is hydrogen, is reductively cyclized using lithium tri-s-butylborohydride as the reducing agent, then the product of the formula V has the relative α-configuration (ie R = o-tolyl, R = H), and if, for example, a compound of the formula VI, in which R is an m-tolyl radical, is reductively cyclized using sodium cyanoborohydride as the reducing agent, then the product of the formula V has the relative β-configuration (ie R ² = H, R ¹ = m-tolyl).

The starting materials of formula VI can expediently thereby can be prepared by using an anhydride of the formula:

VII

80983 * / ö5S8

with a suitable organometallic reagent such as the corresponding Grignard reagent of the formula R% 3g3r, wherein R ^ has the meaning given above, at a temperature in the range from, for example, -70 to 25 ° C and in an organic Solvent or diluent, such as tetrahydrofuran or ether, reacts.

The anhydrides of the formula VII can by dehydrating the corresponding Diacids of the formula:

VIII

can be obtained, for example by reaction with trifluoroacetic anhydride, as described in the examples. Such

■ z

Diacids of the formula VIII, in which R stands for a C ₁ / -alkyl radical and R stands for hydrogen, can in turn conveniently be obtained from the corresponding 2-C, g-alkylsuccinic anhydride, as is described in more detail below in the examples, where R? stands for a methyl radical. Alternatively, all of the diacids of the formula VIII can be obtained by the following reaction chains, starting from dimethyl 2-methoxycarbonylsuccinate.

809834/0558

- te -

2804Q83

MeO ₂ Q

MeO ₂ C

CO ₂ Me

R.Br

+ NaH CR = C _1-1 , -dimethyl oxalate

CO ₂ Me

NaOMe

.0

CO ₂ Me

(Claisen reaction)

MeO ₂ C

(j) _{H? a}

(ii) thermal cyclization

(i) OH "

MeO ₂ C

CO ₂ Me

O ₂ Me

MeO ₂ C

(ii) H ⁺ , heat (-CO ₂ ) (ii) separation-of the cis-isomer

1 2

e) For the production yon compounds of formula I wherein R or R represents a Fnenylradikal comprising a C ₁ _ ^ - carries Alkanoylaminoradikal, is, a compound of formula I, vorin R or R represents a phenyl radical which carries an amino radical , be reacted with an acylating agent derived from a C ₁ _ ^ - alkanoic acid.

A particularly suitable acylating agent is, for example, an anhydride, bromide or chloride of a C _2- ^ alkanoic acid, such as, for example, acetic anhydride, propionic anhydride, acetyl chloride or propionyl bromide. A particularly suitable acylating agent derived from formic acid is, for example, triethyl or trimethyl orthoformate.

809834/0558

The reaction is conveniently carried out at a temperature of, for example O to 100 ° C and preferably at or near room temperature executed. An organic solvent or diluent such as chloroform can be suitably used or the C 1-4 alkaric acid from which the acylating agent is derived derives. In the case of orthoformate, methanol or ethanol can also be used used.

The starting amino compound can conveniently be prepared in situ and acylated, process c) above being carried out simultaneously with process e).

f) For the preparation of compounds of the formula I, wherein R ^ for what is hydrogen, a compound of the formula I in which R is hydrogen can be reacted with an acid.

The process is expediently carried out at an elevated temperature of, for example, from 50 to 120 ^° C. and in an organic solvent or diluent, such as, for example, acetic acid. A suitable acid is, for example, hydrochloric acid or hydrobromic acid.

Then if a pharmaceutically acceptable base addition salt is desired is then a compound of formula II, III or IV is neutralized with a suitable base, and if so then a pharmaceutically acceptable acid addition salt is desired, then

1 2 becomes a compound of the formula I in which R or R is a phenylradilcal which carries an amino radical is reacted with one equivalent of a suitable acid using conventional methods be applied.

As already stated, the compounds of formula I have ulcer-healing properties. These properties can be achieved by Oral or subcutaneous administration of a test compound to rats in which the application of acetic acid to the duodenum produced a duodenal ulcer. The activity will be based on a significant reduction in

809834/0558

- 2Q. -

Size or frequency of duodenal ulcers compared to the ulcers determined by an undosed comparison group. In the case of this test compound, the compounds of formula 1 show an activity at a daily dose of 50 mg / kg or less. The test is carried out over a period of 21 days. At this time there was no evidence of apparent toxicity at the time of administration of the active dose to any of the compounds of formula I found.

¥ enn the compounds of formula I to achieve an ulcer healing effect For warm-blooded animals, they are administered at a daily oral or subcutaneous dose of 50 mg / kg or less, preferably 1 to 10 mg / kg, with the dose being repeated at intervals of 4 to 5 hours if necessary. In humans, this corresponds to a dose of 50 to 500 mg four times a day.

The compounds of the formula I are used in the form of pharmaceutical compositions which contain a compound of the formula I and a pharmaceutically acceptable diluent or carrier. Such pharmaceutical compositions represent a further aspect of the invention.

Particularly suitable compositions may be in a form suitable for oral administration, such as, for example, the form of tablets, capsules, aqueous suspensions, oily solutions or suspensions, emulsions, dispersible powders, granules, syrups or elixirs; or in a form suitable for parenteral administration, such as, for example, the form of sterile injectable aqueous solutions or suspensions or oily solutions or suspensions, or in a form suitable for rectal administration, such as, for example, suppositories. The compositions may be obtained using conventional excipients and using general method, except that it is avoided that heating to a temperature of substantially more than 25 ⁰ C 'is preferred, an expedient

Contains dosage unit for oral or subcutaneous administration 10 to 200 ng of a compound of formula I or an equivalent amount of a pharmaceutically acceptable salt thereof.

In addition to a compound of the formula I, the pharmaceutical Compositions contain one or more agents of who are known to be useful in ulcer healing and to be compatible with the compounds of Formula I. So know, for example, the pharmaceutical compositions or contain several of the following gowns in addition to a compound of formula 1: an antacid such as magnesium trisilicate, an antifoam such as simethicone, a gastric secretion inhibitor such as cimetidine, or a prostaglandin derivative, especially one of the E series.

The invention is further illustrated by the following examples, wherein

1) all evaporations were performed by rotary evaporation under a reduced pressure at ^ 40 ⁰ C, unless otherwise specified ISTJ

2) Petroleum ether (bp 60 to 80 ° C) is referred to as "petroleum ether";

3) the IIKR spectral data at 100 KHz using tetramethylsilane as an internal reference and the conventional ones Abbreviations are used for complex interactions, such as m: Muitiplet, d: Doublet, t: Triplet, q: Quartet;

4) TCAI stands for trichloroacetyl isocyanate; and

5) any reported yields are given for informational purposes only and by no means that of the relevant one Represent the maximum achievable procedure.

809834/0558

example 1

100 mg of (+) - 6a-phenyl-3,3aa, 6,6aa-tetrahydrofuro [3,4-b] furan-2,4-dione were added to 1 ml of sulfuric acid at 20 to 25 ° C. over a period of 15 minutes. 30 mg of potassium nitrate was then added to the solution. The mixture was left to stand at room temperature for 30 minutes and then poured onto 50 g of Sis. 70 mg of a crystalline solid formed, which was separated off and recrystallized from acetone / petroleum ether. It was (+) - 6a-p-nitrophenyl-3,3aa, 6,6aoctetrahydro [3,4-b] furan-2,4-dione, mp 131 to 133 ⁰ C, was obtained.

Example 2

A solution of 2.2 g of 6- (3-tolyl) -6-hydroxy-3a-methyl-3,3aa, 6,6aatetrahydrofuro [3,4-b] furan-2,4-dione in 30 ml of tetrahydrofuran was with Treated sodium cyanoborohydride, and the mixture was ^{stirred at 20 to 25 0} C for 16 h. 5 ml of concentrated hydrochloric acid was then added to the mixture and the tetrahydrofuran was evaporated under reduced pressure. The residue obtained was treated with 30 ml of water and the mixture was stirred at 20-25 ° C for 1 hour. The solid formed was separated by filtration and crystallized from ethyl acetate. 0.9 g of (+) - 6ß- (3-tolyl) -3a-methyl-3, 3acc, 6, 6aa-tetrahydrofuro [3,4-b] -furan-2,4-dione, melting point 167 bis 168 ° C. The necessary furo- [3,4-b] uranium starting material was obtained as follows:

A Grignard solution prepared from 0.0165M 3-bromotoluene and 0.0165M magnesium in 25 ml tetrahydrofuran-4 was added dropwise over 1 hour to a stirred mixture of 0.015M (+) -3cc-methyl-2-oxo-tetrahydrofuran-4ß , 5ß-yl-dicarboxylic acid anhydride and 25 ml of tetrahydrofuran which was maintained during the addition under an argon atmosphere to -70 ⁰ C. The mixture was allowed to warm to 0 ° C and then treated with 5 ml of concentrated hydrochloric acid. The tetrahydrofuran was evaporated under reduced pressure and 30 ml of water was added to the residue. The mixture was then extracted three times with 30 ml of ether. The combined ether extracts were dried over NaoSO and concentrated

809834 / G5S8

28Ü4083

evaporates, 2.2 g of (+) - 6- (3-tolyl) -6-hydroxy-3a-methyl-3,3aa, 6,6aatetrahydrofuro [3 »4-b] furan were obtained, which was obtained from recrystallization from toluene had mp 130-132 ⁰ C.

The (+) - 3a-Hethyl-2-oxo-tetrahydrofuran-4β, 5β-yl-carboxylic acid anhydride starting material was obtained as follows:

A mixture of 13ö Trichloroacetaldehyd g, 109 g of a-methyl-succinic anhydride, 156 g of anhydrous sodium acetate and 10 ml of acetic anhydride was heated with stirring to 120 ⁰ C, an exothermic reaction occurred and the temperature rose to 14O ° C. The Genisch was allowed to cool to 100 ⁰ C, 3 1 of hot water was added and the mixture was filtered. 20 g of activated charcoal was added to the filtrate and the resulting suspension was filtered, whereupon the filtrate was concentrated to a volume of 2 liters under reduced pressure. Acidification of the remaining material with 130 ml of concentrated hydrochloric acid gave 125 g of a solid which was separated off by filtration and recrystallized from acetonitrile. It was (+) -3oc-methyl-5c - obtained with a mp 209-211 ⁰ C i chloromethyl-2-oxo-tetrahydrofuran-4SS-yl-carboxylic acid ^<fcr>.

A solution of 35 g of the above carboxylic acid in 400 ml aqueous 2N ITatriumhydroxid was maintained for 30 min at 60 ⁰ C and then cooled to 20 to 25 ° C and acidified Aiit concentrated hydrochloric acid to a pH of Figure 1. The solution was then evaporated and the residue was extracted six times with 150 ml of boiling ethyl acetate each time. The combined ethyl acetate extracts were evaporated and the solid residue obtained was recrystallized from ethyl acetate. 13.5 g of (+) - 3a-methyl-2-oxo-tetrahydrofuran-4β, 5β-yl-dicarboxylic acid, melting point 193 ° to 195 ° C., are obtained.

3.6 g of trifluoroacetic anhydride were added to a solution of 2.9 g of the above (i) ^ 3a-methyl-2-oxo-tetrahydrofuran-4ß, 5ß-yldicarboxylic acid in 230 ml of anhydrous ether, and the mixture was at Stirred from 20 to 25 ^{° C.} The educated festival

8 09834/0558

28Ü4083

material was then separated by filtration to obtain 2.4 g of (+) - 3a-methyl ~ 2-oxo-tetrahydrofuran-4SS, 5ß-yl-dicarboxylic acid anhydride, mp 169 to 171 ⁰ C, was obtained.

Example 3

Using a similar procedure to Example 2, there were obtained: (+) -6ß- (4-methoxyphenyl) -3a ~ methyl-3, 3aa, 6,6acctetrahydrofuro [3,4-b] furan-2,4-dione, mp 190-191 ⁰ C (crystallized from Ätbylacetat), and (-) - 6ß- (3-ChlorophGnyl) -3a-ßstliyl-3,3aa, 6,6aa-tetr £ Hydrofuro [3,4-b] furan-2 , 4-dione, m.p. 185 to 187 ° C (crystallized from ethyl acetate), with the starting materials (+) - 6- (4-methoxyphenyl) - or (+) - 6- (3-chlorophenyl) -6- Hydroxy-3cc-methyl-3, 3aoc, 6, 6aa-tetrahydrofuro [3,4-b] -furane-2,4-dione. These starting materials were used without purification and were obtained by reacting the Grignard reagent obtained from 4-bromoanisole or 3-bromochlorobensol with (+) - 3oc-methyl-2-oxo-tetrahydrofuran-4β, 5β-yl-dicarboxylic anhydride in a manner similar to obtained in example 1.

Example 4

A solution of 0.6 g of 6 ~ (2-tolyl) -6-hydroxy-3a-ynethyl-3,3aa, 6,6aatetrahydrefuro [3 * 4-bIfuran-2,4-dione in 50 ml of tetrahydrofuran was at -70 ⁰ C stirred under an argon atmosphere, meanwhile. 7 ml of a 1m solution of Lithiura-tri-s-butylborohydride in tetrahydrofuran were added dropwise. The solution was kept at -70 ° C for a further 30 min and then treated with 2 ml of glacial acetic acid and finally allowed to warm to 20-25 ° C. The mixture was evaporated and the residue was acidified with 2N hydrochloric acid. The mixture obtained was kept at 20 to 25 ° C. for 2 hours and then extracted three times with 30 ml of ether each time. The combined ether extracts were dried over Na ^ SO · and evaporated. The residue was triturated with ether to give 0.12 g of a solid which was crystallized from a mixture of toluene and petroleum ether. Included

909834 / 0S58

28Ü4Q83

was (+) - 126 to 129 ⁰ C, obtained 6a- (2-2olyl) -3a-methyl-3,3aa, 6,6aa-tetrahydrofuro- [3,4-bJfuran-2,4-dione, mp.

The 6- (2-tolyl) -6-hydroxy derivative used as starting material was obtained as a solid in a manner analogous to that in the example 2 is described for the 6- (3-tolyl) -6-hydroxy derivative, but using the Grignard reagent of 2-bromotoluene became.

Example 5

A mixture of 117 Eg (+) - 6β-m-tolyl-3a-methyl-3,3a «, 6 _t 6aa-tetrahydrofuro [3,4-b] furan-2,4-dione, 4 ml acetonitrile and 50 ml Water was adjusted to pH 10 at 25 ° C. by adding aqueous 0.1 M sodium hydroxide solution. The mixture was kept at pH 10 for 30 minutes by making a further addition of 0.1% aqueous sodium hydroxide solution. The mixture was then acidified to pH 6 with aqueous 0.1 M hydrochloric acid and evaporated. The residue obtained was dissolved in a mixture of 3.07 ml of O, Im citric acid solution and 1.93 ml of O, 2 M disodium phosphate aqueous solution to obtain a solution which was extracted three times with 10 ml of ethyl acetate. The combined ethyl acetate extracts were _{dried over ITa 2} SO ^ and evaporated and the residue was triturated with ether. The resulting mixture was then filtered and the filtrate was diluted with petroleum ether. (+) - 3a-I'lethyl-5ß- (ß-m-tolyl) -hydro: cymethyl-2-oxo-tetrahydrofuran-4ß-yl-carboxylic acid, melting point 166 to 168 ° C (softening at 140 ° C ) obtained with the following characteristic NMR spectrum:

(1)

80983470558

ft *

28U4083

signal

d / - acetone

S (ppm)

TypeSr

Proton N-rv.

Clutch constant (Hz)

^ / - acetone + TCAI

% (ppm)

Type

Clutch constant (Hz)

3a-Me

1.26

2.33

Aromatic
Protcn.en

3-2-

3.6

4.83

5.2

7.06-7-25

J = 7

J = 2

1.26

2.33

3-2-3.7

5.07

6.2

7.1-7.3

dd

in

J = 7

J _{1 =} 2 J ₂ -S

J = 2

Example 6

A mixture of 80 rag (+) - 6ß-m-tolyl-3a-methyl-3,3aa, 6,6aa-tetrahydrofuro [3,4-b] furan-2,4-dione and. 1 ml of aqueous 2N sodium hydroxide would be stirred at 20 to 25 ° C. for 3 h. The resulting solution was then adjusted to pH 2 with aqueous 5N hydrochloric acid and extracted three times with 5 ml of ethyl acetate each time. The combined extracts were _{dried over Na 2} SO ^, and evaporated at 25 ° C, and the residue was triturated with ether. There were 40 mg of one

809834/0558

28U4083

Obtain solid, which is separated by filtration and dissolved in acetone was dissolved. The resulting solution was stirred and diluted with petroleum ether, a crystalline precipitation of (+) - 3ß-carboxy-4ß, 5ß-dihydroxy-2a-methyl-5ß-m-tolylpentanoic acid, m.p. 165 "to 167 ° C (equalizing at 135 ° C), was obtained, namely with the following characteristic NMR spectrum:

Me

(2)

HO

d, - acetone
6th § (ppm) Type proton
No. Clutch
constant
(Concentration camp) signal 1.20
2.33
2.76
3.01
3.91
if.72
I.
7-0 * 4-
■ · j d
S.
dd
dq
dd
d
i 3
3
1
1
1
1
k J = 7
J ₁ O
J ₂ = 9
J ₂ = 7
J ₁ O
J = 6.5 2 a-CH-,
3α-Η
2ß-H
ίία-Η
5α-Η
Aromatic
Pr -: .-, or.

28UA083

Examples 7 to 9

Using a similar procedure to Example 5, the following mono-lactones of Formula IV were hydrolyzed of the corresponding dilactones of the formula V:

example

Fp cleaning ioc) conditions

7 4-kethoxyphenyl

8 3-chlorophenyl

9 4-nitrophenyl

H methyl H 181-183

H "H 180-182
HH methyl 154-156

crystallizes from ether / petroleum ether

preparative thin layer chromatography on silica *, then crystallized from acetone / petroleum ether

* Eluant: 85: 10: 5 volume mixture of chloroform / acetone / acetic acid (R ^. 0.3).

The Mcno-lactones had the following characteristic NMR structures:

Example 7:

MeO-Ph

(3)

Copy

28U4083

Ib

signal

-Acetone

X ppm)

Type

proton
Ho

Clutch constant (Kz)

dg acetone + TCAI

S (ppn)

Type

Clutch constant (Hz)

3a-Me
36-K

c (p

5a-H

OKe

53-

HO

1.27

3.2-

3.6

3.8

4.78

5.18

Aror.atisclijJ6.88 protons

7-33

πι

2 2

J = 7

J = 2

J = 9 J = 9

1.26

3.2-3.8

d m

3.8 5.04.

6.16

6.90 7.35

dd

d d

J = .7

-ZJ ₂ = B

J =

J = J =

Example 8:

809834/0558

*
signal 53- ΓεΛ ι »! 1.27 Type proton
'No. iuppl \ rngs-
constant
(Hz) 3 α-Me KO 3.2- d 3 J = 7 3.6 m 2 4 a -K J 4.86 5α-Η Aromatdsche
Proorsn 5.26 dd 1 J ₁ = 2 J ₂ = 8 d 1 J = 2 7.2-7.5 m 4th

* in dg-acetone

Example '9:

4-NO ₂ -Ph

(5)

6 (ppm): 1.18 (1 proton, 3B-Me); 2.9 to 3.3 (2 protons, 3α-Η, 4α-H); 4.8 (1 proton, 5α-Η); 5.2 [1 proton, 5 [beta] (-CH)]; 7.7 (2 aromatic Protons); 8.22 (2 aromatic protons): in dg-acetone.

Example 10

Using a procedure similar to that of Example 5, from the corresponding dilactone of the formula V (+) - 2- [5β- (3-

809834/0558

Kitrophenyl) -4ß-hydroxy-2-oxo-tetrahydrofuran-3ß-yl] -2ß-methyl acetic acid, pp 172 to 174 ⁰ C (crystallized from ethyl acetate / ether), obtained with the following characteristic NMR spectrum in d acetone:

(6)

*
signal 1.28 Type proton
No. Coupling _r
constant'
(Hz) H 2.7ο 3B-C-C00H 3.3 d 3 J = 7 3Ö-C-C00H 4.73 dq 1 J _x = 7 J ₂ = OK 3α-Η 5.74 dd 1 J ₁ = IO J ₂ = 4 ϋα-Η 7.6-
8.3 dd 1 J ₁ = * J ₂ = 3 5α-Η d 1 J = 3 ^ Aromatic
Protons m H

Example 11

Using a similar procedure to Example 4, there was obtained (+) - 6a- (3-tolyl) -3a-methyl-3,3aa, 6,6aa-tetrahydrofuro [3,4-b] -furan-2,4-dione , Mp 39 to 90 ° C (after recrystallization from ethanol) from (+) - 6- (3-ToIyI) -6-hydroxy-3a-meth3i-3,3aa, 6,6aa-tetrahydrofaro [3,4-b] furan-2,4-dione obtain.

Examples 12-14

A solution of 1.6 g of (+) - 6β-phenyl-3β-methyl-3,3aa, 6,6aa-tetrahydrofuro [3,4-bjfuran-2,4-dione in 15 nil concentrated nitric acid was kept at room temperature for 18 h and then poured onto 150 g of ice. The crystalline precipitate was collected and chromatographed on a column containing 180 g of silica gel in chloroform by successively eluting with 300 ml of chloroform, 1500 ml of 5% (v / v) acetone in chloroform and then 1500 ml of 10bigen (v / v) acetone in chloroform. The ones with 5 # (V / V) Fractions eluted acetone in chloroform were combined and evaporated and the residue was crystallized from acetonitrile, whereby 0.25 g of (+) - 6β- (2-nitrophenyl) - * 3β-methyl-3,3aa, 6,6aatetrahydrofuro [3,4-b] furan-2,4-dione (Example 12), m.p. 233-235 ° C (dec.).

The fractions eluted with 10% (v / v) acetone in chloroform were combined and evaporated, and the residue was crystallized from acetonitrile. 0.88 g of (+) - 6ß- (4-nitrophenyl) -3ß-methyl-3,3εα, 6,6aa-tetrahydrofuro [3,4-b] furan-2,4-dione (Example 13), mp 224-226 ⁰ C (dec.), obtained. The cutter fluids were evaporated to dryness and the residue was crystallized from ethyl acetate. (+) - 6ß- (3-Nitrophenyl) -3ß-methyl-3, 3acc, 6, 6aa-te trahydrofuro [3,4-b] for uran-2,4-dione (Example 14), mp 182-185 ⁰ C (dec.), obtained.

Examples 15 and 16

A solution of 1.0 g (+) - 6ß-fhenyl-3a-methyl-3,3aa, 6,6aa-tetra-

809834/0558

hydrofuro [3,4-b] furan-2,4-dione in 10 ml of fuming nitric acid was kept at room temperature for 18 h, then poured onto 100 g of ice. The crystalline precipitate formed was collected and chromatographed on a column containing 120 g of silica gel in 5% (v / v) acetone in chloroform, using the same mixed solvent as the eluant and collecting 100 ml fractions. Fractions 7 to 9 were combined and evaporated and the residue was crystallized from ethyl acetate. 0.05 g of (+) - 6ß- (2,4-dinitrophenyl) -3a-methyl-3,3aa, 6,6aa-tetrahydrofuro [ 3,4-bifuran-2,4-dione (Example 15), mp 215 to 218 ⁰ C (dec.), obtained.

Fractions 11 to 16 were combined and evaporated, and the residue was crystallized from acetonitrile. 0.36 g of (+) - 6β- (4-nitrophenyl) -3cc-methyl-3,3aa, 6,6aa-tetrahydrofuro [3,4-bJ-furan-2,4-dione (Example 16), m.p. 245 to 247 ° C (dec.).

Example 17

5 mg of 5% palladium charcoal were added to a solution of 70 mg of (+) - 6β- (4-ICi tropheiiyl) -3β-meth; 1-3, 3aa, 6, 6acc-tetrahydrofuro [3,4-b] f uran-2,4-dione in a mixture of 10 ml of glacial acetic acid and 0.5 ml of acetic anhydride was added, and the mixture was under hydrogen at room temperature and shaken at atmospheric pressure until 20 ml of hydrogen were absorbed. The mixture was then filtered and the filtrate was evaporated to dryness. The residue was purified by preparative layer chromatography on SiIica plates (20 cm × 40 cm × 0.5 mm) using a 1: 3 volume mixture of acetone and chloroform as the eluent. The Eand with R ~ 0.2 was separated and eluted with acetone, whereby 25 mg of (+) - 6ß- (4-acetamidophenyl) -3ß-methyl-3,3aa, 6,6aatetrahydrofuro [3,4-bJfuran-2, 4-dione, mp 199 (crystallized from acetone / petroleum ether) to 201 ⁰ C, was obtained.

Example 18

A suspension of 70 Jjgr + J-öß-CP-C-trophenyl) -3ß-methyl-

o (Γ9 q "3 4 / Os j '

3,3aa, 6,6aa-tetrahydrofuro [3,4-b] furan-2,4-dione in 10 ml of glacial acetic acid was added to a mixture of 10 mg Adam's catalyst and 5 ml glacial acetic acid which had previously been saturated with hydrogen. The mixture was then stirred under hydrogen at room temperature and atmospheric pressure until 18 ml of hydrogen was absorbed had been. The mixture was finally filtered and the filtrate was evaporated to dryness. The residue turned off Acetonitrile crystallizes. (+) - 6ß- (2-aminophenyl) -3ß-methyl-3,3aa, 6,6aa4etrahydrofuro [3,4-b] furan-2,4-dione, Mp up to 250 ° C (dec.).

Example 19

The mother liquors from the crystallization of (+) - 6ß- (4-methoxyphenyl) -3 <x-methyl-3 »3aa, 6,6aoc-tetrahydrofuro [3,4-b] furan-2,4-dione (example 3) were evaporated to dryness. A portion of the residue weighing 1.0 g was then purified by preparative layer chromatography on silica plates (40 cm × 20 cm × 0.5 mm) using a 90: 5: 5 mixture by volume of chloroform, acetone and formic acid as the eluent became. The band with R _f 0.65 was then eluted with acetone. The acetone eluate was evaporated, whereby (+) - 6a- (4-methoxyphenyl) -3a-methyl-3,3aa, 6,6aatetrahydrofuro [3,4-bJfuran-2,4-dione, mp 112-114 ° C. (crystallized from ethyl acetate / petroleum ether).

Example 20

A solution of 100 mg (+) - 6ß- (p-nitrophenyl) -3a-methyl-3,3aa, 6,6aatetrahydrofuro [3,4-b] furan-2,4-dione in 10 ml of a 2% strength ( V / V) mixture of hydrogen bromide in acetic acid was ^{kept at 100 °} C. for 48 h and then evaporated. The residue obtained was purified by preparative layer chromatography on silica plates (40 cm × 20 cm × 0.5 mm) using an 85: 10: 5 mixture by volume of chloroform, acetone and acetic acid as the eluent. The band with R ^ 0.5 was then eluted with acetone and finally the acetone eluate was evaporated to dryness.

809834/0558

In this case were 15 mg (+) - 6ß- (p-lTitrophenyl) -3ß-methyl-3,3aa, 6,6aatetrahydrofuro [3,4-b] furan-2,4-dione, mp 224-226 ⁰ C (after Recrystallization from ethyl acetate / petroleum ether) obtained.

Example 21

A mixture of 50 parts by weight of (+) - 6ß- (4-methoxyphenyl) -3a-methyl-3,3aa, 6,6aa-tetrahydrofuro [3 »^ - b] furan-2,4-dione, 27 parts by weight of lactose and 20 Parts by weight of corn starch were carefully stirred and a paste made from 2 parts by weight of corn starch and 40 parts by weight of water was added and the whole was mixed thoroughly. The Hasse mm obtained was passed through a sieve with a nibble width of 1.0, at 60 ⁰ C to constant weight and then dried mm passed through a sieve with a mesh size of 0.82. 1 part by weight of magnesium stearate was then added and the resulting mixture was compressed into tablets by conventional means. Thus tablets each weighing 100 mg and containing 50 mg of the active ingredient were obtained. They were in a form suitable for oral administration to humans for therapeutic use.

By a similar procedure obtained vairden tablets containing 10, Contained 20, 100 or 200 mg of the active ingredient.

Similarly, any other compound of Examples 1-20 can be substituted for the active ingredient.

809834/0558

Claims (1)

2B04083 Paten ta η s jp r ü c h e 1.) Phenylpentanoic acid derivatives of the formula: 1 2
wherein one of the symbols R and R stands for a phenyl radical which consists of 1 or 2 of halogen atoms and C _1- / -alkyl-, C _1- . -alkoxy-, Nitro, amino and C ₁ --alkanoylamino radicals selected ι ι- ₁ Bears substituents, stands and the other of the symbols R and R ~ represents hydrogen; one of the symbols R ^ and R for hydrogen or a C _{1 L} -alkyl radical and the other ο 4 5 the symbols R- ^ and R represents hydrogen; either R stands for hydrogen and R stands for a hydroxy radical or C f. R and R together form a direct bond; and either R represents hydrogen and R represents a hydroxy radical or R and R together form a direct bond; as the pharmaceutically acceptable salts thereof. Compounds according to claim 1, wherein one of the symbols R and R for a phenyl radical, the 1 or 2 from fluorine, chlorine and Bromine atoms and methyl, ethyl, ethoxy, ethoxy, nitro, Amino, acetamido and propionamido radicals selected sub- and R ² for water carries substituents and the other of the symbols R is hydrogen; one of the symbols Yr - ^J " and R is hydrogen or a methyl or ethyl radical and the other the symbols R- ^ and R stands for hydrogen. 3. Compounds according to claim 1 or 2, wherein one of the symbols R ¹ and R ^{2 is} a 3-methylphenyl, 4-methylphenyl, 4-kethoxy 809834 / 05SB • phenyl, 3-chlorophenyl, 4-chlorophenyl, 2-nitrophenyl, 3-nitrophanyl, 4-! Titrophenyl, 2,4-dinitrophenyl, 2-aminophenyl or 4-acetamidophenyl radical and the other of the symbols R ¹ and R ^{2 is} hydrogen. 4. Compounds according to any one of claims 1 to 3, wherein R and R ' both represent hydrogen and R and R both represent hydroxy radicals stand. c 6 5. Verbir.dur.gon according to ε-ine ^ i of claims 1 to 3, wherein R and R together form a direct bond, R 'for hydrogen 3
and Fi stands for a hydroxy radical. 6. Compounds according to any one of claims 1 to 3, wherein R ^ for Represents hydrogen, R represents a hydroxy radical and R 'and R together form a direct bond. 7. Compounds according to any one of claims 1 to 3, wherein R ^ and R ty Q together and R and R together stand for direct bonds. 8. Compounds according to any one of claims 1 to 7 »in which one of the symbols R 'and R" represents a phenyl radical containing a chlorine atom or carries a methyl or methoxy radical, and the other of the symbols R and R "represents hydrogen. 9. Compounds r.acn a ^ i of claims 1 to 7, wherein one of the 1 2
Synboles R and R for a phenyl radical containing 1 or 2 ritror 1 2 vertical trägx, and the other of the symbols R and R for Hydrogen stands. 10. Compounds according to any one of claims 1 to 7, wherein one of the 12th Symbols R and R for a phenyl radical that is an amino or Acetamido radical carries, stands and the other of the symbols R ρ
and R is hydrogen. 11. Compounds according to any one of claims 1 to 10, wherein one of the 809834/05 5 8 Symbols R · 'and R stands for a methyl radical and the other of the symbols R ^ and R stands for hydrogen. 12. The compound (+) - 6β- (4-methoxyphenyl) -3a-methyl-3,3aa, 6,6aatetrahydro furo [3,4-b] furan-2,4-dione. 13. Pharmaceutically acceptable salts according to one of claims 1 to 11, soft base addition salts of a compound of formula I. of claim 1, wherein at least one of the symbols R and R ° is a hydroxy radical. 14. Base addition salts according to claim 13, which ammonium, aluminum, Alkali metal or alkaline earth metal salts or salts with an aliphatic or cycloaliphatic amine are. 15. Pharmaceutically acceptable salts according to one of claims 1 to 7, 10 or 11, which acid addition salts of a compound of Formula I are where R od < Amino radical carries, stands. 1 2 Formula I are, wherein R or R is a Pheny! Radical, the a 16. Acid addition salts according to claim 15, which acid addition salts of organic or mineral acids. 17. Process for the preparation of the compounds of the formula I according to one of claims 1 to 12, characterized in that that he a) for the preparation of compounds of the formula I, wherein at least 5 7
stc-ns of a symbol R ^ and R 'is hydrogen, a compound of the formula I in which at least one of the Eyrfcole E? and R ⁷ is other than hydrogen, hydrolyzed; b) for the preparation of compounds of formula I, wherein one 1 2 of the symbols R and R for a phenyl radical that has at least one Uitroradical carries, stands and the other the symbol 1 2
bole R and R represents hydrogen, a corresponding one 1 A compound of the formula I in which one of the symbols R and R • j stands for a phenyl radical and the other of the symbols R 2
and R is hydrogen, nitrated; c) for the preparation of compounds of the formula I, wherein one 1 2
of the symbols R vxid Ti for a phenyl radical, at least carries an amino radical, stands, a corresponding compound 1 2 Formation of the formula I, wherein one of the symbols R and R for a phenyl radical that carries at least one nitro radical, 1 2 and the other of the symbols R and R for hydrogen stands, reduced; d) for the preparation of compounds of the formula I in which R and fi 7 8 R together and R 'and R gernei den, a compound of the formula: fi 7 8 R together and R 'and R together form direct bonds VI where R ° is a phenyl radical in either the α or β configuration which radical bears 1 or 2 substituents which are given for R in one of claims 1 to 11 are, however, hydrogen is excluded, subjected to a reductive cyclization; e) for the preparation of compounds of the formula I in which R or 2
R for a phenyl radical, which is a Cj ^ -alkanoylamino radical kal carries, is a compound of the formula I in which R ¹ or R ^{2 is} a phenyl radical which carries an amino radical, with an acylating agent which is different from a C-. λ-alkanoic acid derives, converts; 809834/0558 f) for the preparation of compounds of the formula I in which R represents hydrogen, reacting a compound of the formula I in which R represents hydrogen with an acid; whereupon, if a pharmaceutically acceptable base addition salt is desired, a compound of formula I wherein at least one of the symbols R and R stands for a hydroxy radical, neutralized with a suitable base; and on what one, if a -Dharinazeutisch permissible acid addition salt is 12 it is desired to have a compound of formula I wherein R or R represents a phenyl radical bearing an amino radical, with reacting one equivalent of a suitable acid; where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^{8 have} the meanings given in one of claims 1 to 11, unless stated otherwise. 18. Pharmaceutical compositions, characterized in that they contain a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. 19. Compositions according to claim 18, characterized in that they are one for oral, parenteral or for rectal administration. 20. Oral compositions according to claim 19, characterized in that they are tablets, capsules, aqueous suspensions, oily solutions or suspensions, emulsions, dispersible powders, granules, syrups or elixirs acts. 21. Compositions according to any one of claims 18 to 20, characterized in that they in addition to one Compound of formula I contain one or more agents that 809834/055 « are selected from antacids, antifoams, inhibitors against gastric secretion and prostaglandin derivatives. 809834/0558