FI60704B - PROCEDURE FOR THERAPEUTIC USE OF THERAPEUTIC ACID 2,6-DIMETHYL-3-METHOXICARBONYL-4- (2'-NITROPHENYL) -1,4-DIHYDROPYRIDINE-5-CARBOXYLSYRAISOBUTYL ESTER - Google Patents

Description

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Patent and Structure Management · ....,,. , .__. . (44) Date of issue and date of issue. - riunt · och ragistaratyralsan 'An1ekm utl «gd oeh utUkrifun pubikend 30.11.8l (32) (33) (31) Pyr ^ Atty etuoikeus — Begird priority 05.11.75

Federal Republic of Germany (DE) P 25 ^ 9568.5 (71) Bayer Aktiengesellschaft, Leverkusen, Federal Republic of Germany (DE) (72) Egbert Wehinger, Velbert, Friedrich Bossert, Wuppertal, Arert Heise, Arend Heise , Kurt Stoepel, Wuppertal,

Wulf Vater, Leverkusen, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (710 Oy Kolster Ab (5¾) Method for the preparation of therapeutically useful 2,6-dimethyl-3-methoxycarbonyl-U- (2'-nitrophenyl) -1, lt for the preparation of dihydropyridine-5-carboxylic acid isobutyl ester - For the preparation of therapeutically active 2,6-dimethyl-3-nitoxycarbonyl-L- (2, -nitrophenyl) -1,5-dihydropyridine-5-carboxylic acid isobutyl ester

The present invention relates to a process for the preparation of a novel 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester.

It has already become known that 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained by reacting benzylideneacetic acid ethyl ester with β-aminocrotonic acid ethyl ester or with acetic acid ethyl ester and Beriachia (Knoevenagel, Knoevenagel). Ges.

31, 743 (1898)). It is further known that certain 1,4-dihydropyridines have interesting pharmacological properties (F. Bossert, W. Vater, Die Naturwissenschaften 58, 578 (1971)).

2 60704

Furthermore, it has become known from the applicant's previous DE patent applications 2,117,571 and 2,117,573 that the corresponding dihydropyridines can be used as drugs acting on the coronary arteries. However, according to the state of the art, the recently observed strong and long-lasting coronary effect of the compound prepared according to the invention was not to be expected.

It was found that the new 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester of the formula ex »3" hc-h9c-ooc ^ C00CH3 h3c ^ J j

B

has a very strong and long-lasting coronary effect.

The invention is characterized in that a) 2'-nitrobenzylideneacetic acetobutyl acid butyl ester of the formula X

3 I

H3c "" o is reacted with β-aminocrotonic acid methyl ester (formula III), 1 '. r / \ 3 60704

H N ^ COOCHj C

II

H2 N ch3

III

optionally in the presence of water or inert organic solvents, or B) reacting 2'-nitrobenzylideneacetic acid isobutyl ester (formula II) with acetic acid methyl ester (formula IV), H3 ° CsCH2-C00CH3

IV

and ammonia in the presence of water or inert organic solvents, or C) 2'-nitrobenzylideneacetic acid methyl ester (formula V), annetaan ^ ~ ΝO 2 .c H 2 O / CO 3 CH 3

C

o ch3

V

react with γ-aminocrotonic acid isobutyl ester (formula VI), 60704 H, Cv

HC-H, C-OOC. . H H3C 'C

II

H, C x NH 2 VI

optionally in the presence of water or inert solvents, or D) reacting 2'-nitrobenzylideneacetic acid methyl ester (formula V) with acetic acid isobutyl ester (formula VII), H 3 C-C x x CH 3 'CH, -C00-CH 2 -CH 2' CH,

VII

and ammonia, optionally in the presence of water or inert organic solvents, or E) reacting γ-aminocrotonic acid isobutyl ester (formula VI) with 2-nitrobenzaldehyde (formula VIII),

0 ^ H

VIII

and acetic acid methyl ester (Formula IV) optionally in the presence of water or inert organic solvents, or 5-aminocrotonic acid methyl ester (Formula III) is reacted with 2-nitrobenzaldehyde (Formula VIII) and acetic acid isobutyl ester (Formula IV) or in inert organic solvents.

Surprisingly, the substance of the formula I prepared according to the invention has a very strong effect on the coronary arteries.

Among the corresponding 1,4-dihydropyridine derivatives known from the prior art, it has not been possible to show such a strong and long-lasting coronary effect, especially after enteral administration. In addition, the compound of the invention is less unstable to light than the corresponding known dihydropyridines. It thus enriches the pharmacy due to these special properties.

The compound of the invention is chiral and may exist in stereoisomeric forms which are treated as image and mirror image (enantiomers, antipodes). These, in turn, can occur in different conformations. Both the racemate form and the antipodes are within the scope of the products according to the invention.

According to the starting materials used, the synthesis of the compound according to the invention can be expressed by the following formulas: a) HjCn Sr no2 h3 C \ S ^ n ° 2 HC-H2C-00Cx

h3c / c "η η, ο 'S IT

S *, Hs yC00CH3 ^ Jj CH3 h3 C 0 ff ---- ► J-J- h2n ch3

III

B) H5c. WXN0 H, Cs O '"0 · HC-H2C00CwCv HC-H2C00C' v ^ 'v'COOCHj h3c / c h, cooch3 h3c / 11 If X H2C w H, C ^ N ^“ CHs h3c o + h nh3 0 ch3

II IV

C) h3cv Csl h3cn Sr n ° 2 HC-CH2-00Cs sH X NO2, HC-H2C00C v ^ vCOOCHj

h3c / c cooch3 h3c 'I I

f + H? _► h3canach3 h3 c nh2 ^ u \ n 0 ch3

VI V

7 60704 D) H3CX ζ ^ "° * HC-CH2-00Cn / cooch3

H-C "CH2 + H C

I £ -► I

is <ί · υ \ H, C 0 NHj 0 CH>

VII V

E) H C N ° 2 3 HC-CH2-00Cs / H o-Csh H9C / cooch3 _ ^ H3C m +! C - * xcv cT'g ^ ch3 h3 c nh2

HjCn O'NO2 3 hc-h2 coo - ^^^ cooch3

H3 Π iT

h3c h ch3 F) H3Cn ζ ^ Ν02 HC-H2C00C. , c ^ ch2 d H __► + hn, cooch3 h3 C 0 c 3 1 |

✓'C N

h2 n ch3 H, c, O '”* HC-H2C00 € n ¥ As.C00CH3 H3 cy il H3 CH CH3 8 60704 The starting materials of the formulas II-VIII are known from the literature or can be prepared according to methods known from the literature (Lit. : Org. Reactions XV, 204 ff (1967); ACCOPE J. Amer. Chem. Soc. 67, 1017 (1945); and Houben-Weyl, Methoden der Organ. Chemie VII / 4 230 ff (1968)).

In carrying out the processes A to F according to the invention, the reactants are used in each case in approximately molar amounts. The ammonia used is suitably added in excess.

Suitable diluents are water and all inert organic solvents. These preferably include alcohols such as ethanol, methanol, ethers such as dioxane, diethyl ether or glacial acetic acid, pyridine, dimethylformamide, dimethyl sulfoxide or acetonitrile.

Reaction temperatures can vary widely. In general, work is carried out at a temperature in the range from about 20 to 200 ° C, preferably at 50 to 120 ° C and in particular at the boiling point of the solvent.

The reaction can be carried out at normal pressure, but also at elevated pressure. Usually working at normal pressure.

The following methods of preparation are provided for clarity only, and the preparation of a compound of formula I is not limited to these methods, but any modification of these methods is similarly useful in the preparation of a compound of formula I.

The compound of the invention is a drug substance. In enteral or parenteral use, it causes a strong and long-lasting increase in myocardial blood flow and can therefore be used for the prevention and treatment of ischemic heart disease, especially when accompanied by high blood pressure.

The new active ingredient can be converted in a known manner into customary preparations, such as tablets, capsules, medicaments, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically acceptable carriers or diluents. In this case, the therapeutically active compound must in each case be present in a concentration of 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the stated dosage range.

and '> »'" 60704

The preparations are prepared, for example, by mixing the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, in which case, for example, when water is used as diluent, organic solvents can optionally be used as co-solvents.

Examples of excipients are:

Water, non-toxic organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut-sesame oil), alcohols, (e.g. ethyl alcohol, glycerin), glycols (e.g. propylene glycol, polyethylene glycol); solid carriers such as natural rock powders (e.g. kaolins, clays, talc, chalk), synthetic rock powders (e.g. highly dispersed silica, silicates), sugar (e.g. cane, milk and grape sugar); emulsifiers such as nonionic and anionic emulsifiers (e.g. polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, alkyl sulfonates and aryl sulfonates), dispersants, (e.g. lignin, sulphite waste liquors, methylcellulose and lyose, methylcellulose-lose). (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

The drug is administered in a conventional manner, preferably enterally or parenterally, in particular perlingually (through the surface of the tongue) or intravenously (intravenously).

For enteral use, the tablets may, of course, contain not only said carriers but also additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives such as starch, preferably potato starch, gelatins and the like. Furthermore, fluxes such as magnesium stearate, sodium lauryl sulfate and talc can also be used to make tablets. When aqueous suspensions and / or elixirs for oral use are used, not only the above-mentioned excipients but also various flavoring or coloring agents can be added to the active ingredients.

In the case of parenteral administration, solutions of the active compounds may be employed with appropriate liquid carriers.

, oit <(I .li 10 60704

In general, it has been found advantageous to administer intravenous administration in amounts of about 0.0001 to 1 mg / kg, preferably about 0.0005 to 0.01 mg / kg of body weight, per day for effective results, and enteral administration has a dosage of about 0, 0005 to 10 mg / kg, preferably 0.001 to 0.1 mg / kg body weight, per day.

Nevertheless, it may be necessary to deviate from said amounts, namely depending on the body weight of the test animal or the quality of the route of administration, but also taking into account the species and its individual attitude towards the drug or the time of administration. Thus, in some cases it may be sufficient to use a lower amount than the above-mentioned minimum, while in other cases the said upper limit must be exceeded. When administering larger amounts, it may be advisable to divide this into several single doses and administer during the day. For medical administration to humans, the same dosage range is used.

Significantly, the above also applies! reports.

To determine the blood flow-promoting effect, the substance was administered to dogs and myocardial blood flow was measured using an electromagnetic flow meter.

The substance increases the amount of blood flowing through the heart after intravenous and enteral administration. A particular advantage is its rapid and complete absorption after administration through the tongue surface, so that it also has a strong effect in this application, even at very low doses, with a long duration of action.

The results of studies in dogs after sublingual administration are shown in the following table.

Dosage Increased cardiac flow Decreased blood pressure in% Duration of action half-life in% _new_ 0.003 23 100 0 0.01 46 133 5 0.1 142 184 13

Vff 11 60704

It will be appreciated that the compound of the invention increases myocardial blood flow regardless of dosage, surprisingly at very low effective doses. The onset of action is a few minutes after sublingual administration and always lasts 2-6 hours depending on the dose (the half-life of the effect is given in the table as a more accurate measure of duration of action). At the same time, it causes a mild and also long-lasting reduction in blood pressure, which is usually a great additional benefit in the treatment of coronary heart disease.

The compound according to the invention is therefore suitable for the prophylaxis and treatment of acute and chronic ischemic heart diseases in the broadest sense. The agent can be used as a drug in the prevention and treatment of angina pectoris disorders and seizures, as well as in the treatment of the aftermath of myocardial infarction. It is particularly suitable for use in the treatment of cases in which one of the above-mentioned heart diseases is associated with hypertension.

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13 60704

Preparation Examples 2,6-Dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester

'C ^ HC-OOCU

Hsc / I | d H 3 A) 14.6 g (50 mmol) of 2'-nitrobenzylideneacetic acid butyl ester were heated together with 5.8 g (50 mmol) of β-aminocrotonic acid methyl ester in 80 ml of ethanol under reflux for 20 hours. After cooling the reaction mixture, the solvent was distilled off in vacuo, and a small amount of ethanol was stirred in the oily residue. The product crystallized after a short time, suction filtered and recrystallized from ethanol.

Melting point: 141-142 ° C, yield: 15.2 g (78%).

B) 14.6 g (50 mmol) of 2'-nitrobenzylideneacetic acetic acid isobutyl ester were heated together with 5.8 g (50 mmol) of acetic acid methyl ester and 6 ml (88 mmol) of a 25% aqueous ammonia solution in 80 ml: methanol for 24 hours under reflux. Finally, the solvent was distilled off in vacuo and a small amount of ethanol was stirred in the oily residue. The product crystallized after a short time, suction filtered and recrystallized from ethanol. Melting point: 140-142 ° C, yield: 11.9 g (61%).

C) 12.5 g (50 mmol) of 2'-nitrobenzylideneacetic acid methyl ester were heated together with 7.85 g (50 mmol) of β-aminocrotonic acid butyl ester in 80 ml of ethanol under reflux for 20 hours. After cooling the reaction mixture, the solvent was distilled off in vacuo, the solid residue was triturated with ether, filtered off with suction and recrystallized from ethanol. Melting point: 140-142 ° C, yield: 14.5 g (75%).

D) 12.5 g (50 mmol) of 2'-nitrobenzylidene acetic acid acetate were heated together with 7.85 g (50 mmol) of acetic acid butyl ester and 6 ml (8 mmol) of 75% aqueous ammonia solution. In 80 ml of isobutanol for 15 min. time to reflux. After cooling the reaction mixture, the solvent was distilled off in vacuo. the oily residue crystallized overnight, triturated with ether, suction filtered and recrystallized from ethanol. Melting point: 140-142 ° C, yield: 10.9 g (56%).

E) 7.85 g (50 mmol) of β-aminocrotonic acid isobutyl 1-ester were heated together with 7.6 g (50 mmol) of 2-nitrobenzaldehyde and 5.8 g (50 mmol) of acetic acid methyl ester In 80 ml of ethanol for 24 hours under reflux. After cooling the reaction mixture, the solvent was concentrated in vacuo, the solid residue was triturated with ether, filtered off with suction and recrystallized from ethanol. Melting point 141-142 ° C, yield: 14.5 g (75%).

F) 5.8 g (50 mmol) of β-aminocrotonic acid methyl ester were heated together with 7.6 g (50 mmol) of 2-nitrobenzaldehyde and 7.85 g (50 mmol) of acetic acid butyl ester in 80 ml of ethanol. boiling for an hour. The solvent was finally distilled off in vacuo and the solid residue was recrystallized from ethanol. Melting point: 141-142 ° C, yield 13.6 g (70%).

Claims (3)

60704 Claim: A process for the preparation of a therapeutically useful 2,6-dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester of the formula N, N 2 - (2) H9C-00C ^ _ ^ 'Vv ^ / C0 ° CH3 i X d H d characterized in that A) 2'-nitrobenzylideneacetic acid isobutyl ester of formula (II) o ^ V ^ no2 HC ^ HI hc-h2c ^ C HCO3 1 V 3 l of h3c ^ ^ 0 is reacted with a β-aminocrotonic acid methyl ester of the formula -nitrobenzylideneacetacetic acid butobutyl ester is reacted with an acetic acid methyl ester of the formula h c-cr (iv) J "" ch2-cooch3 and ammonia, optionally in the presence of water or an inert organic solvent, or C) 2'-nitrobenzylideneacetic acetic acid methyl ester, (V) C00CHq K o xch3 you can is reacted with β-aminocrotonic acid isobutyl ester of the formula H-C HC-H9C-00C. H (VI) 3 II c H 3 Cl 2 x 2 H 2 optionally in the presence of water or an inert organic solvent, or D) a 2'-nitrobenzylideneacetic acid methyl ester of formula (V) is reacted with an acetic acid isobutyl ester of the formula 60704 17 H CCl-CH 2 -CH 2 -C 9 -C00 -CH7-CH3 (VII) ^ CH3 and ammonia, optionally in the presence of water or an inert organic solvent, or E) reacting a β-aminocrotonic acid isobutyl ester of formula (VI) with 2-nitrobenzaldehyde of formula (VIII) c CT H and with an acetic acid methyl ester of formula (IV) optionally in the presence of water or inert organic solvents, or F) reacting a β-aminocrotonic acid methyl ester of formula (III) with 2-nitrobenzaldehyde of formula (VIII) and acetic acid butyl ester of formula (VII) as such, in an organic solvent. 18 60704 Patent: For the preparation of therapeutically active 2,6-dimethyl-5-methoxycarbonyl-N- (2 * -nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester with formula II (I) H3C \ 1C00CHo J hc -h9c-ooc 3 «S0 '" [I | H q C CH 9 d HJ kännetecknat därav, att man A) its own 2 * -nitrobenzylideneacetatexyranobutyl ester with formula -I (II) l T- »° 2 Π3υ | H3C 0 med / 3-Aminocrotonsyramethyl ester with the form of h (ci) H2N ch3 J 2 CH 2 -COOCH 3 and ammonia, optionally with water or an inert organic solvent, or C) 2'-nitrobenzylideneacetate isyramethyl ester with the formula formχ, C00CH_ h I x: -HOC-OOC.H (VI) hqc ^ c · ^ 3 II s * "\ H3C nh2 is optionally present in a water or inert solution, or D) is a 2-nitrobenzylideneacetyl ester of methyl ester with formula (V) with acetic acid isobutyl ester of formula; '