CS249149B2 - Method of 2,5-disubstituted 4(3h)-pyrimidones' production - Google Patents

Abstract

Process for preparing 2,5-disubstituted 4- (3H) -pyrimidones of formula (I) in which m is 0 or 1 n is 0 '2 or 3, Z represents an oxygen or sulfur atom; A represents phenyl, furyl or thlenyl group, which groups may be be substituted with dimethylaminomethyl or piperidinomethyl group and their inetoxic, pharmaceutically useful acid addition salts characterized by in that the amino compound is generic of formula II in which m, n, A and Z are as defined above, is reacted with the phenyl formate, whereupon optionally converting the resulting product into its acid addition salt. Produced substances are effective antagonists Histamine H2-receptors inhibit secretion gastric acid and are useful in treatment of peptic ulcers and other conditions induced excessive gastric acid secretion.

Description

A process for the preparation of 2,5-disubstituted 4 (3H) -pyrimidones

2

A process for the preparation of 2,5-disubstituted 4 (3H) -pyrimidones of formula I wherein m is an integer of 0 or 1, n is an integer of 0 '

Z represents an oxygen or sulfur atom and A represents a phenyl, furyl or thlenyl group, which groups may be substituted by a dimethylaminomethyl group or a piperidinomethyl group, and their inetoxic, pharmaceutically acceptable acid addition salts, characterized in that the amino compound of the formula II m, n, A and Z are as defined above, reacted with phenyl formate, whereupon the resulting product is optionally converted to its acid addition salt.

The compounds produced are potent antagonists of the H2-receptors of histamine, inhibit gastric acid secretion and are useful in the treatment of peptic ulcers and other conditions caused by excessive gastric acid secretion.

The present invention provides novel 2 ', 5-disubstituted 4 (3H) -pyrimidones of formula (I)

A-tCt-1 _z > _m Z (αΐ-ΙίΙηΜΗ-'Η in which A, m, Z and n are as defined below, and their non-toxic, pharmaceutically acceptable salts thereof. These compounds are potent antagonists of H2-histamine receptors inhibiting gastric secretion and are useful in the treatment of peptic ulcers and other conditions caused by pathological over secretion of gastric acid.

The first clinically effective H2-receptor antagonist was burinamide (IIIa). This substance inhibits the gastric secretion of animals, including humans, but is poorly absorbed by oral administration.

Metiamide (IIb), which was further evaluated as ^well as to the efficacy of H2-antagonist, is in effect stronger than burinamid and effective in humans after oral administration. However, its clinical utility is limited due to its toxicity (agranulocytosis). Cimetidine (IIc) is as effective as an H2-antagonist as metiamide, but does not induce agranulocytosis and has recently been marketed as an anti-ulcer drug.

N - -!>

O'

H

A .j

Ila; R = H, Z = CH 2, X-S burinamide IIb; R = CH 3, Z = S, X = S metiamide IIc; R = CH 3, Z = S, X = NCN cimetidine

An overview of developments in the field of H2-antagonists, including those discussed in the preceding paragraph, can be found in CR Ganellin et al., Federation Proceedings, 35, 1924 (1976), Drugs of the Future, 1, 13 (1976) and in the references cited therein.

A large number of 2,5-disubstituted pyrimidone histamine H2-receptor antagonists corresponding to the general formula are known in the art.

HN '

And.

N 0

Thus, in European Patent Application No. 4,793, published October 17, 1979, in European Patent Application No. 3,677, published August 22, 1979, in European Patent Application No. 15,138, published September 3, 1980, in European Patent Publication No. No. 24,873, published Mar. 11, 1981, in European Patent Application Ser. 49173, published Apr. 7, 1982 and in World Patent Application No. 8000966, published 15 May 1980 describes the above compound in which R may represent a group bound to the rest of the analogous 2-amino group of compounds of the invention R ¹ and it may be a hydrogen atom, an alkyl group or a substituted alkyl group. None of these applications, however, disclose the above-mentioned compounds substituted at the 5-position by nitro or substituted amino, as is the case with the compounds of this invention and in our related Czechoslovak patents Nos. 249147 and 249 150.

Thus, the invention relates to histamine H2-receptor antagonists which are potent inhibitors of gastric acid secretion in mammals, including humans, and are useful in the treatment of peptic ulcers and other conditions caused or re-induced by gastric acidity. These compounds correspond to the general formula I ^{A (Z} (Cl 4) _n )

where m is a number of 0 or 1, n is a number of 2 or · 3,

Z represents an oxygen or sulfur atom and A represents a phenyl, furyl or thienyl group, which groups may be substituted by a dimethylaminomethyl or piperidinomethyl group, and also include the corresponding non-toxic, pharmaceutically acceptable acid addition salts.

The present invention provides a process for the preparation of compounds of formula I and their salts.

fi

The invention also provides a process for the preparation of intermediates useful for the preparation of compounds of formula I.

The present invention includes all possible tautomeric forms, geometric isomers, optical isomers and zwitterions of the compounds of formula (I), as well as mixtures thereof. While the compounds of formula I are depicted as 4-pyrimidones, it is understood that both these compounds and intermediates for their preparation may exist in the form of tautomeric 4-hydroxypyrimidines, i.e., compounds corresponding to the formula

OH

The term "non-toxic, pharmaceutically acceptable salts" refers to salts of the compounds of formula I with any non-toxic, pharmaceutically acceptable acids. Such acids are well known and include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, succinic acid, oxalic acid, benzoic acid, methanesulfonic acid, tartaric acid, citric acid. , camphorsulfonic acid, levulic acid, and the like. Said salts are prepared by known methods.

At present, 5-formamido-2- [3- (3-piperidinomethylphenoxy) propylamino] -4 (3H) -pyrimidone and its non-toxic, pharmaceutically acceptable acid addition salts appear to be the most preferred compound of formula (I).

In accordance with the invention, the compounds of formula (I) and salts thereof may be prepared by reacting an amino compound of formula (II)

HN

V / Z ^ OJ HD) JNH wherein m, n, A and Z have the above meanings, is reacted with phenyl chloroformate, after which the resulting product is optionally converted to its ^ad: protrudes salt.

The reaction according to the invention is conveniently carried out in an inert solvent such as acetonitrile, preferably at room temperature.

The starting materials of formula (II) can be prepared by the process of our co-pending Czechoslovak Patent Specification No. 249 147, which proceeds according to the following reaction scheme in which m, n, A and Z are as defined above.

Diagram

A (CH 2 _m Z (CH 3) _n NHp +

Jj

R * ^N

NQ <, a non-reactive solvent

About "XA ¹⁰ ?

_λ L JJ

And - (CH ^) _m Z (CH _{z) n} NU Reduction of [H]

un

R ⁸ represents an easily cleavable group such as fluorine, chlorine, bromine or iodine, alkylthio, nitroamino, phenoxy, substituted phenoxy, alkoxy and the like. Suitable leaving groups are known in the art.

The above reactions are carried out in an inert solvent such as methanol or ethanol. The initiation reaction is preferably carried out by heating the reactants to reflux. The reduction can be carried out by treatment with hydrogen gas in the presence of a suitable catalyst, such as Raney nickel, or a reducing catalyst, such as sodium dithionite.

For therapeutic use, the pharmacologically active compounds of formula (I) are normally administered in the form of pharmaceutical compositions comprising at least one of the free base or a non-toxic, pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutically acceptable carrier.

The pharmaceutical compositions may be administered orally, parenterally or rectally in the form of suppositories. A wide variety of dosage forms can be used for these applications. When using a solid carrier, the pharmaceutical preparation may be a tablet, a powder or pellets intended to fill hard gelatine capsules, as well as troches or lozenges. When using a liquid carrier, the pharmaceutical preparation may be a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution or an aqueous or non-aqueous liquid suspension. These pharmaceutical compositions are prepared by conventional techniques, as appropriate for the desired dosage form.

The dosage of the compounds according to the invention depends not only on factors such as the weight of the patient, but also on the desired degree of inhibition of gastric acid secretion and on the efficacy of the compound used. The decision about the appropriate dosage and the number of doses to be administered per day is up to the attending physician. Of course, these dosages and frequency of administration can be varied by adjusting the dosages to the circumstances and needs of the patient. In the case of preferred compounds of the invention, each unit dosage form for oral administration contains from about 2 mg to about 300 mg of active ingredient, most preferably from about 4 mg to about 100 mg of active ingredient. The active ingredient is preferably administered in equal doses from one to four times daily.

It has been found that H 2 -receptor histamine antagonists are potent inhibitors of gastric secretion of animals, including humans [see Brimblecombe et al., J. Int. Copper. Res., 3, 86 (1975). In clinical trials of cimetidine, a histamine H 2 -receptor antagonist, it has been shown to be an effective therapeutic agent in the treatment of peptic ulcers [Gray et al., Lancet, 1, 8 001 (1977)].

The invention is illustrated by the following non-limiting examples. Example 1 illustrates the actual reaction of the invention, and the following examples describe the preparation of starting materials.

Example 1

5-formamido-2- (3- (3-piperidincmethylphenoxy) propylamino) -4 (3H) -pyrimidine

To a suspension of 1.51 g (3.23 mmol) of 5-amino-2- [3- (3-piperidinomethylphenoxy) propylamino] -4 (3 H) -pyrimidium trihydrochloride (prepared in Example 3) in 10 mL of acetonitrile and 2 mL triethylamine (6 ml, 43.3 mmol) was added and the solution was stirred at room temperature for 15 minutes, then evaporated under reduced pressure, the residue was dissolved in acetonitrile (10 ml) and 2.17 g (16.0 mmol) was added. The reaction mixture is evaporated under reduced pressure, the residue is applied to a column of 120 g of silica gel (230-400 mesh) and subjected to flash chromatography using a gradient elution of a mixture of methanol, dichloromethane and ammonium hydroxide in a ratio of 5: 1.

: 95: 0.4 to 10: 90: 0.7. The appropriate fractions were combined and evaporated. 1.04 g of product is obtained, which after recrystallization from absolute ethanol gives the title compound, m.p. 173-174 ° C.

Analysis calculated for C20H27N5O3

% H, 7.06;% N, 18.17; found

% C, 62.19;% H, 6.93;% N, 18.56 (corrected for 3.0% H2O). Example 2

5-Nitro-2- [3- (3-piperidinomethylphenoxy) propylamino] -4- (3H) -pyrimidone

A solution of 8.20 g (33.0 mmol] of 3- (3-piperidinomethylphenoxy jpropylaminu and 6.20 g (32.5 mmol] of 2-methylth ^o-5 Mitra-4-hydroxypyridine dihydrochloride (prepared as described in U.S. Patent No. 4 241056) in 35 ml of ethanol is stirred at reflux for 18 hours, the reaction mixture is evaporated under reduced pressure, the residue is applied to a column of 250 g of silica gel (230-400 mesh) and subjected to flash chromatography using a gradient elution with methanol / methylene chloride The appropriate fractions were combined and evaporated to give the title compound after recrystallization from tetrahydrofuran, m.p. 161-164 ° C.

The NMR spectrum of the product, measured in perdeuterodimethylsulfoxide at 90 MHz, indicated the presence of about 0.25 moles. of tetrahydrofuran.

Analysis: for C 19 H 28 N 5 O 4. 0.25 C8H5O calculated

59.19% · C ,, 6.71% Η, 17.27 '% _; · Ν;

Μ λΊ Ρ7Ρ1ΊΩ

% C, 59.22;% H, 6.70;% N, 17.54 (corrected for 0.19% H2Q).

Example 3

5-Amino-2- [3- (3-piperidinomethylphenoxy) propylamino] -4 (3H) -pyrimidone

A suspension of 0.50 g (1.29 mmol) of 5-nitro-2- [3- (3-piperidinomethylphenoxy) propylamino] -4 (3H) -pyrimidone and a catalytic amount of Raney-nickel (ca. 0.7 mL) in 50 mL of methanol in a Parr apparatus was hydrogenated at 50 psi for 2.75 hours. ; The reaction mixture was filtered and evaporated. The residue is applied to a column of 90 g of silica gel (230-400 mesh) and subjected to flash chromatography using a gradient elution of methanol / methylene chloride containing 1% ammonium hydroxide. Appropriate fractions were combined, evaporated, the semisolid product was acidified with methanolic hydrochloric acid and the title compound precipitated from ether as a dihydrochloride salt melting at 182-184 ° C.

For C19H27N5O2. 2 HCl calculated

% C, 50.87;% H, 6.63;% N, 15.61.

19.76% Cl; found

% C, 49.89;% H, 6.56;% N, 15.48.

19.52% Cl (corrected for 1.3% H 2 O content).

In a separate experiment, the product obtained after flash chromatography was treated with 20 ml of 3.1 N methanolic hydrochloric acid. The mixture was evaporated under reduced pressure and the product dried to give 5.8 g of the title compound as the trihydrochloride.

For C19H27N5O2. 3 HCl. 0.3 CHtO calculated ·

% C, 48.65;% H, 6.60;% N, 14.70.

22.33% Cl;

found

47.54% · C, 6.50% H, 14.54% N,

21.93% Cl (corrected for 1.22% H 2 O content).

The following starting materials of formula II can also be prepared in an analogous manner to Examples 2 and 3: 5-amino-2- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamino] -4 (3H) -pyrimidone.

NMR (100 MHz, perdeuterodimethylsulfoxide, λ values:

8.88 (multiplet, 6H);

8.18 (multiplet, 1H,

7.82 (singlet, 1 H),

7.56 (singlet, 1 H),

7.40 (singlet, 1H,

4.50 (singlet, 2 H),

3.82 (singlet, 2 H),

3.50 (multiplet, 2 H),

2.73 (multiplet, 8H).

Analysis: for C14H2IN5OS2. 3.5 HCl calculated

% C, 38.00;% H, 5.29;% N, 14.99.

13.73% S, 26.57% Cl;

found

% C, 36.12;% H, 4.77;% N, 14.57.

13.90% S, 25.16% Cl.

5-amino-2- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethylamino] -4- (3H) -pyrimidone, the trihydrochloride of which melts at 150-155 ° C.

5-Amino-2- {2 - [(5-dimethylaminomethyl-2-furyl) methylthio] ethylamino] -4 (3H) -pyrimidone, the trihydrochloride of which melts at 127-132 ° C.

Analysis: for C14H21N5O2S. 3 FICI calculated

% C, 38.85;% H, 5.59;% N, 16.18.

7.41% S, 24.58% Cl;

found

% C, 38.97;% H, 5.59;% N / 16.14%;

7.72% S, 23.70% Cl.

VYNALEZU

Claims (2)

SUBJECT A process for the preparation of 2,5-disubstituted 4 (3H) -pyrimidones of formula I ((CH £) | T> NHCHO (!) Where m is a number of 0 or ¹ 1, n is a number of 2 or 3, Z represents an oxygen or sulfur atom and A represents a phenyl, furyl or thienyl group, which groups may be substituted by a dimethylaminomethyl or piperidinomethyl group, and their non-toxic, pharmaceutically acceptable acid addition salts, characterized in that the amino compound is of the general formula II A (CH _{z) m} Z ( NH ₂ (m) in which m, n, A and Z are as defined above, is reacted with phenyl formate, whereupon the resulting product is optionally converted into its acid addition salt. 2. Process according to claim 1, characterized in that the reaction is carried out in an inert solvent, preferably acetonitrile, at room temperature.