CS249149B2 - Process for the preparation of 2,5-disubstituted 4 (3H) -pyrimidones - Google Patents

Abstract

A process for the preparation of 2,5-disubstituted 4-(3H)-pyrimidones of the general formula I in which m is a number with a value of 0 or 1, n is a number 0' with a value of 2 or 3, 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 non-toxic, pharmaceutically usable acid addition salts, characterized in that an amino compound of the general formula II in which m, n, A and Z have the above-mentioned meaning is reacted with phenyl formate, whereupon the resulting product is optionally converted into its acid addition salt. The substances produced are effective antagonists of histamine H2 receptors, inhibit gastric acid secretion and are useful in the treatment of peptic ulcers and other conditions caused by excessive secretion of gastric acid.

Description

{54 j Process for the production of 2,5-disubstituted 4(3H)-pyrimidones

2

Process for the preparation of 2,5-disubstituted 4(3H)-pyrimidones of the general formula I in which m is a number with the value 0 or 1, n is a number 0' with the value 2 or 3,

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 non-toxic, pharmaceutically acceptable acid addition salts, characterized in that the amino compound of the general formula II in which m, n, A and Z have the above-mentioned meaning is reacted with phenyl formate, after which the resulting product is optionally converted into its acid addition salt.

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

The invention describes novel 2^'5-disubstituted 4(3H)-pyrimidones of general formula I

A-tCt-l _z > _m Z (αΐ-ΙίΙηΜΗ-'Η in which A, m, Z and n have the meanings given below, and their non-toxic, pharmaceutically acceptable salts. These compounds are potent histamine H2-receptor antagonists, inhibit gastric acid secretion and are useful in the treatment of peptic ulcers and other conditions caused by pathological excessive secretion of gastric acid.

The first clinically effective H2-receptor antagonist was burinamide (Ila). This substance inhibits gastric secretion in animals, including humans, but is very poorly absorbed when administered orally.

Methamide (lib), which has ^also been evaluated for its efficacy as an H2-antagonist, is more potent than burinamide and is effective in humans when administered orally. However, its clinical utility is limited due to toxicity (agranulocytosis). Cimetidine (lić) is as effective as methamide as an H2-antagonist, but does not cause agranulocytosis and has recently been marketed as an antiulcer drug.

N - — !>

O'

H

A .j

Ila; R=H, Z=CH2, X—S burinamide lib; R=CH3, Z=S, X=S methiamide lic; R=CH3, Z=S, X=NCN Cimetidine

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

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

HN'

A .

N 0

Thus, in European Patent Application No. 4,793, published on October 17, 1979, in European Patent Application No. 3,677, published on August 22, 1979, in European Patent Application No. 15,138, published on September 3, 1980, in European Patent Application No. 24,873, published on March 11, 1981, in European Patent Application No. 49,173, published on April 7, 1982 and in World Patent Application No. 8,000,966, published on May 15, 1980, those compounds mentioned above are described in which R may represent a group analogous to the residue attached to the 2-amino group of the compounds according to the invention and R ¹ may represent a hydrogen atom, an alkyl group or a substituted alkyl group. However, none of these applications discloses the above-mentioned compounds substituted at the 5-position with a nitro group or a substituted amino group, as is the case with the compounds of this invention and our related Czechoslovak patent applications Nos. 249,147 and 249,150.

The invention thus relates to histamine H2-receptor antagonists which are effective inhibitors of gastric acid secretion in mammals, including man, 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 ∙ ) _n

in which m is a number with the value 0 or 1, n is a number with the value 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 group or a piperidinomethyl group, and also includes the corresponding non-toxic, pharmaceutically acceptable acid addition salts.

The subject of the invention is a process for the production of compounds of general formula I and their salts.

fi

The invention also describes a process for the production of intermediates useful for the preparation of compounds of general formula I.

The invention includes all possible tautomeric forms, geometric isomers, optical isomers and zwitterions of the compounds of general formula I, as well as mixtures thereof. Although the compounds of general formula I are drawn as 4-pyrimidones, it is understood that both these substances and the intermediates for their preparation can exist in the form of tautomeric 4-hydroxypyrimidines, i.e., for example, substances corresponding to the general formula

OH

The term "non-toxic, pharmaceutically acceptable salts" refers to salts of compounds of the general formula I with any non-toxic, pharmaceutically acceptable acids. These 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, etc. The salts mentioned are prepared by known methods.

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

In accordance with the invention, the compounds of general formula I and their salts can be prepared by reacting an amino compound of general formula II

HN

V/OJ Z^HD ) Jnh in which m, n, A and Z have the above-mentioned meaning, is reacted with phenyl formate, after which the resulting product is optionally converted into its acid ^addition salt.

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

The starting materials of general formula II can be prepared by the procedure according to our related Czechoslovak patent specification No. 249,147, which proceeds according to the following reaction scheme, in which m, n, A and Z have the meanings given above.

Diagram

A (CH^ _m Z (Chf,) _n NHp+

Jj

R* ^N

NQ<, non-reactive solvent

About "XA ¹⁰ ?"

_λ L JJ

A - ( CH^ ) _m Z (CH _z ) _n NU reduction [H]

un

The symbol R ⁸ represents a readily leaving group, such as a fluorine, chlorine, bromine or iodine atom, an alkylthio group, a nitroamino group, a phenoxy group, a substituted phenoxy group, an alkoxy group, 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 the action of 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 the general formula I are normally administered in the form of pharmaceutical compositions containing as the basic active ingredient at least one of these compounds in the form of the free base or in the form of a non-toxic, pharmaceutically acceptable acid addition salt, in combination with a pharmaceutically acceptable carrier.

Pharmaceutical compositions may be administered orally, parenterally, or rectally in the form of suppositories. A wide variety of dosage forms may be used for these applications. When a solid carrier is used, the pharmaceutical composition may be a tablet, powder, or pellets for filling hard gelatin capsules, troches, or lozenges. When a liquid carrier is used, the pharmaceutical composition may be a syrup, emulsion, soft gelatin capsule, sterile solution for injection, or aqueous or nonaqueous liquid suspension. These pharmaceutical compositions are prepared by conventional techniques as appropriate to the desired dosage form.

The dosage of the compounds of 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 potency of the compound used. The decision on the appropriate dosage and on the number of doses to be administered per day is a matter for the attending physician. These doses and the frequency of their administration can of course be varied by adapting the dosage to the particular circumstances and needs of the patient. In the case of preferred compounds of the invention, each oral dosage unit contains about 2 mg to 300 mg of active ingredient, most preferably about 4 mg to 100 mg of active ingredient. The active ingredient is preferably administered in equal doses one to four times a day.

Histamine H2 receptor antagonists have been found to be effective inhibitors of gastric secretion in animals, including humans [see Brimblecombe et al., J. Int. Med. Res., 3, 86 (1975)]. In clinical trials, cimetidine, a histamine H2 receptor antagonist, has been shown to be an effective therapeutic agent in the treatment of peptic ulcers [Gray et al., Lancet, 1, 8001 (1977)].

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way. The actual reaction according to the invention is illustrated by Example 1, and the following examples describe the preparation of the starting materials.

Example 1

5-formamido-2-(3-(3-piperidinemethylphenoxy)propylamino]-4(3H]-pyrimidone)

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

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

Analysis: for C20H27N5O3 calculated

62.32% C, 7.06% H, 18.17% N; found

62.19% C, 6.93% H, 18.56% N (corrected for 3.0% H2O content). 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)propylamine and 6.20 g (32.5 mmol) of 2-methylth ^; o-5 mitro-4-hydroxypyrimidine (prepared by the procedure described in U.S. Patent No. 4,241,056) in 35 ml of ethanol was stirred at reflux for 18 hours. The reaction mixture was evaporated under reduced pressure, the residue was 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. The product gave the title compound after recrystallization from tetrahydrofuran, melting at 161-164°C.

The NMR spectrum of the product, measured in perdeuterodimethylsulfoxide at 90 MHz, indicates the presence of approximately 0.25 mol of tetrahydrofuran.

Analysis: for C19H28N5O4 . 0.25 CαH5O calculated

59.19% C, 6.71% H, 17.27% _; ·Ν;

M λΊ Ρ7Ρ1ΊΩ

59.22% C, 6.70% H, 17.54% N (corrected for 0.19% H2O content).

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 is hydrogenated in a Parr apparatus for 2.75 hours at a pressure of 0.35 MPa. ; The reaction mixture is filtered and evaporated. The residue is applied to a column of 90 g of silica gel (230 to 400 mesh) and subjected to flash chromatography using a gradient elution with a mixture of methanol and methylene chloride containing 1% ammonium hydroxide. The appropriate fractions are combined, evaporated, the semi-solid product is acidified with methanolic hydrochloric acid and the title compound is precipitated from the solution with ether in the form of the dihydrochloride melting at 182-184 degrees Celsius.

Analysis: for C19H27N5O2 . 2 HCl calculated

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

19.76% Cl; found

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

19.52% Cl (corrected for 1.3% H2O 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 was dried to give 5.8 g of the title compound as the trihydrochloride.

Analysis: for C19H27N5O2 . 3 HCl. 0.3 CHtO calculated·

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

22.33% Cl;

found

47.54% C, 6.50% H, '14.54% N,

21.93% Cl (corrected for 1.22% H2O content).

By an analogous procedure to that in Examples 2 and 3, it is also possible to prepare the following starting materials of general formula II: 5-amino-2-{2-[(5-dimethylaminomethyl-3-thienyl] methylthio] ethylamino]-4(3H)-pyrimidone.

NMR (100 MHz, perdeuterodimethylsulfoxide, δ values:

8.88 (multiplet, 6H),

8.18 (multiplet, lHj,

7.82 (singlet, 1H),

7.56 (singlet, 1H),

7.40 (singlet, 1Hj,

4.50 (single, 2H),

3.82 (singlet, 2H),

3.50 (multiplet, 2H],

2.73 (multiplet, 8H).

Analysis: for C14H2ÍN5OS2 . 3.5 HCl calcd.

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

13.73% S, 26.57% Cl;

found

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

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

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

7.41% S, 24.58% Cl;

found

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

7.72% S, 23.70% Cl.

INVENTION

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.