CS249150B2 - Method of 2,5-disubstituted 4(3h)-pyrimidones' production - Google Patents

Description

Methiamide (IIb), which has been further evaluated as efficacy as H 2 -antagonist, is stronger in potency than burimamide and is effective in humans when administered orally. However, its clinical utility is limited due to its toxicity (agranulocytosis). Cimetidine (IIc), as an Hz-an2 tagonist, is as effective as metiamide, but does not induce agranulocytosis and has recently been marketed as an anti-ulcer drug.

R

X 11

CH ₉ 2CH, C 1 -, NU - C - NHCu.

| g 4 »/ El

H

Ila; R-H, Z-CH 2, X-S burimamide 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), in Drugs et al Future, 1, 13 (1976). and 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

RTak in European patent application no. No. 4,793, published October 17, 1979, European Patent Application No. 3,677, published August 22, 1979, European Patent Application No. 15,138, published September 3, 1980, European Patent Application No. 24,873, published 11 on March 1, 1981, European Patent Application No. 49,173, published April 7, 1982, and World Patent Application No. 6,198,179; No. 8,000,966, issued May 15, 1980, discloses those compounds in which R may be a moiety analogous to the moiety attached to the 2-amino group of the compounds of this invention and R ' may be hydrogen, alkyl or substituted alkyl. However, neither of these applications discloses the above-mentioned 5-substituted compounds with nitro or ¹ optionally substituted amino, as is the case with the compounds of the present invention and in our related Czechoslovak patents Nos. 249147 and 249 149.

Thus, the invention relates to histamine H 1 -receptor antagonists that 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 ^R 1

CH?) ^ (CH? Λη M a '' (n in which m is a number of 0 or 1, n is a Number of 2 or 3,

Z represents an oxygen or sulfur atom,

A represents a phenyl, furyl or thienyl group, which groups may be substituted by dimethylaminomethyl or piperidinomethyl and

R ¹ represents an amino or alkoxycarboinylamino group having up to 4 carbon atoms, and also includes 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. 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-pyrimidonyl, 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

R '

The term "nontoxic ^pharmacist: cally acceptable salts" means salts of compounds of Formula I with any nontoxic 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.

The following compounds currently seem to be the most preferred compounds of formula (I):

1) 5-ethoxycarbonylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] -4 (3H) -pyrimidone,

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

3) 5-amino-2-S2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamino] -4 (3H) -pyrimidone,

4) 5-amino-2- {2 - [(5-piperidinomethyl-3-thienyl) methylthio] ethylamino] -4 (3H) -pyrimone and

5) 5-amino-2- {2 - [(5-dimethylaminomethyl-2-furylmethylthio) ethylamino] -4 (3H) -pyrimidine, and their non-toxic, pharmaceutically acceptable acid addition salts.

According to the invention, the compounds of formula I and their salts can be prepared by the preparation of a compound of formula II

A- (CH2j, Z (CH2j, ₁ NH2 (II)) in which

A, Z, m and n are as defined above and reacted with a compound of formula III

NH

R ⁹ —C — NH?

(III)

NH

AND!

A- (CH] _in Z (CH j _n NH-C-NH 2 [IV] wherein

A, Z, m and n are as defined above, and this compound is reacted with a compound of formula V (n)

R @ c

II

O

CO • L · ¹ A (i

CVQ in which

R ⁹ represents a thioalkoxy group or a radical of formula to form a compound of formula IV wherein:

R ¹¹ is C 1 -C 3 alkoxy to form a compound of formula I wherein R ¹ is alkoxycarbonylamino as defined above, optionally subjected to hydrolysis to give the corresponding compound of formula I wherein R ¹ is amino; and the product obtained is optionally converted into its acid-adione salt.

The reaction according to the invention can be described by the following reaction scheme:

Diagram

A— (CH2) _m Z (CH2) n NH2 (Π)

NH

R ⁹ —C — NH2 (III)

NH

II

A- (CH2) _n Z (CH2) _n NH — C — NH2 (IV)

Hm. _r 'μ-C

R -C ChO II O (A)

OH! ' il | C ~ R ^{! I}

A - f H H Z (a-j R 1 R H 1)

II o

hydrolysis

O

ΑΑ ^ΙΗ ί lib) (i>

The individual reactions are carried out in an inert solvent such as methanol or ethanol. The initial reaction to form the compound of formula (IV) is preferably carried out by heating the reactants under reflux, and the subsequent reaction to prepare compounds of formula (Ia) is preferably carried out at a temperature ranging from room temperature to boiling point. of the reaction solvent under reflux.

For therapeutic use, the pharmacologically active compounds of formula (I) are normally administered in the form of pharmaceutical compositions comprising as the principal active ingredient at least one of these compounds in a free base farm or in the form of a non-toxic pharmaceutically acceptable acid addition salt 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, powder or pellet intended to be filled with hard gelatin capsules, trachea or lozenge. 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 on 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 adapting 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 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 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, which is an antagonist of the histamine H1 receptors, it has been found to be an effective therapeutic agent in the treatment of peptic ulcers [Gray et al., Lancet, 1, 8 001 (1977)]. was compared with cimetidine in various tests, and was found to be more potent than cimetidine as an antagonist of the histamine H2 receptors, as indicated in the following Tables 1 and 2.

Determination of gastric antisecretory activity in the rat was gastrically fist

Male rats (Loing Evans) weighing 240-260 g at the time of insertion of the cannula are used. The shape of the stainless steel cannula and its insertion into the anterior stomach essentially correspond to that described by Pare et al. [Laboratory Animal Science, 27,244 (1977)]. The individual parts of the fistula are marked and the operation is performed exactly as described in the above work. After the operation, the animals are individually housed in a fixed bed covered with sawdust and are not restricted to food and water intake throughout the recovery period. Animals are used for the test no earlier than 15 days after the above operation.

hours before the start of the test, the animals are fasted, but not restricted to water intake. Immediately prior to collection, the cannula is opened and the stomach is gently rinsed with 30 to 40 ml of warm saline or distilled water to remove residual content. The catheter is then screwed into the cannula instead of the screw cap and the test rat is placed in a rectangular transparent plastic cage of dimensions 40 cm (length), 15 cm (width) and 13 cm (height). The bottom of the cage is provided in the center with a slot of 1.5 cm width and 25 cm length, from which the catheter hangs from the cage fixed in the cannula. With this arrangement, the rat is not limited in movement and can move freely throughout the collection. The remainder of the experiment was performed as described by Ridley et al. [Research Comm. Chem. Path. Pharm., 17, 365 (1977)].

The gastric secretions collected within the first hour after washing the stomach are discarded as they may be contaminated. To evaluate the efficacy of the test substance when administered orally, the catheter is removed from the cannula and replaced with a screw cap. Water is administered orally by gavage at a dose of 2 ml / kg and the animal is returned to the cage for 45 minutes. After this time, the cannula cap is unscrewed and replaced with a catheter to which a small plastic container is attached to collect the gastric secretions. The sample is taken for 2 hours (control secretion), then the catheter is removed and replaced with a screw cap. a second sample is taken from the plasmid mass and another sample is taken for 2 hours to determine the effect of the test compound.

To evaluate the efficacy of the test compound for parenteral administration, after the initial sample of secretion, collected 60 minutes, was injected intraperitoneally or subcutaneously at a volume of 2 ml / kg, the vehicle medium also used for administration of the test substance. A sample (control secretion) is taken for two hours, then animals are injected intraperitoneally or subcutaneously with a test compound at a volume of 2 ml / kg and another 2-hour sample is taken. This second secretion is then compared to the control secretion to determine the potency of the test substance.

The collected samples are centrifuged and placed in calibrated centrifuge tubes for volume determination. Using a autobyrette and a pH meter (Radiometer), titratable acidity was determined by titrating a 1 ml sample to pH 7.0 with 0.02 N sodium hydroxide. The titratable acid secretion, in microequivalents, is calculated by multiplying the volume in milliliters by the acidic concentration in milliequivalents per liter.

The results are expressed as percent inhibition versus control. A dose-response curve is constructed and ED 50 values are calculated using regression analysis. Each dose is tested in at least 3 rats and at least three different dose levels are used to construct a dose response curve.

The values obtained are shown in Table 1 below.

Table 1

Gastric antisecretory activity in rat with gastric fist test substance ED 50 [mol mol / kg] relative efficacy (subcutaneous administration) (cimetidine-1.0) cimetidine 3.48 1.0 (2.3-5.5) * * compound from Example 2 - 0.15 26 (0.08-0.2) *) (13—50) *)

Note:

*) Data in brackets represent 95% confidence limit

Determination of gastric antisecretory activity in dogs with Heidenhain sac

Before surgery, hematological and chemical blood tests are performed and the general health of selected bitches is examined. Dogs are vaccinated with Tissue Vax 5 (DHLP - Pitman-Mcore) and housed in conventional pens for 4 weeks to see if they are beginning to develop any disease. 24 hours prior to surgery, dogs are fasted, without otherwise limiting water intake.

Intravenous administration of sodium pentothal (Abbott) at a dose of 25-30 mg / kg induces anesthesia, which is further maintained by methoxyfluoran (Pitman-Moorej). the stomach is removed into the surgical field, the larger curvature is fixed at several points and staples are established at the selected incision line and a pouch is formed from the stomach body to obtain gastric juice. A light, biologically inert material, such as nylon or Delrin, is used to make a cannula whose dimensions and grips are as described by DeVito and Harkiins [J. Appl. Physiol., 14, 138 (1959) After surgery, dogs are given antibiotics and analgesics, and the animals are allowed to recover for 2 to 3 months, followed by experiments as follows:

Before each experiment, the dogs are fasted overnight (about 18 hours), while not restricting the intake of water, then placed in suspension straps and cannulated into the saphenous vein to administer the test substance. Using an infusion pump (Harvard), animals are given continuous infusion (6 ml / hj) of histamine free base (100 µg / kg / h) and chlorphenlramine maleate (0.25 mg per kg / h).

In order to achieve a stable level of acid secretion in dogs, it is allowed to run for 90 minutes, followed by administration of the test substance or normal saline (control) simultaneously with the secretion enhancer in a volume of 0.5 seconds within 30 seconds. ml / kg. When efficacy is determined by oral administration, the active substance is administered by gastric tube in a volume of 5 ml / kg. The infusion agent is then continued to infuse gastric juice samples every 4.5 hours for 15 minutes. The volume of each sample is measured to the nearest 0.5 ml and titrated acidity is determined by titrating 1 ml of the sample to pH 7.0 with 0.02 N sodium hydroxide using an autobyrette and electrometric pH meter (Radiometer). The titratable acid secretion in microequivalents is then calculated by multiplying the volume in milliliters of the acid concentration in milliequivalents per liter.

The results are expressed as percent inhibition versus control. The response shown is the mean of the responses of the 5 dogs dosed. The values are shown in Table 2 below.

Table 2

Gastric antisecretory efficacy in psas Heidenhain sac test substance dose *) maximum inhibition relative efficacy (^ mol / kg) (%) (cimetidine - 1)

(intravenous use) cimetidine 6.0 94 the compound of Example 2 0,094 90 (oral) cimetidine 12.0 95 the compound of Example 2 0.5 86

1.0

1.0

Note:

*] for the compound of Example 2, each dose was tested on 5 dogs each

In addition to the results shown in Table 2, z was ^; It has been reported that both in oral and intravenous administration to dogs, the antisecretory activity of the compound of Example 2 is longer than the antisecretory activity of cimetidine.

The invention is illustrated by the following non-limiting examples.

Example 1

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

A. N- [3- (3-Piperidinomethylphenoxy) propyl] guanidine nitrate

A solution of 3- (3-piperidinomethylphenoxy) propylamine obtained from the dihydrochloride (7.45 g; 30.0 mmol) and 6.04 g (30.0 mmol) of 3,5-dimethylpyrazole-1-carhoxamidine nitrate in 100 ml of absolute ethanol was treated with The reaction mixture was concentrated under reduced pressure and the residue was triturated with ether.

9.82 g of the title compound, m.p. 74-76 ° C.

B. 5-Ethoxycarbonylamino-2- (3- (3-piperidinomethylphenoxy) propylamino] -4 (3H) -pyrimidone

To a mixture of 10.5 g (29.71 mmol) of 3- (3-piperidinomethylphenoxy) propylguanidine nitrate (prepared in Step A) and 6.69 g (29.8 mmol) of ethyl ethoxycarbonylaminoformyl acetate in 57 ml of methanol was added 1.25 g (29.8 mmol) of sodium hydride as a 57% dispersion. The reaction mixture was heated in an oil bath at 60 ° C for 16 hours, then evaporated under reduced pressure and the residue was taken up in acetcinitrile. The cloudy solution was filtered, the filter residue was washed with n-pentane and evaporated. The semi-solid crude product was applied to a column of 250 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 and the solid residue recrystallized from acetonitrile. 171-173 ° C.

Analysis calculated for C 22 H 31 N 5 O 4

% C, 61.52;% H, 7.28;% N, 16.31;

n) 10Qpnn

H, 7.27; N, 16.24.

Example 2

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

Suspension 1.70 g (3.96 mmol) of 5-ethoxycarbonylamino-2- [3- (3-piperidinomethylphenoxy) propylamino] -4 (3H) -pyrimidone in

11.3 ml (28.3 meq of 10% aqueous sodium hydroxide) was heated in an oil bath at 120 DEG C. for 20 minutes, the reaction mixture was neutralized with acetic acid and evaporated under reduced pressure. (230-400 mesh) and flash chromatographed using dichloromethane / methanol / ammonium hydroxide (80: 20: 1) as eluent to give the appropriate fractions containing product and evaporate. the mixture was diluted with ether to give 0.28 g of the title compound as the hydrochloride.

NMR (100 MHz, perdeuterodimethylsulfoxide, δ values):

7.14 (multiplet, 4H);

6.94 (singlet, 1 H),

4.0 (multiplet, 4H)

3.32 (triplet, 2 H),

2.84 (multiplet, 4H),

1.94 (multiplet, 2 H),

1.66 (multiplet, 6H).

For C19H27N5O2. HCl calculated

% C, 57.93;% H, 7.16;% N, 17.78.

9.00% Cl;

found

C 56.67, H 7.27, N 15.60,

8.87% Cl (corrected for 2.37% H2O content).

The following compounds can also be prepared in an analogous manner to Examples 1 and 2:

5-amino-2- {2 - [(5-dimethylaminomethyl-3-thienyl) methylthio] ethylamino] -4 (3H) -pyrimone.

NMR (100 MHz, perdeuterodimethylsulfoxide, S values):

8.88 (multiplet, 6H).

8.18 (multiplet, 1 H),

7.82 (singlet, 1 H),

7.56 (singlet, 1 H),

7.40 (singlet, 1 H),

4.50 (singlet, 2 H),

3.82 (singlet, 2 H),

3.50 (multiplet, 2H).

2.73 (multiplet, 8H).

Analysis: for C14H21N5OS2. 3.5 HCl calculated

% C, 36.00;% 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, 26.16% Cl.

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

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

Analysis: for C14H21N5O2S. 3 HCl 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.

Claims (5)

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 2 or 3, Z represents an oxygen or sulfur atom, A represents a phenyl, furyl or thienyl group, which groups may be substituted by a dimethylaminomethyl or piperidinomethyl group, and R ¹ is amino or alkoxycarbonylamino having up to 4 carbon atoms, the invention and their nontoxic, pharmaceutically acceptable acid addition salts, characterized in that a compound of formula II A - (CH 2) _m Z (CH 2) _n NH 2 (Π) in which A, Z, m and n are as defined above and reacted with a compound of formula III NH R 9 -C 9 NH 2 (III) wherein R ⁹ represents a thioalkoxy group or a radical of formula IN 349150 C Η ' CH to form a compound of formula IV NH II A - (CH 2), Z (CH 2) n NH - C - NH 2 (IV) wherein A, Z, m and n are as defined above, which compound is reacted with a compound of formula V H. Ac i! O A ^H 5 CHO N-C-CO (V) in which R ¹¹ is C 1 -C 3 alkoxy to form a compound of formula I wherein R ¹ is alkoxycarbonylamino as defined above, optionally subjected to hydrolysis to give the corresponding compound of formula I wherein R ¹ is amino, and the product obtained is optionally converted into its acid addition salt. 2. Process according to claim 1, characterized in that the reactions are carried out in an inert solvent, preferably methanol and ethanol. 3. The process according to claim 1, wherein the reaction of the compound of formula II with the compound of formula III is carried out under reflux. 4. The process of claim 1, wherein the reaction of the compound of formula IV with the compound of formula V is carried out at a temperature ranging from room temperature to the reflux temperature of the reaction mixture. 5. A process according to any one of claims 1 to 4, wherein the corresponding starting materials are used to give 5-amino-2- [3- (3-piperidinomethylphenoxy) propylamino] -4 (3H) -pyrimidone, and its non-toxic, pharmaceutically acceptable acid addition salts.