JPS58208280A - Amides, salts thereof, manufacture and pharmaceutical composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to amides having blocking activity against histamine H receptors, salts thereof, methods for producing them, and pharmaceutical compositions containing them as active ingredients.

Histamine receptors are further transformed into H□ receptors (Ash
and 5child, Br1t, J+Pharmac,
Ohmother+1966.27, 427) and H
2 receptor (Black et al., Nature 197
Since it was discovered that gastric acid secretion can be suppressed by selectively inhibiting H2 receptors, histamine H2 receptor antagonists (hereinafter referred to as ``antagonists'') have been developed. A number of products have been proposed as H2-blockers. Therefore, the international common group (InterhatiohalNon)
-proprietary Names) brimamide, methiamide, cimetidine, ranitidine, thiotidine, etchintidine, oxymethicine have formed the subject of numerous scientific publications.

All of the above products have the following structure -NH-C,- in the molecule.
NH-■ 1 (Here, Y is oxygen or sulfur atom, or N-0N
or (representing an EH-NO2 group), this structure is either linear or contained in a ring, as in the case of oxymethicin. Therefore, all the products have two gems per carbon atom (gem-
) It is characterized by having a nitrogen atom.

Cimetidine 2 in which Y is N-0N in structure (I)
-cyano-1-methyl-3-(2-([(5-methylimidazo-/I,-4-yl)methyl]thio]ethyl]guanidine and in structure (I), Y is 0H-NO□ Ranitidine N-(2-((5-((dimethylamino)
-Methyl]furfuryl]thio]ethyl]-N'-methyl-2-nide μm 1.1-ethenediamine is already used in the treatment of gastric and duodenal ulcers.

Belgian Patent No. 888602 discloses that a drug useful against gastric ulcers or a useful antagonist of histamine H2 receptor has the following formula: [wherein n represents an integer of 2 to 4, R is hydrogen, alkyl having 1 to 6 carbon atoms] group (optionally substituted with hydroxy, cyano, amino or phenoxy group), 6 carbon atoms
~6 cycloalkyl groups (substituted with phenyl or alkoxycarbonyl groups having 2 to 7 carbon atoms as required)
, an alkadienyl group having 4 to 7 carbon atoms, an aryl group having 6 to 12 carbon atoms (if necessary, a halogen atom, and cyano, nitro, amino, dialkylamine group having 2 to 10 carbon atoms, tetrazolyl, hydroxy, carbon number Selected from the group consisting of alkoxy having 1 to 6 carbon atoms, benzoyloxy, alkoxycarbonyl having 2 to 7 carbon atoms, sulfamoyl, alkylsulfonyl having 1 to 6 carbon atoms, alkanesulfonamide having 1 to 6 carbon atoms, and alkanoyl having 1 to 2 carbon atoms (substituted with 1 to 3 substituents), or a 5- or 6-membered heterocycle (substituted with a halogen atom or an alkyl having 1 to 2 carbon atoms as necessary), and X is a single bond. or thia group] and their pharmaceutically acceptable addition salts are described and claimed.

Among the compounds described in the said patent, those in formula (II) where R = hydrogen, n = 2 and X = thio,
That is, 2-guanidino-4-((2-formamide)
4) Ethylthiomethyl]thiazole, as a maleate salt, has an activity of suppressing acid secretion in the stomach of rats with an in vivo activity of 0.
Showing the ED5Q of No. 25 (Ghosh et al., Br1t,
J, Pharmacol, 1959.13°54)
.

The above formula (If
), R is a pyridyl group or a phenyl group substituted with an alkanesulfonyl group having 1 to 6 carbon atoms, and R is 6-pyridyl or p-GH2
-5o2- NH-0,H4- compounds are specifically mentioned.

This time, it has been found that nicotinamide 1-oxide, which does not have the above structure (I), has a good antagonizing effect on histamine H2 receptors.

In addition, new amidobenzamides are covered by the Belgian patent No. 8.
Sustamine H from a similar compound described in No. 88602.
It was also found that it has an excellent antagonistic effect on 2 receptors.

Furthermore, it has surprisingly been found that the H2 blocking effect occurs to a satisfactory extent only when the "amide" group is in the meta position of the benzamidophenyl ring.

Therefore, according to one aspect of the present invention, the following formula (ami)
11 and pharmaceutically acceptable salts thereof.

[In the formula, (represents a chenyl group)].

Pharmaceutically acceptable salts include non-toxic salts derived by salting one or two base functions present in the molecule of the compound of formula (1) with an inorganic or organic acid,
For example, hydrochloride, hydrobromide, sulfate, succinate, tartrate, citrate, fumarate, maleate,
4.4'-methylene-bis-(3-hydroxy-2-su7toate) (hereinafter referred to as "remoate"5),
These include 2-naphthalene sulfonate (hereinafter referred to as "nazosylate"), methanesulfone rs salt (hereinafter referred to as "mesylate" 5), P-)luenesulfonate (hereinafter referred to as tosylate), and the like. 'According to another aspect of the present invention, there is provided a method for producing the compound of the formula (1), which comprises converting % ruthio)ethylamine into a compound of the formula (wherein, X is as defined above) in an organic solvent at a temperature between 0° and the boiling point of the solvent used and, if necessary, the compound thus obtained is treated with its pharmaceutically acceptable Consists of conversion into salt.

As suitable functional derivatives it is possible to use activated free acids, anhydrides, mixed anhydrides, chlorides or active esters.

A suitable functional derivative of the acid of formula (2) is represented by the following formula.

(wherein X is as defined above and R' represents a nitrophenyl, methoxyphenyl, trityl or benzhydryl group).

Compounds of formula (VI) are either known in the literature or readily prepared by reacting the acid M with a suitable alcohol or phenol in the presence of a condensing agent such as dicyclohexylcarbodiimide in a solvent such as methylene chloride. can be manufactured.

The reaction temperature was 0. The operation is generally carried out at room temperature or from 60 to 50C, although variations may occur between C and the boiling point of the solvent used. When the reaction is exothermic, such as when chloride is used as the functional derivative of the acid of formula M, it is preferred to carry out the reaction below DC.

As reaction solvent alcohols, such as methanol, or halogenated solvents, such as methylene chloride, dichloroethane, chloroform, etc. are preferably used, but also other organic solvents which are compatible with the reactants used, such as acetonitrile, dioxane, tetrahydrofuran and hexane. Hydrocarbons such as can also be used. If hydrochloric acid or another acid is formed during the reaction, the reaction can be carried out in the presence of a proton acceptor, for example an alkali carbonate or a tertiary amine, which is used to obtain the final product. is not essential.

The reaction is quite fast. After 2-4 hours at room temperature or 30-50C, the reaction is largely complete and the resulting amide of formula (button) is isolated as the free base or one of its salts according to conventional techniques.

The free base can be converted to one of its pharmaceutically acceptable salts by treatment with a solution of the appropriate acid in an organic solvent. If the amide (1) is isolated as a salt, the corresponding free base is separated by alkali hydroxide or carbonate.

The novel compounds of formula (1) of the present invention and their pharmaceutically acceptable salts act as selective antagonists of histamine H2 receptors by selectively inhibiting gastric acid secretion and are therefore useful in the treatment of ulcer diseases. It is.

The selective activity of the products of the invention towards type H2 receptors is confirmed by the absence of type H1 activity in a test in which contractions of isolated guinea pig ileum are induced with histamine.

The antagonistic activity of the amides of the present invention against histamine H2 receptors was determined by the method of Ghosh and Chila (Brit et al.
, J. Pharmacol, 1958.13.5
4) modified by Black et al. (Nature 1
972.236°685), it was confirmed by a test of anti-digestive activity based on antagonism against histamine-induced abnormal secretion in rats administered atropine. According to this study, abnormal gastric acid secretion was induced by intravenously injecting a submaximal dose of histamine equivalent to 15 mc mol/kp/hr, which caused the animals' stomachs to be perfused with physiological solutions at a constant rate. Gastric acid secretion is measured by this.

Shown in Table 1 are the following examples 6.
4 and 1 and code number 5R5793 in the table.
Six representative compounds of the invention designated as 8A, 5R57963A and 5R57957A and four control compounds, namely 2-cyano-1-methyl-3-
[2-[[(5-methylimidazol-4-yl)methyl]thio]ethyl]guanidine (hereinafter referred to by its international common name "cimetidine"), N-(2-1:[5-((
dimethylamino)methyl]-furfuryl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (hereinafter referred to by its international common name "ranitidine"),
and 4-methane-sulfonamido-N-(2-(2-guanidinothiazol-4-ylmethylthio)ethyl]- as described in Belgian Patent No. 888602@), respectively.
(Nsami)'' (hereinafter referred to as "Compound A") and N
-(2-(2-guanidinothiazol-4-ylmethylthio)-ethyl]nicotinamide (hereinafter referred to as "Compound B")
The dose (mcmol/kg in a single administration by intravenous route) (ID50) that suppresses the abnormal gastric acid secretion induced by histane by 50 times (referred to as ``mcmol/kg'' in one administration by the intravenous route). This ID.

represents an index of gastric H2-blocking action.

Table 1 Cimetidine 0.95 1.00 Ranitidine 0.25 3.80 Compound A 1.66 0゜57 Compound B O,287,398R579
38A O,156,33SR57963
A O,06514,6SR57957A
O,109,5 From this table, it can be seen that all representative compounds of the present invention have greater activity than the control compound. More specifically, the representative compounds of the present invention are much more active than other compounds. This result is completely surprising. This is because the chemical difference between 5R57938A and "Compound A" is due to mere positional isomerism.
Moreover, 5R57938A is 10 times more expensive than "Compound A."

The compounds of the invention have low toxicity with respect to their degree of activity. For example, 5R57957A does not cause any mortality when mice are administered 6754 by the intraperitoneal route. Its LD50 is higher than 900 me mol/kg, whereas under the same conditions the LD5 of "Compound B" [1 is 34
2 mc mol/Aq.

Accordingly, another aspect of the present invention provides a pharmaceutical composition containing as an active ingredient an amide of the formula (button), or a pharmaceutically acceptable addition salt thereof.

The pharmaceutical composition of the present invention having H2-blocking action can be prepared for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration by mixing the active ingredient with a customary pharmaceutical carrier. Can be prepared.

This composition can be administered to animals and humans in dosage unit form for the treatment of abnormal gastric acid secretion and peptic ulcers.

In order to obtain the desired H2-blocking effect, the daily dosage of the active ingredient can be varied between 1 and 100 kg/kf of body weight, preferably between 10 and 50 wvkg.

Each unit dose contains from 10 to 1000 η, preferably from 100 to 500 η, of the active ingredient in admixture with the pharmaceutical carrier.
can contain. Take this unit dose once or twice a day.
It can be administered 4 times.

Suitable dosage unit forms include tablets, capsules, powders, granules and oral solutions or suspensions, as well as sublingual dosage forms, suppositories and ampoules for parenteral administration.

When preparing a solid composition in tablet form, the principal active ingredient is mixed with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, Merck, gum arabic, and the like.

The tablets may be coated with sucrose or other suitable substances and may be treated to prolong or delay the activity so that the tablet continuously releases a predetermined amount of active ingredient. I can do it.

A preparation in the form of a syrup or tincture may contain the active ingredient with sweetening agents, methylparaben and propylparaine as preservatives, and flavoring agents and suitable dyes.

Water-dispersible powders or granules can also contain the active ingredient mixed with dispersing or wetting agents, or suspending agents such as polyvinylpyrrolidone, and sweetening or flavoring agents.

For rectal application, suppositories are prepared using binders that melt at rectal temperatures, such as cocoa butter or polyethylene glycols.

For oral administration as drops or for parenteral administration, aqueous suspensions, isocorrosive saline solutions or sterile injection solutions are used, which contain pharmacologically compatible dispersing agents and/or wetting agents. agents such as propylene glycol or butylene glycol.

The active ingredient can also be formulated in the form of microcapsules, possibly containing one or more supports or excipients.

The following examples are intended to specifically illustrate the present invention, but are not intended to limit the scope of the invention.

Example 1 In a solution of 6.1 tons of 2-(2-guanidinothiazol-4-ylmethylthio)ethylamine hydrochloride and 30 tons of triethylamine dissolved in 100 tons of methanol, 5 tons of the hydrochloride of nichenol chloride 1-oxide was added. was added dropwise with stirring at a temperature of -3 DC. This mixture was first mixed with -3
After stirring for 15 minutes at 0 tl' and then for 1 hour at room temperature, it was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 2Qml of water and the solution thus obtained was treated with a concentrated solution of sodium hydroxide. The product was extracted with ethyl acetate containing 10 g of methanol, the solvent was evaporated and the crude oil was extracted with 5 g of methanol.
Methanol:Chloroform 1: as eluent on LO2:
Purification was performed by chromatography using a mixture of 4 and 4. In this way, 3. El N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl-3-pyridinecarboxamide (SR57957) was obtained as a pale yellow oil.

lHNMR-Solvent: DMSO-d6°STMS CPP
m): 2.68 (2H, rn-+t); 3.4
4 (2H, M"+5'); 3.63 (2H, JP)
;6.48(IH,J);6.86CEh);7.46
(I H,'tLd, Js =6Hz, J2
=8 Hz) t l 68 (I Hlddd, J
t=8Hz+ J2:Ja "2Hz); 8.3
0(IHltLdcL, Js = 6Hz s J2”
Ja = 2 Hz) t s, 53 (I Hld
cL, J22 Hz'); 8.83 (I
Hlth).

The signals at 6.83 ppTIL and 8.83 ppTIL disappeared after addition of D20.

To a solution of the thus obtained product dissolved in 251 nl of 95% ethanol, 30 mg of 7-maric acid dissolved in 60 ml of 95% ethanol was added. Pour the precipitate into water 30-
The neutral fumarate salt of N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-6-pyridinecarboxamide 1-oxide (SR579
57A)2.6) was obtained. Melting point 220-222
tl:' (decomposition).

Example 2 N-(2-(2-guanidinothiazo-A.-4-ylmethylthio)ethyl-3-pyridinecarboxamide 1-
To a solution of the neutral 7-malate salt of the oxide 2.2) in 15μ of water, sodium hydroxide was added until a clear basic reaction occurred. The product was extracted with ethyl acetate containing 10% ethanol, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. A viscous liquid 1.71 was thus obtained, which gradually crystallized and solidified as an amorphous solid. N-(
The structure of 2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-6-pyridinecarboxamide 1-oxide was confirmed.

Example 3 0.015 mol of 2-(2-1'anidinothiazole-
4-ylmethylthio)ethylamine and 0.015 moles of 4-nitrophenyl 6-methanesulfonamide were prepared as benzoate (melting point 162-164C, 6-methanesulfonamide benzoic acid in the presence of dicyclohexylcarbodiimide in methylene chloride). and 0.035 mol of triethylamine in 150 nl of methanol was heated at 40 tr for 4 hours without stirring. The solvent was then evaporated under reduced pressure and the residue was dissolved in 20+1 L7I of water and 100- of ethyl acetate.

The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residue was dissolved in 5 QmJ of warm ethyl acetate. The solution was filtered and the filtrate was acidified with hydrogen chloride in Improper Tools. In this way, 6-methanesulfonamide-N-(2-(2-guanidinothiazol-4-ylmethylthio)ethyl]hanzuamide hydrochloride was obtained, and 2
Crystallized with 0TIL of water to form its -hydrate, 5R5
7938A got 2. Melting point 117-120tll
'.

Example 4 2-(2-guanidinothiazol-4-ylmethylthio)ethyleneamine dihydrochlorovys, 5t, triethylamine 3.65y-, and 4-nitrophenyl 6-penzenesulfonamitohanzoate (melting point 175-17
A mixture of 6°7t (prepared from 3-benzenesulfonamide, aromatic acid and 4-di) a7z/-l) in the presence of dicyclohexylcarbodiimide in 8C1 methylene chloride at a temperature of 401Z' After stirring for 90 minutes, it was evaporated to dryness under reduced pressure. The residue was dissolved in 15M ethyl acetate and washed twice with 10 m/V water. The solution was dried over anhydrous sodium sulphate, evaporated and the residue was chromatographed on silica using a 1:1 mixture of chloroform:ethanol. In this way, 3. The 3-inzenesulfonamide N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl] of EH' was obtained as an oily substance. Dissolve this in absolute ethanol,
Treated with fumaric acid dissolved in absolute ethanol. Thus, 6.61 crude products were obtained. This was crystallized with 40 mt of 95-thiethanol and 6-benzenesulfonami)'-N-[2-(2-guanidinothiazole-
Neutral fumarate of 4-ylmethylthio)ethyl]inzamide, 5R57966A1C2oH2□N603S4
・14 C4H40□ was obtained at 2.6. Melting point 169
~141C8 Similarly, reacting 2-(2-guanidinothiazol-4-ylmethylthio)ethylamine dihydrochloride 9 with 4-nitrophenyl 3-acetamitohenzoate and 4-nitrophenyl 6-nicotituylaminobenzoate, respectively. The neutral fumarate salt of 6-acetamido-N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]benzamide and 3-nicotinoylamino-N-(2-(2-guanidinothiazole-4- The neutral fumarate salt of -ylmethylthio)ethyl]inzamide was obtained.

Example 5 Tablet containing one of the products described in Examples 1 to 4 and having the following composition: Active substance 100 ■ Lactose 70 r 11 g Potato starch 40 η Polyvinylpyrrolidone 8 Tn 9 Magnesium stearate 2 - Active substance and 2 Ctose and potato starch was moistened with a 15% alcoholic solution of polyvinylpyrrolidone, the granules formed were passed through a 1-inch sieve, mixed with magnesium stearate and formed into tablets by compression.

Weight of one tablet: 220■.

EXAMPLE 6 Tablets prepared as described in Example 5 are coated in a known manner with a pill coating consisting essentially of sugar and talc, and this surface finish is coated with a pill wax. Wearing. Weight of one pill: 300■.

Example 7 Capsules containing one of the products described in Examples 1 to 4 and having the following composition: Active substance 200 to Cornstarch 90 Datark
10 The active substance and the excipients were intimately mixed and the mixture thus obtained was placed in a dimension 1 gelatin capsule. Contents of 1 capsule: 3
00my0 Example 8 Suppository containing one of the products described in Examples 1 to 4 and having the following composition: Active substance 600■ Suppository material (witepsol W 45) 1,4501
The ng finely ground active substance was suspended in the suppository mass at 67C and the mixture was poured into pre-slightly cooled molds. Weight of one suppository: 1.750mp.

Example 9 Tablet containing one of the products described in Examples 1 to 4 and having the following composition: Active substance 150 ■ Microcrystalline cellulose 75 m9 Lactose 100 ■ Magnesium stearate 7 ■ Talc
18. After each powder was passed through a 0.3-mesh sieve, each component was mixed to obtain a homogeneous mixture, which was compressed into granules. The granules thus obtained were compressed into tablets. Weight of one tablet = 350■.

Example 10 Tablets containing one of the products described in Examples 1 to 4 by operating as described in Example 9 and having the following composition: Active substance 350 rIhg
Microcrystalline cellulose 100■Lactose 125■Magnesium stearate 109Talc
15Tn9 was formulated. Weight of one tablet: 600■.

Example 11 By operating as described in Example 7, gelules containing IQQN9 and 1501119 of 5R57957A were prepared, respectively.

Continued from page 1 Priority claim [Phase] August 13, 1982 [Phase] France (FR) [Yes] 8214126 0 Inventor Romeo Roncutucci France Hari, Ryu, Tournfort 200 Inventor Person: Paolo Carminacci, Italy, Milan, Italy Paccini 24 Procedural Amendment June 10, 1982 Patent Office Examiner (Mr. Patent Office Examiner)■, Minor Case Indication 1988 Patent Application No. 08025'6 Relationship to the case Patent applicant name Sanofi Société Anonymous Kasumigaseki Building Post Office Post Office Box No. 49 No. 7, engraving of the specification to be amended 8, contents of the amendment as shown in the attached sheet (no change in internal statement)

Claims (1)

[Claims] 1) Formula [wherein, X is N→0 or C-NH-A-B group (A is G
O or SO□ group, B is an alkyl group having 1 to 2 carbon atoms or phenyl 1. pyridyl, pyridyl 1-oxide, pyrazinyl or chenyl group) or a pharmaceutically acceptable acid addition salt thereof. 2) N-(2-(2-guanidinothiazol-4-ylmethylthio)ethyl]-6-pyridinecarpoxamito 9
1-oxide or a pharmaceutically acceptable acid addition salt thereof. 3) N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl-3-pyridinecarboxami P1
- Neutral fumarate salt of oxide. 4) 6-methanesulfonamide-N-[:2-(2-guanidinothiazol-4-ylmethylthio)ethyl]benzamide or a pharmaceutically acceptable acid addition salt thereof. 5) 5-benzenesulfonamide Y-N-[:2-(
2-guanidinothiazol-4-ylmethylthio)ethyl]benzamide 9 or a pharmaceutically acceptable acid addition salt thereof. 6) Formula [In the formula, X is N-+O? ,=l! 0-NH-A-B group (A represents Co or S02 group, B has 1 to 6 carbon atoms
Alkyl group or phenyl, pyridyl, pyridyl 1
2-(2-guanidinothiazol-4-ylmethylthio)ethylamine of the formula is reacted with a functional derivative of an acid of the formula (wherein A manufacturing process comprising converting a compound into its pharmaceutically acceptable acid addition salt. 7) Use of a compound of the formula (wherein X is as defined in claim 6 and RO represents a nitrophenyl, methoxy7enyl, trityl or benzhydryl group) as a functional derivative of said acid. The method according to claim 6, characterized in that: 8) The final amide is isolated in the form of its salt, from which the free base is separated by neutralization with an alkali hydroxide or carbonate.
or the method described in paragraph 7. 9) A pharmaceutical composition having an antagonistic effect on histamine H2 receptors, which contains the compound according to any one of claims 1 to 5 as an active ingredient. 10) 10-1000 m mixed with pharmaceutical carrier
10. A pharmaceutical composition according to claim 9, which is in the form of a dosage unit comprising the active ingredient y. 11) Pharmaceutical compositions containing from 100 to 500 μ of active ingredient per dosage unit.