BE902818A - New heterocyclic sulphinyl and thioether cpds. - which inhibit gastric acid secretion or are starting materials - Google Patents

Abstract

Heterocyclic sulphinyl and thioether cpds of the formulae (I) and (VI), and salts of (I), are new, with some exceptions (see provisos (i) to (iv) below). Also, the pharmaceutical use of (I)but without proviso (ii), and the use of (I) to make a pharmaceutical formulation for use in the prevention or inhibition of gastric secretion, but without provisos (i) and (ii), are also claimed. Rc is (sic) a nucleophilic nitrogen, oxygen or sulphur, separated from SOm (I) or S in (VI) by 1,2,3,4 or 5 other atoms; R1, R2, R3, R4 are each independently H, halogen, alkoxy, alkyl, fluoroalkyl, alkanoyl, -S(O)nR, NO2, N(R)2, -NHCOR, or COOH or an ester or amide of COOH, or an adjacent pair may form a -(CH2)x- chain, or a fused on unsaturated carbocyclic or N-heterocyclic ring; x is 3,4 or 5; n is zero, 1 or 2; X is O, S or NR15; R15 is H, -COR, -COOR, alkyl or -alkylene-OCOR; R is H, phenyl or phenyl-alkyl, the phenyl gps being opt. alkyl-substd; with for the new cpds., the provisos that (i) Rc is not gp (a), (ii) when Rc is a nitrogen nucleophile carried on an aryl or heteroaryl gp, then R15 is not -COR in which R is unsubstd. alkyl; (iii) when X is NR15, then Rc does not comprise an unsaturated nitrogen heterocyclic ring other than such a ring substd. by (a) an opt. substd. amino gp., or (b) an N-oxide gp; and (iv) when X is NR15, then Rc does not comprise an alkyl gp. substd. by an opt halo-or alkyl-substd. piperidino gp.

Description

       

  New pharmaceutical heterocyclic polycyclic compounds

  
The present invention relates to new compounds, methods for preparing them and pharmaceutical compositions containing them.

  
Various benzothiazole-2-sulfinamides are

  
known as vulcanization accelerators, for example from EUA patents 2,585,155 and 3,541,060,

  
French patents 1,003,821 and 2,037,001 and the published German patent application OS 1,949,615. Different 2- (pyridylmethylsulfinyl) benzimidazoles are known as pharmaceutical agents from European patent applications Nos. [Deg.] 5129 and 80602 and English patent application 2,134,523, while a number of 2- (heterocyclomethylsulfinyl) Benzimidazoles are described in Swiss patent 623,582, German patent application OS 2,548,340 and French patent 2,392,021.

  
The subject of the present invention is the compounds of formula I

  

  <EMI ID = 1.1>


  
where Rc is an entity made nucleophilic by nitrogen, oxygen or sulfur separated from the SO radical by 1, 2, 3, 4 or 5 other atoms,

  
  <EMI ID = 2.1>

  
each represents a hydrogen or halogen atom or an alkoxy, alkyl or fluoroalkyl radical,

  
  <EMI ID = 3.1>

  
with the carbon atoms to which they are united a nitrogenous heterocycle or unsaturated 6-membered carbocycle,

  
x represents 3, 4 or 5,

  
n represents 0, 1 or 2,

  
X represents 0, S or NR15 '

  
  <EMI ID = 4.1>
-COOR or alkyl, the latter optionally being substituted by -OCOR,

  
R represents a hydrogen atom or phenyl or alkyl radical optionally substituted by phenyl, the phenyl radicals in turn being optionally substituted by alkyl,

  
with the restriction that i) Rc does not represent a

  
  <EMI ID = 5.1>

  
a nitrogenous nucleophilic entity carried by an aryl radical

  
  <EMI ID = 6.1>

  
represents an unsubstituted alkyl radical, iii) when-

  
  <EMI ID = 7.1>

  
unsaturated nitrogen other than such a ring substituted either a) by a substituted or unsubstituted amino radical, or b) by an N-oxido radical and iv) when X represents <EMI ID = 8.1>

  
titrated by a piperidino radical optionally alkyl halo-substituted,

  
and their pharmaceutically acceptable salts.

  
A subject of the invention is also compounds of formula 1 which escape the restriction ii) and their pharmaceutically acceptable salts for use as pharmaceutical agents, and which escape the restrictions i) and ii) for use for the prevention or inhibition of secretion. stomach acid.

  
The invention further relates to a process for the preparation of a compound of formula I, or of a pharmaceutically acceptable salt thereof, which comprises a) the selective oxidation of a corresponding compound of formula VI,
  <EMI ID = 9.1>
  <EMI ID = 10.1>

  
above, b) the preparation of a compound of formula I where X represents <EMI ID = 11.1>

  
except that it cannot represent a hydrogen atom, by reaction of a corresponding compound of formula I

  
  <EMI ID = 12.1>

  
  <EMI ID = 13.1>

  
may represent a hydrogen atom, and Z represents an appropriate leaving radical, or c) the preparation of a compound of formula I carrying a <EMI ID = 14.1>

  
and when desired or necessary, converting the resulting compound of formula I to a pharmaceutically acceptable salt thereof or vice versa.

  
In process a), the oxidation can be carried out in a solvent which is inert under the reaction conditions, for example ethyl acetate, dichloromethane, chloroform or a mixture thereof. The reaction is preferably carried out below the

  
  <EMI ID = 15.1>

  
suitable oxidants for the reaction are peracids, for example m-chloroperbenzoic acid, or t-butyl hydroperoxide in the presence of a suitable catalyst, for example vanadyl acetylacetonate.

  
In process b), the suitable leaving radical may be, for example, a halogen and the reaction may be carried out in a solvent which is inert under the reaction conditions, for example dimethylformamide, in the presence of a base and at a temperature. about 15 to 30 [deg.] C.

  
In process c), the selective reduction can, for example, be carried out chemically under basic conditions, for example by means of hydrazine and Raney nickel, but is preferably carried out

  
  <EMI ID = 16.1>

  
catalyst and ethanol as reaction medium.

  
The compounds of formula VI can be obtained according to known methods, for example by reaction of a compound of formula VII,

  

  <EMI ID = 17.1>


  
  <EMI ID = 18.1>

  
with a compound of formula VIII,

  
Z-Rc VIII where Rc is as defined above and

  
Z represents a suitable leaving radical, for example a halogen (chlorine).

  
The reaction can be carried out in a suitable solvent, for example N, N-dimethylformamide, and in the presence of an acid acceptor, for example potassium carbonate.

  
The compounds of formulas VII and VIII are known or can be obtained from known compounds according to techniques which are themselves known. The preparation of the starting compounds for the above reactions is described in more detail in the application.

  
of British patent n [deg.] 85/09406.

  
The compounds of formula I and the intermediates allowing them to be obtained can be isolated from their reaction mixture according to conventional techniques.

  
The pharmaceutically acceptable salts of the compounds of formula I are in particular the salts formed with suitable inorganic or organic acids, for example with a hydrohalic acid, sulfuric acid, an alkanesulfonic acid, tartaric acid or citric acid. The subject of the invention is furthermore, when the compound of formula I carries a —COOH radical or another acid radical, the salts formed with appropriate inorganic or organic bases, for example the ammonium, alkali metal, metals

  
  <EMI ID = 19.1>

  
zimidazole is itself acidic and can form salts with suitable bases as above.

  
The compounds of formula I and their pharmaceutically acceptable salts are useful because they exert a pharmacological effect in animals, in particular because they prevent or inhibit the secretion of gastric acid, for example during the test set out in Am .J.Physiol., 1982, 243 (6), G505-
510. The compounds of formula I are also useful as intermediates for the synthesis of other chemical agents.

  
The new compounds are therefore indicated for the prevention or inhibition of gastric acid secretion and / or for the treatment of conditions normally involving an exaggerated secretion of gastric acid, for example peptic, duodenal, gastric ulcer or recurrent, dyspepsia, duodenitis, Zollinger-Ellison syndrome, regurgitation and treatment of hemorrhage, e.g. consecutive

  
erosion of ulcers in the upper gastrointestinal tract, especially when a large blood vessel is not involved. The compounds can also be used for the treatment of gastritis or dyspepsia associated with the administration of non-steroidal anti-inflammatory drugs, for the prophylaxis of consecutive gastrointestinal hemorrhage.

  
stress ulcer in severely ill or burned patients, for the prophylaxis of recurrent hemorrhage in patients with peptic hemorrhagic ulcers, before general anesthesia in patients at risk for acid aspiration syndrome ( Mendelson syndrome) and to reduce the risk of bleeding in patients with leukemia, transplant rejection syndrome or severe liver failure. The above conditions can be treated regardless of whether or not they are associated with excess gastric acid secretion.

  
Dosages that may be mentioned are:
a) a high dose initially, for example for 2 to 4 weeks, followed by a maintenance treatment at a lower dose after improvement of the state, for example after healing of the ulcer, b) as in a) ci above, but with maintenance treatment using a cytoprotective agent, for example <EMI ID = 20.1> c) a combined treatment associating a low dose of the compound of the invention with a low and well tolerated dose of a cytoprotective agent and / or an antacid, d) intermittent administration, for example a every other day, which may be suitable as maintenance treatment.

  
For the above applications, the dose administered obviously varies with the nature of the compound, the mode of administration and the treatment chosen. Nevertheless, satisfactory results are generally obtained

  
  <EMI ID = 21.1>. 1982, 243 (6), G505-G510. In humans, the total daily dose indicated is about 1 to 3000 mg, preferably about 5 to 500 mg and more preferably about 10 to 200 mg, and can be administered in partial doses 1 to 6 times daily or in slow release form. Thus, unit dosage forms suitable for administration include about 1.0 to 600 mg of the compound in admixture with a solid or liquid pharmaceutically acceptable diluent, excipient or adjuvant.

  
The compounds of formula I and their pharmaceutically acceptable salts have the advantage of being more easily absorbed, or of being less irritating for the gastrointestinal tract, or of having less toxic side effects or of being more active. or more stable with respect to gastric acidity when administered by ingestion than compounds of a similar structure.

  
The nucleophilic atom which is part of the radical Rc is preferably separated from the radical SO by 4 or more advantageously 3 or 2 atoms and these are preferably carbon atoms. The nucleophilic atom which is part of the radical Rc is such as to be able to express its nucleophilic character under normal physiological conditions, for example at a pH of approximately 7.4 to 1, and is under these conditions more nucleophilic than water . The nucleophilic atom is preferably also basic and the degree of protonation of the nucleophilic atom is related to the pH. However,

  
there must always be a sensitive population of unprotonated nucleophilic atoms, even at low pH.

  
Particular nucleophilic atoms which may be mentioned are in particular the oxygen atom

  
pyridine oxide or hydroxylphenolic, the sulfur atom of a thioether or a thiophenol

  
or a precursor thereof, for example a thioester. The Applicant however prefers that the nucleophilic atom is a nucleophilic nitrogen atom
(which nitrogen atom does not carry a charge). The Applicant particularly prefers that the nucleophilic nitrogen atom exists in the form of an oxime, a hydrazine, a pyridine or more advantageously an amine radical. The amine radical can optionally

  
  <EMI ID = 22.1>

  
as defined above, and is preferably carried by an aromatic cycle, for example by a benzene cycle.

  
Rc radicals which may be mentioned are

  
  <EMI ID = 23.1>

  
which may be the same or different, each represents a hydrogen atom or an alkyl radical and Rx is a ring of formula II, III, IV or V,
  <EMI ID = 24.1>
 
  <EMI ID = 25.1>
 and when y + z does not represent 0, Rx can represent

  
  <EMI ID = 26.1>

  
each represents a hydrogen atom or an alkyl, phenyl or cycloalkyl radical, each of which may be optionally substituted by phenyl, the phenyl radicals being in turn optionally substituted by alkyl, or

  
  <EMI ID = 27.1>

  
  <EMI ID = 28.1>

  
they are united, can form a saturated or unsaturated cycle of 4 to 8 members which can contain 0, 1 or 2 other heteroatoms, which cycle can carry one or more

  
  <EMI ID = 29.1>

  
  <EMI ID = 30.1>

  
different, each represents a hydrogen atom

  
or alkyl radical optionally substituted by halogen or by = 0, cycloalkyl, alkanoyl, phenyl or pyridyl, or else

  
  <EMI ID = 31.1>

  
  <EMI ID = 32.1>

  
with the nitrogen atom and the carbon atoms of the ring

  
  <EMI ID = 33.1>

  
saturated with 4 to 8 links which can contain 0, 1 or 2 other heteroatoms, which cycle can carry one or

  
  <EMI ID = 34.1>

  
A represents a 5 or 6-membered heterocycle containing nitrogen or sulfur which is united to the rest of the molecule by a ring carbon atom,

  
Y represents N or C,

  
when Y represents N, W represents 0 and when

  
  <EMI ID = 35.1>

  
  <EMI ID = 36.1>

  
nyle, cycloalkyl, alkanoyl or alkyl optionally substituted by phenyl.

  
The Applicant prefers that at least one

  
  <EMI ID = 37.1>

  
halogen atom, this can be a chlorine or fluorine atom.

  
  <EMI ID = 38.1>

  
  <EMI ID = 39.1>

  
carbon, the Applicant prefers that this radical contains up to and including 10 and preferably up to and including 6 carbon atoms.

  
The Applicant particularly prefers that

  
  <EMI ID = 40.1>

  
  <EMI ID = 41.1>

  
of nitrogen to which they are united form a ring, which may contain another atom of nitrogen, oxygen and / or sulfur. The Applicant prefers that the cycle is a piperidino or morpholino cycle.

  
The Applicant prefers that the A cycle is aromatic. Examples of rings A which may be mentioned are the rings of thiophene, of pyrazole and preferably of pyrimidine or of pyridine.

  
  <EMI ID = 42.1>

  
obviously not be greater than the number of positions accessible for substitution on cycle A.

  
  <EMI ID = 43.1>

  
presents an ester, the Applicant prefers that it comes from a C1 to C6 alcohol, for example from an alkanol.

  
  <EMI ID = 44.1>

  
amide, this can be, for example an unsubstituted amide or a mono- or dialkylamide.

  
  <EMI ID = 45.1>

  
  <EMI ID = 46.1>

  
are in particular hydrogen atoms or methoxycarbonyl, phenylcarbonyl, methyl, chloro, methoxy radicals,

  
  <EMI ID = 47.1>

  
  <EMI ID = 48.1>

  
chain -CH = CH-CH = CH-.

  
The Applicant prefers that y represents 0 and

  
  <EMI ID = 49.1>

  
  <EMI ID = 50.1>

  
more advantageously all represent H.

  
Specific non-cyclic Rc radicals

  
  <EMI ID = 51.1>

  
hydrogen atoms and methyl, chloro, propyl, methoxy and butyl radicals.

  
  <EMI ID = 52.1>

  
nitrogen and the carbon atoms of the ring to which they are united form a ring, the Applicant prefers that this ring is a piperidino ring, for example N-methylpiperidino.

  
Specific meanings for X are NH, O, S, Nacetyl, NCH20COt-butyl, NCOOethyl and Nmethyl.

  
  <EMI ID = 53.1>

  
acetyl.

  
The subject of the invention is the following specific groups of compounds of formula I,

  

  <EMI ID = 54.1>


  
  <EMI ID = 55.1>

  
or different, each represents a hydrogen or halogen atom or an alkoxy, alkyl or -COOH radical or ester thereof,

  

  <EMI ID = 56.1>


  
  <EMI ID = 57.1>

  
  <EMI ID = 58.1>

  
each represents a hydrogen atom or an alkyl radical,
  <EMI ID = 59.1>
  <EMI ID = 60.1>

  
above and

  
Xc represents NH, Nalcoyle Cl at 6.0 or S, d)

  

  <EMI ID = 61.1>


  
  <EMI ID = 62.1>

  
or different, each represents a hydrogen or halogen atom or alkoxy, alkyl, fluoroalkyl, alkanoyl radical: RdS (O) - or -COOH or ester thereof, or two adjacent between Rld, R2d 'R3d and R4d can, in addition to having the above meanings, form

  
  <EMI ID = 63.1>

-N = CH-CH = CH-,

  
x, n and Xd are as defined above,

  
m represents 1 or 2,

  
Rd represents an alkyl radical optionally substituted by phenyl which in turn is optionally substituted by alkyl,

  
  <EMI ID = 64.1>

  
each represents a hydrogen atom or an alkyl radical, or

  
  <EMI ID = 65.1>

  
  <EMI ID = 66.1> or

  
  <EMI ID = 67.1>

  
to which they are united, can form a saturated or unsaturated ring of 4 to 8 members which can contain 0, 1 or 2 other heteroatoms, which ring can carry one or more substituents Rld and

  
  <EMI ID = 68.1>

  
or different, each represents a hydrogen atom or an alkyl radical optionally substituted by halogen or = 0, cycloalkyl, alkanoyl, phenyl or pyridyl,

  

  <EMI ID = 69.1>


  
  <EMI ID = 70.1>

  
can be identical or different, each represents a hydrogen or halogen atom or an alkoxy, alkyl, fluoroalkyl, alkanoyl, RdS (O) n-, or -COOH or ester thereof, or

  
  <EMI ID = 71.1>

  
in addition to having the above meanings, jointly form a chain - (CH-) -, -CH = CH-CH = CH- or

-N = CH-CH = CH-,

  
x, n, Xd and Rd are as defined above,

  
p represents 0, 1 or 2,

  
Y represents N or C,

  
  <EMI ID = 72.1>

  
and when Y represents C, then W represents -OH or <EMI ID = 73.1> <EMI ID = 74.1> optionally substituted by phenyl, phenyl or cycloalkyl,

  

  <EMI ID = 75.1>


  
  <EMI ID = 76.1>

  
are as defined above,

  
R9f represents a hydrogen atom or an alkyl or cycloalkyl radical, each of which may optionally be substituted by phenyl, the phenyl in turn being optionally substituted by alkyl, or

  
  <EMI ID = 77.1>

  
the carbon atoms of the benzene ring to which the nitrogen atom and R8f are united, form a saturated cycle from 4 to

  
8 links which can contain 0, 1 or 2 other heteroatoms,

  
g)

  

  <EMI ID = 78.1>


  
where A represents a 5 or 6-membered heterocycle containing nitrogen or sulfur,

  
  <EMI ID = 79.1>

  
each represents a hydrogen atom or an alkyl or cycloalkyl radical, each of which may optionally be substituted by phenyl, the phenyl being

  
in turn optionally substituted by alkyl, or

  
  <EMI ID = 80.1>

  
which they are united, can form a saturated cycle of 4 to 8 members which can contain 0, 1 or 2 other heteroatoms, which cycle can carry one or more substituents R, and

  
  <EMI ID = 81.1>

  
h)

  

  <EMI ID = 82.1>


  
  <EMI ID = 83.1>

  
Some of the compounds of formula VI are new and the invention also relates to these new compounds. Particular interest is offered by the compounds of formula VI where y + z is greater than 0 and in particular by these compounds where Rx represents a cycle of formula III.

  
A subject of the invention is also a pharmaceutical composition comprising (preferably in minor proportion) a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient in admixture with a pharmaceutically acceptable adjuvant, diluent or excipient. Examples of suitable adjuvants, diluents or excipients are, for tablets and dragees, lactose, starch, talc or stearic acid; for capsules, tartaric acid or lactose; for suppositories natural or hardened oils and fats; for preparations for injection (i.m. or i.v.) or enemas, water, surfactants and preservatives. The compounds can also be administered transdermally, for example in an ointment base. The compound

  
  <EMI ID = 84.1>

  
preferably a mass median diameter of 0.01 to 10 micrometers. The compound of such a particle size can be obtained by grinding or milling, then, if necessary, particle size classification, for example by sieving. The compositions can also contain preservatives, stabilizers, wetting agents, solubilizers, sweeteners, colors and flavorings. The compositions can, if

  
the thing is desired, to be formulated in a slow release form.

  
If desired, the compounds can be administered together (eg, in admixture) with an acid buffer.

  
The Applicant prefers compositions designed to be administered orally or rectally

  
and to clear their contents in their intestines. The Applicant particularly prefers the compositions

  
which cross the acid regions of the gastrointestinal tract without being affected, for example keratinized formulations.

  
The compounds of formula I are optically active and can be split into their optical isomers according to conventional techniques. The invention therefore also relates to the compounds in the form of their optical isomers or of their mixtures, for example racemic mixtures.

  
The invention is illustrated without being limited by the following examples in which the temperatures are given in degrees centigrade.

  
EXAMPLE 1

  
N, N-Dimethyl-2- (1H-benzimidazol-2-ylsulfinylmethyl) benzene <EMI ID = 85.1> benzene

  
2-dimethylaminobenzyl chloride hydrochloride (8.18 g) is dissolved in dry dimethylformamide (100 ml), 2-mercaptobenzimidazole (5.4 g) and anhydrous potassium carbonate are added to it

  
(11.0 g) and the resulting mixture was stirred overnight at room temperature. The reaction mixture is poured into water and extracted with ethyl acetate, then the extract is washed with water

  
and dried over magnesium sulfate. The solvent is evaporated off and the residue is recrystallized from toluene to obtain 5.68 g of a cream-colored solid. The product is eluted from a rapid chromatography column with dichloromethane: ethyl acetate
(9: 1) as eluent to obtain a colorless solid, m.p. 158-160 [deg.].

  
  <EMI ID = 86.1>

  
calculated, 67.8; H, 6.01; N, 14.85; S, 11.31%

  
  <EMI ID = 87.1> <EMI ID = 88.1> benzene

  
98% m-chloroperbenzoic acid (0.67 g) is gradually added over a few minutes to a stirred solution of the product from stage a) (1.0 g) in dichloromethane (30 ml) at 0 [ deg.]. The reaction mixture is stirred for 0.5 hour, washed with saturated aqueous sodium bicarbonate solution, then with <EMI ID = 89.1>

  
h) i) 2- (1H-2-benzimidazolylthiomethyl) -N, N, 4trimethylbenzenamine, m.p. 159-161 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N-4trimethylbenzenamine, P.F. 133-134 [deg.]

  
i) i) 2- (1H-2-benzimidazolylthiomethyl) -4-chloroN, N-dimethylbenzenamine, m.p. 148-151 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -4chloro-N, N-dimethylbenzenamine, P.F. 148-151 [deg.]

  
j) i) 2- (5-chloro-1H-2-benzimidazolylthiomethyl) N, N-dimethylbenzenamine, P.F. 49-52 [deg.]

  
ii) 2- (5-chloro-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, P.F. 121-123 [deg.]

  
k) i) 2- (5,6-dichloro-1H-2-benzimidazolylthiomethyl) -N, N-dimethylbenzenamine, m.p. 128-130 [deg.]

  
ii) 2- (5,6-dichloro-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, m.p. 147-149 [deg.]

  
1) i) methyl 2- (2-dimethylaminophenylmethylthio) -1H-benzimidazole-5-carboxylate, mp 127-129 [deg.]

  
ii) methyl 2- (2-dimethylaminophenylmethylsulfinyl) 1H-benzimidazole-5-carboxylate, M.P. 130 [deg.]
(decomposition)

  
m) i) N, N-dimethyl-2- (5-methyl-1H-2-benzimidazolylthiomethyl) benzene, P.F. 141-143 [deg.]

  
ii) N, N-dimethyl-2- (5-methyl-1H-2-benzimidazolylsulfinylmethyl) benzene, P.F. 50-52 [deg.]

  
  <EMI ID = 90.1>

  
benzimidazole, P.F. 160-161 [deg.]

  
o) i) 2- (1H-2-benzimidazolylthiomethyl) -N, N-di-brine and dried. The solvent is evaporated off and the residue is eluted from a rapid chromatography column using dichloromethane: ethyl acetate
(7: 3) as eluent to collect 0.6 g of a colorless solid, m.p. 120-121 [deg.].

  
EXAMPLE 2

  
According to the procedure described in Example 1 and using the appropriate starting compounds, the following compounds can be prepared:
a) i) 2- (2-pyridinylmethylthio) benzoxazole,

  
P.F. 46-47 [deg.]

  
ii) 2- (2-pyridinylmethylsulfinyl) benzoxazole

  
  <EMI ID = 91.1>

  
calculated C, 60.5%; H, 3.88; N, 10.9; S, 12.4% found C, 60.31; H, 4.02; N, 10.91; S, 12.36% b) i) 2- (4-methoxy-3,5-dimethyl-2-pyridinylmethylthio) benzoxazole, m.p. 127-128 [deg.]

  
ii) 2- (4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl) benzoxazole, PF 103-105 [deg.] c) i) 2- (4-methoxy-3,5-dimethyl-2- pyridinylmethylthio) benzothiazole, PF 124-125 [deg.]

  
ii) 2- (4-methoxy-3,5-dimethyl-2-pyridinylmethyl sulfinyl) benzothiazole, PF 142-142.5 [deg.] d) i) 5-chloro-2- (2-pyridinylmethylthio) benzoxazole , PF 84-85 [deg.]

  
ii) methyl 5-chloro-2- (2-pyridinylmethylsulfinyl) -benzoxazole, PF 91-93 [deg.] e) i) methyl 2- (2-pyridinylmethylthio) benzoxazole-5carboxylate, PF 85-87 [deg. ]

  
ii) methyl 2- (2-pyridinylmethylsulfinyl) benzoxazole-5carboxylate, mp 87-90 [deg.] f) i) 2- (2-pyridinylmethylthio) benzothiazole,

  
P.F. 52-53 [deg.]

  
ii) 2- (2-pyridinylmethylsulfinyl) benzothiazole, P.F. 106-108 [deg.] ethylbenzenamine, P.F. 127-128 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -N, Ndiethylbenzenamine, P.F. 109 [deg.]

  
  <EMI ID = 92.1>

  
N, N-dimethylbenzenamine, SM: M + 329

  
ii) 2- [2- (5-methoxy-1H-benzimidazolyl) sulfinylmethyl] -N, N-dimethylbenzenamine

  
  <EMI ID = 93.1>

  
calculated C, 60.30; H, 5.65; N, 12.30; S, 9.38% found C, 60.36; H, 5.81; N, 11.89; S, 9.69% q) i) 2- (2-Benzothiazolylthiomethyl) -N, N-dimethylbenzenamine, P.F. 47-48 [deg.]

  
ii) 2- (2-benzothiazolylsulfinylmethyl) -N, N-dimethylbenzenamine, P.F. 72-73 [deg.]

  
r) i) 2- (5-trifluoromethyl-1H-2-benzimidazolylthiomethyl) -N, N-dimethylbenzenamine, m.p. 50-51 [deg.]

  
ii) 2- (5-trifluoromethyl-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, m.p. 50-51 [deg.]

  
  <EMI ID = 94.1>

  
thiomethyl) benzene, P.F. 146-148 [deg.]

  
ii) N, N-dimethyl-2- (5-nitro-1H-2-benzimidazolylsulfinylmethyl) benzene, PF 105-106 [deg.] (decomposition) t) i) [2- (2-N, N- dimethylaminophenylmethylthio) -1H5-benzimidazolyl] phenylmethanone, PF 62 [deg.]

  
ii) [2- (2-N, N-dimethylaminophenylmethylsulfinyl) -

  
  <EMI ID = 95.1>

  
u) i) 2- (5,6-dimethoxy-1H-2-benzimidazolylthiomethyl) -N, N-dimethylbenzenamine, P.F. 93-95 [deg.]

  
ii) 2- (5,6-dimethoxy-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, m.p. 142-144 [deg.]

  
v) i) 5- (1H-2-benzimidazolylthiomethyl) -N, N-2-tri-

  
  <EMI ID = 96.1>

  
ii) 5- (1H-2-benzimidazolylsulfinylmethyl) -N, N-2trimethyl-4-pyrimidinamine, m.p. 189-190.5 [deg.]

  
w) i) N, N-dimethyl-2- (4-trifluoromethyl-1H-2-ben-zimidazolylthiomethyl) benzene, P.F. 93-95 [deg.]

  
ii) N, N-dimethyl-2- (4-trifluoromethyl-1H-2benzimidazolylsulfinylmethyl) benzene, PF 129-130 [deg.] x) i) N- [2- (1H-2-benzimidazolylthio) ethyl] - Nmethylbenzenamine, PF 115-117 [deg.]

  
ii) N- [2- (1H-2-benzimidazolylsulfinyl) ethyl] N-methylbenzenamine, M.P. 148-149.5 [deg.]

  
  <EMI ID = 97.1>

  
P.F. 202-203 [deg.], Withdrawal at 160 [deg.]

  
EXAMPLE 3

  
2- (1H-2-Benzimidazolylsulfinylmethyl) -N, N-dimethyl-6propylbenzenamine a) 2-Methoxy-3-propylbenzoic acid

  
Methyl 2-methoxy-3-propylbenzoate (1.9 g) is dissolved in methanol (300 ml). Sodium hydroxide (16.6 g) in water (100 ml) is added and the mixture is heated at reflux for 3 hours.

  
The solvent is evaporated and the mixture is acidified with dilute hydrochloric acid. We extract the product

  
with ethyl acetate (800 ml), it is washed with water,

  
it is dried over magnesium sulfate and the solvent is evaporated. By extraction of the resulting brown oil with hot pentane, 25.9 g of the compound indicated in the subtitle, P.F. 55-58 [deg.], Are obtained in the form of a yellow solid.

  
b) N- (1,1-Dimethyl-2-hydroxyethyl) -2-methoxy-3propylbenzamide

  
2-methoxy-3-propylbenzoic acid (25.3 g) in dry dichloromethane (400 ml) is heated to reflux with thionyl chloride (17 ml) for

  
3 hours, then the stirring is carried out for 14 hours at room temperature. The solvent is evaporated off and the product is distilled using a ball-tube device (air bath temperature 135 [deg.], 0.35 mm Hg) to obtain 24.1 g of an oil pale yellow. This oil is dissolved in dry dichloromethane (200 ml) and gradually added to a stirred solution of 2-amino2-methylpropanol (20.2 g) in dichloromethane (200 ml)

  
  <EMI ID = 98.1>

  
room temperature for 18 hours. The product is extracted with chloroform (300 ml) and washed with dilute hydrochloric acid (150 ml), sodium bicarbonate solution (150 ml) and brine (100 ml), then dried over magnesium sulfate. After evaporation of the solvent, the compound announced in the sub-title is crystallized from cyclohexane into a white solid
(20.4 g), mp 95-96.5 [deg.].

  
c) 4,5-Dihydro-2- [2-methoxy-3-propylphenyl] -4,4-dimethyloxazole

  
The product from stage b) (20.4 g) is stirred in dry dichloromethane (200 ml) and cooled to

  
0 [deg.]. Thionyl chloride (17 ml) is added and the reaction mixture is stirred for 2 hours at room temperature. The solvent and the thionyl chloride are evaporated, then ether is added to the residue. Water is added to the solid and the mixture is made alkaline with a dilute solution of sodium hydroxide. The product is extracted into ether (500 ml), the solution is washed with brine (150 ml) and dried over magnesium sulfate. The solvent is then evaporated, then the product is purified by rapid chromatography taking as eluent 10% ethyl acetate / 90% ether

  
of petroleum and by distillation in a ball-tube apparatus (temperature of the air bath 135 [deg.], 0.7 mm Hg) to obtain, in the form of a colorless oil, the compound announced in the title (17 g).

  
  <EMI ID = 99.1> methyl-6-propylbenzenamine

  
Dimethylamine (9 ml) is added to dry tetrahydrofuran (120 ml) and the mixture is cooled to -15 [deg.] And stirred under N2 while adding a solution of n-butyllithium (81 ml, 1.6M in hexane). The reaction mixture is stirred at -16 [deg.] For 40 minutes. The product of stage c) (16 g) is added to

  
dry tetrahydrofuran (100 ml) and allow the mixture to warm to room temperature, then stir for 20 hours. The reaction mixture is poured into water and the product is extracted with ethyl acetate (500 ml), then the extract is washed

  
in brine (100 ml) and dried over sulfate

  
magnesium. The solvent is evaporated off and the product is distilled in a ball-tube apparatus (temperature

  
air bath 135 [deg.], 0.25 mm Hg) to obtain, in the form of a pale yellow oil, 16.4 g of the compound mentioned in the subtitle.

  
e) 2-Dimethylamino-3-propylbenzenemethanol

  
The product from stage d) is heated (17.3 g)

  
at reflux in 2M dilute hydrochloric acid

  
(480 ml) for 20 hours. The solvent is evaporated

  
and the residue is dried over phosphorus pentoxide.

  
The product is then dissolved in dry tetrahydrofuran (500 ml), the solution is cooled in ice

  
  <EMI ID = 100.1>

  
tetrahydrofuran (300 ml, 1M in tetrahydrofuran). The reaction mixture is stirred at room temperature for 68 hours, then poured into methanol. The solvent is evaporated off and the product is extracted with ethyl acetate, the extract is washed with sodium bicarbonate solution (150 ml) and brine (150 ml), then dried over sodium sulfate. magnesium. The solvent is evaporated and the product is distilled in a ball-tube apparatus (temperature of the air bath 156 [deg.],

  
1.0 mm Hg) to obtain, in the form of an oil

  
pale yellow, the compound announced in the subtitle (13.2 g).

  
f) 2-Chloromethyl-6-propyl-N, N-dimethylbenzenamine hydrochloride

  
The product from stage e) (13.1 g) is cooled to 0 [deg.] In dry dichloromethane (50 ml) and the solution is stirred while adding thionyl chloride to it.

  
(6 ml). The mixture is heated at reflux for 1.5 hours. The solvent is evaporated off and ethereal HCl is added.

  
The product is collected and then triturated in dry ether to obtain, in the form of a cream solid, 6.8 g of the compound mentioned in the subtitle. Mass spectrum: - m / e 211/213.

  
g) 2- (1H-2-Benzimidazolylthiomethyl) -N, N-dimethyl-6propylbenzenamine

  
The product of stage f) is converted into the compound announced in the following subtitle (P.F. 147-150 [deg.])

  
the method of example la.

  
h) 2- (1H-2-Benzimidazolylsulfinylmethyl) -N, N-dimethyl-6-propylbenzenamine

  
The product from stage g) is converted into the title compound (P.F. 145-147.5 [deg.]) According to the method of example lb.

  
, EXAMPLE 4

  
According to the process described in Example 3

  
and by means of the appropriate starting compounds, the following compounds can be prepared:
a) i) 2- (1H-2-benzimidazolylthiomethyl) -4-methoxyN, N-dimethylbenzenamine, m.p. 144-145 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -4methoxy-N, N-dimethylbenzenamine, PF 130-131 [deg.] b) i) 2- (1H-2-benzimidazolylthiomethyl) -N-ethylN-propylbenzenamine, PF 121 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -N-ethyl-N-propylbenzennamine, P.F. 114 [deg.] <EMI ID = 101.1>

  
1H-benzimidazole, P.F. 74-76 [deg.]

  
EXAMPLE 5

  
  <EMI ID = 102.1>

  
sulfinyl) -1H-benzimidazole a) 1,2,3,4-Tetrahydro-6-methylquinoline

  
Stir at room temperature for

  
18 hours of 6-methylquinoline (5.16 g, 36 millimoles) and of the pyridine / borane complex (13.2 ml, 144 millimoles) in acetic acid (75 ml). Dilute aqueous HCl (30 ml) is added with stirring to the mixture containing the product, then the mixture is acidified (NaOH to
40%, then NaHC03 until pH 8) before extracting it with ethyl acetate (3x). The combined organic extracts are washed with water (3x), dried (Na2SO4) and

  
we evaporate them to obtain a brown oil which we

  
subjected to rapid chromatography. Petroleum ether
(P.Eb. 40-60 [deg.]) / Ether (3: 1) gives, in the form of a solid with low melting point, the compound announced in the subtitle (4.7 g, 67% ). m / e 147 (base peak).

  
b) 1,2,3,4-Tetrahydro-1,6-dimethylquinoline

  
Trimethyloxonium fluoroborate is added
(5.2 g, 3.5 millimoles) to 6-methyltetrahydroquinoline (3.8 g, 25.8 millimoles) in methylene chloride (75 ml) which is stirred at room temperature for 20 hours. The mixture is poured into saturated aqueous sodium hydrogencarbonate and separated

  
the organic layer. The aqueous layer is extracted with

  
  <EMI ID = 103.1>

  
with water (2x), they are dried (Na2SO4) and evaporated to obtain a yellow oil which is subjected to rapid chromatography. Using petroleum ether (P.Eb.

  
40/60 [deg.]) / Ether (5: 1) the compound mentioned in the subtitle is eluted in the form of a pale yellow oil. m / z 161
(PM = base peak), 160, 146, 145, 144, 131, 117, 91, 77.

  
  <EMI ID = 104.1> boxaldehyde

  
Phosphoryl chloride (1.17 ml, 1.982 g, 12.5 mmol) is added dropwise to a solution of the product from stage b) (2.1 g, 10.3 mmol)

  
  <EMI ID = 105.1>

  
of ice and with stirring. The reaction mixture is heated to 120 [deg.] (Momentarily), then held at 80 [deg.] For 2 hours. The mixture is cooled, poured into dilute aqueous NaHCO3 and extracted

  
with ethyl acetate (3x). The combined organic extracts are washed with water (3x), dried (Na2SO4)

  
and they are evaporated to obtain, in the form of a yellow oil, 960 mg (49%) of the compound announced in the subtitle. m / z 189 (PM = base peak), 172, 160, 144, 132,
117, 105, 91.

  
  <EMI ID = 106.1>

  
d) 1,2,3,4-Tetrahydro-8-hydroxymethyl-1.6-dimethylquinoline

  
Sodium borohydride (300 mg, 7.94 mmilimoles) is added little by little to the product of stage c) (1.5 g, 7.94 millimoles) in ethanol with stirring at room temperature over 10 minutes. The mixture is stirred for a further 20 minutes, poured into water and extracted with ethyl acetate (3x). The combined organic extracts are washed with water (2x), dried
(Na2SO4) and evaporated to obtain, in the form of a viscous pale yellow oil, 1.41 g (93%) of the compound announced in the subtitle. m / z (mono TMS derivative) 263 (PM),
248 (base peak), 172, 73.

  
  <EMI ID = 107.1>
1.6-dimethvlquinoline Thionyl chloride is added little by little
(0.8 ml, 1.31 g, 11 millimoles) to the product of stage d)
(1.4 g, 7.33 millimoles) in dry benzene (10 ml) with stirring in a cold water bath. The mixture is allowed to warm up to room temperature

  
(2 hours), then it is heated to 50 [deg.] (1 hour). We

  
it is cooled again and ethereal HCl (2 ml) is added thereto, then it is evaporated to dryness. The resulting brown solid is triturated in ether, then it is collected by filtration to obtain, in the form of a light brown solid, 1.73 g (96%) of the compound mentioned in the sub-title. m / z 209/11 (P.M), 174 (base peak), 158, 145, 131,
119, 91.

  
f) 2- (1,2,3,4-Tetra hydro-1,6-dimethylquinoline --8ylmethylthio) -lH-benzimidazole

  
The product of stage e) is converted into the compound announced in the subtitle (P.F. 85-88 [deg.], Decomposition) according to the method of example la).

  
  <EMI ID = 108.1>

  
ylmethylsulfinyl) -1H-benzimidazole

  
The product from stage f) is converted into the title compound (P.F. 112-113 *) according to the method of example lb).

  
EXAMPLE 6

  
According to the process described in Example 5, and using the appropriate starting compounds, the following compounds can be prepared:
a) i) 2- (1H-2-benzimidazolylthiomethyl) -N, N-3,4,5-pentamethylbenzenamine, m.p. 161.5-162.5 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N-

  
  <EMI ID = 109.1> b) i) 2- (1H-2-benzimidazolylthiomethyl) -4-methoxyN, N-3,5-tetramethylbenzenamine, P.F. 157-158 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -4methoxy-N, N-3,5-tetramethylbenzenamine, PF 138-139 [deg.] c) i) 2- (1H-2-benzimidazolylthiomethyl) -N, N-dimethyl-4- (1,1-dimethylethyl) -benzenamine, PF 166-167 [deg.]

  
ii) 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethyl-4- (1,1-dimethylethyl) benzene, P.F. 130 [deg.]. EXAMPLE 7

  
  <EMI ID = 110.1>

  
dazole a) 1- (2-Dimethylaminophenyl) ethanol

  
A Grignard reagent is prepared from 2-bromo-N, N-dimethylaniline (10.0 g) and magnesium
(1.4 g) in dry ether (60 ml) with iodine (1 crystal). The reagent is cooled to 0 [deg.] And stirred under a nitrogen atmosphere. A solution of acetaldehyde (3.34 ml) in dry ether (20 ml) is added thereto dropwise over 30 minutes. After 1 hour of stirring at 0 [deg.], The mixture is allowed to warm up to room temperature. After another 2 hours, an aqueous ammonium acetate solution is added. After 10 minutes, the layers are allowed to separate. The aqueous layer is extracted with ether and the mixture of ethereal extracts is washed with water and brine, then dried and evaporated to give a dark yellow oil, 7.5 g.

   By rapid chromatography (ether / petroleum ether 1: 1), the desired compound (3.7 g) is obtained in the form of a clear yellow oil.

  
  <EMI ID = 111.1>

  
2.73S (6H) 1.55d (3H).

  
  <EMI ID = 112.1> midazole

  
A solution of 2- (2-dimethylaminophenyl) ethanol (3.6 g) in dry benzene (50 ml) is cooled in an ice bath and thionyl chloride (1.75 ml) is added dropwise. After 1 hour of stirring, the mixture is warmed up to room temperature

  
and the stirring is continued for 2 hours. The mixture is concentrated in vacuo and subjected to azeotropic distillation with benzene. The residue is taken up in dry dimethylformamide (50 ml) and stirred. To this solution is added a solution of 2-mercaptobenzimidazole (3.22 g) in dry dimethylformamide (30 ml), then potassium carbonate
(7.5 g). The mixture is stirred at room temperature for 18 hours, then poured into water containing brine and extracted with ethyl acetate. The mixture of extracts is washed with water and brine, then dried and evaporated to obtain a pale brown solid (6.1 g). By rapid chromatography of the product, a yellowish solid is obtained 3, 4 g.

  
  <EMI ID = 113.1>

  
from stage b) (3 g) in ethyl acetate (350 ml) and a solution of metachloroperbenzoic acid (1.83 g) in ethyl acetate (50 ml) is added thereto. After 1 hour of stirring, the mixture is concentrated in vacuo. The resulting gum is dissolved in the minimum amount of dichloromethane and the solution is applied to a rapid chromatography column. By elution with ether / petroleum ether 1: 1, 1.5 g of the starting compound recovered are obtained, plus the two diastereoisomers of the compound announced in the title: least polar diastereoisomer 437 mg, P.F. 119-120 [deg.] And most polar diastereoisomer 298 mg, P.F. 103-105 [deg.]. EXAMPLE 8

  
2- (1H-benzimidazol-2-ylsulfinylmethyl) -benzenethiol a) 2-Hydroxymethylthiophenol acetate A solution of borane-tetrahydrofuran complex (40 ml, 1M in tetrahydrofuran) is added dropwise to a stirred and cooled solution in ice of thiosalicylic acid (3.08 g) in dry tetrahydrofuran (20 ml) under nitrogen. The mixture is stirred at 0 [deg.] For 1 hour. Methanolic hydrogen chloride is added dropwise until effervescence ends. The mixture is poured into water and extracted with ethyl acetate. The extract in ethyl acetate is washed with dilute hydrochloric acid,

  
with water and brine, then it is dried and evaporated to obtain, in the form of a yellow oil, the compound mentioned in the subtitle (2.9 g).

  
  <EMI ID = 114.1>

  
2.05 sl (1H) b) 2,2'-Dithiobisbenzenemethanol

  
A 2-hydroxymethylthiophenol solution (19 g) is mechanically stirred with basic alumina
(100 ml) in ethanol (400 ml) while bubbling oxygen there for 48 hours. The alumina is separated by filtration and washed with hot ethanol. The ethanol is filtered and evaporated. The residue is crystallized from ethanol to obtain, in the form of white prisms, the title compound (9.33 g), m.p. 136-138 [deg.].

  
c) 2,2'-Dithiobisphenylmethyl chloride

  
2.2'-dithiobisbenzenemethanol is cooled
(500 mg) in a water bath and added dropwise

  
thionyl chloride (350 _, / [pound] liters). The mixture is stirred from time to time for 45 minutes. The excess thionyl chloride is removed in vacuo and an azeotropic distillation is carried out with benzene to obtain, in the form of a clear yellow gum, the compound mentioned in the subtitle (570 mg).

  
  <EMI ID = 115.1>

  
d) 2- (2,2'-Dithiobisphenylmethylthio) -1H-benzimidazole

  
A solution of 2-mercaptobenzimidazole (510 mg) in dry dimethylformamide (5 ml) is added

  
to a mixture of potassium carbonate (547 mg) and 2,2'-dithiobisphenylmethyl chloride (570 mg) in dry dimethylformamide (3 ml). We stir the mixture

  
at room temperature for 3 days, it is poured into water and the precipitate is collected. The solid is washed with water and taken up in dichloromethane. The solution is dried and concentrated in vacuo.

  
By rapid column chromatography, 260 mg of the compound mentioned in the subtitle is obtained in the form of a white solid.

  
NMR (CDCl) 7.1-7.6 m (16H) 4.60s (4H).

  
e) 2- (1H-Benzimidazol-2-ylthiomethyl) benzenethiol acetate

  
A suspension of 2- (2,2'-dithiobisphenylmethylthio) -lH-benzimidazole (11.5 g) in ethanol (200 ml) cooled in ice is stirred while gradually added thereto in 30 minutes of borohydride

  
sodium (806 mg). The mixture is stirred for a further 60 minutes while it is warmed to room temperature. The mixture is stirred at room temperature for 2 hours, acidified with ethanolic hydrogen chloride and stirred for 10 minutes. The mixture is then poured onto a sodium bicarbonate solution and extracted with ethyl acetate. The extracts are washed with water and brine, then dried and concentrated in vacuo. The residue is taken up in dry methylformamide (80 ml) and sodium bicarbonate (7.5 g) is added thereto. The mixture is cooled to 0 [deg.] And added slowly

  
acetic anhydride (6.0 ml). The mixture is allowed to return to room temperature and allowed to stand for 18 hours. It is poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and brine, then dried and evaporated. By rapid chromatography, 3.1 g of crude product are obtained. By crystallization from ethyl acetate, colorless prisms are obtained (1.5 g) of the compound mentioned in the subtitle, PF 134-138 [deg.] F) 2- (1H-benzimidazol-2- acetate) ylsulfinylmethyl) benzenethiol

  
The product from stage e) is converted into the title compound (P.F. 65-68 [deg.]) According to the method of example lb).

  
EXAMPLE 9

  
2 - [(1-acetyl-1H-benzimidazol-2-yl) sulfinyl- acetate

  
  <EMI ID = 116.1> a) 2 - [(l-acetyl-1H-benzimidazol-2-yl) thiomethyl] -benzenethiol acetate

  
2- (2,2'-dithiobisphenylmethylthio) -1H-benzimidazole (1 g) is dissolved in ethanol (20 ml)

  
  <EMI ID = 117.1>

  
sodium (70 mg) and the mixture is stirred for 2 hours. The solution is acidified with ethanolic HCl, stirred for 5 minutes, poured onto a solution of sodium bicarbonate and extracted with ethyl acetate. The extract in ethyl acetate is washed with a sodium bicarbonate solution, water and brine, then dried and evaporated. The resulting oil was dissolved in dry dimethylformamide and sodium bicarbonate (1.86 g) was added thereto. The mixture is stirred under N2 and cooled to 0 [deg.].

  
Acetic anhydride (1.75 ml) is added dropwise and the solution is stirred at 0 [deg.] For 1 hour.

  
The mixture is poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and brine, then dried and evaporated. By rapid chromatography, 370 mg of the compound mentioned in the subtitle is obtained in the form of a colorless solid.

  
  <EMI ID = 118.1> sulfinylméthyllbenzènethiol

  
The product from stage a) is converted into the title compound (m.p. 99-102 [deg.]) According to the method of example lb).

  
EXAMPLE 10

  
2- (1H-2-Benzimidazolylsulfinyl) -N, N-dimethylethylamine

  
Stir together for 3 hours under N2 in an ice and water bath of 2- [2- (N, N-dimethylamino) ethylthio] -3H-benzimidazole (1.7 g, 7.7 millimoles), vanadyl (III) acetylacetonate (200 mg) and

  
t-butyl hydroperoxide (1.5 g of a 70% aqueous solution, 1.05 g, 11.6 millimoles) in dry methylene chloride. Additional aliquots of vanadyl acetylacetonate (200 mg) are added after
40 minutes and 2 hours. The mixture is evaporated to dryness (rotary evaporator at room temperature) and immediately subjected to rapid chromatography, taking chloroform: methanol (5: 1) as eluent.

  
The compound announced under the subtitle (700 mg, 38%) is collected in the form of a pale yellow oil. <1> HRMN (CDC13, 360 MH2) 7.7 (m, 2H); 7.34 (m, 2H);

  
3.52 (m, 1H); 3.35 (m, 1H); 2.97 (m, 1H); 2.81 (m, 1H); 2.35 (2.6H).

  
EXAMPLE 11

  
  <EMI ID = 119.1>

  
pyridinamine a) ethyl 2-Dimethylamino-3-pyridinecarboxylate

  
  <EMI ID = 120.1>

  
while stirring with ethyl 2-chloro-3-pyridine-carboxylate (14.9 g) in dry tetrahydrofuran (100 ml). The reaction mixture is then stirred for 20 hours at room temperature. The solvent is evaporated

  
and the product is extracted with ethyl acetate (400 ml), then the extract is washed with. aqueous sodium bicarbonate solution (100 ml) and brine (100 ml) and dried over magnesium sulfate. The solvent is evaporated and the product is distilled in an apparatus

  
with a ball tube (air bath temperature 137 [deg.], 1.1 mm Hg) to obtain, in the form of a pale yellow oil,
15.4 g of the compound announced in the subtitle.

  
b) 2-Dimethylamino-3-pyridinemethanol

  
A solution of lithium aluminum hydride (44.2 ml, 1M in ether) is gradually added to a solution of the product from stage a) (7.8 g)

  
  <EMI ID = 121.1>

  
heat the mixture at reflux for 1.5 hours and pour it into ice water. The product is extracted into ethyl acetate (500 ml), the extract is washed with

  
brine (2x100 ml), dried over magnesium sulfate and the solvent is evaporated. We distill

  
the product using a ball tube apparatus (air bath temperature 105 [deg.], 0.4 mm Hg) to obtain, in the form of a pale yellow oil, 5.65 g of the compound announced in the subtitle.

  
  <EMI ID = 122.1> pyridine

  
Thionyl chloride (3.25 ml) is added dropwise to a stirred solution of the product from stage b) (5.65 g) in dry dichloromethane (100 ml) at 0 [deg.] Under nitrogen. The reaction mixture is allowed to warm to room temperature and then heated to reflux for 1.5 hours. The solvent is evaporated off and the product is subjected to azeotropic distillation with toluene, then it is triturated in ether. The residue which is a white solid is the compound announced in the subtitle (7.16 g), mp 190-192 [deg.]. <EMI ID = 123.1> pyridinamine

  
The product from stage c) is converted into the compound announced in the following subtitle (P.F. 106-109 [deg.])

  
the method of example la).

  
e) 3- (1H-2-Benzimidazolylsulfinylmethyl) -N, N-dimethyl2-pyridinamine

  
The product from stage d) is converted into the title compound (P.F. 124-126 [deg.]) According to the method of example lb).

  
EXAMPLE 12

  
2- (1H-2-Benzimidazolylsulfinylmethyl) phenol a) .2- (1H-2-Benzimidazolylthiomethyl) phenol

  
Thionyl chloride (16 ml) is added dropwise over 20 minutes to a stirred suspension.

  
and ice-cold 2-hydroxybenzyl alcohol (24.8 g) in

  
dry benzene (60 ml). The solution is allowed to warm to room temperature and is held there for 1 hour. Concentrate the mixture

  
under vacuum to obtain the crude 2-chloromethylphenol.

  
Add potassium carbonate (35 g)

  
to a stirred solution of 2-mercaptobenzimidazole (16 g) in dry dimethylformamide (200 ml) under nitrogen and

  
the mixture is stirred for 20 minutes. We dissolve

  
crude 2-chloromethylphenol in dry dimethylformamide (80 ml) and added to the above mixture. The resulting mixture is stirred at room temperature for 20 hours, poured into water containing

  
brine and extracted with ethyl acetate.

  
The mixture of extracts is washed in ethyl acetate

  
with water and brine, then dry and evaporate. By rapid chromatography, 4.5 g of a white solid are obtained. By crystallization from ethyl acetate, 1.5 g of the compound mentioned in the subtitle are obtained in the form of colorless prisms.

  
  <EMI ID = 124.1>

  
An ice-cold solution of m-chloroperbenzoic acid (72 mg) in dichloromethane is added
(10 ml) to an ice-cold solution of (2-hydroxyphenyl) methylthio-1H-benzimidazole (100 mg) in chloroform (30 ml). The mixture is stirred at 0 [deg.] For 1 hour, then allowed to warm to room temperature. After 3 hours, the mixture is diluted with chloroform, washed with a solution of sodium bicarbonate, a solution of sodium metabisulfite and water, then it is concentrated under vacuum to obtain, in the form of a solid colorless, 75 mg of the title compound.

  
  <EMI ID = 125.1> a) 2-Chloromethylpyridine N-oxide

  
An aqueous solution of 2-chloromethylpyridine hydrochloride (1.64 g) is made alkaline with

  
sodium bicarbonate and extracted with chloroform
(2x15 ml). The chloroform extract is washed with water

  
and brine, then it is dried and filtered.

  
The solution is stirred under nitrogen and m-chloroperbenzoic acid is gradually added thereto over 20 minutes

  
(1.81 g). After 18 hours of stirring at room temperature, the mixture is poured onto a saturated sodium bicarbonate solution, it is extracted with chloroform and the mixture of chloroform extracts is concentrated in vacuo to collect, in the form of an oil yellow which solidifies on standing, 1.31 g

  
of the compound announced in the subtitle.

  
  <EMI ID = 126.1>

  
The product from stage a) is converted into the compound announced in the subtitle (P.F. 148-151 [deg.]) According to the method of example la).

  
c) 2- [2-Pyridinylmethylsulfinyl-N-oxide] -1H-benzimidazole

  
The product from stage b) is converted into the title compound (m.p. 183-184 [deg.], Decomposition) according to the method of example lb).

  
EXAMPLE 14

  
[2- (2-Dimethylaminophenylmethylsulfinyl) -1H-benzimidazol-1-yl] methyl 2,2-dimethylpropanoate

  
A solution of 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine (1.5 g, 5 mmol) and chloromethyl pivalate (1 ml, 6.9) is stirred at 25 [deg.] millimoles) in dry dimethylformamide (20 ml) containing anhydrous potassium carbonate (1.4 g, 10.0 millimoles). The mixture is diluted with water (50 ml) and extracted with ethyl acetate (3x100 ml). The organic phase is washed with brine (2x25 ml), dried over magnesium sulphate, filtered and evaporated to obtain a yellow oil which is purified by rapid chromatography with elution

  
using dichloromethane / ethyl acetate (5: 1). The appropriate fractions are evaporated to leave a yellow oil which solidifies on standing. We grind

  
the solid in pentane, filtered and dried under vacuum (1.2 g), m.p. 70-71 [deg.].

  
We also prepare: -

  
1. 2- (2-dimethylaminophenylmethylsulfinyl) -1H-1-benzimidazole ethyl carboxylate hemihydrate, m.p. 75-77 [deg.],

  
  <EMI ID = 127.1>

  
N, N-dimethylbenzenamine. SM: m / e 313.

  
EXAMPLE 15

  
  <EMI ID = 128.1>
(3H) thione

  
4-toluenesulfonylbenzene-1,2diamine (2.6 g) is dissolved in dimethylformamide (50 ml) and reacted at 60 [deg.] With carbon disulfide
(6 ml) under nitrogen for 18 hours. The cooled solution is poured into ice water to obtain a yellow precipitate of the compound mentioned in the sub-title,

  
  <EMI ID = 129.1>

  
b) N, N-Dimethyl-2- [5- (4-methylphenylsulfonyl) -1H-2benzimidazolylthiomethyl] benzene

  
The product from stage a) is converted into the compound mentioned in the subtitle (P.F. 81 (deg.)) According to the method of example la).

  
c) N, N-Dimethyl-2- [5- (4-methylphenylsulfonyl) -1H-2benzimidazolylsulfinylmethyl] benzene

  
The product from stage b) is converted into the title compound (P.F. 85 [deg.]) According to the method of example lb).

  
EXAMPLE 16

  
According to a process analogous to that of Example 15, the following compounds are prepared:
a) i) 2- (4,7-dimethoxy-1H-2-benzimidazolylthiomethyl) -N, N-dimethylbenzenamine, m.p. 142-144 [deg.],

  
ii) 2- (4,7-dimethoxy-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, P.F. 61 [deg.].

  
EXAMPLE 17

  
2- (1H-2-Benzimidazolylsulfinylmethyl) benzene a) N- (2-Hydroxymethylphenyl) -2.4.6-triethylbenzenesulfonamide

  
An acid solution (2 - ([(2,4,6-

  
  <EMI ID = 130.1> dry tetrahydrofuran (80 ml) in an ice bath under nitrogen and diborane-tetrahydrofuran complex (17.3 ml of 1 molar solution) is added thereto. The reaction mixture is stirred for 3 hours at room temperature, cooled to 0 ° C. and an additional diborane-tetrahydrofuran complex (17.3 ml of 1 molar solution) is added thereto, followed by agitation overnight at room temperature. The reaction mixture is again cooled to 0 [deg.], An additional diborane-tetrahydrofuran complex (17.3 ml of 1 molar solution) is added thereto and stirring is continued at room temperature for 3 hours.

   Diluted hydrochloric acid is continuously added and the mixture is diluted with water, then it is extracted with ethyl acetate, after which the extract is washed with water and dried over magnesium sulfate. The solvent is evaporated to collect 4.0 g of the desired compound which is an oil. The structure is confirmed by NMR and MS.

  
b) N- (2-Chloromethylphenyl) -2,4,6-trimethylbenzenesulfonamide

  
With stirring at room temperature, thionyl chloride (1.15 ml) is added to the product of stage a) (4.0 g) in dry dichloroethane (80 ml).

  
The reaction mixture is stirred for 5 hours,

  
Add a thionyl chloride supplement (0.1 ml) and continue stirring overnight. The reaction mixture is then poured into water

  
and the organic layer is separated from it. The aqueous layer is washed with dichloromethane and the organic solutions are combined, which is dried over magnesium sulphate and the solvent of which is evaporated to obtain, in the form of a pale yellow oil, 4.06 g of the compound indicated in the below. -title.

  
  <EMI ID = 131.1> trimethylphenylsulfonamide

  
The product from stage b) (4.06 g) and 1,3-dihydro-2H-benzimidazol-2-thione (1.9 g) are stirred with anhydrous potassium carbonate (2.1 g) in. dry dimethylformamide (70 ml) for 3 hours.

  
The reaction mixture is poured into water and the precipitated product is collected by filtration, which is washed thoroughly with water and dried to isolate, in the form of a yellowish powder, 4 , 39 g of the desired compound, PF, 202-203 [deg.].

  
d) 2- (1H-2-Benzimidazolylthiomethyl) benzene

  
Methanesulfonic acid (29 ml) is added with stirring at room temperature to the product of stage c) (3.87 g) and to anisole (4.83 ml). The dark red reaction mixture is stirred for 27 hours, poured slowly into an excess of aqueous sodium bicarbonate solution and extracted

  
with ethyl acetate, then the extract is washed with brine and dried. The solvent is evaporated off and the residue is eluted from a rapid chromatography column, taking dichloromethane / ethyl acetate as eluent
(4: 1) to collect, in the form of a light brown solid, 1.43 g of the desired compound, P.F. 270 [deg.] (Fusion

  
at 139 [deg.] and resolidifications).

  
e) 2- (1H-2-Benzimidazolylsulfinylmethyl) benzene

  
The product in stage d) is oxidized in the same way as in Example 1b in order to obtain, after recrystallization from ethanol, the title compound which is a light colorless solid, m.p. 177 [deg.] (Decomposition).

  
EXAMPLE 18

  
2- (5-Amino-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine

  
N, N-dimethyl-2- (5-nitro1H-2-benzimidazolylsulfinylmethyl) benzene is hydrogenated (2.2 g) <EMI ID = 132.1>

  
a pressure of 1 atmosphere for 24 hours. The catalyst is separated and the solvent is evaporated off under

  
  <EMI ID = 133.1>

  
ethyl acetate 1:10) to collect the title compound, m.p. 156-157 [deg.] (decomposition). EXAMPLE 19

  
2- (1H-2-Benzimidazolylsulfinylmethyl) -N-cyclohexylN-methylbenzenamine a) 2- (N-Cyclohexyl-N-methylamino) benzaldehyde

  
  <EMI ID = 134.1>

  
and N-methylcyclohexylamine (11.9 g) at reflux in dimethylformamide (70 ml) containing potassium carbonate (14.49 g) for 5.5 hours, with stirring. The cooled reaction mixture is poured into dilute HCl and extracted into chloroform. The aqueous layer is separated and made alkaline with potassium carbonate and extracted with chloroform, after which the extract is washed with water, dried and

  
it is evaporated to collect the compound announced in the subtitle (11.8 g). SM: M + 217 P. Eb. 174.

  
b) 2- (N-Cyclohexyl-N-methylamino) benzenemethanol

  
The product of stage a) is reduced according to the method of Example 5d to obtain the compound mentioned in the subtitle. SM M + 219, P.Eb.148.

  
c) 2- (1H-2-Benzimidazolylthiomethyl) -N-cyclohexyl-Nmethylbenzenamine

  
The product from stage b) is converted into the compound mentioned in the subtitle according to the method of Example 5. M.P. 165-166 [deg.].

  
d) 2- (1H-2-Benzimidazolylsulfinylmethyl) -N-cyclohexylN-methylbenzenamine

  
The product from stage c) is converted into the title compound under the method of example lb). P.F.132-133 [deg.].


    

Claims (1)

Compound of formula I  <EMI ID = 135.1> where Rc is an entity made nucleophilic by nitrogen, oxygen or sulfur separated from the SO radical by 1, 2, 3, 4 or 5 other atoms, <EMI ID = 136.1> each represents a hydrogen or halogen atom or an alkoxy, alkyl or fluoroalkyl radical,  <EMI ID = 137.1> with the carbon atoms to which they are united, a nitrogen heterocycle or unsaturated 6-membered carbocycle, x represents 3, 4 or 5, n represents 0, 1 or 2,  <EMI ID = 138.1>  <EMI ID = 139.1> -COOR or alkyl, the latter optionally being substituted by -OCOR, R represents a hydrogen atom or phenyl or alkyl radical optionally substituted by phenyl, the phenyl radicals in turn being optionally substituted by alkyl, with the restriction that i) Rc does not represent a  <EMI ID = 140.1> a nitrogenous nucleophilic entity carried by an aryl or heteroaryl radical, R15 is not a radical -COR where R represents an unsubstituted alkyl radical, iii) during-  <EMI ID = 141.1> unsaturated nitrogen other than such a substituted ring is a) by a substituted or unsubstituted amino radical, or b) by an N-oxido radical and iv) when X represents <EMI ID = 142.1> titrated by a piperidino radical optionally alkyl halo-substituted, and their pharmaceutically acceptable salts. 2 - Compound according to claim 1, in the formula in which the nucleophilic entity is separated from the SO radical by 2 or 3 atoms, is more nucleophilic than water which is a basic amine. 3 - Compound according to claim 1, in the formula of which Rc represents a radical of formula  <EMI ID = 143.1> or different, each represents a hydrogen atom or an alkyl radical and Rx is a cycle of formula II, III, IV or V,  <EMI ID = 144.1>    <EMI ID = 145.1>  and when y + z does not represent 0, Rx can represent  <EMI ID = 146.1> each represents a hydrogen atom or an alkyl, phenyl or cycloalkyl radical, each of which may be optionally substituted by phenyl, the phenyl radicals being in turn optionally substituted by alkyl or  <EMI ID = 147.1> they are united, can form a saturated or unsaturated cycle of 4 to 8 members which can contain 0, 1 or 2 other heteroatoms, which cycle can carry one or more  <EMI ID = 148.1>  <EMI ID = 149.1> different, each represents a hydrogen atom or alkyl radical optionally substituted by halogen or by = 0, cycloalkyl, alkanoyl, phenyl or pyridyl, or else  <EMI ID = 150.1>  <EMI ID = 151.1> with the nitrogen atom and the carbon atoms of the ring to which the nitrogen atom and R8 are united form a saturated 4 to 8-membered ring which can contain 0, 1 or 2 other heteroatoms, which ring can carry a or  <EMI ID = 152.1> A represents a 5 or 6-membered heterocycle containing nitrogen or sulfur which is united to the rest of the molecule by a ring carbon atom, Y represents N or C, when Y represents N, W represents 0- and when  <EMI ID = 153.1>  <EMI ID = 154.1> nyle, cycloalkyl, alkanoyl or alkyl optionally substituted by phenyl. 4 - N, N-dimethyl-2- (1H-benzimidazol-2ylsulfinylmethyl) benzene or a pharmaceutically acceptable salt thereof. 5 - 2- (2-pyridinylmethylsulfinyl) benzoxazole, 2- (4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl) benzoxazole, 2- (4-methoxy-3,5-dimethyl-2-pyridinylmethylsulfinyl) benzothiazole, methyl 5-chloro-2- (2-pyridinylmethylsulfinyl) benzoxazole, methyl 2- (2-pyridinylmethylsulfinyl) benzoxazole-5-carboxylate, 2- (2-pyridinylmethylsulfinyl) benzothiazole, N, N-dimethyl-2- (5,6-dimethyl-1H-2-benzimidazolylsulfinylmethyl) benzene, 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N, 4-trimethylbenzenamine, 2- (1H-2-benzimidazolylsulfinylmethyl) -4-chloro-N, N-dimethylbenzenamine, 2- (5-chloro-1H-2-benzimidazolylsulfinylmethyl) dimethylbenzenamine, 2- (5,6-dichloro-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, methyl 2- (2-dimethylaminophenylmethylsulfinyl) -1H-benzimidazole-5-carboxylate, N, N-dimethyl-2- (5-methyl-1H-2-benzimidazolylsulfinylmethyl) benzene, 2- [2- (1-piperidyl) phenylmethylsulfinyl] -1H-benzimidazole, 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N-diethylbenzenamine,  <EMI ID = 155.1> N, N-dimethylbenzenamine, 2- (2-benzothiazolylsulfinylmethyl) -N, N-dimethylbenzenamine, 2- (5-trifluoromethyl-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine,  <EMI ID = 156.1> 2- (5,6-dimethoxy-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, 5- (1H-2-benzimidazolylsulfinylmethyl) -N, N-2-trimethyl-4-pyrimidinamine, N, N-dimethyl-2- (4-trifluoromethyl-1H-2-benzimidazolylsulfinylmethyl) benzene, N- [2- (1H-2-benzimidazolylsulfinyl) ethyl] -N-methylbenzenamine, N, N-dimethyl-2- (1H-2-naphtho [2,3-d] imidazolylthiomethyl) benzene, 2- (2- (1H-benzimidazolyl) sulfinyl) benzene, 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N-dimé-thyl-6-propylbenzènamine, 2- (1H-2-benzimidazolylthiomethyl) -N-ethyl-N-propylbenzenamine, 2- (1H-2-benzimidazolylsulfinylmethyl) -N-ethylN-propylbenzenamine,  <EMI ID = 157.1> benzimidazole, 2- (1,2,3,4-tetrahydro-1,6-dimethylquinoline-8-  <EMI ID = 158.1> pentamethylbenzenamine, 2- (1H-2-benzimidazolylsulfinylmethyl) -4-methoxyN, N-3,5-tetramethylbenzenamine, 2- (1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethyl-4- (1,1-dimethylethyl) benzene,  <EMI ID = 159.1> benzimidazole, 2- (1H-benzimidazol-2-ylsulfinylmethyl) benzenethiol acetate, 2 - [(1-acetyl-1H-benzimidazol-2-yl) sulfinylmethyl] benzenethiol acetate, 2- (1H-2-benzimidazolylsulfinyl) -N, N-dimethylethylamine, 3- (1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethyl2-pyridinamine, 2- (1H-2-benzimidazolylsulfinylmethyl) phenol, 2- (2-pyridinylmethylsulfinyl-N-oxide) -1H-benzimidazole, [2- (2-dimethylaminophenic) 2,2-dimethylpropanoate  <EMI ID = 160.1> ethyl 2- (2-dimethylaminophenylmethylsulfinyl) -1H-1-benzimidazole-carboxylate, 2- [1-methyl- (1H-2-benzimidazolylsulfinylmethyl)] N, N-dimethylbenzenamine,  <EMI ID = 161.1> <EMI ID = 162.1> 2- (4,7-dimethoxy-1H-2-benzimidazolylsulfinylmethyl) -N, N-dimethylbenzenamine, 2- (1H-2-benzimidazolylsulfinylmethyl) benzene, 2- (5-amino-1H-2-benzimidazolylsulfinylmethyl) N, N-dimethylbenzenamine, 2- (1H-2-benzimidazolylsulfinylmethyl) -N-cyclohexyl-N-methylbenzenamine, or a pharmaceutically acceptable salt of any of these compounds. 6 - Pharmaceutical composition, characterized in that it comprises a compound according to any one of the preceding claims in admixture with a pharmaceutically acceptable adjuvant, diluent or excipient. 7 - Pharmaceutical use of a compound of formula I as defined in claim 1 but escaping the restriction ii) or of a pharmaceutically acceptable salt thereof.  <EMI ID = 163.1> as defined in claim 1, but escaping the restrictions i) and ii) for the preparation of a pharmaceutical formulation to be administered for the prevention or inhibition of the secretion of gastric acid. 9 - Process for preparing a compound of formula I, as defined in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it comprises a) the selective oxidation of a corresponding compound of formula VI.  <EMI ID = 164.1>   <EMI ID = 165.1> claim 1, <EMI ID = 166.1>  <EMI ID = 167.1> except that it cannot represent a hydrogen atom, by reaction of a corresponding compound of formula I  <EMI ID = 168.1>  <EMI ID = 169.1> may represent a hydrogen atom, and Z represents an appropriate leaving radical or c) the preparation of a compound of formula I carrying an <EMI ID = 170.1> and when the thing is desired or necessary, the  <EMI ID = 171.1> pharmaceutically acceptable thereof or vice versa. 10 - Compound of formula VI as defined in claim 9, where Rc is as defined in claim 3, y + z is greater than 0 and Rx represents a cycle of formula II.  <EMI ID = 172.1>    <EMI ID = 173.1>