CA1226223A - Pharmaceutical compositions containing benzimidazole compounds - Google Patents
Pharmaceutical compositions containing benzimidazole compoundsInfo
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- CA1226223A CA1226223A CA000409351A CA409351A CA1226223A CA 1226223 A CA1226223 A CA 1226223A CA 000409351 A CA000409351 A CA 000409351A CA 409351 A CA409351 A CA 409351A CA 1226223 A CA1226223 A CA 1226223A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
ABSTRACT
A pharmaceutical preparation containing as active in-gredient a compound of the formula Ia or a therapeutically acceptable salt thereof, in which formula R1 and R2 are the same or different and each selected from the group consisting of H, -COOCH3, -COOC2H5, alkyl containing 1 to 7 carbon atoms, halogen, alkoxy containing 1 to 5 carbon atoms, and alkanoyl containing 1 to 4 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consist-ing of H, CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
provided that (a) at least one of R3, R4 and R5 is selected from the group consisting of CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radical R3, R4 or R5 is selected from the group consisting of OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
in association with a pharmaceutically acceptable carrier, the use of the compounds for inhibiting gastric acid secretion;
compounds included in the formula Ia, and processes for their preparation.
A pharmaceutical preparation containing as active in-gredient a compound of the formula Ia or a therapeutically acceptable salt thereof, in which formula R1 and R2 are the same or different and each selected from the group consisting of H, -COOCH3, -COOC2H5, alkyl containing 1 to 7 carbon atoms, halogen, alkoxy containing 1 to 5 carbon atoms, and alkanoyl containing 1 to 4 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consist-ing of H, CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
provided that (a) at least one of R3, R4 and R5 is selected from the group consisting of CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radical R3, R4 or R5 is selected from the group consisting of OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
in association with a pharmaceutically acceptable carrier, the use of the compounds for inhibiting gastric acid secretion;
compounds included in the formula Ia, and processes for their preparation.
Description
~;~Z6Z;~3 DESCRIPTION
Field of the invention The object of the present invention is to provide come pounds which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the treatment of peptic ulcers.
The present invention relates to the use of a group of benzimidazole derivatives, or therapeutically acceptable salts thereof, for inhibiting gastric acid secretion in mammals and man.
In a more general sense, the invention relates to the use of the compounds for treatment of gastrointestinal inflammatory diseases in mammals and man, including i.e. gastric and duodenal ulcer.
Furthermore it relates to the use of these compounds for treatment of other gastrointestinal disorders, where a gastric anti-secretory effect is desirable i.e. in patients with gastronomes and in patients with acute upper gastrointestinal bleeding. The invention also relates to pharmaceutical compositions containing at least one member of the said group of benzimidazole derivatives, or a therapeutically acceptable salt thereof, as active ingredient.
New compounds, and therapeutically acceptable salts thereof, with-in the said group of benzimidazole derivatives, and to processes for preparation of such new compounds have been made the subject of a divisional application.
Prior art Benzimidazo~e derivatives intended for inhibiting gastric acid secretion are disclosed in the British patent specifications ~2~Z3 1 500 043 and 1 525 958, in the United States patent 4 182 766 and in the European patent specification No. 0 005 129.
The invention This parent application concerns a pharmaceutical pro-parathion containing as active ingredient a compound of the formula R R US IQ
or a therapeutically acceptable salt thereof, in which formula Al and R2 are the same or different and each selected from the group consisting of H, -COUCH, -COOK, alkyd containing 1 to 7 carbon atoms, halogen, alkoxy containing 1 to 5 carbon atoms, and alkanoyl containing 1 to 4 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consist-in of H, SHEA, OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
provided that (a) at least one of R , R and R is selected from the group consisting of SHEA, OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radical R , R or R is selected from the group consisting of OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
in association with a pharmaceutically acceptable carrier.
These pharmaceutical compositions are effective as ~26Z23 inhibitors of gastric juice secretions in mammals and man.
A divisional application has been filed concerning come pounds of the formula R ¦ SKYE
and therapeutically acceptable salts thereof in which formula Al and R2 are the same or different and each selected from the group consisting of H, CF3, NO, -COUCH, -COOK, alkyd containing 1-7 carbon atoms, halogen, alkoxy containing 1-5 carbon atoms, and alkanoyl containing 1-4 carbon atoms;
R is selected from the group consisting of H, alkanoyl containing 1-4 carbon atoms, and carboalkoxy containing 2-6 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consisting of H, SHEA, C2H5, OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3, provided that a) at least one of R , R and R is selected from the group consisting owe SHEA, C2H5, OUCH, C2H5, 2 2 3 OCH2CH2OCH2CH3, and b) when two of R3, R4 and R5 are H, then the remaining radical R , R4 or R5 is selected from the group consisting of OUCH, OOZE, OCH2CH20CH3, and OCH2CH20CH2CH3; and provided that c) when R is H then at least one of R and R are CF3 or N02 .
Jo I, Jo ~L~2262Z3 These novel compounds are effective as inhibitors of gastric acid secretion in mammals and man. The compounds of the formula I and Ian and therapeutically acceptable salts thereof, are stable in gastric juice, which is of importance at oral administration.
In this specification whenever reference is made to for-mute I, the above-referenced definitions of the radicals R, Al, R2, R3, R4 and R5 apply. Whenever reference is made to formula Ian the above-referenced definitions of Al, R2, R3, I and R5 apply. In addition, whenever reference is made to formula It and there is reference to the radical R this is to be understood to be H.
Illustrative examples of the radicals in the formula I
and It are as appropriate.
Alkyd groups Al and R2: methyl, ethyl, n-propyl, i-propel, n-butyl, sec.-butyl, isobutyl, tert.-butyl, n-pentyl, n-Huxley, Natalie. It is preferred that alkyd groups Al and R2 contains 1, 2, 3 or 4 carbon atoms. The preferred alkyd group is methyl.
Halogen Al and R2: sheller, broom, flyer, idea. The preferred halogen groups are sheller and broom.
Alkoxy groups Al and R2: methoxy, ethics, n-propoxy, i-propoxy, n-butoxy, sec.-butoxy, isobutoxy, -tert.-butoxy, n-pentoxy. It is preferred that alkoxy groups Al and R2 contain 1,
Field of the invention The object of the present invention is to provide come pounds which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the treatment of peptic ulcers.
The present invention relates to the use of a group of benzimidazole derivatives, or therapeutically acceptable salts thereof, for inhibiting gastric acid secretion in mammals and man.
In a more general sense, the invention relates to the use of the compounds for treatment of gastrointestinal inflammatory diseases in mammals and man, including i.e. gastric and duodenal ulcer.
Furthermore it relates to the use of these compounds for treatment of other gastrointestinal disorders, where a gastric anti-secretory effect is desirable i.e. in patients with gastronomes and in patients with acute upper gastrointestinal bleeding. The invention also relates to pharmaceutical compositions containing at least one member of the said group of benzimidazole derivatives, or a therapeutically acceptable salt thereof, as active ingredient.
New compounds, and therapeutically acceptable salts thereof, with-in the said group of benzimidazole derivatives, and to processes for preparation of such new compounds have been made the subject of a divisional application.
Prior art Benzimidazo~e derivatives intended for inhibiting gastric acid secretion are disclosed in the British patent specifications ~2~Z3 1 500 043 and 1 525 958, in the United States patent 4 182 766 and in the European patent specification No. 0 005 129.
The invention This parent application concerns a pharmaceutical pro-parathion containing as active ingredient a compound of the formula R R US IQ
or a therapeutically acceptable salt thereof, in which formula Al and R2 are the same or different and each selected from the group consisting of H, -COUCH, -COOK, alkyd containing 1 to 7 carbon atoms, halogen, alkoxy containing 1 to 5 carbon atoms, and alkanoyl containing 1 to 4 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consist-in of H, SHEA, OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
provided that (a) at least one of R , R and R is selected from the group consisting of SHEA, OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radical R , R or R is selected from the group consisting of OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
in association with a pharmaceutically acceptable carrier.
These pharmaceutical compositions are effective as ~26Z23 inhibitors of gastric juice secretions in mammals and man.
A divisional application has been filed concerning come pounds of the formula R ¦ SKYE
and therapeutically acceptable salts thereof in which formula Al and R2 are the same or different and each selected from the group consisting of H, CF3, NO, -COUCH, -COOK, alkyd containing 1-7 carbon atoms, halogen, alkoxy containing 1-5 carbon atoms, and alkanoyl containing 1-4 carbon atoms;
R is selected from the group consisting of H, alkanoyl containing 1-4 carbon atoms, and carboalkoxy containing 2-6 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consisting of H, SHEA, C2H5, OUCH, OOZE, OCH2CH2OCH3, and OCH2CH2OCH2CH3, provided that a) at least one of R , R and R is selected from the group consisting owe SHEA, C2H5, OUCH, C2H5, 2 2 3 OCH2CH2OCH2CH3, and b) when two of R3, R4 and R5 are H, then the remaining radical R , R4 or R5 is selected from the group consisting of OUCH, OOZE, OCH2CH20CH3, and OCH2CH20CH2CH3; and provided that c) when R is H then at least one of R and R are CF3 or N02 .
Jo I, Jo ~L~2262Z3 These novel compounds are effective as inhibitors of gastric acid secretion in mammals and man. The compounds of the formula I and Ian and therapeutically acceptable salts thereof, are stable in gastric juice, which is of importance at oral administration.
In this specification whenever reference is made to for-mute I, the above-referenced definitions of the radicals R, Al, R2, R3, R4 and R5 apply. Whenever reference is made to formula Ian the above-referenced definitions of Al, R2, R3, I and R5 apply. In addition, whenever reference is made to formula It and there is reference to the radical R this is to be understood to be H.
Illustrative examples of the radicals in the formula I
and It are as appropriate.
Alkyd groups Al and R2: methyl, ethyl, n-propyl, i-propel, n-butyl, sec.-butyl, isobutyl, tert.-butyl, n-pentyl, n-Huxley, Natalie. It is preferred that alkyd groups Al and R2 contains 1, 2, 3 or 4 carbon atoms. The preferred alkyd group is methyl.
Halogen Al and R2: sheller, broom, flyer, idea. The preferred halogen groups are sheller and broom.
Alkoxy groups Al and R2: methoxy, ethics, n-propoxy, i-propoxy, n-butoxy, sec.-butoxy, isobutoxy, -tert.-butoxy, n-pentoxy. It is preferred that alkoxy groups Al and R2 contain 1,
2 or 3 carbon atoms. The preferred alkoxy group is methoxy.
Alkanoyl groups R, Al and R : HO-, CHICO-, CH3CH2CO-, ,,.~
~;~2~zz3 SHEA
CH3CH2CH2CO-, HO - CO-. The preferred alkanoyl group Al and R
SHEA
is CHICO. The preferred alkanoyl group R is CHICO.
O O O
.. .. ..
Carboalkoxy groups R: SCHICK-, CH3CH20-C-, CH3CH2CH20-C-, OH Q O O
, 3 " " "
HO - C-, CH3(CH2)30-C-, CH3(CH2)40-C-. It is preferred that SHEA
carboalkoxy groups R contains 2 or 3 carbon atoms. Thus, the groups SCHICK- and CH3CH20CO- are preferred.
The preferred meaning of the radical in compounds of Formula I is H.
Preferred combinations of the radicals in the formulae I and Ian subject, where appropriate, to the provisos a), b) and c) given above, are given in Table 1 below.
Table l Preferred combinations of Al R , R, R , R and R
R and R , R R , R and R , the same or different if the same or different it not indicated otherwise not indicated otherwise . . .
' 3' 2 5 H Ho SHEA, C2H5' OUCH
alkyd, halogen, alkoxy, 2 I C SHEA SHEA, alkanoyl ocH2cH2ocH2cH3 ____________________________________________________________________ H, COUCH, SHEA, C1, Bra , C 3, C2 5, OX
OUCH, CHICO OCH2CH20CH3 ____________________________________________________________________ H, COUCH, SHEA, OUCH, H SHEA, OUCH
CHICO
__________________________________________________________ _________ Jo ~Z2~;~Z3 R and R R R3 R4 and R5 the same or different if the same or different if not indicated otherwise not indicated otherwise H, COUCH, alkyd H H, SHEA, OUCH, OOZE
alkoxy, alkanoyl H, COUCH, COOK, H R : SHEA
alkyd, halogen, alkoxy, R4: OUCH
alkanoyl R : SHEA
________.___________________________________________________________ H, COUCH, COOK, H R3 H
alkyd, alkoxy, R4: OUCH
alkanoyl R : SHEA
___________________________________________________________________ NO, CF3 H R3: OH
R : OUCH
R5: SHEA
___________________________________________________________________ H, COUCH, COOK, H R3: OH
alkyd, alkoxy, R : OUCH
alkanoyl R5: H
___________________________________________________________ _______ H, COUCH, COOK, H R3 H
alkyd, alkoxy, R4: OUCH
alkanoyl R5: H
___________________________________________________________________ H, COUCH, COOK, H R3: OH
alkyd, alkoxy, R : H
alkanoyl R5: SHEA
___________________________________________________________________ H, COUCH, COOK, H R3 H
alkyd, alkoxy, R4: OUCH, OOZE, alkanoyl 2 2 3' _________________________ R H_______________________ ~,.,~,,.
ISLES
. .
R1 and R2, R R3 R4 and R5 the same or different if the same or different if not indicated otherwise not indicated otherwise Ho COUCH CC2H5 H R3: SHEA
alkyd, alkoxy R4: SHEA
alkanoyl R5: SHEA
____________________________________________________________________ The radicals Al and R2 can be bound to the benzimidazole nucleus in any of the positions 4, 5, 6 and 7 as depicted in formulae I and Ian It is preferred that Al and R2 are in position 5 and/or 6.
Preferred individual compounds among those included in the formula It are given in the following Table 2:
Table 2 Preferred individual compounds Al R2 R3 R4 R5 _ . _ _ _ . . ...
OUCH H SHEA OUCH SHEA
COUCH H SHEA OUCH SHEA
COUCH SHEA SHEA OUCH SHEA
COUCH SHEA SHEA OUCH SHEA
COUCH H SHEA OUCH SHEA
SHEA H SHEA OUCH SHEA
COUCH SHEA H SHEA SHEA
OUCH H SHEA SHEA SHEA
COUCH SHEA H OUCH H
COUCH SHEA SHEA OUCH H
CASEY SHEA SHEA SHEA SHEA
COUCH SHEA H OUCH H
. . . _ . _ _ . . . _ , - 7 --; Jo .~, 1~26223 Further preferred individual compounds are those exam-plified in the examples given elsewhere in this specification.
In the prior art cited above, no medicinal use is disk closed for the compounds of the formula Ian Thus, the present invention comprises pharmaceutical compositions containing a compound of the formula It or a therapeutically acceptable salt thereof as active ingredient, and the use of the compounds of the formula It or a therapeutically acceptable salt thereof for inhibiting gastric acid secretion in mammals and man.
The compounds of the formula It wherein Al and R2 are as defined above except CF3 and NO, R is H and R3, R4 and R5 are H, SHEA, OUCH, OOZE, OCH2CH2OCH3 or OCH2CH2OCH2CH3 are generically disclosed as chemical intermediates in the European patent No.
0 005 129. The specific compounds disclosed in the following Table 3 are disclosed in the said European patent No. 0 005 129.
Table 3 Compounds disclosed in European patent no. 0 005 129.
R Al R2 R5 Remark H COUCH SHEA H SHEA SHEA base H SHEA SHEA C~3 H SHEA hydrochloride H COUCH SHEA SHEA SHEA SHEA base The invention claimed in the divisional application, in so far as it concerns compounds of the formula I by themselves, their pharmaceutically acceptable salts, and processes for their preparations, relates to i) the compounds of the formula I wherein R3, R or R
, , 8 ~2Z~;~Z3 is C2~15 ii) the compounds of the formula I wherein R is alkanoyl or carboalkoxy iii) the compounds of the formula I wherein when R is H, and/or R are CF3 or NO.
The preferred compounds within the groups i), ii) and iii) will comprise the same compounds that are indicated as pro-furred in Table 1 above.
The compounds of the formula I (or Ian as appropriate) can be prepared by known methods such as A. reacting a compound of the formula Al = II
N
R
with a compound of the formula in which formulas R, Al, R , R , R and R are as defined previous-lye and wherein one of Al and z2 is SO and the other is a leaving group.
Examples of leaving groups Al and z2 in the compounds II and III are halogens, preferably chlorine, bromide or iodine, azalea radicals, for example, residues of strong organic sulfonic acids, for instance, of an arylsulfonic acid, for example, tussle-- g _ :J.Z2~3 ox, or an alkylsulfonic acid, for example, mesyloxy; alkylmercapto groups, for example, methylmercapto; alkylsulfinyl groups, for example, methylsulfinyl and the like.
Thus, Al or z2 when designating leaving groups may be a reactive esterified hydroxy group.
The reaction of a compound of formula II above with a compound of formula III is conveniently carried out in the presence of a suitable solvent that is inert under the reaction conditions utilized as described hereinafter. The reaction may further be carried out in the presence of a suitable base. Suitable bases include, for example, inorganic bases such as sodium or potassium hydroxide, sodium or potassium hydrides and the like, organic bases such as tertiary amine, for example, triethylamine and the like.
Suitable solvents fox the above described reaction in-elude, for example, alcohols, preferably lower alkanols such as, methanol and ethanol; mixtures of such alcohols with water, ethers, such as, tetrahydrofuran; halogenated hydrocarbons, such as, ethylene chloride and chloroform, and the like.
The reaction of the compounds of formulas II and III may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture. It is pro-furred to carry out the reaction, however, at a temperature at or close to the boiling point of the reaction mixture for the pro-parathion of a compound of the formula It or of the formula I
wherein R is H;
B. reacting a compound of the formula ~62Z3 R
Al-- NH2 IV
Ho wherein R1 and R2 have the same meaning as given above with a come pound of the formula HOOKS N
wherein R3, R4 and R5 have the same meaning as given above, for the formation of a compound of the formula It or formula I wherein R is H;
C. reacting a compound of the formula Al Jo SHIM VI
NO
wherein R, Al and R2 have the meaning given above and M is K, No or H, with a compound of formula wherein R3, R4 and R5 have the meaning given above and Z3 is a reactive esterified h~droxy group, to yield a compound of the Formula I or Ian appropriate.
The reactive esterified hydroxy group Z3 may, as in toe case of Al and z2, be a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydrohalogen acid such as hydrochloric acid, hydrobromic acid, or hydroiodic acid, or ester-fled with sulfuric acid or with a strong organic sulfonic acid such as a strong aroma-tic acid, e.g. benzenesulfonic acid, Brigham-benzenesulfonic acid or 4-toluenesulfonic acid.
D. reduction of a compound of the formula to yield a compound of the formula I, or Ian as appropriate.
E. for the preparation of a compound of the formula I or Ian as appropriate, wherein the radicals Al and/or R2 is COUCH or COOK, reacting a compound of the formula TV \ SHEA R5 IX
R
wherein R, R3, R4 or R5 are as defined above and wherein ye is -COO, or a functionally equivalent derivative thereof, and ye is -COO, or a functionally equivalent derivative thereof, or Al, with SHEA X
or OUCH XI
or a functionally equivalent derivative thereof, to yield a come pound of the formula I or It wherein Al and/or R2 is SCHICK or C SCHICK-This reaction is an ordinary esterification which is carried out in customary manner.
Functionally equivalent derivatives of the hydroxy group in the compounds X and XI are for example halogen such as Of or Bra or -No.
Functionally equivalent derivatives of the carboxyl group ye and ye are for example a metal carboxylate group or an anti-voted carboxyl group, in which case the radicals ye or ye are for example an acid chloride, an alkyd ester, an acid android or a mixed android with formic esters or carboxylic acids, sulphonic or inorganic esters or derivatives obtainable by a reaction between a carboxylic acid and a carbodiimide or similarly function-in compounds such as NlNl-carbonyldiimidazole or N-ethyl-5-phenylisoxazolium-31-sulphonate, the derivative of the carboxyl group ye or ye being a metal carboxylate group when the hydroxyl group in the compounds X or XI is replaced with halogen. A further functionally equivalent derivative of the carboxyl groups ye and Y is the group -ON, in which case a cyanide is reacted with a come pound of the formula X or XI with subsequent hydrolysis to give a compound of the formula I or It wherein Al and/or R2 is SCHICK or
Alkanoyl groups R, Al and R : HO-, CHICO-, CH3CH2CO-, ,,.~
~;~2~zz3 SHEA
CH3CH2CH2CO-, HO - CO-. The preferred alkanoyl group Al and R
SHEA
is CHICO. The preferred alkanoyl group R is CHICO.
O O O
.. .. ..
Carboalkoxy groups R: SCHICK-, CH3CH20-C-, CH3CH2CH20-C-, OH Q O O
, 3 " " "
HO - C-, CH3(CH2)30-C-, CH3(CH2)40-C-. It is preferred that SHEA
carboalkoxy groups R contains 2 or 3 carbon atoms. Thus, the groups SCHICK- and CH3CH20CO- are preferred.
The preferred meaning of the radical in compounds of Formula I is H.
Preferred combinations of the radicals in the formulae I and Ian subject, where appropriate, to the provisos a), b) and c) given above, are given in Table 1 below.
Table l Preferred combinations of Al R , R, R , R and R
R and R , R R , R and R , the same or different if the same or different it not indicated otherwise not indicated otherwise . . .
' 3' 2 5 H Ho SHEA, C2H5' OUCH
alkyd, halogen, alkoxy, 2 I C SHEA SHEA, alkanoyl ocH2cH2ocH2cH3 ____________________________________________________________________ H, COUCH, SHEA, C1, Bra , C 3, C2 5, OX
OUCH, CHICO OCH2CH20CH3 ____________________________________________________________________ H, COUCH, SHEA, OUCH, H SHEA, OUCH
CHICO
__________________________________________________________ _________ Jo ~Z2~;~Z3 R and R R R3 R4 and R5 the same or different if the same or different if not indicated otherwise not indicated otherwise H, COUCH, alkyd H H, SHEA, OUCH, OOZE
alkoxy, alkanoyl H, COUCH, COOK, H R : SHEA
alkyd, halogen, alkoxy, R4: OUCH
alkanoyl R : SHEA
________.___________________________________________________________ H, COUCH, COOK, H R3 H
alkyd, alkoxy, R4: OUCH
alkanoyl R : SHEA
___________________________________________________________________ NO, CF3 H R3: OH
R : OUCH
R5: SHEA
___________________________________________________________________ H, COUCH, COOK, H R3: OH
alkyd, alkoxy, R : OUCH
alkanoyl R5: H
___________________________________________________________ _______ H, COUCH, COOK, H R3 H
alkyd, alkoxy, R4: OUCH
alkanoyl R5: H
___________________________________________________________________ H, COUCH, COOK, H R3: OH
alkyd, alkoxy, R : H
alkanoyl R5: SHEA
___________________________________________________________________ H, COUCH, COOK, H R3 H
alkyd, alkoxy, R4: OUCH, OOZE, alkanoyl 2 2 3' _________________________ R H_______________________ ~,.,~,,.
ISLES
. .
R1 and R2, R R3 R4 and R5 the same or different if the same or different if not indicated otherwise not indicated otherwise Ho COUCH CC2H5 H R3: SHEA
alkyd, alkoxy R4: SHEA
alkanoyl R5: SHEA
____________________________________________________________________ The radicals Al and R2 can be bound to the benzimidazole nucleus in any of the positions 4, 5, 6 and 7 as depicted in formulae I and Ian It is preferred that Al and R2 are in position 5 and/or 6.
Preferred individual compounds among those included in the formula It are given in the following Table 2:
Table 2 Preferred individual compounds Al R2 R3 R4 R5 _ . _ _ _ . . ...
OUCH H SHEA OUCH SHEA
COUCH H SHEA OUCH SHEA
COUCH SHEA SHEA OUCH SHEA
COUCH SHEA SHEA OUCH SHEA
COUCH H SHEA OUCH SHEA
SHEA H SHEA OUCH SHEA
COUCH SHEA H SHEA SHEA
OUCH H SHEA SHEA SHEA
COUCH SHEA H OUCH H
COUCH SHEA SHEA OUCH H
CASEY SHEA SHEA SHEA SHEA
COUCH SHEA H OUCH H
. . . _ . _ _ . . . _ , - 7 --; Jo .~, 1~26223 Further preferred individual compounds are those exam-plified in the examples given elsewhere in this specification.
In the prior art cited above, no medicinal use is disk closed for the compounds of the formula Ian Thus, the present invention comprises pharmaceutical compositions containing a compound of the formula It or a therapeutically acceptable salt thereof as active ingredient, and the use of the compounds of the formula It or a therapeutically acceptable salt thereof for inhibiting gastric acid secretion in mammals and man.
The compounds of the formula It wherein Al and R2 are as defined above except CF3 and NO, R is H and R3, R4 and R5 are H, SHEA, OUCH, OOZE, OCH2CH2OCH3 or OCH2CH2OCH2CH3 are generically disclosed as chemical intermediates in the European patent No.
0 005 129. The specific compounds disclosed in the following Table 3 are disclosed in the said European patent No. 0 005 129.
Table 3 Compounds disclosed in European patent no. 0 005 129.
R Al R2 R5 Remark H COUCH SHEA H SHEA SHEA base H SHEA SHEA C~3 H SHEA hydrochloride H COUCH SHEA SHEA SHEA SHEA base The invention claimed in the divisional application, in so far as it concerns compounds of the formula I by themselves, their pharmaceutically acceptable salts, and processes for their preparations, relates to i) the compounds of the formula I wherein R3, R or R
, , 8 ~2Z~;~Z3 is C2~15 ii) the compounds of the formula I wherein R is alkanoyl or carboalkoxy iii) the compounds of the formula I wherein when R is H, and/or R are CF3 or NO.
The preferred compounds within the groups i), ii) and iii) will comprise the same compounds that are indicated as pro-furred in Table 1 above.
The compounds of the formula I (or Ian as appropriate) can be prepared by known methods such as A. reacting a compound of the formula Al = II
N
R
with a compound of the formula in which formulas R, Al, R , R , R and R are as defined previous-lye and wherein one of Al and z2 is SO and the other is a leaving group.
Examples of leaving groups Al and z2 in the compounds II and III are halogens, preferably chlorine, bromide or iodine, azalea radicals, for example, residues of strong organic sulfonic acids, for instance, of an arylsulfonic acid, for example, tussle-- g _ :J.Z2~3 ox, or an alkylsulfonic acid, for example, mesyloxy; alkylmercapto groups, for example, methylmercapto; alkylsulfinyl groups, for example, methylsulfinyl and the like.
Thus, Al or z2 when designating leaving groups may be a reactive esterified hydroxy group.
The reaction of a compound of formula II above with a compound of formula III is conveniently carried out in the presence of a suitable solvent that is inert under the reaction conditions utilized as described hereinafter. The reaction may further be carried out in the presence of a suitable base. Suitable bases include, for example, inorganic bases such as sodium or potassium hydroxide, sodium or potassium hydrides and the like, organic bases such as tertiary amine, for example, triethylamine and the like.
Suitable solvents fox the above described reaction in-elude, for example, alcohols, preferably lower alkanols such as, methanol and ethanol; mixtures of such alcohols with water, ethers, such as, tetrahydrofuran; halogenated hydrocarbons, such as, ethylene chloride and chloroform, and the like.
The reaction of the compounds of formulas II and III may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture. It is pro-furred to carry out the reaction, however, at a temperature at or close to the boiling point of the reaction mixture for the pro-parathion of a compound of the formula It or of the formula I
wherein R is H;
B. reacting a compound of the formula ~62Z3 R
Al-- NH2 IV
Ho wherein R1 and R2 have the same meaning as given above with a come pound of the formula HOOKS N
wherein R3, R4 and R5 have the same meaning as given above, for the formation of a compound of the formula It or formula I wherein R is H;
C. reacting a compound of the formula Al Jo SHIM VI
NO
wherein R, Al and R2 have the meaning given above and M is K, No or H, with a compound of formula wherein R3, R4 and R5 have the meaning given above and Z3 is a reactive esterified h~droxy group, to yield a compound of the Formula I or Ian appropriate.
The reactive esterified hydroxy group Z3 may, as in toe case of Al and z2, be a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydrohalogen acid such as hydrochloric acid, hydrobromic acid, or hydroiodic acid, or ester-fled with sulfuric acid or with a strong organic sulfonic acid such as a strong aroma-tic acid, e.g. benzenesulfonic acid, Brigham-benzenesulfonic acid or 4-toluenesulfonic acid.
D. reduction of a compound of the formula to yield a compound of the formula I, or Ian as appropriate.
E. for the preparation of a compound of the formula I or Ian as appropriate, wherein the radicals Al and/or R2 is COUCH or COOK, reacting a compound of the formula TV \ SHEA R5 IX
R
wherein R, R3, R4 or R5 are as defined above and wherein ye is -COO, or a functionally equivalent derivative thereof, and ye is -COO, or a functionally equivalent derivative thereof, or Al, with SHEA X
or OUCH XI
or a functionally equivalent derivative thereof, to yield a come pound of the formula I or It wherein Al and/or R2 is SCHICK or C SCHICK-This reaction is an ordinary esterification which is carried out in customary manner.
Functionally equivalent derivatives of the hydroxy group in the compounds X and XI are for example halogen such as Of or Bra or -No.
Functionally equivalent derivatives of the carboxyl group ye and ye are for example a metal carboxylate group or an anti-voted carboxyl group, in which case the radicals ye or ye are for example an acid chloride, an alkyd ester, an acid android or a mixed android with formic esters or carboxylic acids, sulphonic or inorganic esters or derivatives obtainable by a reaction between a carboxylic acid and a carbodiimide or similarly function-in compounds such as NlNl-carbonyldiimidazole or N-ethyl-5-phenylisoxazolium-31-sulphonate, the derivative of the carboxyl group ye or ye being a metal carboxylate group when the hydroxyl group in the compounds X or XI is replaced with halogen. A further functionally equivalent derivative of the carboxyl groups ye and Y is the group -ON, in which case a cyanide is reacted with a come pound of the formula X or XI with subsequent hydrolysis to give a compound of the formula I or It wherein Al and/or R2 is SCHICK or
3 2 F. for the preparation of a compound of the formula I or Ian as appropriate, wherein at least one of R3, R and R5 is OUCH, , I 13 -~L2~:6ZZ3 OOZE, OCH2CH2OCH3 or OCH2CH2OCH2CH3, reacting a compound of the formula I SHEA XII
wherein R, Al and R2, are as defined above and Z3, Z and US
represent either R3, R4 and R5, respectively, or halogen such as Of, Bra F or I, or NO, whereby at least one of Z3, Z4 and Z
represents halogen or NO, with a compound of the formula ROME XIII
wherein R6 is SHEA, C2H5, CH2CH2OCH3 or CH2CH2OCH2CH3, and M is Nay K, or H, to yield a compound of the formula I or It wherein at least one of R , R and R is OUCH, OOZE, OCH2CH2OCH3 or OCH2CH20CH2CH3;
G. for the preparation of a compound of the formula I or It as appropriate, wherein at least one of R3, R and R is OCH2CH2OCH3 or OCH2CH2OCH2CH3, reacting a compound of the formula z7 I S SHEA XIV
wherein R, Al and R2 are as defined above, and z6, z7 and z8 no-present either R3, R4 and R5, respectively, or a radical where Y is halogen, whereby at least one of Z , Z and Z no-~~14 ~1~26~223 present OCH2CH2Y~ with a compound of the formula R --O-M XVI
wherein R is SHEA or CH2CH3 and M is Nay K or H, to yield a come pound of the formula I or It wherein at least one of R , R and R is OCH2CH20CH3 or OCH2CH20CH2CH3.
Method F and Method G represent the known Williamson ether synthesis and are carried out in known manner.
H. for the preparation of a compound of the formula It and formula I wherein R is H, hydrolyzing a compound ox the formula I' wherein Al, R , R3, R and R are as defined above and Z is an alkanoyl group or a carboalkoxy group, to yield a compound of the formula It or formula I wherein R is H.
The radical Z can be an alkanoyl group containing 1-6 carbon atoms or a carboalkoxy group containing 2-6 carbon atoms.
I. reduction of a compound of the formula R \ SHEA XVIII
R O
to yield a compound of the formula I or Ian as appropriate.
6~Z3 J. reduction of a compound of the formula N SKYE XIX
to yield a compound of the formula I or Ian as appropriate.
Depending on the process conditions and the starting materials, the end product of the formula I and It is obtained either as the free base or as a salt. Both the free base and the salts of the end products are included within the scope of the invention. Thus, basic, neutral or mixed salts may be obtained as well as hem, moo, Suzuki or polyhydrates. Acid addition salts of the new compounds may in a manner known per so be transformed into free base using basic agents such as alkali or by ion exchange.
The free bases obtained may also form salts with organic or nor-genie acids. In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts. Examples of such acids are hydrohalogen acids, sulfonic acid, phosphoric acid, nitric acid, and perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, prop ionic acid, succinic acid, glycolic acid, lactic acid, mafia acid, tartaric acid, citric acid, ascorbic acid, malefic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxy-benzoic acid, salicylic acid or p-aminosalicylic acid, embank acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethane ~ZZ~ZZ3 sulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acids;
methionine, tryptophane, Lawson or arginine.
These or other salts of the new compounds, as e.g.
pirates, may serve as purifying agents of the free bases obtained.
Salts of the bases may be formed, separated from solution, and then the free base can be recovered in higher purity from a new salt solution.
The starting materials utilized in the processes A-J are known or may, if they should be new, be obtained according to processes known per so.
In clinical use the active compounds of the formula I
or It will normally be administered orally, rectally or by inject lion in the form of a pharmaceutical preparation which contains the active component either in the form ox free base or in the form of a pharmaceutically acceptable, non-toxic salt, as describe Ed earlier, optionally in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, semisolid or liquid delineate, or a capsule. These pharmaceutical preparations are a further object of the invention. The compounds may also be used without carrier material. Usually the amount of active compound is between 0.1 and 99% by weight of the preparation, for example between 0.5 to 20% by weight in preparations for in-section and between 2 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations con-twining a compound of the formula I or It in the form of dosage _ aye _ 12~26Z23 units for oral administration, the active compound may be mixed with a solid, pulverulent carrier, such as lactose, succors, sorbitol, minutely, a starch such as potato starch, corn starch, or amylopectin, cellulose derivatives or gelatin and may also include a lubricant such as magnesium Stewart, calcium - 16b -` `?
., ,, 1;2~6ZZ3 Stewart or polyethyleneglycol waxes. The mixture is then pressed into tablets. If coated tablets are desired, a core prepared as described above may be coated with a concentra-ted sugar solution which may contain gum Arabic gelatin, talc, titanium dioxide or alternatively with a lacquer dissolved in volatile organic solvents or mixtures of solvents. To this coating various dyes may be added in order to distinguish tablets with different active compounds or with different amounts of the active compound present.
Soft gelatin capsules may be prepared which capsules contain a mixture o-F the active compound or compounds and vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, pulverulent carrier as lactose, succors, sorbitol, minutely, potato starch, corn starch, amylopectin,-cellulose derivatives or gelatin.
Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance in admixture with a neutral fatty base, or they may be prepared in the form of gelatin-rectal capsules which contain the active substance in admixture with a vegetable oil or with paraffin oil.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions contain-in from 0.2% to 20% by weight of the active ingredient, the remainder comprising for example sugar and a mixture of ethanol, water, glycerol and propylene glycol. IF desired such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as - a thickening agent.
Solutions for parènteral administration by injection may be prepared as sterile solution, for example In pyrogen-free ~26Z23 water, of a water soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from 0.5% to 10%
by weight. These solutions may also contain stabilizing agents and/or buffering agents and may be manufactured in different doss age unit ampules.
The dosage at which the active substance are administer-Ed may vary within a wide range and will depend on various factors such as for example the individual requirements of each patient and the manner of administration. In general, oral dosages will be in the range from 100 to 400 mg/day of active substance and intravenous dosages in a range from 5 to 20 mg/day.
The examples exemplify this parent application and the divisional application, as appropriate.
Example 1. Method A. Preparation of 2-[2-(3,5-dimethyl-4-methoxy) pyridylmethylthio]-5-COCH3~6-CH3-benzimidazole 22.2 g (0.1 mole) of 3,5-dimethyl-4-methoxy-2-chloro-methylpyridine hydrochloride and 20.6 g (0.1 mole) of COUCH-CH3-2-mercapto benzimidazole was dissolved in 250 ml methanol thereafter 4 g (0.1 mole) Noah dissolved in 25 ml HO was added.
The mixture was heated to reflex and an additional amount of
wherein R, Al and R2, are as defined above and Z3, Z and US
represent either R3, R4 and R5, respectively, or halogen such as Of, Bra F or I, or NO, whereby at least one of Z3, Z4 and Z
represents halogen or NO, with a compound of the formula ROME XIII
wherein R6 is SHEA, C2H5, CH2CH2OCH3 or CH2CH2OCH2CH3, and M is Nay K, or H, to yield a compound of the formula I or It wherein at least one of R , R and R is OUCH, OOZE, OCH2CH2OCH3 or OCH2CH20CH2CH3;
G. for the preparation of a compound of the formula I or It as appropriate, wherein at least one of R3, R and R is OCH2CH2OCH3 or OCH2CH2OCH2CH3, reacting a compound of the formula z7 I S SHEA XIV
wherein R, Al and R2 are as defined above, and z6, z7 and z8 no-present either R3, R4 and R5, respectively, or a radical where Y is halogen, whereby at least one of Z , Z and Z no-~~14 ~1~26~223 present OCH2CH2Y~ with a compound of the formula R --O-M XVI
wherein R is SHEA or CH2CH3 and M is Nay K or H, to yield a come pound of the formula I or It wherein at least one of R , R and R is OCH2CH20CH3 or OCH2CH20CH2CH3.
Method F and Method G represent the known Williamson ether synthesis and are carried out in known manner.
H. for the preparation of a compound of the formula It and formula I wherein R is H, hydrolyzing a compound ox the formula I' wherein Al, R , R3, R and R are as defined above and Z is an alkanoyl group or a carboalkoxy group, to yield a compound of the formula It or formula I wherein R is H.
The radical Z can be an alkanoyl group containing 1-6 carbon atoms or a carboalkoxy group containing 2-6 carbon atoms.
I. reduction of a compound of the formula R \ SHEA XVIII
R O
to yield a compound of the formula I or Ian as appropriate.
6~Z3 J. reduction of a compound of the formula N SKYE XIX
to yield a compound of the formula I or Ian as appropriate.
Depending on the process conditions and the starting materials, the end product of the formula I and It is obtained either as the free base or as a salt. Both the free base and the salts of the end products are included within the scope of the invention. Thus, basic, neutral or mixed salts may be obtained as well as hem, moo, Suzuki or polyhydrates. Acid addition salts of the new compounds may in a manner known per so be transformed into free base using basic agents such as alkali or by ion exchange.
The free bases obtained may also form salts with organic or nor-genie acids. In the preparation of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts. Examples of such acids are hydrohalogen acids, sulfonic acid, phosphoric acid, nitric acid, and perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxyl or sulfonic acids, such as formic acid, acetic acid, prop ionic acid, succinic acid, glycolic acid, lactic acid, mafia acid, tartaric acid, citric acid, ascorbic acid, malefic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxy-benzoic acid, salicylic acid or p-aminosalicylic acid, embank acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethane ~ZZ~ZZ3 sulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acids;
methionine, tryptophane, Lawson or arginine.
These or other salts of the new compounds, as e.g.
pirates, may serve as purifying agents of the free bases obtained.
Salts of the bases may be formed, separated from solution, and then the free base can be recovered in higher purity from a new salt solution.
The starting materials utilized in the processes A-J are known or may, if they should be new, be obtained according to processes known per so.
In clinical use the active compounds of the formula I
or It will normally be administered orally, rectally or by inject lion in the form of a pharmaceutical preparation which contains the active component either in the form ox free base or in the form of a pharmaceutically acceptable, non-toxic salt, as describe Ed earlier, optionally in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of a solid, semisolid or liquid delineate, or a capsule. These pharmaceutical preparations are a further object of the invention. The compounds may also be used without carrier material. Usually the amount of active compound is between 0.1 and 99% by weight of the preparation, for example between 0.5 to 20% by weight in preparations for in-section and between 2 and 50% by weight in preparations for oral administration.
In the preparation of pharmaceutical preparations con-twining a compound of the formula I or It in the form of dosage _ aye _ 12~26Z23 units for oral administration, the active compound may be mixed with a solid, pulverulent carrier, such as lactose, succors, sorbitol, minutely, a starch such as potato starch, corn starch, or amylopectin, cellulose derivatives or gelatin and may also include a lubricant such as magnesium Stewart, calcium - 16b -` `?
., ,, 1;2~6ZZ3 Stewart or polyethyleneglycol waxes. The mixture is then pressed into tablets. If coated tablets are desired, a core prepared as described above may be coated with a concentra-ted sugar solution which may contain gum Arabic gelatin, talc, titanium dioxide or alternatively with a lacquer dissolved in volatile organic solvents or mixtures of solvents. To this coating various dyes may be added in order to distinguish tablets with different active compounds or with different amounts of the active compound present.
Soft gelatin capsules may be prepared which capsules contain a mixture o-F the active compound or compounds and vegetable oil. Hard gelatin capsules may contain granules of the active compound in combination with a solid, pulverulent carrier as lactose, succors, sorbitol, minutely, potato starch, corn starch, amylopectin,-cellulose derivatives or gelatin.
Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance in admixture with a neutral fatty base, or they may be prepared in the form of gelatin-rectal capsules which contain the active substance in admixture with a vegetable oil or with paraffin oil.
Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions contain-in from 0.2% to 20% by weight of the active ingredient, the remainder comprising for example sugar and a mixture of ethanol, water, glycerol and propylene glycol. IF desired such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as - a thickening agent.
Solutions for parènteral administration by injection may be prepared as sterile solution, for example In pyrogen-free ~26Z23 water, of a water soluble pharmaceutically acceptable salt of the active compound, preferably in a concentration from 0.5% to 10%
by weight. These solutions may also contain stabilizing agents and/or buffering agents and may be manufactured in different doss age unit ampules.
The dosage at which the active substance are administer-Ed may vary within a wide range and will depend on various factors such as for example the individual requirements of each patient and the manner of administration. In general, oral dosages will be in the range from 100 to 400 mg/day of active substance and intravenous dosages in a range from 5 to 20 mg/day.
The examples exemplify this parent application and the divisional application, as appropriate.
Example 1. Method A. Preparation of 2-[2-(3,5-dimethyl-4-methoxy) pyridylmethylthio]-5-COCH3~6-CH3-benzimidazole 22.2 g (0.1 mole) of 3,5-dimethyl-4-methoxy-2-chloro-methylpyridine hydrochloride and 20.6 g (0.1 mole) of COUCH-CH3-2-mercapto benzimidazole was dissolved in 250 ml methanol thereafter 4 g (0.1 mole) Noah dissolved in 25 ml HO was added.
The mixture was heated to reflex and an additional amount of
4 g (0.1 mole) Noah in 25 ml HO was added drops during 15 min.
The mixture was thereafter reflexed during 6 hours thereafter it was cooled and diluted with 500 ml HO. The resulting mixture was extracted with SCHICK, dried and evaporated. The remainder was recrystallized from acetonitrile giving the title substance in the form of free base. Yield: 30 g (85% of the theoretical yield).
MOP.: 139C.
2 v~3 Examples 2-50 The compounds identified by example numbers 2-50 in the following Table 4 were prepared using the same method of prepare-lion as in Example lo The compounds were obtained in the form of their free base. The compound of Example 1 is also included in the table.
Table 4 Identifying data for compounds of the inventions of this parent application and the divisional application, as appropriate.
Example Mop.
no Al R2 R R R4 R5 C
. _ . .
COUCH SHEA H SHEA SHEA H170 (oil) 8 COUCH SHEA H SHEA SHEA SHEA (oil) cont.
r: 1 9 ~Z26;2~3 .
Example Mop.
no Al R2 R R R4 R5 C
11 COUCH SHEA H Kiwi OUCH SHEA 139 COUCH SHEA H ~C2H5 H 90-94 18 COUCH 6 SHEA H H OUCH Ho 184 23 OUCH H H SHEA OUCH . SHEA 110-119 26 clue H. H SHEA OUCH SHEA 180 31 . COUCH SHEA H SHEA H SHEA 125 . _ _ 32 5-C(CH3)3 H H SHEA OUCH SHEA
SHEA SHEA H SHEA. OUCH SHEA
37 5-CF H SHEA OUCH Ho 39 5-C1 clue H SHEA OUCH SHEA
OKAY H H SHEA OUCH SHEA
41 cry . H H SHEA OUCH SHEA
42 OUCH H H OUCH H H cont.
~226223 Example no Al R2 R R3 R4 R5 43 clue H H SHEA SHEA H
SHEA SHEA H SHEA SHEA H
Identifying data for the compounds according to examples 32-50 are given in the following table 5.
Tale 5. NOR data for compounds of the invention Compound according NOR data to example no.
.
32 1.37 ~s,9H), 2.26 ~s,3H), 2.30 ~s,3H), 3.76 ~s,3H), 4.37 ~s,2H), 7.25 clue), 7.49 ~d,lH), 7.57 (d,lH), 8.30 (sly) 33 2.21 ~s,3H), 2.31 ~s,3H), 3.75 ~s,3H), ' 4.7? ~s,2H), 7.64 (d,lH), Bull clue), B.23 sly), B.36 ~d,lH) -cont.
6~Z3 Table 5. NOR data for compounds of -the invention.
continued Compound according NOR data to example no.
34 2.23 (s,3H), 2.28 (s,3H), 2.33 (s,6H), 3.75 (s,3H), 4.33 (s,2H), 7.29 (s,2H), 8.23 (sly) 2.28 (s,3H), 2.33 (s,3H), 2.43 (s,3H), 2.5B (s,3H), 3.81 (s,3H), 4.42 (s,2H~, 6.92 (sly), 7.29 (sly), 8.36 (sly) 36 1.25 (t,3H), 2.25 (s,3H), 2.30 (s,3H), 2.72 (k,2H), 3.76 (s,3H), 4.38 (s,2H), 7.02 (clue), 7.35 (d,lH), 7.45 (d,lH), 8.26 (sly) 37 2.31 (s,3H), 2.35 (s,3H), 3.84 (s,3H), 4.46 (s,2H), 7.51 (clue), 7.70 (d,lH), 7.92 (d,lH), 8.38 (sly) 38 1.25 (s,3H), 1.33 (s,3H), 2.27 (s,3H), 2.33 (s,3H), 3.03 (m,lH), 3.80 (s,3H), 4.51 (s,2H), 7.17 (kiwi), 7.53 (d,lH), - - 7.58 (d,lH), 8.36 Icily) 39 2.22 (s,3H), 2.31 (s,3H), 3.81 (s,3H), 4 7? (s,2H), 7.76 (s,2H), 8.23 (sly) ~.41 (t,3H), 2.30 (s,3H), 2.35 (s,3H), 3.82 (s,3H), 4.10 (k,2H), 4.39 (s,2H), 6.92 (kilt)`, 7.14 (d,lH), 7.52 (d,lH), -- 8.40 sly) cont.
~l2Z6~23 able 5. NOR data for compounds of the invention.
continued Compound according NOR data to example no.
41 2.16 (s,3H), 2.26 (s,3H), 3.71 ~s,3H), 4.68 (s,2H), 7.23 (clue), 7.43 ~d,lH), 7.65 (d,lH), 8.18 (sly) 42 3.80 (s,3H), 3.83 ~s,3H), 4.50 ~s,2H), 6.90 (clue), 7.15 td,lH), 7.24 ~m,2H), 7.53 (d,lH), 8.23 (clue) 43 2.33 (s,3H), 2.35 (s,3H), 4.80 (s,2H), 7.19 (m,2H), 7.52 (d,lH), 7.58 ~d,lH), 8.34 (d,lH) 44 2.34 (s,6H), 3.85 (s,3H), 4.51 ~s,2H), 6.89 (clue), 7.15 (d,lH), 7.15 (d,lH), 7.53 (d,lH), 8.41 (d,lH) 2.16 ~s,6H), 2.38 (s,3H), 2.53 ~s,3H), 4.46 ~s,2H), 6.86 (sly), 6.99 ~d,lH), 7.25 (sly), 8.20 (d,lH) 46 2.26 ~s,3H), 3.86 (s,3H), 3.91 (s,3H), 4.70 (s,2H), 6.87 (m,2H), 7.10 (d,lH), 7.48 (d,lH), 8.42 (d,lH) 47 2.36 (s,6H), 2.65 (s,3H), 3.97 ~s,3H), 4.50 (s,2H), 7.17 (d,lH), 7.84 (sly), 8.24 (sly), 8.41 (d,lH), X
Swiss aye 23940-414 Table 5 continued . . . _ .
Compound according NOR data to example no.
48 2.31 (s,3H), 2.34 (s,3H), 2.64 (s,3H), 4.71 (s,2H), 7.12 (d,lH), 7.59 (d,lH), 7.91 (clue), 8.22 (d,lH), 8.36 (d,lH), cont.
~226~3 I
Table 5. NOR data for compounds ox the invention.
continued Compound according NOR data
The mixture was thereafter reflexed during 6 hours thereafter it was cooled and diluted with 500 ml HO. The resulting mixture was extracted with SCHICK, dried and evaporated. The remainder was recrystallized from acetonitrile giving the title substance in the form of free base. Yield: 30 g (85% of the theoretical yield).
MOP.: 139C.
2 v~3 Examples 2-50 The compounds identified by example numbers 2-50 in the following Table 4 were prepared using the same method of prepare-lion as in Example lo The compounds were obtained in the form of their free base. The compound of Example 1 is also included in the table.
Table 4 Identifying data for compounds of the inventions of this parent application and the divisional application, as appropriate.
Example Mop.
no Al R2 R R R4 R5 C
. _ . .
COUCH SHEA H SHEA SHEA H170 (oil) 8 COUCH SHEA H SHEA SHEA SHEA (oil) cont.
r: 1 9 ~Z26;2~3 .
Example Mop.
no Al R2 R R R4 R5 C
11 COUCH SHEA H Kiwi OUCH SHEA 139 COUCH SHEA H ~C2H5 H 90-94 18 COUCH 6 SHEA H H OUCH Ho 184 23 OUCH H H SHEA OUCH . SHEA 110-119 26 clue H. H SHEA OUCH SHEA 180 31 . COUCH SHEA H SHEA H SHEA 125 . _ _ 32 5-C(CH3)3 H H SHEA OUCH SHEA
SHEA SHEA H SHEA. OUCH SHEA
37 5-CF H SHEA OUCH Ho 39 5-C1 clue H SHEA OUCH SHEA
OKAY H H SHEA OUCH SHEA
41 cry . H H SHEA OUCH SHEA
42 OUCH H H OUCH H H cont.
~226223 Example no Al R2 R R3 R4 R5 43 clue H H SHEA SHEA H
SHEA SHEA H SHEA SHEA H
Identifying data for the compounds according to examples 32-50 are given in the following table 5.
Tale 5. NOR data for compounds of the invention Compound according NOR data to example no.
.
32 1.37 ~s,9H), 2.26 ~s,3H), 2.30 ~s,3H), 3.76 ~s,3H), 4.37 ~s,2H), 7.25 clue), 7.49 ~d,lH), 7.57 (d,lH), 8.30 (sly) 33 2.21 ~s,3H), 2.31 ~s,3H), 3.75 ~s,3H), ' 4.7? ~s,2H), 7.64 (d,lH), Bull clue), B.23 sly), B.36 ~d,lH) -cont.
6~Z3 Table 5. NOR data for compounds of -the invention.
continued Compound according NOR data to example no.
34 2.23 (s,3H), 2.28 (s,3H), 2.33 (s,6H), 3.75 (s,3H), 4.33 (s,2H), 7.29 (s,2H), 8.23 (sly) 2.28 (s,3H), 2.33 (s,3H), 2.43 (s,3H), 2.5B (s,3H), 3.81 (s,3H), 4.42 (s,2H~, 6.92 (sly), 7.29 (sly), 8.36 (sly) 36 1.25 (t,3H), 2.25 (s,3H), 2.30 (s,3H), 2.72 (k,2H), 3.76 (s,3H), 4.38 (s,2H), 7.02 (clue), 7.35 (d,lH), 7.45 (d,lH), 8.26 (sly) 37 2.31 (s,3H), 2.35 (s,3H), 3.84 (s,3H), 4.46 (s,2H), 7.51 (clue), 7.70 (d,lH), 7.92 (d,lH), 8.38 (sly) 38 1.25 (s,3H), 1.33 (s,3H), 2.27 (s,3H), 2.33 (s,3H), 3.03 (m,lH), 3.80 (s,3H), 4.51 (s,2H), 7.17 (kiwi), 7.53 (d,lH), - - 7.58 (d,lH), 8.36 Icily) 39 2.22 (s,3H), 2.31 (s,3H), 3.81 (s,3H), 4 7? (s,2H), 7.76 (s,2H), 8.23 (sly) ~.41 (t,3H), 2.30 (s,3H), 2.35 (s,3H), 3.82 (s,3H), 4.10 (k,2H), 4.39 (s,2H), 6.92 (kilt)`, 7.14 (d,lH), 7.52 (d,lH), -- 8.40 sly) cont.
~l2Z6~23 able 5. NOR data for compounds of the invention.
continued Compound according NOR data to example no.
41 2.16 (s,3H), 2.26 (s,3H), 3.71 ~s,3H), 4.68 (s,2H), 7.23 (clue), 7.43 ~d,lH), 7.65 (d,lH), 8.18 (sly) 42 3.80 (s,3H), 3.83 ~s,3H), 4.50 ~s,2H), 6.90 (clue), 7.15 td,lH), 7.24 ~m,2H), 7.53 (d,lH), 8.23 (clue) 43 2.33 (s,3H), 2.35 (s,3H), 4.80 (s,2H), 7.19 (m,2H), 7.52 (d,lH), 7.58 ~d,lH), 8.34 (d,lH) 44 2.34 (s,6H), 3.85 (s,3H), 4.51 ~s,2H), 6.89 (clue), 7.15 (d,lH), 7.15 (d,lH), 7.53 (d,lH), 8.41 (d,lH) 2.16 ~s,6H), 2.38 (s,3H), 2.53 ~s,3H), 4.46 ~s,2H), 6.86 (sly), 6.99 ~d,lH), 7.25 (sly), 8.20 (d,lH) 46 2.26 ~s,3H), 3.86 (s,3H), 3.91 (s,3H), 4.70 (s,2H), 6.87 (m,2H), 7.10 (d,lH), 7.48 (d,lH), 8.42 (d,lH) 47 2.36 (s,6H), 2.65 (s,3H), 3.97 ~s,3H), 4.50 (s,2H), 7.17 (d,lH), 7.84 (sly), 8.24 (sly), 8.41 (d,lH), X
Swiss aye 23940-414 Table 5 continued . . . _ .
Compound according NOR data to example no.
48 2.31 (s,3H), 2.34 (s,3H), 2.64 (s,3H), 4.71 (s,2H), 7.12 (d,lH), 7.59 (d,lH), 7.91 (clue), 8.22 (d,lH), 8.36 (d,lH), cont.
~226~3 I
Table 5. NOR data for compounds ox the invention.
continued Compound according NOR data
5 to example no. `
49 1.41 (t,3H), 2.27 (s,3H), 2.31 (s,3H), 3.37 (s,3H), 3.94 ~k,2H), 4.41 (s,2H),
49 1.41 (t,3H), 2.27 (s,3H), 2.31 (s,3H), 3.37 (s,3H), 3.94 ~k,2H), 4.41 (s,2H),
6.39 (clue), 7.12 (d,lH), 7.50 (d,lH), aye (sly) 1.17 -(t,3H), 2.61 (k,2H), 2.69 (s,3H), 3.93 (s,6H), 4.43 (s,2H), 7.00 (sly),
7.45 (sly), 8.26 (sly), 8.35 (sly) the starting materials in the examples 1-50 were prepared in accordance with the following:
1) a substituted o-phenylenediamine was reacted with potassium etylxanthate (according to Org. Synch. Vol.
30, p. 56) to Norm a corresponding substituted 2-mercaptobenzimidazole;
, 2) a substituted 2-chloromethylpyridine was prepared by reacting the corresponding 2-hydroxymethylpyridine with thionylchlbride;
3) a substituted 2-chloromethylbenzimidazole was prepared by condensing the o-phenylenediamine with chloroacetic acid.
~L~Z6Z~3 The following examples illustrate how the compounds of the formula I or It can be incorporated in pharmaceutical compositions:
Example 51. Syrup A syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:
2-[2-(3,5-dimethyl-4-methoxy)pyridylmethylthio]--(5-acetyl-6-methyl)benzimidazole Hal 2.0 g Saccharin 0.6 g Sugar 30 0 g Glycerin 5.0 g Flavoring agent 0.1 g Ethanol 96% 10.0 ml Distilled water (sufficient to obtain a final volume of 100 ml) Sugar, saccharin and the acid addition salt were dissolved in 60 g of warm water. After cooling, glycerin and a solution of flavoring agents dissolved in ethanol were added.
To the mixture water was added to obtain a final volume of 100 ml.
The above given active substance may be replaced with other pharmaceutically acceptable acid addition salts.
Example 52. Tablets 2-~2-(3,5-dimethyl-4-methoxy)pyridylmethylthio]-(5-methoxy)-benzimidazole Hal (250 g) was mixed with lactose (175.8 g), potato starch (169.7 g) and colloidal silicic acid (32 g). The mixture was moistened with 10% solution of gelatin and was ground through a 12-mesh sieve. After drying, potato starch (160 g), I;
~226223 talc (50 g) and magnesium Stewart (5 g) were added and the mixture thus obtained was pressed into tablets (10.000), with each tablet containing 25 my of active substance. Tablets can be prepared that contain any desired amount of the active ingredient.
Example 53. Tablets Granules were prepared from 2-~2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-carbomethoxy-6-methhyl)benzimida-zone base (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After drying, the granules were mixed with talc (25 g), potato starch (40 g), and magnesium Stewart (2.50 g) and were pressed into 10.000 tablets.
These tablets are first coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing succors (45%), gum Arabic (5%), gelatin (4%), and distaff (0.2%). Talc and powdered sugar were used for powdering after the first five coatings. The coating was then covered with a 66% sugar syrup and polished with a solution of 10% carnauba wax in carbon tetrachloride.
Example So. Solution for injection 2-[2-(3,5-dimethyl-4-methoxy)pyridylmethylthio]-(5-acetyl-6-methyl)benzimidazole hydrochloride (1 g), sodium chloride (0.6 g) and ascorbic acid (0.1 g) were dissolved in sufficient amount of distilled water to give 100 ml of solution.
This solution, which contains 10 my of active substance for each ml, was used in filling ampules, which were sterilized by heating at 120C for 20 minutes.
jar assay Biological tests Gastric acid secretion inhibiting effect on conscious dogs Test Method Chronic gastric fustily dogs (Heidenhain pouch dogs) were used. These dogs have been surgically provided with a gust-fig Connally in the pouch. Following a 4 weeks' recovery period after surgery, tests were performed once a week on each dog. Food and water were withdrawn 18 hours before each test.
Gastric acid secretion was induced by continuous in-Fusion of histamine at individual doses (100-300 ~mol/kg, h), resulting in sub maximal secretion of gastric acid. At least 2 hours after onset of stimulation, when the gastric acid secretion had reached a steady level, the test compounds in the form of free base suspended in 0.5% Methuselah ~90 HUG, 15.000, Dow Chum. crop.), were given orally by stomach tube. The gastric juice was collected by free flow from the gastric Connally in consecutive 30 minutes samples for 3 hours. The samples were titrated to pi 7.0 with 0.1 M Noah using a Radio-meter automatic titrator and the acid out-put was calculated.
The per cent inhibition of acid secretion was calculated by comparing in each dog the acid output in the tests to the acid output in control tests when only the vehicle was given.
The test results are given in Table 6 below.
.
Swiss Table 6 Gastric acid secretion inhibiting effect on conscious dogs Test compound Dose Effect (~mol/kg) (% inn-bit ion) I -- R R R4_ R5 Comment to the test results It is seen in Table 6 -that the tested compounds after oral administration exhibited a high inhibiting effect on the gastric secretion.
1) a substituted o-phenylenediamine was reacted with potassium etylxanthate (according to Org. Synch. Vol.
30, p. 56) to Norm a corresponding substituted 2-mercaptobenzimidazole;
, 2) a substituted 2-chloromethylpyridine was prepared by reacting the corresponding 2-hydroxymethylpyridine with thionylchlbride;
3) a substituted 2-chloromethylbenzimidazole was prepared by condensing the o-phenylenediamine with chloroacetic acid.
~L~Z6Z~3 The following examples illustrate how the compounds of the formula I or It can be incorporated in pharmaceutical compositions:
Example 51. Syrup A syrup containing 2% (weight per volume) of active substance was prepared from the following ingredients:
2-[2-(3,5-dimethyl-4-methoxy)pyridylmethylthio]--(5-acetyl-6-methyl)benzimidazole Hal 2.0 g Saccharin 0.6 g Sugar 30 0 g Glycerin 5.0 g Flavoring agent 0.1 g Ethanol 96% 10.0 ml Distilled water (sufficient to obtain a final volume of 100 ml) Sugar, saccharin and the acid addition salt were dissolved in 60 g of warm water. After cooling, glycerin and a solution of flavoring agents dissolved in ethanol were added.
To the mixture water was added to obtain a final volume of 100 ml.
The above given active substance may be replaced with other pharmaceutically acceptable acid addition salts.
Example 52. Tablets 2-~2-(3,5-dimethyl-4-methoxy)pyridylmethylthio]-(5-methoxy)-benzimidazole Hal (250 g) was mixed with lactose (175.8 g), potato starch (169.7 g) and colloidal silicic acid (32 g). The mixture was moistened with 10% solution of gelatin and was ground through a 12-mesh sieve. After drying, potato starch (160 g), I;
~226223 talc (50 g) and magnesium Stewart (5 g) were added and the mixture thus obtained was pressed into tablets (10.000), with each tablet containing 25 my of active substance. Tablets can be prepared that contain any desired amount of the active ingredient.
Example 53. Tablets Granules were prepared from 2-~2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-carbomethoxy-6-methhyl)benzimida-zone base (250 g), lactose (175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After drying, the granules were mixed with talc (25 g), potato starch (40 g), and magnesium Stewart (2.50 g) and were pressed into 10.000 tablets.
These tablets are first coated with a 10% alcoholic solution of shellac and thereupon with an aqueous solution containing succors (45%), gum Arabic (5%), gelatin (4%), and distaff (0.2%). Talc and powdered sugar were used for powdering after the first five coatings. The coating was then covered with a 66% sugar syrup and polished with a solution of 10% carnauba wax in carbon tetrachloride.
Example So. Solution for injection 2-[2-(3,5-dimethyl-4-methoxy)pyridylmethylthio]-(5-acetyl-6-methyl)benzimidazole hydrochloride (1 g), sodium chloride (0.6 g) and ascorbic acid (0.1 g) were dissolved in sufficient amount of distilled water to give 100 ml of solution.
This solution, which contains 10 my of active substance for each ml, was used in filling ampules, which were sterilized by heating at 120C for 20 minutes.
jar assay Biological tests Gastric acid secretion inhibiting effect on conscious dogs Test Method Chronic gastric fustily dogs (Heidenhain pouch dogs) were used. These dogs have been surgically provided with a gust-fig Connally in the pouch. Following a 4 weeks' recovery period after surgery, tests were performed once a week on each dog. Food and water were withdrawn 18 hours before each test.
Gastric acid secretion was induced by continuous in-Fusion of histamine at individual doses (100-300 ~mol/kg, h), resulting in sub maximal secretion of gastric acid. At least 2 hours after onset of stimulation, when the gastric acid secretion had reached a steady level, the test compounds in the form of free base suspended in 0.5% Methuselah ~90 HUG, 15.000, Dow Chum. crop.), were given orally by stomach tube. The gastric juice was collected by free flow from the gastric Connally in consecutive 30 minutes samples for 3 hours. The samples were titrated to pi 7.0 with 0.1 M Noah using a Radio-meter automatic titrator and the acid out-put was calculated.
The per cent inhibition of acid secretion was calculated by comparing in each dog the acid output in the tests to the acid output in control tests when only the vehicle was given.
The test results are given in Table 6 below.
.
Swiss Table 6 Gastric acid secretion inhibiting effect on conscious dogs Test compound Dose Effect (~mol/kg) (% inn-bit ion) I -- R R R4_ R5 Comment to the test results It is seen in Table 6 -that the tested compounds after oral administration exhibited a high inhibiting effect on the gastric secretion.
Claims (15)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical preparation containing as active ingredient a compound of the formula Ia or a therapeutically acceptable salt thereof, in which formula R1 and R2 are the same or different and each selected from the group consisting of H, -COOCH3, -COOC2H5, alkyl containing 1 to 7 carbon atoms, halogen, alkoxy containing 1 to 5 carbon atoms, and alkanoyl containing 1 to 4 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consist-ing of H, CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
provided that (a) at least one of R3, R4 and R5 is selected from the group consisting of CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radical R3, R4 or R5 is selected from the group consisting of OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
in association with a pharmaceutically acceptable carrier.
provided that (a) at least one of R3, R4 and R5 is selected from the group consisting of CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radical R3, R4 or R5 is selected from the group consisting of OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
in association with a pharmaceutically acceptable carrier.
2. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; R is H; and wherein R3, R4 and R5 are the same or different and selected from the group consisting of H, CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3.
3. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, CH3, Cl, Br, OCH3 and CH3CO; and wherein R3, R4 and R5 are the same or different and selected from the group consisting of H, CH3, OCH3, and OCH2CH2OCH3.
4. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, CH3, OCH3, and CH3CO; and wherein R3, R4 and R5 are the same or different and selected from the group consisting of CH3 and OCH3.
5. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3, R4 and R5 are the same or different and selected from the group consisting of H, CH3, OCH3, and OC2H5.
6. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3 is CH3; R4 is OCH3 and R5 is CH3.
7. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3 is H, R4 is OCH3 and R5 is CH3.
8. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3 is CH3, R4 is OCH3 and R5 is H.
9. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3 is H, R4 is OCH3 and R5 is H.
10. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3 is CH3, R4 is H and R5 is CH3.
11. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3 is H, R4 is OCH3, OC2H5, OCH2CH2OCH3 or OCH2CH2OCH2CH3, and R5 is H.
12. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1 and R2 are the same or different and each selected from the group consisting of H, COOCH3, COOC2H5, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 3 carbon atoms, and alkanoyl having 1 to 4 carbon atoms; and wherein R3 is CH3, R4 is CH3, and R5 is CH3.
13. A pharmaceutical preparation according to claim 1, con-taining as active ingredient a compound of the formula Ia wherein R1, R2, R3, R4 and R5 are combined as follows:
14. A pharmaceutical composition according to claim 1, con-taining as active ingredient a compound of the formula or a therapeutically acceptable salt thereof.
15. A process for preparing a pharmaceutical preparation containing as an active ingredient a compound of the formula Ia or a therapeutically acceptable salt thereof, in which formula R1 and R2 are the same or different and each selected from the group consisting of H, -COOCH3, -COOC2H5, alkyl containing 1 to 7 carbon atoms, halogen, alkoxy containing 1 to 5 carbon atoms and alkanoyl containing 1 to 4 carbon atoms; and R3, R4 and R5, which are the same or different, are each selected from the group consisting of H, CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
provided that (a) at least one of R3, R4 and R5 is selected from the group consisting of CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radi-cal R3, R4 or R5 is selected from the group consisting of OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
which comprises admixing said compound of formula Ia with a phar-maceutically acceptable carrier.
provided that (a) at least one of R3, R4 and R5 is selected from the group consisting of CH3, OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3, and (b) when two of R3, R4 and R5 are H, then the remaining radi-cal R3, R4 or R5 is selected from the group consisting of OCH3, OC2H5, OCH2CH2OCH3, and OCH2CH2OCH2CH3;
which comprises admixing said compound of formula Ia with a phar-maceutically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8104811 | 1981-08-13 | ||
| SE8104811-8 | 1981-08-13 |
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|---|---|
| CA1226223A true CA1226223A (en) | 1987-09-01 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000409351A Expired CA1226223A (en) | 1981-08-13 | 1982-08-12 | Pharmaceutical compositions containing benzimidazole compounds |
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| Country | Link |
|---|---|
| US (1) | US4746667A (en) |
| EP (1) | EP0074341B1 (en) |
| JP (1) | JPS5839622A (en) |
| KR (1) | KR880001714B1 (en) |
| AT (1) | ATE18765T1 (en) |
| AU (1) | AU556736B2 (en) |
| CA (1) | CA1226223A (en) |
| CS (1) | CS249124B2 (en) |
| CY (1) | CY1450A (en) |
| DD (1) | DD202876A5 (en) |
| DE (1) | DE3270116D1 (en) |
| DK (1) | DK362482A (en) |
| ES (3) | ES514947A0 (en) |
| FI (1) | FI822813L (en) |
| GR (1) | GR76267B (en) |
| HK (1) | HK2189A (en) |
| HU (1) | HU190408B (en) |
| IE (1) | IE54215B1 (en) |
| IL (1) | IL66340A (en) |
| IS (1) | IS1360B6 (en) |
| MY (1) | MY8700139A (en) |
| NO (1) | NO822686L (en) |
| NZ (1) | NZ201538A (en) |
| OA (1) | OA07182A (en) |
| PH (1) | PH18635A (en) |
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| ZA (1) | ZA825106B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
| DE3216843C2 (en) * | 1982-05-05 | 1986-10-23 | Ludwig Heumann & Co GmbH, 8500 Nürnberg | 3-Thiomethyl-pyridine derivatives, processes for their preparation and pharmaceuticals containing these compounds |
| SE8300736D0 (en) * | 1983-02-11 | 1983-02-11 | Haessle Ab | NOVEL PHARMACOLOGICALLY ACTIVE COMPOUNDS |
| IL71664A (en) * | 1983-05-03 | 1987-11-30 | Byk Gulden Lomberg Chem Fab | Fluoroalkoxy compounds,process for their preparation and pharmaceutical compositions containing the same |
| CA1259070A (en) * | 1983-07-01 | 1989-09-05 | Upjohn Company (The) | Substituted 2-¬monoannelated(3,4-,4,5-, and 5,6-)- pyridylalkylenesulfinyl|-benzimidazoles |
| US4575554A (en) * | 1983-12-05 | 1986-03-11 | The Upjohn Company | Substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles as gastric antisecretory agents |
| IL75400A (en) * | 1984-06-16 | 1988-10-31 | Byk Gulden Lomberg Chem Fab | Dialkoxypyridine methyl(sulfinyl or sulfonyl)benzimidazoles,processes for the preparation thereof and pharmaceutical compositions containing the same |
| SE8404065D0 (en) * | 1984-08-10 | 1984-08-10 | Haessle Ab | NOVEL BIOLOGICALLY ACTIVE COMPOUNDS |
| JPS6150979A (en) * | 1984-08-16 | 1986-03-13 | Takeda Chem Ind Ltd | Pyridine derivative and preparation thereof |
| JPS6150978A (en) * | 1984-08-16 | 1986-03-13 | Takeda Chem Ind Ltd | Pyridine derivative and preparation thereof |
| AU568441B2 (en) * | 1984-09-24 | 1987-12-24 | Upjohn Company, The | 2-(pyridylalkenesulfinyl) benzimidazole derivatives |
| JO1406B1 (en) * | 1984-11-02 | 1986-11-30 | سميث كلاين اند فرينش لابوراتوريز ليمتد | Chemical compounds |
| GB8526154D0 (en) * | 1985-02-06 | 1985-11-27 | Kotobuki Seiyaku Co Ltd | 2-substituted cyclo-heptoimidazoles |
| US4738975A (en) * | 1985-07-02 | 1988-04-19 | Takeda Chemical Industries, Ltd. | Pyridine derivatives, and use as anti-ulcer agents |
| AR243167A1 (en) * | 1985-08-24 | 1993-07-30 | Hoechst Ag | Substituted toluidines, process for their preparation, pharmaceutical compositions containing them and their use as gastric secretion inhibitors |
| FI90544C (en) * | 1986-11-13 | 1994-02-25 | Eisai Co Ltd | Process for Preparation as Drug Useful 2-Pyridin-2-yl-methylthio- and sulfinyl-1H-benzimidazole derivatives |
| ATE103912T1 (en) * | 1986-11-13 | 1994-04-15 | Eisai Co Ltd | PYRIDINE DERIVATIVES, THEIR PHARMACEUTICAL COMPOSITIONS, THEIR APPLICATION FOR THE MANUFACTURE OF MEDICINES OF THERAPEUTIC OR PREVENTIVE VALUE AND PROCESS FOR THEIR MANUFACTURE. |
| FI96860C (en) * | 1987-06-17 | 1996-09-10 | Eisai Co Ltd | An analogous method for preparing a pyridine derivative for use as a medicament |
| JP2718945B2 (en) * | 1987-06-17 | 1998-02-25 | エーザイ株式会社 | Pyridine derivative and therapeutic agent for ulcer containing the same |
| US5223515A (en) * | 1988-08-18 | 1993-06-29 | Takeda Chemical Industries, Ltd. | Injectable solution containing a pyridyl methylsulfinylbenzimidazole |
| AT394368B (en) * | 1990-08-07 | 1992-03-25 | Byk Gulden Lomberg Chem Fab | Process for the preparation of 3,4-dialkoxypyridines |
| WO1995011897A1 (en) * | 1993-10-29 | 1995-05-04 | Yoshitomi Pharmaceutical Industries, Ltd. | Pyridine compound and medicinal use thereof |
| US5504082A (en) * | 1992-06-01 | 1996-04-02 | Yoshitomi Pharmaceutical Industries, Ltd. | Pyridine compound and pharmaceutical compostions |
| EP0644191A1 (en) * | 1992-06-01 | 1995-03-22 | Yoshitomi Pharmaceutical Industries, Ltd. | Pyridine compound and medicinal use thereof |
| US5387600A (en) * | 1992-07-30 | 1995-02-07 | Fuji Photo Film Co., Ltd. | Treating arteriosclerosis using benzimidazole compositions |
| JP3559045B2 (en) * | 1994-06-10 | 2004-08-25 | ナウチノ−イススレドバテルスキ インスティテュト ファルマコロギイ ロスシイスコイ アカデミイ メディツィンスキフ ナウク | 2-mercaptobenzimidazole derivatives having pharmacological activity |
| US7230014B1 (en) | 1997-10-14 | 2007-06-12 | Eisai Co., Ltd. | Pharmaceutical formulation comprising glycine as a stabilizer |
| US6245913B1 (en) | 1999-06-30 | 2001-06-12 | Wockhardt Europe Limited | Synthetic procedure for 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole |
| DE10140492A1 (en) | 2001-08-17 | 2003-08-14 | Gruenenthal Gmbh | Hydrates of optionally substituted 2- (2-pyridinyl) methylthio-1H-benzimidazoles and process for their preparation |
| KR101376360B1 (en) | 2004-09-13 | 2014-03-20 | 다케다 야쿠힌 고교 가부시키가이샤 | Method and apparatus for producing oxidized compound |
| US20090143438A1 (en) | 2006-03-10 | 2009-06-04 | Arigen Pharmaceuticals, Inc. | Novel Pyridine Derivative Having Anti-Helicobacter Pylori Activity |
| WO2008057802A2 (en) | 2006-10-27 | 2008-05-15 | The Curators Of The University Of Missouri | Compositions comprising at least one acid labile proton pump inhibiting agents, optionally other pharmaceutically active agents and methods of using same |
| SI2103608T1 (en) | 2006-12-18 | 2012-12-31 | Arigen Pharmaceuticals, Inc. | Helicobacter pylori eradicating agent having inhibitory activity on gastric acid secretion |
| CA2716367C (en) | 2008-02-20 | 2015-05-26 | The Curators Of The University Of Missouri | Composition comprising a combination of omeprazole and lansoprazole, and a buffering agent, and methods of using same |
| JP5543432B2 (en) * | 2009-04-09 | 2014-07-09 | リンク・ジェノミクス株式会社 | Pyridinethio derivatives and pharmaceutical compositions containing them having anti-Helicobacter pylori activity |
| US8722026B2 (en) | 2010-01-06 | 2014-05-13 | Elc Management, Llc | Skin lightening compositions |
| AU2013267022B2 (en) * | 2010-01-06 | 2016-04-21 | Elc Management Llc | Skin lightening compositions |
| US8992897B2 (en) * | 2010-01-06 | 2015-03-31 | Elc Management Llc | Skin lightening compositions |
| IL307576A (en) * | 2016-09-14 | 2023-12-01 | Yufeng Jane Tseng | Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7112208A (en) * | 1971-09-04 | 1973-03-06 | ||
| SE418966B (en) * | 1974-02-18 | 1981-07-06 | Haessle Ab | ANALOGY PROCEDURE FOR THE PREPARATION OF COMPOUNDS WITH Gastric Acid Secretion Inhibitory Effects |
| SE416649B (en) * | 1974-05-16 | 1981-01-26 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF SUBSTANCES WHICH PREVENT Gastric acid secretion |
| IN148930B (en) * | 1977-09-19 | 1981-07-25 | Hoffmann La Roche | |
| SE7804231L (en) * | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
| US4359465A (en) * | 1980-07-28 | 1982-11-16 | The Upjohn Company | Methods for treating gastrointestinal inflammation |
| CH644116A5 (en) * | 1980-08-21 | 1984-07-13 | Hoffmann La Roche | IMIDAZOLE DERIVATIVES. |
| US4472409A (en) * | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
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1982
- 1982-07-16 ZA ZA825106A patent/ZA825106B/en unknown
- 1982-07-16 IL IL66340A patent/IL66340A/en not_active IP Right Cessation
- 1982-08-05 NO NO822686A patent/NO822686L/en unknown
- 1982-08-09 AU AU86978/82A patent/AU556736B2/en not_active Ceased
- 1982-08-09 NZ NZ201538A patent/NZ201538A/en unknown
- 1982-08-10 OA OA57774A patent/OA07182A/en unknown
- 1982-08-10 PH PH27697A patent/PH18635A/en unknown
- 1982-08-11 DE DE8282850166T patent/DE3270116D1/en not_active Expired
- 1982-08-11 AT AT82850166T patent/ATE18765T1/en not_active IP Right Cessation
- 1982-08-11 DD DD82242428A patent/DD202876A5/en not_active IP Right Cessation
- 1982-08-11 KR KR8203613A patent/KR880001714B1/en active Pre-grant Review Request
- 1982-08-11 IE IE1940/82A patent/IE54215B1/en not_active IP Right Cessation
- 1982-08-11 EP EP82850166A patent/EP0074341B1/en not_active Expired
- 1982-08-12 DK DK362482A patent/DK362482A/en not_active Application Discontinuation
- 1982-08-12 JP JP57139276A patent/JPS5839622A/en active Granted
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- 1982-08-12 HU HU822603A patent/HU190408B/en not_active IP Right Cessation
- 1982-08-12 CA CA000409351A patent/CA1226223A/en not_active Expired
- 1982-08-12 PT PT75420A patent/PT75420B/en not_active IP Right Cessation
- 1982-08-12 ES ES514947A patent/ES514947A0/en active Granted
- 1982-08-13 IS IS2749A patent/IS1360B6/en unknown
- 1982-08-13 GR GR69047A patent/GR76267B/el unknown
- 1982-08-13 CS CS826004A patent/CS249124B2/en unknown
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1983
- 1983-06-16 ES ES523344A patent/ES8500265A1/en not_active Expired
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1984
- 1984-04-30 ES ES532044A patent/ES532044A0/en active Granted
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1986
- 1986-12-10 US US06/939,274 patent/US4746667A/en not_active Expired - Fee Related
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1987
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1989
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