NO882001L - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICAL ACTIVE COMPOUNDS. - Google Patents

Abstract

Therapeutically active compounds down the formula. where X means -S- or. 15 means H. CH or CH 2. 2, and R is the same or different and has different meanings and can mean H, halogen, -CN, -CHO, -CF, R can have different meanings and i.a. mean H, Rog Rs equal or different and means H or alkyl Containing 1-5 carbon atoms, R may have different meanings and i.a. means H, alkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, alkenyloxy of 2-5 carbon atoms and physiologically acceptable salts of the compounds I, wherein X is S. Ingredient 1 pharmaceutical preparations.

Description

The purpose of the present invention is to provide new compounds, and therapeutically acceptable salts thereof, which inhibit exogenously or endogenously stimulated gastric acid secretion and provide gastrointestinal cytoprotective effects and thus can be used in the prevention and treatment of gastric

wound.

■j-Pejre-i-iggtrnde -opplrrrrn-e-ts-e—§-j-e-l-de-r— a-n-ven-de-l-se— of the connections

according to the invention or therapeutically acceptable salts deravy_ ^^u^m^ to inhibit gastric acid secretion as well as provide gastrointestinal cytoprotective effects in mammals and humans. More generally, the compounds according to the invention can be used to prevent and treat gastrointestinal inflammatory diseases in mammals and humans, including e.g. gastritis, peptic ulcer and duodenal ulcer. Furthermore, the compounds can be used for the prevention and treatment of other gastrointestinal diseases, where a cytoprotective and/or effect against the secretion of stomach acid is desirable, e.g. in patients with "gastrinoma", in patients with acute upper gastrointestinal bleeding and in patients with chronic and excessive ethanol consumption. The invention also applies to pharmaceutical preparations containing at least one compound according to the invention, or a therapeutically acceptable salt thereof, as active ingredient. In a further aspect, the invention relates to methods for the production of such new compounds and new intermediates in the production of the compounds according to the invention.

Benzimidazole derivatives used for inhibition of excretion

of stomach acid is described in G.B. patent no. 1,500,043 and 1,525,958,

in the U.S. patent 4,182,766, in Epo. patent no. 0.005.129 and in Belgian patent no. 890.024. Benzimidazole derivatives proposed for use in the treatment or prevention of certain gastrointestinal inflammatory diseases are described in Epo. Patent Application No. 0,045,200.

It has been found that the compounds with the formula

important information

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where

X is -S- or

R is H, CH, or C,H,-;

1 2 3 4

R , R , R and R , which are the same or different, are

(a) H

(b) halogen

(c) -CN

(d) -CHO

(e) -CF 3

(h) -CH(OR ) 2

(i)-(Z)n-A-D

(j) aryl,

(k) aryloxy

(1) alkylthio containing 1-6 carbon atoms

(m) -NO 2

(n) alkylsulfinyl containing 1-6 carbon atoms or where

1 2 3 4

(o) adjacent groups R , R , R and R together with the adjacent carbon atoms of the benzimidazole ring form a 5-, 6- or 7-membered monocyclic ring or a 9-, 10- or 11-membered bicyclic ring, which rings

may be saturated or unsaturated and may contain 0-3 heteroatoms selected from N and O, and which rings may optionally be substituted with 1-4 substituents selected from alkyl groups with 1-3 carbon atoms, alkylene radicals containing .4-5 carbon atoms

which give spiro compounds, or two or four of these substituents together form one or two oxo groups

12 3 4 whereby if R , R , R and R together with the nearby ones

carbon atoms in the benzimidazole ring form two rings, they can be

11 12 condensed with each other, in which formulas R and R , which are the same or different, are

(a) aryl,

(b) alkoxy containing 1-4 carbon atoms,

(c) alkoxyalkyloxy containing 1-3 carbon atoms in each

alkoxy part,

(d) arylalkoxy containing 1-2 carbon atoms in the alkoxy part, (e) aryloxy, (f) dialkylamino containing 1-3 carbon atoms in the alkyl parts,

or

(g) pyrrolidino or piperidino, optionally substituted with

alkyl containing 1-3 carbon atoms,

R is (a) alkyl containing 1-4 carbon atoms or

(b) the alkylene containing 2-3 carbon atoms,

Z is -0- or

n is 0 or 1,

A is (a) alkylene containing 1-6 carbon atoms,

(b) the cycloalkylene containing 3-6 carbon atoms, (c) the alkenylene containing 2-6 carbon atoms, (d) the cycloalkenylene containing 3-6 carbon atoms, or

(e) the alkynyl containing 2-6 carbon atoms,

D is (a) -CN

where

R 9 is (a) alkoxy containing 1-5 carbon atoms or

(b) dialkylamino containing 1-3 carbon atoms in the alkyl moieties,

m is 0 or 1,

r is 0 or 1,

Y is (a) -0-

(b) -NH-

(c) -NR<10->,

R<10> is (a) H

(b) alkyl containing 1-3 carbon atoms,

(c) arylalkyl containing 1-2 carbon atoms in the alkyl moiety

or,

(d) aryl,

5

R is (a) H or

0

(b) -C-R<14>,

where

14

R is (a) alkyl containing 1-6 carbon atoms,

(b) arylalkyl containing 1-2 carbon atoms in the alkyl part, (c) aryl,

(d) alkoxy containing 1-4 carbon atoms;

(e) aryloxy containing 1-2 carbon atoms in the alkyl part, (f) aryloxy,

(g) amino,

(h) mono- or dialkylamino containing 1-4 carbon atoms in the alkyl part(s), (i) arylalkylamino containing 1-2 carbon atoms in the alkyl part,

(j) arylamino,

6 8

R and R , which are the same or different, are

(a) H or

(b) alkyl containing 1-5 carbon atoms,

R is (a) H,

(b) alkyl containing 1-8 carbon atoms,

(c) alkoxy containing 1-8 carbon atoms;

(d) alkenyloxy containing 2-5 carbon atoms,

(e) alkynyloxy containing 2-5 carbon atoms,

(f) AlkoxyAlkoxy containing 1-2 carbon atoms in each Alkoxy group, (g) DialkylaminoAlkoxy containing 1-2 Carbon atoms in the alkyl substituents on the amino nitrogen and 1-4 Carbon atoms in the Alkoxy group, (h) Oxacycloalkyl containing an oxygen atom and 3-7

carbon atoms,

(i) oxacycloalkoxy containing 2 oxygen atoms and

4-7 carbon atoms,

(j) oxacycloalkylalkyl containing 1 oxygen atom and

4-7 carbon atoms,

(k) oxacycloalkyl alkoxy containing 2 oxygen atoms and 4-6 carbon atoms or,

6 7 7 8 (1) R and R , or R and R together with the nearby carbon atoms in the pyridine ring form a ring where 6 7 7 8 the part made up by R and R , or R and R , is

-CH=CH-CH=CH

-0-(CH2)p-

-CH2(CH2)p-

-0-CH=CH-

-NH-CH=CH-

where p is 2, 3 or 4 and the 0 and N atoms are always attached to position 4 in the pyridine ring,

and physiologically acceptable salts of the compounds I wherein X is

S,

with the proviso that

(a) not more than one of R , R and R is hydrogen,

(b) when X is SO, R5 is H and R6, R7 and R^ are selected only from hydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy and at the same time more than one of R<1>, R R and R is hydrogen , then R1, R^, R"^ and R4 cannot be selected only from alkyl groups,

halogen, alkoxycarbonyl, alkoxy or alkanoyl,

q) when X is S, R is H, alkanoyl or alkoxycarbonyl, and

6 7 8

R , R and R are only selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy and at the same time more 1 2 3 4 o 1-2 than one of R , R , R and R is hydrogen, so cannot R , R , R<3> and R 4 are selected only from alkyl groups, halogen, alkoxycarbonyl, alkoxy, alkanoyl, trifluoromethyl or NO 2 , (d) when X is SO, one of R 6 , R 1 and R 8 is H and the others two of R<6>, R<7> and R<8> are alkyl, and at the same time more than one of R,

R2, R3 and R4 are hydrogen, so can the radicals R1, R2, R3

4

and R which is not H is not selected only from alkyl, halogen, cyano,

(e) when R , R , R and R are H and at the same time R and R are H or CH3 and R<7> is OCH3, then R<1> is not CF3 when R<2> is H, and R<2>

is not CF3when R1 is H,

are effective as gastrointestinal cytoprotective agents and as inhibitors of gastric acid secretion in mammals and humans as noted above.

Illustrative examples of the various radicals in formula I are as follows. These illustrative examples will be applicable to different radicals depending on the number of carbon atoms prescribed for each radical. It is to be understood that the terms "alkyl" and "alkoxy" encompass linear, branched and cyclic structures.

Halogen: F, Cl, Br, I

Alkyl: CH3, C2H5, n-C3<H>7, i-C3H7, n-C4Hg, sec.-C4Hg,

iso.- C4Hg, tert.-C4Hg, n-C5Hllfn-Cgf^,

Alkylene: -CH2-, -CH2CH2~, -(CH2)3-, -CH^CH-, -(CH^-,

CH3

-(<CH>2)5-, -(<C>H2)6-

Illustrative examples of ring structures comprising R 1 , R 2 ,<3>or<4> are

R or R is

The radical -(Z)n~A - D includes the following radicals. The term (alkyl 1-3c) etc. means alkyl groups containing 1, 2 or 3 carbon atoms.

Further illustrative examples of the radicals of formula I are:

The compounds according to the invention which are sulfoxides (X=SO) have an asymmetric center in the sulfur atom, i.e. these compounds exist as two optical isomers (enantiomers), or if they also contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each of which exists in two enantiomeric forms. Such asymmetric carbon atoms can be the carbon atom to which R1"* is attached (when R<1>^ is different from H) or a carbon atom in any of the substituents.

Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and various mixtures of the two are within the scope of the present invention. It should be understood that all possible diastereomeric forms (pure enantiomers or racemic mixtures) are within the scope of the invention.

The compounds according to the invention which are sulfides (X=S) can be asymmetric due to two or more asymmetric carbon atoms, as described above. The various diastereomeric forms that are possible as well as the pure enantiomers and racemic mixtures are within the scope of the invention.

It should be noted that for all the compounds according to the invention where R 1 is H, the substituents R 1 and R 4 as well as R<2> and R<3> are considered to be equivalent. This is due to the tautomerism in the imidazole part of the benzimidazole nucleus which causes an equilibrium between the two possible ^-NH forms. This is illustrated by the following example: The invention takes into account that compounds which structurally deviate from formula I, after administration to a living organism can be converted into a compound of formula I and in this structural form exert their effect. Such compounds which differ structurally from compounds of formula I are included in the scope of the present invention.

Likewise, certain compounds of formula I may be metabolized to other compounds of formula I before exerting their action. Compounds according to the invention where X is S are thus assumed to exert their antisecretory and cytoprotective activities after metabolism to compounds where X is SO and compounds according to the invention where R is R<14>CO are assumed to exert antisecretory and cytoprotective activities after metabolism to compounds where R 1 is H. These considerations are also a further aspect of the invention.

Furthermore, it is believed that all compounds of formula I where X is SO after administration to a living organism exert their antisecretory and cytoprotective effects after metabolic or pure chemical conversion to other reactive compounds. The same is also the case for compounds of formula I where

X is S, but via initial conversion to the corresponding compounds of formula I where X is SO. These considerations as well as such reactive compounds are in and of themselves included within the scope of the present invention."

Compounds of formula I above can be prepared by the following methods:

a) Oxidation of a compound of formula I,

where X is S and R<15>, R1, R<2>, R<3>, R<4>, R<5>, R<6>, R7 and R8 have the meanings indicated, to give a compound of the same formula I where X is SO. This oxidation can be carried out using an oxidizing agent selected from the group consisting of nitric acid, hydrogen peroxide, peracids, peresters,

ozone, dinitrogen tetraoxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, t-butyl hypochlorite, diazabicyclo-(2,2,2)-octane-bromine complex, sodium metaperiodate, selenium dioxide, rangane dioxide, chromic acid, cerium ammonium nitrate, bromine, chlorine and sulphuryl- chloride. The oxidation usually takes place in a solvent where the oxidizing agent is present in a small excess in relation to the product to be oxidized.

The oxidation can also be carried out enzymatically using an oxidizing enzyme or microbiologically using a suitable micro-organism.

b) Reaction of a compound with formula

with a compound of formula in which formulas R<1>^, R1, R2, R<3>, R<4>, R^, R^, R7 and R8 are as 12 --■ defined previously and where one of Z and Z is SH and the other is a leaving group, to give a compound of formula I where X is S.

12

Examples of leaving groups Z and Z in compounds II

and III are halogens, preferably chlorine, bromine or iodine, acyloxy radicals, e.g. residues of strong organic sulphonic acids, e.g. of an arylsulfonic acid, e.g. tosyloxy or an alkylsulfonic acid, e.g. mesyloxy, alkyl mercapto groups, e.g. methylmercapto, alkylsulfinyl groups, e.g. methylsulfinyl and the like.

12

Z or Z can be a reactive esterified hydroxy group when they thus denote leaving groups. The esterification can be carried out with an organic acid or with an inorganic acid such as e.g. HC1, HBr or H2SC>4.

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 which is inert under the reaction conditions as described later. The reaction can further be carried out in the presence of a suitable base. Suitable bases include e.g. inorganic bases such as sodium or potassium hydroxide, sodium or potassium alkoxide, sodium or potassium hydride and the like, organic bases such as e.g. tertiary amines, e.g. triethylamine etc.

Suitable solvents for the above reactions include e.g. alcohols, preferably lower alkanols such as e.g. methanol and ethanol, mixtures of such alcohols with water, ethers, such as e.g. tetrahydrofuran, halogenated hydrocarbons, such as methylene chloride. Aprotic solvents such as e.g. ethers and halogenated hydrocarbons are necessary when sodium and potassium hydride are used.

The reaction between the compounds of formulas II and III can be carried out at a temperature between ambient temperature and the boiling temperature of the reaction mixture. However, it is preferred to carry out the reaction at a temperature at or near the boiling point of the reaction mixture for preparation.

..of a compound of formula I -where R^ is H.

c) Esterification of a compound of formula

where R15, R5, R6, R7 and R8 are as defined above and Y1, Y2,

3 4 1 2 3 4

Y and Y represent either R , R , R and R according to the above definition, respectively, or the groups (Z)n~A-COOH, COOH and (Z)-A-OH, whereby Z, n and A are as defined above,

9 10

by reaction with or the appropriate alcohol R OH, R<10>OH or carboxylic acid R COOH, to form a compound with

12 3 4

formula I containing a radical R , R , R and/or R which is one of the ester groups (Z)n~A-COOR<9>, COOR10 or (Z)n-A-OCOR<10>.

The esterification is carried out as an ordinary esterification, in the presence of

an acidic catalyst such as sulfuric acid, hydrochloric acid and p-toluenesulfonic acid and, if necessary, in the presence of an inert solvent such as e.g. toluene.

d) Acylation of a compound of formula

where R1^, X, R1, R2, R3, R4, R^, R7 and R8 are as defined above, by reaction with a suitable acylating agent (R 14CO)_=,

R COX 1 , whereby X is a leaving group such as e.g. C~l, N-. and p-nitrophenoxy, R a NCO, where R a is defined by the ratio

R<2>NH is equal to R<14>provided Ra is K when R<14>is amino, for

I<5>14 formation of a compound of formula I where R is R CO

as defined above.

The acylation is preferably carried out in the presence of a base such as e.g. triethylamine, f^CO^ and NaOH and with a solvent such as e.g. tetrahydrofuran, acetonitrile and water. If the benzimidazole part is asymmetrically substituted, both the N(1)- and N(3)-acyl derivatives are normally obtained, and therefore the two component parts must be separated from each other if necessary. This can be done by recrystallization or by extractive or chromatographic techniques.

e) Hydrolysis of a compound of formula

where X, R15, R1, R2, R3, R4, R<6>, R7 and R8 are as defined

above and Z 3 is a suitable N-protecting group such as e.g. alkanoyl, carboalkoxy and trimethylsilyl", to form a compound of formula I wherein R^ is H.

The alkanoyl group in Z<3> can have 1-6 carbon atoms and the carbo- alkoxy group 2-6 carbon atoms. The hydrolysis can be carried out in alkaline solution or in acidic solution, the latter mainly for compounds where X is S,

after which the obtained compound of formula I is optionally, when X is -S-, converted to a physiologically acceptable salt or oxidized to form a compound of formula I where X is -S0-.

Depending on the process conditions and the starting materials, end products of formula I where X is S either as the free base or as a salt are obtained. The final products of formula I where X -SO- is obtained as the free base. Both the free base and the salts of these end products are included within the scope of the invention. Thus basic, neutral or mixed salts can be obtained as well as hemi-, mono-, sesqui- or poly-hydrates. Acid addition salts of the new sulfides can on

in a manner known per se is converted to the free base by using basic agents such as e.g. alkali or by ion exchange.

The free bases obtained by the sulfides can also form salts

with organic or inorganic acids. At the productions

of acid addition salts, such acids are preferably used which form suitable therapeutically acceptable salts. Examples of such acids are hydrohalic acids, sulphonic acid, phosphoric acid, nitric acid and perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulphonic acids,

like for example. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid, maleic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanoic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthylsulfonic acid or sulfanilic acids, methionine, tryptophan, lysine or arginine.

These or other salts of the new sulphide compounds, such as e.g. picrates, can serve as scavengers for the obtained free bases. Salts of the bases can be formed, separated from the solution and then the free base can be recovered in greater purity from a new salt solution.

Obtained racemates can be separated according to known methods, e.g. recrystallization from an optically active solvent, use of microorganisms, reactions with optically active acids that form diastereomeric salts that can be separated, (e.g. separation based on different solubilities of the diastereomers), "acylation of the benzimidazole nitrogen (R<5>=H) or another nitrogen or oxygen atom in a substituent with an optically active activated carboxylic acid (eg, acid chloride), followed by chromatographic separation and deacylation.

Suitable optically active acids for salt formation are the L and D forms of tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphor sulphonic acid or quinic acid, and for acylation O-methylmandelic acid. Preferably, the most active part of the two antipodes is isolated.

As far as diastereomeric mixtures (racemate mixtures) are concerned, these can be separated into stereoisomeric (diastereomeric) pure racemates by means of chromatography or fractional crystallization.

The starting materials used in methods a and c-e are obtained from method b. The starting materials used for method b are in some cases known, but in most cases unknown. However, these unknown starting materials can be obtained using methods known per se.

Starting materials of formula II

where Z<1> is SH can be obtained from the corresponding o-phenylenediamine by reaction with potassium ethyl xanthate (Org. Synth. vol. 30, p. 56) or thiophosgene.

The compounds of formula II where Z<1> is alkylmercapto and alkylsulfinyl can be obtained from the above-mentioned compound or by simple S-alkylation with alkyl halide and by oxidation of the product from the S-alkylation.

The compounds of formula II where Z<1> is halogen or acyloxy can be obtained from compounds of the same formula where Z<1> is OH

by treatment with POCl^, POBr^ and the like or the appropriate acyl halide. The starting material where Z<1> is OH is obtained from the corresponding o-phenylenediamine by reaction with phosgene.

The desired o-phenylenediamines can be obtained from the corresponding substituted benzenes according to methods known per se, e.g. by the successive processes: nitration, reduction, acetylation, nitration, deacetylation and reduction, or from one of the intermediate steps just mentioned.

To obtain an o-phenylenediamine where R is different from H,

14, the acylation (at the group R CO) is preferably carried out in the nitro-aniline step.

Starting materials with the formula

where R 15 is H, can be obtained either from the correspondingly substituted

6 7 8

(R , R and R ) 2-methyl-substituted pyridine-N-oxide via a known exchange to the intermediate 2-pyridinyl methanol or

6 7 7

via a hydroxymethylation of the substituted (R , R and R ) pyridine to give the same intermediate, and then treatment of the 2-pyridinyl methanol with halogenating agents such as thionyl chloride or O-acylation agents such as e.g. p-toluenesulfonyl chloride to give compounds of formula III where Z 2 is respectively halogen and sulfonyloxy groups.

These leaving groups can then be replaced with alkyl mercapto groups by treatment with e.g. sodium alkylmercaptide, which can then be oxidized to an alkylsulfinyl group, or replaced with SH by treatment with e.g. NagH.

For the production of intermediate products with formula

where R<7> is alkoxy, alkenyloxy, alkynyloxy, alkoxyalkyloxy and dialkylaminoalkyloxy, is reacted with a compound of formula VII, where R7 is NO-, with the corresponding sodium alkoxide.

For the preparation of an intermediate of formula VII where R

7 7 8

R or R and R form a ring structure including an oxygen atom at position 4, a compound reacts analogously with

7 6 8

formula VII wherein R is NO 2 and R or R represents hydroxy-alkyl with a non-nucleophilic base.

The following intermediates A) and B) are included in the scope of the invention:

A) New compounds with formula

wherein R1a, R2a, R3a and R4a are the same or different and are selected from the groups

(a) H,

(b) alkyl containing 1-6 carbon atoms, including cycloalkyl, (c) alkoxyalkyl containing 1-3 carbon atoms in the alkoxy part

and 1-6 carbon atoms in the alkyl part,

(d) aryloxyalkyl containing 1-6 carbon atoms in the alkyl part,<!>_(e) arylalkyl containing 1-6 carbon atoms in the alkyl part,

(f) aryl,

(g) alkoxy containing 1-6 carbon atoms,

(h) AlkoxyAlkoxy containing 1-3 carbon atoms in the outer

part and 1-6 carbon atoms in the part closest to the aromatic ring, (i) aryloxyalkyl containing 1-6 carbon atoms in the alkoxy part,

(j) aryl alkoxy containing 1-6 carbon atoms in the alkoxy part

and

(k) aryloxy;

R is

(a) H,

(b) Alkoxycarbonyl containing 1-4 carbon atoms in the alkoxy part, (c) arylAlkoxycarbonyl containing 1-2 carbon atoms in the Alkoxy part, (d) Dialkylaminocarbonyl containing 1-4 carbon atoms in each

alkyl group, or

(e) arylaminocarbonyl,

-let.

and Z is

(a) SH,

(b) Cl or Br

and provided that no more than one of R<l>a, ~R2<a>, R<3a> and R<4a> is H,

are suitable intermediates for the preparation of compounds

12-^4 5 with formula I where respectively R , R , R , R and R have the same meaning

_.la _2a _3a _4a ^5a

as R , R , R , R and R according to method b.

B) New compounds with formula

where R and R are

(a) H or

(b) alkyl containing 1-5 carbon atoms, and

R is

(a) alkenyloxy containing 2-5 carbon atoms, or (b) alkynyloxy containing 2-5 carbon atoms, (c) oxacycloalkyl containing 1 oxygen atom and 3-7 carbon atoms, (d) oxacycloalkyl containing 2 oxygen atoms and 4-7

carbon atoms,

(e) oxacycloalkylalkyl containing 1 oxygen atom and 4-7

carbon atoms,

(f) oxacycloalkyl alkoxy containing 2 oxygen atoms and

4-6 carbon atoms,

or

6ci 7 3. 7ci 8 cl

(g) R and R or R and R together with the adjacent carbon atoms in the pyridine ring form a ring where the -\ -1 , . ^6a _.7a , , _7a n8a the part formed by R and R or R and R is

-CH=CH-CH=CH-

-^Vpa"

-CH2-(CH2)pa-

-0-CH=CH-

where pa is 2, 3 or 4 and the O atom is always attached to position R7a,

Yes

and Z is

(a) SH,

(b) halogen Cl, Br, I or

(c) OH

6 a 8 a

and provided that not more than one of R and R is H are suitable intermediates for the preparation of compounds of formula

6 7 8 6 a 7 a

In which respectively R , R and R have the same meaning as R R

and R 8 a, according to method b.

For clinical use, the compounds according to the invention are compounded into pharmaceutical preparations for oral, rectal, parenteral or other administration. The pharmaceutical preparation contains a compound according to the invention in combination with a pharmaceutically acceptable carrier. The carrier can be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Generally, the amount of active compounds is between 0.1 and 95% by weight of the preparation, between 0.2 and 20% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral administration. The typical daily dose of the active substance varies within a wide range and will depend on various factors such as e.g. the individual needs of each patient, the method of administration and the disease. Generally, oral and parenteral dosages will be in the range from 5 to 500 mg per day of active substance.

The invention is illustrated by means of the following examples.

Example 1

Method a. Preparation of 4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

m-chloroperbenzoic acid, 91% (0.53 g, 0.0028 mol) dissolved in CH2Cl2

(25 ml) and cooled to -^10°C was added with stirring to 4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (0.91 g, 0.0028 mol) dissolved in CH 2 Cl 2 (50 mL) while maintaining the temperature at + 5°C. Stirring was continued at 5°C for 5 minutes and then NaOH (0.34 g, 0.0085 mol) dissolved in water (25 mL) was added with vigorous stirring. The two phases were separated and the aqueous phase was washed with CH 2 Cl 2 (10 mL). More CH 2 Cl 2 (50 ml) was added to the aqueous phase, the pH was adjusted to 9.5 by the addition of 2M HCl and after stirring the phases were separated. The organic phase was dried (Na^O^), filtered and the solvent was evaporated to give an oil which was crystallized from CH 2 CN (15 ml) to give the desired product

(0.3 g, 32%), mp 161°C.

Example 2

Method a. Preparation of 4,6-dimethyl-5-heptyloxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

m-chloroperbenzoic acid, 91% (1.13 g^0.0059 mol) dissolved in CH2C12

"(25 ml) and cooled to -M0°C was added with stirring to

4,6-Dimethyl-5-heptyloxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (2.7 g, 0.0059 mol) dissolved in (50 m^ while the temperature was maintained at -^5°C.

Stirring was continued at 5°C for 10 minutes. The two phases

was separated and then NaOH (0.26 g, 0.0066 mol) dissolved in water (50 mL) was added with vigorous stirring. The two phases were separated. The organic phase was dried (Na 2 SO 4 ), filtered and the solvent evaporated to give a residual oil, which according to NMR comprised 30% unreacted starting material. The oil was chromatographed on a silica gel column using CH^OH-Cf^C^ 5:95

as eluent and then the product was recrystallized from CH 2 CN to give the desired product in crystalline form (0.85 g) 32%), mp 116°C.

For most of the compounds synthesized according to example 2, the chromatographic separation was not carried out.

Example 3

Method b. Preparation of 4,6-dimethyl-5-methoxy-2-[[(3,4-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole.

To 4,6-dimethyl-5-methoxy-2-mercapto-1H-benzimidazole (1.04g, 0.0050 mol) in methanol (50ml) was added (in the following order) NaOH (0.2g, 0 .0050 mol) dissolved in water (2 ml)

and 3,4-dimethyl-2-chloromethylpyridine hydrochloride (0.96 g, 0.0050 mol). The mixture was heated to reflux. NaOH

(0.2 g, 0.0050 mol) dissolved in water (2 ml) was added dropwise

show and then reflux treatment was continued for 3 hours. The mixture was poured onto ice-water (200 ml). Filtration and recrystallization from CH^CN gave the desired product (1.1 g,

67%). NMR data for the final product are given below.

Examples 4 and 5

Method d. Preparation of N<1->benzoyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-thio]-1H-benzimidazole and N<1-> benzoyl-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1H-benzimidazole

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]-thio]-

1H-benzimidazole (3.0 g, 0.009 mol) was dissolved in CH 3 CN (30 mL) and triethylamine (1.9 mL) was added. Benzoyl chloride (1.4 g, 0.010 mol) was added dropwise with stirring over 15 minutes. The mixture was then stirred at 55°C for 45 minutes. The solvent was evaporated and ether added to the residue under ice-cooling. The crystalline residue thus obtained was stirred with water, filtered off and dried to give a white crystalline product mixture (1.9 g, 48%) of the desired two products in a molar ratio of 75:25 (according to HPLC- analysis and NMR). NMR data for the final products are given below.

Example 6

Method d. Preparation of N-methoxycarbonyl-5,6-methylenedioxy-2-[[(4,methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole.

Chloromethyl formate (0.24 g, 0.0026 mol) dissolved in CH 2 Cl 2 (5 mL) was added dropwise to a stirred solution of 5,6-methylene-dioxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methylsulfinyl]

-1H-benzimidazole (0.80 g, 0.0022 mol) and triethylamine in CH 2 Cl 2 (10 mL). The mixture was then stirred at room temperature

for 19 hours. The CH 2 Cl 2 solution was washed with water, dried (MgSO 4 ) and the solvent was evaporated to give the desired product as an oil (0.06 g, 6%). NMR data for the final product are given below.

Example 7

Method d. Preparation of N<1->(N<1->phenylcarbamoyl)-5,6-methylene-dioxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl ]

-1H-benzimidazole.

Phenyl isocyanate (0.20 g, 0.00167 mol) dissolved in CH 2 Cl 2 (5 mL) was added dropwise with stirring to a solution of 5,6-methylenedioxy-2-[[(4-methoxy-3,5-dimethyl- 2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole (0.50 g, 0.00139 mol) and triethylamine (0.28 g, 0.00278 mol) in CH 2 Cl 2 (15 mL). The mixture was then stirred at room temperature for 50 hours. The CH 2 Cl 2 solution was washed with water, dried (MgSO 4 ) and the solvent was evaporated to give the desired product as an oil (0.03 g, 5%). NMR data for the final product are given below.

Example 8

Method e. Preparation of 4,6-dimethyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole.

N 2 -propionyl-4,6-dimethyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g, 0, 0023 mol) was heated in 1M NaOH (15 mL) for 1 hour under stirring and N-j atmosphere. The pH was adjusted to 9.5 by the addition of 2M HCl. Extraction with CH2C12, separation of the phases, drying

of the organic phase, evaporation of the solvent and recrystallization from CH 2 CN gave the desired product (0.30 g, 35%), mp 137°C.

The following table 2 provides data for further examples of compounds according to the invention.

Identifying data for compounds according to the invention

H NMR data for the compounds in Table 2 MHz^

NNR data for the compounds in Table 2. (continued )

NMR data for the compounds in Table 2. (continued)

(NMR data for the compounds in Table 2 (cont.)

NMR data for the compounds in Table 2. (continued)

NMR data for the compounds in Table 2. (continued)

Production of intermediate products

Example 11.

-Method A. Preparation of 4,5,7-trimethyl-2-mercapto-1H-benzimidazole.

2-nitro-3,4,6-trimethylaniline (10.2 g, 0.057 mol) was dissolved

- in 95% ethanol (900 ml) and hydrogenated in the presence of Pd/C catalyst until the theoretical amount of hydrogen was consumed (1 hour). The entire mixture was transferred to another flask and potassium ethyl xanthate (12.8 g, 0.080 mol) dissolved in water (12.5 mL) was added. The mixture was refluxed overnight, 2M NaOH (20 mL) was added and volatiles were evaporated. The residue was dissolved in methanol (300 mL) and the catalyst was filtered off.

of the solvent (200 ml) was evaporated. Water (100 mL) was added and the mixture was acidified with acetic acid (10 mL) dissolved in water (20 mL). The crystalline precipitate was filtered off, washed with water and dried under reduced pressure to give the desired product (7.2 g, 66%), NMR: 6(CDCl 3 ) 2.0 (s,3H), 2.05

(s, 3H), 2.1 (s, 3H), 3.3 (br.s, 1H), 6.5 (s, 1H).

Example 12.

Method B. Preparation of 4,6,7-trimethyl-5-methoxy-2-mercapto-1H-benzimidazole.

;A solution of 4-methoxy-3,5,6-trimethyl-1,2-phenylenediamine (1.8 g,

■0.010 mol) and triethylamine (2.1 g, 0.021 mol) in CHCl 3 (15 mL)

was added dropwise to a stirred solution of thiophosgene (0.60

g, 0.0052 mol) in CHCl 3 (5 mL). The mixture was then stirred at room temperature for 1 hour. Water (15ml) and triethylamine (0.5 g)

was added and the mixture was stirred for 1 hour. The precipitate was filtered off, washed with water and dried in air to give the desired product (0.96 g, 43%), NMR: 6(CDCl 3 ) 2.5(s, 3H) , 2.65

(s, 6H), 3.65 (s, 3H), 12.0 (br.s., 1H).

Example 13.

Method C. Preparation of 4-alkyloxy-3,5-dimethyl-2-pyridinyl methanol.

4-allyloxy-2,3,5-trimethyl-pyridine-N-oxide (4.0 g, 0.021 mol)

was added dropwise with stirring to acetic anhydride (8.0 mL, 0.062 mol) preheated to 80°C, giving a final temperature of 120°C. The mixture was then heated at 80°C for one hour. Methanol (15 mL) was added and the mixture was kept at 80°C for 15 minutes. The volatile substances were evaporated under reduced pressure. 10% HCl (20 mL) was added and the mixture was heated at 90°C for one hour and then cooled to room temperature. Excess 2M NaOH was added and the mixture was extracted with CH 2 Cl 2 . The organic phase was separated and dried. Volatiles were evaporated to give the desired product as an oil (3.0 g, 75%), NMR: 6(CDCl 3 ) 2.1 (s, 3H), 2.25 (s, 3H), 4.4 (m, 2H), 4.65 (s, 2H), 4.75 (s, 1H), 5.2-5.65 (m, 2H), 5.9-6.45 (m, 1H, 8 ,3 (p, 1H).

Example 14.

Method D. Preparation of 4-allyloxy-3,5-dimethyl-2-pyridinyl-methyl-chloride-hydrochloride.

Thionyl chloride (4.8 mL) dissolved in CH 2 Cl 2 (12 mL) was added dropwise to a stirred solution of 4-allyloxy-3,5-dimethyl-2-pyridinyl methanol (8.0 g, 0.041 mol) in CH 2 Cl 2 (80 mL) , while the temperature was kept below 6°C. The mixture was then stirred at room temperature for 45 minutes (final temperature 15°C). Isopropanol (2 ml) was added and the solution was heated briefly at 35°C. The solvent was evaporated and the crystalline residue was recrystallized from ethanol/ether to give the desired product (3.0 g, 29%), mp 115°C.

Pharmaceutical preparations containing a compound according to the invention as active ingredient are illustrated in the following examples.

BIOLOGICAL TESTS

I. Inhibitory effect in vitro on acid secretion in isolated

rabbit gastric glands.

Test method

Preparation of gastric gland

Isolated gastric glands from rabbit were prepared as described by Berglindh et al., Acta physiol. scan. 1976, 96, 150-159.

This method comprises vascular perforation of the rabbit stomach via the gastric arteries, scraping and fine division with scissors of the separated gastric mucosa and digestion with collagenase (0.1%,

Type I, Sigma Chemicals, St. Louis, MO., USA) at 37°C for 60-

90 minutes. The glands are then collected and filtered through nylon cloth to remove coarse fragments. The glands are then incubated at 37°C in a medium containing NaCl 132.4 mM,

KCl 5.4 mM, NaH 2 PO 4 5.0 mM, NaH 2 PO 4 1.0 mM, MgSO 4 1.2 mM,

CaCl 21.0 mM, glucose 10 mM, and 1 mg/ml rabbit albumin, pH 7.4.

Measurement of acid secretion

The acid secretion in the isolated gland preparation was recorded by measuring the uptake of<14>C-labeled aminopyrine in the glands as described by Berglindh et al., Acta physiol. scan. 1976. 97. 401-414. Accumulation of aminopyrine in the glands indicates gastric acid secretion within the glands. The standard media contained

-6 14 10 M C-aminopyrine (Amersham, Great Britain). After the incubation period, the glands were centrifuged, the supernatant liquid was removed and the glands were dried, weighed and dissolved in Soluene -350 (Packard, IU. USA). Samples of the supernatant and the glands were individually counted in a spark counter.

14

The accumulation of C-labelled aminopyrine in the glands was calculated as shown by Berglindh et al., Acta physiol, scand. 1976. 97. 403..

Trial protocol

Glands were incubated for 60 minutes in the presence of 5x10 histamine and the test compound to be investigated. The free base of the test compound was dissolved in methanol. The final concentration of methanol was 1% in the incubation medium, and this had no effect on the aminopyrine accumulation ratio. For each test compound, a complete dose-response curve was developed by testing duplicate doses in the concentration range

-7 -4 10 M to 10 M. The logarithm of that concentration (in M) of the test compounds which gives 50% inhibition of aminopyrine accumulation in the glands (IC₂q) is listed in Table 4 below.

II. Inhibitory effect in vivo on gastric acid secretion in

conscious dogs.

Test method

Dogs with chronic gastric fistula were used. These dogs are surgically equipped with a gastric cannula in the stomach and a fistula in the duodenum which is used for direct administration of the test compounds intraduodenal. After a 4-week post-surgery convalescence period, tests were performed once a week on each dog. Food and water were withdrawn 18 h before each test.

Gastric acid secretion was induced by continuous infusion of histamine in individual doses (100-300 nmol/kg, hour), resulting in submaximal secretion of gastric acid. At least 2 hours after the start of the stimulation, when gastric acid secretion had reached a stable level, the test compounds in the form of the

Cr)

the free base suspended in 0.5% Methocelw (90 HG, 15,000, Dow Chem. Corp.), given intraduodenal in doses from 1 to 87 rmol/kg. Gastric juice was collected by free flow from the gastric cannula in subsequent 30-minute samples for 3 hours. The samples were titrated to pH 7 with 0.1 M NaOH using a Radiometer automatic titrator and the amount of acid was calculated.

- Television

The percentage inhibition of acid secretion was calculated for each dog by comparing the amount of acid in the tests with the amounts of acid in control tests where only the vehicle was administered. The highest inhibitory effect for each compound is listed in Table 5 below.

Comment on the test results

It can be seen from table 4 and table 5 that the tested compounds strongly inhibit gastric acid secretion both in vitro and in vivo.

Claims (1)

1. Analogous method for the preparation of therapeutically active compounds of the formula where 0 X is -S- or -S-; or" C£H£7i R<1> ,R<2> ,R<3> andR<4> , which are the same or different, are (a) H (b) halogen (c) -CN (d) -CHO (e) -CF 3 0 (f ) -C -R 11 0 |Cg_L- -ø-c-R4-3-—\ VUU_^ .& H-(-0R<i3=> )^ -=\ (i) -(Z)n -A-D ( j ) ~«rryi ^v^L (k) iaj^oxy (1) alkylthio containing 1-6 carbon atoms (m) -NO 2 (n) alkylsulfinyl containing 1-6 carbon atoms or wherein (o) adjacent groups R <1> ,R<2> ,R<3> andR<4> together with the adjacent carbon atoms in the benzimidazole ring form a \ e ^ rt & p ^Two-membered monocyclic ring or a 9-y'll0- -or" Derived bicyclic ring which rings W jMm - " X O " fldpt^uLf-may be saturated or unsaturated and may contain /■O^—ireTeTrrartrcr1 -ffl&p—selected -fr-a—N— crg~ =&^^ and which rings can possibly be substituted with \ lr=^—su-b^t-i-tsæ*rt?ei^valg-.t—fj.a_aXk -y4^'r-u-p-per—nretb-4—3—k-a-rt-eB-a-t-onie-F-l alkylene radicals containing 4-5 carbon atoms giving spiro compounds , |cll-e <g> —_t.o_e.Ll.e-r -—-f-i-re—-a-v-, •d Ls s e s^ef^t-l-t-ue-n-t^-r—together— d-an-n-e-p—en—e-l-l-e-r—t-o—ok-s o g-r-u-p p e-r 0 ■ H.- C-^~,—whereby—creT"S"am— itA—,—R2-—R-3—'Ojg—R-4 together nTe' d" —d-e TnæTirTggcndo—k-a-^-øn- a-t-ønie-r i ^benzl-m-i-d-az'oTr"rrrge"n d"a*iTner tT5" -r-i-n-g-e^-4can—d-e—v-æ-re—konHeh s e r tTred—^hverandT'eT~i~h-v-i-l-k-e—f-OTml'e*r R-^ and-~R 1 2 t—& em-er— l-i-ke_eJJ^.r^£o-i^-kj.e^l4,ge.,-~e.^ R11 jur- (a) -as-jO, (b) alkoxy containing 1-4 carbon atoms, j~fe-)- a-l-k-ek-s-y-ai-koxy—i-n-neiio-ldende—1— -3—^karb_crn^rtro"nIeT in every-1 ^aiitok-s^de-l | f("d-) -a-r-y4-a-l-k-ok-s-y—i-nn-eh^Weiiae l~2~l?aTb^n^tome*r'~-i—a-l-kok-sy^" -ete-l-e4i-? | *j-(-e-)- ar-y-l-øk-s-y-H ^-(-f_)_ d-i-a-l-ky-1'amTno inlTérøXa^ende ~k a rb oma-t-øne-p—^& 1 ky 1 dr ejreji-e-,—e-l-l-erl (g) ^- py <-> r-ro-l-i-d-i-no—e-Hre-rj piperidino, optionally substituted with alkyl containing 1-3 carbon atoms; ^ R13 e-r— f-a-) aTKyl lnnénTn*a~enae T=^ T~karbonaTomeT-r^ei-i-e-r^ •CbJ a4-k-y4-en--i-n-neh<)J,d.e.nde=-2—3—kaT -b-øfl -art-om&r.; 0 Z is -O- or -C-; n is 0 or 1; A is (a) alkylene Containing 1-6 carbon atoms, (b) cycloalkylene Containing 3-6 carbon atoms, fr n y 1 £T3--_i.nrx-eh.oJ..d.en4 e--2—6—ka-rb o n-a-t-o ro e-r-, ^ y(-d -) cyki-oa-l-k-y-l-en—rmrehol-dende—3~ 6—ka-r-bona.t.ome-r--r-e-l-l-e-r-| ^-©0 alJiyjiyJ_eii_in,n.eholde'nde==-2-=.6—kanbona=empties=;-J There (a) -CN 0 (b) -C-R <9> , 0 (c) -(Y)m -(C)r - R <10> , where R <9> is (a) alkoxy containing 1-5 carbon atoms, or {(-b-)- d4-a-l-k-y-l-amliro -i-n-nefoo-l-dende——l—-3——ka-r-bona-t-ome-P -"--in- ^ l^ k.yj.-d.ei-en.e.j^ m is 0 or 1; r is 0 or 1; Y is (a) -0-, VW—-—=MH-H i(-e_) ,—.N.R- <10-> ;-! R <10> is (a) H, (b) alkyl containing 1-3 carbon atoms, aiiylal-k-yl—i-n-nehø-M-einie-!^ or (d) -ar-yl;> |^ vu^ R <5> is (a) (b) where R <14> is (a) alkyl Containing 1-6 carbon atoms, (j ) .α-uy-lamino; R <6> and R <8> , which are the same or different, are (a) H or (b) alkyl containing 1-5 carbon atoms; R <7> is (a) H, (b) alkyl containing 1-8 carbon atoms, (c) alkoxy containing 1-8 carbon atoms; (d) alkenyloxy containing 2-5 carbon atoms; (k) oxacycloalkyl alkoxy containing two oxygen atoms and 4-6 carbon atoms, or (1) R<k> and R<7> , or R<7> and R <8> together with the nearby carbon atoms in the pyridine ring form a ring where the part consisting of R <6> and R <7> , or R<6> andR <8> , is -CH=CH-CH=CH -0-(C H2 )p-p= ^.3 -CH2 (CH2 )p-r-l CH3^ where p is 2.3 |e-iie-r—and the 0- ^og-^l atoms are always attached to position 4 in the pyridine ring, and physiologically acceptable salts of compounds I where X is S, with the proviso that (a) not more than one of R^, R<7> and R<8> is hydrogen, (b) when X is SO, R<5> is H and R 6, R 7 and R <8> are selected only from hydrogen, methyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy and at the same time more than one of R <1> , R <2> , R <3> and R<4> are hydrogen, then R 1, R<2> , R<3> and R <4> cannot be selected only from alkyl groups, halogen, alkoxycarbonyl, alkoxy or alkanoyl, (c) when X is S, R <5> is H, alkanoyl or alkoxycarbonyl and r6 , R<7> and R <8> are selected only from hydrogen, methyl, ethyl, methoxy, ethoxy, methoxyethoxy and ethoxyethoxy and at the same time more than one of R<1> ,R<2> ,R 3 and R <4> is hydrogen, then R 1 , R 2 ,R<3> and R<4> cannot be selected only from alkyl groups, halogen, alkoxycarbonyl, alkoxy, alkanoyl, trifluoromethyl or NOg, (d) when X is SO, one of R <6> , R <7> and R <8> is H and the other two of r6 , R <7> and R <8> are alkyl, and at the same time more than one of R <1> , R 2 , R 2 and R 4 is hydrogen, then the radicals R <1> , R <2> , R<3> and R <4> which is not H, is not selected only from alkyl, halogen, cyano, (e) whenR<3> ,R<4> ,R 5 andR<15> are H and simultaneously R<6> andR<8> are H or CH3 and R<7> is 0CH3 , then R<1> is not CF3 when R 2 is H, and R <2> is not CF3 when R <1> is H, characterized by) oxidation of a compound of formula I, where X is S and R 15 , R 1 , R 2 , R 3 , R<4> , R<5> , R 6 , R<7> and R <8> have the meanings given above, to give a compound with the same formula I where X is SO;b) to react-a compound with the formula with a connection with the formula in which formulas ^rI^,R 1,R 2,R 3,R 4,R 5,R<6> , R <7> andR<8> are as defined earlier and where one of Z <1> and Z < 2> is SH and the other is a leaving group, to give a compound of formula I wherein X is S, d) acylation of a compound of formula where R <15> , X,R<1> ,R<2> ,R 3,R 4,R 5,R<6> ,R<7> andR<8> are as defined above, by reaction with an appropriate acylating agent (R <14> C0)20, R^COX1, whereby X <1> is a leaving group such as e.g. Cl, N3 and p-nitrophenoxy, R <a> NCO, whereby Ra is defined by the ratio R <a> NH is equal to R <14> , provided that Ra is potassium when R <14> is amino, to form a compound of formula I where R <5> is R <14> CO as defined above, e) hydrolyzing a compound of the formula where X,R 15,R 1,R 2,R<3> ,R 4,R 6,R<7> and R<8> are as defined above and Z <3> is a suitable N-protecting group such as e.g. alkanoyl, carboalkoxy, and trimethylsilyl, to form a compound of formula I wherein R<5> is H, after which the obtained compound of formula I, if desired, when X is -S-, is converted to a physiologically acceptable salt or oxidized to form a compound of formula I where X is -S0-.