DE3306503A1 - HETEROCYCLIC COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

14th description

The invention relates to heterocyclic derivatives having an effect on histamine receptors. The invention further relates to processes for the preparation of these heterocyclic ones Derivatives, pharmaceuticals containing said derivatives and the use of these derivatives in therapy.

It has now been found that certain heterocyclic derivatives

vate have potent activity as mercury antagonists. These compounds, which are described in more detail below, show, for example, an inhibition of gastric acid secretion when this is stimulated by way of histamine receptors (Ash and Schild, Brit. J. Pharmacol * Chemother, 1966, £ 2, 427). The ability of connections the inhibition can be demonstrated in the perfused rat stomach by the method according to GB-PS 1,565,966. the Method is modified by using sodium pentobarbitone (50 mgAg) as an anesthetic instead of urethane adorns. The ability of the compounds can also be demonstrated in conscious dogs equipped with Heidenhain pouches using the methods described by Black et al., Nature 1972, 236 . 385. The connections antagonize furthermore the effect of histamine on the frequency of contraction of the isolated right atrium of the guinea pig.

Compounds with histamine Hg blocking activity can be used in the treatment of conditions where it is beneficial to lower gastric acidity, particularly gastric and peptic ulcers. she can also be used for prophylaxis in surgical interventions and in the treatment of allergic and inflammatory conditions, of which are known

is that they are caused by histamine. For example, they can either be used alone or in combination used with other active ingredients in the treatment of allergic and inflammatory conditions of the skin the.

The invention relates to compounds of the formula (I)

R ₃ \ -, ( ^J >

N Λ

/ Λ R ₁ RN-AIk-QX- (CH-) Y (CH-) NH-C _n .B

wherein

R _{1 represents} hydrogen, C 1-4 alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl or alkyl which is substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl; and Rg is hydrogen or C 1-4 alkyl; or R ₁ and Rp together men with the nitrogen atom to which they are attached can form a 5- to 10-membered ring, which can be saturated or contain at least one double bond, which can be unsubstituted or which can be replaced by one or more C ₁ -alkyl groups, e.g. methyl groups, or a hydroxyl group can be substituted, and / or which can be a further heteroatom, namely oxygen or Sulfur, may contain;

Alk represents a straight or branched alkylene chain having 1 to 3 carbon atoms; Q stands for a furan or thiophene ring, which has been incorporated into the rest of the molecule by bonds in the 2- and 5-positions, the furan or thiophene ring optionally having a further substituent R ^ t adjacent to the group R ₁ RgN- AIk-, carries; or Q for a thiophene ring whose incorporation into the

Rest of the molecule by bonds in 2 and 4 positions has taken place, the thiophene ring optionally having a further substituent R ^, adjacent to the group

₁₂ carries, with the proviso that when the group R ₁ R ₂ NAIk is in the 4-position, then the group R ^ is in the 5-position; or Q is a benzene ring which has been incorporated into the remainder of the molecule by bonds in the 1- and 3- or 1- and 4-positions;

R ^ represents halogen or C., ^ -alkyl which can be substituted _{by hydroxy or C 1- ^ -AIkOXy;}

X represents oxygen, sulfur, -NH-, methylene or a bond;

Y represents oxygen, sulfur, methylene or a bond;

η has the value 0, 1, 2 or 3 and m is an integer from 2 to 5, with the provisos that (a) the total number of atoms in the chain X (CH ₂ ) _n ^v ( ^CH 2 ^ m ^a S ⁰¹¹ "is a number from 3 to 8, (b) if X and Y are oxygen or sulfur, then η is 2 or 3, (c) if X is -NH-, then Q is a benzene ring and Y stands for methylene or a bond, and (d) if Q stands for a benzene ring, X stands for oxygen and η has the value 1, then m can also have the value 1 and Y can also have the meaning -CHOR ₁ ^ , where R «. ^ is hydrogen or acyl; and

R 1 represents hydrogen, alkyl, alkenyl, aralkyl or C ₂ £ -alkyl which is substituted by hydroxy or alkoxy;

either A is N and B is CR ^; or A is CRe and B is N, where R ^ is either

(A) a straight-chain or branched C _2- ^ -alkyl group which is substituted by two or three hydroxyl, alkoxy or acyloxy groups, the di-

• a · ·

• ft Λ * I »·

hydroxyalkyl group a cyclic acetal or cyclic Ketal structure of the formula

-CH
ι C. CH-
1 I.
O I.
^ O " ^R 7

can form, where ρ has the value 0 or 1 and Rg and Rj , which can be identical or different, each represent hydrogen, a C 1-4 alkyl group or a phenyl group; or

(b) the group (CH ₂ ) QZ (CH ₂ ) Rq, in which q is an integer from 1 to 4 inclusive, r an integer Number from 1 to 6 inclusive, Z is oxygen or sulfur, and

if r has the value 1, R _{Q stands} for the group CH = CH ₂ "alkenyl or the group COR", where R "stands for water substance, hydroxy, alkyl, aralkyl, alkoxy or the group NR ₁₀ R ^ ₁ , where R _{10 is} hydrogen or alkyl and R _{11 is} hydrogen or alkyl, and

when r is an integer from 2 to 6, R _{8 has} one of the meanings given above or additionally

Meaning hydroxy, alkoxy, aryloxy or the group

NR ₁₂ R ₁ ^ may have, where R _{12 is} hydrogen or alkyl and R ₁ »is hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl, with the proviso that the total of q and r is preferably 6 or less ger is; or

(c) the group ( ^CH 2) _x ^s ( ^CH 2) y ^R 15 ^{t where x is} 1 or 2, y is 0 or 1 and R _{1 is} a heteroaryl group; or

(d) an aralkyl or heteroaralkyl group in which the alkyl part is substituted by hydroxy, alkoxy or acyloxy.

In the above formula (I) the term "alkyl ¹¹ as a group or part of a group means that the group is straight-chain or branched and, unless otherwise stated, has 1 to 6 carbon atoms and in particular 1 to 4 carbon atoms, such as methyl or ethyl The term "alkenyl" means that the group preferably has 3 to 6 carbon atoms. The term "cycloalkyl" means that the group has 3 to 8 carbon atoms. The term "aryl" as a group or Part of a group preferably denotes phenyl or substituted phenyl, for example phenyl, which is substituted by one or more C ₁ , -alkyl or C ₁ -alkoxy groups or halogen atoms, for example fluorine atoms. The term "acyl" means an aroyl, aralkanoyl or C ₁ _g -Al kanoyl group, for example acetyl, formyl, phenylacetyl or benzoyl. The term "heteroaryl" as part of a group within the definition of R ₁ means a 5- or 6-membered, monocyclic ring which has 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur fei, contains such as thionyl, pyridyl, furyl or thi azolyl. The heteroaryl ring can be unsubstituted or _{substituted by C 1} , -alkyl, C ₁ , -alkoxy, hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or halogen. The term "heteroaryl" as Part of a group in part (d) of the definition of Rc means a 5- or 6-membered, monocyclic ring which contains a heteroatom from the group consisting of oxygen, nitrogen and sulfur, for example thienyl, pyridinyl or furyl, the ring optionally being replaced by a C ₁ , alkyl group is substituted. The alkyl portion of a heteroaralkyl group is a straight or branched C 1-4 alkyl chain and the heteroaryl ring is attached to the alkyl portion through a carbon atom. The term "heteroaryl" within the definition of R ₁ C means a monocyclic see or bicyclic, unsaturated ring, the 5 to

Contains 10 atoms from the group consisting of carbon, oxygen, nitrogen and sulfur. If the heteroaryl ring is a monocyclic ring then it preferably contains 5 or 6 members. If it is a bicyclic ring then it preferably contains 9 or 10 members. Examples of such heteroaryl rings are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, triazinyl, oxazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, isoquinolyl, quino-IyI, indolyl or benzoxazolyl. The ring structure can be unsubstituted or substituted by one or more groups selected from C ₁ -alkyl, C ₁ -alkoxy or hydroxy.

One aspect of the present invention relates to compounds of the formula (I) in which R ₁ , R ₂ , R ,, Alk, Q, X, Y, η and m have the above definitions, but the further possibilities for m and Y, as given by proviso (d) are excluded, and A stands for N and B stands for CR ₅ or A stands for CRc and B stands for N, where Rc according to the above possibility (a) or according to the above possibility (b) is defined (with the exception that q can only have the value 1 or 2)

Another aspect of the invention relates to compounds of the formula (I) in which R ₁ , R ₂ , R ?, Alk, Q, X, Y, η and m have the above meanings, but the further possibilities for m and Y, which are given by condition (d) are excluded, and where A stands for N and B stands for CR ₅ or A stands for CR ₅ and B stands for N, where Rc has the meaning defined above under option (d).

Preferred compounds of the formula (I) are those in which

R ₁ for C _1-8 -AIlCyI (e.g. methyl, propyl, butyl or heptyl), C ^^ - alkyl which is substituted by a trifluoromethyl group, (e.g. 2,2,2-trifluoroethyl), Cp ^ -alkyl, the is substituted by a hydroxy or a di-C ₁ , -alkylamino group, (e.g. 3-hydroxypropyl or dimethylaminoethyl), C ^ η -cycloalkyl (e.g. cyclohexyl), C, ^ -alkenyl (e.g. allyl), phenyl-C ₁ , alkyl (eg benzyl) or a heteroaryl-C ₁ _, - alkyl group, wherein the heteroaryl ring contains a heteroatom, (eg 2-furylmethyl) group;

R _{2 represents} hydrogen or methyl; or R ₁ R ₂ N denotes a 5- to 8-membered ring which optionally contains a double bond, an oxygen atom or an alkyl (e.g. methyl) substituent (e.g. piperidino, morpholino, 4-methylpiperidino, pyrrolidino, hexamethyleneimines or tetrahydropyridines); Alk is methylene;

Q stands for a benzene ring which has been incorporated into the remainder of the molecule through bonds in the 1- and 3-positions; or a furan ring, which has been incorporated into the rest of the molecule by bonds in 2- and 5-positions and which optionally _{bears a substituent R ^, adjacent to the group R 1} R ₂ NAIk, where R ^ is C ^ - Alkyl (e.g. methyl); or a thiophene ring which has been incorporated into the remainder of the molecule by bonds in the 2- and 4-positions, the substituent R ₁ R ₂ NAIk being in the 2-position; with the provisos that when Q is a benzene ring as just defined, then X is a bond, η is 0, Y is oxygen and m is 3, 4 or 5, or X and Y are both Are oxygen and η and m are both 2, or X is oxygen, Y is CHOH and η and m are both 1; and, if Q is a furan or thiophene ring, as just defined, then X for a

ι ne bond and either Y for sulfur or CHp stands, η has the value 1 and m has the value 2, or Y is Is oxygen, η is 1 and m is 3;

R _{5 represents} hydrogen or alkyl (e.g. methyl); Rc represents a C 1-4 alkyl group which is substituted by two hydroxyl groups, or a 2,2-di-C ₁ -alkyl (e.g. dimethyl) -1,3-dioxolan-4-yl group; or

Rc stands for phenyl-C ₁ , -alkyl (e.g. benzyl) or heteroaryl-Cj, -alkyl (e.g. furylmethyl or pyridylmethyl), the alkyl part being substituted by hydroxy, C _1- ^ - alkanoyloxy (e.g. acetyloxy) or C _1-2 - Alkoxy (e.g. methoxy) is substituted; or

R _{5 represents} the group (CH ₂ ) Z (CH ₂ ) _r R ₈ , where q has the value 1, r has the value 1 to A if Z is oxygen, or r has the value 1 if Z is Is sulfur, and R _{Q is} hydroxy, the group -CHsCH ₂ »di-C ₁ , -alkylamino (eg dimethylamine) or the group CORq, where R« is C ₁ ^ -alkoxy (eg ethoxy) or the group NHR ₁₁ where R _{11 is} C ₁ , -alkyl (ζ.B. methyl); or

Rc represents the group (CH ₂ ) _X S (CH ₂ ) R ₁₅ , where χ has the value 1 and the heteroaryl group R _{15 is} tetrazolyl or thiadiazolyl, each of which is _{substituted by C 1-} ^ -AlKyI (eg methyl), or R _{15 is} furyl; more preferably y has the value 0 and R ₁ = is 1-methyl-1H-tetrazol-5-yl.

Within the preferred meaning of R = compounds in which R- is defined as follows may be viewed as a separate aspect of the invention.

Rc stands for a C ₂ _ _if -alkyl group which is substituted by two hydroxyl groups, or a 2,2-di-C ₁ -alkyl (eg-dimethyl) -1,3-dioxolan-4-yl group; or 35

Rc stands for a phenyl-C ₁ , -alkyl group (e.g. benzyl), in which the alkyl part is replaced by Cj ^ -alkanoyloxy (e.g. acetyloxy) or C _1-2 -AIkOXy (e.g. methoxy) or heteroaryl-C ^ j, -alkyl ( for example furylmethyl or pyridylmethyl) in which the alkyl moiety is substituted by hydroxy, Cj ^ -alkanoyloxy (for example acetyloxy) or C _1-2 -alkoxy (for example methoxy); or

Rc stands for the group (CH ₂ ) Z (CH ₂ ) _r R _Q , in which q has the value 1, r has the value 1 to 4, if 2 is acid

substance, or r has the value 1 if "Z is sulfur and R _{Q is} hydroxy, the group -CH = CH ₂ , di-C ₁ , -alkylamino (eg dimethylamino) or the group CORg, where Rq is C _1- ^ -AIkOXy (eg ethoxy) or the group NHR ₁₁ , where R _{11 is} C ₁ , -alkyl (ζ.B. methyl); or

R _{5 represents} the group (CHg) _x S (CH ₂ ^ ₁ E ^stands » ^wot) ei χ has the value 1 and the heteroaryl group R ₁ ^ is tetrazolyl or thiadiazolyl, which is _{substituted in each case by C 1} , -alkyl (eg methyl) or where R ₁ C is furyl; more preferably y has the value 0 and R ₁ ^ is 1-methyl-1H-tetrazol-5-yl.

A particularly preferred group of compounds has the formula (II)

Me I

/ Μ "

, QX (CH ₂ ) nY (CH ₂ ) m NH - <v

(II)

wherein

R ₁ R ₂ N represents di-C ₁ , -alkylamino (eg dimethylamino), furylmethylamino or pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleneimine ©, more preferably piperidino;

A stands for N and B stands for CR ₅ or A stands for and B stands for N, where

Re for Co ^ -alkyl, which is substituted by two hydroxyl groups, 2,2-di-C ₁ , -alkyl (e.g. dimethyl) -1,3-dioxolan-4-yl or (i-methyl-1H-tetrazol-5- yl) -thiomethyl, or

Rc for phenyl-CL »-alkyl (e.g. benzyl) or heteroaryl-Cj, -alkyl (e.g. furylmethyl or pyridylmethyl), the alkyl part being substituted by hydroxy, or phenyl-Cj, -alkyl (e.g. benzyl), the alkyl part is substituted by C 1-4 alkanoyloxy (for example acetyloxy) or C _1-2 alkOXy ( ² · ^Β · methoxy), or

R _{5 stands} for the group CH ₂ Z (CH ₂ ) _r R ₈ , where R _{Q stands} for hydroxy or di-C ₁ , -alkylamino (for example dimethylamines), Z stands for oxygen and r has the value A; or Rq is the group -CH = CHp or the group CORq, where Rq is C _{1-Z |} -Alkoxy (for example ethoxy), Z stands for oxygen or sulfur and r has the value 1; and where either Q is 1,3-benzene and X is a bond, η is 0, Y is oxygen and m is 3 or 4, more preferably 3; or X stands for oxygen, η has the value 1, Y stands for -CHOH- and m has the value 1; or where Q is 2,5-furan or 2,4-thiophene, X is a bond, Y is sulfur, η is 1 and m is 2; with the proviso that R 1, R ₂ N is DL-C ₁ , -alkylamino when Q is a furan or thiophene ring.

A particularly preferred group of compounds are compounds of the formula (II) in which

either R ₁ R ₃ N is dimethylamine, Q is 2,5-furan, X is a bond, Y is sulfur, η is 1 and m is 2; or R ₁ R ₂ N for dimethylamines or pyrrolidino, piperidino or hexamethyleneimines, more preferably piperidino,

Q is 1,3-benzene, X is a bond, Y is oxygen, η is O and m is 3 or 4, more preferably 3 »has; and

A is N and B is CR ₅ or A is CR ₅

and B is N if Rc is benzyl in which the methylene group is substituted by hydroxy, with the proviso that if Q is a furan ring, then preferably A is N and B is CR ₅ .

Particularly preferred compounds are the following:

5 - [[2 - [[[5 - [(Dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] amino] -1-methyl-a-phenyl-IH-1,2, 4-triazo1-3-methanol;

1-methyl-3 - [[(1-methyl-IH-tetrazol-5-yl) -thio] -methyl] -N- [3- [3- (i-piperidinylmethyl) -phenoxy] -propyl] - 1H-1,2,4-triazol-5-amine;

1-methyl-α-phenyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino J-1H-1,2,4-triazole-3-methanol; 4-methyl-α-phenyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino 3-4H-1,2,4-triazole-3-methanol;

1-methyl-5- [3 - [[(1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazole-3-ethane-1,2-diol;

a- [i-Methyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy ] -propyl] -amino] -1H-1,2,4-triazol-3-yl3-2-pyridinemethanol;

5 - [[2-Hydroxy-3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol;

5 - [[3- [3 - [(Dimethylamino) methyl] phenoxy3-propyi] amino] -1-methyl-α-phenyl-1H-1,2,4-triazole-3-methanol;

5 - [[2 - [[[5 - [(dimethylamino) methyl3-3-thienyl3-methyl3-thio 3-ethyl3-amino 3-1-methyl-a-phenyl-IH-1,2,4-triazole-3-methanol,

and their physiologically acceptable salts. 35

• ·

The invention includes the compounds of formula (I) in Form of the physiologically acceptable salts with inorganic and organic acids. Particularly suitable salts are e.g. the hydrochlorides, hydrobromides, sulfates, methanesulfonates, Acetates, maleates, succinates, citrates, tartrates, fumarates and benzoates. The compounds of formula (I) and their salts can also form hydrates. The hydrates of the compounds of formula (I) are also part of the invention viewed. The compounds of formula (I) may show tautomerism and the formulas are intended to all tautomers lock in. If optical isomers exist then the formulas are intended to include all diastereoisomers and optical Enantiomers include. It should be noted that the invention also includes the bioprecursors of the compounds of the formula

! 5 includes mel (I). The term “bioprecursors ¹ ” is to be understood as meaning compounds which have a different structure than the compounds of the formula (I), but which, after administration to the animal or human, are converted in the body to a compound of the formula (I) .

The compounds of formula (I), preferably in the form of a salt, can be for administration in any desired Way to be phrased. The invention therefore also encompasses medicaments which contain at least one compound according to claim 1 and which are adapted for use in human or veterinary medicine. Such medicines can conventionally using pharmaceutically acceptable carriers or excipients getting produced. If necessary, such drugs can also contain other active ingredients, e.g. H ^ antagonists, contain.

The compounds of formula (I) can therefore be used for ora-Ie, buccal, topical, parenteral or rectal administration be formulated. Oral administration is preferred.

For oral administration, the drug can be in the form for example tablets, capsules, powders, solutions, syrups or suspensions. These forms can be based on conventionally made with acceptable excipients For buccal administration, the doctor can neimittel are in the form of tablets or lozenges which have been formulated in a conventional manner.

The compounds of formula (I) can be used for parenteral administration by bolus injection or continuous Infusion can be formulated. Formulations for injection may be in unit dose form in ampoules or multi-dose containers with the addition of a preservative are presented. The drugs can be in such forms as suspensions, solutions or emulsions in oily or ingestion of aqueous vehicles. You can also use formulation auxiliaries, such as suspension, stabilization or Dispersants included. Alternatively, the active ingredient may be in powder form for reconstitution with a soluble carrier such as sterile, pyrogen-free water available for use.

The compounds (I) according to the invention can also be used in rectal forms, such as suppositories or retention enemas, are formulated, for example, conventional suppository bases, such as cocoa butter or other glycerides, may contain.

For topical application, the compounds of the formula (I) can be used in the form of ointments, creams, gels, lotions, Powders or sprays can be formulated in a conventional manner.

For internal administration, a suitable daily dose regimen of the compounds according to the invention is 1 to 4 Doses up to a total of 5 mg to 1 g / day, before

preferably 5 to 500 mg / day, which depends on the patient's condition in each individual case.

In the methods given below for the preparation of the compounds of the formula (I), it may be necessary at certain reaction stages to protect various reactive substituents in the starting materials for a certain reaction and then to remove the protective group. Such protection and the subsequent removal of the protecting group can be particularly relevant when R ₁ and Rp are hydrogen atoms and / or when R is an alkyl group which bears a hydroxy substituent and / or when Rc contains a hydroxy or amino group. Standard protection and cleavage methods can be used, for example amines being protected by the formation of a phthalimide group which is then cleaved off again by treatment with a hydrazine, for example a hydrazine hydrate, or a primary amine, for example methylamine.

In the following description of the processes which are used to prepare the compounds of the formula (I) or the intermediates suitable for the preparation, R ₁ to R ₁₅ , A, B, Alk, Q, X ₉ Y, Z, n, Unless otherwise stated, m, p, q, r, χ and y in the various formulas are the definitions which have been given in connection with the formula (I).

Compounds of the formula (I) in which Rc represents the group (CH ₂ ) Z (CH ₂ ) _r R ₈ or (CHg) _x S (CH ₂ )! I ₁₅ can be prepared by reaction of a trizole of the formula (I) where Rc is the group R ₅ ^a , where R ₅ ^{0 is} - (CH ₂ ) L or - (CHg) _x L, where L is a leaving group, such as halogen, mesyloxy or tosyloxy, with an anion Z ( CH ₂ ) _r Rg or S (CH ₂ ) R..C can be produced. The anion can be obtained from the corresponding alcohol by treatment with sodium

l or a strong base, such as sodium hydride, in the absence or presence of solvents, for example dimethylformamide, at a temperature in the range from 20 to 120 ⁰ C or from the corresponding thiol by treatment with a base, such as potassium or sodium carbonate, in the presence of a Solvent, for example acetone, can be generated at a temperature in the above range.

The intermediates of the formula (I) in which Rc is the group R _$ ^a , where R ₅ ^{11 is} - (CH ₂ ) L or - (CH ₂ J _x L), can be prepared by adding the corresponding compound, where Rc ^{a is} - (CH ₂ ) OH or (J) with an acid chloride such as thionyl chloride, methanesulfonyl chloride or p-toluenesulfonyl chloride.

The intermediates of the formula (I) in which Rr denotes the group R ₅ ⁰ , where R _c ^a denotes (CH ₂ ) OH or (CH ₂ J _x OH), according to the information in GB-A 2 047 238 and the EP-A-48555 can be prepared.

Compounds of formula (I) can also be prepared by cyclizing a suitable intermediate. Thus, compounds of the formula (I) in which Rc has a meaning other than a straight-chain or branched Coc-alkyl group which is substituted by two or three acyloxy groups, or a dihydroxyalkyl group which forms a cyclic acetal or cyclic ketal structure, or an aralkyl - Or heteroaralkyl group in which the alkyl part is substituted by an acyloxy group, or Y has a meaning other than CHOR ₁ I where R ^. Acyl means, has, by cyclization, a

Compound of Formula (III) _R

"· ¹⁶

RRNAIkQX (CH ₂ ) ^ (CH ₂ J _1n NH-C-NNHY ¹ (UI)

where R ₁ g is a group as defined in connection with R, V «is NCRc- ⁰ and Y ^{1 is} hydrogen

where V is oxygen or sulfur and R ₅ ^{0 is} a group as defined for Rc or a group which can be converted into such a group under the conditions of the cyclization reaction, or V ^{1 is} NH, R ₁ ^ is a group stands for R ¹ and Y 1 stands for CRc, where Y ^{n stands} for sulfur, oxygen or NH Y "

stands; or V ^{1 represents} sulfur or oxygen, Y ^{1 represents}

CRc and R ₁ ^ is a group defined for R 1;

or V ^{1 stands} for NR ₅ , R ₁₆ stands for hydrogen and Y »stands for CRc, where Y" has the above meaning, Y "

getting produced.

Thus, for example, in one embodiment of the cyclization process, a compound of the formula (I), in which A stands for N and B stands for the group CRc, by cyclization of a compound of the formula (IV)

N-CR ^C

Il 3

where V is sulfur or, more preferably, oxygen and U is two hydrogen atoms, in the absence or presence of a solvent, e.g. Hydrogen, such as toluene, a ketone such as acetone, or water, and optionally with heating, for example to a Temperature in the range of 50 to 90 ° C.

It can be advantageous to prepare compounds of the formula (IV) in situ in which U stands for two hydrogen atoms stands by a compound of formula (IV) wherein U is a divalent protecting group which can easily be obtained of two hydrogen atoms, e.g. a benzylidene group, can be split off, stands, produces with an acid, e.g. hydrochloric acid, preferably with heating, under such conditions normally a cyclization to give the corresponding compound of Formula (I) takes place.

In a further embodiment of the cyclization of the compounds of the formula (III), compounds of the formula (I) can be prepared by cyclizing a compound of the formula (V) R ₁₆

R ₁ R ₅ NAIkQX (CH ₅ LY (CH ₅ LNHCNNHC-R ₈ - (V)

V "Y"

wherein R ₁ g a is as R, defined group and either V is NH and Y is ^H sulfur, oxygen or NH, or V is sulfur or oxygen and Y 'stands for NH or R ₁₆ represents hydrogen, V ^{1 stands} for NR and Y "stands for sulfur.

If Y ^M stands for sulfur, then a tautomerism with the adjacent NH group is possible (ie -N = CRc), and the

SH

-SH group can be alkylated under standard conditions. The S-alkylated compound can also be used in the cyclization process.
30th

The cyclization can be carried out in such a way that the compound (V) (e.g. in the temperature range from 80 to 150 ⁰ C) in the absence or presence of a solvent (e.g. acetonitrile or dimethylformamide) or under basic conditions (e.g. using aqueous potassium hydroxide) heated.

In an expedient embodiment of this process, an intermediate of the formula (V) in which FLg is a group as defined for R ^{1, V 1 is} NH and Y "is oxygen; or FLg is hydrogen, V is NFU and Y "stands for oxygen, in situ by reaction of an aminoguanidine (VI)

YY16

(Vl)

with an acid RcCOOH or with an activated derivative thereof. Suitable activated derivatives are acid halides, e.g. acid chlorides, alkyl chloroformates, acid anhydrides including mixed anhydrides (e.g. acetic acid-formic anhydride), esters such as alkyl esters, orthoesters [e.g. Trialkyl orthoesters such as RcC (OEt),] and (i-alkyl-2-pyridinyl) esters, or derivatives, those formed from a coupling agent such as carbonyldiimidazole or a carbodiimide such as dicyclohexylcarbodiimide have been.

The acid and the aminoguanidine (VI) can be heated, wherein under such conditions the cyclization of the intermediate (V) takes place directly, whereby a Compound of formula (I) is obtained. In the case of an activated derivative, an aprotic solvent, e.g., tetrahydrofuran, can be used at temperatures from ambient to reflux temperature. if an acyl chloride is used as the activated derivative, the reaction can also be carried out in the presence of a base, e.g.

a tertiary amine such as pyridine, which can also be used as a solvent, can be carried out.

In general, intermediates of the formula (IV) can be prepared from the corresponding diamines by methods which are analogous to those as described in GB-A 2,047,238. Intermediate products of the

ι rael (V) can be prepared from suitable diamines to be prepared by methods that are analogous to those such as are described in GB-A 2023133 and EP-A 48,555th The aminoguanidines (VI) can be prepared according to GB-A 2 023 and EP-A 48555.

Compounds of the formula (I) in which Alk is CH ₂ , can be prepared by using an aldehyde of the formula (VII)

treated with an amine R ₁ R ₂ NH, for example in a solvent such as tetrahydrofuran, or an alkanol, for example ethanol, and then reduced, for example a Hydride reducing agents, such as an alkali or alkaline earth metal borohydride, for example sodium borohydride or lithium aluminum hydride, or hydrogen and a metal catalyst, such as palladium or platinum, are used. The reactions can be carried out at a temperature from 0 to 80 ⁰ C. leads to be.

The intermediates of the formula (VII) can be prepared from compounds of the formula (VIII)

WQX (CH ₂ ) _n Y (CH ₂ ) _m NH ₂ (VIII)

in which W is a protected aldehyde group, for example a cyclic acetal such as an ethylene acetal, can be prepared by methods analogous to those described for the preparation of compounds of the formula (I) from the corresponding diamine.

ι Compounds of formula (I) in which R _{c is} an aralkyl or heteroaralkyl group in which the alkyl part is substituted by hydroxy, can be prepared in such a way that the suitable aldehyde or the suitable ketone with an organolithium compound ArLi or one Grignard reagent ArMgHaI, where Ar is a suitable aryl, aralkyl, heteroaryl or heteroaralkyl group and Hai is halogen. The reaction may in a suitable solvent such as an ether, eg diethyl ether, tetrahydrofuran or a mixture thereof, at a temperature of from -70 to 5O ⁰ C, preferably -70 to 20 ^0C, for reaction with ArLi and from 0 to 50 ° C to be carried out for the implementation with ArMgHaI. The aldehyde or ketone starting material can be prepared as described in GB-A 2,075,007 and EP-A 48555.

Compounds of the formula (I) in which Re has one meaning has, in compounds of the formula (I) in which Rc has a different meaning, according to standard methods of inner transformation to be transformed.

Thus, compounds in which Re is a straight-chain or branched Cg.g-alkyl group which is substituted by two or three acyloxy groups, or in which Rc is an aralkyl or heteroaralkyl group in which the alkyl part is substituted by an acyloxy group, or Y is CHOR ₁ ^, where R ^^ has the meaning acyl, can be prepared in such a way that the corresponding alcohol is reacted with an activated derivative (for example an acid chloride or an acid anhydride) of a suitable acid. The reaction can be carried out at room temperature, if appropriate in the presence of a solvent (e.g. pyridine, tetrahydrofuran, acetone or dimethylformamide) and preferably in the presence of a base (e.g. pyridine,

ι triethylamine or an alkali metal carbonate, such as potassium carbonate) be performed.

Compounds in which Rc is a straight-chain or branched C ₂ C -alkyl group which is substituted by two or three alkoxy groups, or Rc is an aralkyl or heteroaralkyl group in which the alkyl part is substituted by an alkoxy group, can be selected from corresponding alcohol by treatment with a halogenating agent, eg thionyl chloride, and then reacting the resulting halogen compound with a suitable alkanol in the presence of sodium at a temperature in the range of 20 to 50 ⁰ C. Alternatively, the intermediate halogen compound can be treated with a suitable alkanol in a solvent such as dimethylformamide in the presence of a strong base such as sodium hydride at a temperature in the range from 20 to 100 ° C.

Compounds in which Rc is the group (CH ₂ ) _q Z (CH ₂ ) _r R3, where R _{Q is} NR ₁₂ R ₁ , and R ₁₂ and R _{1 are} each hydrogen or alkyl, can be selected from the corresponding alcohol, in which R _Q is hydroxy, by treatment with a reagent capable of _{converting the group R Q} into a leaving group, e.g. thionyl chloride, and then reacting the resulting compound of formula (I) in which R ^ is ( CH ₂ ) Z (CH ₂ ) L, where L is a leaving group, e.g. halogen, with ammonia or a suitable amine R ₁₂ R ₁₅ NH, preferably in a solvent such as an alkanol, e.g. ethanol, at a temperature im Range from 80 to 120 ⁰ C can be produced.

Compounds in which R _{8 is} the group NHR ₁₂ can be used in compounds in which R _{Q is} the group NR ₁₂ R ₁ ,

ι where R ₁ , either an acyl group or an aryl or alkylsulfonyl group, can be converted by reaction with an activated derivative of the appropriate carboxylic acid or sulfonic acid.

Suitable activated derivatives are e.g. acid halides, e.g. acid chlorides, alkyl chloroformates, acid anhydrides, including mixed anhydrides (e.g. acetic acid-formic anhydride ), and esters such as alkyl esters and orthoesters.

The reaction with an acid halide is preferably carried out in the presence of a base, e.g. an inorganic base, such as sodium hydroxide, or an organic base such as triethylamine or pyridine. The reaction with an alkyl chloroformate is preferably carried out in the presence a base such as potassium carbonate or triethylamine in a solvent such as dimethylformamide. The reaction with an acid anhydride is carried out in the absence or in the presence of a solvent such as pyridine, carried out.

Compounds in which R _{Q is} the group -CONR ₁₀ R ₁₁ can be prepared by reacting an activated derivative of the corresponding carboxylic acid in which Rq is the group -CO ₂ H, for example an ester, with ammonia or a suitable amine HNR ₁₀ R ₁₁ in a suitable solvent (e.g. an alcohol such as ethanol) at a

Temperature of 20 to 120 ⁰ C converts. 30th

Compounds in which R- represents the group -CH (CH ₉ ) CH-

-? ι <· Pi

OH OH

is, can be in the corresponding compounds in which Re is the group

-CH (CH ₉ ) ^ CH
ι ^ pi

«Β"

includes, by reaction with an aldehyde or ketone RgRyCO, e.g. acetone, in the presence of an acid, e.g. p-toluenesulphonic acid, being transformed. The reaction is carried out in the absence or presence of a solvent, e.g. Benzene, carried out at a temperature between room temperature and reflux temperature.

If the product of any of the above processes is a free base or an acid addition salt, in particular where a physiologically acceptable salt is required, the salt can be formed in a conventional manner. So For example, a generally applicable method for salt formation is to use appropriate amounts of the free Base and the acid in a suitable solvent, e.g.

B. an alcohol such as ethanol, or an ester such as ethyl acetate to mix. The conversion also closes the internal conversion of a salt of the compound of formula (I) into another salt.

The invention is illustrated in the examples. The temperatures are expressed in C ^0.

In the absence of any information to the contrary, Merck Kieselgel 60 (7734) was used as the silica gel for the column chromatography.

TLC refers to thin layer chromatography. This and the preparative chromatography were on silica carried out using one of the following solvent systems in the absence of any information to the contrary became:

System A: dichloromethane / ethanol / 0.88 ammonia (50: 8: 1);

System B: dichloromethane / ethanol / 0.88 ammonia (25: 8: 1);

System C: dichloromethane / ethanol / 0.88 ammonia (100: 8: 1);

System D: ethyl acetate / isopropanol / water / OJSe ammonia (25: 15: 8: 2);

System E: dichloromethane / ethanol / 0.88 ammonia (75: 8: 1). .

Production example 1

Methyl N- [2,3-diacetyloxypropionyl] -1-methyl-2- (phenyl methylene) -hvdrazine-carboximidothioate 13.8 g of diacetylglyceric acid were refluxed in 50 ml of thionyl chloride for 4 hours. The solution was evaporated in vacuo and azeotroped with 3 x 50 ml toluene to give an oil which was used without further purification. This oil was dissolved in 100 ml of dichloromethane and added dropwise to a solution of 15.4 g of methyl 1-methyl-2- (phenylmethylene) hydrazine carboximidothioate hydrochloride in 250 ml of dichloromethane and 19 ml of triethylamine, which had previously been dissolved for 0.5 h at 20 ° had been stirred, given. The reaction mixture was stirred for 15 h at 20 ° before the addition of water. The organic phase was separated, dried (MgSO 4) and evaporated to leave a residue (7 g) which was chromatographed using ether as the eluent to give the title compound as a yellow, waxy solid (4.6 g).

NMR (CDCl ₃ ): 2.16 (s, 1H), 2.2-2.7 (m, 3H), 4.58-5.45 (m, 3H), 6.57 (s, 3H), 7.67 (s, 3H), 7.85 (s, 3H), 7.93 (s, 3H).

Production example 2

Methyl-Nl ^ -acetyloxy-l ^ -iphenyl ^ acetyljj-i-methyl ^ - (phenylmethylene) -hydra2ln-carboximidothioate A solution of 11.35 g of acetyl chloride in 50 ml of dry ether slowly became a solution of 20 g of mandelic acid in 100 ml of ether added. The solution was refluxed for 3 days before evaporating to leave a light yellow oil. This oil was refluxed with 31 g of thionyl chloride for 3 hours. The thionyl chloride was removed by azeotropic distillation with toluene, leaving an oil (27.7 g) which was used without further purification.

This oil was dissolved in 50 ml of toluene and made into a suspension of 5.8 g of triethylamine and 6.9 g of methyl 1-methyl-2- (phenylmethylene) hydrazine carboximidothioate hydrochloride given in 180 ml of dry toluene. The reaction mixture was stirred at room temperature for 15 h and poured into water and extracted with ether. The organic extract was dried (MgSO ^) and evaporated to give the title compound as a creamy solid (6.3 g).

NMR (CDCl ₃ ): 2.25 (s, 1H), 2.3-2.8 (m, 10H), 3.95 (s, 1H), 6.7 (β, 3H), 7.8 ( s, 3H), 7.9 (s, 3H).

Production example 3

(a) 2- [2-Hydroxy-3- [3- (1-piperidinylmethyl) phenoxy] -

propvli-IH-isoindole-1.3- (2H) -dione

A mixture of 9.10 g of 2- (oxiranylmethyl) -1H-isoindole-1,3- (2H) -dione and 8.55 g of 3- (1-piperidinylmethyl) phenol Heated to 130 ° for 10 min under nitrogen. The resulting mixture was dissolved in 100 ml of chloroform, with Washed 2 × 25 ml of 1N sodium hydroxide solution, dried (MgSO ^) and evaporated to give the title compound as a gum (17.65 g).

TLC = system C; Rf 0.60.

(b) 1-Amino-3- [3 - [(i-piperidinylmethyl) phenoxy] -2- propanol

A solution of 17.6 g of 2- [2-hydroxy-3- [3- (i-piperidinylmethyl) phenoxy] propyl] -1H-isoindole-1,3- (2H) -dione and 2.5 g of hydrazine hydrate in 60 ml of ethanol was refluxed for 3 h heated. The resulting mixture was evaporated to a solid residue dissolved in 30 ml of 1N hydrochloric acid was suspended. The whole was filtered. The filtrate was made alkaline with an excess of potassium carbonate and extracted with 3 × 40 ml of isopropanol. The isopropanol extracts were dried (NagCO,) and turned into a Evaporated gum chromatographed using System A. Crystallization of the product from n-hexane / ether (20: 1) gave the title compound in

! 5 Form of colorless grains (7.7 g; mp. 74 to 76.5 °.

Production example 4

5 - [[3- (3-Formylphenoxy) -propyl] -amino] -1-methyl- <x-phenyl- 1H-1 ^^ - triazole ^ -methanol acetate (ester) A solution of 6.0 g of 3 - [3- (i, 3-Dioxolan-2-yl) phenoxy] propanamine and 11.33 g of compound A (compound A was methyl-N- [2-acetyloxy- [2- (phenyl ) acetyl]] - 1-methyl-.2- (phenylmethylene) hydrazine carboximidothioate) in 300 ml of toluene was stirred at 20 ° for 4 h.

30 ml of 5N hydrochloric acid was added and the mixture was stirred for a further 18 h at 20 °. The acidic layer was separated with toluene which was alkaline with 2N sodium carbonate washed and extracted with ethyl acetate. The extract was dried and evaporated, whereby a gum (9.0 g) based on activated alumina [Phase Separations Ltd. was obtained. (UGL)] under Using ether / ethyl acetate / methanol (50: 50: 1) as the eluent was chromatographed. In this way the title compound (1.4 g) was obtained as a foam.

TLC = system C; Rf 0.7.

example 1

1 -Methyl-5- [3- [[(1 -piperidinylmethyl) -phenoxy 3-propyl-3- amino1-1H-1 _t 2 _t A-trlazol-5-ethane-1,2-diol. Hemicitrate To a mixture of 2.69 g of methyl N- [2,3-diacetyloxypropionyl3-1-methyl-2- (phenylmethylene) hydrazine carboximidothioate in 100 ml of toluene was added 1.5 g of 3- [3- (i -Piperidinylmethyl) -phenoxy3-propanamine was added and the resulting solution was stirred for 16 h at 20 ° before 25 ml of 5N hydrochloric acid were added. The two-phase mixture was stirred vigorously for a further 16 hours. The acidic layer was separated and the toluene layer was washed with 2N hydrochloric acid. The combined acidic layers were washed with toluene before basifying and then saturated with solid sodium carbonate. The basic solution was extracted with ethyl acetate and the combined organic extracts were dried (MgSO ^) and evaporated. The residue (2.0 g) was chromatographed using chloroform / methanol (5s1) as the eluant to give a foam (0.6 g).

The foam was dissolved in 20 ml of ethyl acetate with the aid of 4 ml of methanol and with a stoichiometric Treated amount of citric acid in 20 ml of ethyl acetate under nitrogen. The suspension was 0.5 h at 20 ° stirred, the resulting compound collected and dried in vacuo to give the title compound as a white solid (0.53 g) was obtained; Mp. 73 to 74 ° (softening). TLC s system Dj Rf 0.46.

Example 2 (a)

5 - [[2-Hydroxy-3- [3- (1-piperidinylmethyl) -phenoxy3-propyl3- amino1-1-methyl-a-phenyl-1H-1 «2.4-triazole-5-methanol. A solution of 2.0 g 1-amino-3- [3- (i-piperidinylmethyl) phenoxy3-2-propanol and 3 »19 g methyl-N- [2-acetyloxy- [2- (phenyl) acetyl 33-1-methyl-2] - (Phenylmethylene) hydrazine carboximidothioate (compound A) in 60 ml of toluene was stirred for 4 h at 20 °. 9 ml of 5N hydrochloric acid were added,

ι and the mixture was stirred for 16 h at 20 ° and 15 min heated in a steam bath. The acidic layer was separated, washed with toluene, with a saturated aqueous layer Sodium bicarbonate solution made alkaline, washed with toluene and the aqueous layer with 5N sodium hydroxide solution made alkaline. The basic layer was extracted with 3 x 100 ml of hot A-methyl-2-pentanone and the Extracts were washed with brine, dried and concentrated in vacuo to a volume of 150 ml, whereby crystallization occurred. The resulting solid (1.2 g) was collected on a filter and Recrystallized from 2-propanol to give the title compound (0.63 g) as a white solid; Fp. 154 to 157 °. .

.15 Analysis for: ^C 25 ^H 33 ^N 5 ° 3

calculated: C 66.5% H 7.4% N 15.5% found: 66.2 7.2 15.2

Example 2 (b)

Similarly, 1.5 g of compound A and 0.74 g of 3- [3- (dimethylamino) methyl] phenoxy] propanamine were made, with the exception that the 4-methyl-2-pentanone extract was in vacuo was evaporated and that the residue (1.3 g) was chromatographed using system A as the eluent, 5 - [[3- [3 - [(dimethylamino) methyl! phenoxy3-propyl] amino] -1-methyl -ct-phenyl-1H-1,2,4-triazole-3-methanol hydrate (0.3 $ obtained as a white foam. Analysis for: C ₂₂ H ₂₉ N ₅ O ^ IH ₂ O

Calculated: C 63.9% H 7.59% N 16.9% found: 63.7 7.3 16.6

NMR (CDCl ₅ -DMSO) 2.4-2.92 (m, 6H), 3.05-3.33 (m, 3H), 4.4 (s, 1H), 4.65 (br.s, 1H), 5.58 (br.s, 1H), 5.98 (t, 2H), 6.4-6.75 (s + s + q, 7H), 7.85 (s, 6H), 8 , 0 (quint, 2H)

Example 2 (c)

In a similar way, 1.5 g of compound A and 0.99 g of 2- [2- [3- (1-piperidinylmethyl) phenoxy] ethoxy] ethanamine, with the exception that the aqueous phase was extracted with 6 50 ml of hot ethyl acetate with a pH of 7 and that using dichloromethane / ethanol / 0.88 ammonia (80: 8: 1) was chromatographed, i-methyl-cc-phenyl-5 - [[2- [2- [3- (i-piperidinylmethyl) -phenoxy] -ethoxy] ethyl] -aminoJ-1H-1, 2,4-triazole-3-methanol (0.45 g) obtained as a clear gum.

Analysis for: ^C 26 ^H 35 ^N 5 ° 3

Calculated: C 67.0796 H 7.5896 N 15.0496

found: 66.95 7.75 14.65

NMR (CDCl ₃ ): 2.4-2.9 (m, 6H), 3-3.35 (m, 3H), 4.3 (s, 1H), 5.6 (t, 1H), 5, 95 (m, 2H), 6.27-6.8 (m, 5H), 6.67 (2xs, 6H), 7.75 (m, 4H), 8.56 (m, 6H).

Example 2 (d)

5 - [[2 - [[[5 - [(dimethylamino) methyl I-3-thienyl] methyl] thio] ethyl] amino] -1-methyl-a-phenyl-IH-1,2,4 -triazole-3- methanol

A solution of 1.09 g of 4 - [[[2- (aminoethyl)] thio] methyl] -N, N-dimethyl-2-thiophene-methanamine and 2 g of compound A in 40 ml of toluene were stirred at 20 ° for 4 h. 5 ml of 5N hydrochloric acid were added and the mixture was stirred at 20 ° for 16 h and then heated on a steam bath for 10 min. The acidic layer was basified to pH 3 with sodium bicarbonate, washed with toluene, on alkalized to pH 9 with sodium carbonate and extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to give a gum which, using System C as an eluent was chromatographed to give the title compound (0.45 g) was obtained as a straw colored foam.

NMR (CDCl ₅ + IMSO): 2.35-2.85 (m, 5H), 3.01 (s, 1H) _f

3.12 (b, ^V 1H), 4.33 (s, 1H), 4.62 (t, 1H), 5.75 (br., 1H), 6.40 (s, 2H), 6.45 (s, 2H), 6.55 (s, 3H), 6.5-6.7 (t, 2H), 7.35 (t, 2H), 7.75 (s, 6H); TLC β system A; Rf 0.5.

Example 3

(a) 1-Methyl-N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] -3 - [(2-propenyloxy) methyl] -1H-1,2,4-triazole- 5 -amln

3.59 g of 1-methyl-5 - [[3- [3- (i-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazole-3-methanol were dissolved in 10 ml of thionyl chloride and the mixture was refluxed for 15 minutes. The orange solution was reduced under The pressure was evaporated, leaving a gum which was stirred in 35 ml of water at 20 °. Sodium bicarbonate and sodium carbonate (3g) were added and the suspension was stirred with ethyl acetate. The organic Phase was separated off, dried with sodium carbonate for 1 h and evaporated in vacuo, giving an oil became. This oil was dissolved in 10 ml of allyl alcohol and made into a solution of 0.3 g of sodium in 8 ml of allyl alcohol given. The reaction mixture was heated on a steam bath for 6 h, poured into water and washed with ethyl acetate extracted. The organic phase was extracted with 2N hydrochloric acid. The acidic extract was made with potassium carbonate basified to pH 9 and extracted with ethyl acetate. Evaporation of the organic extracts provided an oil (1.1 g) made using dichloromethane / ethanol / ammonia (70: 8: 1) was chromatographed as the eluent to give the title compound as Oil (0.4 g) was obtained.

Analysis for: ^C 22 ^H 33 ^N 5 ° 2

calculated: C 66.14% H 8.33% N 17.53% found: 65.64 8.46 17.44 TLC = system C; Rf 0.4.

ι (b) In a similar manner from 3.59 g of 1-methyl-5 - [[3- [3- (i-piperidinylmethyl) phenoxy] -propyl] -amino] -iH-1 _f 2, 4-triazole-3-methanol and 10 ml of thionyl chloride and subsequent addition of a solution of 0.3 g of sodium in 10 g of butane-1 _t 4-diol to give the 4 - [[i-methyl-5 - [[3- [3 - (i-piperidinylraethyl) -phenoxy] -propyl] -amino-1H-1,2,4-triazol-3-yl] -methoxy] -butanol compound with ethanol (2: 1) (0.87 g) . Analysis for: C ₂₃ H ₂₇ N ₅ O ₃ I ^ C ₂ H ₅ OH

calculated: C 63.4O # H 8.87 # N 15.41 # found: 63.12 8.81 15.56

NMR (CDCl ₃ ): 2.8 (t, 1H), 3.0-3.3 (m, 3H), 5.4 (br.t, 1H), 5.62 (s, 2H), 5, 95 (t, 2H), 6.4 (m, 6H), 6.5 (s, 3H), 6.6 (s, 2H), 7.0 (br., 1H), 7.6 (m, 4H), 7.9 (m, 2H), 8.1-8.7 (m, 10H).

Example 4 (a)

Ethyl - [[[1-methyl-5 - [[3- [3- (1-piperidinylmethyl) -phenoxy] -propyl] -amino] -1H-1,2,4-triazol-3-yl] -methyl] thio] acetate hemihydrate

7.2 g of 1-methyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazole-3-methanol (Compound B) were added dissolved in 30 ml of thionyl chloride at 20 ° and refluxed for 15 min. The cooled solution was evaporated in vacuo and the oil was dissolved in 30 ml of water. It was carefully made alkaline with solid sodium bicarbonate and 3 g of sodium carbonate was added. The mixture was extracted with ethyl acetate. The extract was dried (Na ₂ CO ₃ ; 1h) and evaporated to give an oil

was obtained.

The resulting oil was dissolved in 100 ml of acetone and heated under reflux for 16 h with 2.76 g of anhydrous potassium carbonate and 2.4 g of ethyl mercaptoacetate. The mixture was partitioned between aqueous potassium carbonate solution and ethyl acetate. The ethyl acetate extract was dried

net and evaporated. The residue (5.1 g) was chromatographed using System E as the eluant, giving the title compound (2.9 g) as a light yellow oil was obtained.

Analysis for: C ₂₅ H ₃₅ N ₅ O ₃ S.! / 2H ₂ O

Calculated: C 58.7 # H 7, 1% N 14.996 found: 58.7 7.6 14.8

NMR (CDCl ₃ ): 2.75 (dd, 1H), 3-3.33 (m, 3H), 5.45 (t, 1H), 5.66-6 (q + t, 4H), 6, 23-6.7 (s + s + q + s + s, 11H), 7.61-7.86 (m, 6H), 8.45 (m, 6H), 8.7 (t, 3H).

The following compounds were similarly prepared from Compound B and the corresponding starting materials manufactured.

4 (b) 1.41 g of Compound B, 0.506 g of 5-mercapto-i-methyltetrazole, and 0.54 g of potassium carbonate, with the exception that the mixture was chromatographed using System C to give an oil (1.0 g ), which was dissolved in ethyl acetate and treated with an excess of ethereal hydrochloric acid, gave 1-methyl-3 - [[(i-methyl-1H-tetrazol-5-yl) -thio] -methyl] -N- [ 3- [3- (ipiperidinylmethyl) -phenoxy3-propyl3-1H-1,2,4-triazol-5-amine dihydrochloride sesquihydrate (0.6 g) as a white powder; Fp .: slow softening above 40 °.

NMR (D ₂ O): 2.6, 2.9-3.0 (m, 4H), 5.7-5.9 (m, 6H), 6.04 (s, 3H), 6.4- 6.6 (s + m, 7H), 7.05 (t, 2H),

7.9-8.6 (m, 8H).
30th

4 (c) 1.41 g of Compound B, 0.52 g of 2-mercapto-5-methyl-1,3,4-thiadiazole, and 0.54 g of potassium carbonate, except that the mixture is chromatographed using System C. gave 1-methyl-3 - [[(5-methyl-1,3,4-thiadiazol-2-yl) -thio3-methyl3-N- [3- [3- (i-piperidinylmethyl) -phen-

l oxy] propyl] -1H-1,2,4-triazol-5-amine (0.62 g) as a white Powder; Mp 63 °; at 72 to 74 ° melting with softening.

Analysis for: ^C £ 2 ^H 31 ^K

Calculated: C 55.896 H 6.6 # N 20,

found: 55.9 6.7 20.7

Example 5

3 - [[4- (Dimethylamino) butoxy] methyl] -1-methyl-N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] -1H-1,2,4-triazole- 5-amine

0.5 g of 4 - [[1-Methy1-5 - [[3- [3- (1-piperidinylmethyl) -phenoxy] -propyl] -amino J-1H-1,2,4-triazol-3-yl] Methoxy] butanol were dissolved in 10 ml of thionyl chloride and stirred at 20 ° for 1.5 h. The solution was evaporated in vacuo and the residue dissolved in 20 ml of water and made alkaline with solid sodium bicarbonate and sodium carbonate (^ g). The mixture was extracted with ethyl acetate and the extract dried (Na ₂ CO; 1 h). It was evaporated and the remaining oil dissolved in ethanolic dimethylamine (3396, 15 ml) and the solution heated in an autoclave at 80 ° C. for 8 h. The solution was evaporated and the remaining oil (0.3 g) chromatographed using System A as the eluant to give the title compound (0.2 g) as a light yellow oil.

NMR (CDCl ₃ ): 1.74 (dd, 1H), 3-3.32 (m, 3H), 5.48 (t, 1H), 5.58 (s, 2H), 5.86 (2, 2H), 6.24-6.64 (s + s + m, 9H), 7.48-8 (m + s, 14H), 8.21-8.68 (m, 10H) ..

TLC = system B; Rf 0.55.

Example 6

a- (2-Furanyl) -1-methyl-5 - [[3- [3- (1-piperidinylmethyl) - phenoxv1-propvl1-amino1-1H-1.2 _t 4-triazol-3-roethanol n-butyllithium (1, 55 M in n-hexane, 5.96 ml) was added dropwise to a stirred solution of 0.61 ml of furan in 20 ml of anhydrous tetrahydrofuran under nitrogen at -40 °.

ι give. The stirred solution was allowed to warm slowly to 20 °, refluxed for 3 h and added dropwise at 0 ° to a solution of 1.0 g of 1-methyl-5-C [3- [3- (1-piperidinylmethyl) phenoxy] -propyl] -amino 3-1H-1,2,4-triazole-3-carb-5 oxaldehyde in 10 ml of tetrahydrofuran. The resulting solution was stirred at 20 ° for 18 h. 20 ml of water was added and the mixture was concentrated. It was extracted with ethyl acetate and the extract dried and evaporated. The remaining oil (0.9 g) was chromatographed using System E to give the title compound (0.16 g) as a brown oil. NMR (CDCl ₅ ): 2.6 (m, 1H), 2.76 (t, 1H), 3.06-3.08 (m, 2H), 3.23 (m, 1H), 3.65 ( m, 2H), 4.25 (s, 1H), 5.48 (t, 1H), 5.86 (t, 2H), 6.38 (q, 2H), 6.45 (s, 3H), 6.56 (s, 2H), 7.62 (m, 4H), 7.88 (quint, 2H),

8.36 (m, 6H)
TLC β system A; Rf 0.7.

B ice ό ie 1 7

3- (2,2-Dimethyl-1,3-dioxolan-4-yl) -1-methyl-N- [3- [3- (ipiperidinylmethyl) phenoxy] propyl] -1H-1,2 _f 4- triazol-5- amine

A solution of 0.08 g of 1-methyl-5 - [[3- [3- (1-piperidinylmethyl) -phenoxy] -propyl] -amino 3-1H-1,2 ^ -triazole-S-ethane-1, 2-diol, 2.0 ml of 2,2-dimethoxypropane and 0.03 g of 4-toluenesulfonic acid in 10 ml of acetone were stirred at 20 ° for 16 h. The mixture was evaporated and partitioned between 2N sodium carbonate and ethyl acetate. The ethyl acetate extracts were dried and evaporated. The remaining oil (0.07 g) was chromatographed using System E as the eluant to give the title compound (0.025 g) as an amber gum. NMR (CDCl ₃ ): 2.78 (t, 1H), 3.08-3.23 (m, 3H), 4.96 (dd, 1H), 5.48 (t, 1H), 5.72 ( dd, 1H), 5.80 (t, 1H), 5.88 (t, 2H), 6.37 (q, 2H), 6.46 (s, 3H), 6.55 (s, 2H), 7.62 (m, 4H), 7.87 (m, 2H), 8.4-8.6 (m, 9H)

• ·

48
TLC = system D; Rf 0.7.

Example 8

N-methyl - [[[1-methyl-5 - [[3- [3- (ΐ-piperidinylmethyl) -phen-5 oxy] -propyl] -amino] -1H-1,2,4-triazole-3- yl3-methyl] thio3- acetamide

A solution of O, A g of ethyl - [[[i-methyl-5 - [[3- [3- (ipiperidinylmethyl) -phenoxy] -propyl] -amino] -1H-1,2,4-triazole-3- yl] methyl] thlo] acetate in ethanolic methylamine (33%, 20 ml) under nitrogen was refluxed for 30 h, cooled and evaporated in vacuo. The residue was dissolved in 20 ml of 2N hydrochloric acid and washed with ethyl acetate. The acidic layer was basified with potassium carbonate, extracted with ethyl acetate and the extract dried and evaporated to give an oil (0.28 g) which was chromatographed using System E as the eluent to give the title compound (0.13 g ) was obtained as an oil. NMR (CDCl ₃ ): 2.46 (br.s, 1H), 2.79 (t, 1H), 3.07 (m, 2H),

3.22 (dd, 1H), 5.34 (t, 1H), 5.85 (t, 2H), 6.4

(s + q, 4H), 6.46 (s, 3H), 6.56 (s, 2H), 6.72 (s, 2H), 7.19 (d, 3H), 7.63 (m, 4H), 7.86 (m, 2H), 8.42 (m, (4H), 8.57 (m, 2H)
TLC = system A; Rf 0.7.

Example 9

1 -Methyl-a-phenyl-5 - [[3- [3- (1-piperidinylmethyl) -phenoxy] -propyl] -amino3-1H-1 ^^ - triazole-S-methanol compound with fumaric acid and ethyl acetate ( 40; 56; 5) 0.72 g of 3- [3- (i-piperidinylmethyl) phenoxy] propanamine and 1.1 g of methyl N- [2-acetyloxy- [2- (phenyl) acetyl 33-1 methyl 2- (phenylmethylene) hydrazine carboximidothioate were heated together as a melt for 2 hours at 60 °, whereby a gum was obtained. The gum was dissolved in toluene and stirred with 5N hydrochloric acid for 15 hours. The pH

ι the aqueous phase was adjusted to 7 with sodium carbonate, and it was washed with toluene and ethyl acetate. The aqueous phase was adjusted to pH with sodium carbonate set from 10 and extracted with ethyl acetate. The 5 organic extracts with a pH of 10 were dried (MgSO ^) and evaporated to leave an oil (1.1 g). This oil was made using dichloromethane / ethanol / 0.88 Chromatograph ammonia (150: 8: 1) as the eluent, a white solid (0.25 g) was obtained; Mp. 42 to 52 °. 0.112 g of this solid was dissolved in ethyl acetate and with a solution of Treated 0.03 g of fumaric acid in ethyl acetate, causing the title compound to precipitate. She turned out to be whiter Solid (0.095 g), m.p. 80 °, collected.

Free base NMR (CDCl ₅ ) 2.4-2.9 (m, 6H), 3.0-3.4 (m, 3H), 4.31 (s, 1H), 5.56 (t, 1H ), 5.93 (t, 2H), 6.3-6.7 (q + s + s, 7H), 7.5-7.75 (m, 4H), 7.92 (m, 2H), 8.3-8.7 (m, 6H).

Example 10

4-Methyl-a-phenyl-5 - [[3- [3- (1-piperidinylmethyl) -phenoxy] - • propvl1-amlno1-4H-1.2 «4-triazole-3-methanol A mixture of 30.4 g of DL -Mandelic acid and 22.35 g of N-Amino-N ¹ -methyl-N ¹¹ - [3- [3- (1-piperidinylmethyl) -phenoxy] -propyl] -guanidine hydroiodide was heated from 40 to 125 ° and at 125 ° ° held as a melt for 6 h.

The hot melt was extracted with 250 ml of hot water and the aqueous extract with solid sodium carbonate made alkaline to pH 8. The extract was extracted into ether. The ether extract was at 5 ° cooled to give a white solid which was washed with boiling ethyl acetate to give the title compound was obtained as a white solid (0.18 g); Mp. 186 to 188 °.

Δτίο 1 VAA if 5 τ * Γ * M TJ Π

nl ld X jr OXS X <-H ^ OC ^^ r ^ M ^ C ^ O

Calculated: C 68.9% H 7.6% N 16.196 found: 68.9 7.7 16.0.

Example 11

[4-Methyl-a-phenyl-5 - [[3- [3- (1-piperidinylmethyl) -phenoxy] -propyl] -amino] -4H-1,2,4-triazole-3-methanol] -acetate- (ester) hydrate
A solution of 0.10 g of 4-methyl-o-phenyl-5 - [[3- [3- (1-piperidinylmethyl) phenoxy] propyl] amino] -4H-1,2,4-triazole -3-methanol and 0.03 ml of acetic anhydride in 2 ml of pyridine were stirred for 16 h at room temperature. Saturated sodium carbonate solution was added and the suspension was extracted with ethyl acetate. The organic phase was washed with water and brine and evaporated under reduced pressure. The residue was crystallized from isopropyl acetate to give the title compound as a white solid (0.074 g); M.p. 89 to 91 ^° C

Analysis for: C ₂ ^ H ₃₅ N ₅ O ₃ H ₂ O

Calculated: C, 65.396, H, 7.496, N, 14.1 # found: 64.9, 7.5, 13.8

Example 12

α- [1-methyl-5 - [[3- [3- (1-piperidinylmethyl) -phenoxy] -pro pyli-amino 1-1H-1.2 _t 4-triazol-5-vl "l-2-pyridinemethanol n- Butyllithium (1.6 M in n-hexane, 8.12 ml) was added dropwise over 15 minutes to a stirred solution of 2-bromopyridine (1.86 g; 1.12 ml) in 10 ml of anhydrous ether at -70 The brown solution was stirred at -70 ° for 0.5 h before a solution of 2.0 g of 1-methyl-5 - [[3- [3- (i-piperidinylmethyl) phenoxy] propyl ] -amino] -1H-1,2,4-triazole-3-carboxaldehyde in 20 ml of anhydrous tetrahydrofuran was added dropwise at -70 ° The solution was stirred for 2 h at -40 ° before the addition of 20 ml of water and the mixture stand overnight at 20 °

ι relaxed. The mixture was concentrated, extracted with ethyl acetate and the extract dried and evaporated to give an oil (2.5 g) which was chromatographed using System E as the eluent to give a solid (0.48 g). This was crystallized from ethyl acetate, whereby the title compound (0.25 g) was obtained as a white powder, m.p. 152-154 ° (dec.).
Analysis for: ^C 24 ^H 32 ^N 6 ° 2

calculated : C 66, 09 i H 7th , 4 N 19th , 2 # found : 65, 9 7th 19th ,1 B ice ό i e 1

5 - [[2 - [[[5 - [(Dimethy! Amino) methyl] -2-furanyl] methyl] thio] ethyl3-amino3-1-methyl-α-phenyl-1 ^^ - 1, 2,4-triazole-3- methanol dihydrochloride

A solution of 3.09 g of 2 - [[[5 - [(Diroethylamino) methyl] -2-furanyl] methyl] thio] ethanamine and 5.9 g of methyl-N- [2-acetyloxy- [2- (phenyl) acetyl]] - 1-methyl-2- (phenyl- methylene) hydrazine carboximidothioate in 110 ml of toluene was stirred at room temperature for 3 h. Another 0.3 g Methyl N- [2-acetyloxy- [2- (phenyl) acetyl]] - 1-methyl-2- (phenylmethylene) hydrazine carboximidothioate were added and the mixture was stirred at room temperature for 1.5 hours. Then 22.5 ml of 2N hydrochloric acid was added to the reaction mixture and the mixture was left on a steam bath for 1 hour heated. The aqueous layer was adjusted to pH 6 with potassium carbonate and washed with 2 × 30 ml of toluene. The acidified aqueous layer was made alkaline with potassium carbonate and with diethyl ether and ethyl acetate extracted. The combined organic extracts were dried and evaporated, leaving a brown gum stayed behind. This was chromatographed on silica using dichloromethane / ethanol / ammonia (65: 8: 1), yielding a brown gum (1.35 g)

ι was. This was dissolved in methyl acetate and washed with treated with ethereal hydrogen chloride to give a white solid which was triturated with dry ether to give the title compound (1.3 g) as a fine white solid; Mp. 55 to 60 ° (softening) .

NMR (CD ₃ OD): 2.5 (m, 5H), 3.3 (d, 1H), 3.6 (d, 1H), 4.15 (s, 1H), 5.6 (s, 2H), 6.3 (m, 7H), 7.15 (m, 8H).

Example 14

5 - [[3- [3 - [[(2-Furanylraethyl) -amino] -methyl] ~ phenoxy] -propyl] -amino] -1-methyl-a-phenyl-1H-1,2,4-triazole- 3- methanol

A solution of 1.0 g of 5 - [[3- (3-Formylphenoxy) propyl] amino] -1-methyl-a-phenyl-1H-1,2,4-triazole-3-methanol- acetate (ester) and 5 ml of furfurylamine in 30 ml of ethanol was stirred for 1.5 h at 21 ° before a suspension of 1.3 g of sodium borohydride in 10 ml of ethanol was added. The mixture was then stirred at 21 ° for a further 16 h. 20 ml of water were added, the mixture was used to remove Concentrated ethanol and the aqueous residue extracted with 4-methylpentan-2-one. The extract was dried and evaporated to give an oil, excess furfurylamine was removed in vacuo, the residue dissolved in 2N hydrochloric acid, the acidic layer washed with ethyl acetate, alkaline with sodium carbonate made (pH 9) and extracted with 4-methylpentan-2-one. The extract was washed with water, dried and evaporated to give a brown gum (0.65 g) which was dried over silica (Merck # 7729) using of system C was chromatographed as the eluent, the title compound (0.5 g) being a light orange Rubber was obtained.

TLC = system C; Rf 0.35
35

NMR (CDCl ₃ ): 2.50 (db, 2H), 2.6-2.84 (M, 5H), 3.14-3.4 (m, 2H), 3.24 (d, 1H), 3.70 (dd, 1H), 3.82 (dd, 1H), 4.28 (s, 1H), 5.5 (t, 1H), 5.92 (t, 2H), 6.23 (s , 2H), 6.25 (s, 2H), 6.44 (q (dt), 2H), 6.56 (s, 3H), 6.6-8 (m, 2H), 7.94 (m , 2H).

Example 15

3 - [[[(2-Furanyl) methyl] thio] methyl] -1-methyl-N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] -1H-1,2, 4-triazole- 5-aroine

A solution of 3.59 g of 1-methyl-5 - [[3- [3- (i-piperidinylmethyl) phenoxy] propyl] amino] -1H-1,2,4-triazole-3-methanol in 10 ml of thionyl chloride was heated on a steam bath for 10 min. The solution was evaporated to dryness and the residue dissolved in water. Sodium bicarbonate was added to the solution until no foaming occurred more. 3 g of sodium carbonate was added and the suspension was extracted with ethyl acetate. The organic one The extract was dried and evaporated to give a brown oil (4.1 g).

A portion of this oil (3.2 g) was dissolved in 40 ml of absolute ethanol and added dropwise at 5 ° to a solution of 1.14 g of furfuryl mercaptan and 0.34 g of sodium in 20 ml of absolute ethanol. The suspension was at 18 h Let stand room temperature, filtered and the filtrate evaporated to dryness. The residue was dissolved in 0.2N Dissolved hydrochloric acid, washed with ethyl acetate and made alkaline with excess solid sodium carbonate.

The basic solution was extracted with ethyl acetate. The organic extract was dried and evaporated, whereby an oil (2.2 g) was obtained which was purified by column chromatography using chloroform as an eluent was purified to give the title compound as an oil (1.2 g)

TLC = system C; Rf 0.45

NMR (CDCl ₃ ): 2.7 (d, 1H), 2.8 (t, 1H), 3.0-3.4 (m, 3H), 3.8 (m, 2H), 5.5 ( t, 1H), 5.95 (1, 2H), 6.25 (s, 2H), 6.3-6.7 (m, 9H), 7.5-8.1 (m, 6H), 8 , 5 (m, 6H) 5

Example 16

5- (Methoxyphenylmethyl) -4-methyl-N - [[3- [3- (1-piperidinylmethyl) -phenoxy] -propy1] -4H-1 ^^ - triazole ^ -amine compound with tartaric acid (1: 1 )

A solution of 0.37 g of 4-methyl-cc-phenyl-5 - [[3- [3- (ipiperidinylmethyl) phenoxy] propyl] amino] -4H-1,2,4-triazole-3-methanol in 3.0 ml of thionyl chloride was stirred at room temperature for 0.5 h. The solvent was in vacuo removed. The remaining pink foam was dissolved in 10 ml of dry methanol and added dropwise to one Given a solution of 0.17 g of sodium in 10 ml of dry methanol. The reaction solution was left at room temperature for 0.5 h stirred, poured into water and extracted with ethyl acetate. The organic extract was dried and evaporated, whereby a gum (0.3 g) was obtained. This rubber. was dissolved in ethyl acetate and washed with excess Treating tartaric acid in ethyl acetate to give the title compound as a white solid (0.26 g); Fp. 88 ° (softening).

NMR (CD ₃ OD): 2.5-3.1 (m, 9H), 4.5 (ε, 1H), 5.6 (s, 2H), 5.8 (s, 2H), 5.9 (t, 2H), 6.48 (t, 2H), 6.60 (s, 3H), 6.80 (s, 3H), 6.85 (m, 4H) _f 7.85 (m, 2H), 8 , 2 (m, 6H).

Example 17

5 - [[2 - [[[5 - [(Dimethylamino) methyl] -2-furanyl] methyl] thio] ethyl] amino] -1-methyl-ct-phenyl-1Hj-1,2, 4-triazole- 3-methanol

A solution of 3.09 g of 2 - [[5 - [(Dimethylamine) methyl] -2-furanylmethyl] thio] ethanamine and 5.9 g of methyl-N- [2-acetyloxy- [2Hphenyl) acetyl]] - i-methyl-2- (phenylmethylene) -

ι hydrazine carboximidothioate (compound A) in 110 ml of toluene was stirred for 3 h at room temperature and a further 0.3 g of compound A was added. The mixture was stirred for a further 1.5 hours at room temperature, and 22.5 ml of 2N hydrochloric acid were added. The mixture was then heated on a steam bath for 1 hour. The aqueous layer was adjusted to pH 6 with potassium carbonate and washed with toluene. The acidified aqueous layer was then made alkaline with potassium carbonate and extracted with diethyl ether and ethyl acetate. The combined organic extracts were dried and evaporated to leave a brown gum which was chromatographed using dichloromethane / ethanol / ammonia (65: 8: 1) to leave a brown gum (1.95 g). A portion of this gum (0.5 g) was dissolved in dry tetrahydrofuran and "Florisil ⁿ (an activated magnesium silicate) and filtered. The filtrate was concentrated to a small volume to give the title compound (0.32 g) was obtained as a white solid , M.p. 121-122.5 °.

Analysis for

calculated: C 59.8 # H 6.8 * N 17.496 " mg / tablet found: 60.0 6.9 17.3. 5.0 - 125.0 Examples of medicines 293.5-173.5 Tablets 1.5 Active ingredient 300.0 microcrystalline cellulose USP Magnesium stearate BP Compression weight

The active ingredient is sieved through a 250 µm sieve, with mixed with the extenders and compressed using 9 mm diameter punches. Others can Strengths are made by changing the compression weight and using appropriate punches.

The tablets can be made using suitable film-forming polymers such as hydroxypropylmethyl cellulose, be film coated using standard techniques. Alternatively, the tablets can also be coated with sugar.

Capsules mg / capsule

Active ingredient 5.0 - 125.0

Starch 150O ⁺ (USP) 243.5-123.5

Magnesium stearate BP 1.5

Filling weight. 250.0

A form of directly compressible starch

The active ingredient is sieved through a 250 μm sieve and with mixed with the extenders. The mixture is filled into No. 2 hard gelatin capsules in a suitable machine. Other doses can be made by changing the fill weight and, if necessary, changing the capsule size.

Injectable preparations for intravenous Verab submission

% (W / v)

Active ingredient 0.20-0.50

Water for injection B.P to 100.0

Sodium chloride can be added to improve tonicity adjust the solution, and the pH can be adjusted to that of maximum stability using either diluted acid or alkali.

The solution is prepared, clarified and placed under nitrogen or some other inert gas in ampoules with suitable Size filled, which are closed by melting the glass. The injectable preparation is through Sterilized by heating in an autoclave using one of the acceptable cycles. Alternatively can

the solution can be sterilized by filtration and filled into sterile ampoules under aseptic conditions will.

Syrup mg / 5 ml can

Active ingredient 5.0 - 250.0

Sucrose 2795.0-2550.0

Glycerin 500.0

Buffer)

Flavor) as required
Dye)
distilled water to 5.0 ml

The active ingredient, the buffer, the flavoring, the preservative and the coloring agent are dissolved in part of the water. The rest of the water is ^{heated to about 80 °} C. and sucrose is dissolved in this water and cooled. The two solutions are mixed together, adjusted to volume and clarified by filtration. Alternatively, the active ingredient, sucrose, buffer, flavoring, coloring and preservative can be mixed and the powder can be filled into bottles for later reconstitution by adding water.

In the above examples, the active ingredient is preferably 5 - [[2 - [[[5 - [(dimethylamino) methyl] -2-furanyl] -raethyl] -thio] -ethylj-amino] -1-methyl-a-phenyl -IH-1,2,4-triazole-3-methanol in the form of a physiologically acceptable salt such as the hydrochloride.

End of description.

Claims (10)

V KRAUS & WEISERT 3306503 PATENT LAWYERS AND APPROVED REPRESENTATIVES IN FRONT OF THE EUROPEAN PATENT OFFICE DR. WALTER KRAUS DI PLO MCH EM IK ER · D R.-IN Q. AN N EKÄT E WEISERT DI PL.-1 NG. SPECIALIST DIRECTION CHt-MIE RMGARDSTRASSE 15 · D-8OOO MÜNCHF N 71 ■ TELEPHONE OB!) / 797O77-7U7ü7B. T E LE XO 5 - 21 2 1 5 6 kpet d TELEGRAM KRAU & PATENT 3609 WK / My GLAXO GROUP LIMITED London, W1Y 8DH, England Heterocyclic compounds, processes for their preparation and pharmaceuticals containing these compounds Claims Pl .J Heterocyclic compounds of the general formula (I) wherein R _{1 represents} hydrogen, C ₁ _ _{1 / f} -alkyl, cycloalkyl, alkenyl, aralkyl, heteroaralkyl, trifluoroalkyl or alkyl which is substituted by hydroxy, alkoxy, amino, alkylamino, dialkylamino or cycloalkyl; and Rp is hydrogen or C ₁ _ ^ - alkyl; or R ₁ and R ^ with the nitrogen atom to which they are attached can form a 5- to 10-membered ring, which can be saturated or contain at least one double bond, which can be unsubstituted or which is replaced by one or more C ₁ , -Alkyl groups or a hydroxyl group may be substituted and / or which may contain a further heteroatom from the group consisting of oxygen and sulfur; Alk represents a straight or branched alkylene chain having 1 to 3 carbon atoms; Q stands for a furan or thiophene ring which has been incorporated into the rest of the molecule by bonds in the 2- and 5-positions, the furan or thiophene ring optionally bearing a further substituent R ^ attached to the group R ₁ RpN- AIk- adjoins, or Q stands for a thiophene ring which has been incorporated into the remainder of the molecule by bonds in the 2- and A-positions, the thiophene ring optionally bearing a further substituent R ^ attached to the group R ₁ R ₉ NAIk adjoins, with the proviso that if the group R ₁ R ₂ NAIk is in the 4-position, then the group R ^ is in the 5-position; or Q is a benzene ring which has been incorporated into the remainder of the molecule through bonds in 1- and 3- or 1- and 4-positions; R ^ for halogen or Cj ^ -alkyl, replaced by hydroxy or C1-4 alkoxy may be substituted; X represents oxygen, sulfur, -NH-, methylene or a bond; ι y for oxygen, sulfur, methylene or a Bond stands; η has the value 0, 1, 2 or 3 and m is an integer from 2 to 5, with the provisos that (a) the total number of atoms in the chain X (CH2) _n Y (CH ₂ ) _{m is} an integer Number from 3 to 8, (b) if X and Y are oxygen or sulfur, then η is 2 or 3, (c) if X is -NH-, then Q is a benzene ring and Y is methylene or 6yne Is bond, and (d) if Q is a benzene ring, X is oxygen and η has the value 1, then m can also have the value 1 and Y can also have the meaning -CHOR ₁ ^, where R ₁ ^ is hydrogen or acyl; and Rj stands for hydrogen, alkyl, alkenyl, aralkyl or Cp.g-alkyl which is substituted by hydroxy or alkoxy is, stands; where either A is N and B is CRc; or A Is CRc and B is N; and where Rc (A) a straight-chain or branched C ₂ ^ g -AlkVlgruppe which is substituted by two or three hydroxyl, alkoxy or acyloxy groups, or the dihydroxyalkyl group is a cyclic acetal or cyclic ketal structure of the formula 25th can form, where ρ has the value 0 or 1 and Rg and which can be the same or different, each for hydrogen, a C ^^ - alkyl group or a phenyl group stand; or (b) the group (CH ₂ ) Z (CH ₂ ) _r Rg, in which q is an integer from 1 to 4, r is an integer from 1 to 6, Z is oxygen or sulfur, and when r has the value 1, R _{Q stands} for the group CH = CH ₂ , alkenyl or the group CORq, where R «stands for hydrogen, hydroxy, alkyl, aralkyl, alkoxy or the group NR ₁₀ R ₁₁ , where R _{10 stands} for Is hydrogen or alkyl and R _{11 is} hydrogen or alkyl, and when r is an integer from 2 to 6, R _{Q has} one of the meanings given above or in addition Hydroxy, alkoxy, aryloxy or the group NR ₁₂ R _1, ^l) can ^{edeu th} ', wherein R ₁₂ is hydrogen or alkyl, and R _1, is hydrogen, alkyl, acyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl; or (c) the group (CHg) _x S (CH ₂ ) ^ ₁ Ct where χ is 1 or 2, y is O or 1 and R ₁ C is a heteroaryl group; or (d) an aralkyl or heteroaralkyl group in which the alkyl part is substituted by hydroxy, alkoxy or acyloxy; as well as the physiologically acceptable salts and hydrates thereof. 2. Compounds according to claim 1, characterized in that R ₁ door _C1-8 alkyl, Cj ^ alkyl, which is substituted by a trifluoromethyl, C ₂ _ ^ - alkyl substituted by hydroxy or a di-C _1, alkylamino group substituted ißtt Cc 7 cycloalkyl, C c-alkenyl, phenyl-C1, -alkyl or a heteroaryl- ^, -alkyl group, the heteroaryl ring containing a heteroatom; R _{2 represents} hydrogen or methyl; or R ₁ R ₂ N denotes a 5- to 8-membered ring which optionally contains a double bond, an oxygen atom or an alkyl substituent; Alk is methylene; Q for a benzene ring, which has been incorporated into the rest of the molecule through bonds in the 1- and 3-positions, or a furan ring, which has been incorporated into the remainder of the molecule through bonds in the 2- and 5-positions and optionally one Substituents R ^, adjacent to the group R ₁ R ₂ NAIk, where R ^ stands for C ₁ -if -alkyl, or a thiophene ring, which has been incorporated into the rest of the molecule by bonds in 2- and 4-positions, where the substituent R ₁ R ₂ NAIk is in the 2-position, with the proviso that if Q is a benzene ring, as defined above, then X is a bond, η has the value 0, Y is oxygen and m is 3 _t 4 or 5, or X and Y are both oxygen and η and m are both 2, or X is oxygen, Y is CHOH and η and m are both 1; and wherein, when Q is a furan or thiophene ring as defined above, then X is a bond and either Y is sulfur or CH ₂ , η is 1 and m is 2, or X is oxygen, η is 1 and m is 3; R 1 represents hydrogen or alkyl; R _{5 represents} a Cg ^ -alkyl group which is substituted by two hydroxyl groups, or a 2,2-di-C ₁ , -alkyl-1,3-dioxolan-4-yl group; or R _{5 represents} phenyl-Cj, -alkyl or heteroaryl-Cj, -alkyl, the alkyl part of which is substituted by hydroxy, C 1-4 alkanoyloxy or C _1-2 alkoxy; or R _{5 represents} the group (CH ₂ ) Z (CH ₂ ) ^ ₈ , where q has the value 1, r has the value 1 to 4 when Z is oxygen, or r has the value 1 when Z is sulfur, and R ₈ is hydroxy, the group -CH = CH _2, di-C _1, alkylamino or the group CORQ, where R "is C ₁ _ ^ - alkoxy or the group NHR _11, where R ₁₁ is C ₁ , -alkyl; or R _{5 stands} for the group (CH ₂ ) _X S (CH ₂ ) 1I ₁₅ , where χ is 1 and the heteroaryl group R _{15 is} tetrazoyl or thiadiazolyl, each _{substituted by C 1-3} -AlCyI, or R _{15 is} furyl stands. 3. Compounds according to claim 1, characterized in that R ₁ for C ^ Q-alkyl, C ^ -alkyl, which is represented by a tri- fluoromethyl group is substituted, C _2- ^ -alkyl which is substituted by hydroxy or a di-C ₁ , -alkylamino group, C ₅ -y-cycloalkyl, C, ^ -alkenyl, phenyl-Cj, -alkyl or a heteroaryl-Cj, -alkyl group, where the heteroaryl ring contains a hetero atom; R _{2 represents} hydrogen or methyl; or R ₁ R ₂ N denotes a 5- to 8-membered ring which optionally contains a double bond, an oxygen atom or an alkyl substituent; Alk is methylene; Q for a benzene ring which has been incorporated into the remainder of the molecule through bonds in the 1- and 3-positions; or a furan ring whose incorporation into the rest of the molecule through bonds in 2- and 5 positions has been made and, if applicable, one Substituents R ^, adjoining the group R ₁ R ₂ NAIk, where R ^ is C ^ -alkyl; or a thiophene ring which has been incorporated into the remainder of the molecule through bonds in the 2- and 4-positions, the substituent R ₁ R ₂ NAIk being in the 2-position; with the provisos that when Q is a benzene ring as defined above, then X is a bond, η has the vert O, Y stands for oxygen and m has the value 3, 4 or 5, or X and Y stand for oxygen and η and m both the value 2, or X is oxygen, Y is CHOH and η and m are both 1; and if Q is a furan or thiophene ring as defined above, then X is ι stands for a bond, and either Y stands for sulfur or ₂ , η has the value 1 and m has the value 2, or Y stands for oxygen, η has the value 1 and m has the value 3; FU represents hydrogen or alkyl; Rc represents a C ₂ _ ^ - alkyl group which is substituted by two hydroxyl groups, or a 2,2-di-C ₁ , -alkyl-i, 3-dioxolan-4-yl group; or Rc for phenyl-C ₁ , -alkyl, in which the alkyl part is substituted by C, j ^ -alkanoyloxy or C _1-2 -alkoxy, or heteroaryl-Cj, -alkyl, in which the alkyl part is substituted by hydroxy, C ₁ ^ - Alkanoyloxy or C ₁ ^ ₂ alkOXy is substituted; Rc represents the group (CH ₂ ) Z (CH ₂ ) _r Rg, in which q has the value 1, r has the value 1 to 4 if Z is oxygen, or r has the value 1 if Z is sulfur , and Rg is hydroxy, the group -CHeCH ₂ , di-C ₁ , -alkylamino or the group CORq, in which R _{Q is} C _1- ^ alkoxy or the group NHR ₁₁ , where R _{11 is} C _1- ^ - alkyl; or R _{5 stands} for the group (CHg) _x S (CH ₂ ) ^ ₁₅ , in which χ has the value 1 and the heteroaryl group R _{15 is} tetrazolyl or thiadiazolyl, each _{substituted by C 1} , -alkyl, or R _{15 is} furyl. 4. Heterocyclic compounds of the general formula (II) Me ^X N — A (H) ^R 1 ^R 2 ^NCH 2 ^{QX (CH} 2) _m ^Y « ^CH 2 ⁾ n, ^NH -4 _N ^ wherein R ₁ R ₂ N represents di-C ₁ , -alkylamino, furylmethylamino or pyrrolidino, piperidino, 4-methylpiperidino, tetrahydropyridino or hexamethyleneimines; A stands for N and B stands for CR ₅ or A stands for and B stands for N, where Rc for C ^^ - alkyl which is substituted by two hydroxyl groups, 2,2-di-C ₁ »-alkyl-1,3-dioxolan-4-yl 5 or (i-methyl-1H-tetrazol-5-yl ) -thiomethyl; or Rc for phenyl-C. , -Alkyl or heteroaryl-Cj, -alkyl, in which the alkyl part is substituted by hydroxy, or phenyl-C. , -alkyl, in which the alkyl part is replaced by C «. Λ-alkanoyloxy or C _1-2 alkoxy is substituted; or Rc stands for the group CH ₂ Z (CH ₂ ) _r Rg, where R _{Q stands} for hydroxy or di-C ₁ »-alkylamino, Z stands for oxygen and r has the value 4; or R _{Q is} the group -CHeCH ₂ or the group CORq, where R _{Q is} C _1- ^ - alkoxy, Z is oxygen or sulfur and r is 1; and either Q for 1,3-benzene and X for a bond stands, η has the value O, Y is oxygen and α is 3 or 4; or X is oxygen, η is 1, Y is -CHOH- and m is 1; or Q stands for 2,5-furan or 2,4-thiophene, X stands for is a bond, Y is sulfur, η is 1 and m is 2; with the proviso that R ₁ R ₂ N for Di-C. , -alkylamino when Q is a furan or thiophene ring; as well as the pharmaceutically acceptable salts and hydrates thereof. 5. Heterocyclic compounds of the general formula (II) ι what either R ₁ R ₂ N stands for dimethylamine) βtent, Q stands for 2,5-furan, X is a bond, Y stands for sulfur, η has the value 1 and m has the value 2; or R-RpN for dimethylamino or pyrrolidino, Piperidino or Hexamethyleneimine) .Q stands for 1,3-benzene X is a bond, Y is oxygen, η is O and m is 3 or 4; and A stands for N and B stands for CR ₅ , or A stands for CRc and B stands for N, where Rc stands for benzyl whose methylene group is substituted by hydroxy. 6. 5-C [2-C [[5 - [(Dimethylamine) methyl] -2-furanyl] methyl] thio] ethyl I-amino J-1-methyl-a-phenyl-IH-1,2 , 4- triazole-3-methanol and the physiologically acceptable salts thereof. 7. Heterocyclic compounds according to claim 1, namely 1-Methyl-3 - [[(i-methyl-1H-tetrazol-5-yl) -thio] -methyl] -N- [3- [3- (1 -piperidinyimethyl) -phenoxy-3-propyl 3-1H -1,2,4-triazoi - ^ - amine, 1-Hethyl-a-phenyl-5 - [[3-C 3- (1-piperidinylmethyl) -phenoxy] -propyl3-amino 3-1H-1,2,4-triazole-3-oethanol, 4-Methyl-a-phenyl-5-C [3- [3- (1-piperidiny! Methyl) -phenoxy-3-propyl-3-amino 3-4H-1,2,4-triazole-3-methanol and the physiologically acceptable salts thereof. 8. Heterocyclic compounds according to claim 1, namely 1-methyl-5- [3- [C (1-piperidinylmethyl) phenoxy 3-propyl3-amino3-1H-1,2,4-triazole-3-ethane-1,2-diol, α- [1 -methyl-5- [[3V3- (1-piperidinylmethy 1) -phenoxy 3 ~ propyl3-amino 3-1H-1,2,4-triazol-3-yl3-2-pyridinemethanol, 5 - [[2-Hydroxy-3- [3- (1 -piperidinylmethyl) phenoxy] - propyl] -amino] -1-methyl-a-phenyl-1H-1,2,4-triazole-3-methanol, 5 - [[3- [3 - [(Dimethylamino) -methyl] -phenoxy] -propyl] -amino] -1-methyl-oc-phenyl-1H-1 ^, A-triazole ^ -methanol, 5 - [[2 - [[[5 - [(Dimethylamino) methyl] -3-thienyl] methyl] thio] ethyl] amino] -1-methyl-a-phenyl-IHri, 2,4- triazole-3-methanol and the physiologically acceptable salts thereof. ίο 9. Process for the preparation of compounds of Formula (1) according to claim 1, characterized in that one (a) for the preparation of compounds in which R _{5 is} the group (CH ₂ ) Z (CH ₂ ) _r R ₈ or (CH ₂ J _x S (CH ₂ ) fl _i5 , a triazole of the formula (I), in which Rc stands for the group R ₅ ^a , where R _c ^{a has} the meaning - (CH ₂ ) L or - (CHg) _x L and L stands for a leaving group with an anion ^e Z (CH ₂ ) _r R ₈ or ^O S (CH ₂ ) Jl ₁₅ converts; (b) for the preparation of compounds in which Rc has a meaning other than a straight-chain or branched C _2-p g-alkyl group which is substituted by two or three acyloxy groups, or a dihydroxyalkyl group which forms a cyclic acetal or cyclic ketal structure, or an aralkyl or heteroaralkyl group in which the alkyl part is substituted by an acyloxy group, or Y has a meaning other than CHDR ₁₄ , where R _{14 is} acyl, a compound of the formula ^R 16 R ₄ R ₉ NAIkQX (CH ₉ ) Y (CH ₉ ) JiH-C-NNHY ¹ (III) ^{Ί <:} έ. η έ m _n wherein R ₁ g is a group as _{defined for R 3} , V stands for NCR ₅ ⁰ and Y * stands for hydrogen, V for V Oxygen or sulfur and R ₅ ^{0 is} a group as _{defined for R 5} or a group under the conditions of ι cyclization reaction in such a group is convertible group; or V stands for NH, Rg stands for a group as defined for R and Y ^{1 stands} for CR _C , where Y " yn represents sulfur, oxygen or NH; or V is sulfur or oxygen, Y * is CR _C and R ₁ ^ NH is a group as defined for R; or V ^{1 is} NR ^, R ₁ c is hydrogen and Y ^{1 is} CR ₁ -, where Y ^{n has} the above meaning, cyclizes; (c) for the preparation of compounds in which Alk is CH ₂ , an aldehyde of the formula (VII) ³ I. / ^ a (VII) OHC-OX (CH ₂ ) Y (CH) NH / if ^V ' treated with an amine R ₁ R ₂ NH, and then carrying out a reduction; (d) for the preparation of compounds in which Rc is an aralkyl or heteroaralkyl group in which the Alkyl part is substituted by hydroxy, means the suitable aldehyde or the suitable ketone with a Organolithium compound ArLd. or a Grignard reagent ArMgHaI, where Ar is a suitable aryl, aralkyl, heteroaryl or heteroaralkyl group and Hai is halogen; (e) for the preparation of compounds in which R is a straight-chain or branched C ₂ _g-alkyl group, which is substituted by two or three acyloxy groups, or R- is an aralkyl or heteroary! group in which the alkyl part is substituted by an acyloxy group, or Y is CHOR ₁ ^, where R ₁ ^ is acyl , the corresponding alcohol with a ι reacts activated derivative of a suitable acid; (f) for the preparation of compounds in which R c is a linear or branched C _2- g-alkyl group which is substituted by two or three alkoxy groups, or Rc is an aralkyl or heteroaralkyl group, in which the alkyl moiety is substituted by an alkoxy group, means reacting the corresponding alcohol with a halogenating agent and then reacting the resulting halogen compound with a suitable alkanol; (g) for the preparation of compounds in which Rc is the group (CH _{2) q} ^{Z (CH} 2) _r ^{R 8} * * ° ^{οβ1 R} 8 ^{represents 101} IΛ3 and R ₁₂ and R _1, each represents hydrogen or alkyl, to the corresponding alcohol, in which R _Q is hydroxy is reacted with a reagent capable of converting the group Rg into a leaving group, and the resulting compound of formula (I) _{wherein R E is} (CH ₂ ) Z (CH ₂ ) _p L, wherein L is a leaving group then with ammonia or an appropriate amine R ₁₂ R ₁ ^ NH converts; (h) for the preparation of compounds in which R _{8 is} the group NR ₁₂ R ₁ , where R _{1 is} an acyl group or an aryl or alkylsulfonyl group, the corresponding compound in which R _{Q is} the group NHR ₁₂ , with an activated derivative of the appropriate carboxylic acid or sulfonic acid; (i) For the preparation of compounds in which Rg stands for the group -CONR ₁₀ R ₁₁ , an activated derivative of the corresponding carboxylic acid in which R _{Q stands} for -CO ₂ H is reacted with ammonia for a suitable amine HNR ₁₀ R ₁₁ ; or (J) to make compounds where Rc the group 13 -CH (CH ₉ VCH- ι <- P ι includes the corresponding compound in which Rc includes the group -CH- (CH ₀ ) -CH- with an aldehyde or ι ^ pi
OH OH Reacts ketone RgFUCO in the presence of an acid; and optionally the compound of formula (I) obtained converted into a salt. 10. Medicinal product, characterized in that there is a Compound of formula (I) according to claim 1 together with at least one pharmaceutically acceptable carrier or diluent.