DE2949464A1 - BENZOXADIAZOLES AND BENZOTHIADIAZOLES, THEIR PRODUCTION AND USE - Google Patents

Description

500-5494

The present invention relates to benzoxadiazoles and Benzothiadiazoles which have a 4-dihydropyridine part.

The present invention relates in particular to compounds of the formula I,

wherein

R, hydrogen, alkyl (C, _ ₆ ), hydroxyalkyl (C _3-6 ), alkoxyalkyl (C ₃ _ ₆ ), alkenyl (C _3-5 ), alkynyl (C _3-5 ), cycloalkyl ^ - _), CycloalkylalkyKC. _Q), phenylalkyl (C_ _Q) j / 4-0 / -y

means is v / obei unsubstituted or the phenyl ring mean by one, two or three substituents independently selected from halogen, hydroxy, alkyl (C ,,) -alkoxy or (C _1-4), substituted _- or phenylalkenyl (~ Cg) ,

R_ and R_ independently of one another for hydrogen,

C _1-6 ), phenylalkyl (C _7-10 ), cycloalkyl (C _3-7 ) or cycloalkylalkyl (C _4-fi ) stand, R ₃ and R ₄ independently of one another _{stand for CN, COR 7} , COOR ₇ ,

S (O) R-. or COO-A-N η 7 -

stand in what

Means 0, 1 or 2,

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R _? Alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _-6 ), alkoxyalkyl (C ^ _-6 ), hydroxyalkoxyalkyl ( ^C 4-8 * 'aroinoalkyKC ^ g), alkyl (C _1- .) Aminoalkyl * ^C 2-6 ^' ^di ^ ¹ ^ ¹ (C _1-4 )] aminoalkyl, phenyl, phenylalkyl (C _7-1Q ), a 5- or 6-membered heterocyclic ring which contains a nitrogen, oxygen or sulfur atom as a hetero atom and can also contain 1, 2 or 3 ring nitrogen atoms, or a 5- or 6-membered heterocyclic ring, which contains a nitrogen, oxygen or sulfur atom as a hetero atom and can also contain 1, 2 or 3 ring nitrogen atoms, is substituted alkyl (C _1-4 ),

A is alkylene (C _1-6 ),

R _ft and Rg independently of one another for either

Alkyl (C _1-6 ), alkenyl (C _3-6 .), AlkInYl (C _3-6 ), cycloalkyl (C _3- ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl

20 ^(c 26 ⁾ '

2 2

(C._g), aminoalkyl (C _2-6 ), alkyl (C _1-4 ) aminoalkyl (C _2-6 ), di [alkyl (C _1-4 )] aminoalkyl, phenyl or phenylalkyKC _-10 ), or

R ₀ and R _n together with the nitrogen atom form a 5-, 6- or 7-membered ring which, if appropriate, may contain oxygen, sulfur or a group = NR .. "as a further heteroatom, in which R _{10 is} alkyl (C _{1- 4} ) means, and

R, for hydrogen, halogen, alkyl (C ..), alkoxy (C, _.), Alkylthio (C _1-4 ), alkylsulfonyl (C _1-4 ), trifluoromethyl, nitro, hydroxy, azido, amino, alkyl ( C,.) -Amino, di [alkyl (C,.)] Amino, alkanoyl (C, c) amino, carbalkoxy (C " _c ), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl (C _1-4 ) sulfamyl or Di [alkyl (C _1-4 )] sulfamyl, and

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X represents oxygen or sulfur, with the proviso that if R ₁ is Viasserstoff, alkyl (C ₁ _ _6), alkenyl (C ₃ _ _6), alkynyl (C _3-5>, cycloalkyl (C _3-7) , Cycloalkylalkyl (C _4-8 ), phenylalkyl (C _7-9 'or phenylal-5 kenyl (C_, ₂ ), where the phenyl ring is unsubstituted or by one, two or three substituents which are independently halogen, hydroxy, alkyl ( C ₄ ) or alkoxy (C, ₄ ) is substituted,

R and R ₅ independently of one another are hydrogen or alkyl

(C _1-6 ),

R, hydrogen, halogen, alkyl (C, Λ, alkoxy (C,. ), Alkylthio (C _1-4 ), alkylsulfonyl (C _1-4 ), trifluoririethyl, nitro or hydroxy, and

X is oxygen or sulfur, then at least one of the substituents R- and R. has a meaning other than COR ₇ , where R _{7 is} alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-5 ), Cycloalkyl

(C- _), cycloalkylalkyKC. _R ) stands and another

11 4-0 yy Has meaning as COOR, where R is

Alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _2-6 ), alkoxyalkyl ( C _3-6 ) or hydroxyalkoxyalkyl (C _4-8 ).

Each of the above-mentioned alkyl groups containing 1-6 carbon atoms preferably has 1-4 carbon atoms, in particular 1 or 2 carbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl containing 1-4 carbon atoms preferably has 1 or 2 carbon atoms. The hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino group in the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl part in COOR ₇ is preferably not bonded to the α-carbon atom and is preferably on the terminal carbon atom. Any hydroxyalkyl, alkoxyalkyl,

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Hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl group preferably has an ethylene or propylene part which is substituted by hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino. The alkyl part of cycloalkylalkyl conveniently represents methyl. Halogen means fluorine, chlorine or bromine and especially stands for chlorine. Cycloalkyl or the cycloalkyl part of cycloalkylalkyl conveniently denotes cyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl, alkynyl or phenylalkenyl in R or COOR ₇ is preferably not in the α, β position. Alkenyl or alkynyl preferably has 3-5 carbon atoms. Alkenyl conveniently represents allyl or 2-methylallyl. Suitably, alkynyl means propynyl. Phenylalkenyl preferably has the trans configuration and means, for example, cinnamyl. If R 1 is an optionally substituted phenylalkyl, the phenyl ring is preferably unsubstituted. If the phenyl ring is substituted 2 or 3 times, the substituents are preferably the same.

If R_ stands for alkyl, this is preferably branched. If R _{7 is} a heterocyclic ring, this means, for example, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazidinyl, pyridazinyl, piperidazinyl, or piperidazinyl .

If Rg and R _g together with the nitrogen atom to which they are attached form a heterocyclic ring, this is preferably saturated and represents, for example pyrrolidine, piperidine, piperazine, N-alkylpiperazine, morpholine, azepane, diazepane or N-Alkyldiazepan.

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R ₁ preferably represents hydrogen. R- expediently has the same meaning as R ₅ . R conveniently denotes alkyl. R and / or R.

suitably mean COOR ₇ or COO-AN

R_ conveniently represents alkyl, preferably branched alkyl, or alkoxyalkyl, in which the alkoxy part is preferably branched. -A conveniently stands for ethylene. R _Q and R ₉ conveniently denote alkyl or phenylalkyl.

Erf indungsgemäss leads to compounds of formula I,

by in compounds of the formula II,

^R 6-

II

HC = Y where R ₆ and X have the above meaning, and -HC = Y i) formyl,

ii) a group of the formula -HC = CC (= Z) R-

^R 3 or

HC-C (= Z) R ₂ iii) a group of the formula "HC

HC-C (= Z ') R _C I ⁵

^R 4

wherein Z and Z 'are independently oxygen or NR, and R ₁ ^- R ₅ have the above meanings be seated, the group -HC = Y by the group of formula III,

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^R l wherein R ₁ -R ₁ . have the above meaning, replaced.

The process can be carried out in a manner known for analogous dihydropyridine syntheses, for example according to Hantzsch. If the group -HC = Y stands for formyl, and if compounds of the formula I in which R has the same meaning as R ₅ and R _{3 has} the same meaning as R.
are to be produced, it is advisable to combine a compound of the formula II with a compound of the formula IV,

R-CO-CIl ₂ -R ₄ IV

wherein R. and R have the above meaning, in the presence a compound of the formula V,

wherein R ^ has the above meaning to implement.

It is preferred to use at least 2 moles of a compound of the formula IV per mole of a compound of the formula Optionally, a compound of the formula II with a compound of the formula VI,

R ₅ -C (NH-R ₁ J = CH-R ₄ VI

in which R ₁ , R ₄ and R _{5 are as defined} above, are reacted.

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Preferably, at least 2 moles of a compound of the formula VI are used per mole of a compound of the formula II. Preferably R ^ is hydrogen.

If the group -HC = Y stands for formyl, and especially if compounds of the formula I are to be prepared in which R »is different from R ₅ and / or R- is different from R., you can also use a compound of the formula II with a Compound of formula IV and a compound of formula VII,

where R., R "and R_ have the above meaning, implement.

A compound of the formula VI can be used as an intermediate during the reaction of a compound of the formula IV with a compound of the formula V arise. A compound of the formula II in which the group -HC = Y represents a group ii) or iii) can be used as an intermediate in the

above reactions arise. But you can also after
other processes.

Optionally or in particular for the preparation of compounds of the formula I in which R ~ is different from R_

20 and / or R, different from R., it is expedient to

a compound of the formula II in which -HC = Y is a group ii) with a compound of the formula IV or VI, and, where necessary to react with a compound of the formula V. A compound of formula II wherein -HC = Y for a Group iii) can be formed as an intermediate.

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In the above reactions it is possible that in certain cases, when R1, R2, R, and R1 are not the same, that more than one isomer of formula I is formed. These can be carried out in a manner known per se, e.g. column or thin-layer chromatography be separated.

If one starts out from a compound of the formula II in which -HC = Y stands for a group iii), then it is a cyclization reaction. If Z and Z 'each stand for oxygen, then an amine of the formula V should be present be.

The above reactions can all be carried out under the same conditions.

The process is expediently carried out in solution. Suitable solvents are water, ethanol, dioxane, dimethylformamide, dimethyl sulfoxide, pyridine or Glacial acetic acid. The reaction temperatures are between 20 and 160 ° C, preferably between 60 and 12Ό ° C.

If the preparation of the starting compounds is not described, these are known or analogous to known connections can be established.

The compounds of the formula I with basic groups can be converted into their acid addition salts in a manner known per se be convicted and vice versa. The acids are e.g. maleic acid, oxalic acid, methanesulfonic acid, Hydrochloric acid and hydrobromic acid are suitable.

The compounds of the formula I are distinguished by favorable pharmacodynamic properties. In particular

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They cause an expansion of the coronary arteries and have a beneficial effect against angina pectoris. The compounds of the formula I also increase blood flow to the brain and the leg muscles. They also have calcium antagonistic and antihypertensive effects.

The compounds of the formula I with basic groups can also be pharmaceutically acceptable in the form of their Acid addition salts are administered which have the same level of activity as the free ones Bases.

The invention encompasses pharmaceutical preparations, the compounds of the formula I together with pharmaceutical contain usable carriers or diluents. They can be produced in a manner known per se are and are available, for example, as tablets, coated tablets or capsules.

The compounds of Examples 1, 8 and 16 are preferred.

In a group of compounds means

R _{1 is} hydrogen, alkyl (C _1-6 ), hydroxyalkyl (C _2-6 ), alkoxyalkyl (C- ₆ ), alkenyl (C _3-5 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ) Cycloaikylalkyl (C ₄ _ _8), phenylalkyl (C _7-9) or phenylalkenyl (Cq _-12) f where the phenyl ring is unsubstituted or substituted by 25 one, zv / egg or three substituents independently selected Kalogen, hydroxy, Alkyl (C ,,) or AlkOXy (C _1-4 ), is substituted,

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1 * 2 and R, - independently represent hydrogen, alkYl (C _1-6 ) or phenylalkyl (C _7-10 ), R ₃ and R ₄ independently represent CN, COR-, COOR ₇ or S (O) _n R ₇ , wherein
η means 0, 1 or 2,

R ₇ AIkYl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-5 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _2-6 ), Alkoxyalkyl (C _3-6 ), hydroxyalkoxyalkyl (C _4-8 ), aminoalkyl (C _2-6 ), alkyl (C _1-4 ) aminoalkyl * ^C 2-6 * 'P ⁰⁰¹¹ Y ¹ ' phenylalkyl (C _7-10 ), a 5- or 6-membered heterocyclic ring which contains a nitrogen, oxygen or sulfur atom as a heteroatom or is substituted by a 5- or 6-membered heterocyclic ring which contains a nitrogen, oxygen or sulfur atom as a heteroatom Alkyl (C _1-4 ) denotes, R ₆ denotes hydrogen, halogen, alkyl (C, ·), alkoxy (C _1-4 ), alkylthio (C _1-4 ), alkylsulfonyl (C _1-4 ), trifluoromethyl, Nitro, hydroxy, azido, amino, alkyl (C ,,) amino, alkanoyl (C, _-c -) amino, carbalkoxy (C _{? -C} .), Aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl (C _1-4 ) sulfamyl or di [alkyl (C ,.)] sulfamyl, and

X represents oxygen or sulfur, with the proviso that, if R _{1 represents} hydrogen, alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ) , Cycloalkylalkyl (C _4-8 ), phenylalkyl (C _7-9 ) or phenylalkenyl (Cg _-12 ), the phenyl ring being unsubstituted or substituted by one, two or three substituents which, independently of one another, are halogen, hydroxy, alkyl

(C _1-4 ) or AlkOXy (C _1-4 ), is substituted, R ₂ and R ₅ independently of one another are hydrogen or alkyl

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R ₆ hydrogen, halogen, AlKyI (C _1-4 ), AlkOXy (C _1-4 ), alkylthio (C _1-4 ), alkylsulfonyl (C _1-4 ), trifluoromethyl, nitro or hydroxy, and

X is oxygen or sulfur, then at least one of the substituents R. and R. has a

τ Τ

other meaning than COR ₇ , in which R _{7 stands} for alkyl (C _1-6 ), alkenyl (C _3-6 J, alkynyl (C _3-5 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ) and has a meaning other than COOR ₇ ¹¹ , in which R ₇ ^{11 represents} alkyl (C _1-6 ), alkenyl (C _3-5 ), alkynyl (C _3-5 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _2-6 ), alkoxyalkyl (C _3-6 ) or hydroxyalkoxyalkyl (C _4-8 ).

In another group of compounds means

15 R ₁ hydrogen, alkyl (C _1-6 ), hydroxyalkyl (C _3-6 ), alkoxyalkyl (C _3-6 K alkenyl (C _3-6 ), alkynyl (C _3-5 ), cycloalkyl (C _3-7 ), Cycloalkylalkyl (C _4-8 ), phenylalkyl (C _7-9 ) or phenylalkenyl (C _9-12 ), the phenyl ring being unsubstituted or substituted by one, two or three

Substituents which are independently halogen, hydroxy, alkyl (C _1-4 ) or AlkOXy (C _1-4 ) are substituted,

R ₉ and R ₁ - independently of one another are hydrogen, alkyl (C _1-6 ) or phenylalkyl (C _7-10 ),

R, stands for COO-A-N, and

, stands for CN, COR. ,, C00R_, S (0) R or COO-A-N 7 7 η /

wherein

η 2 means

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R ₇ AlKyI (C _1-6), alkenyl (C _3-6), alkynyl (C _3-6), cycloalkyl (C ₃ _ _7), cycloalkylalkyl (C _4-8), hydroxy (C "), alkoxyalkyl (C -, -), hydroxyalkoxyalkyl (C._g), aminoalkyl (C _3-6 ), alkyl (C _1-4 ) aminoalkyl ^ 2-6 * ' ^{vh & n} y ^{1 or} phenylalkyl (C _7-10 ) means,

A stands for alkylene (C, _ß ),

R _fi and Rq independently of one another either for AlkyKC, r), AlkenyKC, ·), AlkinyKC, _c ), Cyclo-

X ~ DJ ^- D JD

alkyl (C _3-7 ), cycloalkylalkyl (C _4-3 ), hydroxyalkyl ( ^C 2-6 ^{) f} AikoxyaikyKCß-s) / hydroxyalkoxyalkyl ( ^C 4_q) 'aminoalkyl (C _2-6 ), alkyl (C _1-4 ) aminoalkyl ^(C 2-6 ⁾ 'Ph ^ y ^{1 or} phenylalkyl (C _7-10 ), or

R ₀ and R _n together with the nitrogen atom form a 5-, 6- or 7-membered ring, which can optionally ^{contain as a further heteroatom oxygen, sulfur or a group =} ^ ~ ^R ₁₀ , in which R-_ alkyl (C _1- .) means, and

R ₆ stands for hydrogen, halogen, AlkyMC ^,), alkoxy ^(C _1-4 ^{) /} alkylthio (C 1-4), alkylsulfonyl (C _1-4 ), trifluoromethyl, nitro, hydroxy, azido, amino, alkyl (C _1-4 ) amino, alkanoyl (C _1-5 ) amino, carbalkoxy (C _3-5 ), aminocarbonyl, trifluoromethoxy, cyano or sulfamyl, and
X stands for oxygen or sulfur.

In another group of compounds means

R ₁ hydrogen, AlkyKC ^ g), alkenyl (C _3-6 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), phenylalkyl (C _7-9 ) or phenylalkenyl (C _9-12 ), the phenyl ring being unsubstituted or substituted by one, two or three substituents which are independent of one another

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Halogen, hydroxy, alkyl (C, J or alkoxy (C.,) mean, is substituted,

R ₂ and R ₁ - are each independently hydrogen, alkyl (C ₁ _ _6), phenylalkyl, cycloalkyl * 5 * ^C 3-7 or cycloalkylalkyl (C _4-8), R ₁ and R. (C _ _10?) stand independently of one another for COR ₇ or

TT

COOR-, in which

R ₇ ¹ is alkyl (C _1-6), alkenyl (C ₃ _ _{6), (3-5} C), cycloalkyl (C _{3-7), (4-3} C) alkynyl means cycloalkylalkyl, and

R ₇ ¹¹ for alkyl (C _1-6 ), alkenyl (C _3-5 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _2-6 ), Alkoxyalkyl (C _3-6 ) or hy-

hydroxyalkoxyalkyl (C. _o );

4- 0

R ₆ represents hydrogen, halogen, alkyl (C _1-4 ), alkoxy (C _1-4 ), alkylthio (C _1-4 ), alkylsulfonyl (C _1-4 ), trifluoromethyl; Nitro or hydroxy, and X stands for oxygen or sulfur, with the proviso that at least one of the substituents R 1 and R _{5 is} phenylalkyl (C _7-10 ), cycloalkyl (C _3-7 ) or cycloalkylalkyl (C. _O ).

4-0

Another group of compounds are compounds of the formula I in which

R ₁ for alkyl (C _1-6 ), alkoxyalkyl (C _3-5 ), alkenyl (C _3-5 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ), R ~ and Rj. Independently of one another for hydrogen or

Alkyl (C _1-6 ), and
R ₃ and R. independently of one another represent COOR ₇ , in which R _{7 has} a meaning other than phenylalkyl.

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These compounds surprisingly have more advantageous pharmacological effects than one for Connections of this type would be expected, e.g. a long-lasting dilatation of the coronary vessels and good compatibility.

In another group of compounds means

R ₁ AIiCyI (C _1- ,.), Hydroxyalkyl (C _0-4 ;), alkoxy

alkyl (C ₃ _ ₆ ), alkenyl (C _3-6 ), alkynyl (C _3-6 ), cycloalkyMC, _), cycloalkylalkyl (C _{A ö} ), phenylalkyl (C_ _Q )

10 or phenylalkenyl (C _9-12 ), where the phenyl

ring is unsubstituted or substituted by one, two or three substituents which, independently of one another, are halogen, hydroxy, alkYl (C _1-4 ) or alkOXy (C _1-4 ),

I ^ R_ and R- are independently hydrogen, alkYl (C _1-6 ), phenylalkyl (C _7-10 ), cycloalkyl (C _3-7 ) or cycloalkylalkyl (C _4-8 ) _f
R ₃ and R ₄ independently of one another represent CN, COR ₇ ,

COOR-, S (O) R ₇ or COO-AN, in which n, R_, A, ^R 9 R _fi and Rq have the above meaning, and the above condition applies, where R ^ and R _{4 are} not both at the same time for COOR ₇ are, wherein R _{7 is} alkyl (C _1-6 ).

In another group of compounds means

R ₁ alkyl (C _1-6 ), alkenyl (C _3-5 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ),

R ₂ and R ₅ are independently hydrogen or alkyl (C _1-6 ),

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R ₃ and R. independently of one another represent CN, COR-,

COOR, S (O) R ₇ or COO-AN, where n, R ₇ , A,

R ₉

R _Q and R _{n have the} above meaning, and the ohen ö y

mentioned requirement applies, where R- and R. do not both simultaneously _{stand for COOR 7} , in which R _{7 is} alkyl (C _1-6 ).

In a subgroup stands

R ₆ for alkylsulfonyl (C._ ₄ ), hydroxy, azido, amino, alkyl (C _1-4 ) amino, di [alkyl (C- ,,)] amino, alkanoyl (C, ₅ > amino, aminocarbonyl, trifluoromethoxy, Sulfamyl, alkyl (C1-3) sulfamyl or di [alkyl (C1-3)] sulfamyl.

In another group of compounds means

R. hydrogen, alkyl (Cg), hydroxyalkyl (C ^ _-6 ), alkoxy-15 alkyl (C ₃ _ ₆ ), alkenyl (C _3-5 ), alkynyl (C _3-6 ), cyclo-

alkyl (C ₃ _ _7), cycloalkylalkyl (C _4-8), phenylalkyl (C _g _ ₉₎ or Phenyl alkenyl (Cq _{-, 2)!,} wherein the phenyl ring is unsubstituted or substituted by one, two or three substituents independently Halogen, 20 hydroxy, alkyl (C,.) Or alkoxy (C, _.) ,

is substituted,

R ₂ and R- independently represent hydrogen, alkyl (C _1-6 ), phenylalkyl (C _7-10 ), cycloalkyl (C _3-7 ), or cycloalkylalkyl (C _4-8 ),
R and R. stand independently for CN, COR ₇ ,

^ - ^R 8 COOR-, S (O) R_ or COO-AN, where n, R ₇ , A,

R ₉

R ₀ and R _{n have the} above meaning, and the above ο y

mentioned requirement applies, where R- and R _{4 are} not un-

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independently of one another for COR_, in which R. is alkyl (C 1), alkenyl (C _3-6 ), alkynyl (C _3-6 ), or COOR ₇ , in which R_ has a meaning other than phenyl or phenylalkyl.

In the examples below are the temperatures given in degrees Celsius and are uncorrected.

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Example 1: 4- (2,1,3- Benzoxa diazolvl-4) -2,6-dinethyl-1,4-dihydro-3-methoxycarbonyl-pyridine-5-carboxylic acid benzyl ester

3 g of 2,1,3-benzoxadiazole-4-aldehyde, 3.9 g of acetoacetic acid? .Urebenzyl ester, 2.3 g of ß-aminocrotonic acid methyl ester and 10 ml of ethanol are stirred together for 6 hours heated to reflux. The reaction mixture is then evaporated and the oily residue over Chromatographed silica gel with chloroform / ethyl acetate (8: 1), the title compound being obtained from cyclohexane / diisopropyl ether recrystallized at 131-136 °, is obtained.

Using the procedure described in Example 1 and appropriate starting compounds, e.g. a compound of the formula II in which -HC = Y is the group i), and compounds of the formulas IV and V, and for Examples 2-9 and 12-16 conveniently a compound of the formula II in which -HC = Y for a group ii), as well as a compound of the for-

20 mel VI, one arrives at the following compounds of

Formula I, v / orin y indicates the position of the dihydropyridine residue:

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E.g

M.p.

2 H 3 H 4th H 5 H 6th H 7th H

10 H 11 H 12th H 13th H

CH.

CH.

CH.

CK.

CH.

CH.

CH.

CH.

CH

CH

CN COOC ₂ H ₅

CN CN CN COOCH,

CH ₃ COO (CH ₂ )

COO

COO

COO

CH ₃ COO (CH ₂ ) ₂ N (CH ₃ )

COO-i-Bu ^CH 3 H O 4th 123-124.5 N> SO ₂ CH ₃ CH ₃ H O 4th 204-205 CO COOC ₂ H ₅ CH ₃ H O 4th 167-177 CO
.0 ·
CT) COOC ₂ H ₅ CH ₃ H S. 4th 187-190 COOCH ₂ CH (CH ₃ J ₂ CH ₃ H S. 4th 166-171 COC _C H_
DD CH ₃ H O 4th 192-201 CH ₃ COOC ₂ H ₅ CH ₃ H O 4th 180-184 ** CH ₂ C ₆ H ₅
CH ₃
CH ₂ C ₆ H ₅ COOC ₂ H ₅ CH ₃ H S. 4th 173-175 ** 3> 2 COO (CH ₀ ) ^ N (CH ₀ J ₀
2 2 3 2 CH ₃ H O 4th 188-191 *
F umarat 3> 2 COO (CH ₂ J ₂ N (CH ₃ J ₂ CH ₃ H S. 4th 156-159
Fumarate J ₂ COOC ₀ H- CH ₃ H O 4th 3> 2 COOC ₂ H ₅ CK ₃ H S. 4th 166-176
Hydrogen
fumarate

E.g.

X y m.p.

O CO OO

14 H CH ₃ COO (CH ₂ ) ₂ N;

15 H CH ₃ COO (CH ₂ )

16 H CH.

17 18 19 20

Δ Δ Δ

H Δ

COO (CH ₂ )

COOC ₂ H ₅ COOCH,

COOCH.

.CH.

CH ₃
CH ₂ C ₆ H ₅

.CH ₃
CH _n C ^ H ,.

COOC ₂ H ₅

COOCH.

COOCH

COOCH.

COOC ₂ H ₅

CH ₃ H S. 5 oil CH ₃ H 0 5 oil CH ₃ H 0 4th 182-195 ** CH ₃ H 0 4th 97-99 CH H 0 4th 160-163 Δ H 0 4th 118-120 Δ H 0 4th 110-112

* Decomposition ** hydrochloride

3700 / IG / SE

CO tn CO *>

Claims (3)

Sandoz Patent GnbH Case 500-5494 Loerrach Benzoxadiazoles and Benzothiadiazoles, their preparation and use Claims X »' Benzoxadiazoles or benzothiadiazoles of formula I, wherein R ₁ is hydrogen, AlRyI (C _1-6), hydroxyalkyl (C _3-6), alkoxyalkyl (C ₃ _ _6), alkenyl (C _3-5), alkynyl (C _3-5), cycloalkyl (C ₃ _ ₇ ), Cycloalkylalkyl (C _4-8 ), phenylalkyl (C _7-9 ) or phenylalkenyl (C _9-12 ), the phenyl ring being unsubstituted or substituted by one, two or three substituents which, independently of one another, are halogen, 030026/0728 ORIGINAL INSPECTED - 2 - 500-5494 Hydroxy, alkyl (C. ₄ ) or alkoxy (C ,,) is substituted,
R "and R ₁ . independently for hydrogen, Alkyl (C _1-6 ), phenylalkyl (C _7-10 ), cycloalkyl (C _3-7 ) 5 or cycloalkylalkyl (C. _O ), 4 ~ ο RJ and R. independently of each other for CN, COR ₇ , COOR-, S (O) R ₇ or COO-AN are wherein R ₉
η means 0, 1 or 2, R ₇ alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-5 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _2-6 ), Alkoxyalkyl (C _3-6 ), hydroxyalkoxyalkyl i ^C 4_o) / aminoalkyl (C _2-6 ), alkyl (C,.) Aminoalkyl (C _2-6 ), di [alkyl (C _1- .)] Aminoalkyl, phenyl, Phenylalkyl (C _-10 ), a 5- or 6-membered hetero- cyclic ring which contains a nitrogen, oxygen or sulfur atom as a hetero atom and additionally 1, 2 or 3 ring ticks toffator.e can contain, or by a 5- or 6-membered heterocyclic ring, which is a heterocyclic atom contains a nitrogen, oxygen or sulfur atom and can also contain 1, 2 or 3 ring nitrogen atoms, means substituted alkyl (C _1-4 ),
A is alkylene (C _1-6 ), 25 R _ß and R »independently of one another either for Alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _2-6 ), alkoxyalkyl (C 1-6), hydroxyalkoxyalkyl (C _4-8 ), aminoalkyl (C _2-6 ), alkyl (C _1- .) Aminoalkyl 30 * ^C 2-6 ^} ' ^Di i ^alk Y ^{1 (} ' ^C i- ^ ] aminoalkyl, phenyl or phenylalkyl (C _7-10 ), or 030026/0728 - 3 -. 500-5494 Rg and Rg together with the nitrogen atom form a 5-, 6- or 7-membered ring, which may optionally _{contain as a further heteroatom oxygen, sulfur or a group = NR Q} , where R _{10 is} AIkVl (C _1-4 ), and R ₆ for hydrogen, halogen, alkyl (C,.), Alkoxy (C, _,), alkylthio (C _1-4 ), alkylsulfonyl (C _1-4 ), trifluoromethyl, nitro, hydroxy, azido, amino, alkyl ( C, -) - amino, di [alkyl (C,.)] Amino, alkanoyl (C, _ ₅ ) amino, carbalkoxy (C _r ), aminocarbonyl, trifluorine ethoxy, cyano, sulfair.yl, alkyl (C _{1 -4} ) sulfamyl or di [alkyl (C, _.)] Sulfamyl, and X represents oxygen or sulfur, with the proviso that if R ₁ f for V.'asserstof, alkyl (C _{1 p),} alkenyl (C ₃ _ _6), alkynyl (C _3-5), cycloalkyl (C _{3 -7} ), cycloalkylalkyl (C ₄ _g), phenylalkyl (C _7-9 : or phenylalkenyl (Cq _-12 ), the phenyl ring being unsubstituted or substituted by one, two or three substituents which, independently of one another, are halogen, hydroxy, alkyl ^ ^C l-4 ^ ^or AIkOXV denote (C _1-4), is substituted, R and Rn independently V, ^T on Hydrogen or alkyl R ₆ hydrogen, halogen, AlKyI (C _1- -), Alkylthio (C _1-4) alkylsulfonyl (C ₁ _ _4), trifluoromethyl, nitro or hydroxy, and X is oxygen or sulfur, then has at least one of the substituents R- and R- a other meaning than COR ₇ , in which R _{7 is} alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-5 ), cycloalkyl (C- _), cycloalkylalkyl (C. ") And another TT II Has meaning as COOR, where R _{7 is} 030026/0 728 - 4 - 500-5494 Alkyl (C _1-6 ), alkenyl (C _3-6 ), alkynyl (C _3-6 ), cycloalkyl (C _3-7 ), cycloalkylalkyl (C _4-8 ), hydroxyalkyl (C _2-6 ), alkoxyalkyl ( C _3-6 ) or hydroxyalkoxyalkyl (C. _o ). 2. Process for the preparation of compounds of the formula I, characterized in that compounds are used of formula II, HC = Y wherein R and X have the above meaning, and -HC = Y i) formyl,
ii) a group of the formula -HC = CC (= Z) R or ^R 3 HC-C (= Z) R ₂ iii) a group of the formula -HC HC-C (= Z *) R ^R 4 denotes in which Z and Z ¹ independently of one another represent oxygen or IJR. stand and R ₁ ^- Rc have the above meaning, the group -HC = Y through the group of formula III, 030026/0728 _ 5-500-5494 III wherein R ₁ ^- Rc have the above meaning, replaced. 3. Medicinal products, characterized by a content of compounds of the formula I. 030026/0728