NL8401932A - 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATIONS AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. - Google Patents

Description

f - i - $ * * - 1,4-dihydropyridine derivatives, their preparation and pharmaceutical preparations containing them.

The present invention relates to 1,4-dihydropyridine derivatives, their preparation and pharmaceutical preparations containing them.

The invention particularly relates to the compounds of formula I, wherein 10 R 1 represents hydrogen, cycloalkyl of 3 to 7 carbon atoms, or optionally substituted alkyl of 1 to 6 carbon atoms, and R 1 independently of each other is hydrogen or alkyl of 1 to 6 carbon atoms represent -15, R ^ represents alkyl of 1 to 12 carbon atoms or independently has the meaning indicated below for -AR ^, including the reservation therein, 20 R ^ represents hydroxyl, alkoxy of 1 to 12 12 carbon atoms, -OCQRg, -NR ^ Rg or -N ^, wherein

Rg represents: alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms, or bisphenylalkyl of 13 to 18 carbon atoms, these three radicals optionally being mono or the same or different di- or the same or different trisubstituted in the phenyl rings. with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl or halogen with an atomic number of 9 to 53, a 5-membered heteroaryl radical with 1 heteroatom from the series of nitrogen 8401932 - 2 - r '+' substance , oxygen and sulfur or 2 hetero atoms from the series nitrogen and either nitrogen, or oxygen or sulfur, or a 6-membered heteroaryl radical with 1 to 5 nitrogen atoms, R_ represents hydrogen or the above represents R.

7 6 has the meaning indicated,

Rg represents hydrogen, alkyl of 1 to 6 carbon atoms or -COR ^, where 10 Rq has the meanings indicated above for R, -N ^ represents: a 5-, 6- or 7-membered heterocyclic ring, optionally containing, if saturated or 6- or 7-membered, a further heterolid from the series oxygen, sulfur and = NR ^ q, wherein R10 represents either hydrogen or the meaning indicated above for Rg, 20 A stands for alkylene with 2 to 14 carbon atoms and Q represents a fused, fully unsaturated ring system with a total of at least 2 different ring hetero atoms and having an aromatic character, it being understood that, in the case of R 1 hydroxyl, alkoxy has 1 to 6 carbon atoms, -N ^ as defined above or -NR '^ R'g, where -30 in R' ^ represents hydrogen, alkyl of 1 to 6 carbon atoms, unsubstituted phenyl or unsubstituted phenylalkyl of 7 to 10 carbon atoms and 8401932% f - 3 - R 'hydrogen or alkyl with 1 to

O

Represents 6 carbon atoms, A represents alkylene of 7 to 14 carbon atoms, 5 and their ammonium salts, wherein R ^ represents any of the tertiary amino groups defined above for R ^ and is quatrified with a group of the formula AlkY, wherein Alk alkyl is 1 to 4 carbon atoms and Y represents an acid residue.

These compounds are hereinafter briefly referred to as "the compounds of the invention".

Some of the compounds of the invention are covered by the very general content of European Patent Specification 42089.

Part of the compounds of the invention also fall under the very general content of European patents 88276 and 94159. These were published in September and November 1983 respectively, ie at a later date than the priority date of the present application, 20 June 21, 1983.

However, none of the compounds mentioned in the above European publications are covered by the scope of the present invention.

Still other compounds related to the compounds of the invention are described in European patent 150, German Offenlegungsschrift 29 49 464 and 29 49 491, Belgian patent 890311, European patent 71819 and 80220, and German Offenlegungs. 33 20 616.

In particular, the above publications do not mention compounds which are the same as the compounds of the invention. The compounds of the invention have a particularly interesting pharmaceutical profile.

A preferred group of compounds of the invention consists of the compounds of formula 1a, where 3401932 ► '«' f - 4 - in R represents hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio with 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon-5 atoms, halogen with an atomic number of 9 to 35, trifluoromethyl, nitro or hydroxyl, R ^ means: hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl of 3 to 6 carbon atoms, wherein the double bond is separated from the nitrogen atom by at least one carbon atom not participating in the double bond, alkyl with 3 to 6 carbon atoms, the triple bond by at least one carbon atom not participating in the triple bond. from the nitrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkylalkyl with 4 to 8 carbon atoms, hydroxyalkyl with 2 to 6 carbon atoms, the hydroxy portion being separated from the nitrogen atom by at least 2 carbon atoms, alkoxyalkyl with 2 to 6 carbon atoms or phenyl of 7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, wherein the double bond is separated from the nitrogen atom by at least one carbon atom not participating in the double bond and the latter two radicals optionally mono- or equal to the phenyl ring or different di- or equal or different trisubstituted with independently alkyl of 1 to 4 carbon atoms, air 25 koxy of 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35 or hydroxyl, alkylcarbonyloxyalkyl of 2 to 6 carbon atoms in the alkylcarbonyl - and in the alkylene portion and in which oxygen passes through at least 2 carbon atoms of the nitrogen atom uncle is separated, dialkylaminoalkyl having independently 1 to 6 carbon atoms in the alkyl moieties and 2 to 6 carbon atoms in the alkylene moiety, where the amino group is separated by at least 2 carbon atoms from the nitrogen atom, or morpholinoalkyl having 2 to 6 carbon atoms in the alkylene portion, wherein the morpholino portion is separated by at least 35 2 carbon atoms from the nitrogen atom, 84 0 1 9 3 2 ^ 2 * - 5 - and Rg have the above meaning, R ^ represents alkyl of 1 to 12 carbon atoms or independently the below -A.3 !! * has the meaning indicated, 5 Ra represents hydroxyl, alkoxy of 1 to 12 carbon atoms, -OCORg, -NR ^ Ra, or as defined above, wherein

Rg, Ra and Ra have the meanings indicated above for Rg, Rg and Rg, respectively, 10 Aa means alkylene with 2 to 14 carbon atoms and X represents oxygen or sulfur, provided that, a) in case R Hydroxyl or -Ngjals as defined above -15 means, Aa stands for alkylene with 7 to 14 carbon atoms and b) in case R, for alkoxy with 1 to 12 carbon atoms or -NR ^ Rg, in which R ^ means: hydrogen, alkyl of 1 to 6 carbon atoms, unsubstituted phenyl or unsubstituted phenyl of 7 to 10 carbon atoms and & *

Rg represents hydrogen or alkyl of 1 to 6 carbon atoms,

cL

25 A alkylene of 9 to 14 carbon atoms

SL

and their ammonium salts, wherein R ^ represents any of the tertiary amino groups defined above for R ^ and is quatrified with a group defined above by the formula AlkY.

In a subset of compounds of formula 1a, A means alkylene of 9 to 14 carbon atoms. In another subgroup, R ^ does not represent alkoxy. In another subgroup, Rg and Ra mean -NR ^ Ra or as defined above.

84 0 1 9 3 2 i * <- 6 -

A preferred group of compound of the formula 1a consists of the compounds of the formula 1aa, in which R 1, R 8, R 8 and X have the above meaning, H 3.

5 Rg represents alkyl of 1 to 6 carbon atoms,

SiQ, 3 »R ^ has the meaning indicated above for R ^ and A means alkylene with 2 to 14 carbon atoms, with the proviso that a) in the case of R ^ means hydroxyl or -Nj ^ as defined above, Aaa for alkylene with 7 to 14 carbon atoms and

SS

15 b) in case R, for alkoxy with 1 to 12 carbon - £ * * * a? material atoms or -NR ^ Rg, in which R ^ and Rg have the above meanings,

SS

A means alkylene of 9 to 14 carbon atoms

SS

20 and their ammonium salts, wherein R ^ represents one of the tertiary amino groups defined above for R ^ and is quaternized with an above-defined group of the formula AlkY.

In a subset of connections to the

SS

Formula 1aa means A alkylene with 9 to 14 carbon atoms.

SS

In another subgroup does not stand for alkoxy. In a gg s s other subgroup, R ^ stands for -NR ^ Rg or -Nj ^ as defined above.

A further preferred group of compounds of the formula 1a consists of the compounds of the formula 1ab, in which sR, R, Rg, Rg and X have the above meanings, sb

Rg alkyl of 1 to 12 carbon atoms means 35 or independently has the meaning indicated for -Aa ^ Ra ^ 8401932 <* m - 7 - below, 3.b

RaD stands for hydroxyl, alkoxy with 1 to 12 carbon atoms, -OCQRg or -NR ^ Rg, in which 3L £ L 21 R £, R and R0 have the above meanings 5 and

Aa stands for alkylene with 2 to 14 carbon atoms, with the proviso that a) in case R means hydroxyl, sib ^ 10 Aao stands for alkylene with 7 to 14 carbon atoms and € tb b) in case R. for alkoxy with 1 up to 12 carbon a 'a' ^ a * a 'material atoms or -NR ^ Rg, in which R-, and Rg have the above meaning, "ib represents 15A alkylene with 9 to 14 carbon atoms and their ammonium salts, in which Rf ^ for an 'ab. . ! . 4 of the tertiary amino groups defined above for R ^ and quattrified with a group as defined above with the formula AlkY.

In a subset of compounds of the clb formula 1ab, A means alkylene of 9 to 14 carbon atoms.

In another subgroup, Rf ^ does not represent alkoxy. In another subgroup, Rg and Ra mean as defined above -NR ^ Rg.

A further preferred group of compounds of the formula 1a consists of the compounds of the formula 1aaa, wherein

cL

R, R.j, R ^, Rg and X have the above meanings 30,

Rg represents alkyl of 1 to 6 carbon atoms,

cL & cL

R, represents hydroxyl, alkoxy with 1 to 12 ^ cL 3--3. * 33 3 carbon atoms, -C0R- or -NRZR-, in which R., R_ and R_ have the above-mentioned meaning above and which means 8401932 »* - 8 - aaa A alkylene with 2 to 14 carbon atoms, with the proviso that a) in case R 1 represents hydroxyl, 5 Δ represents alkylene of 7 to 14 carbon atoms and

3L3, gL

b) in case R stands for alkoxy with 1 to 12 carbon atoms or -NRy Rg, in which Ry and Rg have the above meanings,

SLSiel

10 A means alkylene of 9 to 14 carbon atoms and their ammonium salts, wherein R 1 for one of the above is for R 1. defined tertiary amino groups and is quaternized with a group as defined above with the formula AlkY.

In a subset of compounds of formula Iaaa, A means alkylene of 9 to 14 carbon atoms. In another subgroup, R ^ does not represent alkoxy. In another subgroup, R ^ aa as defined above means -NR ^ Ra.

Other groups and subgroups of the compounds of the invention are formed by the compounds of the formula fa, 1aa, 1ab and 1aaa, wherein R 1 represents hydrogen or alkyl of 1 to 4 carbon atoms, preferably hydrogen or methyl, especially hydrogen , the one in which R 2 and R 1 represents hydrogen or alkyl of 1 to 4 carbon atoms, in particular methyl, the one in which R represents hydrogen and the one in which X represents oxygen and combinations thereof and optionally their corresponding as defined above 30 , quaternary salts.

Another preferred group of compounds of the invention consists of the compounds of formula 1b, wherein R.j, R2, Rg and Q have the above meaning, 8401932 φ * - 9 -

*YOU

IC alkyl of 1 to 12 carbon atoms means 3 b b or independently has the meaning indicated for -A below, r]? for hydroxyl, alkoxy with 1 to 12 carbon-b ^ bb 5 substance atoms, -OCORg, -NR ^ Rg, or -N ^ as defined above, where R ^, and R ,, the above for R ,, R_, respectively - 0 / 0O / where appropriate R_ have the meaning and ® b A ° represents alkylene of 9 to 14 carbon atoms and their ammonium salts, in which R stands for a b 4 of the tertiary amino groups defined above for R “and is quaternized with a group as defined above with the formula AlkY.

In a subset of compounds of the formula 1b, R ^ does not represent alkoxy. In another subgroup b o b b R ° and r mean “-NR“ r ° or -N ^ as defined above.

A preferred group of compounds of the formula Ib consists of the compounds of the formula Iba, in which bb R 1, R 1, R 1, R 1, A and Q have the above meanings and where R 1 represents alkyl of 1 to 6 carbon atoms and their ammonium salts, wherein R stands for one of the tertiary amino groups defined above for R 2 and is quaternized with a group as defined above with the formula AlkY.

In a subset of compounds of the formula 1ba, R ^ does not represent alkoxy. In a further sub-group, R 1 means -NR-R 1 or -Scarves defined above.

A further preferred group of compounds of the formula 1b consists of the compounds of the formula 1bb, wherein RJ,, R-, A and Q have the above meanings 35, 8401932 i * - 10 - bb BZ for alkyl of 1 to 12 carbon atoms * ^ b bb stands or independently has the meaning indicated below for -AR ^ »bb R? means: hydroxyl, alkoxy with 1 to 12 ^ b b b 5 carbon atoms, -0C0R ° or -NR-.R-, in which b ° b D ° R °, R ° and R ° have the above meanings 6 t 7 8.. NBB and their ammonium salts, wherein R represents one of the tertiary amino groups defined above for R 2 and is quatrified with a group as defined above having the formula AlkY.

In a subgroup of compounds of the formula bb bb, R ^ does not represent alkoxy. In another subgroup, R ^ and R ^ mean -NR ^ Rg as defined above.

A further preferred group of compounds of the formula 1b consists of the compounds of the formula 1baa, in which bcL bb b R ^, R ^, Rg, R ^, R ^, A and Q have the above meanings. . bb and their ammonium salts, wherein R stands for a bb of the tertiary amino groups defined above for R 2 and is quaternized with a group as defined above with the formula AlkY.

In a subgroup of compounds of the formula 1baa bb, R represents not alkoxy. In another sub-bb ** b b 25 group, R ^ ° as defined above means -NR ^ Rg.

Further groups and subgroups of compounds of the invention consist of the compounds of formulas 1b, 1ba, 1bb and 1baa, wherein R 1 represents R 1 as defined above, in particular hydrogen or alkyl, preferably hydrogen or methyl, in particular hydrogen, the one in which R 1 and R 1 signify hydrogen or alkyl of 1 to 4 carbon atoms, in particular methyl, the one in which Q represents a group of the formula 3 wherein R and X have the above meanings, especially those in which R signifies hydrogen and those in which X signifies oxygen and combinations thereof and optionally their corresponding quaternary salts as defined above.

Another group of compounds of the invention consists of the compounds of the formula 1p, wherein R 1 represents hydrogen or alkyl of 1 to 4 carbon atoms, and R 1 independently of alkyl for 1 to 4 carbon atoms R @ 1 alkyl represents from 1 to 6 carbon atoms or independently has the meaning indicated below, R ^ means: hydroxyl, alkoxy of 1 to 6 carbon atoms, -OCORg, -NR ^ Rg, or -NgP, wherein r | represents aflcyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 10 carbon atoms or bisphenylalkyl of 13 to 16 carbon atoms, these three radicals optionally mono- or the same or different di- or the same or different trisubstituted on the phenyl rings by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxyl or halogen with an atomic number from 9 to 53, a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 hetero atoms from the series nitrogen and either 30 nitrogen, either oxygen or sulfur, or a 6-membered heteroaryl radical having 1 to 4 nitrogen atoms, R 1 means hydrogen, alkyl of 1 to 4 carbon atoms, or excluding 35 alkyl of 1 to 6 carbon atoms, the 8401932 - 12 - above for R? has the indicated meaning, o R 1, represents hydrogen or alkyl with 1 to

O

6 carbon atoms, or -COR ^, y wherein R ^ has the meaning of 5 above for Rg, means: a 5-, 6- or 7-membered, saturated heterocyclic ring, which, if necessary, if 6- or 7- is empty, a further heterolid of the series 10 contains oxygen, sulfur and = NR ^ q, in which R ^ represents either hydrogen or has the meaning indicated above for R ^, A represents straight-chain alkylene with 2 to 14 carbon-15 atoms and for a fused, fully unsaturated ring system with a total of at least 2 different ring heteroatoms and with at least one aromatic ring, with the proviso that, in the case of R 1 hydroxyl, alkoxy with 1 to 6 carbon atoms, -Njj5 as defined above or -NR ^ '^ Rg' ^ means, where

Ry1 ^ represents hydrogen, alkyl of 1 to 6 carbon atoms, unsubstituted phenylalkyl or unsubstituted phenylalkyl of 7 to 10 carbon atoms and Rg '^ hydrogen or alkyl of 1 to 6 carbon atoms means A straight chain alkylene of 7 to 14 carbon - means 30 atoms and their ammonium salts, wherein R ^ represents one of the tertiary amino groups defined above for R ^ and is quaternized with a group as defined above with the formula AlkY.

35 In a subgroup of compounds of the formula 8401932 - 13 - mule lp Rg means alkyl with 1 to 6 carbon atoms, in another subgroup this symbol represents alkyl with 1 to 3 carbon atoms, in another subgroup it means -A ^ R ^, where A? and R ^ have the above meanings, in another subgroup does not represent alkoxy, in another subgroup A ^ means straight chain alkylene of 7 to 14 carbon atoms, in another subgroup A ^ stands of straight chain alkylene of 9 to 14 carbon atoms, other subgroup means R ^ hydroxyl, alkoxy of 1 to 6 carbon atoms, -OCORg or -NR ^ Rg, where Rg, R ^ and r | have the above meaning and combinations thereof and optionally their corresponding quaternary salts as defined above.

Another group of compounds of the invention consists of the compounds of formula I, wherein s 1 R 1 and independently of one another represent alkyl of 1 to 5 carbon atoms,

Rg represents alkyl of 1 to 12 carbon atoms, 20 R ^ represents hydroxyl, alkoxy of 1 to 4 carbon atoms, -OCORg, -NRfRg, or -Nj ^, where

Rg means alkyl of 1 to 4 carbon atoms or phenyl, Ry represents hydrogen, alkyl of 1 to 4 carbon atoms, optionally on the phenyl ring with alkoxy of 1 to 4 carbon atoms, or halogen with an atomic number of 9 to 53 mono- or the same or different disubstituted phenylalkyl of 7 g to 10 carbon atoms, -COR ^, where g

Rg alkyl of 1 to 4 carbon atoms means, or optionally on the phenyl ring with alkoxy of 1 to 4 carbon atoms, hydroxyl or halogen with an atomic number 8401932 32 * - 14 - from 9 to 53 mono- or equal or different disubstituted phenyl or fe- nylalkyl of 7 to 10 carbon atoms, gRO represents hydrogen or alkyl of 1 to 4 carbon of 5 atoms, which is -N-1 for piperidine or piperazine, both substituted in the 4-position with methyl, benzyl or optionally on one or both phenyl rings with halogen having an atomic number of 9 to 53 or alkoxy having 1 to 4 carbon atoms mono- or the same or differently disubstituted bisphenyl, and

Q

A represents alkylene of 2 to 14 carbon atoms, with the proviso that g means in case: hydroxyl, alkoxy of 1 to 4 carbon atoms, -N ^ s as defined above or -NR ^ R g, 20 where s * represents hydrogen, alkyl of 1 to 4 carbon atoms, or unsubstituted phenylalkyl of 7 to 10 carbon atoms, and 25

Rg has the above meaning, A alkylene having 7 to 14 carbon atoms means g and their ammonium salts, wherein R ^ represents one g of the tertiary amino groups defined above for R ^ and is quaternized with a group as defined above with the formula AlkY.

In a subgroup of compounds of the formula 1s, A means alkylene with 7 to 14 carbon atoms, in another subgroup this symbol represents alkylene with 9 8401932 ê, * «- 15 - up to 14 carbon atoms and In another subgroup branched.

In a further subset of compounds of the invention, Rg, Ry and / or Rg signify substituted fe-nyi, substituted phenylalkyl or substituted bisphenylalkyl.

In a further subgroup hydrogen or alkyl with 1 to 6 carbon atoms, in a further subgroup R 1 and R 1 independently represent alkyl with 10 1 to 4 carbon atoms, in a further subgroup R 8 represents alkyl with 1 to 6 carbon atoms, in a further subgroup Rg as defined above means -A ^ R ^, in a further subgroup A means straight chain alkylene and R ^ has the above for r | indicated meaning, including the corresponding caveat, in a further subgroup, Rg, Ry and Rg have respectively indicated above for Rg, Ry and Rg respectively, in a further subgroup -ii_ have indicated the above for 3 -N_ ^ meaning, in a further subgroup Q is bi-

D

cyclically, in a further subgroup R 1 represents alkoxy of 20 to 6 carbon atoms, in a further subgroup substituted or unsubstituted phenylalkyl contains 7 to 10 carbon atoms in the phenylalkyl skeleton and substituted or unsubstituted bisphenylalkyl 13 to 16 carbon atoms in the bisphenylalkyl skeleton, in a further subgroup, Ry has the meaning indicated above for Ry. In a further subgroup, the common non-fused phenyl rings are substituted.

R.j preferably has the meaning indicated for Rj. R 1 preferably means hydrogen. In case this symbol does not represent hydrogen, it preferably means unsubstituted alkyl, cycloalkyl, optionally substituted phenylalkyl, alkoxyalkyl or mcrfolino, preferably unsubstituted alkyl or alkoxyalkyl, preferably unsubstituted alkyl. In case R 1 represents alkoxyalkyl, the alkoxy portion is preferably separated by at least 2 carbon atoms from 3401932-16 - the nitrogen atom.

and / or R ,. preferably mean alkyl.

Rg preferably represents alkyl. If this symbol has the meaning indicated above for -AR ^, it is preferably identical with -AR ^.

R ^ preferably represents hydroxyl, -OCORg, -NR ^ Rg or -Ν ^.

Q preferably contains at least 3 heteroatoms in total, preferably 3 heteroatoms. The symbol preferably represents a bicyclic ring system. Preferred groups Q are 2,1,3-benzoxadiazolyl and 2,1,3-benzothiadiazolyl, especially 2,1,3-benzoxadiazolyl. In case Q represents a ring system containing a benzene ring component, the 1,4-dihydropyridinyl radical is preferably bonded to this benzene ring component, preferably at a location of the benzene ring component, which is in the vicinity of further ring components.

A is preferably unbranched. The group preferably contains 7 to 14, preferably 9 to 14, especially 10 carbon atoms.

Alk preferably means methyl.

Y preferably represents the remainder of an inorganic acid, for example mesyl or halogen, in particular iodine.

Rg preferably represents alkyl, phenyl, phenyl-25 alkyl or bisphenylalkyl, especially phenyl.

Ry preferably represents hydrogen, alkyl, phenylalkyl or bisphenylalkyl.

Rg preferably represents hydrogen, alkyl or -CORg.

Preferably R 1 and R 8 either mean hydrogen, or one of R 1 and R 8 represents alkyl and the other represents alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl.

Rg preferably represents alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or 8401932-17VL optionally substituted bisphenylalkyl.

As defined above, it is preferably saturated. The group is preferably 6-membered. The symbol preferably means 1-piperazinyl. In case the group 6- or 7-5 is empty, it preferably still contains a heterolid = NR ^ q.

preferably has a meaning other than hydrogen. The symbol preferably means alkyl, optionally substituted phenylalkyl, or optionally substituted bisphenylalkyl.

X preferably represents oxygen.

10 R preferably represents hydrogen.

The radical of the formula III is preferably bound in its 4-position to the 4-position of a 1,4-dihydropyridinyl radical.

Cycloalkyl of 3 to 7 carbon atoms preferably contains 15, 5 or 6, especially 5 or 6 carbon atoms.

Alkyl of 1 to 12 carbon atoms and / or alkoxy of 1 to 12 carbon atoms preferably contain 1 to 6, especially 1 to 4 carbon atoms, they preferably represent methyl, ethyl or isopropyl. Alkyl of 1 to 6 carbon atoms preferably contains 1 to 4, especially 1 or 2 carbon atoms and especially means methyl. When alkyl of 1 to 6 or 1 to 4 carbon atoms is a phenyl ring or amino substituent, it preferably contains 1 or 2 carbon atoms and especially means methyl. Where alkoxy of 1 to 4 carbon atoms is a phenyl ring substituent, it preferably contains 1 or 2 carbon atoms and especially means methoxy. In case halogen having an atomic number from 9 to 53 is a phenyl ring substituent, it preferably means chlorine, bromine or iodine, especially chlorine or iodine. Alkenyl and / or alkinyl preferably contain 3 carbon atoms. The cycloalkyl portion of cycloalkylalkyl preferably contains 3, 5 or 6, especially 5 or 6, carbon atoms. The alkylene portion of cycloalkylalkyl and / or of phenylalkyl preferably contains 1 or 2 carbon atoms and in particular means methylene. The alkylene portion of phenylalkenyl preferably contains 3 carbon atoms. The alkylene portion of hydroxyalkyl of 2 to 6 carbon atoms and / or of alkoxyalkyl of 2 to 6 carbon atoms preferably contains 2 or 3, in particular 2 carbon atoms. The hydroxy portion of hydroxyalkyl and / or of hydroxyalkoxyalkyl and / or the amino portion of aminoalkyl are preferably bonded to the furthest terminal carbon atom.

In case a phenyl ring occurs in a substituent, it is preferably unsubstituted. In case it is substituted, it is preferably mono-substituted, preferably in the para position.

If disubstituted, it is preferably substituted in ortho or meta and in para position.

When trisubstituted, it is preferably substituted in meta-meta and para mode. The substituents of a phenyl ring substituent are preferably alkoxy and / or halogen.

When a phenyl ring is poly-substituted, the substituents are preferably identical.

The amino portion of aminoalkyl is preferably substituted, especially disubstituted. Preferred substituents of the amino portion of aminoalkyl are alkyl and / or optionally substituted phenylalkyl. The amino portion of aminoalkyl is preferably disubstituted with alkyl and optionally substituted phenylalkyl.

In bisphenylalkyl, the two phenyl rings 25 can be attached to the same or different carbon atoms. They are preferably bonded to the same carbon atom. Preferably bisphenylalkyl means bisphenylmethyl.

A 5-membered heteroaryl radical as defined above preferably means pyrrolyl, furyl or thienyl. A 6-membered heteroaryl radical as defined above preferably represents pyridinyl, in particular 4-pyridinyl.

Phenylalkyl preferably contains 7 to 10 carbon atoms. Bisphenylalkyl preferably contains 13 to 16 carbon atoms.

35 Halogen with an atomic number from 9 to 53 preferably denotes bromine or iodine. Halogen with an atomic number from 9 to 35 preferably means chlorine.

The compounds of the invention are obtained by a process which is characterized in that a corresponding compound of the formula II in which R 1, R 1 and Q have the above meanings, Z represents a reactive group and Z 'is either a reactive group means, although it has the meaning indicated above for -OR1, efficiently converts.

The method of the invention can be carried out in analogy to known methods.

The choice of the most suitable preparation mode variant naturally depends on the nature of, for example, the substituents -AR 1 and R 2.

A preparation variant can for instance be an esterification. A suitable reactive group Z or Z 'in this case is, for example, 1H-imidazol-1-yl. This preparation variant 20 is suitable, for example, for the conversion into a hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or substituted or unsubstituted aminoalkyl substituent. Thus, a corresponding compound of the formula II is reacted with a corresponding diol, amido / alcohol, ester / alcohol or amino alcohol. As a solvent, for example, dioxane or an excess of the reaction partner is suitable.

Another preparation variant can, for example, be an amination. This preparation variant is suitable, for example, for conversion into an aminoalkyl substituent. For example, a reactive group Z or Z 'is a group -O-A-ZT ™, wherein A has the above meaning and Z ”represents chlorine, bromine or a group R 2 -SO 2 -O-, in which phenyl, tolyl or means lower alkyl. Zr 'preferably means mesyloxy. The amination can be immediate, ie the reaction takes place immediately with an amine containing the substituent to be introduced 8401932

"V

Contains, or medium, to introduce a primary amino group, by conversion to a corresponding phthalimidoalkyl derivative, for example, by reaction with sodium or potassium phthalimide and subsequent reaction with hydrazine of the al- 5 thus obtained phthalimidoalkyl derivative. The indirect method is preferred if the substituent to be introduced is a primary aminoalkyl group.

A further preparation variant can be, for example, an acylation of a primary or secondary amine. For example, a reactive group Z or Z 'represents the corresponding primary or secondary aminoalkoxy group. A corresponding compound of the formula II is therefore reacted with a corresponding acyl derivative, for example an N-hydroxy succinic imide ester. As a solvent, for example, dioxane is suitable.

A further preparation variant can for instance be an acylation of an alcohol. A reactive group Z or ZT is then, for example, the corresponding hydroxyalkoxy group. Thus, a corresponding compound of the formula II is reacted with a corresponding acyl derivative, for example an acyl halide. The conversion preferably takes place in the presence of a strong base, such as, for example, N-ethyl diisopropylamine. As a solvent, for example, methylene chloride is suitable.

A further preparation variant can for instance be an etherification. A reactive group Z or Z 'is then, for example, a group -A-A-Z1', in which A and Z "have the above meanings. The conversion preferably takes place under strongly alkaline conditions.

If Z 'represents a reactive group in the starting material, a group -Ak ^ can be formed simultaneously in the 3- or 5-position of the 1,5-dihydropyridinyl skeleton.

Quaternary ammonium salts can be prepared by analogy with known methods, for example, by reaction with corresponding (lower) alkyl iodides. For example, an alcohol such as 8401932% - 21 - methanol is suitable as a solvent.

If potentially reactive groups, such as hydroxyl or primary or secondary amino, are present, it may be advisable to first carry out the process of the invention with the groups in protected form, for example for phenolic hydroxyl in the form of a benzyloxy group, or for aliphatic hydroxyl in the form of a tetrahydropyranyloxy group, or for amino in the form of an acylamino or phthalimido group and then transferring the protected groups into the desired substituents, for example benzyloxy in hydroxyl, for example hydrogenolytic tetrahydropyranyloxy in hydroxyl, for example by acid hydrolysis and protected amino in unprotected amino, for example by hydrolysis or hydrazinolysis.

The compounds of the invention can be recovered and purified from the reaction mixture in a known manner.

The compounds of the invention may exist in free form or optionally in salt form. The free forms are normally neutral, except where ionizable substituents are present. For example, salt forms may exist where ionizable substituents such as amino or phenolic hydroxyl are present. Salt forms can be obtained from the compounds in free form in a known manner and vice versa. For the formation of acid addition salts. suitable acids are, for example, hydrochloric acid, malonic acid, p-toluene sulfonic acid and methane sulfonic acid. Bases suitable for the formation of anionic salts are, for example, sodium and potassium hydroxide.

If the radicals in positions 2 and 6 and / or in positions 3 and 5 of the 1,4-dihydropyridinyl radical are different, the 4-position carbon atom is asymmetrically substituted. The corresponding compounds of the invention can therefore occur in racemic form or in the form of the single oenantiomer.

The single enantiomers can be obtained in analogy by known methods.

8401932 it \ - 22 -

The starting materials can be recovered in analogy to known methods, for example by direct cyclization to the 1,4-dihydropyridinyl skeleton.

Insofar as the preparation of the necessary starting materials is not described, these are known, they can be prepared in known manners, for example in analogy with the ones described here, or in analogy with methods known per se.

In the following examples, all temperatures in ° C, without correction, are given.

Example I: 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2? 6-dimethyl-3-pyridinecarboxylic acid (10-hydroxydecyl) ester (esterification of the imidazolide with alcohol).

A mixture of 5.2 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5- (1H-imidazol-1-ylcarbonyl) -2,6-dimethyl- is heated 3-pyridine carboxylic acid isopropyl ester and 44.5 g of decan-1,10-diol at 120 ° oil bath temperature for 2 hours. Ether is added after cooling. The excess decan-1,10-diol crystallizes out.

After filtration and evaporation of the ether in vacuo, the product is chromatographed on silica gel under light pressure using methylene chloride / ether as an eluent. The title compound (oil) is obtained. 30 NMR spectrum (CDCl 3) (ppm): 0.97 (3H, d, J = 6Hz), 1.22 (3H, d, J = 6Hz), 1.15-1.65 (16H, m ), approx.2.32 (6H, 2s), 3.63 (2H, t, J = 6Hz), 3.99 (2H, m), 4.91 (1i, m, J = 6Hz), 5, 48 (1H, s), 5.92 (1H, s), 7.3 (2H, m), 7.62 (1i, m).

35 8401932 a -23-

Example II: 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid / 10- (N-benzy Ime thy lamino) decy1 / -5 ester (direct amination of the mesylate).

^ 4.6 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6,6-dimethyl-3-pyridinic acid (10-methanesulfonyloxydecyl) ester are dissolved and 2.2 ml of N-benzylmethyl-amine in 50 ml of ether, evaporate the mixture in vacuo and heat the product at 80 ° for 3 hours. The mixture is then dissolved in ether, the solution is washed with cold 1N sodium hydroxide, the ether phase is dried over magnesium sulfate and evaporated in vacuo.

The product is purified by chromatography on silica gel using methylene chloride / ethanol 19: 1 as an eluent. The title compound (free base: oil, hydrochloride: amorphous) is obtained.

NMR spectrum of the free base (CDCl 3) ((ppm): Q, 98 (3H, d, J - 6Hz), 1.25 (3H, d, J - 6Hz), 1.15-1.8 ( 16H, m), 2.2 (3H, s), 2.34 (6H, s), 2.25-2.45 (2H, m), 3.5 (2H, s), 4.0 (2i , t, J = 25Hz), 4.92 (1H, m, J = 6Hz), 5.48 (1H, s), 5.98 (1H, s), 7.2-7.7 (8H, m).

The medylate used as starting product is obtained by reacting 4.3 g of the title compound of Example I and 4.3 ml of N-ethyl diisopropylamine in 90 ml of methylene chloride at 0 ° with dropwise addition of 1.0 ml of metal. thanesulfonic acid chloride and stirring the mixture in an ice bath for 90 minutes. The solution is then washed with cold 2N hydrochloric acid solution and the organic phase is dried over magnesium sulfate and evaporated in vacuo.

35 8401932 - 24 -

Example III: 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid QO-aminodecyl) ester 5 (Amination of the mesylate via the phthalimido derivative).

2.2 g of 4- (2,1,3-benzoxadiazol-4-yl) - 1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyl) ester are dissolved in 44 ml of dimethylformamide, add 2.2 g of potassium phthalimide and stir the mixture at 80 ° bath temperature for 3 hours. The solution is then cooled, filtered, washed with 100 ml of methylene chloride and the filtrate is cleaned by shaking 8 times with cold 2N hydrochloric acid solution and then evaporated in vacuo. The product is chromatographed on silica gel under light pressure using ether as the eluent.

The resulting 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine carboxylic acid (10-phthalimidodecyl) ester ( oil) in 40 ml of ethanol, add 1.0 ml of hydrazine hydrate and heat the solution at reflux for 30 minutes. After filtration and washing with methylene chloride, the solution is extracted with ice-cold water and the organic phase is evaporated in water. The product is chromatographed on silica gel under light pressure using methylene chloride / methanol (containing ammonia) 9: 1 as an eluent. The title compound (mp 102 DEG - from ether) is obtained.

30 9401032 - 25 -

Example IV; 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6,6-dimethyl-3-pyridinecarboxylic acid / 10- / 3- (4-hydroxy-3- iodophenyl) - 5 1-oxo-propylamino / decyl / ester (Amidation of the amine).

A solution of 0.5 g of 4- (2,1,3-10-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10) is heated -aminodecyl) ester and 0.4 g of 3- (4-hydroxy-3-iodophenyl) -propionic acid-N-hydroxy succinic imide ester in 15 ml of dioxane at 120 ° bath temperature for 30 minutes. The solution is cooled, diluted with methylene chloride and extracted with cold saturated sodium bicarbonate in water. The organic phase is dried over magnesium sulfate, evaporated in vacuo and the product is chromatographed on silica gel under light pressure using 49: 1 methylene chloride / ethanol as an eluent. The title compound (amorphous) is obtained.

HMR spectrum (CDCl ^) & (ppm): 0.99 (3H, d, J = 6Hz), 1.1-1.9 (19H, m), 2.35 (6H, s), 2.43 (2H, t, J = 7Hz), 2.9 (2H, t, J »7Hz), 3.23 (2H, q, J» 5Hz), 4.02 (2H, t, J = 6Hz), 4 .96 (1H, 25m, J »6Hz), 5.53 (1H, s), approx.5.62 (1H, wide), approx.6.55 (2H, wide), 6.9 (1H, d, J = 8Hz), 7.1 (1H, 2d, J * 8Hz and 2Hz), 7.25-7.75 (4H, m).

30 8401932 * Μ - 26 -

Example V: 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-benzoyloxydecyl) ester 5 (Acylation of the alcohol)

To a solution of 2.2 g of the title compound of Example I and 1.3 g of N-ethyl diisopropylamine in 30 ml of methylene-chloride, 1.2 g of benzoyl chloride are added at 20 ° and the solution is stirred at 40 ° for 1 hour. The reaction mixture is then diluted with ether and washed successively with water, 1N sodium hydroxide and 1N hydrogen chloride solution, dried over magnesium sulfate and evaporated in vacuo. The product is purified by silica gel chromatography using methylene chloride / ether 9: 1 as an eluent. The title compound (amorphous) is obtained.

NMR spectrum (CDCl 3) & (ppm): 0.99 (3H, d, J »20 6Hz), 1.02-1.9 (19H, m), 2.35 (6H, s), 3, 99 (2H, t, J 6Hz), 4.33 (2H, t, J = 6Hz), 4.93 (1H, m, J - 6Hz), 5.5 (1H, s), 6.08 (1H s), 7.15-8.15 (8H, m).

Example VI: 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-25 dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid / 10- (N-benzylmethylamino) decyl 7 ester 30, (esterification of the midazolide with amino alcohol).

A solution of 4 g of 4- (2,1,3-benzoxadiazo-4-yl) -1,4-dihydro-5- (1H-imidazol-1-ylcarbonyl) -35 2,6-dimethyl-3- is heated pyridine carboxylic acid isopropyl ester and 7.0 g of 10- (N- § A f) 1 λ. ·; ^ -27- «« ft

V

methylbenzylamino) decan-1-ol in 150 ml of dioxane at reflux temperature for 16 hours. The mixture is then evaporated in vacuo and the product is heated at 80 ° for 3 hours. The product is purified by silica gel chromatography using methylene chloride / ethanol 19: 1 as an eluent. The title compound is obtained (free base: oil, hydrochloride: amorphous).

NMR spectrum: see example II.

The amino alcohol used as starting product is obtained as follows: a) In a solution of 20 g of decan-1,10-diol and 20 ml of N-ethyl diisopropylamine in 800 ml of methylene chloride and 100 ml of acetone, a solution of 4 is added at 30 ° C. 5 ml of 15-methanesulfonic acid chloride in 60 ml of methylene chloride and stir the mixture at room temperature for 1 hour. The methanesulfonic acid (10-hydroxydecyl) ester (melting point 48 ° - from ether, after chromatography on silica gel using methylene chloride / ether 2: 1 as eluent) is obtained.

B) A mixture of 8.5 g of the mesylate obtained as described above under a) and 12.3 g of N-methylbenzylamine is heated at 80 ° for 2 hours. 10- (N-methyl-benzylamino) dacan-1-ol (oil, after chromatography on silica gel using ether as eluent) is obtained.

25

Example VII: 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6,6-dimethyl-3-pyridinecarboxylic acid (10-aethoxydecyl) ester.

30 (etherification of the mesylate).

2.3 g of 4- (2,1,3-henzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarbon-35 acid (10-methanesulfonyloxydecyl) are allowed ester in 30 ml of methanol with 0.5 840 1 9 3 2 - 28 g of potassium methylate and heat the mixture at reflux for 4 hours. After evaporation in vacuo, the product is dissolved in ether, the solution is washed with 1N hydrochloric acid solution, the organic phase is dried over magnesium sulfate and evaporated. The product is purified by silica gel chromatography using ether / hexane 1: 1 as an eluent. The title compound (oil) is obtained.

NMR Spectrum (CDCl 3) (ppm): 0.98 (3H, d, J -10 6Hz), 1.1-1.9 (19H, m), 2.32 (H, s), 3.35 (3H, s), 3.39 (2H, t, J = 6Hz), 4.0 (2H, t, J = 6Hz), 4.95 (1H, m, J = 6Hz), 5.5 (1H , s), 6.3 (1H, s), 7.2-7.8 (3H, m).

15 8401932 - 29 -

(3 I I

cd · η · Η 4J

I Ο,> * β Wi so _ 30 05 O '._

μ cn -vj- & μι ρί cn / -. / —S / ~ s “® C O« O

gj I jj »o r-t Ή w M Ol 71 Ή · Ή CQ CO CO C / 2 IM Ή sr Cd« “M>, '/ - ^ * * *? ? V V oi C-u λ T3 c + I »<(¾ ei ^ LiwC-'S-C 'o cd o> —i <u ►>, -η · ή ή ή ν_Λ w w ^ w

o μ fl ft TB js TB

H: £! s s s <u 50 O <Ü 7 (Ni! 2 λ-s ft

SO CM

cd ü K

·· CLi CJ

ft ö s_p (N

0 .¾ M N S d S

_ H Pd Μ grandma • 2 λ-s λ-sf λ-ν λ-s 3 o <U JZL (D <U CS! ® ï ss π s S ^ 7 S · ΨΚϊ !! Ι! ® «LJ Τ ' ^ 7 § po-cd ooooo ga Tg aaa cS * <00000 22322®

W § ^ "cM Osl ^" cM '”cM / ~ CM CM CM CM CM CM CM

«5 8SSS3 8 8 8 8 8 3 ^ v s_ / v- / w w w w ^ N— 'w Tj I! I I I I! I 1! 1 00 1 a ^ S Tl and l, u / -Γ Η μ μ s-ι m η M aa ft ft QJ CM-U 1¾ ft .¾ .¾ ft ft gg * H Η J3 S3 W Ή · Η · Η · Η * H rt HO 3 · TB Ü 7 cc 1

7 2 <N ell <D <U 0) <U a) O <u OJ QJ OJ

• 8 2 * S £ S S S gggsss 0 <u 0 ° § ^ oT g «e b a ss a ss κ a ss 0) _

00 C

pH Cd S '* rHpHr-irHtH 777777

Is r r r r r r * r * r * f '8! ffTTT T tt f f ί 2 »I ^ S ^ 2 o 0 0 0 0 0 ^

Si? nnnnn 2 2 3 3 2 2 2.tj cd cd cd cd cd cd cd ed <d cd cd S3 · Η · Η · Η · Η -Η · Η · Η · «· Η · Η · Η Η3 -ΰ τΒ Ό TB Τ3 2 2 2 2 2 2 * cdcdcdcdcd cd cd cd cd cd cd

> cu Π Π Ν X X ^ Η S

0 * 00000 000000 ώ .2, ννννν 222333 m.2 iBCSCC cccccc .2 ΰ (uojcucuai cuq) cu <oajai ** * ΛϋϋϋΛ -P? "P *? ·? *? I 1 I I I I I 1 I 1! CO CO CO CO CO CO CO CO CO CO <0 ^

Λ - Λ A A ft A A

N CM CM CM CM CM CM CM CM CM CM

4J

IS Μ H

1 13>>

2 λ, ί t3 Η Η Μ M

«J.HMiH«. »>>>> Ü0OO · IH l-t Η Η M λ-s λ-s Ü O O <U H CM p— * * *"

M ft>. Ft 3 MHHfHMW

MrH? | H! -F H W M H

I TB j, II

S-i H W r-t M

0 <U-H Cd H W> Η H

si ss ^ as a a a a a a 3401932 - 30 - / "s ^ ^ N / - \ CO tó / '- N / - ^ COW WW WW W wwWW WWWw S- ^

Λ A * V Λ ΛΑ A /% / *** \ A A A A A ^ / ^ S

prf psi SB B S B i + Β Β Β Β B + I

Ow OO o OW WWWWWWWW w mnj nj n) <DO O) (UG) <D (U <U <U <D <1) Ü) 1 I aaaaa saaaaaaa aa) cm (ua <d <u (uaSacutu a 2 soiosaojoo swt ^ · | f.-.- if

CM S Β I JN b £ O ^ N

nn SO U cm B BB C y S M

BM u <n iB ο ao a I O I

/ -N y-v / -s S, B ^ υ <N 11.1 JZL 1.2L

iê 1¾ Ui i ΟΟΙΟΡΦ ^ εΓ r kb s a i'- '<u sss sr ilia a OO O'S "OB g OOOOOOOO o / —s ✓ — v rs O / * s SZJ ^ ^ ^ <^ · / * S ^ ^

CM n (M rCM CS iTi CMCMCMCMMCMMM CM

SB S <· -> BB * S BBBBBBBB B

8 8 8 cm Go cm oooooooo o WW w 32 ww QJ wwv-'W'w'ww'— '^

II I CJ II U I I! I I I I I I

v v I l μ μ μ μ μ μμμμμμμμ> -i

(YOUR fii-fii BB S puBBBBP-iBPh S

2 Η · Η · Η · Η Η Η · Η · Η · Η · Η · γΗ · Η · Η · Η · Η ai <0 <u <u ο ο 0) ο <υ α> cdoojojo ο as aa aa a ssaaaaaa a

BB BB BB B BBBBBBBB B

r- (r — 4 Η H Η HHI — I rl Η Η τ — I Η H rI r-1 ^ f1 ΐ ^ ^ ^ Τ 'Τ'ΐ'ΐΤ'ΐ'ΐ'ΐΐ Τ' f? TT TT T ίίί ί TT f T f

, —I, —I i — I <—I Η H i — I H i — It — I Η Η H r- <I — I H

OO OO OO o oooooooo o

N N NN NN N N- NNNNNNN N

cd cd cd cd cd cd cd cdcddcdcdcdcdcd cd • Η · Η · Η »H -Η · Η · Η · Η · Η Ή <Η · Μ · ι-Ι τ-Ι · Η · Η BB BB BB Β BBBBBBBB Β cd cd yard cö cd cd cd cdcdcdcdcddcdcd cd

X! * J I * !! *! S

8 o oo OO O OOOOOOOO o eg eg NN eg m eg cgcgcgcgcgegegeg n ec öö co c ficcececc c d) (U <UCU 0) 0) 0) 000) 00) 0) 00 0) ff ff f f f ffffffff f

(Ö cO cn co ¢ 0 co cocococococococo CO

f \ A AA AA Λ ΑΑΑΑΑΑΛΑ A

γ— τ— 'r — r —- T— t—

A A AA AA A AAAA AAAA A

CN) CM (N <N CM CM IN CMiNNlNCMlNiNiN CM

S '

Η Η W Η I H * H

>> HH HW H >> «A> y-s> aa ϊ> ααΙ — iMl — 4Mi-4 / —n ^ ITi ** λ>>>>> un h

A A A A A CM Λ A A A aM ^ "" MCM

HW HW WW W hWWHHWHWWWW

HH HH HH Η HHHHHHHHH H

H

Cd H cdjOOBOHH

H HH> HHHHHHH H

hm h HH h S

as as aa a aaaaaaaa a 8401932 - 31 - O _ _ rn Qi ✓ — s • «« «« ".XX". ".

55555556 6 65 igagassiaaa lla 4-1) 4 4 ^ Ί "s s« «v. E a * af * sT * g g g i s g

o u o o o o SRS

<n <n ° ouuüu sgooffitSgE S gs ssg-riiczzss) 2) * l 0 os soooo 2 2 2> ί £ f ί ί ί ί 5 · 3 * 5 * §§ëê§SS§ sss ι ι ι ι ι ι 1 I lil 0) PU Ph At J 1¾ 1¾, ¾ .¾ .¾ 6

a · μ * w -M a · η ^ H

ü ^ üs asaa laa a-apsssKMa! 13 amsi fffffffr fff 'f'fffffft ι T ι -LJLJL ^ r-irHr-itW r-l r-4 r-4

ssssssss I I I

3 «e« ι «λ« 2 2 .2 .2 .η '4 --3' 4 '4' 4 '4 4 -g

«CeajcU222w« XX

§ § g § g § 3 o O O O

1 § § g g g g g sss ggSSSSjjoj «« «ffffffff fff Λ ή Λ A« «« π «^ Γ ^ - · ^ -Τ-Τ-Τ-Τ-Τ-

CM Ν Ν Ν Ν Μ Ν Ν CXCMCX

^ μ ase5> - „s-Η £ = ·. Μ -Η = - 5 J J J - _Γ ", S δ. Δ δ δ δ δ δ δ δ δ Μ Μ Μ> Μ Μ Μ Μ ι_ι Η Μ I” * W..

ι_ι ι — ι Μ W Η XI

! Χ 1-11 — I W Μ S> ^ w χ; XI X χ X X b -bbb aasassaa a a ti 8401932 w * »- 32 -

v'— V ΛΝ / -S / -N

co co co co

A ft A A

P4 pi {Pd N. ^ S- / s- / d) 'o co

R-J

Ë CU 0) <U (U r-l 3 a a a a ft § 3 U 6

r-v PQ U

i ico w + J · Η i>

3d) H

PP rd co II II

4J Pu 3 o O 3 S o o u g ^ co O O O + 3 o o o ^ n 3 - - - s + j ^

/ - \ / -% / ”\ O

N N N »-

ca cd ca / -N

O O O CM

- 'w w jii iii υ W' J-i ί-ι ί-ι Onion

Pm Pm Pm Pm

-Η -rl -rl * rl r-M

r ^

CU

0 r-l

S-l> ·> tH

CU -3>.

O 4J C

(U CU CU 3 CQ 0) <1) s a s s h g h

II II II

Sm 3 cu <u ja • rl a Pm ca cd cd cd

r-1 rM rU r-M

Px ^

lil I

-it · -ie -d · si ·

III I

r-M r-l r-l r-l O O O N N N N i-l

Cd td 3 3 >> r-l

• H 'rl Ή Ή 4J! >> t — I

fl fl 'Ö 3 N> i cd 3 3 3 PP C Λ

X i <J {χ! X I <U 4J

0 0 0 O C PP M

N N N N

d 3 c c II II II

3 3 3 3

J3 JP JP rü 3 N U

T T I I M PP w co η n co

AAI) A

r— r— r— f-

A A A A

CM (N CM CM

r \

CO

H

r- \ / a-a «CO O '

> Η Η I

3 H

Η Η H

Pi> <£.

1401932 - 33 - JJ + J I> », OO 00 M f £ 3 _Lrti OC3 = 3 s * -3 8. & 1, I. -s i s j tj5 ° ggg! § I «« «® S ^ .2¾¾ 5 Jo g« »y xoo

^ ° Ψ u u «-d T M n g,« N

g J> 2uo oc ^ 00¾ Sew

% SÜ II: 11¾ * «s? a I

• 5 ^ · ^. 5 Cm S-uJj jj S · η öo Ρϊ f & 3 f &: i .s i * 51

-. 11 * f s 2 s I 2 2 1 2 1 S

T ^ o -S · μ S -S ΐ h · β> «λ S O - o 5 ï« g & S 2 £ ö £

7 7> *>. § £ * «-7 * 2 S I H

ris ί g>? 5 §? S «7 Ϊ * 3 O * H 'iR- LXW Λ Jj Tj <· O 01 I ÜJ | tw0 * vT -M> T + JW δ -is =” 3 3 "" T' «- ST ^ ë τ κ - °

8 8 “! 5 2 5¾ j; {5 3 J sS

Ϊ --3 83 t »f s H rS-S

S3 »S3" Hh If, 3? = §3 = 0 g w g i J '7 Λμ-ü H>, s a

b 6 7 öfw 00Μ o O 3 OO-MM

ö È ^ 5 JL Μι — I * T3 Nt— <0) ΝΦΦΦ 2 ° ^. 2 2 -a S>. 2 * * g «'g S- *

I: Λ-11 ill I g g i -I

511 5 1 Ifl g; Hi! tie 11 e ii.5 f I: f || - s §? § s? : - s Λ: ·! 13: s * «T! I i III o s * 3 * έ: S Ö &! 5 $ 111 $ || hole M .. a T a II f; j ajaeo a) om> gg „g §IsI § £ ~ £ Λ o <u, ϋ <r> Φ M JJ h> Sm« § 1 Λ ii'i '3 § 82 IS !; V g β «d >> e« 2 >> g «£, g, g, a% Hi H TcBo S ί 5 ^ luSoS oeo op ^ £ w> 2, 3> y MO OOÜOO 00 <JOS 3 2 °“ loo 1 4) 2 „2> ^: u> ^

It 11 IΠ a II? · 3 13 11 tf.s- 2 5 5 2 2 2> .mc llg'l "J ^ p {« H CU I · Η <U ft ft P fe1 fi * R, - W Λ d 0) M r-4 3 Ü «I * H * g? n * £ fi ·“> ω> -. oo op>. g ö7ü.2 c? d & "wc.m § g« * H § 8 ο MS Η 5 j S Η · Η Ο ΛΙ> 5 S3 3 b! {5 S S £ 3 «£ 83m | * _

1 8 ° I 3 2 0 3 -3 3 2 I -3323 f I II

2 § 3: .2 t 3 J 338J | 38 I * f si: I g \: g g I * si .-. 38 «% -u QO.SO ÖASO Q CM> O QCM> a. Q03> ~ S 3 3 * 8401932 € * * - 34 - I μ Vi rH 3 ff 3>, I flJ 'rl 3 3 oo ö S ,, tj <“. * Ο Ό ÖQ <UH w 3 T) 3 ο · η cu 3 co μ · μ μ 3 μ μ> ο cu μ 3 3 μ cu o r-ι α · η rj 0> S> <US 3 0>, OO 3 ÖO 3 o

Wcu ^ CU ft μ ft .ii oopj cu cu o μ 3 μ rj <U na <U O ft

μ 3 3. 3 "IO

cu 3 μ 3 3 3 3 öo S ÖQ 3 3> «Ai rj

1 μ>> 3 >> O

1Λ · Η O ÖO, Ο · »-» N * - 13 ÖO 3, ri Ö 03 3 · μ 3 Yes 3 β μ 3 t) · μ -μ '* ~ i .ft 3 au μ μ · μ μ · η >> s μ μ 3 £ 2 ω 12 350 3 Ν ί> 3 Ή «• Η μ ο Ν 8 ö> μ • 3 ÖO> β ο 3 -ΐ Ο γ-Ι I · η Ο · Ό S3

Sf · η η μ> μ _ 3 νι ft ·> μ η μ 03 31¾ 3> · Ji Η Ο Ο Τ3 33 ΐ μ | μ Ο ΌΤ)> 3 33 / - ^ CU Ό Ό · Η μ Μ> γΗ>, μ 3 S S3 30>, 3 3 3 μ μ-0 35 ΐμ3 3 β 3 03> μ ^ fcü_Q 6 3> 00 30 I μ μ μ Η Ό μ 1—13 0 μ Ö0> ι 33 3 030 ÖO · Γ-ιΟ ΌΤ) 3μ Ν / - \> • '“I γΗ · Η 3" nj * 5 β 3γημ ο μ 3Ό> μ • η> 1 3 μ Ό Μ 3 · η ο _ 3 Ό Ο · Η Ü 3 μ Ö0 · η Ö0 & 33 μ · μ 3 · η μ ϊ — ι 3 £ Ό μ 3S> μ Η> ι · Η μ

SorH> μ Μ> Λ 33

ν ό 3 3 με χμ μ S

3 · Η · ι-ι 3 30 _ 3 * Ί 3 β Ö0 3 Ο τ — I μ ^ Ό β i-4ft, Π · Η 3 3 r £ 5> i WS η-4 ft 3 I Τ — I Η > 03 33 3 tj «μ 00 3 Τί 3 ^ 3 ^ 3 3 8 μμ« μ 3 μ r-ι ι- <μ 33 3 »- W μ 3 33 03 μ • η-, 3 ·> I rO 3 ομ ο Μ μ μ cm ο μ μ Ό μ * 00 ο Λ 2 °? ν — ι τ— 3 3 η · μ ^> ο ο μ | v_i> _q g 3 r-ιμ Ό 3 <· I μ 33 33, 3 μ 3 μ μ, 3 3 3 hf1-1 333 · Η 33 3> 6 3 μ 3 «μ μωμμ 3 Μ ϋ ν >> öo μ, ϋ 3 SPSP S <2 • μ 3 w 3 · μμ · Η a Ö 3 ^ 3 3 ο 3 · η 3 3 3 · μ · μ Η μ, η 8 Ό μ ^ μι-ι τ) μ μμ £ Τι 3, η, η Ο βμ Η 3 3 3 · Η 3 μ 3 · Η · Η 3 33 00Ο3Λ Ö03 003}, ft Ν 1—133 3 > μ 6 μ S <ο ι-ι μ c <3 3 μ μ3 30 33, ϋ · η μ> ^ η 1¾00>,

3 fl ί Η 30 3 Η Vi Ü-P

3} · μϋ>, 33 rC 33 μ ÖOO ομ ο μ »3 οο at ο ο ο μ>, 3 Ο μ ^! μΒ <3-33> 0 ft ft rO rO ft 1-1 ftO η,,>

Ml μ M3 M ^ i τ- »ÖOfO ^ CÖ ÖOO Ö0C3. 25 3lcnu 33 33 3 0 S g 3 ii>, 3μ 33 33> ί> 0>, μ> <} ÖO β Ö03> 3 3 μ »3 OO μ3 μ3 J3 · Η00 • η μ o ft · η · μ> 3 μ μ 3 3 3 3 0 33 30 "22 _5 · η η

ε μ μ ÖO SSi-j'OO

CO * Η <Ü CU CO · τ4 CO (U cö 5 ö Η p-iHdOO r-i + J rH nd CÖH ö »HCÖ cö!> Co cd co cd öOg cd & kO g 0 4Juu (ü« öi aio a) cd · η o öoa) Q Μ Ή LO OM Q> P <NH> g

y - \ / -S

kO r »CO <3 ^ O

8401932 a ~ - 35 - / - s ^ r-i r-4 2 2

r-1 r-4 ° C

o O Cd CÖ CC ΐ Λ Π) CO 4J + i ja js <u <u V 4J r * r *

O) o) C C

* r-l · ι-Ι

C C

• ft · ι-ί * ”·« -! * C Ό W f "· 1

nO ^ ÖO ÖO

'ao ~ aü i i i σ> σ »i i i i I I i * * * *

A A

, - O O

o II II II »

§ cc o O

§ WW WW

p co c <u> o yes g ^ 3 8, ί I ï ï I I I I I I I '1 S>' 5, +, I +

H

Ό

C

• H

<u> <u Ό C ·· CO u g 1 ^ 33.1125,11111 .....

M I ΰ c co "-. I + I I +

flj iH

4J 0) ca C C O <u ü Ό

• H

You 3

CSr-1 CHIW t «lw H- | IW H-l <4-1 UJ

x * .2 .2 -2 .2 .3 ë s o .2 .2 o I I I ë I I I

& § s. "S" ooooiis'S'saiiiSiii «öCöCö'g'g ^^ yes ^" S'a "S'S" uü ^

® Η H

_S.W Η HH Μ H> mwm «1- |, -,> ^ £ ί! Τιϋ ^^ 0υ00>

84 0 1 9 3 Z

- 36 - / -s -'v ^ O 'O ·; _), _ [r-l i- * f * r-l 0 0 O o o o d d e d ö d nj ni 3 5 2 2

Yy y rd rd rö

M £ WW WW

(U o (U <U (U <u (-o d ö ö c .¾ · Η · Η · Η * W ·> - * iH iW £ <“* £ £ T3 ig Ό * d T3

So'oi I | 1 I 60 ÖO I I I I I I60Ö0I I

U ~ 1 00 in m «·>" * *

O O O O O O

II II II II I II

u o u o o o C · C- w ^ w vw oo oo oo vO 00 CO CO 00 o

T- | l 1 I ICOCOllIllt ^ CM

| + +1 I + I I

oo oo oo

CV) <N -T <1 * CO CO

7 + 1 1 1 1 1 +? 1 1 1 1 "7 + 1 I

IM y-1 LM LM <W im * W * W <W * W * W * W

oo Mil) | -i (ü ^ a) l-1 (ÜW oo

οοο · ηο · ηο · ηο · ρηοο o mcMogggoo> HO

coco S '- * S' - * S> - * Sr- * S '* 3' ^^ ® S 2 S 2 2 2> - * 2 τ- ^ δΟΛοδοΛΟδοοοΟ '^ -' ^ - ΛπΙηίπΙΛΛΟίβ LH'w ' udl'Orn'O-d'Odl'Udldl ^ dl C dd ö C d Ü d

H

| a_ |

Crt_Q O Ti (U MM Μ M ►> MMM

PBse e g e sgöögasgBg || S ö ü a η ö a aaaHöSöööSöa 8401932 - 37 - i i i Μ 3 3

N

U-l o

+ J

CO

i-l <U! -)

U 3 cd 3 S N U

Ο cd Ο cd r-1 ε 35 3 U M-4

+ J-U

II I j§ g + Y + j 3 3 o o N N (D 3 • Η · ι-ϊ

<U «+ J

W · Η 1W

cd Ό 'ΰ 3 3 3 cd cd <11 H fi' r-i 3 3 5 • ^ 330 it i H N N>> + J -P <U CU 0) 3 t-l

T3 wC 3Ϊ 3 U

aa ö «cd cd« $ 3>>> ω μ ε β ε Λ Η-IH Ρ 1 1>> ο ο ο <u ^ >>> ·> - »> d 3 'r1 Η 3« «« £ y_I ^ ^ 33 10 33 Ρ1 g.2 >> o 3ÖÖÖ g Γ-Ι 0) <U CO · Η · Η · Η · Η * ° TS m II Β «Β Ö d W ^ '3! 3 „J3 ϋ CW ö Η Λ Μ> <j Μ 1—1 Μ 8401932 1> <« Ê - 38 -

The compounds of the invention in free form or optionally in the form of their physiologically acceptable salts are distinguished by interesting pharmacological properties. They can be used as medicines.

They show typical actions for calcium channel blockers. They show a pronounced muscle-relaxing effect, in particular on the smooth muscles, as evidenced by vasodilatory and blood pressure-lowering effects observed in standard tests. For example, in the test on the anesthetized cat, they effected using "tracer" micro-bullets (R. Hof et al., Basie Res. Cardiol. 75, 1980_7 747-756 and 76 (1981) 630-638; R. Hof et al J. Cardio-vasc Pharmacol. 4 / 1982J 352-362) coronary vasodilation, an increase in skeletal muscle bleeding and a decrease in blood pressure after intravenous administration from about 3 to about 300 µg / kg, for example from about 10 to about 100 µg / kg.

A decrease in blood pressure was also noted in the awake spontaneously hypertonic rat (method of Gerold and Tschirki, Arzneimittelforschung 18 / 1968_ / 1285) after administration of about 1 to about 10 mg / kg po. The compounds work longer than known standard compounds and they are suitable, for example, for once-a-day administration. Moreover, the compounds are absorbed particularly well perorally.

They are therefore suitable as calcium channel blockers for the prophylaxis and therapy of coronary insufficiency, for example Angina 30 pectoris, - further circulatory disturbances, for example in the limbs, such as lameness from time to time and spasms, for example colic, - asthma, for example by exerted asthma and 8401932 * - 39 - - hypertonia.

They also exhibit a vasodilatory action on the capillary blood vessels in the carotid region and the vaso-constrictive action of serotonin is thereby suppressed and the associated dysregulation inhibited. They are therefore suitable for the prophylaxis and treatment of migraine and vascular headaches, such as "cluster headache", in particular for the interval treatment (prevention) of migraine. Preferred in this indication are compounds which exert a relatively modest effect on blood pressure and peripheral blood vessels.

For the above medicinal uses, the dose to be used naturally varies with the substance used, mode of administration and desired treatment. In general, however, satisfactory results are achieved with a daily dose of about 1 mg to about 200 mg, and administration may be in 1 to 3 partial doses or as a retard form if necessary. Suitable dosage forms for, for example, oral or non-oral administration generally contain from about 0.3 to about 200 mg, optionally in addition to solid or liquid carriers. For example, a suitable daily dose is about 5 to about 50 mg.

Preference is given to the compounds mentioned in the titles of Examples II, V, XIV, XXIX and XLI, in particular Examples II and XIV.

Preferred in the prophylaxis and treatment of migraine and vascular headaches are the compounds wherein Q represents a 2,1,3-benzthiadiazolyl moiety.

The compounds of the invention can be administered in free form or optionally in the form of their physiologically acceptable salts, preferably acid addition salts alone or in suitable dosage form. The drug forms, for example, a capsule suitable for, for example, sublingual administration, or a tablet, can be prepared by analogy with known methods. The invention therefore also relates to pharmaceutical preparations containing the compounds of the invention in free form or optionally in the form of their physiologically acceptable salts, and to the manufacture of these pharmaceutical preparations. In the manufacture of these preparations, the auxiliaries and carriers customary in pharmacy can be used.

10 8401932

Claims (4)

A new compound, characterized in that it has the formula 1, wherein R 1 represents hydrogen, cycloalkyl of 3 to 7 carbon atoms, or optionally substituted alkyl 5 of 1 to 6 carbon atoms, and R 1. independently represent hydrogen or alkyl of 1 to 6 carbon atoms, Rg represents alkyl of 1 to 12 carbon atoms or independently has the meaning indicated below for -AR ^, including the reservation therein, R ^ stands for hydroxyl, alkoxy of 1 to 12 carbon atoms, -OCORg, -NR ^ Rg or -Ng, wherein Rg represents alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 7 to 12 carbon atoms or bisphenylalkyl of 13 20 to 18 carbon atoms, these three radicals optionally mono-or equal or different di- or equal or different trisubstituted in the phenyl rings with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, hydroxyl or halogen with an atomic number of 9 to 53, a 5-membered heteroaryl radical with 1 heteroatom from the series of nitrogen 8401932 9 - 42 - u dust, oxygen and sulfur or 2 hetero atoms from the series nitrogen and either 1 nitrogen, or oxygen, or sulfur, or a 6-membered heteroaryl radical with 1 to 5. nitrogen atoms,! R_ represents hydrogen or the above represents R '7 6; has the indicated meaning, \ Rg stands for hydrogen, alkyl with t to 6 carbon atoms or -CORg, in which: 10 Rg has the meanings indicated above for R ^, 'I represents: a 5-, 6- or 7 -membered 1 heterocyclic ring, optionally, in: - if it is saturated or 6- or 7-membered, containing a further heterolid from the series of oxygen, sulfur and = NR, wherein 1U represents R10 or hydrogen either; I the meaning indicated above for RV 1. i j, j i 20 A for alkylene of 2 to 14 carbon atoms j I I! and: Q represents a canceled, completely unsaturated ring-j system with a total of at least 2 different ring hetero atoms and having an aromatic i i 25 character; on the understanding that, i! | in case R 1, hydroxyl, alkoxy with 1 to 6 carbon atoms, -N 2 means as defined above or -NR 1, R 1 g, where! 30 in j R '^ stands for hydrogen, alkyl with 1 to 6 carbon atoms, not! substituted phenyl or not! substituted phenylalkyl of 35 to 10 carbon atoms and 8401932 * - 43 - Rfg represents hydrogen or alkyl of t to 6 carbon atoms, A represents alkylene of 7 to 14 carbon atoms, 5 and their ammonium salts, wherein R 1 represents any of the above for R defined tertiary amino groups and quaternized with a group of the formula AlkY, wherein Alk represents alkyl of 1 to 4 carbon atoms and Y represents an acid residue, in free form or optionally in salt form. A compound according to claim 1, characterized in that it has 4- (2,1,3-benzoxadiazol-4-yl) -1,4-di-hydro-5-sulfopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid - / 10- (N-benzylmethylamino) -decyl / ester, in free form or in salt form. A process for preparing a compound defined in any one of the preceding claims, characterized in that a corresponding compound of the formula 2, wherein Rj, Rl, R5 and Q have the above meanings, Z stands for a reactive group and Z 'either means a reactive group or has the meaning indicated above for -OR ^, converts efficiently and the compound thus obtained into free form or possibly in salt form wins. 4. Pharmaceutical preparation, characterized in that it contains a compound defined in claim 1 or 2 in free form or in the form of a physiologically acceptable salt. 35 8401932 'Jx wN \ RjOOC— [jji — COO —AR), Γ JT X "l!" 00vC "" - »° R' t JX la Re X'Rr QR? R ^ OOCNr ^ YC00_AbRJ | b QP Ri A \ f R'P ° ° CyL C0 ° “A” R? Ri 1b r ^ n ^ r1 ^ lp co ° | ^ CV? Nxx Rfooc-jP ^ -COO-ASR ^ Re 1T'Rl R ° aÖOC JT C00-AaVa H is TT r ^ n ^ r, laa bb 9 b bb R r3 odc I coo-ar, vXjX · * »? Boc f coo-AbBib R R1 N 1 bb Re 1fX 1 02 nb V ^ N / X RvyNs Rh ^ OCl C00-AbRf Rj OOC mn Aab Dab i? X Tl T vXr 'rAiAr 1 11 Daachnr η ™ ΑαααΓΛααα z I * »^ 0C 1 coo-A * R,) bM z'-OC JLcO-Z 1 R, a 1aaa WNX JX ctK * R 2% Α.ν / 4 3 '8401932'