CH663616A5 - 1,4-DIHYDROPYRIDINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME. - Google Patents

Description

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

The invention relates in particular to the compounds of the formula I.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

3rd

663 616

Q

wherein

Ri hydrogen; Cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl having 1 to 6 carbon atoms;

R2 and Rs independently represent hydrogen or alkyl having 1 to 6 carbon atoms;

R> for alkyl having 1 to 12 carbon atoms or independently has the meaning given below for -AR4,

R4 stands for; Hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCORe; -NR7R8; or -NB; wherein

Re means; Alkyl of 1 to 6 carbon atoms; Phenyl, phenylalkyl with 7 to 12 carbon atoms or bisphenylalkyl with 13 to 18 carbon atoms, these three radicals optionally being mono- or identical or differently di- or identical or differently trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number of 9 to 53; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur; or a membered heteroaryl radical having 1 to 4 nitrogen atoms;

R7 represents hydrogen or has the meaning given above for Rs;

Rs stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; or -COR9, in which R9 has the meaning given above for Re;

-NB means: a 5-, 6- or 7-membered heterocyclic ring which, if saturated and optionally 6- or 7-membered, contains a further hetero-member from the series oxygen, sulfur and = NR10, where Rio means either hydrogen or the has the meaning given above for Re;

A represents alkylene of 2 to 14 carbon atoms; and Q represents a fused, completely unsaturated ring system with at least 2 different ring heteroatoms in total and with an aromatic character;

with the proviso that if

R4 hydroxy; Alkoxy of 1 to 6 carbon atoms; -NB as defined above; or -NR5R6 means wherein

R5 stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and

Rè represents hydrogen or alkyl of 1 to 6 carbon atoms;

then A represents alkylene with 7 to 14 carbon atoms; and their ammonium salts, in which R4 is one of the tertiary amino groups defined above for R4 and is quaternized with a group of the formula AlkY, in which Alk is alkyl having 1 to 4 carbon atoms and Y is the rest of an acid.

Hereinafter, these compounds are briefly referred to as “the compounds according to the invention”.

Some of the compounds according to the invention fall under the very general disclosure of Bayer EP 42 089.

Some of the compounds according to the invention also fall under the very general disclosure of Bayer EP 88 276 and Takeda EP 94 159. These publications took place in September 1983 and November 1983, respectively. on a later date than that for the inventive

Connections claimed priority date, June 21, 1983.

1 However, none of the compounds specifically disclosed in the above-mentioned European publications fall within 5 the scope of the present invention.

Further disclosures relating to the compounds related to the compounds according to the invention provide e.g. represents:

Sandoz EP 150 10 Sandoz DOS 29 49 464 Sandoz DOS 29 49 491 Sandoz BE 890 311 Bayer EP 71819 Fisons EP 80 220 15 Sandoz DOS 33 20 616.

The publications mentioned above do not suggest any specific compounds similar to the compounds according to the invention. The compounds 20 according to the invention have a particularly interesting pharmacological profile.

A preferred group of compounds according to the invention consists of the compounds of the formula Ia

35

wherein

R stands for: hydrogen; Alkyl of 1 to 4 carbon atoms; Alkoxy of 1 to 4 carbon atoms; Alkylthio of 1 to 4 carbon atoms; Alkylsulfonyl with 1 to 4 carbon-40 atoms; Halogen with an atomic number from 9 to 35; Trifluoromethyl; Nitro; or hydroxy;

Ri means: hydrogen; Alkyl of 1 to 6 carbon atoms; Alkenyl having 3 to 6 carbon atoms, the double bond being separated from the nitrogen atom by at least one carbon atom which is not involved in 45 of the double bond; Alkynyl having 3 to 6 carbon atoms, the triple bond being separated from the nitrogen atom by at least one carbon atom which is not involved in the triple bond; Cycloalkyl of 3 to 7 carbon atoms; Cycloalkylalkyl 50 having 4 to 8 carbon atoms; Hydroxyalkyl of 2 to 6 carbon atoms, the hydroxy part being separated from the nitrogen atom by at least 2 carbon atoms; Alkoxyalkyl of 2 to 6 carbon atoms; or phenylalkyl with 7 to 9 carbon atoms or phenylalkenyl with 9 to 55 12 carbon atoms, where the double bond is separated from the nitrogen atom by at least one carbon atom not involved in the double bond, and where the latter two radicals are optionally mono- or identical or different in the phenyl ring 60 are identical or different trisubstituted by, independently of one another, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halogen having an atomic number of 9 to 35 or hydroxy; Alkylcarbonyloxyalkyl having 2 to 6 carbon atoms in the alkylcarbonyl and in the alkylene part, and wherein oxygen is separated from the nitrogen atom by at least 2 carbon atoms; Dialkylaminoalkyl with independently 1 to 6 carbon atoms in the alkyl part and with 2 to 6 carbon atoms in the alkyl part, and where the amino

663 616

4th

no group is separated from the nitrogen atom by at least 2 carbon atoms; or morpholinoalkyl having 2 to 6 carbon atoms in the alkylene part, the morpholino part being separated from the nitrogen atom by at least 2 carbon atoms;

R.2 and Rs have the meaning given above;

R! for alkyl having 1 to 12 carbon atoms or independently has the meaning given below for -AaRl;

Rl stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCORl; -NR7RI; or -NB as defined above; wherein

RI, Ra and Rl have the meaning given above for R7, R7 and Rs;

Aa is alkylene of 2 to 14 carbon atoms; and

X represents oxygen or sulfur;

with the provisos that

a) if Rl is hydroxy or -NB as defined above, then Aa is alkylene of 7 to 14 carbon atoms, and b) if Rl is alkoxy of 1 to 12 carbon atoms or -NRa Rl, wherein

R? means: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and

Rl represents hydrogen or alkyl having 1 to 6 carbon atoms,

then Aa means alkylene with 9 to 14 carbon atoms; and their ammonium salts, in which R1 is one of the tertiary amino groups defined above for R1 and is quaternized with a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula Ia, Aa means alkylene with 9 to 14 carbon atoms. In another subgroup, R1 is not alkoxy. In another subgroup, R! and Rl -NR7RI or -NB as defined above.

A preferred group of compounds of the formula Ia consists of the compounds of the formula Iaa

R

R.

'2

wherein

R, Rï, R2, Rs and X have the meaning given above,

Rja stands for alkyl with 1 to 6 carbon atoms;

Rla has the meaning given above for Rl; and

Aaa is alkylene of 2 to 14 carbon atoms; with the provisos that a) if Rla denotes hydroxy or -NB as defined above, then Aaa represents alkylene with 7 to 14 carbon atoms; and b) if Rla for alkoxy with 1 to 12 carbon atoms or -NR? Rl 'is where R7' and Rl 'are as defined above,

then Aaa means alkylene with 9 to 14 carbon atoms; and their ammonium salts, in which Rla is one of the tertiary amino groups defined above for Raa and is quaternized with a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula Iaa, Aaa means alkylene having 9 to 14 carbon atoms. In another subgroup, Raa does not stand for alkoxy. In another subgroup, Raa stands for -NRfRl or -NB as defined above.

Another preferred group of compounds of the formula Ia consists of the compounds of the formula lab lab

XX

wherein

R, Ri, R2, Rs and X have the above meaning,

"Have meaning,

Rlb means alkyl with 1 to 12 carbon atoms or have.

independently has the meaning given below for -AabRtab;

Rlb stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCORl; or -NRfRl; wherein

Rl, Ra and Rl have the above meaning; and

Aab represents alkylene having 2 to 14 carbon atoms; with the provisos that a) if Rlb is hydroxy, then Aab is alkylene having 7 to 14 carbon atoms; and b) if Rlb is alkoxy having 1 to 12 carbon atoms or -NRf Rl, in which Ra and Rl have the above meaning,

then Aab means alkylene with 9 to 14 carbon atoms; and their ammonium salts, in which Rlb represents one of the tertiary amino groups defined above for Rab and is quaternized with a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula lab, Aab means alkylene with 9 to 14 carbon atoms. In another subgroup, Rlb does not represent alkoxy. In another subgroup, R! B and Rab mean -NRfRl as defined above.

Another preferred group of compounds of the formula Ia consists of the compounds of the formula Iaaa

R

100C

XX

R,

2nd

wherein

R, Rï, R25 Rs and X have the above meaning,

R! Aa is alkyl of 1 to 6 carbon atoms;

Raaa stands for: Hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCORl or -NRfRl, in which Ra, Ra and Rl have the above meaning; and

Aaaa means alkylene of 2 to 14 carbon atoms; with the provisos that a) if Raaa is hydroxy, then Aaaa is alkylene having 7 to 14 carbon atoms; and

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

663 616

b) if Raaa is alkoxy having 1 to 12 carbon atoms or -NRf Rl ', where Rf' and Rl 'are as defined above, then Aaaa is alkylene having 9 to 14 carbon atoms;

and their ammonium salts, in which Raaa stands for one of the tertiary amino groups defined above for Rfa and is quaternized with a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula Iaaa, Aaaa means alkylene having 9 to 14 carbon atoms. In another subgroup, Raaa does not represent alkoxy. In another subgroup, Raaa means -NRfRl as defined above.

Further groups and subgroups of compounds according to the invention are the compounds of the formula Ia, Iaa, lab and Iaaa in which R? Is hydrogen or alkyl having 1 to 4 carbon atoms, preferably hydrogen or methyl, in particular hydrogen; those in which R2 and Rs are hydrogen or alkyl having 1 to 4 carbon atoms, especially methyl; those in which R is hydrogen; and those in which X represents oxygen; and their combinations;

and optionally their corresponding quaternary salts as defined above.

Another preferred group of compounds according to the invention consists of the compounds of the formula Ib

R3OOC

IjC

COO-AbRj where

Ri, R>, R5 and Q have the above meaning;

Rb is alkyl of 1 to 12 carbon atoms or independently has the meaning given below for -AbRb;

Rb stands for: hydroxy; 1 to 12 carbon alkoxy

-NB;

atoms; -OCOR0; -NR? Rs; or as defined above wherein Rg, Rb and Rs have the meaning given above for R6, R7 and Rs, respectively; and

Ab means alkylene of 9 to 14 carbon atoms; and their ammonium salts, in which Rb stands for one of the tertiary amino groups defined above for Rb and is quaternized with a group of the formula AlkY as defined above.

In a subset of compounds of formula Ib, Rb is not alkoxy. In another subgroup, R3 and Rb mean -NRbRs or -NB as defined above.

A preferred group of compounds of the formula Iba consists of the compounds of the formula Iba

R ^ OOCv ^

C00-AbRÌJ

is based on a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula Iba, Rb does not represent alkoxy. In another subgroup, Rb means -NRbRb or -NB as defined above.

Another preferred group of compounds of the formula Ib consists of the compounds of the formula Ibb

Rbb00C

C00-Ab-Rjb

Ibb

20th

25th

30th

Ib where

Ri, R2, Rs, Abn and Q have the above meaning;

Rbb represents alkyl having 1 to 12 carbon atoms or independently has the meaning given below for -AbRbb;

Rbb means: hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCORb; or -NRbRb; wherein

Rb, Rb and Rb have the above meaning;

and their ammonium salts, in which Rbb stands for one of the tertiary amino groups defined above for Rbb and is quaternized with a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula Ibb, Rbb does not represent alkoxy. In another subgroup, Rbb and Rbb mean -NRbRs as defined above.

Another preferred group of compounds of the formula Ib consists of the compounds of the formula Ibaa

35

rÎ53ooc ff

3 -4

C00-AbRbb

JLJL

Ibaa

50

55

Iba

K1

wherein

Ri, R2, Rba, Rbb, Rs, Ab and Q have the above meaning; and their ammonium salts, in which Rbb represents one of the tertiary amino groups defined above for Rbb and is quaternized with a group of the formula AlkY as defined above.

In a subgroup of compounds of the formula Ibaa, Rbb does not represent alkoxy. In another subgroup, Rbb means -NRbRb as defined above.

Further groups and subgroups of compounds according to the invention consist of the compounds of the formulas Ib, Iba, Ibb and Ibaa, in which R 1 for R as defined above? stands, in particular for hydrogen or alkyl, preferably hydrogen or methyl, in particular hydrogen; those in which R2 and Rs are hydrogen or alkyl having 1 to 4 carbon atoms, especially methyl; those in which Q represents a group of the formula wherein

R 1, R 2, R 4, Rs, Ab and Q have the above meaning and Rja is alkyl having 1 to 6 carbon atoms; and their ammonium salts, in which Rb represents one of the tertiary amino groups defined above for Rb and quaternized

N '

65

where R and X are as defined above, in particular ^ those in which R is hydrogen; and those in which X is oxygen; and their combinations;

663 616

and optionally their corresponding quaternary salts as defined above.

Another group of compounds according to the invention consists of the compounds of the formula Ip,

• Qp in which

R1 represents hydrogen or alkyl having 1 to 4 carbon atoms;

RS and IS independently of one another represent alkyl having 1 to 4 carbon atoms;

RP3 is alkyl of 1 to 6 carbon atoms or independently has the meaning given below for -ApRS;

RS means: hydroxy; Alkoxy of 1 to 6 carbon atoms; -OCORS; -NR9RS; or -N | wherein

R§ stands for: alkyl with 1 to 6 carbon atoms; Phenyl, phenylalkyl having 7 to 10 carbon atoms or bisphenylalkyl having 13 to 16 carbon atoms, these three radicals optionally being mono- or identical or differently di- or identical or differently trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number of 9 to 53; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur; or a membered heteroaryl radical having 1 to 4 nitrogen atoms;

R5 means: hydrogen; Alkyl of 1 to 4 carbon atoms; or with the exception of alkyl having 1 to 6 carbon atoms has the meaning given above for RS;

Rl represents: hydrogen or alkyl having 1 to 6 carbon atoms; or means -CORS, in which RS has the meaning given above for RS;

-Nb means: a 5-, 6- or 7-membered, saturated heterocyclic ring which, if it is 6- or 7-membered, optionally contains a further hetero-member from the series oxygen, sulfur and = NRß, in which Ri? either represents hydrogen or has the meaning given above for R9;

A represents unbranched alkylene of 2 to 14 carbon atoms; and

Qp stands for a fused, completely unsaturated two-ring system with at least 2 different ring heteroatoms in total and with at least one aromatic ring;

with the proviso that if

RS hydroxy; Alkoxy of 1 to 6 carbon atoms; -N £ as defined above; or -NRt'pRj'p; wherein

R7'p stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and

Rs'p is hydrogen or alkyl of 1 to 6 carbon atoms;

then Ap means unbranched alkylene of 7 to 14 carbon atoms;

and their ammonium salts, in which RS is one of the tertiary amino groups defined above for RS and is quaternized with a group of the formula AlkY as defined above.

In a subset of compounds of formula Ip, RB means alkyl of 1 to 6 carbon atoms; in another subgroup it stands for alkyl with 1 to 3 carbon atoms; in another sub-group it means -ApRS, where Ap and RS have the above meaning; in another subgroup, RS is not alkoxy; in another subgroup, Ap means unbranched alkylene of 7 to 14 carbon atoms; in another subgroup Ap stands for unbranched alkylene with 9 to 14 carbon atoms; in another subgroup, R means hydroxy; Alkoxy of 1 to 6 carbon atoms; -OCORS; or -NRBRS, where RS, RS and RS have the above meaning; and their combinations,

and optionally their corresponding quaternary salts as defined above.

A preferred group of compounds according to the invention consists of the compounds of the formula Is

R, OOC

H

wherein

Ri and Rl independently represent alkyl of 1 to 4 carbon atoms;

R! Means alkyl of 1 to 12 carbon atoms;

Rl stands for: hydroxy; Alkoxy of 1 to 4 carbon atoms; -OCORl; -NR7RI; or -N |; wherein

Rl is alkyl of 1 to 4 carbon atoms or phenyl;

R? stands for: hydrogen; Alkyl of 1 to 4 carbon atoms; optionally in the phenyl ring by alkoxy having 1 to 4 carbon atoms or halogen having an atomic number of 9 to 53 mono- or identically or differently disubstituted phenylalkyl having 7 to 10 carbon atoms; -CORI, wherein Rl is alkyl of 1 to 4 carbon atoms; or optionally in the phenyl ring by alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number from 9 to 53 mono- or identically or differently disubstituted phenyl or phenylalkyl with 7 to 10 carbon atoms;

R1 represents hydrogen or alkyl having 1 to 4 carbon atoms;

-Nb represents piperidine or piperazine, both substituted in the 4-position by methyl, benzyl or optionally in one or both phenyl rings by halogen with an atomic number from 9 to 53 or alkoxy with 1 to 4 carbon atoms mono- or identical or differently disubstituted bisphenylmethyl ; and

As represents alkylene of 2 to 14 carbon atoms; with the proviso that if

Rl means: hydroxy; Alkoxy of 1 to 4 carbon atoms; -Nb as defined above; or -NR7RI, wherein

R! for hydrogen; Alkyl of 1 to 4 carbon atoms; or unsubstituted phenylalkyl having 7 to 10 carbon atoms; and

Rl has the above meaning;

then A is alkylene of 7 to 14 carbon atoms; and their ammonium salts, in which R1 is one of the tertiary amino groups defined above for R1 and is quaternized with a group of the formula AlkY as defined above.

In a subset of compounds of formula Is, As is alkylene of 7 to 14 carbon atoms; in another subgroup it stands for alkylene with 9 to 14 Koh6

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

663 616

len atoms; it is unbranched in another subgroup.

In a further subgroup of compounds according to the invention, R 1, Rv and / or Rs are substituted phenyl, substituted phenylalkyl or substituted bisphenylalkyl.

In a further subgroup, R 1 is hydrogen or alkyl having 1 to 6 carbon atoms; in a further subgroup, R2 and Rs independently of one another represent alkyl having 1 to 4 carbon atoms; in a further subgroup, R3 represents alkyl having 1 to 6 carbon atoms; in another subgroup, R3 means -ApRS as defined above; in a further subgroup, A denotes unbranched alkylene and Rf has the meaning given above for RS, including the corresponding measure; in another subgroup, Re, R? or Rs has the meaning given above for R?, RB or RS; in a further subgroup, -Nb has the meaning given above for -Nß; in another subgroup, Q is bicyclic; in a further subgroup Rt stands for alkoxy with 1 to 6 carbon atoms; in a further subgroup, substituted or unsubstituted phenylalkyl contain 7 to 10 carbon atoms in the phenylalkyl skeleton and substituted or unsubstituted bisphenylalkyl contain 13 to 16 carbon atoms in the bisphenylalkyl skeleton; in another subgroup, R? the meaning given above for RS. In a further subgroup, all non-fused phenyl rings are substituted.

Ri preferably has the above for R? given meaning. Rï is preferably hydrogen. If it is not hydrogen, it preferably means unsubstituted alkyl, cycloalkylalkyl, optionally substituted phenylalkyl, alkoxyalkyl or morpholino, preferably unsubstituted alkyl or alkoxyalkyl, preferably unsubstituted alkyl. If R? Alkoxyalkyl means, the alkoxy part is preferably separated from the nitrogen atom by at least 2 carbon atoms.

R2 and / or Rs are preferably alkyl.

R3 preferably represents alkyl. If it has the meaning given above for -AR4, it is preferably identical to -AR4.

R4 preferably represents hydroxy, -OCORe, -NR? Rs or -NB.

Q preferably has at least 3 heteroatoms in total, in particular 3 heteroatoms. It preferably represents a bicyclic ring system. Preferred groups Q represent 2,1,3-benzoxadiazolyl and 2,1,3-benzothiadiazolyl, in particular 2,1,3-benzoxadiazolyl. If Q represents a ring system which contains a benzene ring component, the 1,4-dihydropyridinyl radical is preferably bound to this benzene ring component, preferably in a position of the benzene ring component which is adjacent to further ring components.

A is preferably unbranched. It preferably has 7 to 14, preferably 9 to 14, in particular 10 carbon atoms.

Alk preferably means methyl.

Y preferably represents the residue of an inorganic acid, e.g. for mesyl or halogen, especially for iodine.

Re is preferably alkyl, phenyl, phenylalkyl or bisphenylalkyl, especially phenyl.

R7 preferably represents hydrogen, alkyl, phenylalkyl or bisphenylalkyl.

Re is preferably hydrogen, alkyl or -COR9.

Preferably R7 and Rs are both hydrogen, or one of R7 and Rs is alkyl and the other is alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl.

R9 preferably represents alkyl, optionally substituted phenyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl.

As defined above, -NB is preferably saturated. It is 5, preferably 6-membered. It preferably means 1-piperazinyl. If it is 6 or 7-membered, it preferably contains a further hetero-link = NR10. Rio preferably has a different meaning than hydrogen. It preferably means alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl.

X preferably represents oxygen.

R is preferably hydrogen.

The rest

20 is preferably bound in its 4-position to the 4-position of the 1,4-dihydropyridinyl radical.

Cycloalkyl with 3 to 7 carbon atoms preferably contains 3, 5 or 6, in particular 5 or 6, carbon atoms.

Alkyl having 1 to 12 carbon atoms and / or alkoxy 25 having 1 to 12 carbon atoms preferably contain 1 to 6, in particular 1 to 4, carbon atoms, they are preferably methyl, ethyl or isopropyl. Alkyl having 1 to 6 carbon atoms preferably contains 1 to 4, in particular 1 or 2, carbon atom (s), it means in particular 30 methyl. If alkyl with 1 to 6 or with 1 to 4 carbon atoms represents a phenyl ring or amino substituent, it preferably contains 1 or 2 carbon atoms and in particular means methyl. If alkoxy having 1 to 4 carbon atoms represents a phenyl ring substituent, it preferably contains 1 or 2 carbon atoms and in particular means methoxy. If halogen with an atomic number of 9 to 53 represents a phenyl ring substituent, it preferably means chlorine, bromine or iodine, in particular chlorine or iodine. Alkenyl and / or alkynyl preferably contain 40 carbon atoms. The cycloalkyl part of cycloalkylalkyl preferably contains 3.5 or 6, in particular 5 or 6, carbon atoms. The alkylene part of cycloalkylalkyl and / or of phenylalkyl preferably contains 1 or 2 carbon atoms, it means in particular methylene. The 45 alkenylene portion of phenylalkenyl preferably contains 3 carbon atoms. The alkylene part of hydroxyalkyl with 2 to 6 carbon atoms and / or of alkoxyalkyl with 2 to 6 carbon atoms preferably contains 2 or 3, in particular 2, carbon atoms. The hydroxy part of hydroxyalkyl 50 and / or of hydroxyalkyl and / or the amino part of aminoalkyl are preferably attached to the most distant, end-chain carbon atom.

If a phenyl ring occurs in a substituent, it is preferably unsubstituted. If it is substituted, it is preferably monosubstituted, preferably in the para position. If it is disubstituted, it is preferably substituted in the ortho or meta and in the para position. If it is trisubstituted, it is preferably substituted in the meta-meta and para positions. Alkoxy and / or halogen are preferred sub-60 substituents of a phenyl ring substituent. If a phenyl ring is polysubstituted, the substituents are preferably identical.

The amino part of aminoalkyl is preferably substituted, in particular disubstituted. Preferred substituents 65 of the amino part of aminoalkyl are alkyl and / or optionally substituted phenylalkyl. The amino part of aminoalkyl is preferably disubstituted by alkyl and optionally substituted phenylalkyl.

663 616

8th

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

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

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

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

The compounds according to the invention are obtained by a process which is characterized in that corresponding compounds of the formula II

Q

Z'-OC

: o-z where

Ri, R2, Rs and Q have the above meaning,

Z stands for a reactive group and

Z 'either denotes a reactive group or has the meaning given above for -OR3,

appropriately converted.

The process for the preparation of the compounds according to the invention can be carried out analogously to known methods.

The choice of the most suitable process variant naturally depends on the nature of e.g. the substituents -AR3 and R3.

A process variant can e.g. represent an esterification. A suitable reactive group Z or Z 'in this case is e.g. lH-imidazole-l-yl. This process variant is suitable e.g. for conversion to a hydroxyalkyl, amino-alkyl, alkoxyalkyl, acyloxyalkyl or substituted or unsubstituted aminoalkyl substituent. A corresponding compound of the formula II is reacted with a corresponding diol, amido / alcohol, ester / alcohol or amino alcohol. Suitable solvents are e.g. Dioxane or an excess of the reactant.

Another process variant can e.g. represent an amination. This process variant is suitable e.g. for conversion to an aminoalkyl substituent. A reactive group Z or 71 represents e.g. represents a group -O-A-Z ", in which A has the above meaning and Z" is chlorine, bromine or a group Rz-S02-0-, in which Rz is phenyl, tolyl or lower alkyl. Z "preferably means mesyloxy. The amination can be immediate, ie the reaction takes place directly with an amine which contains the substituent to be introduced, or indirectly, for introducing a primary amino group, by reaction in a corresponding phthalimidoalkyl derivative, for example by reaction with sodium or potassium phthalimide and subsequent reaction with hydrazine of the phthalimido-alkyl derivative thus obtained The indirect method is preferred if the substituent to be introduced represents a primary aminoalkyl group.

Another process variant can e.g. represent an acylation of a primary or secondary amine. A reactive group Z or Z 'then represents e.g. represents the corresponding primary or secondary aminoalkoxy group. A corresponding compound of formula II is thus reacted with a corresponding acyl derivative, e.g. an N-hydroxysuccinimide ester. Suitable solvents are e.g. Dioxane.

Another process variant can e.g. represent an acylation of an alcohol. A reactive group Z or Z '

then puts e.g. represents the corresponding hydroxylakoxy group. Thus, a corresponding compound of formula II with a corresponding acyl derivative, e.g. an acyl halide. The reaction is preferably carried out in the presence of a strong base, e.g. N-ethyldiisopropylamine. Suitable solvents are e.g. Methylene chloride.

Another process variant can e.g. represent a etherification. A reactive group Z or Z 'then represents e.g. represents a group -O-A-Z ", in which A and Z" have the above meaning. The reaction is preferably carried out under strongly alkaline conditions.

If in the starting material Z 'stands for a reactive group, a group -AR4 can arise simultaneously in the 3- or 5-position of the 1,4-dihydropyridinyl skeleton.

Quaternary ammonium salts can be prepared analogously to known methods, e.g. by reaction with corresponding (lower) alkyl iodides. Suitable solvents are e.g. an alcohol like methanol.

If there are potentially reactive groups, such as hydroxyl or primary or secondary amino, it may be appropriate to carry out the process according to the invention with these groups in a protected form, e.g. for phenolic hydroxy in the form of a benzyloxy group, or for aliphatic hydroxy in the form of a tetrahydropyranyloxy group, or for amino in the form of an acylamino or phthalimido group, and then converting the protected groups to the desired substituents, e.g. Benzyloxy in hydroxy, e.g. hydrogenolytic, tetrahydropyranloxy in hydroxy by acid hydrolysis; and protected amino in unprotected amino, e.g. by acidic hydrolysis or hydrazinolysis.

The compounds according to the invention can be isolated and purified from the reaction mixture in a known manner.

The compounds according to the invention can be in free form or optionally in salt form. The free forms are normally neutral, unless there are ionizable substituents. Salt forms can exist, e.g. if ionizable substituents, such as amino or phenolic hydroxy, are present. Salt forms can be obtained from the compounds in free form in a known manner and vice versa. Suitable acids for the formation of acid addition salts are e.g. Hydrogen chloride, malonic acid, p-toluenesulfonic acid and methanesulfonic acid. Suitable bases for the formation of anionic salts are e.g. 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 carbon atom in the 4-position is asymmetrically substituted. The corresponding compounds according to the invention can therefore occur in racemic form or in the form of the individual enantiomers.

The individual enantiomers can be obtained analogously to known methods.

The starting products can be obtained analogously to known methods, e.g. by direct cyclization to the 1,4-dihydropyridinyl skeleton.

Insofar as the production of the required starting materials is not described, they are known or can be produced by methods known per se or analogously to the methods described here or analogously to methods known per se.

In the following examples, all temperatures are given in degrees Celsius without corrections.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

Example 1 :

4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-iso-propoxycarbo-

nyl-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- (1 H-imidazol-1-yl-carbonyl) -2,6-dimethyl- 3-pyridinecarboxylic acid isopropyl ester and 44.5 g of decane-l, 10-diol are heated to an oil bath temperature of 120 ° for 2 hours. After cooling, ether is added. The excess decane-l, 10-diol crystallizes out. After filtering and evaporating the ether in vacuo, the product is chromatographed on silica gel under slight pressure, using methylene chloride / ether as the eluent. The title compound (oil) is obtained.

NMR spectrum (CDCb) ô (ppm): 0.97 (3H, d, J = 6Hz), 1.22 (3H, d, J = 6Hz), l, 15-l, 65 (16H, m), approx.2.32 (6H, 2s), 3.63 (2H, t, J = 6Hz), 3.99 (2H, m), 4.91 (lH, m, J = 6Hz), 5.48 ( lH, s), 5.92 (1H, s), 7.3 (2H, m), 7.62 (lH, m).

Example 2:

4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbo-

nyl-2,6-dimethyl-3-pyridinecarboxylic acid- [10- (N-benzylmethy-

lamino) decyI] esters

(direct amination of the mesylate)

4.6 g of 4- (2,1-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyl) ester and 2 , 2 ml of N-benzylmethylamine are dissolved in 50 ml of ether, the mixture is evaporated in vacuo and the product is heated at 80 ° for 3 hours. The mixture is then dissolved in ether, the solution washed with cold IN sodium hydroxide, the ether phase dried over magnesium sulfate and evaporated in vacuo. The product is purified by chromatography on silica gel using methylene chloride / ethanol 19: 1 as the eluent. The title compound (free base: oil; hydrochloride: amorphous) is obtained.

NMR spectrum of the free base (CDCh) S (ppm): 0.98 (3H, d, J = 6Hz), l, 25 (3H, d, J = 6Hz), l, 15-l, 8 (16H, m),

2.2 (3H, s), 2.34 (6H, s), 2.25-2.45 (2H, m), 3.5 (2H, s),

4.0 (2H, t, J = 6Hz), 4.92 (1H, m, J = 6Hz), 5.48 (1H, s), 5.98 (1H, s), 7.2-7 , 7 (8H, m).

The mesylate used as the starting product is obtained by reacting 4.3 g of the title compound from Example 1 and 4.3 ml of N-ethyldiisopropylamine in 90 ml of methylene chloride at 0 ° with 1.0 ml of methanesulfonic acid chloride, and the mixture is stirred for 90 minutes in an ice bath . The solution is then washed with cold 2N hydrochloric acid solution and the organic phase is dried over magnesium sulfate and evaporated in vacuo.

Example 3:

4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonon-2,6-dimethyl-3-pyridinecarboxylic acid (10-aminodecyl) ester (amination of the mesylate via phthalimido derivative )

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

The 4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-

663 616

Phthalimidodecyl) ester (oil) is dissolved in 40 ml of ethanol, 1.0 ml of hydrazine hydrate is added and the solution is heated to boiling temperature under reflux for 30 minutes. After filtering off and washing with methylene chloride, the solution is extracted with ice-cold water and the organic phase is evaporated in vacuo. The product is chromatographed under slight pressure on silica gel using methylene chloride / methanol (containing ammonia) 9: 1 as the eluent. The title compound (mp 102 ° - from ether) is obtained.

Example 4:

4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid- [10- [3- (4-hydroxy-3 -iodphenyl) -1 -oxo-propylamino] -decyl] ester (amidation of the amine)

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

NMR spectrum (CDCb) 5 (ppm): 0.99 (3H, dJ = 6Hz), 1.1-l, 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 ( 1 H, m, J = 6Hz), 5.53 (lH, s), approx.5.62 (1H, broad), approx.6.55 (2H, broad),

6.9 (1H, d, J = 8Hz), 7.1 (1H, 2d, J = 8Hz and 2Hz), 7.25-7.75 (4H, m).

Example 5:

4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-benzoyloxydecyl) ester

(Acylation of alcohol)

1.2 g of benzoyl chloride are added at 20 ° to a solution of 2.2 g of the title compound of Example 1 and 1.3 g of N-ethyldiisopropylamine in 30 ml of methylene chloride, 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 hydrochloric acid solution, dried over magnesium sulfate and evaporated in vacuo. The product is purified by chromatography on silica gel using methylene chloride / ether 9: 1 as the eluent. The title compound (amorphous) is obtained.

Nuclear Magnetic Resonance Spectrum (CDCb) 4 (ppm): 0.99 (3H, d, J = 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 6:

4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbo-

nyl-2,6-dimethyl-3-pyridinecarboxylic acid- [10- (N-benzylmethy-

lamino) decyl] esters

(Esterification of imidazolide with amino alcohol)

A solution of 4 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dih-ìydro-5- (1 H-imidazol-1 -ylcarbonyl) -2,6-dimethyl-3- pyridincar-jbonic acid isopropyl ester and 7.0 g lO- (N-methylbenzylamino) idecan-lo) in 150 ml dioxane is heated to reflux temperature for 16 hours. The mixture is then evaporated in vacuo and the product heated to 80 ° for 3 hours. The product is purified by chromatography on silica gel with

9

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

663 616

Purification of methylene chloride / ethanol 19: 1 as eluent. The title compound (free base: oil; hydrochloride: amorphous) is obtained.

NMR spectrum: see Example 2.

The amino alcohol used as the starting product is obtained as follows:

a) A solution of 4.5 ml of methanesulfonic acid chloride in 60 ml of methylene chloride is added dropwise to a solution of 20 g of decane-1, 10-diol and 20 ml of N-ethyldiisopropylamine in 800 ml of methylene chloride and 100 ml of acetone and the The mixture is stirred at room temperature for 1 hour. The methanesulfonic acid (10-hydroxydecyl) ester (mp. 48 ° - from ether, after chromatography on silica gel using methylene chloride / ether 2: 1 as the 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 to 80 ° for 2 hours. 10- (N-Methylbenzylamino) decan-l-ol (oil; after chromatography on silica gel using ether as eluent) is obtained.

10th

Example 7:

4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonon-2,6-dimethyl-3-pyridinecarboxylic acid (10-methoxydecyl) esters (etherification of the mesylate)

2.3 g of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyl) ester in 30 ml of methanol are reacted with 0.5 g of potassium methylate and the mixture is heated to reflux temperature for 4 hours. After evaporation in

The product is dissolved in ether in vacuo, the solution is washed with IN 1 hydrochloric acid solution, the organic phase is dried over magnesium sulfate and evaporated. The product is purified by chromatography on silica gel using 1: 1 ether / hexane as eluent. The title compound (oil) is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl3) 8 (ppm) (: 0.98 (3H, d, J = 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 (1 H, s), 6.3 (1 H, s), 7.2-20 7.8 (3H, m).

The following compounds of formula I are obtained in an analogous manner starting from the corresponding starting products:

Example No.

Analog to example no.

R1 R2

AR,

Rç configuration in the 4-position of the 1,4-di-hydropyridiny residue

8th

9

10th

11 IIa

12

13

14

15

16

17th

18th

19th

20th

21st

22

23

24th

25th

26

26a 26b 26c 26d

1 1 1 1 1

22 *; 6

21); 6 2; 6 2; 6 2; 6 2; 6

23); 6

24); 6 2; 6

2; 6 2; 6 2; 6 2; 6

22); 6 21); 6

2; 6; -10> 2; 6 2; 6 2; 6

2,1,3-fenzoxadiazo

-y!

H

Me iPr

2,1,3-fienzoxadiazo

-yl

H

Me iPr

2,1,3-benzoxadiazo

-y!

H

Me

Me

2,1,3-benzoxadiazo

-yl

H

Me

- (CH2) 9Me

2,1,3-benzoxadiazo

-yl

H

Me

Et

2,1,3-fienzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yl

H

Me iPr

2,1,3-benzoxadiazo

-yl

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me

Hey

2,1,3-benzoxadiazo

-yi

H

Me

Et

2,1,3-ßoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-B> enzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

2,1,3-benzoxadiazo

-yi

H

Me iPr

CHj CH, CHj CH, CHj ch2

CH,

ch2

CH, CH. CH. CH,

, 0H 0H

, 0H "0H

10u 10N (He) Bz 10N (Me) Bz 10NO-CH (Phe) 2 10N (He) Bu 10N (Me) CH2CH2Phe

UÜA

10 2

10N (He) Bz 10N (Me) Bz without He 10N (Me) CH2-®- <We

- (CH2) 1QN (Me) CH2CH2 - ^ - OMe He

- (cM2) 10-'O "CH (P-F-ph ^ 2e

- (CH ^ NfMeJCHg- ^ g6 - (CH2) 5N (Me) CH2CH2- @ gte - (CH2) 1QN3-CHPhe2 - (CH2), 0Nli-cHPhe2

- (CH2) 1QNHHe - (CH2) 1Q0-Me

- (CH2) io ~ CN- (o-MeO) Phe - (CH2) lo "N3 ~ CH (phe) 2

Me

<+) (R)

Me

<-) ($)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

(-) (S)

Me

(+) (R)

Me

(R.S)

Me

(R.S)

No

(R.S)

Me

(R.S)

Me

(R.S)

Me

(RjS)

Me

(R.S)

Me

(R.S)

Hey

(R.S)

Me

(R.S)

Me

■ (R.S)

Me

H (S)

Me

(+) (R)

Me

(R.S)

Me

(R.S)

Me

(R.s)

Me

(R.S)

11

663 616

Ex. '

Analogous to

No.

Example number

26 e

2; 6

27th

28

35); 22); 6

29

33> 6>; 23>; 6

30th

2; 6

31

4; 6

32

4; 6

33

4; 6

34

4; 6

35

4 ', 6

36

4; 6

37

4; l7>

38

4; l7>

39

4; 17)

40

5; solve>

41

18>

41a

1

42

.9)

Bu =

R1 R2

Ar,

Configuration in the 4-position of the 1,4-dihy-dropyridinyl residue '

2,1,3 ^ 8enzoxadiazol-4-yl

2,1,3-benzoxadiazol-4-yl 2,1,3-benzoxadiazol-4-yl 2,1,3-benzoxadiazol-4-yl 2,1,3-ßenzoxadiazol-4-yl

2,1,3-3en2oxadiazol-4-yl 2,1,3-ßenzoxadiazol-4-yl 2,1,3-benzoxadiazol-4-yl 2,1,3-benzoxadiazol-4-yl 2,1,3 -benzoxadiazol-4-yl 2,1,3-ßenzoxadiazol-4-yl d, \, 3-ß enzoxadiazol • 2,1,3-B enzoxadi azole -2,1,3-B enzoxadiazol ■

-4-yl l-4-yl -4-yl

2,1,3-benzoxadiazol-4-yl 2,1,3-benzoxadiazol-4-yt

2,1,3-benzoxadiazol-4-yl

2,1,3-benzoxadiazol-4-yl

H - Me iPr

H Me iPr

H Me iPr

H Me

Me

H Me iPr

H Me iPr

K Me iPr

H Me

Me

H Me iPr

H Me iPr

H Me iPr

H Me iPr

H Me iPr

H Me iPr

H Me iPr

H Me iPr

H Me iPr

-OH

(CH2ho-0-ßz ch2) 10nh2 ch2) 10nh2

^ 2 ^ 10NH2

^ 2 ^ 10 ^ 2

ch2) 2nhcoch2ch2 <dr-

CH2) 5NHCOCH2CH2- <g ^^ H

ch2) 1onhcoch2ch2- ^ ~ oh ch2)] 0nhcoch2 - ^ - oh ch2), 0nhcoch2ch2- ^ j oh chgj ^ nhcoch ^ - ^ - j- oh

CH2) 10NHC0Me CH2) 1QNHCOtBu

CH2) 1QNHCOPhe

CH2) 10OCOtBu

CH2) 1Q0C0Phe

- (CH2) 100Me

Me

(R.S)

Hey

(+) (R)

Me

H (S)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

H (S)

Me

(+) (R)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

(R.S)

Me

(R.S)

H Me iPr - (CH2), 0N (+) Me3l ("}

Me

(r.S)

Bz Et

= Benzyl = ethyl iPr = isopropyl Me = methyl Phe = P'henyl tBu = tert-butyl

(R, S) = in racemic form

1 The (+) - (4R) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid- ( 10-methanesulfonyloxydecyl) ester is obtained as an oil starting from the alcohol of Example 8, as described in Example 2 for the corresponding racemate.

2 The (-) - (4S) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid- ( 10-methanesulfonyloxydecyl) ester is obtained as an oil starting from the alcohol of Example 9, as described in Example 2 for the corresponding racemate.

3 The 4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyl) ester used as the starting product is obtained starting from from the compound of Example 10 as described in Example 2 for the corresponding 5-isopropoxycarbonyl compound.

4 The 4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-ethoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-methanesulfonyloxydecyi) ester used as the starting product is obtained starting from from the compound of Example IIa as described in Example 2 for the corresponding 5-isopropoxycarobnyl compound.

5 The (+) - (4R) - and, or (-) - (4S) -4- (2, l, 3-benzoxadiazol-4-yl) -l, 4-dihydro-5-isopropoxycarbonyl-2, 6-dimethyl-3-pyridinecarboxylic acid (10-phthalimidodecyl) esters are obtained as an oil, starting from the mesylate described in footnote 1) or footnote 2), as described in Example 3 for the corresponding racemate.

6 The 4- (2, l, 3-benzoxadiazol-4-yl) l, 4-dihydro-5-methoxycarobnyl-2,6-dimethyl-3-pyridinecarboxylic acid (10-phthalimidodecyl) ester used as the starting product is obtained from the mesylate compound described in footnote 3), as described in Example 3 for the corresponding 5-isopropoxycarbonyl compound.

7 The amido alcohol used as the starting product is obtained by reacting the corresponding amino alcohol with the suitable acylating agent.

8 The alcohol / ester used as the starting product is obtained by reacting an excess of the corresponding diol with the corresponding axylation agent.

9 Starting from 1.4 g of the compound of Example 17 in the form of the free base, dissolved in 20 ml of methanol, by reaction with 0.21 ml of methyl iodide for 4 hours at room temperature.

10 Analogous to example 2, but by splitting off the benzyl protective group from the compound of example 2 as the last stage, using hydrogen over palladium 10% on carbon in methanol.

663 616 12

Physical characterization data for the compounds in the table above is as follows:

Example mp. [A] o [a] o

No.

8th

no oil

+ 20 °

+ 28 °

(c = 1 g / dl in ethanol)

9

no oil

-20 °

-28 °

(c = 1 g / dl in ethanol)

10th

no oil

-

_

-

11

no oil

-

_

IIa no

-

_

_

12

ch amorphous

-14 °

-19 °

(c = 0.9 g / dl in ethanol)

13

ch amorphous

+ 13 °

+ 19 °

(c - 0.9 g / dl in ethanol)

14

at 130 °

-

_

-

15

b oil

-

-

_

16

b oil

-

_

-

17th

at 95 °

-

-

_

18th

ch amorphous

-

-

-

19th

ch amorphous

-

-

-

20th

ch amorphous

-

-

-

21st

ch amorphous

-

-

-

22

ch amorphous

-

-

-

23

ch amorphous

-

-

-

24th

ch amorphous

-

-

-

25th

at 130 °

-12 °

-16 °

(e = 0.5 g / dl in ethanol)

26

at 130 °

+ 12 °

+ 18 °

(c = 0.7 g / dl in ethanol)

26a am amorphous

-

»

-

26b b oil; ch amorphous

-

-

-

26c b oil; ch amorphous

-

-

-

26d b oil; ch amorphous

-

-

-

26e b oil; ch amorphous

-

-

-

27th

b 84 °

+ 24 °

+ 33 °

(c = 0.8 g / dl in ethanol)

28

b 83 °

-24;

-33 °

(c = 0.6 g / dl in ethanol)

29

b 105 °

-

-

_

30th

b 102 °

-

_

_

31

n amorphous

-

-

-

32

n amorphous

-

-

-

33

n amorphous

-

-

-

34

n amorphous

-

-

~

35

n amorphous

-13 °

-18 °

(c = 0.5 g / dl in ethanol)

36

n amorphous

+ 13 °

+ 20 °

(c = 0.5 g / dl in ethanol)

37

no oil

-

-

-

38

n amorphous

-

-

-

39

n amorphous

-

-

-

40

no oil

-

-

_

41

(see example 5)

41a

(see example 7)

42

-98 °

-

_

b = in the form of the free base ch = in the form of the acid addition salt with hydrochloric acid fu = in the form of the acid addition salt with fumaric acid n = in free, neutral form

The compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts are distinguished by interesting pharmacodynamic properties. They can be used as a medicine. The term “pharmaceutical composition” used above stands for medicinal products.

They show typical effects for calcium antagonists. They have a pronounced muscle relaxant effect, in particular on smooth muscles, as can be seen from the determination of vasodilating and hypotensive activity in standard tests. So they effect e.g. in the anesthetized cat test using tracer microspheres (R. Hof et al., Basic Res. Cardiol. 75 [1980] 747-756 and 76 (1981) 630-638; R. Hof et al., J. Cardiovasc. Pharmacol. 4 [1982] 352-362) coronary vasodilation, a 60 increase in blood flow in the skeletal muscles and a decrease in blood pressure after intravenous administration of about 3 to about 300 jig / kg, e.g. from about 10 to about 100 Hg / kg.

A decrease in blood pressure is also seen in the 65 awake, spontaneously hypertensive rat (method of Gerold and Tschirki, drug research 18 [1968] 1285) after administration of about 1 to about 10 mg / kg p.o. detected. The compounds are longer-acting than known standard ver

13

663 616

bindings, e.g. for once-daily administration. The compounds are also particularly well absorbed orally.

They are therefore suitable as calcium antagonists for the prophylaxis and therapy of

Coronary insufficiency, e.g. Angina pectoris;

- further circulation disorders, e.g. in the limbs, such as intermittent limping and spasms, e.g. cholic;

Asthma, e.g. exercise-related asthma; and

- hypertension.

They also have a vasodilating effect on the capillary blood vessels in the carotid area; the vaso-constrictive effect of serotonin is suppressed and the associated dysregulation inhibited. They are therefore suitable for the prophylaxis and treatment of migraines and vascular headaches, such as "cluster headache", in particular for interval treatment (prevention) of migraines. Preferred in this indication are those compounds which have a relatively modest effect on blood pressure and peripheral blood vessels.

For the above-mentioned uses as medicaments, the dose to be used naturally varies depending on the substance used, the mode of administration and the desired treatment. In general, however, satisfactory results are achieved with a daily dose of approximately 1 mg to approximately 200 mg; if necessary, it can be administered in 1 to 3 portions or as a slow-release form. Suitable dosage forms for e.g. Oral or non-oral administration generally contain from about 0.3 mg to about 200 mg in addition to solid or liquid vehicle substances. A suitable daily dose is e.g. about 5 mg to about 50 mg.

The title compounds of Examples 2, 5, 14, 29 and 41, in particular Examples 2 and 14, are preferred.

Preferred in the prophylaxis and treatment of migraines and vascular headaches are those compounds in which Q represents a 2,1,3-benzothiadiazole radical.

The compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts, preferably acid addition salts, can be administered alone or in a suitable dosage form. The dosage forms, e.g. a capsule suitable for e.g. Sublingual administration, or a tablet, can be prepared analogously to known methods. The invention therefore also relates to pharmaceutical preparations which contain the compounds according to the invention in free form or, if appropriate, in the form of their physiologically tolerable salts, and to the preparation of these pharmaceutical preparations in a manner known per se. The auxiliaries and excipients commonly used in pharmacy can be used for their manufacture.

G

Claims (4)

663 616 2. Compounds according to claim 1 are compounds of the formula Is C00-A R H wherein Rl and Ri are independently alkyl of 1 to 4 carbon atoms; Rj is alkyl of 1 to 12 carbon atoms; Rl stands for: hydroxy; Alkoxy of 1 to 4 carbon atoms; -OCORl; -NR7RI; or -NBS; wherein Rl is alkyl of 1 to 4 carbon atoms or phenyl; R7 stands for: hydrogen; Alkyl of 1 to 4 carbon atoms; optionally in the phenyl ring by alkoxy having 1 to 4 carbon atoms or halogen having an atomic number of 9 to 53 mono- or identically or differently disubstituted phenylalkyl having 7 to 10 carbon atoms; -COR®, wherein Rl is alkyl having 1 to 4 carbon atoms; or optionally in the phenyl ring by alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number from 9 to 53 mono- or identically or differently disubstituted phenyl or phenylalkyl with 7 to 10 carbon atoms; R1 represents hydrogen or alkyl having 1 to 4 carbon atoms; -NBS for piperidine or piperazine, both substituted in the 4-position by methyl, benzyl or optionally in one or both phenyl rings by halogen with an atomic number from 9 to 53 or alkoxy with 1 to 4 carbon atoms mono- or identically or differently disubstituted bisphenylmethyl ; and As represents alkylene of 2 to 14 carbon atoms; with the proviso that Rl means: hydroxy; Alkoxy of 1 to 4 carbon atoms; -NBS as defined above; or -NR7RI, wherein Rl 'for hydrogen; Alkyl of 1 to 4 carbon atoms; or unsubstituted phenylalkyl having 7 to 10 carbon atoms; and Rl has the above meaning; then A is alkylene of 7 to 14 carbon atoms; and their ammonium salts, in which R1 is one of the tertiary amino groups defined above for R1 and is quaternized with a group of the formula AlkY as defined above. 2nd PATENT CLAIMS 1. The compounds of formula I Q COO-AR, wherein Ri hydrogen; Cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl having 1 to 6 carbon atoms; Ri and Rs are independently hydrogen or alkyl of 1 to 6 carbon atoms; R3 for alkyl with 1 to 12 carbon atoms or independently has the meaning given below for -AR4, R4 stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCORs; -NR7R8; or -NB; wherein Re means: alkyl of 1 to 6 carbon atoms; Phenyl, phenylalkyl with 7 to 12 carbon atoms or bisphenylalkyl with 13 to 18 carbon atoms, these three radicals optionally being mono- or identical or differently di- or identical or differently trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy or halogen with an atomic number of 9 to 53; a 5-membered heteroaryl radical with 1 heteroatom from the series nitrogen, oxygen and sulfur or 2 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl radical with 1 to 4 nitrogen atoms; R7 represents hydrogen or has the meaning given above for Rö; Rg stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; or -COR? means in which Rs has the meaning given above for Re; -NB means: a 5-, 6- or 7-membered heterocyclic ring which, if saturated and optionally 6- or 7-membered, contains a further hetero-member from the series oxygen, sulfur and = NR10, where Rio means either hydrogen or the has the meaning given above for Rö; A represents alkylene of 2 to 14 carbon atoms; and Q represents a fused, completely unsaturated ring system with at least 2 different ring heteroatoms in total and with an aromatic character; with the proviso that if R4 hydroxy; Alkoxy of 1 to 6 carbon atoms; -NB as defined above; or -NR5; means; wherein R $ stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and Ri represents hydrogen or alkyl of 1 to 6 carbon atoms; then A represents alkylene with 7 to 14 carbon atoms; and their ammonium salts, in which R4 is one of the tertiary amino groups defined above for R4 and is quaternized with a group of the formula AlkY, in which Alk is alkyl having 1 to 4 carbon atoms and Y is the residue of an acid, in free form or in salt form. 3. A compound according to claims 1 and 2 is 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-isopropoxycarbonyl-2,6-dimethyl-3-pyridine- carboxylic acid [10- (N-benzylmethy-lamino) -decyl] ester, in free form or in salt form. 4. Pharmaceutical preparation containing compounds according to claims 1 to 3 in free form or in salt form.