Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to 1,4-dihydropyridine derivatives, their preparation and pharmaceutical preparations containing them.
• the invention relates in particular to the compounds of the formula I.
• R 1 is hydrogen, cycloalkyl of 3 to 7 carbon atoms; or optionally substituted alkyl having 1 to 6 carbon atoms;
• R 2 and R 5 independently of one another are hydrogen or alkyl having 1 to 6 carbon atoms
• R 3 for alkyl having 1 to 12 carbon atoms or independently has the meaning given below for -AR 4 , including the proviso;
• R 4 stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms; -OCOR 6 ; -NR 7 R 8 ; or -N B ; wherein
• R 6 represents : alkyl having 1 to 6 carbon atoms; Phenyl, phenylalkyl with 7 to 12 carbon atoms or bisphenylalkyl with 13 to 18 carbon atoms, these three
• Residues optionally in the phenyl rings are mono- or identical or different di- or identical or different trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy having 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 heteroatoms from the series nitrogen and either nitrogen, oxygen or sulfur; or a 6-membered heteroaryl radical with 1 to 4 nitrogen atoms;
• R 7 represents hydrogen or has the meaning given above for R 6 ;
• R 6 has the meaning given
• A represents alkylene of 2 to 14 carbon atoms
• 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 R 4 is hydroxy; Alkoxy of 1 to 5 carbon atoms; as defined above or -NR ' 7 R' 8 means where
• R 7 represents: hydrogen, alkyl having 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms;
• R 8 represents hydrogen or alkyl of 1 to 6 carbon atoms; then A stands for alkylene with 7 to 14 carbon atoms. and their ammonium salts in which R 4 is one of the tertiary amino groups defined above for R 4 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.
• Weather disclosures relating to compounds related to the compounds of the invention provide e.g. represents:
• a preferred group of compounds according to the invention consists of the compounds of the formula Ia
• 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 of 1 to 4 carbon atoms; Halogen with an atomic number from 9 to 35; Trifluoromethyl; Nitro; or hydroxy; 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 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 of 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
• R 2 and R 5 have the meaning given above; for alkyl with 1 to 12 carbon atoms or independently those below for has the meaning given; stands for: hydroxy; Alkoxy with 1 to 12 carbon natom atoms; ; or as defined above wherein and have the meaning given above for R 7 , R 7 or R 8 ;
• a a denotes alkylene with 2 to 14 carbon atoms
• X represents oxygen or sulfur; with the provisos that, a) if Hydroxy or as defined above means then A a stands for alkylene with 7 to 14 carbon atoms, and b) if f xy with 1 to 12 carbon atoms or - is where ⁇ means: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and for hydrogen or alkyl with 1 to 6 carbons is atoms, then A a is alkylene having 9 to 14 carbon atoms; and their ammonium salts, in which for. one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• a a denotes alkylene with 9 to 14 carbon atoms. Another subgroup says not for alkoxy. Mean in another group or as defined above
• a preferred group of compounds of the formula Ia consists of the compounds of the formula Iaa
• R, , R 2 , R e and X have the meaning given above, represents alkyl having 1 to 6 carbon atoms; the above for has the meaning given; and Alkylene having 2 to 14 carbon atoms; with the provisos that a) if tydroxy or as defined above means then A aa represents alkylene with 7 to 14 carbon atoms; and b) if for alkoxy having 1 to 12 carbon atoms or
• a aa denotes alkylene having 9 to 14 carbon atoms; and their ammonium salts, in which for one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• a aa alkylene with 9 to 14 carbon atoms In another
• Another preferred group of compounds of the formula Ia consists of the compounds of the formula lab
• R, R 2 , R 5 and X have the above meaning.
• Alkyl with 1 to 12 carbon atoms means or unab ⁇ pending the below for has the meaning given; stands for: hydroxy alkoxy with 1 to 12 carbon atoms; -OCOR., Or; wherein have the above meaning; and
• a ab is alkylene of 2 to 14 carbon atoms; with the provisos that a) if Is hydroxy, then A is alkylene of 7 to 14 carbon atoms; and b) if for alkoxy with 1 to 12 carbon atoms or stands in what and 'meaning above hold, then A represents alkylene having from 9 to 14 carbon atoms; and their ammonium salts, in which for one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• Another preferred group of compounds of the formula Ia consists of the compounds of the formula Iaaa
• R 1 , R 2 , R 5 and X have the above meaning, Means alkyl of 1 to 6 carbon atoms;
• R 4 aa for: hydroxy; Alkox hydrocarbon atoms; or where the above meaning have?
• a aaa is alkylene of 2 to 14 carbon atoms; with the provisos that a) if Is hydroxy, then A aaa is alkylene of 7 to 14 carbon atoms; and b) if for alkoxy having 1 to 12 carbon atoms or stands in what have the above meaning, then A aaa is alkylene having 9 to 14 carbon atoms; and their ammonium salts, in which stands for one of the tertiary amino groups defined above and is quaternized with a group of the formula AlkY as defined above.
• a aaa means alkylene having 9 to 14 carbon atoms. Another subgroup says not for alkoxy, in other sub group means as defined above.
• Is hydrogen or alkyl having 1 to 4 carbon atoms, preferably hydrogen or methyl, in particular hydrogen; those in which R 2 and R 5 are hydrogen or alkyl with 1 to 4 carbon atoms, in particular methyl; those in which R is hydrogen; and those where X is oxygen; and their combinations;
• Another preferred group of compounds according to the invention consists of the compounds of the formula Ib
• R 1 , R 2 , R 5 and Q have the above meaning;
• Alkyl with 1 to 12 carbon atoms means or independently the below for has the meaning given; stands for: hydroxy; Alkoxy of 1 to 12 carbon atoms; or as defined above wherein have the meaning given above for R 6 , R 7 or R 8 ; and
• A represents alkylene of 9 to 14 carbon atoms; and their ammonium salts, in which for one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• compounds of formula Ib not for alkoxy mean in another subgroup and or as defined above
• a preferred group of compounds of the formula Ib consists of the compounds of the formula Iba
• R 1 , R 2 , , R 5 , A b and Q are as defined above and are alkyl having 1 to 6 carbon atoms; and their ammonium salts, in which for one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• R 1 , R 2 , R 5 , A b and Q have the above meaning; stands for alkyl with 1 bohlenstoffatomen or independently below has the meaning given; means: hydroxy; Alkoxy of 1 to 12 carbon atoms; or - in what have the above meaning; and their ammonium salts, in which for one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• Another preferred group of compounds of the formula Ib consists of the compounds of the formula Ibaa
• R 1 , R 2 , , R 5 , A and Q have the above meaning; and their ammonium salts, in which for one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• AlkY as defined above.
• R 1 is as defined above stands, in particular for hydrogen or alkyl, preferably hydrogen or methyl, in particular hydrogen; those in which R 2 and R 5 are hydrogen or alkyl having 1 to 4 carbon atoms, especially methyl; those in which Q is a group of the formula in which R and X are as defined above, stands, in particular those in which R is hydrogen; and those where X is oxygen; and their combinations; 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
• alkyl of 1 to 4 carbon atoms represents hydrogen or alkyl of 1 to 4 carbon atoms; and independently represent alkyl of 1 to 4 carbon atoms;
• Alkyl with 1 to 6 carbon atoms means or independently has the meaning given below for -A P R 4 P ; means: hydroxy; Alkoxy of 1 to 6 carbon atoms; wherein represents: alkyl of 1 to 6 carbon atoms; Phenyl, Phenylalkyl with 7 to 10 carbon atoms or bisphenylalkyl with 13 to 16 carbon atoms, these three radicals optionally in the phenyl rings being mono- or identical or differently di- or identical or differently trisubstituted by alkyl having 1 to 4 carbon atoms, alkoxy having 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;
• A represents unbranched alkylene of 2 to 14 carbon atoms
• Q P 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;
• R 7 'P stands for: hydrogen; Alkyl of 1 to 6 carbon atoms; unsubstituted phenyl; or unsubstituted phenylalkyl of 7 to 10 carbon atoms; and
• R 8 'P represents hydrogen or alkyl of 1 to 6 carbon atoms; then A p represents unbranched alkylene of 7 to 14 carbon atoms; and their ammonium salts, in which for one of the above for defi is tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• Another group of compounds according to the invention consists of the compounds of the formula Is
• A represents alkylene of 7 to 14 carbon atoms; and their ammonium salts, in which for one of the above for defined tertiary amino groups and is quaternized with a group of the formula AlkY as defined above.
• a s denotes alkylene having 7 to 14 carbon atoms; in another subgroup it stands for alkylene with 9 to 14 carbon atoms; it is unbranched in another subgroup.
• R 6 , R 7 and / or R 8 are substituted phenyl, substituted phenylalkyl or substituted bisphenyl alkyl.
• R 1 is hydrogen or alkyl having 1 to 5 carbon atoms; in a further subgroup, R 2 and R 5 independently of one another represent alkyl having 1 to 4 carbon atoms; in a further subgroup, R 3 represents alkyl having 1 to 6 carbon atoms; in another subgroup, R 3 is as defined above ; in a further subgroup, A denotes unbranched alkylene and R 4 has the meaning given above, including the corresponding meaning In another subgroup, R 6 , R 7 and R 8 have the above for respectively.
• R 4 represents alkoxy having 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 bisphenyl alkyl contain 13 to 16 carbon atoms in the bisphenylalkyl skeleton; in a another subgroup, R 7 has the meaning given above. In a further subgroup, all non-fused phenyl rings are substituted.
• R 1 preferably has the meaning given above. preferably means hydrogen.
• it is not hydrogen, it preferably means unsubstituted alkyl, cycloalkyl alkyl, optionally substituted phenylalkyl, alkoxyalkyl or morphol ino, preferably unsubstituted alkyl or
• Alkoxyalkyl preferably unsubstituted alkyl. If alkoxyalkyl means, the alkoxy part is preferably separated from the nitrogen atom by at least 2 carbon atoms.
• R 2 and / or R 5 are preferably alkyl.
• R3 preferably represents alkyl. If it has the meaning given above for -AR 4 , it is preferably identical to -AR 4 .
• R 4 preferably represents hydroxy, -OCOR 6 , -NR 7 R 8 or.
• 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 one
• A is preferably straightforward. It preferably has 7 to 14, preferably 9 to 14, in particular 10 carbon atoms,
• Alk preferably means methyl
• Y preferably represents the remainder of an inorganic acid, for example mesyl or halogen, in particular iodine.
• R 6 preferably denotes alkyl, phenyl, phenylalkyl or bisphenylalkyl, in particular phenyl,
• R 7 preferably represents hydrogen, alkyl, phenylalkyl or bisphenylalkyl.
• R 8 is preferably hydrogen, alkyl or -COR 9 .
• R 7 and R 8 are preferably either hydrogen, or one of R 7 and R 8 is alkyl and the other is alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylal kyl.
• R 9 preferably represents alkyl, optionally substituted
• Phenyl optionally substituted phenylalkyl or optionally substituted bisphenylal kyl.
• R 10 preferably has a meaning other than hydrogen. It preferably means alkyl, optionally substituted phenylalkyl or optionally substituted bisphenylalkyl.
• X preferably represents oxygen.
• R is preferably hydrogen.
• the rest are preferably in his
• 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 having 1 to 12 carbon atoms preferably contain 1 to 6, in particular 1 to 4, carbon atoms, and are preferably methyl, ethyl or isopropyl.
• Alkyl with 1 to 6 carbon atoms preferably contains 1 to 4, in particular 1 or 2, carbon atom (s), it means in particular methyl.
• 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.
• 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.
• 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 3 carbon atoms.
• the cycloalkyl part of cycloalkylalkyl preferably contains 3.5 or 6, in particular 5 or 6, carbon atoms.
• the alkyl part of cycloalkylalkyl and / or of phenylalkyl preferably contains 1 or 2 carbon atoms, it means in particular methylene.
• the alkenylene portion of phenylalkenyl preferably contains 3 carbon atoms.
• the alkyl 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 portion of hydroxyalkyl and / or of hydroxyalkoxyalkyl and / or the amino portion of aminoalkyl are preferably attached to the most distant, end-chain carbon atom.
• 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 position. Alkoxy and / or halogen are preferred 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 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.
• 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.
• 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,
• Halogen with an atomic number from 9 to 53 preferably means bromine or iodine
• halogen with an atomic number from 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
• R 1 , R 2 , R 5 and Q have the above meaning, Z represents a reactive group and
• Z ' either represents a reactive group or has the meaning given above for -OR 3 , appropriately converted.
• the method according to the invention can be carried out analogously to known methods.
• a process variant can represent an esterification, for example.
• a suitable reactive group Z or Z 'in this case is, for example, IH-imidazol-1-yl.
• This process variant is suitable, for example, for conversion into a hydroxyalkyl, amidoalkyl, alkoxyalkyl, acyloxyalkyl or substituted or unsubstituted aminoalkyl substituent. So a corresponding compound of formula II with a corresponding diol, amido / alcohol, ester / alcohol or implemented amino alcohol.
• Suitable solvents are, for example, dioxane or an excess of the reactant.
• a further process variant can be an amination, for example.
• This process variant is suitable, for example, for conversion into an aminoalkyl substituent.
• a reactive group Z or Z ' represents, for example, a group -OA-Z'', in which A is as defined above and Z "is chlorine, bromine or a group R z -SO 2 -O, in which R z is phenyl, tolyl or lower alkyl Z "preferably denotes mesyloxy.
• the amination can be immediate, ie the reaction is carried out 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 phthalimidoalkyl 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 V then represents e.g. represents the corresponding primary or secondary aminoalkoxy group.
• a corresponding compound of formula II is thus treated with a corresponding acyl derivative, e.g. an N-hydroxysuccinimide ester.
• Suitable solvents are e.g. Dioxane.
• Another process variant can be, for example, an acylation of an alcohol.
• a reactive group Z or Z 'then represents, for example, the corresponding hydroxyalkoxy group.
• a corresponding compound of the formula II with a corresponding one Acyl derivative, such as an acyl halide implemented.
• the reaction is preferably carried out in the presence of a strong base, such as N-ethyldiisopropylamine.
• a suitable solvent is, for example, methylene chloride.
• 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.
• a group -AR 4 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 as a solvent is e.g. an alcohol like methanol.
• 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, 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 converting the protected groups into the desired substituents, for example benzyloxy in hydroxy, for example, hydrogenolytically; Tetranydro-pyranyloxy in hydroxy, for example by acid hydrolysis; and protected amino in unprotected amino, for example by acid 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 in a known manner from the compounds in free form and vice versa.
• Suitable acids for the formation of acid addition salts are e.g. Hydrogen chloride, malonic, p-toluenesulfonic and methanesulfonic acid.
• Suitable bases for the formation of anionic salts are e.g. Sodium and potassium hydroxide.
• 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.
• game 1 4- (2, 1, 3-benzoxadiazol-4-yl) -1, 4-dihydro-5-isopropoxycarbonyl 1-2, 6-dimethy1-3-pyridinecarboxylic acid (10-hydroxydecyl) ester
• Example 2 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid [10- (N-benzylmethylamino) decyl] ester
• the mesylate used as the starting product is obtained by reacting 4.3 g of the title compound of Example 1 and 4.3 ml of N-ethyldiisopr ⁇ pylamine 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-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid (10-aminodecyl) ester
• Example 4 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid [10- [3- (4-hydroxy-3 -iodphenyl) -1-oxo-propylamino] decyl] ester (amidation of the amine)
• Example 5 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbony1-2, 6-dimethy1-3-pyridinecarboxylic acid (10-benzoyloxydecyl) ester
• Example 6 4- (2, 1, 3-Benzoxadiazo1-4-y1) -1, 4-dihydro-5-isopropoxycarbonyl 1-2, 6-dimethy1-3-pyridinecarboxylic acid [10- (N-benzylmethylamino) decyl] ester
• NMR spectrum see Example 2.
• the amino alcohol used as the starting product is obtained as follows: a) One is at 30 ° 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 Solution of 4.5 ml of methanesulfonic acid chloride in 60 ml of methylene chloride is added dropwise and the mixture is stirred at room temperature for 1 hour.
• 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 medicaments.
• a decrease in blood pressure is also seen in the 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 compounds, e.g. for once-daily administration.
• the compounds are also particularly well absorbed orally,
• Coronary insufficiency e.g. Angina pectoris
• Asthma e.g. exertional asthma
• 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 carriers.
• a suitable daily dose is e.g. about 5 mg to about 50 mg.
• Preferred in the prophylaxis and treatment of migraines and vascular headaches are those compounds in which Q represents a 2,1,3-benzothiadiazplyl residue.
• the compounds according to the invention in free form or optionally in the form of their physiologically tolerable salts, preferably acid addition salts, can be used alone or in a suitable manner Dosage form are administered.
• the pharmaceutical forms for example a capsule suitable for, for example, 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 carriers customary in pharmacy can be used for their production.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Hydrogenated Pyridines (AREA)
• Plural Heterocyclic Compounds (AREA)

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ID=4255028

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• 1984
  • 1984-06-13 WO PCT/CH1984/000094 patent/WO1985000169A1/de unknown
  • 1984-06-13 CH CH784/85A patent/CH663616A5/de not_active IP Right Cessation
  • 1984-06-14 DE DE3421992A patent/DE3421992A1/de not_active Withdrawn
  • 1984-06-18 BE BE1/011042A patent/BE899937A/fr not_active IP Right Cessation
  • 1984-06-18 GB GB08415523A patent/GB2142021B/en not_active Expired
  • 1984-06-18 NL NL8401932A patent/NL8401932A/nl not_active Application Discontinuation
  • 1984-06-18 FR FR8409628A patent/FR2549058B1/fr not_active Expired
  • 1984-06-19 SE SE8403268A patent/SE8403268L/sv not_active Application Discontinuation
  • 1984-06-19 DK DK299784A patent/DK299784A/da not_active Application Discontinuation
  • 1984-06-19 IT IT48415/84A patent/IT1199143B/it active
  • 1984-06-19 IL IL72152A patent/IL72152A0/xx unknown
  • 1984-06-20 LU LU85423A patent/LU85423A1/fr unknown
  • 1984-06-20 AU AU29564/84A patent/AU2956484A/en not_active Abandoned
  • 1984-06-20 JP JP59128387A patent/JPS6013789A/ja active Pending
  • 1984-06-21 ZA ZA844725A patent/ZA844725B/xx unknown

Patent Citations (4)

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