CA1221700A - Substituted 4-aminomethylene-chromans and -chromenes, processes for their preparation and their use in medicaments - Google Patents
Substituted 4-aminomethylene-chromans and -chromenes, processes for their preparation and their use in medicamentsInfo
- Publication number
- CA1221700A CA1221700A CA000444553A CA444553A CA1221700A CA 1221700 A CA1221700 A CA 1221700A CA 000444553 A CA000444553 A CA 000444553A CA 444553 A CA444553 A CA 444553A CA 1221700 A CA1221700 A CA 1221700A
- Authority
- CA
- Canada
- Prior art keywords
- methyl
- aminomethyl
- acid addition
- addition salt
- acceptable acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to substituted 4-aminomethylene-chromans and chromenes of Formula (I) infra, as well as methods for making of said chromans and chromenes,compositions containing said chromans and chromenes and methods for the use of said chromans, chromenes and compositions containing said chromans and chromenes. The compounds and compositions of the invention are useful for their circulation influencing activity:
(I)
The invention relates to substituted 4-aminomethylene-chromans and chromenes of Formula (I) infra, as well as methods for making of said chromans and chromenes,compositions containing said chromans and chromenes and methods for the use of said chromans, chromenes and compositions containing said chromans and chromenes. The compounds and compositions of the invention are useful for their circulation influencing activity:
(I)
Description
~22~7~
-1- 23189-56~2 The present invention relates to substituted 4-amino-me-thylene-chromans and creaminess, a plurality owe processes for their preparation and their use in medicaments, especially in agents which influence the circulation.
The novel compounds can be represented by -the following formula (I):
~12 R13 R7 R8 Rio 3 SHEA - N - C - C - X R14 (I) 4 9 Roll R6 Al in which -A- represents a single bond or a double bond Al and R2 are identical or different and represent hydrogen Cl-C6-alkyl C5-C7-cycloalkyl phenol (which is unsub-stituted or substituted by Cl-C4-alkyl, halogen and/or Cluck-alkoxy), or C7-Cg-aralkyl (whose aureole radical is unsubstituted or substituted by C1-C4-alkyl halogen and/or C1-C4-alkoxy) or Al and R2 conjointly with the enclosed C atom of -the Crimean ring form a 4-membered to 7-membered carbocyclic ring;
R3 to X6 are identical or different and represent hydrogen hydroxyl halogen C1-C6-alkyl C5-C7-cycloalkyl phenol (which is unsubstitute~ or substituted by C1-C4-alkyl, halogen and/or Cl-C4-alkoxy), C7-Cg-aralkyl (whose aureole radical is unsubstituted or substituted by C~-C4-alkyl, halogen and/or C~-C4--alkoxy), or Cl-C4-alkoxy;
R7, I R9, Rio and Roll are identical or different and represent hydrogen or Cl-C6-al]cyl;
X represents a single bond, ethylene (which is unsub-stituted, monosubstituted or disubstituted by Cl-C4-alkyl), oxygen or -NR17;
wherein R17 represents hydrogen or Cl-C4-alkyl or R17 together with R7 forms a C2-alkylene ring-closing member and R12, R13, R14, R15 and R16 are identical or different and represent hydrogen, hydroxyl, halogen, Cl-C6-alkyl, I or C6-cycloalkyl, bouncily, Cl-C4-alkoxy, trifluoromethyl, or R12 and .R13 and R14 together form a Cl-C3-alkylenedioxy group or a -CH=CH-CH=CH group.
Their pharmaceutically safe acid addition salts are also included.
Suitable alkyds in the substltuents arestraight-chain or branched Cl-C6-alkyl radicals.
As examples of alkyd radicals there may be mentioned methyl, ethyl, propel, isopropyl, bottle, isobutyl, and left.-bottle.
Suitable cycloalkyl radicals Al, R2, R3, R4, R5, R6 and R12 to R16 are those with 5-7, especially with 5 or 6 carbon atoms, for example, cyclopentyl, cyclohexyl and cycloheptyl.
`:~
TV
Suitable optionally substituted aralkyl radicals Al, R2, R3 to R6 and R12 to R16 are those with 7 to 9 carbon atoms, preferably whose aliphatic part contains 1 to 5 carbon atoms, and whose aromatic part is a phenol. The following aralkyl radicals may be mentioned as examples: bouncily, phenol-ethyl and phenylpropyl, bouncily being preferred.
Alkoxy R3 to R6 and R12 to R16 is straight-chain or branched alkoxy with 1 to 4, carbon atoms. Methoxy, ethics, n- and i-propoxy and n-, i- and t-butoxy may be mentioned as examples.
As halogens R3 to R6 and R12 to ~16 t y mentioned fluorine, chlorine, bromide and iodine, those preferred being fluorine, bromide and chlorine.
If the radicals Al and R2 together with the carbon atoms which they enclose form a carbocyclic ring, then these may be 4- to 7-membered rings. As examples of carbocyclic radicals there may be mentioned cyclobutane, cyclopentane, cycle-hexane and cycloheptane.
Suitable substituents of the phenol and aralkyl radicals Al to R6 are substituents which do not undergo change under the reaction conditions. Examples which may be mentioned are the halogens, such as fluorine, chlorine, bromide and iodine, a Cl-C4-alkyl group and a Cl-C4-alkoxy group.
As examples of acids for the preparation of the salts there may be mentioned sulfuric acid, hydrochloric acid, organic carboxylic acids such as mafia acid, citric acid, fumaric acid and acetic acid, or organic sulphonic acids such as naphthalene -1,5-disulphonic acid.
The salts of the compounds of the formula (I) can be obtained in a simple manner by conventional salt-forming methods, for example by dissolving the base and adding the acid, and can be isolated in a known manner, for example by filtering off, and be purified if desired.
'I
I
Particularly preread compounds of the formula (I) are those in which Al and R2, which may be identical our different, represent hydrogen or Cl-C4-alkyl or together with the carbon atom which they enclose form a carbocyclic Us- or Crying, R3 to R6, which may be identical or different, denote hydra-gent hydroxyl, C]-C4-alkyl, Cl-C4~alkoxy or chlorine, R7 to Roll, which may be identical or different, represent hydrogen or Cl-C4-alkyl, X represents a single bond, oxygen, ethylene or -NR17, wherein R17 denotes hydrogen or Cl-C3-alkyl or R17 I
together with R7 forms an ethylene ring-closing member and R12 to R16, which may be identical or different, denote hydrogen, chlorine, cyclohexyl, C1-C4-alkyd, C1-C3-alkoxy or trifluoromethyl, or R12 and R13 or R13 and R14 together form a methyl-enedioxy group or a -CH=CH-CH=CH- group.
As examples of novel compounds of the formula (I) there may be mentioned: 4-~-phenylethyLaminomethyl-10 Crimean, 4-3-phenylethylam;nomethyl-~,2 dimethylchroman, 4-~-phenylethylaminomethyl-2-isopropylchroman, phenol-ethylaminoethyl-2-methyl-2-propyl-chroman, phenol-ethylam1nomethyl-2,2-d;ethylchroman, 4-~-phenylethyl-aminomethyl-2-spirocyclopentachroman, 4-~-phenylethyl-15 aminomethyl-2-spirocyclohexachroman, 4-~-phenylethyl-aminomethyl-2-hexylchroman~ 4-~-phenylethylaminomethyl-
-1- 23189-56~2 The present invention relates to substituted 4-amino-me-thylene-chromans and creaminess, a plurality owe processes for their preparation and their use in medicaments, especially in agents which influence the circulation.
The novel compounds can be represented by -the following formula (I):
~12 R13 R7 R8 Rio 3 SHEA - N - C - C - X R14 (I) 4 9 Roll R6 Al in which -A- represents a single bond or a double bond Al and R2 are identical or different and represent hydrogen Cl-C6-alkyl C5-C7-cycloalkyl phenol (which is unsub-stituted or substituted by Cl-C4-alkyl, halogen and/or Cluck-alkoxy), or C7-Cg-aralkyl (whose aureole radical is unsubstituted or substituted by C1-C4-alkyl halogen and/or C1-C4-alkoxy) or Al and R2 conjointly with the enclosed C atom of -the Crimean ring form a 4-membered to 7-membered carbocyclic ring;
R3 to X6 are identical or different and represent hydrogen hydroxyl halogen C1-C6-alkyl C5-C7-cycloalkyl phenol (which is unsubstitute~ or substituted by C1-C4-alkyl, halogen and/or Cl-C4-alkoxy), C7-Cg-aralkyl (whose aureole radical is unsubstituted or substituted by C~-C4-alkyl, halogen and/or C~-C4--alkoxy), or Cl-C4-alkoxy;
R7, I R9, Rio and Roll are identical or different and represent hydrogen or Cl-C6-al]cyl;
X represents a single bond, ethylene (which is unsub-stituted, monosubstituted or disubstituted by Cl-C4-alkyl), oxygen or -NR17;
wherein R17 represents hydrogen or Cl-C4-alkyl or R17 together with R7 forms a C2-alkylene ring-closing member and R12, R13, R14, R15 and R16 are identical or different and represent hydrogen, hydroxyl, halogen, Cl-C6-alkyl, I or C6-cycloalkyl, bouncily, Cl-C4-alkoxy, trifluoromethyl, or R12 and .R13 and R14 together form a Cl-C3-alkylenedioxy group or a -CH=CH-CH=CH group.
Their pharmaceutically safe acid addition salts are also included.
Suitable alkyds in the substltuents arestraight-chain or branched Cl-C6-alkyl radicals.
As examples of alkyd radicals there may be mentioned methyl, ethyl, propel, isopropyl, bottle, isobutyl, and left.-bottle.
Suitable cycloalkyl radicals Al, R2, R3, R4, R5, R6 and R12 to R16 are those with 5-7, especially with 5 or 6 carbon atoms, for example, cyclopentyl, cyclohexyl and cycloheptyl.
`:~
TV
Suitable optionally substituted aralkyl radicals Al, R2, R3 to R6 and R12 to R16 are those with 7 to 9 carbon atoms, preferably whose aliphatic part contains 1 to 5 carbon atoms, and whose aromatic part is a phenol. The following aralkyl radicals may be mentioned as examples: bouncily, phenol-ethyl and phenylpropyl, bouncily being preferred.
Alkoxy R3 to R6 and R12 to R16 is straight-chain or branched alkoxy with 1 to 4, carbon atoms. Methoxy, ethics, n- and i-propoxy and n-, i- and t-butoxy may be mentioned as examples.
As halogens R3 to R6 and R12 to ~16 t y mentioned fluorine, chlorine, bromide and iodine, those preferred being fluorine, bromide and chlorine.
If the radicals Al and R2 together with the carbon atoms which they enclose form a carbocyclic ring, then these may be 4- to 7-membered rings. As examples of carbocyclic radicals there may be mentioned cyclobutane, cyclopentane, cycle-hexane and cycloheptane.
Suitable substituents of the phenol and aralkyl radicals Al to R6 are substituents which do not undergo change under the reaction conditions. Examples which may be mentioned are the halogens, such as fluorine, chlorine, bromide and iodine, a Cl-C4-alkyl group and a Cl-C4-alkoxy group.
As examples of acids for the preparation of the salts there may be mentioned sulfuric acid, hydrochloric acid, organic carboxylic acids such as mafia acid, citric acid, fumaric acid and acetic acid, or organic sulphonic acids such as naphthalene -1,5-disulphonic acid.
The salts of the compounds of the formula (I) can be obtained in a simple manner by conventional salt-forming methods, for example by dissolving the base and adding the acid, and can be isolated in a known manner, for example by filtering off, and be purified if desired.
'I
I
Particularly preread compounds of the formula (I) are those in which Al and R2, which may be identical our different, represent hydrogen or Cl-C4-alkyl or together with the carbon atom which they enclose form a carbocyclic Us- or Crying, R3 to R6, which may be identical or different, denote hydra-gent hydroxyl, C]-C4-alkyl, Cl-C4~alkoxy or chlorine, R7 to Roll, which may be identical or different, represent hydrogen or Cl-C4-alkyl, X represents a single bond, oxygen, ethylene or -NR17, wherein R17 denotes hydrogen or Cl-C3-alkyl or R17 I
together with R7 forms an ethylene ring-closing member and R12 to R16, which may be identical or different, denote hydrogen, chlorine, cyclohexyl, C1-C4-alkyd, C1-C3-alkoxy or trifluoromethyl, or R12 and R13 or R13 and R14 together form a methyl-enedioxy group or a -CH=CH-CH=CH- group.
As examples of novel compounds of the formula (I) there may be mentioned: 4-~-phenylethyLaminomethyl-10 Crimean, 4-3-phenylethylam;nomethyl-~,2 dimethylchroman, 4-~-phenylethylaminomethyl-2-isopropylchroman, phenol-ethylaminoethyl-2-methyl-2-propyl-chroman, phenol-ethylam1nomethyl-2,2-d;ethylchroman, 4-~-phenylethyl-aminomethyl-2-spirocyclopentachroman, 4-~-phenylethyl-15 aminomethyl-2-spirocyclohexachroman, 4-~-phenylethyl-aminomethyl-2-hexylchroman~ 4-~-phenylethylaminomethyl-
2-cyclopentylchroman, 4-~-phenylethylaminomethyl-2-cyclo-hexylchroman, 4-~-phenylethylaminomethyl-2-phenylchroman, 4-~-phenylethylaminomethyl-2-benzylchroman, phenol-20 ethylaminomethyl-2H-chromene, 4-~-phenylethylaminomethyl-2,2-dimethylchromene, 4~-phenylethylam;nomethyl-2-spirocyclopentachromene, 4-~-phenylethylaminomethyl-6-methyl-2-spirocyclopentachroman, 4 ~-phenylethylamino-methyl-7-methyl-2,2-dimethylchroman, 4-~-phenylethyl-25 am;nomethyl-7-methyl-2-spirocyclopentachro~an, I
phenylethylaminomethyl 6~chloro-chroman, 4-~-phenylethyl-am;nomethyl-b-chloro-2-spirocyclopentachroman, I -phenol-ethylaminomethyl-6-methoxy-2,2-dimethylchroman, I
phenylethylaminomethyl-6-methoxy-2-spirocyclopentaashore-30 man, I phenylethylaminomethyl-7-methoxy-2-spirocyclo pentachromanO I -phenylethylaminomethyl-7-phenyl-2-spirocyclopentachroman, 4-~-phenylethylaminomethyl 6,8-dichloro-2-spirocyclohexachroman9 4-~-phenylethylamino-methyl-5-hydroxy-2~2-d;methylchroman, 4-~-phenylethyl~
35 aminomethyl-5-hydroxy-2~spirocyclopentachroman, I -phenol-ethylaminomethyl-6-hydroxy-Z-spirocyclopentachromaan, lo A 22 08~
4-~-phenyLethylam;nomethyl-6-methyl-2-spirocycloheexam Crimean, 4- ~phenylethylaminomethylo7-methyl-2,Z-di-methylchromene, 4-~-phenylethyl3minomethyl-6-chloro-2,2-d;methylchromene, I -phenylethylaminomethyl~6~chloro~20 5 spirocyclopentachromene, 4- ~phenylethylaminomethyl-6-methoxy-2H-chromene, 4-~-phenylethylaminomethyl-6-methoxy-2-spirocyclopentachromene, I -phenylethylaminomethyl-7-methoxy-2,2-dimethylchromene, 4 ~phenylethylaminomethyl-7-methoxy-2-isopropyl-2H-chromene, 4-~-phenylethylamino-10 methyL~7-phenyl-2-spirocyclopentachromene, I -phenol-ethylaminomethyl-6,8-dichloro-2H-chromene, 44 -phenol-ethylaminomethyl-5-hydroxy~2-spirocyclopentachromeone, 4-~-t4-chlorophenyl)-ethylaminomethyl-2-spirocycloopenta-Crimean, 4-~-t3,4-dichlorophenyl)-ethylaminomethyl-2,2-15 d;methylchroman, 4-~-(3-methylphenyl)-ethylaminomethyl-2~isopropylchroman, 4-~-(4-isopropylphenyl)-ethylam;no-methyl-2,2-d;ethylchroman, 4-~-(3-methoxyphenyl)-ethyl-aminomethyl-2-spirocyclopentachroman, 4- ~t4-ethoxyphenyl)-ethylaminomethyl-2-spirocyclohexachroman, I 3,4-d;-methoxyphenyl)-ethylam;nomethyl-chromanO I -(3,4-methyl-enedioxyphenyl)-ethylaminomethyl-2,2-d;methylchromman, 4-~-t3,4,5-trimethoxyphenyl)-~thylam;nomethyl-2-meethyl-2-isopropyl-chroman, 4-~-t4-hydroxyphenyl)-ethylamino-methyl-2~2~diethylchroman, 4- ~t4~trifluoromethylphenyl)-ethylaminomethyl-2-spirocyclopentachroman, sheller-4-trifluoromethylphenyl)-ethyLaminomethyl-2 pi recycle-hexachroman~ I (1-naphthyl)-ethylaminomethyl-2-spiro-cyclohexachroman, 4-~-(2-naphthyl)-ethjlaminomethyl-2,2-dimethylchroman, 4-~-(4-chlorophenyl)-ethylaminomethyl~
2-sp;rocyclohexachronene, I phenyl-a-methyle~hyl~-aminomethyl-2-spirocyclohexachroman~ 4-t funneled-methylethyl)-aminomethyl-2,2-dimethylchroman~ phenol-a-ethylethyl)-aminomethyl~2-cyclopentylchroman~ I
phenyl-~methylethyl)-aminomethyl-2,2-diethylchromaan 35 4-(~-phenyl-a-methylethyl)-aminom~thyl-2-spirocycllo-pentachromene~ I ~phenylpropylaminomethyl-2-spirocyclo-lo A 22 OBOE
.
to pentachroman, 4-~-phenylpropylaminomethyl-2,2-d;methyl-Crimean, 4-~-phenylpropylaminomethyl-6-methyl-2,2-di-methylchroman, 4-~-(3,4-methylenedioxYPhenYl)~PrOpyl-aminomethyl-2-spirocyclopentachroman~ 4-C~-(4-chloro-5phenyl3-a-methylpropyl]-aminomethyl-2-isopropyl-2HH-Crimean, 4-~-phenoxyethylaminomethyl-2~2-dimethylchroman, 4-~-phenoxyethylaminomethyl-2-spirocyclopentachromman, 4- ~phenoxyethylaminomethyl-Z-spirocyclohexachroman, 4-~-phenoxyethylaminomethyl-2-spirocyclopentachrommine, 104-~-phenoxyethylaminomethyl-6~methyl-2,2-dimethylcCrimean, Iphenoxyethylam;nomethyL-7-methyl-2-spirocyclopentaa-Crimean, 4~-phenoxyethylaminomethyl-6-chloro-2-spiro~
cyclohexachromanO I -phenoxyethylaminomethyl-6-methoxy-Crimean, 4-~-phenoxye~hylaminomethyl-6-methoxy-2-phenyl-15 Crimean, 4- ~phenoxyethylaminomethyl-7-methoxy-2-iso-propylchroman, 4-~-phenoxyethylaminomethyl-7-phenylo2~2-dimethylchroman, 4-~-phenoxyethylaminomethyl-6,8-dichloro-2-spirocyclohexachromanr I -phenoxyethylaminomethyl-6,8-d;methyl-2-hexylchroman, 4- ~phenoxyethylaminomethyl-5-20 hydroxychroman, I phenoxyethylaminomethyl-6-hydroxy-2-spirocyclopentachroman, 4-~-phenoxyethylaminomethyl-6-methyl-2,2-d;methylchromene, 4-~-(4-chloroph~r,oxy)-ethylaminomethylchroman, I 3,4 dichlorophenoxy)-ethylaminomethyl-2,2-dime~hylchroman, 4-~-(3-methylphen-25 oxy)-ethylaminomethyl-2 methyl-2-isopropylchroman~ I
(4-isopropylphenoxy)-ethylaminomethyl-2,2-diethylcCrimean, 4-~-t4-ethoxyphenoxy)-ethylaminomethyl-2-spirocycLLucks-Crimean 4-~-(3,4-dimethoxyphenoxy)-ethylaminomethyl~2 spirocycLopentachroman, 4-~-(3,4-methylenedioxyphenoxy)-30 ethylam;nomethyl 2,2-dimethylchroman, 4-~-(3,4,5-trimeth~
oxyphenoxy)-ethylaminomethyl-2-cyclopentylchroman,, I
(4-hydroxyphenoxy) ethylaminomethyl-2,2-diethylchroman~
4-~-(4-chlorophenoxy)-ethylaminomethyl-2H-chromenee, 4-~-phenoxy-a-methylethyl) aminomethyl-2-spirocyslo-35 hexachroman, 4-(~-phenoxy-~-methylethyl~ aminomethyl-2,2-diethylchroman, 4-(~-phenoxy-a-methylethyl)-aminomethyl~
lo A 22 084 2-spirocyclopentachromene, 4-t~-phenyl-a-methylpropyl)-aminomethyl-2H-chromene~ 4-t~-phenyl-a-methylpropyl)-aminomethyl-21spirocyclopentachromene, 4-(r-phenyl~x-methylpropyl)-aminomethyl-2,2-dimethylchroman, phenol-5~-methylpropyl)-aminomethyL-2-spirocyclopentachromman, 4-(~-phenyl-a-methylpropyl)-aminomethyl-6-methyl-22,2-dimethylchroman, I phenyl-a-methylpropyl)-aminomethyl-6-chloro-2-spirocyclohexachroman~ I ~phenyl-a-methyl-propyl)-aminomethyl-7-methoxy-2-benzylchroman, I
10 phenol-a-methylpropyl)-aminomethyl~7-phenyl-2-cyclopentyll-Crimean, I -phenyl~-methylpropyl)-aminomethyl-6,8-dichlorochroman, -phenyl-a-methylpropyl)-aminomethyl-6,8-dimethyl-2-cyclohexylchroman, 4-t~-phenyl-a-methyl-propyl)-aminomethyl-S-hydroxy-2-spirocyclopentachrRoman 154-t~-phenyl~a-methylpropyl)-aminomethyl-6-hydroxycCrimean, 4-t~-3,4-methylenedioxyphenyl-a-methylpropyl)-aminno-methylchroman, 4-(~-3~4-methylenedioxyphenyL-~-methyl-propyl3-aminomethyl-2,2-dime~hylchroman, methyl-enedioxyphenyl-a-methylpropyL) aminomethyl-2-isopropyl-20 Crimean, 4-~-3,4-methylenedioxyphenyl-a-methylpropyl)-aminomethyl-2,2-diethylchroman, 4-t ~3,4-m~thylenedisxy-phenyl-a-methylpropyl)-aminomethyl-2-spirocycLopenNat Crimean, 4-(~-3,4-methylenedioxyphenyl-a-methylpropyl~-. aminomethyl-2-spirocyclohexachroman, I 3,4-methylene-25dioxyphenyl-a-methylpropyl)-aminomethyl-7-methyl-22 spirocyclopentachroman, 4-(~-~,4~methylenedioxyphenyl a-methylpropyl)-aminomethyl-~ chloro-2-spirocyclopenta-Crimean, I 3,4-methylenedioxyphenyl-a-methylpropyl)-aminomethyl-6-methoxy-2-spirocyclopentachroman~ I 3,4-30methylenedioxyphenyl-X-methylpropyl)-aminomethyl-7Matthew-oxy-2-spirocyclopentachroman~ 4-t~-3,4-methylenedioxy-phenyl-X-methylpropyl)-aminomethyl-7-phenyl-2 spirocyclo-pentachroman, 4-t ~3,4-methylenedioxyphenyL- methyl-propyl)-aminomethyl-2,2-dimethylchromene, I Matthew-35ylenedloxyphenyl-a-methylpropyl)-aminomethyl-2-spiif cyclopent~chromene, 4 t~-3-trifluoromethylphenyl-~-methyl~
lo _ 22 084 '7~3~
- ED -propyl)-am;nomethyl-2-spirocyclopentachroman, 4- -3,4-dimethoxyphenyl-~-methylpropyl)-aminomethyl-2-spirrecycle-pentachroman, 4-(~-2~4-dimethoxyphenyl-~-methylpropyl)-aminomethyl-2-spirocyclopentachroman, 4-(~-4-chlorophenyl-5a-methylpropyl)-aminomethyl-2-spirocyclopentachromman 4-(~-3,4,5-trimethoxyphenyl-a-methylpropyl)-aminommethyl-2-spirocyclopentachroman, -3,4-dimethoxyphenyl-a-methylpropyl)-aminomethyl~2-spirocyclopentachromenno, 4-t~-4-chlorophenyl-a-methylpropyl)-aminomethyl-Z--Spiro-10 cyclopentachromen, 4-~-phenylaminoethylaminomethyl-2,2-dimethylchroman, 4-~-phenylaminoethylaminomethyl-2-spiro-cyclopentachroman, 4-~-phenylaminoethylaminomethyl-2-spirocyclopentachromene, 4-~-(4-chlorophenyl)-amino-ethylaminomethyl-2-spirocyclohexachroman, Dow-15chlorophenyl~-aminoethylaminomethyl-2,2-dimethylchRoman, 4-~-(4-isopropylphenyl)-aminoethylaminomethyl-2-cyyokel-hexylchroman, 4- ~(4-ethoxyphenyl)-am;noethylaminomethyl-2-spirocyclohexachroman, 4-(N-phenylpiperaz;n-N'-yl-methyl)-2,2-dimethylchroman, 4-(N-phenylpiperazin-N'-yl-2Q methyl) ~-spirocyclopentachroman, 4-~N-phenylpiperazin-N'-ylmethyl)-2-spirocyclohexachroman, 4-SN-phenylpiper-azin-N'-ylmethy~)-7-methyl-2,2-dimethylchroman~ 4-(N-phPnyl-piperazin-N'-ylmethyl)-6-chloro~2-spirocyclopentacCrimean, 4-(N-phenylpiperazin-N'-ylmethyl)-6-methoxy-2-spirno-25 cyclohexachroman, 4-(N-phenylpiperazin~N~-ylmethyl)-7-methoxy-2,2-d;ethylchroman, 4-N-~4-chlorophenyl)-piper-azin-N'-ylmethyl-2-spirocyclohexachroman, 4-N-(3,4~di-chlorophenyl)-piperaz;n-N'-ylmethyl-2,2-dimethylchRoman, 4-N-(3,4-dichlorophenyl)-piperazin-N'-ylmethyl-2-hHuxley 30 Crimean, 4 N-(3,4-dimethoxyphenyl) piperazin-N'-ylmethyl-2-spirocyclopentachroman, 4-N-~3~-methylenedioxyphenyl)-piperazin~N'-ylmethyl-2,2-dimethylchroman, 4-N-(3,4,5-trimethoxyphenyl)-piperazin-N'-ylmethyL-2-methyl-2propel-Crimean, ~-(Nophenylpiperazin-N'-yLmethyl)-2H-chromeneO
354-(N-phenylpiperazin-N'~ylmethyl)-2,2-dimethylchroomened 4-(N-phenylp;perazin-N'-methyl~-6-methyl-2~2-dimetthy-ye A 22 084 I
Crimean, 4-(N-phenylpiperazin-N'-yLmethyl)-6-chloro-2-spirocyclopentachromeneO 4-~N-phenylpiperazin-N'-yl-methyl)-6-methoxy-2-spirocyclohexachromene, 4-~N-phenyl-piperazin-N'-ylmethyl)-7-methoxy-2,2-diethylchromeone, 54-~N-phenylpiperazin-N'-ylmethyl)-7-p~enyl-2-benzyyule-Crimean ~-(N-phenylpiperazin-N'-ylmethyl~-5-hydroxy~
2,2-dimethylchromene, 4-N-(4-chlorophenyl)-piperazin-N'-ylmethyl-2-spirocyclopentachromene~ 4-N-(3,4-dichloro-phenyl)-piperazin~N'-ylmethyl-2,2-dimethylchromenee, 10~-N-~3-methylphenyl)-pipera2in-N'~ylmethyl-2-methyyule-propylchromene~ 4-N-(4 isopropylphenyl)-piperazin-N'-yl-methyl-2,2-diethylchromene, 4-N-(3~methoxyphenyl3-piper-azin-N'-yLmethyl-2-spirocyclopentachromene, 4-N-(4-eth-oxyphenyl)-piperazin-N'-ylmethyl-2-spirocyclohexacchrome 15 one, 4-N-(3~4-dimethoxyphenyl)-piperazin-N'-ylmethyl-Crimean, ~-N-(3,4-methylenedioxyphenyl)-piperazin-N'-ylmethyl-2~2-dimethylchromene, No ~3,4,5-trimethoxy-phenyl)-piperazin-N'-ylmethyl-~-isopropyl-2H-chrommine, 4-N-(4-hydroxyphenyl)-piperazin-N'-ylmethyl-2,2-dii-I ethylchromene, 4-N-~tri~luoromethylphenyl)-piperazin-N-ylmethyl~2-sp;rocyclopentachromene and 4-N-(3-chloro-4-tr;fluoromethyl~-piperazin-N-ylmethyl-2 spirocyclo-hexachromene.
The following compounds may be mentioned espouse-25 ally: 4-~-t3,4-methylenedioxyphenyl)-a-methylpropyl~-am;nomethyl-Z-spirocyclopentachroman, 4~(~-phenylethyl~-am;nomethyl-2-spirocyclopentachroman, ~-N-3,4 dichloro-phenyl-piperazin-N'-ylmethyl-2,2-dimethylchromene,, ~-~-phenoxyethyl-aminomethyl-2-spirocyclopentachroomen, 304-c~-f3~4~5-trimethoxyphenyl)-a-methylpropyl~-2-sppin cycLopentachroman and I 3-trif(uoromethylphenyl~-a-methylpropyl~ 2-~pirocyclopentachroman.
The invention moreover relates to various pro-cusses for the preparation of the compounds of the for-35 mute I).
Ethereal A 22 0~4 I
A) chroman-4-carbaldehydes of the formula (II) Rj~, (II) in which R1, R2, R3, R4, R5 and R6 have the above-mentioned meaning are reacted with amine of the formula (III) EN--C--~--X Roy ~III) I I Rio Rl5 on which R7, R8, R9, ROD, R11~ R12' R13~ R~4~
R15~ R16, R17 and X have the above mentioned meaning on the presence of reducing agents, or B) amine of the formula (IV) R ego IVY
I
I
15 or of the formula TV) TV) lo A 22 084 on Shea R1, R2, R3, R4, R5 and R6 have the above-mentioned meaning are reacted with carbonyl compounds of the formula (VI) ill Al I; TV) in which R8 to R16 have the above mentioned meaning, with the proviso that X does not represent NR17, on the presence of reducing agents, or lo C) halides of the formula YO-YO) Ray CRY
t V I I ) I
on which R1, R2, R3~ R4~ R5 and R6 have the above-mentioned meaning and lo Y represents bromide or chlorine, are reacted with the amine of the formula (III) in the presence of an acid-bind;ng agent.
Complex metal hydrides may be mentioned as ox-apples of reducing agents which can be employed in process variants A and B. Alkali metal borohydrides~
alkali metal cyanoborohydrides Andre alkali metal clan-ales, especially sodium compounds or lithium compounds, are preferred. Specifically, sodium bordered, sodium cyanoborohydride or lithium alienate may be mentioned.
It us also possible to employ catalytically activated hydrogen at elevated pressures and temperatures.
lo A 22 084 '7~3~
The reducing agents can be employed in quantities ranging from equivalent amounts to an excess of 100 %, preferably equivalent amounts to an excess of 20 X, net-ate to the carbonyl compound employed.
The acid-binding agents employed in preparation variant C are known bases. Examples which may be men-toned are alkaline earth metal hydroxides or alkali metal hydroxides such as sodium hydroxide and/or poles-slum hydroxide, alkaline earth metal carbonates or alkali metal carbonates such as sodium bicarbonate or potassium carbonate, and organic nitrogen bases such as ~riethyl-amine, tributylamine or benzyltrimethyLammonium hydroxide.
These ac;d-binding agents can be employed in quantities ranging from equivalent amounts to an excess of 100 X, preferably from equivalent amounts to an excess of 20 X, relative to the halogen compound employed.
The reactions according to the invention are carried out in solvents. Suitable solvents are all those which are inert to the particular reaction; the follow-in may be mentioned as being preferred: alcohols swishes methanol, ethanol, isopropanol or tert.-butanol, ethers such as deathly ether, diisopropyl ether, twitter-hydrofuran or Dixon, hydrocarbons such as hexane, cyclohexane, Bunsen or Tulane, chlorohydrocarbons such as ethylene chloride, chloroform, carbon twitter-chloride or chlorobenzene, or mixtures of such solvents.
The reaction temperatures can be varied over a substantial range. In general the reaction us carried out between -50 and 150C, preferably -10 to 120C.
In carrying out the process according Jo the invention it is preferred to react 0.5 Jo 2 mow of the amine of the formula (III) or of the carbonyl compound of the formula VOW) per mow of the Crimean or Crimean compound. A molar ratio of the reactants of 1-1 is part-ocularly preferred. If an excess is used, then it is preferred Jo employ an excess of amine of the formula lo A 22 084 I
~III) or of carbonyl compound of the formula VOW).
The reaction products can be isolated by distill Litton, crystallising-out, concentration and recrystal-ligation or chromatographic separation.
5 The chroman-4-aldehydes of the formula (II) are prepared from creaminess by hydroformylation in accord-ante with the following equation:
I Coquette R4 Roy OR R JO OR
R6 I 2 R6 Al The process is characterized in that the OH-1û creaminess are reacted with carbon monoxide and hydrogen on the presence of metal catalysts of sub-group 8 of the periodic table, at temperatures of 80 to 250C and pressures of 20-1,000 bar.
As examples of the chroman-4-carbaldehydes there may be mentioned: 4~fcrmylchroman, 4-formyl-2-methyl-Crimean, 4-formyl~2~2-dimethylchroman, 4-formyl-2-propyl-Crimean, 4-formyl-2-isopropylchroman, 4-formyl-2,2-di~
ethylchroman, 4-formyl-2-methyl-2-propylchroman, formula-2-hexylchroman, 4-formyl-2-cyclopentylchromanO formula-2-cyclohexylchroman~ 4-formyl-2-sp;rocyclopentachroman, 4-formyl;2-spirocyclohexachroman, 4-formyl-6-methyl-2-spirocyclopentachroman~ 4-formyl-7-methyl-2-spirocyclo-pentachroman, 4-formyl-6,8-d;methyl-2-spirocyclopenta-Crimean, 4-formyl-6-chloro-2-spirocyclopentachroman, 4-formyl-6-methoxy-2-spirocyclopentachroman~ formula-7-methoxy-2-sp;rocyclopentachroman, 4-formyl-7-isopro-poxy-2-spirocyclopentachroman, 4-formyl-7-phenoxy~2-spirocyclopentachroman~ 4-formyl-7-benzyloxy-2-sp;ro-cyclopentachroman, 4-formyl-7-phenyl-2-spirocyclopenta-lo A 22 084 Crimean, 4-formyl-6-methyl-2,2-d;methylchroman, formula-6~chloro-2,2-dimethylchroman, 4-formyl-7-methoxy-2,2-d;methylchroman~ 4-formyl-6-methyl-2-spirocyclohexa~
Crimean and 4-formyl-7-methoxy-2-spirocyclohexachroman.
S A large proportion of the amine of the formula Tao) employed in the preparation of the compounds accord dung to the invention is known compare, for example, 8e;lste;ns Handbuch don organischen Chemise (~e;lstein's Handbook of Organic Chemistry) 172~ III 639, IV 663;
12; 543, 1096, 1145" I 473,, 494, II Z87, 591,~ 623, III/
IV ~93; those not previously known can be obtained by analogous methods.
us examples of the amine of the formula Tao) there may be mentioned: 2-phenylethylamine, sheller 15 phenyl)-ethylamine, 2-(4-chlorophenyl) ethyl amine, 2-(3,4-dichlorophenyl)-ethylamine, 2-(3-methylphenyl)-ethyl amine, 2-(2,4~dimethylphenyL)-ethylamine, 2-(2-methyl-4-chlorophenyl)-ethylamine, 2-(4-hydroxyphenyl)-ethyl amine, 2-~4-methoxyphenyl)-ethylamine, 2-t3,4-di-20 methoxyphenyl)-ethylamine, I 0~-naphthyl3-ethylamine, I ~naphthyl)-ethylamine, 2-(304-methylenedioxyphenyl )-ethylam;ne, 3-phenyl~propylamine, 2-phenylpropylamine,
phenylethylaminomethyl 6~chloro-chroman, 4-~-phenylethyl-am;nomethyl-b-chloro-2-spirocyclopentachroman, I -phenol-ethylaminomethyl-6-methoxy-2,2-dimethylchroman, I
phenylethylaminomethyl-6-methoxy-2-spirocyclopentaashore-30 man, I phenylethylaminomethyl-7-methoxy-2-spirocyclo pentachromanO I -phenylethylaminomethyl-7-phenyl-2-spirocyclopentachroman, 4-~-phenylethylaminomethyl 6,8-dichloro-2-spirocyclohexachroman9 4-~-phenylethylamino-methyl-5-hydroxy-2~2-d;methylchroman, 4-~-phenylethyl~
35 aminomethyl-5-hydroxy-2~spirocyclopentachroman, I -phenol-ethylaminomethyl-6-hydroxy-Z-spirocyclopentachromaan, lo A 22 08~
4-~-phenyLethylam;nomethyl-6-methyl-2-spirocycloheexam Crimean, 4- ~phenylethylaminomethylo7-methyl-2,Z-di-methylchromene, 4-~-phenylethyl3minomethyl-6-chloro-2,2-d;methylchromene, I -phenylethylaminomethyl~6~chloro~20 5 spirocyclopentachromene, 4- ~phenylethylaminomethyl-6-methoxy-2H-chromene, 4-~-phenylethylaminomethyl-6-methoxy-2-spirocyclopentachromene, I -phenylethylaminomethyl-7-methoxy-2,2-dimethylchromene, 4 ~phenylethylaminomethyl-7-methoxy-2-isopropyl-2H-chromene, 4-~-phenylethylamino-10 methyL~7-phenyl-2-spirocyclopentachromene, I -phenol-ethylaminomethyl-6,8-dichloro-2H-chromene, 44 -phenol-ethylaminomethyl-5-hydroxy~2-spirocyclopentachromeone, 4-~-t4-chlorophenyl)-ethylaminomethyl-2-spirocycloopenta-Crimean, 4-~-t3,4-dichlorophenyl)-ethylaminomethyl-2,2-15 d;methylchroman, 4-~-(3-methylphenyl)-ethylaminomethyl-2~isopropylchroman, 4-~-(4-isopropylphenyl)-ethylam;no-methyl-2,2-d;ethylchroman, 4-~-(3-methoxyphenyl)-ethyl-aminomethyl-2-spirocyclopentachroman, 4- ~t4-ethoxyphenyl)-ethylaminomethyl-2-spirocyclohexachroman, I 3,4-d;-methoxyphenyl)-ethylam;nomethyl-chromanO I -(3,4-methyl-enedioxyphenyl)-ethylaminomethyl-2,2-d;methylchromman, 4-~-t3,4,5-trimethoxyphenyl)-~thylam;nomethyl-2-meethyl-2-isopropyl-chroman, 4-~-t4-hydroxyphenyl)-ethylamino-methyl-2~2~diethylchroman, 4- ~t4~trifluoromethylphenyl)-ethylaminomethyl-2-spirocyclopentachroman, sheller-4-trifluoromethylphenyl)-ethyLaminomethyl-2 pi recycle-hexachroman~ I (1-naphthyl)-ethylaminomethyl-2-spiro-cyclohexachroman, 4-~-(2-naphthyl)-ethjlaminomethyl-2,2-dimethylchroman, 4-~-(4-chlorophenyl)-ethylaminomethyl~
2-sp;rocyclohexachronene, I phenyl-a-methyle~hyl~-aminomethyl-2-spirocyclohexachroman~ 4-t funneled-methylethyl)-aminomethyl-2,2-dimethylchroman~ phenol-a-ethylethyl)-aminomethyl~2-cyclopentylchroman~ I
phenyl-~methylethyl)-aminomethyl-2,2-diethylchromaan 35 4-(~-phenyl-a-methylethyl)-aminom~thyl-2-spirocycllo-pentachromene~ I ~phenylpropylaminomethyl-2-spirocyclo-lo A 22 OBOE
.
to pentachroman, 4-~-phenylpropylaminomethyl-2,2-d;methyl-Crimean, 4-~-phenylpropylaminomethyl-6-methyl-2,2-di-methylchroman, 4-~-(3,4-methylenedioxYPhenYl)~PrOpyl-aminomethyl-2-spirocyclopentachroman~ 4-C~-(4-chloro-5phenyl3-a-methylpropyl]-aminomethyl-2-isopropyl-2HH-Crimean, 4-~-phenoxyethylaminomethyl-2~2-dimethylchroman, 4-~-phenoxyethylaminomethyl-2-spirocyclopentachromman, 4- ~phenoxyethylaminomethyl-Z-spirocyclohexachroman, 4-~-phenoxyethylaminomethyl-2-spirocyclopentachrommine, 104-~-phenoxyethylaminomethyl-6~methyl-2,2-dimethylcCrimean, Iphenoxyethylam;nomethyL-7-methyl-2-spirocyclopentaa-Crimean, 4~-phenoxyethylaminomethyl-6-chloro-2-spiro~
cyclohexachromanO I -phenoxyethylaminomethyl-6-methoxy-Crimean, 4-~-phenoxye~hylaminomethyl-6-methoxy-2-phenyl-15 Crimean, 4- ~phenoxyethylaminomethyl-7-methoxy-2-iso-propylchroman, 4-~-phenoxyethylaminomethyl-7-phenylo2~2-dimethylchroman, 4-~-phenoxyethylaminomethyl-6,8-dichloro-2-spirocyclohexachromanr I -phenoxyethylaminomethyl-6,8-d;methyl-2-hexylchroman, 4- ~phenoxyethylaminomethyl-5-20 hydroxychroman, I phenoxyethylaminomethyl-6-hydroxy-2-spirocyclopentachroman, 4-~-phenoxyethylaminomethyl-6-methyl-2,2-d;methylchromene, 4-~-(4-chloroph~r,oxy)-ethylaminomethylchroman, I 3,4 dichlorophenoxy)-ethylaminomethyl-2,2-dime~hylchroman, 4-~-(3-methylphen-25 oxy)-ethylaminomethyl-2 methyl-2-isopropylchroman~ I
(4-isopropylphenoxy)-ethylaminomethyl-2,2-diethylcCrimean, 4-~-t4-ethoxyphenoxy)-ethylaminomethyl-2-spirocycLLucks-Crimean 4-~-(3,4-dimethoxyphenoxy)-ethylaminomethyl~2 spirocycLopentachroman, 4-~-(3,4-methylenedioxyphenoxy)-30 ethylam;nomethyl 2,2-dimethylchroman, 4-~-(3,4,5-trimeth~
oxyphenoxy)-ethylaminomethyl-2-cyclopentylchroman,, I
(4-hydroxyphenoxy) ethylaminomethyl-2,2-diethylchroman~
4-~-(4-chlorophenoxy)-ethylaminomethyl-2H-chromenee, 4-~-phenoxy-a-methylethyl) aminomethyl-2-spirocyslo-35 hexachroman, 4-(~-phenoxy-~-methylethyl~ aminomethyl-2,2-diethylchroman, 4-(~-phenoxy-a-methylethyl)-aminomethyl~
lo A 22 084 2-spirocyclopentachromene, 4-t~-phenyl-a-methylpropyl)-aminomethyl-2H-chromene~ 4-t~-phenyl-a-methylpropyl)-aminomethyl-21spirocyclopentachromene, 4-(r-phenyl~x-methylpropyl)-aminomethyl-2,2-dimethylchroman, phenol-5~-methylpropyl)-aminomethyL-2-spirocyclopentachromman, 4-(~-phenyl-a-methylpropyl)-aminomethyl-6-methyl-22,2-dimethylchroman, I phenyl-a-methylpropyl)-aminomethyl-6-chloro-2-spirocyclohexachroman~ I ~phenyl-a-methyl-propyl)-aminomethyl-7-methoxy-2-benzylchroman, I
10 phenol-a-methylpropyl)-aminomethyl~7-phenyl-2-cyclopentyll-Crimean, I -phenyl~-methylpropyl)-aminomethyl-6,8-dichlorochroman, -phenyl-a-methylpropyl)-aminomethyl-6,8-dimethyl-2-cyclohexylchroman, 4-t~-phenyl-a-methyl-propyl)-aminomethyl-S-hydroxy-2-spirocyclopentachrRoman 154-t~-phenyl~a-methylpropyl)-aminomethyl-6-hydroxycCrimean, 4-t~-3,4-methylenedioxyphenyl-a-methylpropyl)-aminno-methylchroman, 4-(~-3~4-methylenedioxyphenyL-~-methyl-propyl3-aminomethyl-2,2-dime~hylchroman, methyl-enedioxyphenyl-a-methylpropyL) aminomethyl-2-isopropyl-20 Crimean, 4-~-3,4-methylenedioxyphenyl-a-methylpropyl)-aminomethyl-2,2-diethylchroman, 4-t ~3,4-m~thylenedisxy-phenyl-a-methylpropyl)-aminomethyl-2-spirocycLopenNat Crimean, 4-(~-3,4-methylenedioxyphenyl-a-methylpropyl~-. aminomethyl-2-spirocyclohexachroman, I 3,4-methylene-25dioxyphenyl-a-methylpropyl)-aminomethyl-7-methyl-22 spirocyclopentachroman, 4-(~-~,4~methylenedioxyphenyl a-methylpropyl)-aminomethyl-~ chloro-2-spirocyclopenta-Crimean, I 3,4-methylenedioxyphenyl-a-methylpropyl)-aminomethyl-6-methoxy-2-spirocyclopentachroman~ I 3,4-30methylenedioxyphenyl-X-methylpropyl)-aminomethyl-7Matthew-oxy-2-spirocyclopentachroman~ 4-t~-3,4-methylenedioxy-phenyl-X-methylpropyl)-aminomethyl-7-phenyl-2 spirocyclo-pentachroman, 4-t ~3,4-methylenedioxyphenyL- methyl-propyl)-aminomethyl-2,2-dimethylchromene, I Matthew-35ylenedloxyphenyl-a-methylpropyl)-aminomethyl-2-spiif cyclopent~chromene, 4 t~-3-trifluoromethylphenyl-~-methyl~
lo _ 22 084 '7~3~
- ED -propyl)-am;nomethyl-2-spirocyclopentachroman, 4- -3,4-dimethoxyphenyl-~-methylpropyl)-aminomethyl-2-spirrecycle-pentachroman, 4-(~-2~4-dimethoxyphenyl-~-methylpropyl)-aminomethyl-2-spirocyclopentachroman, 4-(~-4-chlorophenyl-5a-methylpropyl)-aminomethyl-2-spirocyclopentachromman 4-(~-3,4,5-trimethoxyphenyl-a-methylpropyl)-aminommethyl-2-spirocyclopentachroman, -3,4-dimethoxyphenyl-a-methylpropyl)-aminomethyl~2-spirocyclopentachromenno, 4-t~-4-chlorophenyl-a-methylpropyl)-aminomethyl-Z--Spiro-10 cyclopentachromen, 4-~-phenylaminoethylaminomethyl-2,2-dimethylchroman, 4-~-phenylaminoethylaminomethyl-2-spiro-cyclopentachroman, 4-~-phenylaminoethylaminomethyl-2-spirocyclopentachromene, 4-~-(4-chlorophenyl)-amino-ethylaminomethyl-2-spirocyclohexachroman, Dow-15chlorophenyl~-aminoethylaminomethyl-2,2-dimethylchRoman, 4-~-(4-isopropylphenyl)-aminoethylaminomethyl-2-cyyokel-hexylchroman, 4- ~(4-ethoxyphenyl)-am;noethylaminomethyl-2-spirocyclohexachroman, 4-(N-phenylpiperaz;n-N'-yl-methyl)-2,2-dimethylchroman, 4-(N-phenylpiperazin-N'-yl-2Q methyl) ~-spirocyclopentachroman, 4-~N-phenylpiperazin-N'-ylmethyl)-2-spirocyclohexachroman, 4-SN-phenylpiper-azin-N'-ylmethy~)-7-methyl-2,2-dimethylchroman~ 4-(N-phPnyl-piperazin-N'-ylmethyl)-6-chloro~2-spirocyclopentacCrimean, 4-(N-phenylpiperazin-N'-ylmethyl)-6-methoxy-2-spirno-25 cyclohexachroman, 4-(N-phenylpiperazin~N~-ylmethyl)-7-methoxy-2,2-d;ethylchroman, 4-N-~4-chlorophenyl)-piper-azin-N'-ylmethyl-2-spirocyclohexachroman, 4-N-(3,4~di-chlorophenyl)-piperaz;n-N'-ylmethyl-2,2-dimethylchRoman, 4-N-(3,4-dichlorophenyl)-piperazin-N'-ylmethyl-2-hHuxley 30 Crimean, 4 N-(3,4-dimethoxyphenyl) piperazin-N'-ylmethyl-2-spirocyclopentachroman, 4-N-~3~-methylenedioxyphenyl)-piperazin~N'-ylmethyl-2,2-dimethylchroman, 4-N-(3,4,5-trimethoxyphenyl)-piperazin-N'-ylmethyL-2-methyl-2propel-Crimean, ~-(Nophenylpiperazin-N'-yLmethyl)-2H-chromeneO
354-(N-phenylpiperazin-N'~ylmethyl)-2,2-dimethylchroomened 4-(N-phenylp;perazin-N'-methyl~-6-methyl-2~2-dimetthy-ye A 22 084 I
Crimean, 4-(N-phenylpiperazin-N'-yLmethyl)-6-chloro-2-spirocyclopentachromeneO 4-~N-phenylpiperazin-N'-yl-methyl)-6-methoxy-2-spirocyclohexachromene, 4-~N-phenyl-piperazin-N'-ylmethyl)-7-methoxy-2,2-diethylchromeone, 54-~N-phenylpiperazin-N'-ylmethyl)-7-p~enyl-2-benzyyule-Crimean ~-(N-phenylpiperazin-N'-ylmethyl~-5-hydroxy~
2,2-dimethylchromene, 4-N-(4-chlorophenyl)-piperazin-N'-ylmethyl-2-spirocyclopentachromene~ 4-N-(3,4-dichloro-phenyl)-piperazin~N'-ylmethyl-2,2-dimethylchromenee, 10~-N-~3-methylphenyl)-pipera2in-N'~ylmethyl-2-methyyule-propylchromene~ 4-N-(4 isopropylphenyl)-piperazin-N'-yl-methyl-2,2-diethylchromene, 4-N-(3~methoxyphenyl3-piper-azin-N'-yLmethyl-2-spirocyclopentachromene, 4-N-(4-eth-oxyphenyl)-piperazin-N'-ylmethyl-2-spirocyclohexacchrome 15 one, 4-N-(3~4-dimethoxyphenyl)-piperazin-N'-ylmethyl-Crimean, ~-N-(3,4-methylenedioxyphenyl)-piperazin-N'-ylmethyl-2~2-dimethylchromene, No ~3,4,5-trimethoxy-phenyl)-piperazin-N'-ylmethyl-~-isopropyl-2H-chrommine, 4-N-(4-hydroxyphenyl)-piperazin-N'-ylmethyl-2,2-dii-I ethylchromene, 4-N-~tri~luoromethylphenyl)-piperazin-N-ylmethyl~2-sp;rocyclopentachromene and 4-N-(3-chloro-4-tr;fluoromethyl~-piperazin-N-ylmethyl-2 spirocyclo-hexachromene.
The following compounds may be mentioned espouse-25 ally: 4-~-t3,4-methylenedioxyphenyl)-a-methylpropyl~-am;nomethyl-Z-spirocyclopentachroman, 4~(~-phenylethyl~-am;nomethyl-2-spirocyclopentachroman, ~-N-3,4 dichloro-phenyl-piperazin-N'-ylmethyl-2,2-dimethylchromene,, ~-~-phenoxyethyl-aminomethyl-2-spirocyclopentachroomen, 304-c~-f3~4~5-trimethoxyphenyl)-a-methylpropyl~-2-sppin cycLopentachroman and I 3-trif(uoromethylphenyl~-a-methylpropyl~ 2-~pirocyclopentachroman.
The invention moreover relates to various pro-cusses for the preparation of the compounds of the for-35 mute I).
Ethereal A 22 0~4 I
A) chroman-4-carbaldehydes of the formula (II) Rj~, (II) in which R1, R2, R3, R4, R5 and R6 have the above-mentioned meaning are reacted with amine of the formula (III) EN--C--~--X Roy ~III) I I Rio Rl5 on which R7, R8, R9, ROD, R11~ R12' R13~ R~4~
R15~ R16, R17 and X have the above mentioned meaning on the presence of reducing agents, or B) amine of the formula (IV) R ego IVY
I
I
15 or of the formula TV) TV) lo A 22 084 on Shea R1, R2, R3, R4, R5 and R6 have the above-mentioned meaning are reacted with carbonyl compounds of the formula (VI) ill Al I; TV) in which R8 to R16 have the above mentioned meaning, with the proviso that X does not represent NR17, on the presence of reducing agents, or lo C) halides of the formula YO-YO) Ray CRY
t V I I ) I
on which R1, R2, R3~ R4~ R5 and R6 have the above-mentioned meaning and lo Y represents bromide or chlorine, are reacted with the amine of the formula (III) in the presence of an acid-bind;ng agent.
Complex metal hydrides may be mentioned as ox-apples of reducing agents which can be employed in process variants A and B. Alkali metal borohydrides~
alkali metal cyanoborohydrides Andre alkali metal clan-ales, especially sodium compounds or lithium compounds, are preferred. Specifically, sodium bordered, sodium cyanoborohydride or lithium alienate may be mentioned.
It us also possible to employ catalytically activated hydrogen at elevated pressures and temperatures.
lo A 22 084 '7~3~
The reducing agents can be employed in quantities ranging from equivalent amounts to an excess of 100 %, preferably equivalent amounts to an excess of 20 X, net-ate to the carbonyl compound employed.
The acid-binding agents employed in preparation variant C are known bases. Examples which may be men-toned are alkaline earth metal hydroxides or alkali metal hydroxides such as sodium hydroxide and/or poles-slum hydroxide, alkaline earth metal carbonates or alkali metal carbonates such as sodium bicarbonate or potassium carbonate, and organic nitrogen bases such as ~riethyl-amine, tributylamine or benzyltrimethyLammonium hydroxide.
These ac;d-binding agents can be employed in quantities ranging from equivalent amounts to an excess of 100 X, preferably from equivalent amounts to an excess of 20 X, relative to the halogen compound employed.
The reactions according to the invention are carried out in solvents. Suitable solvents are all those which are inert to the particular reaction; the follow-in may be mentioned as being preferred: alcohols swishes methanol, ethanol, isopropanol or tert.-butanol, ethers such as deathly ether, diisopropyl ether, twitter-hydrofuran or Dixon, hydrocarbons such as hexane, cyclohexane, Bunsen or Tulane, chlorohydrocarbons such as ethylene chloride, chloroform, carbon twitter-chloride or chlorobenzene, or mixtures of such solvents.
The reaction temperatures can be varied over a substantial range. In general the reaction us carried out between -50 and 150C, preferably -10 to 120C.
In carrying out the process according Jo the invention it is preferred to react 0.5 Jo 2 mow of the amine of the formula (III) or of the carbonyl compound of the formula VOW) per mow of the Crimean or Crimean compound. A molar ratio of the reactants of 1-1 is part-ocularly preferred. If an excess is used, then it is preferred Jo employ an excess of amine of the formula lo A 22 084 I
~III) or of carbonyl compound of the formula VOW).
The reaction products can be isolated by distill Litton, crystallising-out, concentration and recrystal-ligation or chromatographic separation.
5 The chroman-4-aldehydes of the formula (II) are prepared from creaminess by hydroformylation in accord-ante with the following equation:
I Coquette R4 Roy OR R JO OR
R6 I 2 R6 Al The process is characterized in that the OH-1û creaminess are reacted with carbon monoxide and hydrogen on the presence of metal catalysts of sub-group 8 of the periodic table, at temperatures of 80 to 250C and pressures of 20-1,000 bar.
As examples of the chroman-4-carbaldehydes there may be mentioned: 4~fcrmylchroman, 4-formyl-2-methyl-Crimean, 4-formyl~2~2-dimethylchroman, 4-formyl-2-propyl-Crimean, 4-formyl-2-isopropylchroman, 4-formyl-2,2-di~
ethylchroman, 4-formyl-2-methyl-2-propylchroman, formula-2-hexylchroman, 4-formyl-2-cyclopentylchromanO formula-2-cyclohexylchroman~ 4-formyl-2-sp;rocyclopentachroman, 4-formyl;2-spirocyclohexachroman, 4-formyl-6-methyl-2-spirocyclopentachroman~ 4-formyl-7-methyl-2-spirocyclo-pentachroman, 4-formyl-6,8-d;methyl-2-spirocyclopenta-Crimean, 4-formyl-6-chloro-2-spirocyclopentachroman, 4-formyl-6-methoxy-2-spirocyclopentachroman~ formula-7-methoxy-2-sp;rocyclopentachroman, 4-formyl-7-isopro-poxy-2-spirocyclopentachroman, 4-formyl-7-phenoxy~2-spirocyclopentachroman~ 4-formyl-7-benzyloxy-2-sp;ro-cyclopentachroman, 4-formyl-7-phenyl-2-spirocyclopenta-lo A 22 084 Crimean, 4-formyl-6-methyl-2,2-d;methylchroman, formula-6~chloro-2,2-dimethylchroman, 4-formyl-7-methoxy-2,2-d;methylchroman~ 4-formyl-6-methyl-2-spirocyclohexa~
Crimean and 4-formyl-7-methoxy-2-spirocyclohexachroman.
S A large proportion of the amine of the formula Tao) employed in the preparation of the compounds accord dung to the invention is known compare, for example, 8e;lste;ns Handbuch don organischen Chemise (~e;lstein's Handbook of Organic Chemistry) 172~ III 639, IV 663;
12; 543, 1096, 1145" I 473,, 494, II Z87, 591,~ 623, III/
IV ~93; those not previously known can be obtained by analogous methods.
us examples of the amine of the formula Tao) there may be mentioned: 2-phenylethylamine, sheller 15 phenyl)-ethylamine, 2-(4-chlorophenyl) ethyl amine, 2-(3,4-dichlorophenyl)-ethylamine, 2-(3-methylphenyl)-ethyl amine, 2-(2,4~dimethylphenyL)-ethylamine, 2-(2-methyl-4-chlorophenyl)-ethylamine, 2-(4-hydroxyphenyl)-ethyl amine, 2-~4-methoxyphenyl)-ethylamine, 2-t3,4-di-20 methoxyphenyl)-ethylamine, I 0~-naphthyl3-ethylamine, I ~naphthyl)-ethylamine, 2-(304-methylenedioxyphenyl )-ethylam;ne, 3-phenyl~propylamine, 2-phenylpropylamine,
3-~4-chlorophenyl~-propylamine, 2-(4~chLorophenyl~-propylamine, 3-t4-methylphenyl)-propylamine~ methyl-25 phenyl)-propylamine, 3-t4~methoxyphenyl)-propylamine~
2-~3~4-dimethoxyphenyl) propylamine, 3-(3,4-methylene-dioxyphenyl)-propylam;ne~ 2-amino-~phenyl-butane, 2-amino-4-t4-chlorophenyl)-butane, Amman methyl-phenyl)-butane, 2-amino-4-(4-trifluoromethylphenyl)-30 butane 2-amino-4-(4-isopropylphenyl)-butane, Amman-(3,4-dichlorophenyl)-butane, 2-amino-4-(2-methoxyphenyl)-butane, 2 amino-40(3~methoxyphenyl) butane, 2-amino-4-t4-methoxyphenyl)-butane, 2-amino-4-~-propoxyphenyl)-butane, 2 amino-4-~3,4-dimethoxyphenyl)-bu~ane, 2-amino-35 4-t3,4-methylenedioxyphenyl)-butane, 3-amino-5-phenyl pontoon, 3-amino-5 (3,4-methylenedioxyphenyl)-pentane~
lo A 22 084 '7 Lo 2-phenyl~1-methyl-ethylamine, phenol dim ethyl-ethyl amine, 2-phenyl-1,~-diethyl-ethylamine, phenol-2,2-dimethyl-ethylamine, 2-phenyl-2,2-diethyl-ethylamine, 2-phenyl-N-methyl-ethylamine, Z-phenyl-N-ethyl-ethylamine, 2-phenyl-N-isopropyl-ethylamine, 2-(4-chlorophenyl)-N-methyl-ethylamine, 2-t4-methoxyphenyl)-N-methyl-ethyl-amine, 2-~4-isopropylphenyl)-N-methyl-ethylamine, phony-oxyethylamine~ 2-~4-methylphenoxy)-ethylamine, 2-t4-tert.-butylphenoxy)-ethylamine, 2-~4-chlorophenoxy)-ethyl amine, ~-~4-trifluoromethylphenoxy)-ethylamine, 2-(3-ethoxyphenoxy)-ethylamine, 2-(4-methoxyphenoxy)-ethyl amine 2 (4-isopropoxyphenoxy)-ethylamine, phonics-propylamine, 2-(4-fluorophenoxy)-propylamine, phonics-butane amine, 2-phenoxy-N-methyL-ethylamine, phonics-N-ethyl-ethylamine, 2-phenoxy-N-isopropyl-ethylamine, N-phenyl-ethylenediamine, N~(4-chlorophenyl)-ethylene-Damon N-(3~4-dichlorophenyl)-e~hylenediamine, No methylphenyl)-ethylenediamine, N-(4-isopropylphenyl)-ethylenediamine, N-(4-trifluoromethylphenyl)-ethylene-Damon, N-(4-hydroxyphenyl)-ethylenediamine, N-(2-methoxy-phenyl)-ethylenediamine, N-(4-ethoxyphenyl)-ethylene-Damon, N-phenyl-N'-methyl-ethylenediamine, N-phenyl-N'-ethyl-ethylenediamine, N-(4-chlorophenyl)-N'-isopropyl-ethylene Diane N-phenyl-N-me~hyl-ethylenediamine, 2-amino-3-anilino-propane, 3-amino-4-anilino-butane, 2-amino-2-methyl-3-anilino-propane, 2-amino-2-methyl-3-(4-chloroanilino)-propane, 1-amino-2-anil;no-propane, 1-amino-2-anilino-butane, 1-amino~=2~methyl-2~anilino-propane, Amman methyl-2-(4-methoxyanilino)-propane, N-phenylpiperazine, N-~2-chlorophenyl)-piperazine, N~(4-~hlorophenyl)-piper-amine, N-(3,4-dichlorophenyl)-piperazine, No ruffler-methylphenyl)-piperazine, N-~3-trifluoromethylphenyl)-piperazine, N-(3~trifluoromethyl-4-chlorophenyl~-piper-amine, N-(2--methoxyphenyl)-piperazine, N-(2-e~hoxyphenyl)-piperazine, N ~2-isopropoxyphenyl)-piper3zine~ No lo A 22 084 methoxyphenyl~-p;perazine, N (4-methoxyphenyl)-p;per-amine, N-(3~4-d;me~hoxyphenyl)-piperazine, N-t3,4-meth-ylenedioxyphenyl)-p;perazine, N-(4-methylphenyl)-pipera-zinc, N-(3,4-dimethylphenyl)-piperazine, N-(2,4-dimethyl-phenyl)-piperazine~ N-(2,5-dimethylphenyl)-piperazine, N-t4-ethylphenyl)-piperazine, N-(4-isopropylphenyl)-piperazine, N-(4-tert.-butylphenyl)-piperazine and N-So cyclohexylphenyl)-piperazine~
Some of the amine of the formula (IV) employed in the preparation of the compounds according to the invention are known (JO mud Chum. 1982, 393). Those not previously known can be prepared by analogous moth-ohs.
In doing so, the starting materials are Crimean-US 4-ones which are reacted with trime~hylsilyl cyanide, as indicated in the following equation 3 R3 NC Owl ISSUE) 3 R ( C H 3 ) 3 R 2 The 4-cyano-4-trimethylsilyloxychromans thus produced can be hydrogenated by means of lithium aluminum hydrides to give 4-aminomethyl~4-hydroxychromans~ as in-dilated on the following equation:
I NC Ooze (SHEA ) 3 5 SHEA
I Lowe aye I
The ~-aminomethyl-4-hydroxychromans can be con-vented by dehydrating agents into the 4-aminomethyl-2H-creaminess of the formula SIX) as shown in the equat;onbelow~
lo A 22 084 :~;22~'7~
R3 HO C~2NH2 R3 SHEA
R4 H2 R4~h pi Jo O R2 I R2 The am;nomethylchromenes can be converted to the aminomethylchromans by hydrogenation, as in the follow-in equation:
R Jo I
t us however, also possible to eliminate in-methylsilanol from the 4-cyano-~-tr;methylsilyloxychro-mans by means of phosphorus oxychlor;de and thus isolate
2-~3~4-dimethoxyphenyl) propylamine, 3-(3,4-methylene-dioxyphenyl)-propylam;ne~ 2-amino-~phenyl-butane, 2-amino-4-t4-chlorophenyl)-butane, Amman methyl-phenyl)-butane, 2-amino-4-(4-trifluoromethylphenyl)-30 butane 2-amino-4-(4-isopropylphenyl)-butane, Amman-(3,4-dichlorophenyl)-butane, 2-amino-4-(2-methoxyphenyl)-butane, 2 amino-40(3~methoxyphenyl) butane, 2-amino-4-t4-methoxyphenyl)-butane, 2-amino-4-~-propoxyphenyl)-butane, 2 amino-4-~3,4-dimethoxyphenyl)-bu~ane, 2-amino-35 4-t3,4-methylenedioxyphenyl)-butane, 3-amino-5-phenyl pontoon, 3-amino-5 (3,4-methylenedioxyphenyl)-pentane~
lo A 22 084 '7 Lo 2-phenyl~1-methyl-ethylamine, phenol dim ethyl-ethyl amine, 2-phenyl-1,~-diethyl-ethylamine, phenol-2,2-dimethyl-ethylamine, 2-phenyl-2,2-diethyl-ethylamine, 2-phenyl-N-methyl-ethylamine, Z-phenyl-N-ethyl-ethylamine, 2-phenyl-N-isopropyl-ethylamine, 2-(4-chlorophenyl)-N-methyl-ethylamine, 2-t4-methoxyphenyl)-N-methyl-ethyl-amine, 2-~4-isopropylphenyl)-N-methyl-ethylamine, phony-oxyethylamine~ 2-~4-methylphenoxy)-ethylamine, 2-t4-tert.-butylphenoxy)-ethylamine, 2-~4-chlorophenoxy)-ethyl amine, ~-~4-trifluoromethylphenoxy)-ethylamine, 2-(3-ethoxyphenoxy)-ethylamine, 2-(4-methoxyphenoxy)-ethyl amine 2 (4-isopropoxyphenoxy)-ethylamine, phonics-propylamine, 2-(4-fluorophenoxy)-propylamine, phonics-butane amine, 2-phenoxy-N-methyL-ethylamine, phonics-N-ethyl-ethylamine, 2-phenoxy-N-isopropyl-ethylamine, N-phenyl-ethylenediamine, N~(4-chlorophenyl)-ethylene-Damon N-(3~4-dichlorophenyl)-e~hylenediamine, No methylphenyl)-ethylenediamine, N-(4-isopropylphenyl)-ethylenediamine, N-(4-trifluoromethylphenyl)-ethylene-Damon, N-(4-hydroxyphenyl)-ethylenediamine, N-(2-methoxy-phenyl)-ethylenediamine, N-(4-ethoxyphenyl)-ethylene-Damon, N-phenyl-N'-methyl-ethylenediamine, N-phenyl-N'-ethyl-ethylenediamine, N-(4-chlorophenyl)-N'-isopropyl-ethylene Diane N-phenyl-N-me~hyl-ethylenediamine, 2-amino-3-anilino-propane, 3-amino-4-anilino-butane, 2-amino-2-methyl-3-anilino-propane, 2-amino-2-methyl-3-(4-chloroanilino)-propane, 1-amino-2-anil;no-propane, 1-amino-2-anilino-butane, 1-amino~=2~methyl-2~anilino-propane, Amman methyl-2-(4-methoxyanilino)-propane, N-phenylpiperazine, N-~2-chlorophenyl)-piperazine, N~(4-~hlorophenyl)-piper-amine, N-(3,4-dichlorophenyl)-piperazine, No ruffler-methylphenyl)-piperazine, N-~3-trifluoromethylphenyl)-piperazine, N-(3~trifluoromethyl-4-chlorophenyl~-piper-amine, N-(2--methoxyphenyl)-piperazine, N-(2-e~hoxyphenyl)-piperazine, N ~2-isopropoxyphenyl)-piper3zine~ No lo A 22 084 methoxyphenyl~-p;perazine, N (4-methoxyphenyl)-p;per-amine, N-(3~4-d;me~hoxyphenyl)-piperazine, N-t3,4-meth-ylenedioxyphenyl)-p;perazine, N-(4-methylphenyl)-pipera-zinc, N-(3,4-dimethylphenyl)-piperazine, N-(2,4-dimethyl-phenyl)-piperazine~ N-(2,5-dimethylphenyl)-piperazine, N-t4-ethylphenyl)-piperazine, N-(4-isopropylphenyl)-piperazine, N-(4-tert.-butylphenyl)-piperazine and N-So cyclohexylphenyl)-piperazine~
Some of the amine of the formula (IV) employed in the preparation of the compounds according to the invention are known (JO mud Chum. 1982, 393). Those not previously known can be prepared by analogous moth-ohs.
In doing so, the starting materials are Crimean-US 4-ones which are reacted with trime~hylsilyl cyanide, as indicated in the following equation 3 R3 NC Owl ISSUE) 3 R ( C H 3 ) 3 R 2 The 4-cyano-4-trimethylsilyloxychromans thus produced can be hydrogenated by means of lithium aluminum hydrides to give 4-aminomethyl~4-hydroxychromans~ as in-dilated on the following equation:
I NC Ooze (SHEA ) 3 5 SHEA
I Lowe aye I
The ~-aminomethyl-4-hydroxychromans can be con-vented by dehydrating agents into the 4-aminomethyl-2H-creaminess of the formula SIX) as shown in the equat;onbelow~
lo A 22 084 :~;22~'7~
R3 HO C~2NH2 R3 SHEA
R4 H2 R4~h pi Jo O R2 I R2 The am;nomethylchromenes can be converted to the aminomethylchromans by hydrogenation, as in the follow-in equation:
R Jo I
t us however, also possible to eliminate in-methylsilanol from the 4-cyano-~-tr;methylsilyloxychro-mans by means of phosphorus oxychlor;de and thus isolate
4-cyano-2H-chromenes, as indicated in the following equal lion analogously to a method from Chemistry Letters 1979, owe R3 ON Owe (OR ) R3 I
F~4 3 3 R
R5~ 0 R2 I Joy 2 the 4-cyano~2H--chromenes can then be hydrogenated directly or stops to give the 4-am;nome~hylchromans, as represented in the following equation:
lo A 22 084 I
I 2 4~2 n R1 1 As examples of the 4-aminomethyl-2H-chromenes there may be mentioned: 4-aminomethyl-2H-chromene, 4-am;nonethyl-2-methyl-2H-chromer,e, 4-am;nomethyl-2~2-dimethyl-chromene, 4-aminomethyl-2 propyl-2H-chromene, ~-aminomethyl-2-;sopropyL-2H-chromene, 4-aminomethyl-2,2-diethyl-chromene, 4-aminomethyl-2-methyl-2-propyl-chro-Mooney 4-aminomethyl-2-hexyl-2H-chromene, 4-aminomethyl-2-cyclopentyl-2H-chromene, 4-aminomethyl-2-cyclohexyl-lo Crimean, 4~aminomethyl-2-spirocyclopentachromene, 4-am;nomethyl-2-spirocyclohexachromene, 4 am;nomethyl-6-methyl-2-spirocyclopentachromene, 4-aminomethyl-7-methyl-2-spirocyclopentachromene, 4-aminomethyl-6~8-dimethyl 2-sp;rocyclopentachromene, 4-aminomethyl-6-chloro-Z-spirocyclopentachromene, 4-aminomethyl-6-methoxy-2-spirocyclopentachromene, 4-aminomethyl-7-methoxy-2-spiro-cyclopentachromene, 4~aminomethyl-7-isopropoxyo2-spiro~
cyclopentachromene, 4-aminomethyl-7-phenoxy-2-spirocyclo-pentachromene, 4-aminome~hyl~7-ben~yloxyo2-sp;rocyclo-pentachromene, 4-am;nomethyl-7-phenyl-2-sp;rocyclopenta-Crimean, 4-aminomethyl-6-methyl-2-spirocyclohexachromene, 4-amino~ethyl-6-chloro-2-spirocyclohexachromene, 4-amino-methylo7-methoxy 2-spirocyclohexachromene, 4-aminomethyl 6-methylo2,2-dimethylchromene and 4~aminomethyl~7-meth-oxy-2,2-d;methylchromene~
Some of the amine of the formula (V) employed in the preparation of the compounds according Jo the invention are known (J. med. Chum. 1982, OWE whose not previously known can be obtained by analogous methods, for example as described above.
lo A 22 084 ED
ho examples of the 4-aminomethylchromans there may be mentioned: 4-aminomethyl-chroman, 4-aminomethyl-2-methyl-chroman, 4-aminomethyl-2,2~dimethyl-chroman, 4-aminomethyl-2-propyl Crimean, 4-aminomethyl-~-iso-
F~4 3 3 R
R5~ 0 R2 I Joy 2 the 4-cyano~2H--chromenes can then be hydrogenated directly or stops to give the 4-am;nome~hylchromans, as represented in the following equation:
lo A 22 084 I
I 2 4~2 n R1 1 As examples of the 4-aminomethyl-2H-chromenes there may be mentioned: 4-aminomethyl-2H-chromene, 4-am;nonethyl-2-methyl-2H-chromer,e, 4-am;nomethyl-2~2-dimethyl-chromene, 4-aminomethyl-2 propyl-2H-chromene, ~-aminomethyl-2-;sopropyL-2H-chromene, 4-aminomethyl-2,2-diethyl-chromene, 4-aminomethyl-2-methyl-2-propyl-chro-Mooney 4-aminomethyl-2-hexyl-2H-chromene, 4-aminomethyl-2-cyclopentyl-2H-chromene, 4-aminomethyl-2-cyclohexyl-lo Crimean, 4~aminomethyl-2-spirocyclopentachromene, 4-am;nomethyl-2-spirocyclohexachromene, 4 am;nomethyl-6-methyl-2-spirocyclopentachromene, 4-aminomethyl-7-methyl-2-spirocyclopentachromene, 4-aminomethyl-6~8-dimethyl 2-sp;rocyclopentachromene, 4-aminomethyl-6-chloro-Z-spirocyclopentachromene, 4-aminomethyl-6-methoxy-2-spirocyclopentachromene, 4-aminomethyl-7-methoxy-2-spiro-cyclopentachromene, 4~aminomethyl-7-isopropoxyo2-spiro~
cyclopentachromene, 4-aminomethyl-7-phenoxy-2-spirocyclo-pentachromene, 4-aminome~hyl~7-ben~yloxyo2-sp;rocyclo-pentachromene, 4-am;nomethyl-7-phenyl-2-sp;rocyclopenta-Crimean, 4-aminomethyl-6-methyl-2-spirocyclohexachromene, 4-amino~ethyl-6-chloro-2-spirocyclohexachromene, 4-amino-methylo7-methoxy 2-spirocyclohexachromene, 4-aminomethyl 6-methylo2,2-dimethylchromene and 4~aminomethyl~7-meth-oxy-2,2-d;methylchromene~
Some of the amine of the formula (V) employed in the preparation of the compounds according Jo the invention are known (J. med. Chum. 1982, OWE whose not previously known can be obtained by analogous methods, for example as described above.
lo A 22 084 ED
ho examples of the 4-aminomethylchromans there may be mentioned: 4-aminomethyl-chroman, 4-aminomethyl-2-methyl-chroman, 4-aminomethyl-2,2~dimethyl-chroman, 4-aminomethyl-2-propyl Crimean, 4-aminomethyl-~-iso-
5 propyl-chroman, aminomethyl-2~2-diethyl-chroman, 4-aminomethyl-2-methyl-2-propyl-chroman, 4~aminomethyl-2-hexyl-chroman, 4-aminomethyl-2-cyclopentyl-chroman, 4-aminomethyl-2-cyclohexyl-chroman, 4-aminomethyl-2~
spirocyclopenta-chroman, 4-aminomethyl~2-spirocyclohexa-10 Crimean ~-aminomethyl-6-methyl-2-spirocyclopenta-chroman, 4-aminomethyl-7-methyl-2-spirocyclopenta-chroman, 4-aminomethyl-6,8-dimethyl-2-spirocyclopenta-chromann, ~-aminomethyl-6-chloro-2-spirocyclopenta-chroman~ 4-aminomethyl-6-methoxy-2-spirocyclopenta-chroman, 4-amino-15 methyl-7-methoxy-2-spirocyclopenta-chroman, 4-amino-methyl-8-isopropoxy-2-spirocyclopenta-chroman~ 4-amino-methyl-7-phenoxy-2-spirocyclopenta-chroman, 4-amino-methyl-7-benzyloxy-2-spirocyclopenta-chroman, 4-amino-methyl-7-phenyl-2-spirocyclopenta-chroman, 4-aminomethyl-20 6-me~hyl-2-spirocyclohexachroman, ~-aminomethyl-6-chloro-2-spirocyclohexachroman, ~-aminomethyl-7-methoxy-2-spiro~
cyclohexachroman, 4-aminomethyl~6-methyl-2,2-d;methyl-Crimean and ~-am;nomethyl-7-methoxy-2,2-dimethylchroman.
A high proportion of the carbonyl compounds of 25 the formula TV) used in the preparation of the process according to the invention are known tcompareO for example, Beilste;ns Handbuch don organ;schen whom biliousness Handbook of Organic Chemistry) 6, 151~ II
152; 7, 292, 303, 304, 314, I 154, 161, 162, I II 226, 30 233~ 236, 243)~ whose not previously known can be pro-pared by analogous methods L
As examples of the carbonyl compounds there may be mentioned: phenylacetaldehyde, ~-chlorophenylacet-alluded, 3-chlorophenylacetaldehyde, 4-chlorophenylace~-35 alluded, 3,4-dichlorophenylacetaldehyde, 4-methylphenyl-acetaldehyde, ~-isopropylphenylacetaldehyde~ 3-methoxy lo A 2Z 084 '7~3~
phenylacetaldehyde, 4-ethoxyphenylacetaldehyde, Dow-methoxyphenylace~aldehyde, 3,4-methylenedioxyphenylacet-alluded ~-phenylpropionaldehyde, ~-phenylpropionalde-Hyde ~-(4-chlorophenyl)-propionaldehyde, try-5 fluoromethylphenyl)-propionaldehyde~ -t4-trifluoromethyl-phenyl)-propionaldehyde~ ~-(4-methoxyphenyl)-propionalde-Hyde ~(3,4 dimethoxyphenyl)-propionaldehyde, ~-(3,4-methylenedioxyphenyl-propionaldehyde, phenoxy-acetalde-Hyde 4-chlorophenoxyacetaldehyde, ~,4-dichloro-phenoxy-10 acetaldehyde, 2,4-dichlorophenoxyacetaldehyde, Dow-methylphenoxyacetaldehyde, 4-methoxyphenoxyacetaldehyde, 3,4-dimethoxyphenoxyacetaldehyde, 3,4-methylenedioxy-phenylacetaldehyde, phenylacetone~ 4-chlorophenylacetone~
3,4-dichlorophenylacetone, 4-methylphenylacetone, 4-15 methoxyphenylacetone, 3,4-dimethoxyphenylacetone, 3,4-methylenedioxyphenylace~one, benzylacetone, (sheller-benzyl)-acetone, (40trifluoromethylbenzyl)-acetone, (4-methoxybenzyl)-acetone, (3,4-dimethoxybenzyl)oacetone, (3,4-methylenedioxybenzyl)-acetone, phenoxyacetone, 20 (4-chlorophenoxy)-acetone, (3,4-dichlorophenoxy)-acetone~
(2,5-dimethylphenoxy)-acetone, (4-methoxyphenoxy)-acet-one, (3,4-dimethoxyPhenoxy)-acetone and t3,4-methylene dioxyphenoxy)-acetone.
Some of the halides of the formula tVII) employed 25 in the preparation of the compounds according to the on-mention are known (Tetrahedron 230 1893 S1967)). Those not previously known can be prepared by an analogous method or from 4-methyl-2H-chromenes CHeterocyclic Compounds, Volt 31, Ed. GYP. Ellis (New York 1977), page 30 11 et seq.] by halogenation with N-bromosuccinimide or N-chlorosuccinimide (~ohl-Ziegler reaction As examples of the 4-halogenomethylchromenes there may be mentioned: 4-chloromethyl~2H-chromene, 4-bromomethyl-2-methyl Crimean, 4-bromomethyl-2~2-35 d;methylchromene, 4-bromomethyl-2-isopropyl-2H-chromene, 4-chlorometh~l-2,2-diethylchrsmeneO 4-chLoromethyl-2 lo A 22 084 methyl-2-propyl-chromene, 4-bromomethyl-2-hexyl-2H-chro-mine, I~-bromomethyl-2-cyclopentyl-2H-chromene, Brigham-methyl-2-cyclohexyl-2H Crimean, 4-bromomethyl-2-spiro-cyclopentachromene, 4-bromomethyl-2-spirocyclohexachromene, 4-bromomethyl-6-methyl-2-spirocyclopentachromene, Brigham-methyl-7-methyl-2-spirocyclopentachromene, 4-bromomethyl-
spirocyclopenta-chroman, 4-aminomethyl~2-spirocyclohexa-10 Crimean ~-aminomethyl-6-methyl-2-spirocyclopenta-chroman, 4-aminomethyl-7-methyl-2-spirocyclopenta-chroman, 4-aminomethyl-6,8-dimethyl-2-spirocyclopenta-chromann, ~-aminomethyl-6-chloro-2-spirocyclopenta-chroman~ 4-aminomethyl-6-methoxy-2-spirocyclopenta-chroman, 4-amino-15 methyl-7-methoxy-2-spirocyclopenta-chroman, 4-amino-methyl-8-isopropoxy-2-spirocyclopenta-chroman~ 4-amino-methyl-7-phenoxy-2-spirocyclopenta-chroman, 4-amino-methyl-7-benzyloxy-2-spirocyclopenta-chroman, 4-amino-methyl-7-phenyl-2-spirocyclopenta-chroman, 4-aminomethyl-20 6-me~hyl-2-spirocyclohexachroman, ~-aminomethyl-6-chloro-2-spirocyclohexachroman, ~-aminomethyl-7-methoxy-2-spiro~
cyclohexachroman, 4-aminomethyl~6-methyl-2,2-d;methyl-Crimean and ~-am;nomethyl-7-methoxy-2,2-dimethylchroman.
A high proportion of the carbonyl compounds of 25 the formula TV) used in the preparation of the process according to the invention are known tcompareO for example, Beilste;ns Handbuch don organ;schen whom biliousness Handbook of Organic Chemistry) 6, 151~ II
152; 7, 292, 303, 304, 314, I 154, 161, 162, I II 226, 30 233~ 236, 243)~ whose not previously known can be pro-pared by analogous methods L
As examples of the carbonyl compounds there may be mentioned: phenylacetaldehyde, ~-chlorophenylacet-alluded, 3-chlorophenylacetaldehyde, 4-chlorophenylace~-35 alluded, 3,4-dichlorophenylacetaldehyde, 4-methylphenyl-acetaldehyde, ~-isopropylphenylacetaldehyde~ 3-methoxy lo A 2Z 084 '7~3~
phenylacetaldehyde, 4-ethoxyphenylacetaldehyde, Dow-methoxyphenylace~aldehyde, 3,4-methylenedioxyphenylacet-alluded ~-phenylpropionaldehyde, ~-phenylpropionalde-Hyde ~-(4-chlorophenyl)-propionaldehyde, try-5 fluoromethylphenyl)-propionaldehyde~ -t4-trifluoromethyl-phenyl)-propionaldehyde~ ~-(4-methoxyphenyl)-propionalde-Hyde ~(3,4 dimethoxyphenyl)-propionaldehyde, ~-(3,4-methylenedioxyphenyl-propionaldehyde, phenoxy-acetalde-Hyde 4-chlorophenoxyacetaldehyde, ~,4-dichloro-phenoxy-10 acetaldehyde, 2,4-dichlorophenoxyacetaldehyde, Dow-methylphenoxyacetaldehyde, 4-methoxyphenoxyacetaldehyde, 3,4-dimethoxyphenoxyacetaldehyde, 3,4-methylenedioxy-phenylacetaldehyde, phenylacetone~ 4-chlorophenylacetone~
3,4-dichlorophenylacetone, 4-methylphenylacetone, 4-15 methoxyphenylacetone, 3,4-dimethoxyphenylacetone, 3,4-methylenedioxyphenylace~one, benzylacetone, (sheller-benzyl)-acetone, (40trifluoromethylbenzyl)-acetone, (4-methoxybenzyl)-acetone, (3,4-dimethoxybenzyl)oacetone, (3,4-methylenedioxybenzyl)-acetone, phenoxyacetone, 20 (4-chlorophenoxy)-acetone, (3,4-dichlorophenoxy)-acetone~
(2,5-dimethylphenoxy)-acetone, (4-methoxyphenoxy)-acet-one, (3,4-dimethoxyPhenoxy)-acetone and t3,4-methylene dioxyphenoxy)-acetone.
Some of the halides of the formula tVII) employed 25 in the preparation of the compounds according to the on-mention are known (Tetrahedron 230 1893 S1967)). Those not previously known can be prepared by an analogous method or from 4-methyl-2H-chromenes CHeterocyclic Compounds, Volt 31, Ed. GYP. Ellis (New York 1977), page 30 11 et seq.] by halogenation with N-bromosuccinimide or N-chlorosuccinimide (~ohl-Ziegler reaction As examples of the 4-halogenomethylchromenes there may be mentioned: 4-chloromethyl~2H-chromene, 4-bromomethyl-2-methyl Crimean, 4-bromomethyl-2~2-35 d;methylchromene, 4-bromomethyl-2-isopropyl-2H-chromene, 4-chlorometh~l-2,2-diethylchrsmeneO 4-chLoromethyl-2 lo A 22 084 methyl-2-propyl-chromene, 4-bromomethyl-2-hexyl-2H-chro-mine, I~-bromomethyl-2-cyclopentyl-2H-chromene, Brigham-methyl-2-cyclohexyl-2H Crimean, 4-bromomethyl-2-spiro-cyclopentachromene, 4-bromomethyl-2-spirocyclohexachromene, 4-bromomethyl-6-methyl-2-spirocyclopentachromene, Brigham-methyl-7-methyl-2-spirocyclopentachromene, 4-bromomethyl-
6,~-dimethyl-2-spirocyclopentachromene, 4-bromomethyl-3-chloro-2~spirocyclopentachromene, 4-bromomethyl-6-meth-oxy-2-spirocyclopentachromene~ 4-bromomethyl-7-methoxy-2-spirocyclopentachromene~ 4-bromomethyl-7-isopropoxy-2-spirocyclopentachromene, 4-bromomethyl-7-phenoxy-2-spirocyclopentachromene, 4-bromomethyl-7-benzyloxy-2-spirocyclopentachromene, 4-bromomethyl-7-phenyl-2-spiro-cyclopentachromene~ 4-bromomethyl-6-methyl-2,2-dimethyl-Crimean, 4-bromomethyl-6-chloro-2,2-dimethylchromene, 4-bromomethyl-7-methoxy-2,~-dimethylchromene, Brigham-methyl-6-methyl-2-spirocyclohexachromene and 4 broom-methyl-7-methoxy-2-spirocyclohexachromene.
The Crimean and Crimean derivatives according I to the invention surprisingly show an anti-hypertensive action and can therefore be employed, in the free form or in the form of their pharmaceutically safe acid add-lion salts, as medicaments.
The novel compounds have a broad and diverse pharmacological action spectrum and a surprisingly long duration of action.
Specifically, the following principal actions were demonstrable in animal experiments 1. The tone of the smooth muscle ox the vessels is greatly lowered under the action of the compounds. This Yascular-spasmolyt;c action may occur in the entire Yes-cuter system or manifest itself in a more or less idol-axed manner on circumscribed vascular regions (such as, for example, the central nervous system). The compounds are therefore particularly suitable for use as cerebral therapeutic agents lo A I 0~4 of I -2. The compounds lower the blood pressure of norm-tonic and hypertonic animals and can accordingly be used as anti-hypertensive agents.
By virtue of these properties the compounds according to the invention are suitable for the trophy-taxis of acute and chronic ischaemic cardiac disorders in the broadest sense, for the therapy of hypertension and for the treatment of cerebral and peripheral blood circulation disturbances The new active compounds can be converted in a known manner into the customary formulations, such as tablets capsules, drudges, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert, nontoxic pharmaceutically suitable excipients or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, that is Jo say in amounts which suffice to achieve the dosage range in-dilated.
The formulations are prepared for example by extending the active compounds with solvents and/or exci-pints, optionally Thea the use of emulsifiers and/or dispersing agents and, for example when using water as a delineate, organic solvents can optionally be used as auxiliary solvents.
Examples of auxiliary substances which may be mentioned are: water non-toxic organic solvents, such as paraffins (for example petroleum fractions), vegetable owls tfsr example groundnut oil/sesame oily, alcohols Thor example ethyl alcohol and glycerol), glycoLs (for example propylene glycol and polyethylene glycol), solid excip;ents, such as, for example natural rock powders Thor example Collins alumnus talc and Shylock Sweeney-tic rock powders (for example highly disperse silica and silicates), sugars for example cane sugar, lactose and glucose), emulsifiers (for example polyoxyethylene fatty lo A 22 084 acid esters, polyoxyethylene fatty alcohol ethers alkyd-sulphonates and arylsulphonates)9 dispersing agents (for example lignin, sulfite waste liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (for 5 example magnesium Stewart, talc, Starkey acid and sodium lauryl-sulphate).
Administration is effected in the customary manner, preferably orally or parenterally~ especially per lingually or intravenously. In the case of oral use 10 the tablets can, of course, also contain, in addition to the exc1pients mentioned, additives such as sodium aft-rate, calcium carbonate and dicalcium phosphate, together with various additional substances such as starch, prefer-ably potato starch gelatin and the like. Furthermore, 15 lubricants, such as magnesium Stewart, sodium laurel-sulfite and talc can be co-used when making tablets. In the case of aqueous suspensions and/or elixirs which are untended for oral use, the active compounds can be mixed hit various flavour-improving agents or colorants in 20 addition to the above mentioned auxiliary substances In the case of parenteraL use solutions of the active compounds, employing suitable liquid excipients, can be used.
In general it has proved advantageous, in the 25 case of intravenous administration, Jo administer amounts of about 0.001 to 10 mg~k~, preferably about OWE to 5 mg/kg of body weight daily to achieve effective results and on the case of oral administration the dosage is about 0.5 to 30 mg/kg, preferably 1 to 10 mg/kg of body weight 30 daily.
Nevertheless it can at tomes be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the export mental animal or of the nature of the administration 35 method, but also because of the species of animal and the individual behavior towards the ~ed;cament, and the lo A 22 084 I
nature of the formulation of the medicament and the time at which, or interval over which, the administration takes place. Thus it can suffice, in some cases, to manage with less than the above mentioned minimum amount, S whilst in other cases the upper limit mentioned must be exceeded where relatively large amounts are ad minis-toned, it can be advisable to divide these into several individual administrations over the course of the day.
The same dosage range is envisaged for administration in human medicine. The general sense of the above comments also applies again.
Examples of toe leprechaun of intermediates for preparation variant B
1.
I-" OX i ( SUE I
30 ml of boron trifluoride ether ate are added drops to a mixture of 528 9 t4.8 molt of trim ethyl-sill cyanide and 969 g ~4~8 molt of 2-spirocyclopenta-chroman-4-one with cooling and stirring, at a rate such that the temperature does not exceed 40-50; the mixture is then stirred for 5 hours at room temperature and left to stand overnight. Thereafter it is degassed in a high vacuum at a temperature of 50 By this means, the pro-duct is obtained as a viscous oil, in 85-95% yield accord-in to gas chromatography. it is sufficiently pure for further reactions.
The following were prepared in a similar manner:
I arc osi(C~3 I welting point 65-7 lo A 22 084 I
I sicken Jo 3) SUE melting point 36-8 SUE
clue OSi(C~ I melting point 68-70 I OX i ( C~3 I
C~3~ melting point 66-8 ho OX i ( SUE 3:1 6) melting point 71 3 I Sue I I
5 Saab Owl 8 EYE O C L Lo I
by 16.4 9 of lithium aluminum hydrides are mixed with 600 ml of dry tetrahydrofuran and a solution of 120 g of 2-spirocyc lopenta-4-cyano-4 t rimethylsiLyloxy-chroman 10 t89% pure) in 1~0 ml of dry tetrahydrofuran is added drops, whilst stirring and cooling with acetonetsolid lo A 22 084 ._ carbon dioxide (Nitrogen atmosphere, exclusion of moist-urea internal temperature < 20C).
The mixture is allowed to come to room tempera-lure whilst being stirred, is then heated for 3 hours 5 to the reflex temperature, and is allowed to cool.
16.4 g of water are cautiously added drops, followed by 49~2 9 of to X strength potassium hydroxide solution.
After the mixture has stood overnight it is filtered, the mother liquor is concentrated in vacua and the nest-10 due is triturated with 135 ml of ether. The white crystalline product obtained is filtered off. 35-57 g are obtained. The ethereal mother Liquor is concentrated and the residue taken up in 100 ml of methanol, boiled with a small amount of potassium hydroxide for 1 hour 15 and worked up. This method serves to complete the sill ether hydrolysis. In thus way, a total of 66 g of white crystals YO-YO. of theory) are obtained; melting point The following were prepared in a similar manner:
9) I CONE melting point 100 En SWEENEY
10) SHEA melting point 73 I Ho CE~NEb 11) melting point 98-100 lo A 22 084 I
I I NO
SHEA melting point 94 Of I'<
13) melting point 104-6 I SUE I
14)C~ 0 melting point 93 15)~3,N~2 ho 2 liters of Tulane and 190 9 of toluenesulphonic acid MindWrite are boiled under a water separator until azeotropic drying is complete 233 9 (1 molt of Spiro-cyclopenta-4-hydroxy-4-am;nomethylchroman are added to the cooled mixture and the whole is heated to the boil 10 for 5 hours, during which about 18 cc of water are sop-crated off. After the mixture has cooled a small amount of solid is filtered off and the Tulane phase is stirred with excess concentrated sodium hydroxide solution.
After phase separation, the Tulane solution is washed with water and irked up in the usual manner. 140 9 ~65X of Thor boiling point one mm Hug.
The following were prepared in a similar manner:
lo A 22 084 --` ~Z2~
C~2 163 boiling point 132-8/0.4 mm Hug 17) SWEENEY boiling point 120-5/0.5 mm Hug I
c~3 18) SUE No boiling point 139-144/0.2 mm Hug I
19) CONE boiling point 145/0u25 mm Hug I
5 SHEEHAN boiling point 147-9/0~3 mm Hug Clue I ~}~
I
50 9 of 2-spirocyclopenta-4-am;nomethyl-chrom 3uene, in the presence of 300 ml of methanol and 10 9 of Rangy nickel are catalytically hydrogenated for about 10 4.5 hours in a pressure autoclave at 60 and 100 bar Ho pressure. The catalyst is then filtered off and the filtrate is concentrated and fractionated.
lo A 22 084 I
Boiling point 150-54/0.9 mm Hug; 40 9 of color-Less liquid about 80% of theory).
The fulling were prepared in a similar manner:
22) C~2 Up 135-40/0.4 mm Hug Jo 5 23) Up 110-12/0.3 mm Hug I
24) Up 132-36/0.3 mm Hug SUE
25) I Up 135-8/0.3 mm Hug I .
I
26) C1 Up 144-8/0.3 mm Ho ON
27) lo A 2Z 084 _, 429 g of 2-spirocyclopenta-4-cyano-4-trimethyl-silyloxy-chroman (89 X strength) are introduced into 2.2 lyres of absolute pardon. 694 9 of phosphorus oxychloride are added drops, resulting in a slightly 5 exothermic reaction. The mixture is heated to the boil , since the reaction becomes more vigorous on arming After having been boiled under reflex for 10 hours and cooled, the batch is cautiously poured onto a mixture of about liters of crushed ice and 1 lithe 10 of concentrated hydrochloric acid. The precipitate formed us filtered off, washed with water and taken up in Tulane; the Tulane solution is shaken with active charcoal and extracted by shaking with sodium bicarbonate solution. After the solution has been dried with sodium 15 sulfite, the Tulane is evaporated off in vacua and the residue is crystallized from methylcyclohexane, in the presence of active charcoal; 180 9 ~67X of theory) are obtained as pale grew crystals of melting point 50. The product can be distilled. Boiling point 135/0.2 mm Hug. Melt-20 in point of the pure White crystals: 58-59.
ON
28) 400 g of 2-spirocyclopenta-4 cyano-chromen-3-ene in 1,800 ml of tetrahydrofuran are hydrogenated over 40 9 of palladium on charcoal I strength) at 40 45 25 under 50 bar pressure After conventional working-up, 360 9 to 90~ of theory) of white crystals, of boiling point 131-5/0.3 mm and melting point ~4-5g are obtained I
29) lo A 2 08 I
50 9 of 2-spirocyclopenta-4-cyanochroman, in the presence of 200 ml of methanol, 50 ml of Liquid ammonia and 10 9 of Rangy cobalt are catalytically hydrogenated for about 3.5 hours in a pressure autoclave at 90C and 100 bar Ho pressure. The catalyst is then filtered off and the filtrate is concentrated and fractionated.
Boiling point 130-140/0.35 mm Hug; 40 9 of colorless loud (about 80% of theory) identical with the product from Example 21).
30) Examples of the preparation of intermediates of preparation variant C
C~2 By I
SHEA
176 g (1 molt of 2,2,4-trimethylchromene are disk solved in 1 lithe of carbon tetrachloride which has been dried over phosphorus pent oxide and 178 9 I molt of N bromo-succinimide and 2 9 of azo-bis-isobutyronitrile are added. The mixture us slowly heated to the boil and us boiled for 1 hour. When it has cooled, the precipi late is filtered off ~succinimide). The mother liquor is concentrated on vacua. 255 9 of a brown oil which is 89X pure according to gas chromatography ( 90X of theory) are obtained; the material can be employed directly for further reactions. The product distill at 105-9/0.28 mm. It can be characterized as the purred-ilium bromide (melting point 186-7).
The following WAS prepared in a similar manner:
Kiwi By 31) Oily not stable to distillation;
melting point of the pyridinium bromide 165-7 lo A 22 084 I
.
Examples_accordin~ to the invention 32) Preparation according to process variant A
SUE N~-CE2 I 43 Of I
12.1 9 S0.1 molt of phenylethylamine are added to 19.0 9 (0.1 molt of 2,2~dimethyl-4-formyl-chroman in 100 ml of methanol whilst stirring at room temperature, with gentle cooling, and the mixture is then stirred for 1.5 hours. Thereafter, 4.5 9 of sodium Burnett are added and the mixture is stirred for a further day, con-cent rated and worked up with ethyl acetate/~ater. The ethyl acetate phase is washed with water, dried and con-cent rated. The residue is dissolved in ether and dry hydrogen chloride is passed through the solution. The precipitate formed is filtered off, stirred with water and filtered off It is dried and recrystallized from acetonitrile~ 20.5 9 no White crystals t62 X of theory), of melting point owe 33) Preparation according to process variant B
C~2 C~ I I
SUE
12 9 (0.1 molt of phenylacetaLdehyde are reacted with 21.7 9 ~0.1 molt of 2-spirocyclopenta-4~aminomethyl-Crimean and worked up, as in the example given above.
19.5 9 S55X of theory) of white crystals, of melting point 202-3.
34) Preparation according to process variant B
A solution of 6.5 of 2,2~spirocyclopenta-4-aminomethylchrom-3-ene and So g of 4 m-trifLuoromethyl-phenyl-butan 2-one in 30 ml of Tulane is heated to the lo A 22 084 boil under a water separator for 30 minutes and then concentrated at 50/~0 mm Hug. The oily residue is dissolved in 50 ml of tetrahydrofuran and added drop-wise, at about 20C, to a suspension of 5 9 of Lyle in 150 ml of THY. The mixture is then stirred for 5 hours at the reflex temperature and us cooled to 10C; 5 ml of water and 15 ml of 15% strength potassium hydroxide solution are successively added cautiously, and this mix-lure us stirred for 1 hour at 20 and then filtered The filtrate is concentrated and the concentrate distilled.
Yield: 6.6 9 of almost colorless owl, boiling point 200-210/0.03 mm Hug 35) Preparation according to process variant C
Of CHIN -Of Cell Us 25 9 Tao molt of N~3,4-dichlorophenyl-p;per-amine and 11.1 9 ~0.11 molt of triethylamine are together introduced into 55 ml of toluener and 27.8 9 ~0.11 molt of 2,2-dimethyl-4-bromomethylchrom-3-ene are added drops In the course thereof, a precipitate separates out and the temperature rises to about 45C. Stirring is con-tinted for 3 hours and the mixture is left to stand over-night It is then thoroughly stirred with excess ON
sodium hydroxide solution and the Tulane phase is spear-axed off, washed with water and dried with sodium sulk plate. After the solvent has been distilled off, the product starts to precipitate. The crystallization is completed by adding petroleum ether. After filtering off the product and drying it, 27.5 9 t62X of theory) of White crystals of melting point 108C, are obtained.
The following were prepared in a similar manner:
lo A 22 D84 36) according to processes A and B
SHEA SUE C~2 bowling point 175-8/
0.2 mm Hug 37) according to processes A and B
I C~2 C~2 C~2 melting point of the hydra-chloride 253-6 S 38) according to processes A and B
melting point of the hydra-I chloride 2~5-8 39) according to processes A and B
Of NICE SUE
Jo boiling point 180 5/
U~15 mm Hug 40~ according to processes A and SHEA I I
melting point of the hydra-En chloride 220-3 lo A 22 084 - .~2~7~
41) according to processes A and B
I I SHEA I
~3~7 boiling point 175-9/
SHEA 0.25 mm Hug 42) according to processes A and B
C~2 I I
boiling point 172-7/
kiwi I I 0.25 mm Hug 5 43) according to processes A and B
I I I
boiling point 190-5/
I 5 ` 0.65 mm Hug 44) according to processes A and B
SHEA I I
resin 45) according to processes A and B
I -N~-C~C~ Of melting point of the hydra-chloride 180-2 46) according to processes A and B
SHEA
I C~2 C~[2 KIWI
melting point of the hydra-chloride 198-20n lo A 22 084 47) according to processes A and B
SHEA Shea SHEA I 0C~3 melting point of the hydra-chloride 214-6 48) according to processes A and B
I
C~2 I
l melting point of the hydra-chloride 212 I according to processes A and B
I SUE (C~3 I molting point of the hydra-chloride 190 50) according to processes A and I
SHEA I SUE smelting point of the hydra-chloride 231 51) according to processes A and B
Of No CUE - bullying point 198-?03/
0.1 mm Hug lo A 22 084 - 52) according to processes A and B
EYE EKE Of boiling point 183-190/
0.15 mm Hug 53) according to processes A and B
Jo EYE NH I boiling point 171-7/
0~15 mm Hug 5 54) according to processes A and B
Ago C3~ Con boiling point 184-9/
0.4 mm Hug 55) according to processes A and B
SUE SEIKO boiling point 168-75/
0.25 mm Hug 56) according to processes A and B
SUE
I NE cue melting point of the hydra-chloride 208-10 lo A 22 084 I
57) according to processes A and 3 SWOONS OH.
2 boiling point 185-95/
CF3 0.1 mm Hug 58) according to processes A and 9 I -SUE
SUE boiling point 188-94/
One mm Hug I
59) according to processes A and B
I -SUE I
resin 60) according to process A
I -NE FEZ SUE -boiling point 190-6/
0~2 mm Hug 61) according to process h EYE
I assay C3~-~ boiling point 181-3/
0.15 mm Hug lo A 22 08~
I
62) according to process A
I
SWOONS SWEENEY boiling point 195-202/
0.25 mm Hug 63) according to process A
Of I -NH-C~ I I
melting point of the hydra-chloride 170-2 5 64) according to process A
I Coequal melting point of the hydra-chloride 168-70 65) according to process A
Of SUE NICE CON melting point of the hydra-chloride 185 66) according to process A
I NO
melting point of the hydra-I chloride 202~4 67) according to processes A and B
I SHEA I I
boiling point 178-82/
0.15 mm Hug lo A 22 084 - I -68) according to processes A and B
H -No OH -C~-0 Of 2 Z boiling point 185-7/
0.2 mm Hug 69~ according to processes A and B
I -CH2CH2-0- Of melting point of the hydra-chloride 185 7 5 70) according to processes A and B
C~2~ I I SHEA
melting point of the hydra-~-YJL_I chloride 102~4 71) according to processes A and B
3 boiling point 198-205/
Dn15 mm Hug 72) according to processes A and B
SHEA CHIHUAHUAS bullying point Z07-15/
0,15-mm Hug lo A 22 0~4 73) according to process C
C~2~
3 melting point 93-4 pa 74) according to process C
C~2~
~C~3 melting point lZO-1 Elm 5 75) according to process C
Kiwi o I
Chat melting point 94-6 I
76) according to process C
I
C~[2-~
s melting point 92-3 I
77~ according to process C
I -I C4 Jo -left.
melting point wow SHEA
78) according to process C
SUE
I
SUE melting point 88-9 lo A 22 OOZE
~Z~'7~
79) according to process C
I
I I boiling point 193-9/
0.3 mm Hug I
80) according to process C
I OOZE' I melting point 88 c~3 81) according to process C
I
~C~3 Of melting point 72 c~3 82) according to process C
Jo F3 I Of me fling pot nut 104-5 I
I
83) according to process C
I
SWISS
SUE molting point 77 I
lo A 22 08 I
84) according to process C
SHEA OF
SUE melting point 146 c~3 85) according to process C
~C2 us SUE ) melting point 83 SHEA
Us S 86) according to process C
CFa 0 . 1 5 m m H g Cams 87) according to process C
I
I a melting point 1210 SHEA
I according to process C
ooze I melting point 84 SHEA , , Us lo A 22 084 89) according to process C
C I
I
I boiling point 189-94/
Ho 0.1 mm Hug SHEA
90) according to process C
boiling point 191-9/
En SUE 0.2 mm Hug 91~ according to process C
OH C~2-Ho melting point 170-1 SHEA
92) according to process A
CON boiling point 180-4/
0.15 mm Hug 93) according to process C
, I
melting point 117-9 94) according to procPcs C
SHEA- Of melting point 118-20 lo A 22 0~4 ~2~7~3~
95) according to process C
I I I I
I bowling point 198-203/
c~3 0.8 mm Hug 96) according to processes B and C
H-C(CE~ I SUE -Of I boiling point 175-80/
0.2 mm Ho I
5 97) according to processes A and B
-NH-CH-cE~ SUE
boiling point 191-6/
0.1 mm Hug 98) according to processes A and B
Of E~-N~-CH-C~Ga~ Of bowl in point 201-212/
0.2 mm Hug 99) according to processes A and B
Ç~-N~-C~-CH2CE~ boiling point 182-7/
0.2 mm Hug e A 22 084 100) according to processes A and C, ~C}~3 ,C~2 -SCHICK I 0C~3 boiling point 205-9/
0.1 mm Hug 101) according to processes A and OOZE
SUE CHIHUAHUAS C~2 -OOZE
boiling point 202-10l 1 0.15 mm Hug 5 102) according to processes A and B
SUE SHEA
SUE -C~2C~2- -OUCH
C~3boiling point 204 12/
1 0.1 mm Hug 103) according to processes A and B
I
SINUSES
boiling point 171-4/
0.1 mm Hug 104) according to processes A and B
SUE Mocha I Of SWISS OUCH
I I - i b O 1 Lint point 189-96 1 lo A 22 084 105) according to processes A and B
c~3 Of CE2--N~C~2CE~;
boiling point 190-8/
0.2 mm Hug 106) according to processes A and Of ON CUE
boiling point Z0$-15/
0.1 mm Hug 107) according to processes A and ~E2-~~~C~~cE2iC~
C~3 boiling point 198-206/
0.1 mm Hug 108) according to processes A and a f~3 ~NH-C~-C~; C1~3$
boiling point 205-12/
0.1 mm Hug 109) according to processes A and a EYE
SUE boiling point 200-5/
0.15 my Hug lo A 22 084 I
c~3 Silas SUE I
Kiwi boiling point 185-92/
0~1 mm Hug 111) according to processes A and B
YE
C~2~ SHEA
En boiling point 181-7t I 0.1 mm Hug S 112) according to processes A and B
I
C~2 SCHICK KIWI
2 5 boiling point 198~204/
0.15 mm Hug 113) according to processes A and B
EYE I SHEA I Jo boiling point 190-2/
Us U.15 mm Hug 114) according to processes A and B
C~2 I Lowe e Ho I) boiling point 199~204 0.1 mm Hug lo A 22 084 _ I
115) according to processes B and C
I
I H-c~2 C}~2 by OWE
boy lung point 210-215/
0.1 mm Hug 116) according to processes A and B
I
NO Ha - C~2 - Clue boy King point 215-8/
0.1 mm Hug 5 117) according to processes B and C
C~2 -~-C~-C~ I
boy lying point 200-2û5/
0.1 mm Hug 118) according to processes A and B
I
CROOK
boy l i no pox nut 195-200/
0.05 mm Hug 119) according to processes B and C
I
SHEA go boy lying point 220/0.12 mm Hug lo A 22 084 I
I -120) according to processes A and B
SHEA
[SHEA SICKISH
boiling point 240/0.1 mm Hug Examples of the preparation of chroman-4-car~aldehydes (starting product for preparation variant A) 5 Example 121 SHEA
oh A mixture of 12 9 of Rh~tC6H5)3P~Cl3, 96 9 of triphcnylphosphine and 660 ml of Tulane is introduced into a 3 lithe stainless steel autoclave and a mixture 10 of 665 (3~58 molt of 2-spirocyclopentachrom-3-ene is pumped in slowly in the course of 6 hours at 160-70C
internal temperature and a C0/H2 pressure of initially 150 and later 300 bar. The mixture is stirred for a further hour at 17ûC and is distilled after the pressure has : 15 been released 327 9 ~42% of theory) of 2-spirocyclo-pentachroman~4-carbaldehyde are obtained as an almost colorless liquid of boiling point 127-30/0~1 mm Hug.
Example 122 - - COO
¢$~
0-083 9 of Rh~tC6H5-CH2)2Si3Cl3 and 500 ml of Tulane are stirred for 1 hour on an autoclave at 170 and 170 bar C0/H2 pressure The mixture is alloyed to cool to 135 and 558 9 (3 molt of 2-~pirscyclopenta-Crimean dissolved in 6Q0 ml of Tulane, are pumped lo A 22 084 Lo in over the course of 3 hours, whilst maintaining a pressure of 250-280 bard After the mixture has been cooled, brought to atmospheric pressure and degassed, the solvent is stripped off in vacua and the liquid residue is fractionated. 518 9 t80~ of theory) of colorless liquid, of boiling point 127-30/0~3 mm Hug.
The following were prepared in a similar manner to that described in Example 122 SHEA
boiling point 120-5/0.3 mm Hug KIWI
boiling point 90-95/0~5 mm Hug KIWI
Of boiling point 120/0~2 mm Hug I
boiling point 106-10/0.04 mm Hug SHEA
En boiling point 121-610~3 mm Hug KIWI
ZOO SUE boiling point 143-50/0.15 mm Hug KIWI
C boiling point 110/0.05 mm Hug lo A 22 084 _ .
The Crimean and Crimean derivatives according I to the invention surprisingly show an anti-hypertensive action and can therefore be employed, in the free form or in the form of their pharmaceutically safe acid add-lion salts, as medicaments.
The novel compounds have a broad and diverse pharmacological action spectrum and a surprisingly long duration of action.
Specifically, the following principal actions were demonstrable in animal experiments 1. The tone of the smooth muscle ox the vessels is greatly lowered under the action of the compounds. This Yascular-spasmolyt;c action may occur in the entire Yes-cuter system or manifest itself in a more or less idol-axed manner on circumscribed vascular regions (such as, for example, the central nervous system). The compounds are therefore particularly suitable for use as cerebral therapeutic agents lo A I 0~4 of I -2. The compounds lower the blood pressure of norm-tonic and hypertonic animals and can accordingly be used as anti-hypertensive agents.
By virtue of these properties the compounds according to the invention are suitable for the trophy-taxis of acute and chronic ischaemic cardiac disorders in the broadest sense, for the therapy of hypertension and for the treatment of cerebral and peripheral blood circulation disturbances The new active compounds can be converted in a known manner into the customary formulations, such as tablets capsules, drudges, pills, granules, aerosols, syrups, emulsions, suspensions and solutions using inert, nontoxic pharmaceutically suitable excipients or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, that is Jo say in amounts which suffice to achieve the dosage range in-dilated.
The formulations are prepared for example by extending the active compounds with solvents and/or exci-pints, optionally Thea the use of emulsifiers and/or dispersing agents and, for example when using water as a delineate, organic solvents can optionally be used as auxiliary solvents.
Examples of auxiliary substances which may be mentioned are: water non-toxic organic solvents, such as paraffins (for example petroleum fractions), vegetable owls tfsr example groundnut oil/sesame oily, alcohols Thor example ethyl alcohol and glycerol), glycoLs (for example propylene glycol and polyethylene glycol), solid excip;ents, such as, for example natural rock powders Thor example Collins alumnus talc and Shylock Sweeney-tic rock powders (for example highly disperse silica and silicates), sugars for example cane sugar, lactose and glucose), emulsifiers (for example polyoxyethylene fatty lo A 22 084 acid esters, polyoxyethylene fatty alcohol ethers alkyd-sulphonates and arylsulphonates)9 dispersing agents (for example lignin, sulfite waste liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (for 5 example magnesium Stewart, talc, Starkey acid and sodium lauryl-sulphate).
Administration is effected in the customary manner, preferably orally or parenterally~ especially per lingually or intravenously. In the case of oral use 10 the tablets can, of course, also contain, in addition to the exc1pients mentioned, additives such as sodium aft-rate, calcium carbonate and dicalcium phosphate, together with various additional substances such as starch, prefer-ably potato starch gelatin and the like. Furthermore, 15 lubricants, such as magnesium Stewart, sodium laurel-sulfite and talc can be co-used when making tablets. In the case of aqueous suspensions and/or elixirs which are untended for oral use, the active compounds can be mixed hit various flavour-improving agents or colorants in 20 addition to the above mentioned auxiliary substances In the case of parenteraL use solutions of the active compounds, employing suitable liquid excipients, can be used.
In general it has proved advantageous, in the 25 case of intravenous administration, Jo administer amounts of about 0.001 to 10 mg~k~, preferably about OWE to 5 mg/kg of body weight daily to achieve effective results and on the case of oral administration the dosage is about 0.5 to 30 mg/kg, preferably 1 to 10 mg/kg of body weight 30 daily.
Nevertheless it can at tomes be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the export mental animal or of the nature of the administration 35 method, but also because of the species of animal and the individual behavior towards the ~ed;cament, and the lo A 22 084 I
nature of the formulation of the medicament and the time at which, or interval over which, the administration takes place. Thus it can suffice, in some cases, to manage with less than the above mentioned minimum amount, S whilst in other cases the upper limit mentioned must be exceeded where relatively large amounts are ad minis-toned, it can be advisable to divide these into several individual administrations over the course of the day.
The same dosage range is envisaged for administration in human medicine. The general sense of the above comments also applies again.
Examples of toe leprechaun of intermediates for preparation variant B
1.
I-" OX i ( SUE I
30 ml of boron trifluoride ether ate are added drops to a mixture of 528 9 t4.8 molt of trim ethyl-sill cyanide and 969 g ~4~8 molt of 2-spirocyclopenta-chroman-4-one with cooling and stirring, at a rate such that the temperature does not exceed 40-50; the mixture is then stirred for 5 hours at room temperature and left to stand overnight. Thereafter it is degassed in a high vacuum at a temperature of 50 By this means, the pro-duct is obtained as a viscous oil, in 85-95% yield accord-in to gas chromatography. it is sufficiently pure for further reactions.
The following were prepared in a similar manner:
I arc osi(C~3 I welting point 65-7 lo A 22 084 I
I sicken Jo 3) SUE melting point 36-8 SUE
clue OSi(C~ I melting point 68-70 I OX i ( C~3 I
C~3~ melting point 66-8 ho OX i ( SUE 3:1 6) melting point 71 3 I Sue I I
5 Saab Owl 8 EYE O C L Lo I
by 16.4 9 of lithium aluminum hydrides are mixed with 600 ml of dry tetrahydrofuran and a solution of 120 g of 2-spirocyc lopenta-4-cyano-4 t rimethylsiLyloxy-chroman 10 t89% pure) in 1~0 ml of dry tetrahydrofuran is added drops, whilst stirring and cooling with acetonetsolid lo A 22 084 ._ carbon dioxide (Nitrogen atmosphere, exclusion of moist-urea internal temperature < 20C).
The mixture is allowed to come to room tempera-lure whilst being stirred, is then heated for 3 hours 5 to the reflex temperature, and is allowed to cool.
16.4 g of water are cautiously added drops, followed by 49~2 9 of to X strength potassium hydroxide solution.
After the mixture has stood overnight it is filtered, the mother liquor is concentrated in vacua and the nest-10 due is triturated with 135 ml of ether. The white crystalline product obtained is filtered off. 35-57 g are obtained. The ethereal mother Liquor is concentrated and the residue taken up in 100 ml of methanol, boiled with a small amount of potassium hydroxide for 1 hour 15 and worked up. This method serves to complete the sill ether hydrolysis. In thus way, a total of 66 g of white crystals YO-YO. of theory) are obtained; melting point The following were prepared in a similar manner:
9) I CONE melting point 100 En SWEENEY
10) SHEA melting point 73 I Ho CE~NEb 11) melting point 98-100 lo A 22 084 I
I I NO
SHEA melting point 94 Of I'<
13) melting point 104-6 I SUE I
14)C~ 0 melting point 93 15)~3,N~2 ho 2 liters of Tulane and 190 9 of toluenesulphonic acid MindWrite are boiled under a water separator until azeotropic drying is complete 233 9 (1 molt of Spiro-cyclopenta-4-hydroxy-4-am;nomethylchroman are added to the cooled mixture and the whole is heated to the boil 10 for 5 hours, during which about 18 cc of water are sop-crated off. After the mixture has cooled a small amount of solid is filtered off and the Tulane phase is stirred with excess concentrated sodium hydroxide solution.
After phase separation, the Tulane solution is washed with water and irked up in the usual manner. 140 9 ~65X of Thor boiling point one mm Hug.
The following were prepared in a similar manner:
lo A 22 084 --` ~Z2~
C~2 163 boiling point 132-8/0.4 mm Hug 17) SWEENEY boiling point 120-5/0.5 mm Hug I
c~3 18) SUE No boiling point 139-144/0.2 mm Hug I
19) CONE boiling point 145/0u25 mm Hug I
5 SHEEHAN boiling point 147-9/0~3 mm Hug Clue I ~}~
I
50 9 of 2-spirocyclopenta-4-am;nomethyl-chrom 3uene, in the presence of 300 ml of methanol and 10 9 of Rangy nickel are catalytically hydrogenated for about 10 4.5 hours in a pressure autoclave at 60 and 100 bar Ho pressure. The catalyst is then filtered off and the filtrate is concentrated and fractionated.
lo A 22 084 I
Boiling point 150-54/0.9 mm Hug; 40 9 of color-Less liquid about 80% of theory).
The fulling were prepared in a similar manner:
22) C~2 Up 135-40/0.4 mm Hug Jo 5 23) Up 110-12/0.3 mm Hug I
24) Up 132-36/0.3 mm Hug SUE
25) I Up 135-8/0.3 mm Hug I .
I
26) C1 Up 144-8/0.3 mm Ho ON
27) lo A 2Z 084 _, 429 g of 2-spirocyclopenta-4-cyano-4-trimethyl-silyloxy-chroman (89 X strength) are introduced into 2.2 lyres of absolute pardon. 694 9 of phosphorus oxychloride are added drops, resulting in a slightly 5 exothermic reaction. The mixture is heated to the boil , since the reaction becomes more vigorous on arming After having been boiled under reflex for 10 hours and cooled, the batch is cautiously poured onto a mixture of about liters of crushed ice and 1 lithe 10 of concentrated hydrochloric acid. The precipitate formed us filtered off, washed with water and taken up in Tulane; the Tulane solution is shaken with active charcoal and extracted by shaking with sodium bicarbonate solution. After the solution has been dried with sodium 15 sulfite, the Tulane is evaporated off in vacua and the residue is crystallized from methylcyclohexane, in the presence of active charcoal; 180 9 ~67X of theory) are obtained as pale grew crystals of melting point 50. The product can be distilled. Boiling point 135/0.2 mm Hug. Melt-20 in point of the pure White crystals: 58-59.
ON
28) 400 g of 2-spirocyclopenta-4 cyano-chromen-3-ene in 1,800 ml of tetrahydrofuran are hydrogenated over 40 9 of palladium on charcoal I strength) at 40 45 25 under 50 bar pressure After conventional working-up, 360 9 to 90~ of theory) of white crystals, of boiling point 131-5/0.3 mm and melting point ~4-5g are obtained I
29) lo A 2 08 I
50 9 of 2-spirocyclopenta-4-cyanochroman, in the presence of 200 ml of methanol, 50 ml of Liquid ammonia and 10 9 of Rangy cobalt are catalytically hydrogenated for about 3.5 hours in a pressure autoclave at 90C and 100 bar Ho pressure. The catalyst is then filtered off and the filtrate is concentrated and fractionated.
Boiling point 130-140/0.35 mm Hug; 40 9 of colorless loud (about 80% of theory) identical with the product from Example 21).
30) Examples of the preparation of intermediates of preparation variant C
C~2 By I
SHEA
176 g (1 molt of 2,2,4-trimethylchromene are disk solved in 1 lithe of carbon tetrachloride which has been dried over phosphorus pent oxide and 178 9 I molt of N bromo-succinimide and 2 9 of azo-bis-isobutyronitrile are added. The mixture us slowly heated to the boil and us boiled for 1 hour. When it has cooled, the precipi late is filtered off ~succinimide). The mother liquor is concentrated on vacua. 255 9 of a brown oil which is 89X pure according to gas chromatography ( 90X of theory) are obtained; the material can be employed directly for further reactions. The product distill at 105-9/0.28 mm. It can be characterized as the purred-ilium bromide (melting point 186-7).
The following WAS prepared in a similar manner:
Kiwi By 31) Oily not stable to distillation;
melting point of the pyridinium bromide 165-7 lo A 22 084 I
.
Examples_accordin~ to the invention 32) Preparation according to process variant A
SUE N~-CE2 I 43 Of I
12.1 9 S0.1 molt of phenylethylamine are added to 19.0 9 (0.1 molt of 2,2~dimethyl-4-formyl-chroman in 100 ml of methanol whilst stirring at room temperature, with gentle cooling, and the mixture is then stirred for 1.5 hours. Thereafter, 4.5 9 of sodium Burnett are added and the mixture is stirred for a further day, con-cent rated and worked up with ethyl acetate/~ater. The ethyl acetate phase is washed with water, dried and con-cent rated. The residue is dissolved in ether and dry hydrogen chloride is passed through the solution. The precipitate formed is filtered off, stirred with water and filtered off It is dried and recrystallized from acetonitrile~ 20.5 9 no White crystals t62 X of theory), of melting point owe 33) Preparation according to process variant B
C~2 C~ I I
SUE
12 9 (0.1 molt of phenylacetaLdehyde are reacted with 21.7 9 ~0.1 molt of 2-spirocyclopenta-4~aminomethyl-Crimean and worked up, as in the example given above.
19.5 9 S55X of theory) of white crystals, of melting point 202-3.
34) Preparation according to process variant B
A solution of 6.5 of 2,2~spirocyclopenta-4-aminomethylchrom-3-ene and So g of 4 m-trifLuoromethyl-phenyl-butan 2-one in 30 ml of Tulane is heated to the lo A 22 084 boil under a water separator for 30 minutes and then concentrated at 50/~0 mm Hug. The oily residue is dissolved in 50 ml of tetrahydrofuran and added drop-wise, at about 20C, to a suspension of 5 9 of Lyle in 150 ml of THY. The mixture is then stirred for 5 hours at the reflex temperature and us cooled to 10C; 5 ml of water and 15 ml of 15% strength potassium hydroxide solution are successively added cautiously, and this mix-lure us stirred for 1 hour at 20 and then filtered The filtrate is concentrated and the concentrate distilled.
Yield: 6.6 9 of almost colorless owl, boiling point 200-210/0.03 mm Hug 35) Preparation according to process variant C
Of CHIN -Of Cell Us 25 9 Tao molt of N~3,4-dichlorophenyl-p;per-amine and 11.1 9 ~0.11 molt of triethylamine are together introduced into 55 ml of toluener and 27.8 9 ~0.11 molt of 2,2-dimethyl-4-bromomethylchrom-3-ene are added drops In the course thereof, a precipitate separates out and the temperature rises to about 45C. Stirring is con-tinted for 3 hours and the mixture is left to stand over-night It is then thoroughly stirred with excess ON
sodium hydroxide solution and the Tulane phase is spear-axed off, washed with water and dried with sodium sulk plate. After the solvent has been distilled off, the product starts to precipitate. The crystallization is completed by adding petroleum ether. After filtering off the product and drying it, 27.5 9 t62X of theory) of White crystals of melting point 108C, are obtained.
The following were prepared in a similar manner:
lo A 22 D84 36) according to processes A and B
SHEA SUE C~2 bowling point 175-8/
0.2 mm Hug 37) according to processes A and B
I C~2 C~2 C~2 melting point of the hydra-chloride 253-6 S 38) according to processes A and B
melting point of the hydra-I chloride 2~5-8 39) according to processes A and B
Of NICE SUE
Jo boiling point 180 5/
U~15 mm Hug 40~ according to processes A and SHEA I I
melting point of the hydra-En chloride 220-3 lo A 22 084 - .~2~7~
41) according to processes A and B
I I SHEA I
~3~7 boiling point 175-9/
SHEA 0.25 mm Hug 42) according to processes A and B
C~2 I I
boiling point 172-7/
kiwi I I 0.25 mm Hug 5 43) according to processes A and B
I I I
boiling point 190-5/
I 5 ` 0.65 mm Hug 44) according to processes A and B
SHEA I I
resin 45) according to processes A and B
I -N~-C~C~ Of melting point of the hydra-chloride 180-2 46) according to processes A and B
SHEA
I C~2 C~[2 KIWI
melting point of the hydra-chloride 198-20n lo A 22 084 47) according to processes A and B
SHEA Shea SHEA I 0C~3 melting point of the hydra-chloride 214-6 48) according to processes A and B
I
C~2 I
l melting point of the hydra-chloride 212 I according to processes A and B
I SUE (C~3 I molting point of the hydra-chloride 190 50) according to processes A and I
SHEA I SUE smelting point of the hydra-chloride 231 51) according to processes A and B
Of No CUE - bullying point 198-?03/
0.1 mm Hug lo A 22 084 - 52) according to processes A and B
EYE EKE Of boiling point 183-190/
0.15 mm Hug 53) according to processes A and B
Jo EYE NH I boiling point 171-7/
0~15 mm Hug 5 54) according to processes A and B
Ago C3~ Con boiling point 184-9/
0.4 mm Hug 55) according to processes A and B
SUE SEIKO boiling point 168-75/
0.25 mm Hug 56) according to processes A and B
SUE
I NE cue melting point of the hydra-chloride 208-10 lo A 22 084 I
57) according to processes A and 3 SWOONS OH.
2 boiling point 185-95/
CF3 0.1 mm Hug 58) according to processes A and 9 I -SUE
SUE boiling point 188-94/
One mm Hug I
59) according to processes A and B
I -SUE I
resin 60) according to process A
I -NE FEZ SUE -boiling point 190-6/
0~2 mm Hug 61) according to process h EYE
I assay C3~-~ boiling point 181-3/
0.15 mm Hug lo A 22 08~
I
62) according to process A
I
SWOONS SWEENEY boiling point 195-202/
0.25 mm Hug 63) according to process A
Of I -NH-C~ I I
melting point of the hydra-chloride 170-2 5 64) according to process A
I Coequal melting point of the hydra-chloride 168-70 65) according to process A
Of SUE NICE CON melting point of the hydra-chloride 185 66) according to process A
I NO
melting point of the hydra-I chloride 202~4 67) according to processes A and B
I SHEA I I
boiling point 178-82/
0.15 mm Hug lo A 22 084 - I -68) according to processes A and B
H -No OH -C~-0 Of 2 Z boiling point 185-7/
0.2 mm Hug 69~ according to processes A and B
I -CH2CH2-0- Of melting point of the hydra-chloride 185 7 5 70) according to processes A and B
C~2~ I I SHEA
melting point of the hydra-~-YJL_I chloride 102~4 71) according to processes A and B
3 boiling point 198-205/
Dn15 mm Hug 72) according to processes A and B
SHEA CHIHUAHUAS bullying point Z07-15/
0,15-mm Hug lo A 22 0~4 73) according to process C
C~2~
3 melting point 93-4 pa 74) according to process C
C~2~
~C~3 melting point lZO-1 Elm 5 75) according to process C
Kiwi o I
Chat melting point 94-6 I
76) according to process C
I
C~[2-~
s melting point 92-3 I
77~ according to process C
I -I C4 Jo -left.
melting point wow SHEA
78) according to process C
SUE
I
SUE melting point 88-9 lo A 22 OOZE
~Z~'7~
79) according to process C
I
I I boiling point 193-9/
0.3 mm Hug I
80) according to process C
I OOZE' I melting point 88 c~3 81) according to process C
I
~C~3 Of melting point 72 c~3 82) according to process C
Jo F3 I Of me fling pot nut 104-5 I
I
83) according to process C
I
SWISS
SUE molting point 77 I
lo A 22 08 I
84) according to process C
SHEA OF
SUE melting point 146 c~3 85) according to process C
~C2 us SUE ) melting point 83 SHEA
Us S 86) according to process C
CFa 0 . 1 5 m m H g Cams 87) according to process C
I
I a melting point 1210 SHEA
I according to process C
ooze I melting point 84 SHEA , , Us lo A 22 084 89) according to process C
C I
I
I boiling point 189-94/
Ho 0.1 mm Hug SHEA
90) according to process C
boiling point 191-9/
En SUE 0.2 mm Hug 91~ according to process C
OH C~2-Ho melting point 170-1 SHEA
92) according to process A
CON boiling point 180-4/
0.15 mm Hug 93) according to process C
, I
melting point 117-9 94) according to procPcs C
SHEA- Of melting point 118-20 lo A 22 0~4 ~2~7~3~
95) according to process C
I I I I
I bowling point 198-203/
c~3 0.8 mm Hug 96) according to processes B and C
H-C(CE~ I SUE -Of I boiling point 175-80/
0.2 mm Ho I
5 97) according to processes A and B
-NH-CH-cE~ SUE
boiling point 191-6/
0.1 mm Hug 98) according to processes A and B
Of E~-N~-CH-C~Ga~ Of bowl in point 201-212/
0.2 mm Hug 99) according to processes A and B
Ç~-N~-C~-CH2CE~ boiling point 182-7/
0.2 mm Hug e A 22 084 100) according to processes A and C, ~C}~3 ,C~2 -SCHICK I 0C~3 boiling point 205-9/
0.1 mm Hug 101) according to processes A and OOZE
SUE CHIHUAHUAS C~2 -OOZE
boiling point 202-10l 1 0.15 mm Hug 5 102) according to processes A and B
SUE SHEA
SUE -C~2C~2- -OUCH
C~3boiling point 204 12/
1 0.1 mm Hug 103) according to processes A and B
I
SINUSES
boiling point 171-4/
0.1 mm Hug 104) according to processes A and B
SUE Mocha I Of SWISS OUCH
I I - i b O 1 Lint point 189-96 1 lo A 22 084 105) according to processes A and B
c~3 Of CE2--N~C~2CE~;
boiling point 190-8/
0.2 mm Hug 106) according to processes A and Of ON CUE
boiling point Z0$-15/
0.1 mm Hug 107) according to processes A and ~E2-~~~C~~cE2iC~
C~3 boiling point 198-206/
0.1 mm Hug 108) according to processes A and a f~3 ~NH-C~-C~; C1~3$
boiling point 205-12/
0.1 mm Hug 109) according to processes A and a EYE
SUE boiling point 200-5/
0.15 my Hug lo A 22 084 I
c~3 Silas SUE I
Kiwi boiling point 185-92/
0~1 mm Hug 111) according to processes A and B
YE
C~2~ SHEA
En boiling point 181-7t I 0.1 mm Hug S 112) according to processes A and B
I
C~2 SCHICK KIWI
2 5 boiling point 198~204/
0.15 mm Hug 113) according to processes A and B
EYE I SHEA I Jo boiling point 190-2/
Us U.15 mm Hug 114) according to processes A and B
C~2 I Lowe e Ho I) boiling point 199~204 0.1 mm Hug lo A 22 084 _ I
115) according to processes B and C
I
I H-c~2 C}~2 by OWE
boy lung point 210-215/
0.1 mm Hug 116) according to processes A and B
I
NO Ha - C~2 - Clue boy King point 215-8/
0.1 mm Hug 5 117) according to processes B and C
C~2 -~-C~-C~ I
boy lying point 200-2û5/
0.1 mm Hug 118) according to processes A and B
I
CROOK
boy l i no pox nut 195-200/
0.05 mm Hug 119) according to processes B and C
I
SHEA go boy lying point 220/0.12 mm Hug lo A 22 084 I
I -120) according to processes A and B
SHEA
[SHEA SICKISH
boiling point 240/0.1 mm Hug Examples of the preparation of chroman-4-car~aldehydes (starting product for preparation variant A) 5 Example 121 SHEA
oh A mixture of 12 9 of Rh~tC6H5)3P~Cl3, 96 9 of triphcnylphosphine and 660 ml of Tulane is introduced into a 3 lithe stainless steel autoclave and a mixture 10 of 665 (3~58 molt of 2-spirocyclopentachrom-3-ene is pumped in slowly in the course of 6 hours at 160-70C
internal temperature and a C0/H2 pressure of initially 150 and later 300 bar. The mixture is stirred for a further hour at 17ûC and is distilled after the pressure has : 15 been released 327 9 ~42% of theory) of 2-spirocyclo-pentachroman~4-carbaldehyde are obtained as an almost colorless liquid of boiling point 127-30/0~1 mm Hug.
Example 122 - - COO
¢$~
0-083 9 of Rh~tC6H5-CH2)2Si3Cl3 and 500 ml of Tulane are stirred for 1 hour on an autoclave at 170 and 170 bar C0/H2 pressure The mixture is alloyed to cool to 135 and 558 9 (3 molt of 2-~pirscyclopenta-Crimean dissolved in 6Q0 ml of Tulane, are pumped lo A 22 084 Lo in over the course of 3 hours, whilst maintaining a pressure of 250-280 bard After the mixture has been cooled, brought to atmospheric pressure and degassed, the solvent is stripped off in vacua and the liquid residue is fractionated. 518 9 t80~ of theory) of colorless liquid, of boiling point 127-30/0~3 mm Hug.
The following were prepared in a similar manner to that described in Example 122 SHEA
boiling point 120-5/0.3 mm Hug KIWI
boiling point 90-95/0~5 mm Hug KIWI
Of boiling point 120/0~2 mm Hug I
boiling point 106-10/0.04 mm Hug SHEA
En boiling point 121-610~3 mm Hug KIWI
ZOO SUE boiling point 143-50/0.15 mm Hug KIWI
C boiling point 110/0.05 mm Hug lo A 22 084 _ .
7~6~
129) SHEA
~C3~7 - i boiling point 110/0~5 mm Hug SHEA
130) En 2 boiling point 110-5/0.5 mm Hug 5 ~31) SHEA
I boiling point 165-70/0,05 mm Hug 132) I
En bowling point 110-115/0.2 mm Hug 134) I boiling point 145-50/0.1 mm Hug I
135) I
boiling point 152-157/0.1 mm Hug c~3 CUED
136) boiling point 161~3/0~05 mm Hug lo A 22 084 I
- I -137) boy lying point 155-162/0.09 mm Hug 138) I
boy lying point 154-61/0.1 mm Hug 5 139~
CUED
boy lying point 152-9/0.03 mm Hug ~~<~> .
140) CUED
Jo bowling point 159-66~0.07 mm Hug 141) 10~`cH2-cH2~ boy lying point 163-9/0.,05 mm Hug 142) Of boiling point 170-8J0.0~ mm Hug SWISH
lo A Z2 OBOE
ye \
143) Of C~3 boiling point 173-5/0.05 mm Hug 144) boiling point one mm Hug boiling point 180-6/0.04 mm Hug 146) I
boiling point ODE mm Hug 147~
C2H5 boiling point 188 ODE mm Hug 148) boiling point 160-6/0.06 mm Hug Example 122 was repeated, using the following catalyst:
a) C02tC0)~
b) CRh~C0)2Cl32 c) Rh~PPH3)3Cl d) RhtPPH3)3Cl lo A 22 084 en Rho no (C2Hs)2Fe~PpH2~3 Fly I RhCl3 x 3H20 g) Rh(C8H14)2Cl h) Rh(C0)2acac3 i) HCotC0)3CP(Bu)3]3 k) Rh4~C0)12 l) Rn3tCo)12 m) Ir(CO)CPPH3]2Cl In all cases a colorless liquid of boiling point 127-3D/0.3 mm Hug was obtained in good yields.
lo A 22 084 -Test of anti hypertensive action on renallv hypertonic dogs Method _ _ Beagle hounds of both sexes are used. For a direct measure-mint of the blood pressure the animals are fitted with a permanent catheter in the aorta. To obtain experimental hypertension the right aorta renewals was stenosed.
The systolic and diastolic blood pressure and the heart rate are continuously recorded in conscious, freely moving hounds using a radio telemetry system. The data are received by an on-line data acquisition system (DAY 10/4; manufac-tuner: if via a transceiver combination and evaluated by a programmable computer (Multi 4; manufacturer: Inter-technique). The data are delivered as hourly mean values of all the recorded blood pressure responses.
The test substances are dissolved in polyethylene glycol 400 and are administered orally in a gelatin capsule. The blood pressure is measured during a period ox an hour preceding administration and for up to 16 hours following administration.
The minimum dose is the lowest dose with which a reduction in blood pressure of at least 15 mmHg is reached.
Results ubstance Minimum dose (mg/kg pro,) JO reduction in blood pressure Example 97 3,15 10 Example 102 1,00 9 Example 118 Lowe 16 lo A 22 084 '7~30 - 59 _ Test of the anti hypertensive action on spontaneously hype-tonic rats:
Method The blood pressure is measured indirectly on the tails of conscious rats by means of an inflatable cult and an infrasonic pulse recorder D along the BOUCKE-BRECHT method. During the whole test, including a two-hour proadministration period, the animals are individually contained in plastic tubes heated to about 30C and surrounded by a water-jacket. The inflatable rubber cult is positioned at the start of the tail and the pulse recorder a-t a distance of 3 cm therefrom. In order to obtain uniform measuring results for the repeated measurements the place of measurement on the tail is marked with Indian ink.
Measurements are taken when the cult pressure falls, the pressure present in the cult on recurrence of the pulsations being equal to the systolic blood pressure in the rats' tails.
The substances are applied orally in the for of a sup-pension by means of a probing. The systolic blood pressure is measured prior to administration and 1, 2, 4, 6 and I
hours following administration of the substances. Each does is tested in at least 3 animals. On each test day an us-treated group is tested parallel to the treated animals as a control means.
The minimum dose is the lowest dose at which a reduction in blood pressure of at least 15 mmHg is achieved.
Substance minimum dose (m ok Jo.
q P _) Example 97 10,0 Example 102 1,0 lo A 22 084
129) SHEA
~C3~7 - i boiling point 110/0~5 mm Hug SHEA
130) En 2 boiling point 110-5/0.5 mm Hug 5 ~31) SHEA
I boiling point 165-70/0,05 mm Hug 132) I
En bowling point 110-115/0.2 mm Hug 134) I boiling point 145-50/0.1 mm Hug I
135) I
boiling point 152-157/0.1 mm Hug c~3 CUED
136) boiling point 161~3/0~05 mm Hug lo A 22 084 I
- I -137) boy lying point 155-162/0.09 mm Hug 138) I
boy lying point 154-61/0.1 mm Hug 5 139~
CUED
boy lying point 152-9/0.03 mm Hug ~~<~> .
140) CUED
Jo bowling point 159-66~0.07 mm Hug 141) 10~`cH2-cH2~ boy lying point 163-9/0.,05 mm Hug 142) Of boiling point 170-8J0.0~ mm Hug SWISH
lo A Z2 OBOE
ye \
143) Of C~3 boiling point 173-5/0.05 mm Hug 144) boiling point one mm Hug boiling point 180-6/0.04 mm Hug 146) I
boiling point ODE mm Hug 147~
C2H5 boiling point 188 ODE mm Hug 148) boiling point 160-6/0.06 mm Hug Example 122 was repeated, using the following catalyst:
a) C02tC0)~
b) CRh~C0)2Cl32 c) Rh~PPH3)3Cl d) RhtPPH3)3Cl lo A 22 084 en Rho no (C2Hs)2Fe~PpH2~3 Fly I RhCl3 x 3H20 g) Rh(C8H14)2Cl h) Rh(C0)2acac3 i) HCotC0)3CP(Bu)3]3 k) Rh4~C0)12 l) Rn3tCo)12 m) Ir(CO)CPPH3]2Cl In all cases a colorless liquid of boiling point 127-3D/0.3 mm Hug was obtained in good yields.
lo A 22 084 -Test of anti hypertensive action on renallv hypertonic dogs Method _ _ Beagle hounds of both sexes are used. For a direct measure-mint of the blood pressure the animals are fitted with a permanent catheter in the aorta. To obtain experimental hypertension the right aorta renewals was stenosed.
The systolic and diastolic blood pressure and the heart rate are continuously recorded in conscious, freely moving hounds using a radio telemetry system. The data are received by an on-line data acquisition system (DAY 10/4; manufac-tuner: if via a transceiver combination and evaluated by a programmable computer (Multi 4; manufacturer: Inter-technique). The data are delivered as hourly mean values of all the recorded blood pressure responses.
The test substances are dissolved in polyethylene glycol 400 and are administered orally in a gelatin capsule. The blood pressure is measured during a period ox an hour preceding administration and for up to 16 hours following administration.
The minimum dose is the lowest dose with which a reduction in blood pressure of at least 15 mmHg is reached.
Results ubstance Minimum dose (mg/kg pro,) JO reduction in blood pressure Example 97 3,15 10 Example 102 1,00 9 Example 118 Lowe 16 lo A 22 084 '7~30 - 59 _ Test of the anti hypertensive action on spontaneously hype-tonic rats:
Method The blood pressure is measured indirectly on the tails of conscious rats by means of an inflatable cult and an infrasonic pulse recorder D along the BOUCKE-BRECHT method. During the whole test, including a two-hour proadministration period, the animals are individually contained in plastic tubes heated to about 30C and surrounded by a water-jacket. The inflatable rubber cult is positioned at the start of the tail and the pulse recorder a-t a distance of 3 cm therefrom. In order to obtain uniform measuring results for the repeated measurements the place of measurement on the tail is marked with Indian ink.
Measurements are taken when the cult pressure falls, the pressure present in the cult on recurrence of the pulsations being equal to the systolic blood pressure in the rats' tails.
The substances are applied orally in the for of a sup-pension by means of a probing. The systolic blood pressure is measured prior to administration and 1, 2, 4, 6 and I
hours following administration of the substances. Each does is tested in at least 3 animals. On each test day an us-treated group is tested parallel to the treated animals as a control means.
The minimum dose is the lowest dose at which a reduction in blood pressure of at least 15 mmHg is achieved.
Substance minimum dose (m ok Jo.
q P _) Example 97 10,0 Example 102 1,0 lo A 22 084
Claims (47)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a compound of the formula (I) (I) in which -A- represents a single bond or a double bond, R1 and R2 are identical or different and represent hydrogen, C1-C6-alkyl, C5-C7-cycloalkyl, phenyl (which is unsubstituted or substituted by C1-C4-alkyl, halogen and/or C1-C4-alkoxy), or C7-C9-aralkyl (whose aryl radical is unsub-stituted or substituted by C1-C4-alkyl, halogen, and/or C1-C4-alkoxy), or R1 and R2 conjointly with the enclosed C atom of the chroman ring form a 4-membered to 7-membered carbocyclic ring;
R3 to R6 are identical or different and represent hydrogen, hydroxyl, halogen, C1-C6-alkyl, C5-C7-cycloalkyl, phenyl (which is unsubstituted or substituted by C1-C4-alkyl, halogen and/or C1-C4-alkoxy), C7-C9-aralkyl (whose aryl radical is unsubstituted or substituted by C1-C4 alkyl, halogen and/or C1-C4-alkoxy), or C1-C4-alkoxy;
R7, R8, R9, R10 and R11 are identical or different and represent hydrogen or C1-C6-alkyl;
X represents a single bond, methylene (which is unsubstituted, monosubstituted or disubstituted by C1-C4-alkyl, oxygen or -NR17, wherein R17 represents hydrogen or C1-C4-alkyl or R17 together with R7 forms a C2-alkylene ring-closing member and R12, R13, R14, R15 and R16 are identical or different and represent hydrogen, hydroxyl, halogen, C1-C6-alkyl, C5- or C6-cycloalkyl, benzyl, C1-C4-alkoxy, trifluoromethyl, or R12 and R13 or R13 and R14 together form a C1-C3-alkylenedioxy group or a -CH=CH-CH=CH- group, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
A) when a compound of formula (I) wherein -A- represents a single bond is required, reacting a chroman-4-carbaldehyde of the formula (II) (II) in which R1, R2, R3, R4, R5 and R6 have the meanings given above with an amine of the formula (III) (VI) in which R8 to R16 have the meanings given above with the proviso that X does not represent NR17, in the presence of a reducing agent, or C) when a compound of the formula (I) in which A
represents a double bond is required, reacting a compound of the formula (VII) (VII) in which R1, R2, R3, R4, R5 and R6 have the meanings given above and Y represents bromine or chlorine with the amine of the formula (III) as defined in process variant A) in the presence of an acid-binding agent, and when required, converting the product of any process variant into a pharmaceutically acceptable acid addition salt thereof.
R3 to R6 are identical or different and represent hydrogen, hydroxyl, halogen, C1-C6-alkyl, C5-C7-cycloalkyl, phenyl (which is unsubstituted or substituted by C1-C4-alkyl, halogen and/or C1-C4-alkoxy), C7-C9-aralkyl (whose aryl radical is unsubstituted or substituted by C1-C4 alkyl, halogen and/or C1-C4-alkoxy), or C1-C4-alkoxy;
R7, R8, R9, R10 and R11 are identical or different and represent hydrogen or C1-C6-alkyl;
X represents a single bond, methylene (which is unsubstituted, monosubstituted or disubstituted by C1-C4-alkyl, oxygen or -NR17, wherein R17 represents hydrogen or C1-C4-alkyl or R17 together with R7 forms a C2-alkylene ring-closing member and R12, R13, R14, R15 and R16 are identical or different and represent hydrogen, hydroxyl, halogen, C1-C6-alkyl, C5- or C6-cycloalkyl, benzyl, C1-C4-alkoxy, trifluoromethyl, or R12 and R13 or R13 and R14 together form a C1-C3-alkylenedioxy group or a -CH=CH-CH=CH- group, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
A) when a compound of formula (I) wherein -A- represents a single bond is required, reacting a chroman-4-carbaldehyde of the formula (II) (II) in which R1, R2, R3, R4, R5 and R6 have the meanings given above with an amine of the formula (III) (VI) in which R8 to R16 have the meanings given above with the proviso that X does not represent NR17, in the presence of a reducing agent, or C) when a compound of the formula (I) in which A
represents a double bond is required, reacting a compound of the formula (VII) (VII) in which R1, R2, R3, R4, R5 and R6 have the meanings given above and Y represents bromine or chlorine with the amine of the formula (III) as defined in process variant A) in the presence of an acid-binding agent, and when required, converting the product of any process variant into a pharmaceutically acceptable acid addition salt thereof.
2. The compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.
3. The process according to claim 1, in which in the starting materials, R1 and R2, are identical or different, and represent hydrogen or C1-C4-alkyl or together with the carbon atom to which they are attached represent a carbocyclic C5- or C6-ring, R3 to R6, are identical or different, and denote hydro-gen, hydroxyl, C1-C4-alkyl, C1-C4-alkoxy or chlorine, R7 to R11, are identical or different, and represent hydrogen or C1-C4-alkyl, X represents a single bond, oxygen,methylene or -NR17, R17 denotes hydrogen or C1-C3-alkyl or R17 together with R7 forms an ethylene ring-closing member and R12 to R16, are identical or different, and denote hydrogen, chlorine, cyclohexyl, C1-C4-alkyl, C1-C3-alkoxy or trifluoromethyl, or R12 and R13 or R13 and R14 together form a methylenedioxy group or -CH=CH-CH=CH-.
4. A process according to claim 1, in which in the starting materials R1 and R2 are identical or different and represents hydrogen, methyl, ethyl, n-propyl, i-propyl or cyclohexyl, or together with the carbon atom to which they are attached represents a carbocyclic C5- or C6- ring R3 to R6 are identical or different and represent hydrogen, methyl, chlorine or methoxy, provided that when one of R3 to R6 is other than hydrogen, the others are hydrogen, R7 to R11 are identical or different and represent hydrogen, methyl or ethyl, X represents a single bond, oxygen, methylene or -NR17, R17 denotes hydrogen, methyl, ethyl or together with R7 forms an ethylene ring-closing member, and R12 to R16 are identical or different and denote hydrogen, chlorine, methoxy, methyl, trifluoromethyl, cyclohexyl, tert.-butyl or ethoxy, provided that not more than three of R12 to R16 are other than hydrogen at the same time or R12 and R13 or R13 and R14 together form a methylenedioxy or -CH=CH-CH=CH-.
5. The process according to claim 1, 3 or 4, wherein the reaction of process variant A) or B) is carried out using a complex metal hydride as the reducing agent.
6. The process according to claim 1, 3 or 4, wherein the starting material of the formula (II) in process variant A) is prepared by the (III) in which R7, R3, R9, R10, R11, R12, R13, R14, R15, R16,R17 and X have the meanings given above, in the presence of a reducing agent, or B) reacting an amine of the formula (IV) (IV) or of the formula (V) in which R1, R2, R3, R4, R5 and R6 have the meanings given above with a carbonyl compound of the formula (VI) hydroformylation of a 2H-chromene compound of the formula in which R1, R2, R3, R4, R5 and R6 are as defined in claim 1, 3 or 4.
7. The process according to claim 1, 3 or 4, wherein the starting material of the formula (IV) in process variant B) is prepared by:
(1) reacting trimethylsilyl cyanide (CH3)3SiCN with a chroman-4-one of the formula in which R1, R2, R3, R4, R5 and R6 are as defined in claim 1, 2 or 3, to produce a corresponding 4-cyano-4-trimethylsilyloxychroman, (2) hydrogenating the thus obtained product to produce a cor-responding 4-aminomethyl-4-hydroxychroman, and (3) dehydrating the thus obtained product to produce the desired 4-aminomethyl-2H-chromene.
(1) reacting trimethylsilyl cyanide (CH3)3SiCN with a chroman-4-one of the formula in which R1, R2, R3, R4, R5 and R6 are as defined in claim 1, 2 or 3, to produce a corresponding 4-cyano-4-trimethylsilyloxychroman, (2) hydrogenating the thus obtained product to produce a cor-responding 4-aminomethyl-4-hydroxychroman, and (3) dehydrating the thus obtained product to produce the desired 4-aminomethyl-2H-chromene.
8. The process according to claim 1, 3 or 4, wherein the starting material of the formula (V) in process variant B) is prepared by:
[a] (1) reacting trimethylsilyl cyanide (CH3)3SiCN with a chroman-4-one of the formula in which R1, R2, R3, R4, R5 and R6 are as defined in claim 1, 2 or 3, to produce a corresponding 4-cyano-4-trimethylsilyloxychroman, (2) hydrogenating the thus obtained product to produce a corresponding 4-aminomethyl-4-hydroxychroman, (3) dehydrating the thus obtained product to produce a corresponding 4-aminomethyl-2H-chromene, and (4) hydrogenating the thus obtained chromene to produce the desired 4-aminomethyl-chroman, or [b] (1) reacting trimethylsilyl cyanide with the chroman-4-one of the formula as defined above to produce a corresponding 4-cyano-4-trimethylsilyloxychroman, (2) eliminating trimethylsilanol to produce a corresponding 4-cyano-2H-chromene, and (3) hydrogenating the thus obtained cyano chromene to produce the desired 4-aminomethyl-chroman.
[a] (1) reacting trimethylsilyl cyanide (CH3)3SiCN with a chroman-4-one of the formula in which R1, R2, R3, R4, R5 and R6 are as defined in claim 1, 2 or 3, to produce a corresponding 4-cyano-4-trimethylsilyloxychroman, (2) hydrogenating the thus obtained product to produce a corresponding 4-aminomethyl-4-hydroxychroman, (3) dehydrating the thus obtained product to produce a corresponding 4-aminomethyl-2H-chromene, and (4) hydrogenating the thus obtained chromene to produce the desired 4-aminomethyl-chroman, or [b] (1) reacting trimethylsilyl cyanide with the chroman-4-one of the formula as defined above to produce a corresponding 4-cyano-4-trimethylsilyloxychroman, (2) eliminating trimethylsilanol to produce a corresponding 4-cyano-2H-chromene, and (3) hydrogenating the thus obtained cyano chromene to produce the desired 4-aminomethyl-chroman.
9. A process for the preparation of 4-[.gamma.-(3,4-methylenedioxyphenyl)-.alpha.-methyl]-propyl-aminomethyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(A) reacting 2-amino-4-(3,4-methylenedioxyphenyl)-butane with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-2-spirocyclopenta-chroman with 4-(3,4-methylenedioxyphenyl)butan-2 one in the presence of a reducing agent, and if required, converting the resulting product obtained in any variant into a pharmaceutically acceptable acid addition salt thereof.
(A) reacting 2-amino-4-(3,4-methylenedioxyphenyl)-butane with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-2-spirocyclopenta-chroman with 4-(3,4-methylenedioxyphenyl)butan-2 one in the presence of a reducing agent, and if required, converting the resulting product obtained in any variant into a pharmaceutically acceptable acid addition salt thereof.
10. The process according to claim 9, wherein the reaction of process variant (A) or (B) is carried out in the presence of a complex metal hydride as the reducing agent.
11. The process according to claim 10, wherein the complex metal hydride is sodium borohydride or lithium aluminum hydride.
12. The process according to claim 9, 10 or 11, wherein the product is obtained as the free amine.
13. 4-[.gamma.-3,4-Methylenedioxypllenyl)-.alpha.-methyl]-propyl-aminomethyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 9, 10 or 11 or an obvious chemical equivalent thereof.
14. A process for the preparation of 4-(.beta.-phenylethyl)-aminomethyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(A) reacting 2-phenylethylamine with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting phenylacetaldehyde and 2-spirocyclopenta-4-amino-methyl-chroman in the presence of a reducing agent, and if required, converting the resulting product obtained in any variant into a pharmaceuti-cally acceptable acid addition salt thereof.
(A) reacting 2-phenylethylamine with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting phenylacetaldehyde and 2-spirocyclopenta-4-amino-methyl-chroman in the presence of a reducing agent, and if required, converting the resulting product obtained in any variant into a pharmaceuti-cally acceptable acid addition salt thereof.
15. The process according to claim 14, wherein process variant (B) is employed and the reacting is carried out using a complex metal hydride as the reducing agent.
16. The process according to claim 15, wherein the complex metal hydride is sodium borohydride.
17. The process according to claim 14, 15 or 16, wherein the product is obtained as the hydrochloride.
18. 4(.beta.-Phenylethyl)-aminomethyl-2-spirocyclopentachroman or a phar-maceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 14, 15 or 16 or by an obvious chemical equivalent thereof.
19. A process for the preparation of 4-N-3,4-dichlorophenyl-piperazin-N'-yl-methyl-2,2-dimethyl-chromene or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
reacting N-3,4-dichlorophenyl-piperazine with 2,2-dimethyl-4-bromo or -chloromethylchrom-3-ene in the presence of an acid-binding agent, and if required, converting the resulting product into a pharmaceuti-cally acceptable acid addition salt thereof.
reacting N-3,4-dichlorophenyl-piperazine with 2,2-dimethyl-4-bromo or -chloromethylchrom-3-ene in the presence of an acid-binding agent, and if required, converting the resulting product into a pharmaceuti-cally acceptable acid addition salt thereof.
20. The process according to claim 19, wherein 2,2-dimethyl-4-bromo-methylchrom-3-ene is reacted with the piperazine compound in the presence of an organic nitrogen base.
21. 4-N-3,4-Dichlorophenyl-piperazin-N'-y1-methyl-2-2,dimethyl-chromene or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 19 or 20 or by an obvious chemical equiva-lent thereof.
22. The process according to claim 19 or 20, wherein the product is obtained as the free amine.
23. A process for the preparation of 4-.beta.-phenoxyethyl-amino-methyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(A) reacting 2-phenoxyethylamine with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting 2-spirocyclopenta-4-aminomethyl-chroman with phen-oxyacetaldehyde in the presence of a reducing agent, and if required, converting the resulting product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
(A) reacting 2-phenoxyethylamine with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting 2-spirocyclopenta-4-aminomethyl-chroman with phen-oxyacetaldehyde in the presence of a reducing agent, and if required, converting the resulting product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
24. The process according to claim 23, wherein the reaction of process variant (A) or (B) is carried out in the presence of a complex metal hydride as the reducing agent.
25. The process according to claim 24, wherein the complex metal hydride is sodium borohydride or lithium aluminum hydride.
26. The process according to claim 23, 24 or 25, wherein the product is obtained as the free amine.
27. 4-.beta.- Phenoxyethyl-amino-methyl-2-spirocyclopentachroman, or a phar-maceutically acceptable acid addition salt thereof whenever prepared or produced by the process of claim 23, 24 or 25 or by an obvious chemical equivalent thereof.
28. A process for the preparation of 4-[.gamma.-(3,4,5-trimethoxyphenyl)-.alpha.-methyl]-propylamino-methyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(A) reacting 2-amino-4-(3,4,5-trimethoxyphenyl)butane with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting 2-spirocyclopenta-4-aminomethyl-chroman with 4-(3,4,5-trimethoxyphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
(A) reacting 2-amino-4-(3,4,5-trimethoxyphenyl)butane with 4-formyl-2-spirocyclopenta-chroman in the presence of a reducing agent, or (B) reacting 2-spirocyclopenta-4-aminomethyl-chroman with 4-(3,4,5-trimethoxyphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
29. The process according to claim 28, wherein the reaction of process variant (A) or (B) is carried out in the presence of a complex metal hydride as the reducing agent.
30. The process according to claim 29, wherein the complex metal hydride is sodium borohydride or lithium aluminum hydride.
31. The process according to claim 28, 29 or 30, wherein the product is obtained as the free amine.
32. 4-[.gamma.-3,4,5-trimethoxyphenyl)-.alpha.-methyl]-propylamino-methyl-2-spirocyclopentachroman, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 28, 29 or 30 or by an obvious chemical equivalent thereof.
33. A process for the preparation of 4-[.gamma.-(3,4-methylenedioxyphenyl)-.alpha.-methyl]propylamino-methyl-7-methoxy-2-spirocyclopeentachroman or a pharma-ceutically acceptable acid addition salt thereof, which process comprises:
(A) reacting 2-amino-4-(3,4-methylenedioxyphenyl)butane with 4-formyl-7-methoxy-2-spirocyclopentachroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-7-methoxy-2-spirocyclopentachroman with 4-(3,4-methylenedioxyphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
(A) reacting 2-amino-4-(3,4-methylenedioxyphenyl)butane with 4-formyl-7-methoxy-2-spirocyclopentachroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-7-methoxy-2-spirocyclopentachroman with 4-(3,4-methylenedioxyphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
34. The process according to claim 33, wherein the reaction of process variant (A) or (B) is carried out in the presence of a complex metal hydride as the reducing agent.
35. The process according to claim 34, wherein the complex metal hydride is sodium borohydride or lithium aluminum hydride.
36. The process according to claim 33, 34 or 35, wherein the product is obtained as the free amine.
37. 4-[.gamma.-(3,4-Methylenedioxyphenyl)-.alpha.-methyl]propylamino-methyl-7-methoxy-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 33, 34 or 35 or by an obvious chemical equivalent thereof.
38. A process for the preparation of 4-[.gamma.-(3,4-methylenedioxyphenyl)-.alpha.-methyl]propylamino-methyl-7-methyl-2-spirocyclopentachroman or a pharma-ceutically acceptable acid addition salt thereof, which process comprises:
(A) reacting 2-amino-4-(3,4-methylenedioxyphenyl)butane with 4-formyl-7-methoxy-2-spirocyclopentachroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-7-methyl-2-spirocyclopentachroman with 4-(3,4-methylenedioxyphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
(A) reacting 2-amino-4-(3,4-methylenedioxyphenyl)butane with 4-formyl-7-methoxy-2-spirocyclopentachroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-7-methyl-2-spirocyclopentachroman with 4-(3,4-methylenedioxyphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any process variant into a pharmaceutically acceptable acid addition salt thereof.
39. The process according to claim 38, wherein the reaction of process variant (A) or (B) is carried out in the presence of a complex metal hydride as the reducing agent.
40. The process according to claim 39, wherein the complex metal hydride is sodium borohydride or lithium aluminum hydride.
41. The process according to claim 38, 39 or 40, wherein the product is obtained as the free amine.
42. 4-[.gamma.-(3,4-Methylenedioxyphenyl)-.alpha.-methyl]propylamino-methyl-7-methyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 38, 39 or 40 or by an obvious chemical equivalent thereof.
43. A process for the preparation of 4-[.gamma.-(3-trifluoromethylphenyl)-.alpha.-methyl]propylamino-methyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
(A) reacting 2-amino-4-(3-trifluoromethylphenyl)butane with 4-formyl-1-2-spirocyclopentachroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-2-spirocyclopentachroman with 4-(3-trifluoromethylphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any reaction variant into a pharmaceutically acceptable acid addition salt thereof.
(A) reacting 2-amino-4-(3-trifluoromethylphenyl)butane with 4-formyl-1-2-spirocyclopentachroman in the presence of a reducing agent, or (B) reacting 4-aminomethyl-2-spirocyclopentachroman with 4-(3-trifluoromethylphenyl)butan-2-one in the presence of a reducing agent, and if required, converting the product obtained in any reaction variant into a pharmaceutically acceptable acid addition salt thereof.
44. The process according to claim 43, wherein the reaction of process variant (A) or (B) is carried out in the presence of a complex metal hydride as the reducing agent.
45. The process according to claim 44, wherein the complex metal hydride is sodium borohydride or lithium aluminum hydride.
46. The process according to claim 43, 44 or 45, wherein the product is obtained as the free amine.
47. 4-[.gamma.-(3-Trifluoromethylphenyl]-.alpha.-methyl]propylamino-methyl-2-spirocyclopentachroman or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 43, 44 or 45 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3300004.2 | 1983-01-03 | ||
| DE19833300004 DE3300004A1 (en) | 1983-01-03 | 1983-01-03 | SUBSTITUTED 4-AMINOMETHYLENE CHROMANE OR CHROME, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1221700A true CA1221700A (en) | 1987-05-12 |
Family
ID=6187648
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000444553A Expired CA1221700A (en) | 1983-01-03 | 1984-01-03 | Substituted 4-aminomethylene-chromans and -chromenes, processes for their preparation and their use in medicaments |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4563458A (en) |
| EP (1) | EP0114374B1 (en) |
| JP (1) | JPS59176275A (en) |
| KR (1) | KR840007225A (en) |
| AT (1) | ATE20889T1 (en) |
| AU (1) | AU561578B2 (en) |
| CA (1) | CA1221700A (en) |
| DE (2) | DE3300004A1 (en) |
| DK (1) | DK1284A (en) |
| ES (1) | ES8406881A1 (en) |
| FI (1) | FI76331C (en) |
| GR (1) | GR79463B (en) |
| HU (1) | HUT35659A (en) |
| IL (1) | IL70585A (en) |
| NO (1) | NO834666L (en) |
| PT (1) | PT77898B (en) |
| ZA (1) | ZA839693B (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2567056A (en) * | 1948-02-18 | 1951-09-04 | Cora B Sands | Steam-heated ironing board |
| GB8323293D0 (en) * | 1983-08-31 | 1983-10-05 | Zyma Sa | Substituted flavene and thioflavene derivatives |
| DE3411993A1 (en) * | 1984-03-31 | 1985-10-10 | Bayer Ag, 5090 Leverkusen | SUBSTITUTED BENZOPYRANS, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
| FR2618437B1 (en) * | 1987-07-23 | 1989-11-17 | Rhone Poulenc Sante | NOVEL BENZOPYRAN DERIVATIVES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| EP0325964A1 (en) * | 1988-01-15 | 1989-08-02 | Abbott Laboratories | Aminomethyl-chroman and -thiochroman compounds |
| US5140039A (en) * | 1988-01-15 | 1992-08-18 | Abbott Laboratories | Aminomethyl-thiochroman compounds |
| US5185364A (en) * | 1988-01-15 | 1993-02-09 | Abbott Laboratories | Aminomethyl-chroman and -thiochroman compounds |
| US4931221A (en) * | 1988-12-30 | 1990-06-05 | Ppg Industries, Inc. | Photochromic spiropyran compounds |
| FR2642069B1 (en) * | 1989-01-20 | 1991-04-12 | Rhone Poulenc Sante | NOVEL BENZOPYRAN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4980089A (en) * | 1989-07-12 | 1990-12-25 | Ppg Industries, Inc. | Photochromic spiropyran compounds |
| US5066818A (en) * | 1990-03-07 | 1991-11-19 | Ppg Industries, Inc. | Photochromic naphthopyran compounds |
| EP0450689A1 (en) * | 1990-04-02 | 1991-10-09 | Akzo Nobel N.V. | New isochromane derivatives |
| DE4012338A1 (en) * | 1990-04-18 | 1991-10-24 | Bayer Ag | SUBSTITUTED PYRIDAZINONES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PEST CONTROL |
| US5200116A (en) * | 1990-07-23 | 1993-04-06 | Ppg Industries, Inc. | Photochromic chromene compounds |
| US5244602A (en) * | 1990-12-03 | 1993-09-14 | Ppg Industries, Inc. | Photochromic naphthopyrans |
| US5585042A (en) * | 1992-02-24 | 1996-12-17 | Transitions Optical, Inc. | Photochromic naphthopyrans |
| US5238981A (en) * | 1992-02-24 | 1993-08-24 | Transitions Optical, Inc. | Photochromic naphthopyrans |
| US5274132A (en) * | 1992-09-30 | 1993-12-28 | Transitions Optical, Inc. | Photochromic naphthopyran compounds |
| US5464567A (en) * | 1994-04-08 | 1995-11-07 | Transitions Optical, Inc. | Photochromic tetraphenyl naphthodipyrans |
| US5395567A (en) * | 1994-04-18 | 1995-03-07 | Ppg Industries, Inc. | Photochromic spironaphthopyran compounds |
| US5645767A (en) * | 1994-11-03 | 1997-07-08 | Transitions Optical, Inc. | Photochromic indeno-fused naphthopyrans |
| US5744070A (en) * | 1995-12-20 | 1998-04-28 | Transitions Optical, Inc. | Photochromic substituted naphthopyran compounds |
| US5955520A (en) * | 1996-06-17 | 1999-09-21 | Ppg Industries, Inc. | Photochromic indeno-fused naphthopyrans |
| US5698141A (en) * | 1996-06-17 | 1997-12-16 | Ppg Industries, Inc. | Photochromic heterocyclic fused indenonaphthopyrans |
| US5723072A (en) * | 1996-06-17 | 1998-03-03 | Ppg Industries, Inc. | Photochromic heterocyclic fused indenonaphthopyrans |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH648030A5 (en) * | 1980-12-15 | 1985-02-28 | Sandoz Ag | BENZOPYRANE ALLYLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE. |
-
1983
- 1983-01-03 DE DE19833300004 patent/DE3300004A1/en not_active Withdrawn
- 1983-12-13 US US06/560,786 patent/US4563458A/en not_active Expired - Fee Related
- 1983-12-16 NO NO834666A patent/NO834666L/en unknown
- 1983-12-22 AU AU22782/83A patent/AU561578B2/en not_active Ceased
- 1983-12-22 DE DE8383112952T patent/DE3364779D1/en not_active Expired
- 1983-12-22 EP EP83112952A patent/EP0114374B1/en not_active Expired
- 1983-12-22 AT AT83112952T patent/ATE20889T1/en not_active IP Right Cessation
- 1983-12-27 PT PT77898A patent/PT77898B/en unknown
- 1983-12-29 ZA ZA839693A patent/ZA839693B/en unknown
- 1983-12-30 JP JP58252391A patent/JPS59176275A/en active Pending
- 1983-12-30 FI FI834872A patent/FI76331C/en not_active IP Right Cessation
- 1983-12-30 IL IL70585A patent/IL70585A/en not_active IP Right Cessation
- 1983-12-31 KR KR1019830006357A patent/KR840007225A/en not_active Application Discontinuation
-
1984
- 1984-01-02 HU HU845A patent/HUT35659A/en unknown
- 1984-01-02 ES ES528619A patent/ES8406881A1/en not_active Expired
- 1984-01-02 DK DK1284A patent/DK1284A/en not_active Application Discontinuation
- 1984-01-03 CA CA000444553A patent/CA1221700A/en not_active Expired
- 1984-01-03 GR GR73413A patent/GR79463B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUT35659A (en) | 1985-07-29 |
| EP0114374A1 (en) | 1984-08-01 |
| IL70585A0 (en) | 1984-03-30 |
| NO834666L (en) | 1984-07-04 |
| US4563458A (en) | 1986-01-07 |
| FI834872A0 (en) | 1983-12-30 |
| DK1284A (en) | 1984-07-04 |
| IL70585A (en) | 1987-02-27 |
| DE3364779D1 (en) | 1986-08-28 |
| FI76331B (en) | 1988-06-30 |
| ZA839693B (en) | 1984-08-29 |
| DK1284D0 (en) | 1984-01-02 |
| ATE20889T1 (en) | 1986-08-15 |
| AU561578B2 (en) | 1987-05-14 |
| DE3300004A1 (en) | 1984-07-12 |
| ES528619A0 (en) | 1984-08-16 |
| FI834872A (en) | 1984-07-04 |
| KR840007225A (en) | 1984-12-06 |
| EP0114374B1 (en) | 1986-07-23 |
| FI76331C (en) | 1988-10-10 |
| PT77898B (en) | 1986-04-11 |
| PT77898A (en) | 1984-01-01 |
| JPS59176275A (en) | 1984-10-05 |
| AU2278283A (en) | 1984-07-05 |
| ES8406881A1 (en) | 1984-08-16 |
| GR79463B (en) | 1984-10-30 |
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