CA1170258A - 5-substituted 9-cyanomethylene-dithieno [3,4-b:4',3'-e]-azepines, their preparation and therapeutic agents which contain these compounds - Google Patents
5-substituted 9-cyanomethylene-dithieno [3,4-b:4',3'-e]-azepines, their preparation and therapeutic agents which contain these compoundsInfo
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- CA1170258A CA1170258A CA000387495A CA387495A CA1170258A CA 1170258 A CA1170258 A CA 1170258A CA 000387495 A CA000387495 A CA 000387495A CA 387495 A CA387495 A CA 387495A CA 1170258 A CA1170258 A CA 1170258A
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- cyanomethylene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
Abstract of the disclosure: 5-substituted 9-cyanomethyl-ene-dithieno[3,4-b:4',3'-e]-azepines, processes for thelr preparation, and therapeutic agents which contain these compounds and can be used as sedatives, hypnotlc drugs, tranquilizers, neuroleptic drugs or anti-Parkinson drugs.
Description
~ 17025~
The present invention relates to 5-substituted 9--cyanomethylene-dithieno[3,4-b:4',3'-e~-azepines, processes for their preparation, and therapeutic agents which contain these compounds and can be used as sedatives, hypnotics, tranquillizers, neuroleptics or anti-Parkinson drugs.
It is known that tricyclic ring systems having a dibenzo structure on a central heterocyclic 7-membered rlng, which may con~ain ~ bagic ~iclo radlc~ or cx~lmI~lo N-methylpiperazinyl, can display neuroleptic effects.
Such tricyclic ring systems are, for example, N-methyl-piperazinyl derivatives of dibenzoLb,e~[l,~-diazepines ~clozapine?, dibenzo~b,f~ rl,4~-thiazepines (clotiapine), dibenzo[b,f~ ~1,4~-oxazepines (loxapine) and morphanthri-dines (perlapine), as mentioned, for example, in the review by J~ Schmutz in Arzneim.-Forsch. 25 (l975?, 712-720.
German Laid Open Patent Application 2,918,778 proposes 6-substituted ll-alkylene-morphanthridines having valuable pharmacological properties. The present applica-tion relates to dithienoC3,4-b 4',3'-e~ derivatives, which have a different pharmacological action profile. --~ e have found that 5-substituted 9-cyanomethylene-dithieno[3,4-b:~',3'-e]-az_pines of the qeneral ~ormula I
~, , .
~ ~7~25~
The present invention relates to 5-substituted 9--cyanomethylene-dithieno[3,4-b:4',3'-e~-azepines, processes for their preparation, and therapeutic agents which contain these compounds and can be used as sedatives, hypnotics, tranquillizers, neuroleptics or anti-Parkinson drugs.
It is known that tricyclic ring systems having a dibenzo structure on a central heterocyclic 7-membered rlng, which may con~ain ~ bagic ~iclo radlc~ or cx~lmI~lo N-methylpiperazinyl, can display neuroleptic effects.
Such tricyclic ring systems are, for example, N-methyl-piperazinyl derivatives of dibenzoLb,e~[l,~-diazepines ~clozapine?, dibenzo~b,f~ rl,4~-thiazepines (clotiapine), dibenzo[b,f~ ~1,4~-oxazepines (loxapine) and morphanthri-dines (perlapine), as mentioned, for example, in the review by J~ Schmutz in Arzneim.-Forsch. 25 (l975?, 712-720.
German Laid Open Patent Application 2,918,778 proposes 6-substituted ll-alkylene-morphanthridines having valuable pharmacological properties. The present applica-tion relates to dithienoC3,4-b 4',3'-e~ derivatives, which have a different pharmacological action profile. --~ e have found that 5-substituted 9-cyanomethylene-dithieno[3,4-b:~',3'-e]-az_pines of the qeneral ~ormula I
~, , .
~ ~7~25~
- 2 - O.Z. OOS0/03a704 R ~ l C
where Rl and R2 are hydrogen or halogen, especially chlor-ine, and A is -NR3R4, where R3 and R4, together with the nitrogen atom linking them, are a S-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, an additional nitrogen present being ` unsubstituted or substituted by alkyl of l to 3 carbon ' ~ atoms, hydroxyalkyl of 2 o~. 3 carbon atoms, alkoxyalkyl, : ~ where alk~l and alkoxy are of l to 3 carbon atoms, cyclo- -:~ ~ alkyl or cycloalkylmethyl, w~ere cycloaikyl is o~ 3to 7 carbon : -10 ~ atoms or:a~vnyl of 2 to 5 carbon atoms, and may additionally ~e sub-stituted by oxygen~in the form of an N oxlde,;or A ls~-NHR5, where R5~1s ~ -anuxY~kyl~of 2 to 7 oarbon;atoms,:the~amlne~nltrogen belng:
unsubstituted or substltuted by~lower~alkyl~of~ l;to~S car-bon atoms:or being a constituent:o~ a ~5-membered to 7-membered~s:aturated~ring, which may:contain nltrogen or~: ~
oxygen~ as~a further hetero-atom, a nltrogen~present~bèlng~ ~:
substltuted~by;lower alkyl~;of l~to~3;;oarbon~stoms~or-hydroxy-alkyl of 2 or 3 carbon atoms,~and thel~r physiologlcally tolerated acid additlon~;salts~have val~uable pharmacologlcal 20 ~ propertieS.~
: The radicals Rl:and R~are, in:~par~icular, hydro-gen and chlorine, and in e~specially~ preferred compounds Rl is hydrogen and R2 is hydrogen or ohlorïne.
Examples~of -NR3R4 radicals A~are plperazinyl, :: :
:: i `~ ~
.
~17025~
where Rl and R2 are hydrogen or halogen, especially chlor-ine, and A is -NR3R4, where R3 and R4, together with the nitrogen atom linking them, are a S-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, an additional nitrogen present being ` unsubstituted or substituted by alkyl of l to 3 carbon ' ~ atoms, hydroxyalkyl of 2 o~. 3 carbon atoms, alkoxyalkyl, : ~ where alk~l and alkoxy are of l to 3 carbon atoms, cyclo- -:~ ~ alkyl or cycloalkylmethyl, w~ere cycloaikyl is o~ 3to 7 carbon : -10 ~ atoms or:a~vnyl of 2 to 5 carbon atoms, and may additionally ~e sub-stituted by oxygen~in the form of an N oxlde,;or A ls~-NHR5, where R5~1s ~ -anuxY~kyl~of 2 to 7 oarbon;atoms,:the~amlne~nltrogen belng:
unsubstituted or substltuted by~lower~alkyl~of~ l;to~S car-bon atoms:or being a constituent:o~ a ~5-membered to 7-membered~s:aturated~ring, which may:contain nltrogen or~: ~
oxygen~ as~a further hetero-atom, a nltrogen~present~bèlng~ ~:
substltuted~by;lower alkyl~;of l~to~3;;oarbon~stoms~or-hydroxy-alkyl of 2 or 3 carbon atoms,~and thel~r physiologlcally tolerated acid additlon~;salts~have val~uable pharmacologlcal 20 ~ propertieS.~
: The radicals Rl:and R~are, in:~par~icular, hydro-gen and chlorine, and in e~specially~ preferred compounds Rl is hydrogen and R2 is hydrogen or ohlorïne.
Examples~of -NR3R4 radicals A~are plperazinyl, :: :
:: i `~ ~
.
~17025~
- 3 - O.Z. ooso/o3a7oa homopiperazinyl, piperidinyl and morpholinyl radicals.
Particularly preferred -NR3R4 radicals are the 4-methylpiperazinyl, 4-methyl-4-oxy-piperazinyl, 4-ethyl-piperazinyl and N-methyl-homopiperazinyl radical.
In -NHR5, R5 is preferably the 2-dimethylamino-ethyl or 2-piperidin-1-yl-ethyl radical.
It is to be noted that the compounds according to the invention of the formula I exist ~as the cis/trans isomers Ia and b A A
RZ ~ ~1 2 NC H H CN
Ia Ib If desired, the cis/trans isomers can be separa-ted, for example by fractional crystall~ization or by column chromatography.
On the basis of the above definitions, examples of compounds;~which are particularly~preferred~and effective are as follows: cis/trans-9-cyanomethylene-5-(4-methyl-pipera-zin-l-yl)-dithienot3,4-b:4',3'-e~azeplne, cis-9-cyanomethy-lene-5-(4-methyl-piperazin-1-yl)-dithieno~3,4-b:4',3'-e]-azepine, trans-9-cyanomethylene-5-(4-methyl-piperazin-l~yl)-dithieno~3,4-b:4',3'-e~azepine,~cis/trans-9-pyanomethylene-5-(4-methyl-4-oxy-piperazin-1-yl;)-dithieno~3,4-b:4',3' e~-azepine, cis/trans-9-cyanomethylene-5-(4-ethyl-piperazin-l-yl)-dithieno~3,4-b:4',3'-e~azepine, cis/trans-9-cyano-methylene-5-(N'-uethyl-homopiperazin-l-yl)-dithieno-.
~ 1702~8
Particularly preferred -NR3R4 radicals are the 4-methylpiperazinyl, 4-methyl-4-oxy-piperazinyl, 4-ethyl-piperazinyl and N-methyl-homopiperazinyl radical.
In -NHR5, R5 is preferably the 2-dimethylamino-ethyl or 2-piperidin-1-yl-ethyl radical.
It is to be noted that the compounds according to the invention of the formula I exist ~as the cis/trans isomers Ia and b A A
RZ ~ ~1 2 NC H H CN
Ia Ib If desired, the cis/trans isomers can be separa-ted, for example by fractional crystall~ization or by column chromatography.
On the basis of the above definitions, examples of compounds;~which are particularly~preferred~and effective are as follows: cis/trans-9-cyanomethylene-5-(4-methyl-pipera-zin-l-yl)-dithienot3,4-b:4',3'-e~azeplne, cis-9-cyanomethy-lene-5-(4-methyl-piperazin-1-yl)-dithieno~3,4-b:4',3'-e]-azepine, trans-9-cyanomethylene-5-(4-methyl-piperazin-l~yl)-dithieno~3,4-b:4',3'-e~azepine,~cis/trans-9-pyanomethylene-5-(4-methyl-4-oxy-piperazin-1-yl;)-dithieno~3,4-b:4',3' e~-azepine, cis/trans-9-cyanomethylene-5-(4-ethyl-piperazin-l-yl)-dithieno~3,4-b:4',3'-e~azepine, cis/trans-9-cyano-methylene-5-(N'-uethyl-homopiperazin-l-yl)-dithieno-.
~ 1702~8
- 4 - o.Z. 0050/03470 C3,4-b:4',3'-e~azepine, cis/trans-3-chloro-9-cyanomethy-lene-5-(4-methyl-piperazin-1-yl)-dithieno~3,4-b:4',3'-e~-azepine and cis/trans-9-cyanomethylene-5-(piperazin-1-yl)-dithieno~3,4-b:4',3'-e]azepine.
As the Examples show, separation into the cis-and trans-isomers can be carried out in an individual case ~ithout excessive expense.
The compounds according to the invention of the formula I are prepared by a process wherein a compound of the formula II
~ ~N ~
R ~ 1 II
C
where R1 and R2 have the meanings and preferred meanings given in the case of formula I and Z is a nucleofugic leaving group,~ is reacted~with a nucleophile AH, where A
has the meanings given in;the case of formula I, and the product lS separateù, if desired, into the pure cis- and trans-isomers, and/or~the resulting~compound is converted, if desired, into the N-oxide and/or into the acid addition salt o~ a physlologically tolerated~acid~
Nucleofugic ~1eaving groups~Z are halogen, in parti-20~ cular bromine and chlorine. ~
The reaction is advantageously~oarried out in the presence of an excess of the amine or alcohol AH used, ~ which simultaneously serves as the solvent and, if appro ; priate, as an acld acceptor. Where relevant, an inert solvent can be used, such as a cyclic saturated ether, in .
~17V2~8 _ 5 _ o.~. OoSo/03470 particular tetrahydrofuran or dioxane, benzene or a ben-zene hydrocarbon, such as toluene, xylene, mesitylene or decahydronaphthalene, or an aprotic polar solvent, such as dimethylformamide. The reaction is as a rule carried out at from 80 to 150C, preferably from 90 to 120C, and generally has ended within from 3 to 10 hours. It may be advantageous to exclude atmospheric oxygen and to work under an inert gas, for example under nitrogen.
The nucleophile AH is advantageously used in from 2-fold to20-fold or more molar excess.
A compound of the formula I is converted into the N-oxide in a conventional manner, advantageously using aqueous hydrogen peroxide (30 % strength by weight) in ethanolic solution. Conversion to the acid addition salt of a physiologically tolerated acid is likewise effec-.
ted in a conventional manner.
The starting compounds of the formula~II areobtained by a process~wherein~ a 9-cyanomethylene-dithi-eno[3,4-b:4',3'-e]-4,5-dihydro-azepin-S-one of the formula H
III
where Rl and R2 have the meanings glven in the case of formula II, and an excess o-f a halogenating agent, in par-ticular phosphorus oxychloride or phosphor~s tribromide, are refluxed or heated at not more than 120C, ~or 3 -117~5~
.
- 6 - O.Z. oO50/03470a
As the Examples show, separation into the cis-and trans-isomers can be carried out in an individual case ~ithout excessive expense.
The compounds according to the invention of the formula I are prepared by a process wherein a compound of the formula II
~ ~N ~
R ~ 1 II
C
where R1 and R2 have the meanings and preferred meanings given in the case of formula I and Z is a nucleofugic leaving group,~ is reacted~with a nucleophile AH, where A
has the meanings given in;the case of formula I, and the product lS separateù, if desired, into the pure cis- and trans-isomers, and/or~the resulting~compound is converted, if desired, into the N-oxide and/or into the acid addition salt o~ a physlologically tolerated~acid~
Nucleofugic ~1eaving groups~Z are halogen, in parti-20~ cular bromine and chlorine. ~
The reaction is advantageously~oarried out in the presence of an excess of the amine or alcohol AH used, ~ which simultaneously serves as the solvent and, if appro ; priate, as an acld acceptor. Where relevant, an inert solvent can be used, such as a cyclic saturated ether, in .
~17V2~8 _ 5 _ o.~. OoSo/03470 particular tetrahydrofuran or dioxane, benzene or a ben-zene hydrocarbon, such as toluene, xylene, mesitylene or decahydronaphthalene, or an aprotic polar solvent, such as dimethylformamide. The reaction is as a rule carried out at from 80 to 150C, preferably from 90 to 120C, and generally has ended within from 3 to 10 hours. It may be advantageous to exclude atmospheric oxygen and to work under an inert gas, for example under nitrogen.
The nucleophile AH is advantageously used in from 2-fold to20-fold or more molar excess.
A compound of the formula I is converted into the N-oxide in a conventional manner, advantageously using aqueous hydrogen peroxide (30 % strength by weight) in ethanolic solution. Conversion to the acid addition salt of a physiologically tolerated acid is likewise effec-.
ted in a conventional manner.
The starting compounds of the formula~II areobtained by a process~wherein~ a 9-cyanomethylene-dithi-eno[3,4-b:4',3'-e]-4,5-dihydro-azepin-S-one of the formula H
III
where Rl and R2 have the meanings glven in the case of formula II, and an excess o-f a halogenating agent, in par-ticular phosphorus oxychloride or phosphor~s tribromide, are refluxed or heated at not more than 120C, ~or 3 -117~5~
.
- 6 - O.Z. oO50/03470a
5 hours in a conventional manner, in the presence or absence of a solvent and in the presence or absence of a ca.talytic amount of N,N-dimethylaniline, and, after the excess phosphorus halide has been distilled off and the mixture has been worked up in an aqueous two-phase system, the resulting imino-chloride or -bromide is isolated by extraction with a chlorohydrocarbon, such as chloroform or methylene chloride.
The novel 9-cyanomethylene-dithienor3,4-b:4',3'-e~-4,5-dihydro-azepin-5-onesof the formula II~ where Rl and R2 have the meanings given in the case of formula I~are prepared by carbonyl-olefination, by reactlng a dithieno-r3 ~ 4-b:4',3'-e~-4,5-dihydro-azeplne-5,9-dione of the for-mula lV
H //
S IV
with a phosphonate of~the formula:Va R0~: 0 CHxy~ Va:
: ~ R0 where R is;alkyl Or 1 to 3 carbon atoms and.~X and:Y have the meanings given in the~case of formula II,: under the conditions of the Wittig-Horner reaction, in an inert sol-~:
vent, preferably dim~thylformamide, and~in the presence : 20 : 0~ one molar equivalent of a base, preferably a sodium alcoholate or sodium hydrlde or sodium amide, at from 20 : to 80C, or with a phosphonium salt of the formula Vb ~1702~
_ 7 _ O.Z. 0050/034704 ,+ Cl Vb Ph-P -CHXY
. Ph where Ph is phenyl and X and Y have the meanlngs given in the case of formula Va, under the conditions of the classi-cal Wittig reaction, in an aprotic organic solvent, in particular a saturated aliphatlc or saturated cyclic ether, such as diethyl ether, tetrahydrofuran or dioxane, or, pre-ferably, in dimethylformamide, and in the presence of one molar equivalent of a base, ln particular an alkali metal alcoholate, preferably sodium methylate or ethylatej or sodium hydride, sodi.um amide or an organometallic compound, : 10 such as butyl-lithium, at Prom 20 to 100C.
If~requ~red, ~the praduct is-then~converted into a compound:of~the formula III where Rl~and/or~R2 are chloriné
or bromine~by halogenation with the~equivalent~amount of chlorine~or bromine:in an inert:organic~solvent, preferably~
a~halohydrocarbon, such as ~carbon:tetrachlorlde~, chloro-~form or~methylene chloride,~at room temperature.
However, as descrlbed~ln~the~Examples,~th}s halo- ~ ~
genation~ can a~a~ntageously~be carri~ed out, in:the:same: ~ -manner,~ at~ the final stage~, ie. on~a compound of the ~ ~ormula I.
The novel~ dithienoC3,4-b 4',3' e~4,5-dihydro-aze-pine-5,9-diones~of:the formula IV where Rl and R2 ha~e the - Meanings:given in the case of:formula:I are prepared by , :~ Schmidt ring enlargementof the 4,8-dihydro-benzo-:
: ~ [1,2-c~:4,5-c'~-dithiophene-4,8-dione of the formula VI
~7~258 - 8 - O.Z. 0050/034704 ~ ~ ~ VI
S~ ~ 3 O
This reaction is carried out in a conventional manner, by taking up the 4,8-dihydro-benzo-~l,2-c:4,5-c'~dithiophene-4,8-dione in a mixture of a chlorohydrocarbon, preferably methylene chlorlde, and con-centrated sulfuric acid (volume ratio from l : 2 to l : l) and introducing l moIar equivalent of sodium azide a little at a time at from O to 30C, with thorough stir-~ :
ring.
The halo-derivatives of the dithieno~3,4-b:4',3'-e~-4,5-d1hydro-azep1ne-S,9-d10ne of the formula IV can~be pre-; pared by direct halogenation ln an;organic so1ventr pre-ferab1y a;halohydrooarbon,~at from~O to~80C.
The starting material:4,a-dihydro-benzo- ~
2-o:4Js-oll~-dlthlophene-4~8-dione~o*~the~::rormula~vI nas been~disclosed~in the literature~D.W~.H. Ma~owel~l and J.C.~Wisowaty, J.~Org. Chem~ 37 ~(1972~)~17~12)~
In~addition~to the compound~s~mentioned i~ the~
Examples, the~fo;llowing~compounds~may also~be men-tioned:;ci 9/ trans-9-cyanomethylene~-5-(4-cyclopropyl-piper-~
azin-l-yl)-dith1eno[3,4-b 4i,3'~-e~azepine,~ols/trans-9-;; cyanomethylene-5-(4-cy:clopropylmethyl-piperazln-1-y1)-di-thienor3,4-b:4'`,3~ azep1ne, ols~/~trans-9-oyanomethyl-5-(4-propin-2-yl-piperaz~in-l-yl)~-dithienoC3~,4-b 4',3'-e~- ~
azepine and c~is/trans-3-bromo-9-oyanomethylene-5-(4-methyl-~ p~lperaz1n-l-yl)-dlthieno~3,4-b:4',~3'-e3;azepine.
: , 11~025~
_ g _ o,z, ooSo/03~70 The compounds of the formula I according to the invention are as a rule obtained in the form of yellowish or yellow crystals and can be purified by recrystalliza-tion from the usual organic solvents, preferably from a lower alcohol, such as ethanol, or by column chr~mato-graphy.
If required, the compounds are separated into the individual cis- and trans-isomers by fractional crystal-lization in a chlorohydrocarbon, preferably methylene chloride, a lower monohydric alcohol, preferably methanol or ethanol, or a-saturated cycloaliphatic hydrocarbon, preferably cyclohexane, or by column chromatography, in particular in methylene chloride and methanol in a volume ratio from 99 : 1 to 85 : 15.
The free 5-substituted 9-cyanomethylene-dithieno-C3,4-b:4',3'-e~azepines of the formula I can be converted to addition salts of pharmacologically tolerated acids in a conventional manner, preferably by adding one equivalent of the appropriate acid~to a solution of the compound.
~xamples of pharmaceutically tolerated acids are hydro-chloric acid, maleic acid and methanesulfonic~acid.
The compounds according to the~invention exhibit valuable pharmacological properties. They can be used as sedatives, hypnotics, tranquillizers, neuroleptics ;~
or anti-Parklnson drugs. ~ A compound according to the invention may possess a combinabion of several of the actions mentioned. In some cases, an individual pure isomer obtained by separation of isomers may preferentially display an action.
t 17~2~8 - 10 - O.Z. 0050/0347C
From the results of the pharmacological experi-ments carried out, the substances according to the invention are useful as sedatives/hypnotics, minor or major tranquillizers and anti-Parkinson drugs ~y virtue of their sedative/tranquillizing, muscle-relaxing and anti-monaminergic action and their anticholinergic action on the central nervous system.
The following methods were used to analyze-their action: ---1. Sedative action 4 - 8 groups each of 3 female NMRI mice are given the compound orally. The orientation hypermotility ` induced by a new environment is determined photoelectric-ally, for a period of 30 minutes, starting 30 minutes after administration of the substances.
, The ED5C% is the dose which produces a 50 % reduc-tion in orientation hypermotility compared to placebo-treated control animals.
2. Muscle-relaxing action : : ~
The measurement~ls based on~quantlflcation of the tonic extension reflex in the gastrocnemius in rabbits (Teschendorf et al., Arch. Pharmacol. exp. Path. 266 ; ~ ~1970)1462). The rabbit is kept ln~a special appara-tus which allows it to flex its paw at the talocalcanean .
Joint in a defined and reproduclble manner. The flex-ing triggers off a tonic extension reflex in the calf muscles. ~ The electrical activity of the muscle dur-ing the contraction is recorded, and the individual pul ses are counted. The extension (lasting 5 seconds) is 2~8 , - 11 - O.Z. 0050/03470 repeated at intervals of one minute. When a constant number of pulses(control value) has been reached, the test substance is administered intravenously. The numbers of pulses following the administration are compared with the initial values.
3. Antimethamphetamine action Methamphetamine . HCl (2.5 mg/kg administered intravenously) regularly causes the following symptoms in rats: motor restlessness, searching and sniffing movements, fur standing on end, and tremor (Janssen et al., Aræneim.-Forsch.tDrug Res. 13 (1963), 205; and Randrup et al., Psychopharmacologia 11 (1967), 300). The test substance~
are administered intraperitoneally 30 minutes before meth-amphetamine. The substance is considered to have an effect if no sniffing movements are observed for a period : - --of 5 minutes after the injection of methamphetamine. The -mean inhibition dose (ED50%) is determined, by means of ` probit analysis, as the~dose which prevents the occur-rence-of the symptom in half the animals.
4. Antlc~holinergic action on the~central nervous system :
To test the anticholinergic action on the central nervous system, cholinerglc stimulation is triggered off by pilocarplne. After rapid~intravenous injection of -~
pilocarpine.HCl (50 m~kg)~rats display alternati~g scratching mov~ments of thelr rearpaws; further symptoms triggered of~in ~he central nervous system are jaw movements and tremors.Flow of saliva and chromodacryorrhea may be observed as signs of peripheral superexcitation (Kreiskott, Arch. exp. Path.
Pharma~. 247 (1964), 317). The test substances are ~702~ -- 12 - o.z. oO50/03 70~
administered intraperitoneally 30 minutes before pilocar-pine. The substance is considered to have an effect if no scratching is observed for a period of 2 minutes after the injection of pilocarpine. For this symptom, the mean inhibition dose (ED50%) is determined, by means of probit analysis by the method of Finney, as the dose of the test substance which suppresses the scratching in half the animals.
In these experiments (cf. Table 1), the compounds according to the invention were shown to have significant sedative/hypnotic effects which were about as powerful as those of the reference substance clozapine. They have a muscle-relaxing action which is somewhat weaker than that of clozapine, but as powerful as that of perlapine.
The antimonaminergic action (methamphetamine anta-gonism) may be evaluated as a parameter of the neuroleptic quality of a drug. The compounds according to the inven-tion are as powerful as or significantly (up to 7 times) more pcwer~ul ~ than the comparative compounds clozapine and perlapine.
The compounds also have an interesting anticholi-nergic action on the central nervous system, whlch in some cases is significantly more powerful than that~of the reference substances. This type of action suggests that the novel substances can be used as anti-Parkinson drugs. On the other hand, because of this anticholinergic action on the central nervous system, no extra-pyramidal motor dis-turbances are to be expected when the compounds are used as neuroleptics; such a connection is assumed for ~~~
1 1 7~56 -- 13 -- 0,Z. 0050/03k704 clozapine and should have a particularly advantageous effect in the case of the compounds according to the invention.
.
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- 14 - O.Z. 0050/0347G4 .
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- 15 - O.Z. 0050/03~70 Accordingly, the present invention also relates to a therapeutic agent which in addition to conventional carriers and diluents contains a compound of the formula I, or a pha~macogically tolerated acid addition salt thereof, as the active compound.
The therapeutic agents are prepared in a conven-~ional manner by compounding an appropriate dose with the conventional carriers or diluents and the conventional industrial auxiliaries, in accordance with the desired --route of administration. Suitable doses for man are from 10 to 100 mg.
The novel compounds may be employed in the conven-tional solid or liquid pharmaceutical forms, such as tab-lets, capsules, powders, granules, dragees or solutions.
These are prepared in a conventional manner, and to do so the active compounds can be mixed with the conventional pharmaceutical auxiliaries, such as talc, gum arabic, suc-rose, lactose, cereal starch or corn starch, potato flour, magnesium stearate, alginates, gum tragacanth~ carraghen-ates, polyvinyl alcohol, polyvinylpyrrol~idone,~aqueous ornon-aqueous carriers, wetting agentsj dispersants, emulsi-fiers and/or preservatives (cf. L.G. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics). The formu-lations thus obtained normally contain from 0.001 to 99%
by weight of the active compound.
The preferred formulations are those suitable for oral administration. Examples of these are tablets, film tablets, dragees, capsules, pills, powders, solutions, suspensions and depot forms. Parenteral formulations, - - \
~ 1702~
.
- 16 - O.Z~ 0050/03~70a such as injection solutions, may also be used. Supposi-tories are a further example of suitable formulations.
Appropriate tablets may be obtained, for example, by mixing the active compound with conventional auxili-aries, for example inert diluen-ts, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbon-ate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of a plurality of layers.
Correspondlngly, dragees can be prepared by coat-ing cores, prepared similarly to the tablets, with agents conventionally used in dragee coatings, for example colli-done or shellac, gum arabic, talc, titanium dioxide or ; sugar. The dragee coating~can also~consist of~ a plura-lity of layers, and the auxiliaries mentioned above in :
connection with tablets may be used therein.
Solut~ions or suspensions containing the active com-pounds according to the invention~may additionally contain :
flavor improvers, such as vanillin or orange extract.
They may also contain suspending agents, such as sodium carboxymethylcellulose,~or preservatives, such as p-hydroxy-benzoates. ~ Capsules containing the active compounds may be prepared, for examp~le, by mlxing the active compound with an inert carrier, such as lactose or sorbitol, and encapsulating the mixture in gelatin capsules. Suitable ~02S~
- 17 - O.Z. oo5o/o347Ga suppositories can be prepared, for example, by mixing the active compounds with appropriate carriers, such as neut-ral ~ats or polyethylene glycol or their derivatives.
The Examples which follow illustrate the present invention:
Cis- and trans-9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithieno r3 ~ 4-bO4',3'-e~azepine a) 140 ml of phosphorus oxychloride and 1.5 ml of N,N-dimethylaniline are added to 14.0 g (54 mmoles)of 9-cyanomethylene-4,5-dihydro-dithienoC3,4-b 4',3'-e~azepin-5-one (cis/trans-isomer mixture) and the mixture is re-fluxed under nitrogen for 1 hour. After all the excess phosphorus oxychloride and dimethylanilinehave been dis-tilled off under reduced pressure from an oil pump, the residue is partitioned between methylene chloride and water, the aqueous phase is extracted twic~e more wlth methylene chloride and the combined organic phases are washed thoroughly with dilute HCl and water. Drying ~; and concentrating the organio phase gives 14.4 g (96 %) of 5-chloro-9-cyanomethylene-dithieno[3,4-b:4',3'-e]azepine, which is~sufficiently pure for the further reaction.
50 ml of~M-methyl-piperazine aré added to 14.4 a .
(52 mmoles) o~ 5-chloro-9-cyanomethylene-dithieno-[3,4-b:4',3'-e]azepine and the mlxture is stlrred under nitrogen at 110C for 2 to 3 hours. Afterhaving been cooled, the dark homogeneous reaction mixture is poured onto ice-water and the yellowish crude 9~yancmethylene-5-(4-methyl-piperazin-l-yl)-dithienoC3,4-b 4',3'-e~azepine is ~170~58 - 18 - O.Z. 0050/03~70 filtered off with suction. After the crude product has been dried in an oven under reduced pressure, it is recrystal-lized from ethanol, with the addition of active charcoal, or purified by column chromatography (silica gel, mobile phase: a 95/5 mixture of methylene chloride and methanoi). 13.6 g (85 %) of yellowish 9-cyanomethy-lene-5-(4-methyl-piperazin-1-yl)-dithieno¦3,4-b:4',3~-el-azepine are obtained in the form of a cisttrans-isomer mix-ture of melting point 148-151C.
b) To separate the cis/trans-isomers, the isomer mix-ture is subjected to fractional crystallization from etha-nol. 6.5 g of yellow crystals which, according to the thin layer chromatogram (silica gel, mobile phase: an 85/
15 mixture of toluene and methanol), chiefly consist of the non-polar cis-isomer a are isolated as the first fraction.
After the filtrate has been concentrated, the resi-due is digested in about 80 ml of boiling cyclohexane and the insoluble constituents are filtered off with suction, under the influence of heat.~ After havlng washed the prod-uct with a little cyclohexane, 20 1 g of yellow crystals, which, according to the thin layer chromatogram ~silica gel, mobile phase: an 85/15 mixture of toluene and metha-nol) chiefly consist of the polar trans-isomer b, are obtained.
Subsequent crystallization of the enriched products from ethanol and cyclohexanone gives the cis- and trans-isomers in virtually pure forms. Melting point: cis-isomer: 200-201C, trans-isomer: 197-198C.
1 1702~
- 19 - o.z. 0050/03g70~z CH3 ,CH3 ~N) ~N ) ~5 ~S
CN N
Cls trans Cis/trans-3-chloro-9-cyanomethylene-5-(4-methylpiperazin-l-yl)-dithieno[3,4-b:4',3'-e~azepine 4.8 g (14 mmoles) of 9-cyanomethylene-5-(4-me-thyl-piperazin-l-yl)-dithieno~3,4-b:4'j3'-elazepine (cis/trans-isomer mi`xture) are dissolved in 160 ml of methylene chlor-ide. 1.0 g (14 mmoles) of chlorine is then slowly passsd in with thorough stirring (a finely crysta111ne ~ '' solid precip1tatss). Ths mixturs 1S stirred~for a~furthsr 2 hours at room temperature and is then poured onto ice-10~ ~ water.~ After ~the m1xture has bsen~rendsred~baslc~with sodium hydroxlde~solution,~ths;organic phase~is~s~eparated off,~the aqus~ous~phass~is sxtractsd sevsral~tlmes~with msthy1sne~chloride and~the~combinsd organ1c~phasss are drlsd in a conventional~manner. ~ ~Ths cruds~product~
'obtained~on concentratlng the organic~phase is dis501ved ~
in a little bo1ling ethanol, active charcoal is added, the mixture is filtered hot and~the solut1on is concentrated to a small volume. 45 % of cis/trans-3-chloro-9-cyano-methy1sne-5-~4-methyI-pipsrazin-l-y'lj-d}thieno~3,4-b:4',3'-e]-~ azepine having a melting point of 208-211C crystallize in ; ~ , .
.. '' " , : .
1 ~70258 - 20 - O.Z. 0050/034704 the cold.
Cis/trans-9-cyanomethylene-4,5-dihydro-dithieno-¦354-b:4',3'-e~azepin-5-one The intermediate 9-cyanomethylene-4,5-dihydro-di-thieno~3,4-b:4',3'-e~azepin-5-one is prepared by carbonyl-olefination of 4,5-dihydro-dithienor3,4-b:4',3'-e~azepine-5,9-dione by the Wittig-Horner reaction or by the classi-cal Wittig synthesis:
26.4 g (112 mmoles) of 4,5-dihydro-dithieno-r3,4-b:4',3'-e~azepine-5,9-dione are dissolved in 300 ml of dimethylformamide, under the influence of heat, and the solution is stirred under nitrogen. 24.8 g (140 mmoles) of diethyl cyanomethylphosphonate and 24.6 g (140 mmoles) of sodium ethylate (30 %) dissolved ln 30 ml of dimethyl-formamide are then simultaneously a,nd slowlyadded dropwise (an intensification of color and increase in temperature indicate the start of the Wittig reaction). After the mixture has been stirred at room temperature for 12 hours, the reaction product i5 poured onto ice-water and the solid which precipitates is filtered off~with suction.
After the crude product has been washed thoroughly with water, it is dried and recrystallized from ethan~l.
Yield: 26.5 g (92 %) of 9-cyanomethylene-4,5-dihydro-di-thienoL3,4-b:4',3'-e~azepin-5-one as colorless crystals having a melting point of 253C (decomposition).
Classical Wittig process: 1 molar equivalent of 30 %
strength sodium methylate solution is added dropwise, or 1 molar equivalent of sodium hydride is added, to tri-~ 17~2S~
- 21 - o.z. ooSo/03~70 phenyl-cyanomethyl-phosphonium chloride in dimethylform-amide and, finally, 1 molar equivalent of a solution of 4,5-dihydro-dithieno~3,4-b:4',3'-e~azepine-5,9-dione in dimethylformamide is added. The reaction mixture is then stirred`at 50 to 80C for 5 to 8 hours and is subse-quently poured onto ice-water and extracted several times ~ith methylene chloride. After the organic phase has been dried and concentrated, the crude product is recrys-tallized from ethanol. Yield: 61 % of colorless crys-tals having a decomposition point of 251-253C.
4,5-Dihydro-dithieno r3 ~ 4-b:4',3'-e]azepine-5,9-dione The intermediate 4,5-dihydro-dithieno-[3,4-b:4~,3~-eJazepine-5-dione is prepared by Schmidt ring extension:
30.4 g (138 mmoles) of 4,8-dihydro-benzo-[1,2-c:4,5-c'~dithiophene-4,8-dione are suspended in 200 ml of methylene chloride; 280 ml of concentrated sulfuric acid are then added dropwise, with ice-cooling and stir-ring. A total of 13.0 g (200 mmoles~) of scdium azlde is then introduced a little at a time into the well stirred reaction mixture at 0C over a period of 2 hours. The mixture is then stirred at room temperature for 8 to 10 hours. The reaction mlxture is poured carefully into 3 1 of ice-water, with thorough stirring, and the solid which precipitates after a short time is filtered off with suction. The crude product is washed with a large amount of water until it gives a neutral reaction, and is dried at 50C under reduced pressure.
/
.
~ 17~2~8 - 22 - O.Z. 0o5o/o3a7oa 28.0 g (86 %) of a light solid which has a melting point of 267-270C and is sufficiently pure for the fur-ther reaction are isolated.
Cis/trans-9-cyanomethylene-5-(4-methyl-4-oxy-piperazin-l-yl)-dithieno[3,4-b:4',3'-e~azepine.2H20 3.5 g (11 mmoles) of cis/trans-9-cyanomethylene-5-~4-methyl-piperazin-1-yl)-dithieno[3,4-b:4',3'-e~azepine are dissolved in 100 ml of hot ethanol, and 1.5 ml of 30%
strength hydrogen peroxide are added. After the mixture has been refluxed for 5 hours, the excess hydrogen perox-ide is decomposed by introducing a small platinum foil into the reaction mixture and refluxing the mixture for 2 hours. When the reaction mixture has been filtered, it is concentrated, and the resulting N-oxide is purified by column chromatography (silica gel,;mobile phase: a 95/5 mixture of methylene chloride and methanol).
1.8 g (50 %) of yellow crys-tals having a melting point of 137-140G are isolated EXAMPLE 6 ~ ~
Cis/~trans-9-cyanomethylene-5-(4-ethyl-piperazin-1-yl)-:
dithienoL3,4-b:4',3'-e~azeplne This compound is synthesized by a method similar to that in Example la, using N-ethylpiperazine. After column chromatography (sillca gel, mobile phase: a 95/5 mixture of methylene chloride andmethanol), ye~ow cry3tals havlng a meltlng point of 118-121C are obtained.
` 1170258 - 23 - O.Z. 0050/03~70 Cis/trans-9-cyanomethylene-5-(N'-methyl-homopiperazin-l-yl)-dithieno[3,4-b:4',3'-eJazepine.H20 This compound is synthesized by a method similar to that in Example la, using N-methyl-homopiperazine.
Purification by column chromatography (silica gel; a 95/5 mixture of methylene chloride and methanol) gives yellow crystals having a melting point of 124-126C.
Cis/trans-9-cyanomethylene-5-~2-(piperidin-1-yl)-ethyl-amino~-dithieno r3 ~ 4-b:4',3'-e~azepine.l/2H20 This compound is synthesized by a method similar to that in Example la, using 2-piperidin-1-yl-ethylamine. -~ .
Purification by column chromatography (silica gel; a 95/5 mixture of methylene chloride and methanol) gives y~ow crys- -tals having a melting point of 112-I14C.
Cis/trans-9-cyanomethylene-5-piperazin-1-yl-dlthieno-~3,4-b:4',3'-e~azepine .
This compound is synthesized by a~method slml}ar to that in Example la, using 5 molar equivalents of piper-azine and increasing the~aminolysis~temperature to 140C.
;~ 20 After the reaction melt has cooled, it is taken up in methylene chloride,~the organic phase is thoroughly washed three times with water and the crude product is purified by column chromatography (silica gel; a 95/5 mixture of methylene ch}oride and methanol) to give yellow crystals having a melting point of 94-96C.
Examples of pharmaceutical iormulations:
25~
- 24 - o.Z. 0050/034704 Examples of tablets 1. An active compound of ~ormula I 10 mg Lactose 200 mg Methylcellulose 15 mg Corn starch 50 mg Talc 11 mg ' Magnesium stearate . 4 mg 2. An active compound of formula I 20 mg Lactose -- . ~ 178 mg Avicel 80 mg Polywax 6000 20 mg Magnesium stearate 2 mg .
3. An active compound of formula I 50 mg Polyvinylpyrrolidone (mean molecular weight 25,000) 170 mg.
Polyethylene glycol (mean molecular weight 4,000): 14 mg Hydroxypropylmethylcellulose ~ 40 mg Talc ~ ~ 4 mg Magnesium stearate ~ 2 mg The active compound is moistened with a 10 %
stréngth aqueous solution of polyvinyIpyrrolidone and forced through a sieve of 1.0 mm~mesh slze, and the gran- :
ules are drled at 50C. They are then mixed wlth poly-ethylene glycol (mean molecular weight 4,000), hydroxy-propylmethylcellulose, talc and magnesium stearate, and the mixture is pr:ssed to glve tabIets weighing 280 mg.
7~2S~
- 25 -O.Z. 0oso/o3a7oa 4. Examples of dragees An active compound of formula I 60 mg Lactose 90 mg Corn starch 60 mg Polyvinylpyrrolidone 6 mg Magnesium stearate 1 mg The active substance, lactose and corn starch are mixed, moistened with an 8 % strength aqueous salution of the polyvinylpyrrolidone, and granulated by passing through a 1.5 mm sieve. The granules are dried at 50C and again forced through a 1.0 mm sieve. The material thus obtained is mixed with magnesium stearate and the mixture is pressed to form dragee cores. These are coated in a conventional manner with a sheIl conslsting essentially of sugar and talc.
5 Capsule formulation An active compound of formula I 5 mg Magnesium stearate 2.0 mg Lactose 19.3~mg
The novel 9-cyanomethylene-dithienor3,4-b:4',3'-e~-4,5-dihydro-azepin-5-onesof the formula II~ where Rl and R2 have the meanings given in the case of formula I~are prepared by carbonyl-olefination, by reactlng a dithieno-r3 ~ 4-b:4',3'-e~-4,5-dihydro-azeplne-5,9-dione of the for-mula lV
H //
S IV
with a phosphonate of~the formula:Va R0~: 0 CHxy~ Va:
: ~ R0 where R is;alkyl Or 1 to 3 carbon atoms and.~X and:Y have the meanings given in the~case of formula II,: under the conditions of the Wittig-Horner reaction, in an inert sol-~:
vent, preferably dim~thylformamide, and~in the presence : 20 : 0~ one molar equivalent of a base, preferably a sodium alcoholate or sodium hydrlde or sodium amide, at from 20 : to 80C, or with a phosphonium salt of the formula Vb ~1702~
_ 7 _ O.Z. 0050/034704 ,+ Cl Vb Ph-P -CHXY
. Ph where Ph is phenyl and X and Y have the meanlngs given in the case of formula Va, under the conditions of the classi-cal Wittig reaction, in an aprotic organic solvent, in particular a saturated aliphatlc or saturated cyclic ether, such as diethyl ether, tetrahydrofuran or dioxane, or, pre-ferably, in dimethylformamide, and in the presence of one molar equivalent of a base, ln particular an alkali metal alcoholate, preferably sodium methylate or ethylatej or sodium hydride, sodi.um amide or an organometallic compound, : 10 such as butyl-lithium, at Prom 20 to 100C.
If~requ~red, ~the praduct is-then~converted into a compound:of~the formula III where Rl~and/or~R2 are chloriné
or bromine~by halogenation with the~equivalent~amount of chlorine~or bromine:in an inert:organic~solvent, preferably~
a~halohydrocarbon, such as ~carbon:tetrachlorlde~, chloro-~form or~methylene chloride,~at room temperature.
However, as descrlbed~ln~the~Examples,~th}s halo- ~ ~
genation~ can a~a~ntageously~be carri~ed out, in:the:same: ~ -manner,~ at~ the final stage~, ie. on~a compound of the ~ ~ormula I.
The novel~ dithienoC3,4-b 4',3' e~4,5-dihydro-aze-pine-5,9-diones~of:the formula IV where Rl and R2 ha~e the - Meanings:given in the case of:formula:I are prepared by , :~ Schmidt ring enlargementof the 4,8-dihydro-benzo-:
: ~ [1,2-c~:4,5-c'~-dithiophene-4,8-dione of the formula VI
~7~258 - 8 - O.Z. 0050/034704 ~ ~ ~ VI
S~ ~ 3 O
This reaction is carried out in a conventional manner, by taking up the 4,8-dihydro-benzo-~l,2-c:4,5-c'~dithiophene-4,8-dione in a mixture of a chlorohydrocarbon, preferably methylene chlorlde, and con-centrated sulfuric acid (volume ratio from l : 2 to l : l) and introducing l moIar equivalent of sodium azide a little at a time at from O to 30C, with thorough stir-~ :
ring.
The halo-derivatives of the dithieno~3,4-b:4',3'-e~-4,5-d1hydro-azep1ne-S,9-d10ne of the formula IV can~be pre-; pared by direct halogenation ln an;organic so1ventr pre-ferab1y a;halohydrooarbon,~at from~O to~80C.
The starting material:4,a-dihydro-benzo- ~
2-o:4Js-oll~-dlthlophene-4~8-dione~o*~the~::rormula~vI nas been~disclosed~in the literature~D.W~.H. Ma~owel~l and J.C.~Wisowaty, J.~Org. Chem~ 37 ~(1972~)~17~12)~
In~addition~to the compound~s~mentioned i~ the~
Examples, the~fo;llowing~compounds~may also~be men-tioned:;ci 9/ trans-9-cyanomethylene~-5-(4-cyclopropyl-piper-~
azin-l-yl)-dith1eno[3,4-b 4i,3'~-e~azepine,~ols/trans-9-;; cyanomethylene-5-(4-cy:clopropylmethyl-piperazln-1-y1)-di-thienor3,4-b:4'`,3~ azep1ne, ols~/~trans-9-oyanomethyl-5-(4-propin-2-yl-piperaz~in-l-yl)~-dithienoC3~,4-b 4',3'-e~- ~
azepine and c~is/trans-3-bromo-9-oyanomethylene-5-(4-methyl-~ p~lperaz1n-l-yl)-dlthieno~3,4-b:4',~3'-e3;azepine.
: , 11~025~
_ g _ o,z, ooSo/03~70 The compounds of the formula I according to the invention are as a rule obtained in the form of yellowish or yellow crystals and can be purified by recrystalliza-tion from the usual organic solvents, preferably from a lower alcohol, such as ethanol, or by column chr~mato-graphy.
If required, the compounds are separated into the individual cis- and trans-isomers by fractional crystal-lization in a chlorohydrocarbon, preferably methylene chloride, a lower monohydric alcohol, preferably methanol or ethanol, or a-saturated cycloaliphatic hydrocarbon, preferably cyclohexane, or by column chromatography, in particular in methylene chloride and methanol in a volume ratio from 99 : 1 to 85 : 15.
The free 5-substituted 9-cyanomethylene-dithieno-C3,4-b:4',3'-e~azepines of the formula I can be converted to addition salts of pharmacologically tolerated acids in a conventional manner, preferably by adding one equivalent of the appropriate acid~to a solution of the compound.
~xamples of pharmaceutically tolerated acids are hydro-chloric acid, maleic acid and methanesulfonic~acid.
The compounds according to the~invention exhibit valuable pharmacological properties. They can be used as sedatives, hypnotics, tranquillizers, neuroleptics ;~
or anti-Parklnson drugs. ~ A compound according to the invention may possess a combinabion of several of the actions mentioned. In some cases, an individual pure isomer obtained by separation of isomers may preferentially display an action.
t 17~2~8 - 10 - O.Z. 0050/0347C
From the results of the pharmacological experi-ments carried out, the substances according to the invention are useful as sedatives/hypnotics, minor or major tranquillizers and anti-Parkinson drugs ~y virtue of their sedative/tranquillizing, muscle-relaxing and anti-monaminergic action and their anticholinergic action on the central nervous system.
The following methods were used to analyze-their action: ---1. Sedative action 4 - 8 groups each of 3 female NMRI mice are given the compound orally. The orientation hypermotility ` induced by a new environment is determined photoelectric-ally, for a period of 30 minutes, starting 30 minutes after administration of the substances.
, The ED5C% is the dose which produces a 50 % reduc-tion in orientation hypermotility compared to placebo-treated control animals.
2. Muscle-relaxing action : : ~
The measurement~ls based on~quantlflcation of the tonic extension reflex in the gastrocnemius in rabbits (Teschendorf et al., Arch. Pharmacol. exp. Path. 266 ; ~ ~1970)1462). The rabbit is kept ln~a special appara-tus which allows it to flex its paw at the talocalcanean .
Joint in a defined and reproduclble manner. The flex-ing triggers off a tonic extension reflex in the calf muscles. ~ The electrical activity of the muscle dur-ing the contraction is recorded, and the individual pul ses are counted. The extension (lasting 5 seconds) is 2~8 , - 11 - O.Z. 0050/03470 repeated at intervals of one minute. When a constant number of pulses(control value) has been reached, the test substance is administered intravenously. The numbers of pulses following the administration are compared with the initial values.
3. Antimethamphetamine action Methamphetamine . HCl (2.5 mg/kg administered intravenously) regularly causes the following symptoms in rats: motor restlessness, searching and sniffing movements, fur standing on end, and tremor (Janssen et al., Aræneim.-Forsch.tDrug Res. 13 (1963), 205; and Randrup et al., Psychopharmacologia 11 (1967), 300). The test substance~
are administered intraperitoneally 30 minutes before meth-amphetamine. The substance is considered to have an effect if no sniffing movements are observed for a period : - --of 5 minutes after the injection of methamphetamine. The -mean inhibition dose (ED50%) is determined, by means of ` probit analysis, as the~dose which prevents the occur-rence-of the symptom in half the animals.
4. Antlc~holinergic action on the~central nervous system :
To test the anticholinergic action on the central nervous system, cholinerglc stimulation is triggered off by pilocarplne. After rapid~intravenous injection of -~
pilocarpine.HCl (50 m~kg)~rats display alternati~g scratching mov~ments of thelr rearpaws; further symptoms triggered of~in ~he central nervous system are jaw movements and tremors.Flow of saliva and chromodacryorrhea may be observed as signs of peripheral superexcitation (Kreiskott, Arch. exp. Path.
Pharma~. 247 (1964), 317). The test substances are ~702~ -- 12 - o.z. oO50/03 70~
administered intraperitoneally 30 minutes before pilocar-pine. The substance is considered to have an effect if no scratching is observed for a period of 2 minutes after the injection of pilocarpine. For this symptom, the mean inhibition dose (ED50%) is determined, by means of probit analysis by the method of Finney, as the dose of the test substance which suppresses the scratching in half the animals.
In these experiments (cf. Table 1), the compounds according to the invention were shown to have significant sedative/hypnotic effects which were about as powerful as those of the reference substance clozapine. They have a muscle-relaxing action which is somewhat weaker than that of clozapine, but as powerful as that of perlapine.
The antimonaminergic action (methamphetamine anta-gonism) may be evaluated as a parameter of the neuroleptic quality of a drug. The compounds according to the inven-tion are as powerful as or significantly (up to 7 times) more pcwer~ul ~ than the comparative compounds clozapine and perlapine.
The compounds also have an interesting anticholi-nergic action on the central nervous system, whlch in some cases is significantly more powerful than that~of the reference substances. This type of action suggests that the novel substances can be used as anti-Parkinson drugs. On the other hand, because of this anticholinergic action on the central nervous system, no extra-pyramidal motor dis-turbances are to be expected when the compounds are used as neuroleptics; such a connection is assumed for ~~~
1 1 7~56 -- 13 -- 0,Z. 0050/03k704 clozapine and should have a particularly advantageous effect in the case of the compounds according to the invention.
.
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- 14 - O.Z. 0050/0347G4 .
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:1~ 0 ~ = ~ N
' ::
c,~ ~: al ~d : ~3 ~
O ~ ~ Q 0: ;.
~ C~ ~ r~
, ~: C~ ~ :
:
: ~: : : :: :
:: :
:
~ 17~25~
- 15 - O.Z. 0050/03~70 Accordingly, the present invention also relates to a therapeutic agent which in addition to conventional carriers and diluents contains a compound of the formula I, or a pha~macogically tolerated acid addition salt thereof, as the active compound.
The therapeutic agents are prepared in a conven-~ional manner by compounding an appropriate dose with the conventional carriers or diluents and the conventional industrial auxiliaries, in accordance with the desired --route of administration. Suitable doses for man are from 10 to 100 mg.
The novel compounds may be employed in the conven-tional solid or liquid pharmaceutical forms, such as tab-lets, capsules, powders, granules, dragees or solutions.
These are prepared in a conventional manner, and to do so the active compounds can be mixed with the conventional pharmaceutical auxiliaries, such as talc, gum arabic, suc-rose, lactose, cereal starch or corn starch, potato flour, magnesium stearate, alginates, gum tragacanth~ carraghen-ates, polyvinyl alcohol, polyvinylpyrrol~idone,~aqueous ornon-aqueous carriers, wetting agentsj dispersants, emulsi-fiers and/or preservatives (cf. L.G. Goodman and A. Gilman, The Pharmacological Basis of Therapeutics). The formu-lations thus obtained normally contain from 0.001 to 99%
by weight of the active compound.
The preferred formulations are those suitable for oral administration. Examples of these are tablets, film tablets, dragees, capsules, pills, powders, solutions, suspensions and depot forms. Parenteral formulations, - - \
~ 1702~
.
- 16 - O.Z~ 0050/03~70a such as injection solutions, may also be used. Supposi-tories are a further example of suitable formulations.
Appropriate tablets may be obtained, for example, by mixing the active compound with conventional auxili-aries, for example inert diluen-ts, such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium carbon-ate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of a plurality of layers.
Correspondlngly, dragees can be prepared by coat-ing cores, prepared similarly to the tablets, with agents conventionally used in dragee coatings, for example colli-done or shellac, gum arabic, talc, titanium dioxide or ; sugar. The dragee coating~can also~consist of~ a plura-lity of layers, and the auxiliaries mentioned above in :
connection with tablets may be used therein.
Solut~ions or suspensions containing the active com-pounds according to the invention~may additionally contain :
flavor improvers, such as vanillin or orange extract.
They may also contain suspending agents, such as sodium carboxymethylcellulose,~or preservatives, such as p-hydroxy-benzoates. ~ Capsules containing the active compounds may be prepared, for examp~le, by mlxing the active compound with an inert carrier, such as lactose or sorbitol, and encapsulating the mixture in gelatin capsules. Suitable ~02S~
- 17 - O.Z. oo5o/o347Ga suppositories can be prepared, for example, by mixing the active compounds with appropriate carriers, such as neut-ral ~ats or polyethylene glycol or their derivatives.
The Examples which follow illustrate the present invention:
Cis- and trans-9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithieno r3 ~ 4-bO4',3'-e~azepine a) 140 ml of phosphorus oxychloride and 1.5 ml of N,N-dimethylaniline are added to 14.0 g (54 mmoles)of 9-cyanomethylene-4,5-dihydro-dithienoC3,4-b 4',3'-e~azepin-5-one (cis/trans-isomer mixture) and the mixture is re-fluxed under nitrogen for 1 hour. After all the excess phosphorus oxychloride and dimethylanilinehave been dis-tilled off under reduced pressure from an oil pump, the residue is partitioned between methylene chloride and water, the aqueous phase is extracted twic~e more wlth methylene chloride and the combined organic phases are washed thoroughly with dilute HCl and water. Drying ~; and concentrating the organio phase gives 14.4 g (96 %) of 5-chloro-9-cyanomethylene-dithieno[3,4-b:4',3'-e]azepine, which is~sufficiently pure for the further reaction.
50 ml of~M-methyl-piperazine aré added to 14.4 a .
(52 mmoles) o~ 5-chloro-9-cyanomethylene-dithieno-[3,4-b:4',3'-e]azepine and the mlxture is stlrred under nitrogen at 110C for 2 to 3 hours. Afterhaving been cooled, the dark homogeneous reaction mixture is poured onto ice-water and the yellowish crude 9~yancmethylene-5-(4-methyl-piperazin-l-yl)-dithienoC3,4-b 4',3'-e~azepine is ~170~58 - 18 - O.Z. 0050/03~70 filtered off with suction. After the crude product has been dried in an oven under reduced pressure, it is recrystal-lized from ethanol, with the addition of active charcoal, or purified by column chromatography (silica gel, mobile phase: a 95/5 mixture of methylene chloride and methanoi). 13.6 g (85 %) of yellowish 9-cyanomethy-lene-5-(4-methyl-piperazin-1-yl)-dithieno¦3,4-b:4',3~-el-azepine are obtained in the form of a cisttrans-isomer mix-ture of melting point 148-151C.
b) To separate the cis/trans-isomers, the isomer mix-ture is subjected to fractional crystallization from etha-nol. 6.5 g of yellow crystals which, according to the thin layer chromatogram (silica gel, mobile phase: an 85/
15 mixture of toluene and methanol), chiefly consist of the non-polar cis-isomer a are isolated as the first fraction.
After the filtrate has been concentrated, the resi-due is digested in about 80 ml of boiling cyclohexane and the insoluble constituents are filtered off with suction, under the influence of heat.~ After havlng washed the prod-uct with a little cyclohexane, 20 1 g of yellow crystals, which, according to the thin layer chromatogram ~silica gel, mobile phase: an 85/15 mixture of toluene and metha-nol) chiefly consist of the polar trans-isomer b, are obtained.
Subsequent crystallization of the enriched products from ethanol and cyclohexanone gives the cis- and trans-isomers in virtually pure forms. Melting point: cis-isomer: 200-201C, trans-isomer: 197-198C.
1 1702~
- 19 - o.z. 0050/03g70~z CH3 ,CH3 ~N) ~N ) ~5 ~S
CN N
Cls trans Cis/trans-3-chloro-9-cyanomethylene-5-(4-methylpiperazin-l-yl)-dithieno[3,4-b:4',3'-e~azepine 4.8 g (14 mmoles) of 9-cyanomethylene-5-(4-me-thyl-piperazin-l-yl)-dithieno~3,4-b:4'j3'-elazepine (cis/trans-isomer mi`xture) are dissolved in 160 ml of methylene chlor-ide. 1.0 g (14 mmoles) of chlorine is then slowly passsd in with thorough stirring (a finely crysta111ne ~ '' solid precip1tatss). Ths mixturs 1S stirred~for a~furthsr 2 hours at room temperature and is then poured onto ice-10~ ~ water.~ After ~the m1xture has bsen~rendsred~baslc~with sodium hydroxlde~solution,~ths;organic phase~is~s~eparated off,~the aqus~ous~phass~is sxtractsd sevsral~tlmes~with msthy1sne~chloride and~the~combinsd organ1c~phasss are drlsd in a conventional~manner. ~ ~Ths cruds~product~
'obtained~on concentratlng the organic~phase is dis501ved ~
in a little bo1ling ethanol, active charcoal is added, the mixture is filtered hot and~the solut1on is concentrated to a small volume. 45 % of cis/trans-3-chloro-9-cyano-methy1sne-5-~4-methyI-pipsrazin-l-y'lj-d}thieno~3,4-b:4',3'-e]-~ azepine having a melting point of 208-211C crystallize in ; ~ , .
.. '' " , : .
1 ~70258 - 20 - O.Z. 0050/034704 the cold.
Cis/trans-9-cyanomethylene-4,5-dihydro-dithieno-¦354-b:4',3'-e~azepin-5-one The intermediate 9-cyanomethylene-4,5-dihydro-di-thieno~3,4-b:4',3'-e~azepin-5-one is prepared by carbonyl-olefination of 4,5-dihydro-dithienor3,4-b:4',3'-e~azepine-5,9-dione by the Wittig-Horner reaction or by the classi-cal Wittig synthesis:
26.4 g (112 mmoles) of 4,5-dihydro-dithieno-r3,4-b:4',3'-e~azepine-5,9-dione are dissolved in 300 ml of dimethylformamide, under the influence of heat, and the solution is stirred under nitrogen. 24.8 g (140 mmoles) of diethyl cyanomethylphosphonate and 24.6 g (140 mmoles) of sodium ethylate (30 %) dissolved ln 30 ml of dimethyl-formamide are then simultaneously a,nd slowlyadded dropwise (an intensification of color and increase in temperature indicate the start of the Wittig reaction). After the mixture has been stirred at room temperature for 12 hours, the reaction product i5 poured onto ice-water and the solid which precipitates is filtered off~with suction.
After the crude product has been washed thoroughly with water, it is dried and recrystallized from ethan~l.
Yield: 26.5 g (92 %) of 9-cyanomethylene-4,5-dihydro-di-thienoL3,4-b:4',3'-e~azepin-5-one as colorless crystals having a melting point of 253C (decomposition).
Classical Wittig process: 1 molar equivalent of 30 %
strength sodium methylate solution is added dropwise, or 1 molar equivalent of sodium hydride is added, to tri-~ 17~2S~
- 21 - o.z. ooSo/03~70 phenyl-cyanomethyl-phosphonium chloride in dimethylform-amide and, finally, 1 molar equivalent of a solution of 4,5-dihydro-dithieno~3,4-b:4',3'-e~azepine-5,9-dione in dimethylformamide is added. The reaction mixture is then stirred`at 50 to 80C for 5 to 8 hours and is subse-quently poured onto ice-water and extracted several times ~ith methylene chloride. After the organic phase has been dried and concentrated, the crude product is recrys-tallized from ethanol. Yield: 61 % of colorless crys-tals having a decomposition point of 251-253C.
4,5-Dihydro-dithieno r3 ~ 4-b:4',3'-e]azepine-5,9-dione The intermediate 4,5-dihydro-dithieno-[3,4-b:4~,3~-eJazepine-5-dione is prepared by Schmidt ring extension:
30.4 g (138 mmoles) of 4,8-dihydro-benzo-[1,2-c:4,5-c'~dithiophene-4,8-dione are suspended in 200 ml of methylene chloride; 280 ml of concentrated sulfuric acid are then added dropwise, with ice-cooling and stir-ring. A total of 13.0 g (200 mmoles~) of scdium azlde is then introduced a little at a time into the well stirred reaction mixture at 0C over a period of 2 hours. The mixture is then stirred at room temperature for 8 to 10 hours. The reaction mlxture is poured carefully into 3 1 of ice-water, with thorough stirring, and the solid which precipitates after a short time is filtered off with suction. The crude product is washed with a large amount of water until it gives a neutral reaction, and is dried at 50C under reduced pressure.
/
.
~ 17~2~8 - 22 - O.Z. 0o5o/o3a7oa 28.0 g (86 %) of a light solid which has a melting point of 267-270C and is sufficiently pure for the fur-ther reaction are isolated.
Cis/trans-9-cyanomethylene-5-(4-methyl-4-oxy-piperazin-l-yl)-dithieno[3,4-b:4',3'-e~azepine.2H20 3.5 g (11 mmoles) of cis/trans-9-cyanomethylene-5-~4-methyl-piperazin-1-yl)-dithieno[3,4-b:4',3'-e~azepine are dissolved in 100 ml of hot ethanol, and 1.5 ml of 30%
strength hydrogen peroxide are added. After the mixture has been refluxed for 5 hours, the excess hydrogen perox-ide is decomposed by introducing a small platinum foil into the reaction mixture and refluxing the mixture for 2 hours. When the reaction mixture has been filtered, it is concentrated, and the resulting N-oxide is purified by column chromatography (silica gel,;mobile phase: a 95/5 mixture of methylene chloride and methanol).
1.8 g (50 %) of yellow crys-tals having a melting point of 137-140G are isolated EXAMPLE 6 ~ ~
Cis/~trans-9-cyanomethylene-5-(4-ethyl-piperazin-1-yl)-:
dithienoL3,4-b:4',3'-e~azeplne This compound is synthesized by a method similar to that in Example la, using N-ethylpiperazine. After column chromatography (sillca gel, mobile phase: a 95/5 mixture of methylene chloride andmethanol), ye~ow cry3tals havlng a meltlng point of 118-121C are obtained.
` 1170258 - 23 - O.Z. 0050/03~70 Cis/trans-9-cyanomethylene-5-(N'-methyl-homopiperazin-l-yl)-dithieno[3,4-b:4',3'-eJazepine.H20 This compound is synthesized by a method similar to that in Example la, using N-methyl-homopiperazine.
Purification by column chromatography (silica gel; a 95/5 mixture of methylene chloride and methanol) gives yellow crystals having a melting point of 124-126C.
Cis/trans-9-cyanomethylene-5-~2-(piperidin-1-yl)-ethyl-amino~-dithieno r3 ~ 4-b:4',3'-e~azepine.l/2H20 This compound is synthesized by a method similar to that in Example la, using 2-piperidin-1-yl-ethylamine. -~ .
Purification by column chromatography (silica gel; a 95/5 mixture of methylene chloride and methanol) gives y~ow crys- -tals having a melting point of 112-I14C.
Cis/trans-9-cyanomethylene-5-piperazin-1-yl-dlthieno-~3,4-b:4',3'-e~azepine .
This compound is synthesized by a~method slml}ar to that in Example la, using 5 molar equivalents of piper-azine and increasing the~aminolysis~temperature to 140C.
;~ 20 After the reaction melt has cooled, it is taken up in methylene chloride,~the organic phase is thoroughly washed three times with water and the crude product is purified by column chromatography (silica gel; a 95/5 mixture of methylene ch}oride and methanol) to give yellow crystals having a melting point of 94-96C.
Examples of pharmaceutical iormulations:
25~
- 24 - o.Z. 0050/034704 Examples of tablets 1. An active compound of ~ormula I 10 mg Lactose 200 mg Methylcellulose 15 mg Corn starch 50 mg Talc 11 mg ' Magnesium stearate . 4 mg 2. An active compound of formula I 20 mg Lactose -- . ~ 178 mg Avicel 80 mg Polywax 6000 20 mg Magnesium stearate 2 mg .
3. An active compound of formula I 50 mg Polyvinylpyrrolidone (mean molecular weight 25,000) 170 mg.
Polyethylene glycol (mean molecular weight 4,000): 14 mg Hydroxypropylmethylcellulose ~ 40 mg Talc ~ ~ 4 mg Magnesium stearate ~ 2 mg The active compound is moistened with a 10 %
stréngth aqueous solution of polyvinyIpyrrolidone and forced through a sieve of 1.0 mm~mesh slze, and the gran- :
ules are drled at 50C. They are then mixed wlth poly-ethylene glycol (mean molecular weight 4,000), hydroxy-propylmethylcellulose, talc and magnesium stearate, and the mixture is pr:ssed to glve tabIets weighing 280 mg.
7~2S~
- 25 -O.Z. 0oso/o3a7oa 4. Examples of dragees An active compound of formula I 60 mg Lactose 90 mg Corn starch 60 mg Polyvinylpyrrolidone 6 mg Magnesium stearate 1 mg The active substance, lactose and corn starch are mixed, moistened with an 8 % strength aqueous salution of the polyvinylpyrrolidone, and granulated by passing through a 1.5 mm sieve. The granules are dried at 50C and again forced through a 1.0 mm sieve. The material thus obtained is mixed with magnesium stearate and the mixture is pressed to form dragee cores. These are coated in a conventional manner with a sheIl conslsting essentially of sugar and talc.
5 Capsule formulation An active compound of formula I 5 mg Magnesium stearate 2.0 mg Lactose 19.3~mg
6. Injection solution An active compound of formula I 10 mg :: :
Sodium chloride 9 mg Distil1ed watsr, to~make up to 1.0 ml . :
Sodium chloride 9 mg Distil1ed watsr, to~make up to 1.0 ml . :
Claims (18)
1. Process for the preparation of a compound of the general formula I
I
wherein R1 and R2 are hydrogen or halogen, and A is -NR3R4, .
where R3 and R4, together with the nitrogen atom linking them, are a 5-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, an additional nitrogen present being unsubstituted or substituted by alkyl of 1 to 3 carbon atoms, hydroxyalkyl of 2 or 3 carbon atoms, alkoxyalkyl, where alkyl and alkoxy are of 1 to 3 carbon atoms, cycloalkyl or cycloalkylmethyl, where cyclo-alkyl is of 3 to 7 carbon atoms or alkynyl of 2 to 5 carbon atoms, and may additionally be substituted by oxygen in the form of an N-oxide, or A is -NHR , where R5 is aminoalkyl of 2 to 7 carbon atoms, the amine nitrogen being unsubstituted or substituted by lower alkyl of l to 5 carbon atoms or being a constituent of a 5-membered:to 7-membered saturated ring, which may contaln nitrogen or oxygen as a further hetero-atom, a nitrogen present being substituted by lower alkyl of 1 to 3 carbon atoms or hydroxyalkyl of 2 or 3 carbon atoms, and its physiologically tolerated acid addition salts, said process which comprises reacting a compound of the formula II
II
where R1 and R2 have the above meanings and Z is a nucleofugic leaving group, with a nucleophile AH, where A has the above meanings, and, if desired, converting the resulting compound into the N-oxide and/or into the acid addition salt of a physiologically tolerated acid.
I
wherein R1 and R2 are hydrogen or halogen, and A is -NR3R4, .
where R3 and R4, together with the nitrogen atom linking them, are a 5-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, an additional nitrogen present being unsubstituted or substituted by alkyl of 1 to 3 carbon atoms, hydroxyalkyl of 2 or 3 carbon atoms, alkoxyalkyl, where alkyl and alkoxy are of 1 to 3 carbon atoms, cycloalkyl or cycloalkylmethyl, where cyclo-alkyl is of 3 to 7 carbon atoms or alkynyl of 2 to 5 carbon atoms, and may additionally be substituted by oxygen in the form of an N-oxide, or A is -NHR , where R5 is aminoalkyl of 2 to 7 carbon atoms, the amine nitrogen being unsubstituted or substituted by lower alkyl of l to 5 carbon atoms or being a constituent of a 5-membered:to 7-membered saturated ring, which may contaln nitrogen or oxygen as a further hetero-atom, a nitrogen present being substituted by lower alkyl of 1 to 3 carbon atoms or hydroxyalkyl of 2 or 3 carbon atoms, and its physiologically tolerated acid addition salts, said process which comprises reacting a compound of the formula II
II
where R1 and R2 have the above meanings and Z is a nucleofugic leaving group, with a nucleophile AH, where A has the above meanings, and, if desired, converting the resulting compound into the N-oxide and/or into the acid addition salt of a physiologically tolerated acid.
2. Process according to claim 1, wherein R1 and R2 are hydrogen, chlorine or bromine and A is piperidine, piperazine or homopiperazine, in which any ring nitrogen atom present is substituted by H, methyl, e-thyl, .beta.-hydroxyethyl, cyclopropyl or propynyl and may be in the form of the N-oxide.
3. Process according to claim 1, wherein R1 is hydrogen or chlorine and A is 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-l-yl, 4-methyl-4-oxy-piperazin-1-yl or N'-methyl--homopiperazin-l-yl.
4. Process for the preparation of cis/trans-9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithienno [3,4-b:
4',3'-e]azepine, which comprises reacting 5-chloro-9-cyano-methylene-dithieno-[3,4-b:4',3'-e]azepine with N-methyl--piperazine to obtain a cis/trans-isomer mixture, then if desired, separating the cis/trans-isomers.
4',3'-e]azepine, which comprises reacting 5-chloro-9-cyano-methylene-dithieno-[3,4-b:4',3'-e]azepine with N-methyl--piperazine to obtain a cis/trans-isomer mixture, then if desired, separating the cis/trans-isomers.
5. Process for the preparatlon of cis/trans-9-cyanomethylene-5-(4-methyl-oxy-piperazin-1-yl)-dithieno [3,4-b:4',3'-e]azepine, which comprises reacting 5-chloro-9--cyanomethylene-dithieno-[3,4-b:4',3'-e]azepine with N'-methyl-piperazine to obtain a cisjtrans-isomer mixture, then converting the latter into the N-oxide.
6. Process for the preparation of cis/trans-9--cyanomethylene-3-chloro-5-(4-methyl-piperazin-1-yl)-dithieno [3,4-b:4',3'-e]azepine, which comprises reacting 5-chloro-9--cyanomethylene-dithieno-[3,4-b: 4',3'-e]azepine with N-methyl-piperazine to obtain a cis/trans-isomer mixture, then converting the latter with chlorine.
7. Process for the preparation of cis/trans-9--cyanomethylene-5-(4-ethyl-piperazin-1-yl)-dithieno[3,4-b:
4',3'-e]azepine, which comprises reacting 5-chloro-9-cyanomethylene-dithieno-[3,4-b:4',3'-e]azepine with N--ethylpiperazine to obtain a cis/trans-isomer mixture, then if desired, separating the cis/trans-isomers.
4',3'-e]azepine, which comprises reacting 5-chloro-9-cyanomethylene-dithieno-[3,4-b:4',3'-e]azepine with N--ethylpiperazine to obtain a cis/trans-isomer mixture, then if desired, separating the cis/trans-isomers.
8. Process for the preparation of cis/trans-9--cyanomethylene-5-(N'-methyl-homopiperazin-l-yl)-dithieno [3,4-b:4',3'-e]azepine, which comprises reacting 5-chloro-9-cyanomethylene-dithieno-[3,4-b:4',3'-e]azepine with N-methyl-homopiperazine to obtain a cis/trans-isomer mixture, then if desired, separating the cis/trans-isomers.
9. A 5-substituted 9-cyanomethylene-dithieno-[3,4-b:4',3'-e]azepine of the general formula I
I
wherein R1 and R2 are hydrogen or halogen, and A is -NR3R4, where R3 and R4, together with the nitrogen atom linking them, are a 5-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, an additional nitrogen present being unsubstituted or substituted by alkyl of 1 to 3 carbon atoms, hydroxyalkyl o 2 or 3 carbon atoms, alkoxyalkyl, where alkyl and aIkoxy are of 1 to 3 carbon atoms, cycloalkyl or cycloalkylmethyl, where cycloalkyl is of 3 to 7 carbon atoms or alkynyl of 2 to 5 carbon atoms, and may additionally be substituted by oxygen in the form of an N-oxide, or A is -NHR5, where R5 is aminoalkyl of 2 to 7 carbon atoms, the amine nitrogen being unsubstituted or substituted by lower alkyl of 1 to 5 carbon atoms or being a constituent of a 5-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, a nitrogen present being substituted by lower alkyl of 1 to 3 carbon atoms or hydroxyalkyl of 2 or 3 carbon atoms, and its physiologically tolerated acid addition salts, whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.
I
wherein R1 and R2 are hydrogen or halogen, and A is -NR3R4, where R3 and R4, together with the nitrogen atom linking them, are a 5-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, an additional nitrogen present being unsubstituted or substituted by alkyl of 1 to 3 carbon atoms, hydroxyalkyl o 2 or 3 carbon atoms, alkoxyalkyl, where alkyl and aIkoxy are of 1 to 3 carbon atoms, cycloalkyl or cycloalkylmethyl, where cycloalkyl is of 3 to 7 carbon atoms or alkynyl of 2 to 5 carbon atoms, and may additionally be substituted by oxygen in the form of an N-oxide, or A is -NHR5, where R5 is aminoalkyl of 2 to 7 carbon atoms, the amine nitrogen being unsubstituted or substituted by lower alkyl of 1 to 5 carbon atoms or being a constituent of a 5-membered to 7-membered saturated ring, which may contain nitrogen or oxygen as a further hetero-atom, a nitrogen present being substituted by lower alkyl of 1 to 3 carbon atoms or hydroxyalkyl of 2 or 3 carbon atoms, and its physiologically tolerated acid addition salts, whenever obtained by a process as claimed in claim 1 or its obvious chemical equivalents.
10. A compound of the formula I as claimed in claim 9, wherein Rl and R2 are hydrogen, chlorine or bromine and A
is piperidine, piperazine or homopiperazine, in which any ring nitrogen atom present is substituted by H, methyl, ethyl, .beta.-hydroxyethyl, cyclopropyl or propynyl and may be in the form of the N-oxide, whenever obtained by a process as claimed in claim 2 or its obvious chemical equivalents.
is piperidine, piperazine or homopiperazine, in which any ring nitrogen atom present is substituted by H, methyl, ethyl, .beta.-hydroxyethyl, cyclopropyl or propynyl and may be in the form of the N-oxide, whenever obtained by a process as claimed in claim 2 or its obvious chemical equivalents.
11. A compound of the formula I as claimed in claim 9, where R1 is hydrogen, R2 is hydrogen or chlorine and A is 4-methyl-piperazin-1-yl, 4-ethyl-piperazin-l-yl, 4-methyl-4-oxy-piperazin-l-yl or N'-methyl-homopiperazin-l-yl, whenever obtained by a process as claimed in claim 3 or its obvious chemical equivalents.
12. Cis/trans-9-cyanomethylene-5-(4-methyl-piperazin-l-yl)-dithieno [3,4-b:4',3'-e]azepine, whenever obtained by a process as claimed in claim 4 or its obvious chemical equivalents.
13. Cis-9-cyanomethylene-5-(4-methyl-piperazin-l-yl)-dithleno[3,4-b:4',3'-e]azepine, whenever obtained by a process as claimed in claim 4 or its obvious chemical equivalents.
14. Trans-9-cyanomethylene-5-(4-methyl-piperazin-1-yl)-dithieno[3,4-b:4',3'-e]azepine, whenever obtained by a process as claimed in claim 4 or its obvious chemical equivalents.
15. Cis/trans-9-cyanomethylene-5-(4-methyl-oxy-piperazin-l-yl)-dithieno[3,4-b 4',3'-e]azepine, whenever obtained by a process as claimed in claim 5 or its obvious chemical equivalents.
16. Cis/trans-9 cyanomethylene-3-chloro-5-(4-methyl-piperazin-l-yl)-dithieno[3,4-b:4',3'-e]azepine, whenever obtained by a process as claimed in claim 6 or its obvious chemical equivalents.
17. Cis/trans-9-cyanomethylene-5-(4-ethyl-piperazin-l-yl)-dithieno[3,4-b:4',3'-e]azepine, whenever obtained by a process as claimed in claim 7 or its obvious chemical equivalents.
18. Cis/trans-9-cyanomethylene 5-(N'-methyl-homopiperazin-1-yl)-dithieno[3,4-b:4',3'-e]azepine, whenever obtained by a process as claimed in claim 8 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3037971.6 | 1980-10-08 | ||
| DE19803037971 DE3037971A1 (en) | 1980-10-08 | 1980-10-08 | 5-SUBSTITUTED 9-CYANMETHYLENE DITHIENO (3,4-B: 4 '3'-E) -AZEPINE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1170258A true CA1170258A (en) | 1984-07-03 |
Family
ID=6113891
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000387495A Expired CA1170258A (en) | 1980-10-08 | 1981-10-07 | 5-substituted 9-cyanomethylene-dithieno [3,4-b:4',3'-e]-azepines, their preparation and therapeutic agents which contain these compounds |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0050212B1 (en) |
| JP (1) | JPS5788179A (en) |
| AT (1) | ATE5820T1 (en) |
| CA (1) | CA1170258A (en) |
| DE (2) | DE3037971A1 (en) |
| DK (1) | DK152289C (en) |
| IE (1) | IE51635B1 (en) |
| ZA (1) | ZA816927B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3309719A1 (en) * | 1983-03-18 | 1984-09-20 | Basf Ag, 6700 Ludwigshafen | 2,3,5,6-TETRA-SUBSTITUTED P-BENZOQUINONES, THEIR PRODUCTION AND USE |
| DE3524744A1 (en) * | 1985-07-11 | 1987-01-15 | Basf Ag | 4-SUBSTITUTED 10-CYANMETHYLENE THIENO (4,3-E) -BENZO-AZEPINE |
| DE3524743A1 (en) * | 1985-07-11 | 1987-01-15 | Basf Ag | METHOD FOR PRODUCING 4,5-DIHYDRO-DITHIENO- (3,4-B: 4 ', 3'-E) -AZEPINE-5,9-DION |
| DE3717069A1 (en) * | 1987-05-21 | 1988-12-08 | Basf Ag | 5-SUBSTITUTED 10-CYANMETHYLENE THIENO (3,4-B) -BENZO-AZEPINE |
| DE3717068A1 (en) * | 1987-05-21 | 1988-12-08 | Basf Ag | 4-SUBSTITUTED 10-CYANMETHYLENE PYRROLO (4,3-E) -BENZO-AZEPINE |
| US20110217387A1 (en) * | 2008-05-16 | 2011-09-08 | Axis, Inc. | Pharmaceutical composition for treatment of fibromyalgia |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH560220A5 (en) * | 1971-11-26 | 1975-03-27 | Wander Ag Dr A | 4-(1-piperazinyl)-10h-thieno (3,2-c) (1) benzaepines - - antipsychotics, sedatives, hypnotics or muscle relaxants |
| DE2918778A1 (en) * | 1979-05-10 | 1980-11-20 | Basf Ag | 6-SUBSTITUTED 11-ALKYLENE MORPHANTRIDINE |
-
1980
- 1980-10-08 DE DE19803037971 patent/DE3037971A1/en not_active Withdrawn
-
1981
- 1981-09-17 EP EP81107343A patent/EP0050212B1/en not_active Expired
- 1981-09-17 DE DE8181107343T patent/DE3161895D1/en not_active Expired
- 1981-09-17 AT AT81107343T patent/ATE5820T1/en not_active IP Right Cessation
- 1981-10-01 JP JP56154922A patent/JPS5788179A/en active Granted
- 1981-10-06 IE IE2330/81A patent/IE51635B1/en unknown
- 1981-10-07 DK DK443881A patent/DK152289C/en active
- 1981-10-07 ZA ZA816927A patent/ZA816927B/en unknown
- 1981-10-07 CA CA000387495A patent/CA1170258A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| EP0050212B1 (en) | 1984-01-11 |
| DE3037971A1 (en) | 1982-05-13 |
| IE812330L (en) | 1982-04-08 |
| EP0050212A1 (en) | 1982-04-28 |
| ZA816927B (en) | 1982-10-27 |
| DK443881A (en) | 1982-04-09 |
| ATE5820T1 (en) | 1984-01-15 |
| DE3161895D1 (en) | 1984-02-16 |
| DK152289B (en) | 1988-02-15 |
| JPS5788179A (en) | 1982-06-01 |
| IE51635B1 (en) | 1987-01-21 |
| DK152289C (en) | 1988-07-11 |
| JPH0243754B2 (en) | 1990-10-01 |
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