DE3044542A1 - BENZYLIDE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THE SAME - Google Patents
BENZYLIDE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THE SAMEInfo
- Publication number
- DE3044542A1 DE3044542A1 DE19803044542 DE3044542A DE3044542A1 DE 3044542 A1 DE3044542 A1 DE 3044542A1 DE 19803044542 DE19803044542 DE 19803044542 DE 3044542 A DE3044542 A DE 3044542A DE 3044542 A1 DE3044542 A1 DE 3044542A1
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- Germany
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- group
- general formula
- müller
- hydrogen atom
- syn
- 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.)
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Links
- 238000000034 method Methods 0.000 title claims description 4
- 229940126601 medicinal product Drugs 0.000 title claims 2
- 150000001875 compounds Chemical class 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000012965 benzophenone Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000012876 carrier material Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 2
- 238000005744 Teer Meer reaction Methods 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004455 differential thermal analysis Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- FIAINKIUSZGVGX-UHFFFAOYSA-N (1-amino-1-oxopropan-2-yl)azanium;chloride Chemical compound Cl.CC(N)C(N)=O FIAINKIUSZGVGX-UHFFFAOYSA-N 0.000 description 1
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 1
- WKNMKGVLOWGGOU-UHFFFAOYSA-N 2-aminoacetamide;hydron;chloride Chemical compound Cl.NCC(N)=O WKNMKGVLOWGGOU-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- -1 amine compound Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Die Erfindung betrifft Benzylidenderivate, ein Verfahren zu ihrer Herstellung und ihre Anwendung in der Therapie,' d.h. diese Verbindungen als Wirkstoffe enthaltende Arzneimittel .The invention relates to benzylidene derivatives, a process for their preparation and their use in therapy, ' i.e., drugs containing these compounds as active ingredients.
Die erfindungsgemäßen Verbindungen entsprechen der nachstehenden allgemeinen Formel IThe compounds according to the invention correspond to the following general formula I.
NR3R4 NR 3 R 4
(I)(I)
in derin the
η und m unabhängig voneinander 1, 2 oder 3 R.. ein Wasserstoffatom oder ein Halogenatom, R2 ein Wasserstoffatom oder, ein Halogenatom, R3 und R. unabhängig voneinander Wasserstoffatome,η and m independently of one another 1, 2 or 3 R .. a hydrogen atom or a halogen atom, R 2 a hydrogen atom or a halogen atom, R 3 and R. independently of one another hydrogen atoms,
Alkylgruppen oder Acylgruppen,Alkyl groups or acyl groups,
R1- ein Wasserstoffatom oder eine Alkylgruppe und Rg eine Aminogruppe, eine Alkylaminogruppe, eine Dialkylaminogruppe, eine Hydroxyalkylaminogruppe oder einen stickstoffhaltigen Heterozyklus, der ein weiteres Heteroatom aufweisen und/oder eine Alkylgruppe tragen kann, bedeuten, wobei die Alkylgruppen 1 bis 4 Kohlenstoffatome aufweisen... ·R 1 - denotes a hydrogen atom or an alkyl group and Rg denotes an amino group, an alkylamino group, a dialkylamino group, a hydroxyalkylamino group or a nitrogen-containing heterocycle which can have a further heteroatom and / or carry an alkyl group, the alkyl groups having 1 to 4 carbon atoms. .. ·
130 036/0557130 036/0557
TER MEER · MÜLLER ■ STEINMEISTEFTTER MEER · MÜLLER ■ STEINMEISTEFT
-S YNTHELABO SET 43-S YNTHELABO SET 43
Eine besonders bevorzugte Gruppe von erfindungsgemäßen
Verbindungen schließt jene Verbindungen der allgemeinen Formel I ein, in der R1 ein Chloratom in der 5-Stellung
und R2 ein Wasserstoffatom oder ein Halogenatom bedeuten.
In dieser Gruppe sind besonders bevorzugt jene Verbindungen der allgemeinen Formel I, in der R_. und R.
Wasserstoffatome, ^
Aminogruppe (NH„) bedeutenA particularly preferred group of compounds according to the invention includes those compounds of the general formula I in which R 1 is a chlorine atom in the 5-position and R 2 is a hydrogen atom or a halogen atom. In this group, those compounds of the general formula I in which R_. and R. hydrogen atoms, ^
Amino group (NH ") mean
ein Wasserstoffatom und Rfi einea hydrogen atom and R fi a
Die erfindungsgemäßen Verbindungen können in den beiden nachstehenden stereochemischen syn- und anti-Formen vorliegen: The compounds of the invention can be used in both the following stereochemical syn and anti forms exist:
NR3R4 NR 3 R 4
OR,OR,
synsyn
antianti
Im allgemeinen erfolgt die Trennung durch fraktionierte Kristallisation.In general, the separation is carried out by fractional crystallization.
Die als Zwischenprodukte anfallenden hydroxylierten Verbindungen der allgemeinen Formel III können ebenfalls in der syn- und in der anti-Form vorliegen.The hydroxylated compounds of the general formula III obtained as intermediates can also be used in the syn- and anti-form.
Weiterhin können die Verbindungen, bei denen die Gruppe Rceine Alkylgruppe darstellt, in Form des Racemats oder der Enantiomeren vorliegen, welche Formen ebenfalls Gegenstand der Erfindung sind.Furthermore, the compounds in which the group Rceine Represents alkyl group, in the form of the racemate or the Enantiomers are present, which forms are also the subject of the invention.
130036/0557130036/0557
TER MEER ■ MÜLLER · STEINMEISTERTER MEER ■ MÜLLER · STEINMEISTER
SET 43SET 43
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I können gemäß dem folgenden Reaktionsschema hergestellt werden:The compounds of the general formula I according to the invention can according to the following reaction scheme getting produced:
(Vn ( Vn
(III)(III)
(RJ(RJ
2'm2'm
NR3R4 NR 3 R 4
C=OC = O
- CH2OH- CH 2 OH
(ID(ID
NR3R4 NR 3 R 4
= N - CH2 - CH2OH= N - CH 2 - CH 2 OH
NR-,RNR-, R
CHCH
1V 1 V
- COR,- COR,
= N - CII - COR.= N - CII - COR.
(D(D
130036/0557130036/0557
TER MEER · MÜLLER · STEINMEISTBFf-TER SEA MÜLLER STEINMEISTBFf-
S frlTMELABO SET 43S frlTMELABO SET 43
Die als Ausgangsmaterialien eingesetzten Benzophenone der allgemeinen Formel II sind bekannt. Auch die Amine der allgemeinen Formel IV sind bekannt.The benzophenones of the general formula II used as starting materials are known. The amines too of the general formula IV are known.
Die Umsetzung des Benzophenons der allgemeinen Formel II mit dem Äthanolamin erfolgt bei einer Temperatur von 100 bis 1400C.The reaction of the benzophenone of the general formula II with the ethanolamine is conducted at a temperature of 100 to 140 0 C.
Die Umsetzung des hydroxylgruppenhaltigen Zwischenprodukts der allgemeinen Formel III mit der Aminverbindung der allgemeinen Formel IVThe reaction of the hydroxyl-containing intermediate of the general formula III with the amine compound of general formula IV
- CH - COR- CH - COR
(IV)(IV)
die gegebenenfalls in Form des Hydrochlorids eingesetzt wird, erfolgt bei einer Temperatur von 20 bis 1500C in einem polaren protischen oder aprotischen Lösungsmittel, wie Methanol, Äthanol, Dimethylsulfoxid oder Dimethylformamid. which is optionally used in the form of the hydrochloride, takes place at a temperature of from 20 to 150 ° C. in a polar protic or aprotic solvent, such as methanol, ethanol, dimethyl sulfoxide or dimethylformamide.
Die Verbindungen der allgemeinen Formel I, in denen die Gruppe R-. ein Wasserstoffatom und die Gruppe R. eine Acylgruppe bedeuten, kann man ausgehend von den entsprechenden Verbindungen der allgemeinen Formel I, in der R-. und R4 Wasserstoffatome darstellen, durch Acylierung in beispielsweise Pyridin herstellen.The compounds of general formula I in which the group R-. is a hydrogen atom and the group R. is an acyl group, starting from the corresponding compounds of the general formula I in which R-. and R 4 represent hydrogen atoms, prepared by acylation in, for example, pyridine.
Die folgenden Beispiele dienen der weiteren Erläuterung der vorliegenden Erfindung. Die Struktur der Verbindungen wurde über das Infrarotspektrum oder das kernmagnetische Resonanzspektrum (NMR-Spektrum) bestätigt. In der nachfolgenden Tabelle I sind die gemäß den Beispielen hergestellten Verbindungen zusammengestellt. Die mit einemThe following examples serve to further illustrate the present invention. The structure of the connections was confirmed by the infrared spectrum or the nuclear magnetic resonance spectrum (NMR spectrum). In the following Table I lists the compounds prepared according to the examples. The one with a
130036/0557130036/0557
■ ■ : SYNT5JELAB0 TER MEER · MÜLLER ■ STEINMEISTEr? -- · - SEi'' 43■ ■: SYNT5JELAB0 TER SEA · MÜLLER ■ STEINMEISTEr? - · - SEi '' 43
Sternchen bezeichneten Schmelzpunkte wurden durch Differentialthermoanalyse gemessen.Melting points indicated by asterisks were measured by differential thermal analysis.
2-JJN- (ot-Phenyl-2-amino-5-chlor-benzylidenyl) -amino]]-acetamid, syn-Form und anti-Form2-JJN- (ot-phenyl-2-amino-5-chlorobenzylidenyl) -amino]] acetamide, syn form and anti form
Formel I: R^Cl-5, R3=R3=R4=R5=H, Rg=NH2 Formula I: R ^ Cl-5, R 3 = R 3 = R 4 = R 5 = H, Rg = NH 2
. 2~£ν- (<x-Phenyl-2-amino-5-chlor-benzylidenyl) -. 2 ~ £ ν- (<x-phenyl-2-amino-5-chlorobenzylidenyl) -
äthanolethanol
Man erhitzt 30 g 2-Amino-5-chlor-benzophenon .in 85 ml .Ethanolamin unter Rühren während 4 Stunden unter einer inerten Atmosphäre auf 1350C. Nach dem Abkühlen gießt man die Reaktionsmischung in 1,5 1 Wasser. Man extrahiert das gebildete öl mit Chloroform, wäscht die organische Phase 4-mal mit Wasser, trocknet über Magnesiumsulfat, filtriert und dampft bis zur beginnenden Kristallisation ein. Man filtriert das Produkt ab und kristallisiert es aus Chloroform um. Nach der Filtration, dem 3-maligen Waschen mit Äther und dem Trocknen im Exsikkator erhält man ein Produkt mit einem Schmelzpunkt von 128°C. Dieses Produkt liegt in der anti-Form vor. ' .The mixture is heated 30 g of 2-amino-5-chloro-benzophenone .in 85 ml .Ethanolamin with stirring for 4 hours under an inert atmosphere at 135 0 C. After cooling, it is poured into 1.5 1 of water. The oil formed is extracted with chloroform, the organic phase is washed 4 times with water, dried over magnesium sulfate, filtered and evaporated until crystallization begins. The product is filtered off and recrystallized from chloroform. After filtration, washing 3 times with ether and drying in a desiccator, a product with a melting point of 128 ° C. is obtained. This product is in the anti form. '.
. 2-Qi- (oC-Phenyl^-amino-S-chlor-benzylidenyl) -amino]-. 2-Qi- (oC-Phenyl ^ -amino-S-chlorobenzylidenyl) -amino] -
acetamid .acetamide.
Man löst 33 g Glycinamid-hydrochlorid in 300 ml Dimethylsulfoxid und löst in dieser Lösung 27,4 g 2-jjyi- 4x.~phenyl-2-amino-5-chlor-benzylidenyl) -arnino]-äthanol. Man erhitzt die Mischung während 6 Stunden auf 6O0C und gießt dann in 4 1 Wasser. Man extrahiert 4-mal mit 500 ml Chloroform. Man vereinigt die orga-Dissolve 33 g of glycinamide hydrochloride in 300 ml of dimethyl sulfoxide and dissolved in this solution, 27.4 g of 2-jjyi- 4x. ~ P henyl-2-amino-5-chloro-benzylidenyl) -arnino] -ethanol. The mixture is heated for 6 hours at 6O 0 C and then poured into 4 1 water. It is extracted 4 times with 500 ml of chloroform. The organizational
130036/0557130036/0557
- S/NTHELABO- S / NTHELABO
TER MEER · MÜLLER · STElNMEISTErK- ' SET 43TER MEER MÜLLER STElNMEISTErK- 'SET 43
- 10 -- 10 -
nischen Phasen, wäscht sie 4-mal mit 1 1 Wasser, trocknet über Magnesiumsulfat, filtriert und dampft zur Trockene.ein.niche phases, washed 4 times with 1 l of water, dried over magnesium sulfate, filtered and evaporated to dryness.
Man wäscht den .erhaltenen Feststoff 3-mal mit Äther filtriert ihn ab und trocknet ihn in einem Exsikkator. In dieser Weise erhält man die Mischung aus der syn-Form und der anti-Form.The solid obtained is washed 3 times with ether filter it off and dry it in a desiccator. In this way the mixture is obtained from the syn form and the anti form.
Durch Umkristallisation aus einer Methanol/Äther-Mischung gewinnt man die syn-Verbindung.The syn compound is obtained by recrystallization from a methanol / ether mixture.
Man dampft die bei der Umkristallisation anfallenden Mutterlaugen zur Trockene ein und erhält einen Feststoff, den man aus Äthanol umkristallisiert. Es handelt sich hierbei um die anti-Verbindung.The mother liquors obtained during the recrystallization are evaporated to dryness and a solid is obtained, which is recrystallized from ethanol. This is the anti compound.
Die syn-Verbindung schmutzt bei 1800C unter Zersetzung (gemessen durch Differentialthermoanalyse).The syn-compound dirty (measured by differential thermal analysis) at 180 0 C with decomposition.
Die anti-Verbindung schmutzt bei 143,50C und dann bei 177°C (gemessen durch Differentialthermoanalyse). Diese Messungen zeigen, daß die anti-Verbindung sich beim Erhitzen in die syn-Verbindung umwandelt.The anti-connection dirty (measured by differential thermal analysis) at 143.5 0 C and then at 177 ° C. These measurements show that the anti compound converts to the syn compound when heated.
2-fjS- (oc-Phenyl-2-amino-5-chlor-benzylidenyl) -amino[]-2-2-fjS- (oc-Phenyl-2-amino-5-chlorobenzylidenyl) -amino [] - 2-
methyl-acetamid (anti-Racemat-Form)methyl-acetamide (anti-racemate form)
Formel I: R^Cl-5, R3=R3=R4=H, R5=CH3,Formula I: R ^ Cl-5, R 3 = R 3 = R 4 = H, R 5 = CH 3 ,
130036/0557130036/0557
TER MEER · MÜLLER · STEINMEISTERTER MEER · MÜLLER · STEINMEISTER
•SVWTKELABO• SVWTKELABO
- 11 -- 11 -
Man erhitzt 17,6 g (0,1413 Mol) dl-Alaninamid-hydrochlorid und 12,95 g (0,0471 Mol) 2-Qj- (ot-Phenyl-^-amino-S-chlorbenzylidenyl)-amino^-äthanol in der anti-Form in 80 ml Dimethylsulfoxid während 10 Stunden auf 60°C, dann während 16 Stunden auf 700C, dann während 16 Stunden auf 800C und schließlich während 8 Stunden auf 9O0C. Man gießt dann die Reaktionsmischung langsam unter Rühren in 2,5 1 Wasser, läßt auskristallisieren, saugt den unlöslichen Feststoff ab, wäscht ihn mit Wasser und trocknet ihn schnell in der Kälte über Phosphorpentoxid. Man erhält einen klebrigen gelben Feststoff.17.6 g (0.1413 mol) of dl-alanine amide hydrochloride and 12.95 g (0.0471 mol) of 2-Qj- (ot-phenyl- ^ - amino-S-chlorobenzylidenyl) -amino ^ -ethanol are heated in the anti form in 80 ml of dimethylsulfoxide for 10 hours at 60 ° C, then for 16 hours at 70 0 C, then for 16 hours at 80 0 C and finally for 8 h at 9O 0 C. It then the reaction mixture is poured slowly with stirring in 2.5 l of water, allowed to crystallize, the insoluble solid is filtered off with suction, washed with water and dried quickly in the cold over phosphorus pentoxide. A sticky yellow solid is obtained.
Man rührt die Verbindung in etwa 100 ml kaltem Äther, filtriert dann einen unlöslichen feinen Feststoff ab, spült mit geringen Mengen des gleichen Lösungsmittels in der Kälte und trocknet im Vakuum bei Raumtemperatur. Man erhält einen sehr hellen, beigefarbenen Feststoff·. Man löst ihn in der Wärme in Isopropyläther und der minimalen Menge Äthylacetat. Man filtriert ein Harz ab, läßt den Feststoff über Nacht im Kühlschrank auskristallisieren, saugt ab, wäscht und trocknet ( bei 4O0C über Phosphorpentoxid im Vakuum) und erhält die Titel verbindung mit einem Schmelzpunkt von 143,5 - 144°C.The compound is stirred in about 100 ml of cold ether, an insoluble fine solid is then filtered off, rinsed with small amounts of the same solvent in the cold and dried in vacuo at room temperature. A very light, beige-colored solid is obtained. Dissolve it in the warmth in isopropyl ether and the minimal amount of ethyl acetate. The mixture is filtered from a resin, leaving the solids in the refrigerator overnight to crystallize out, filtered off, washed and dried (at 4O 0 C over phosphorus pentoxide in vacuo) to give the title compound having a melting point 143.5 to 144 ° C.
In der nachstehenden Tabelle sind die gemäß den obigen Beispielen und die gemäß weiterer Beispiele erhaltenen Verbindungen zusammengestellt.The table below shows the compounds obtained in accordance with the above examples and in accordance with further examples compiled.
130036/0557130036/0557
coco CD OCD O coco
CD O cn cn CD O cn cn
N-CH-COR,N-CH-COR,
(0C)S ehme1ζpunkt
( 0 C)
antisyn
anti
143,5 und 177*181-182 *
143.5 and 177 *
J Mischung
/aus der syn-
lund der anti-
\ Form
V 15/85 Γ syn
J mixture
/ from the syn-
lund the anti
\ Shape
V 15/85
164,5 .180 '
164.5.
aus der s.yn-
und der anti
Form
50/50mixture
from the s.yn-
and the anti
shape
50/50
to !to !
> H> H
■ m ■ m
\l\ l
\ m\ m
! 3D! 3D
D (S) D (S)
m com co
cn in !μ κcn in! μ κ
CO CDCO CD
cncn
tata
FORTSETZUNG DER TABELLE ITABLE I CONTINUED
COCO O CD COO CD CO cncn
CD CJICD CJI er»he"
(0C)Melting point
( 0 C)
der syn- und
der anti-Form
50/50Mix of
the syn- and
the anti form
50/50
3 'CH
3 '
,1 15,1 15th
! I! I.
U)U)
i co J-, Μι*i co J-, Μι *
1-3 S.' 1-31-3 pp. ' 1-3
IU) M t-< ! > IU) M t- <! >
oi ° oi °
cn!cn!
TER MEER · MÜLLER · STEINMEISTEn^-TER SEA MÜLLER STEINMEISTEn ^ -
SYUI'HELABO SET 43SYUI'HELABO SET 43
- 14 -- 14 -
Die Verbindungen der allgemeinen Formel I besitzen interessante pharmakologische Wirkungen, die bei ihrer pharmakologisehen Untersuchung ermittelt wurden.The compounds of general formula I have interesting pharmacological effects that in their pharmacological examination were determined.
Die akute Toxizität, die an Mäusen des Stammes CD 1 ermittelt wurde' liegt bei lntraperitonealer Verabreichung oberhalb 1000 mg/kg und bei oraler Verabreichung oberhalb 2000 mg/kg.The acute toxicity which was determined in mice of the CD 1 strain is above this in the case of intraperitoneal administration 1000 mg / kg and when administered orally above 2000 mg / kg.
Bei der Untersuchung, der antagonistischen Wirkung gegen die durch die Verabreichung von Bicuculin an Mäuse verursachten Krämpfe (D.R. Curtis et al, Brain Res. 33 (1971) 57; P. Worms et al, Life Science 25 (1979) 607) beträgt die aktive Dosis 50 % (DA,-n) , d.h. die Dosis, die 50 % der Tiere gegen die Wirkung des Bicuculins schützt, etwa 5 mg/kg bei lntraperitonealer Verabreichung und liegt bei oraler Verabreichung zwischen 4,5 bis 17 mg/kg.When examined, the antagonistic effect against the convulsions caused by the administration of bicuculin to mice (DR Curtis et al, Brain Res. 33 (1971) 57; P. Worms et al, Life Science 25 (1979) 607) is the active one Dose 50% (DA, - n ), ie the dose which protects 50% of the animals against the action of bicuculin, about 5 mg / kg for intraperitoneal administration and between 4.5 and 17 mg / kg for oral administration.
Bei dem "Eating test" (R.J. Stephens, Brit.J. Pharmacol. (1973) 146) werden die untersuchten Verbindungen in variierenden Dosierungen auf oralem Wege an Mäuse verabreicht. Für jede Dosis wird der Prozentsatz der Zunahme des Futterverbrauchs im Vergleich zu den Kontrolltieren ermittelt. In der nachstehenden Tabelle II sind die mit verschiedenen Dosierungen der Verbindungen der allgemeinen Formel I ermittelten Prozentsätze zusammengestellt:In the "Eating test" (R.J. Stephens, Brit.J. Pharmacol. (1973) 146) the compounds investigated are administered orally to mice in varying doses. For at each dose the percentage of the increase in feed consumption compared to the control animals is determined. In Table II below shows the values determined for the compounds of general formula I with various dosages Percentages compiled:
ρ.ο.Dose mg / kg
ρ.ο.
10
303
10
30th
+ 25 bis + 68
+ 20 bis + 91+ 7 to + 44
+ 25 to + 68
+ 20 to + 91
130036/0557130036/0557
TER MEER · MÜLLER · STEINMEISTER . - _ ggy 53TER MEER · MÜLLER · STEINMEISTER. - _ ggy 53
- 15 -- 15 -
Die Untersuchungen zeigen, daß die erfindungsgemäßen Verbindungen antikonvulsive und/oder anxiolytische Wirkungen entfalten, beispielsweise zur Behandlung der Epilepsie, von Krämpfen und der Angst eingesetzt werden können.The studies show that the compounds according to the invention have anticonvulsant and / or anxiolytic effects can be used, for example, to treat epilepsy, cramps and anxiety.
Gegenstand der Erfindung sind daher auch Arzneimittel, die die obengenannten Verbindungen der allgemeinen Formel I als Wirkstoffe neben üblichen Bindemitteln, Trägermaterialien und/oder Hilfsstoffen enthalten. Diese Arzneimittel können in jeder beliebigen pharmazeutischen Form vorliegen, die auf oralem oder parenteralem Wege verabreicht werden können, beispielsweise in Form von Gelkügelchen, Gelatinekapseln, Tabletten, Kapseln, Dragees und Suspensionen.The invention therefore also relates to medicaments which contain the abovementioned compounds of the general formula I as active ingredients in addition to conventional binders, carrier materials and / or auxiliaries. These medicines can be in any pharmaceutical form administered by the oral or parenteral route can, for example in the form of gel beads, gelatin capsules, tablets, capsules, coated tablets and suspensions.
Die tägliche Dosierung kann sich von 5 bis 500 mg erstrecken. The daily dosage can range from 5 to 500 mg.
130036/0557130036/0557
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7929139A FR2470116A1 (en) | 1979-11-27 | 1979-11-27 | BENZYLIDENIC DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3044542A1 true DE3044542A1 (en) | 1981-09-03 |
Family
ID=9232118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19803044542 Withdrawn DE3044542A1 (en) | 1979-11-27 | 1980-11-26 | BENZYLIDE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THE SAME |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5692852A (en) |
| AT (1) | AT372077B (en) |
| AU (1) | AU535262B2 (en) |
| BE (1) | BE886361A (en) |
| CA (1) | CA1145760A (en) |
| DE (1) | DE3044542A1 (en) |
| DK (1) | DK503180A (en) |
| ES (1) | ES8107168A1 (en) |
| FR (1) | FR2470116A1 (en) |
| GB (1) | GB2063867B (en) |
| GR (1) | GR72133B (en) |
| IL (1) | IL61568A (en) |
| IT (1) | IT1134469B (en) |
| LU (1) | LU82958A1 (en) |
| NL (1) | NL8006427A (en) |
| NO (1) | NO803561L (en) |
| NZ (1) | NZ195654A (en) |
| PT (1) | PT72114B (en) |
| SE (1) | SE8008279L (en) |
| ZA (1) | ZA807389B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8220421A (en) * | 1982-07-30 | 1984-06-01 | Inst Organicheskogo Sinteza Ak | Carcinostatic compsns. for lung cancer treatment - comprise condensation prods. of amino-isopropyl phenyl ketone with e.g. substd. amine(s) or hydrazine(s) or aminoacid derivs. |
| US5278191A (en) * | 1988-08-31 | 1994-01-11 | G. D. Searle & Co. | Diphenylmethylaminoacetamide derivatives as anti-convulsants |
| EP4627902A3 (en) | 2018-09-14 | 2026-01-14 | Precision Planting LLC | Fluid control assembly and system |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1497456A (en) * | 1964-06-15 | 1967-10-13 | Clin Byla Ets | Ortho-amino aryl ketimines, heterocyclic compounds attached to them and preparation of these various bodies |
-
1979
- 1979-11-27 FR FR7929139A patent/FR2470116A1/en active Granted
-
1980
- 1980-11-26 NZ NZ195654A patent/NZ195654A/en unknown
- 1980-11-26 AT AT0577780A patent/AT372077B/en active
- 1980-11-26 NO NO803561A patent/NO803561L/en unknown
- 1980-11-26 CA CA000365550A patent/CA1145760A/en not_active Expired
- 1980-11-26 IL IL61568A patent/IL61568A/en unknown
- 1980-11-26 NL NL8006427A patent/NL8006427A/en not_active Application Discontinuation
- 1980-11-26 IT IT26247/80A patent/IT1134469B/en active
- 1980-11-26 GR GR63468A patent/GR72133B/el unknown
- 1980-11-26 ES ES497146A patent/ES8107168A1/en not_active Expired
- 1980-11-26 PT PT72114A patent/PT72114B/en unknown
- 1980-11-26 JP JP16736380A patent/JPS5692852A/en active Pending
- 1980-11-26 GB GB8037869A patent/GB2063867B/en not_active Expired
- 1980-11-26 DE DE19803044542 patent/DE3044542A1/en not_active Withdrawn
- 1980-11-26 AU AU64730/80A patent/AU535262B2/en not_active Ceased
- 1980-11-26 DK DK503180A patent/DK503180A/en not_active Application Discontinuation
- 1980-11-26 LU LU82958A patent/LU82958A1/en unknown
- 1980-11-26 ZA ZA00807389A patent/ZA807389B/en unknown
- 1980-11-26 BE BE0/202944A patent/BE886361A/en not_active IP Right Cessation
- 1980-11-26 SE SE8008279A patent/SE8008279L/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| NICHTS-ERMITTELT * |
Also Published As
| Publication number | Publication date |
|---|---|
| ES497146A0 (en) | 1981-10-01 |
| IT8026247A0 (en) | 1980-11-26 |
| AT372077B (en) | 1983-08-25 |
| FR2470116A1 (en) | 1981-05-29 |
| IL61568A0 (en) | 1980-12-31 |
| DK503180A (en) | 1981-05-28 |
| IT1134469B (en) | 1986-08-13 |
| NL8006427A (en) | 1981-07-01 |
| AU535262B2 (en) | 1984-03-08 |
| GB2063867A (en) | 1981-06-10 |
| BE886361A (en) | 1981-05-26 |
| LU82958A1 (en) | 1982-06-30 |
| ZA807389B (en) | 1981-11-25 |
| GB2063867B (en) | 1983-09-14 |
| FR2470116B1 (en) | 1983-07-18 |
| PT72114A (en) | 1980-12-01 |
| AU6473080A (en) | 1981-06-04 |
| JPS5692852A (en) | 1981-07-27 |
| PT72114B (en) | 1981-09-29 |
| NO803561L (en) | 1981-05-29 |
| GR72133B (en) | 1983-09-19 |
| SE8008279L (en) | 1981-05-28 |
| IL61568A (en) | 1984-12-31 |
| ES8107168A1 (en) | 1981-10-01 |
| ATA577780A (en) | 1983-01-15 |
| NZ195654A (en) | 1982-05-31 |
| CA1145760A (en) | 1983-05-03 |
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Free format text: KAPLAN, JEAN-PIERRE, CHEVILLY LARUE, FR RAIZON, BERNARD, VIGNEUX, FR |
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