Process for preparing derivatives of 9-aminoalkylfluorenes or their pharmaceutically acceptable salt

专利摘要:
A 9-aminoalkylfluorene of formula <CHEM> wherein: R<1> is hydroxy, cyano, CONR<6>R<7> in which R<6> and R<7> are independently hydrogen or alkyl; n is an integer from 3 to 5; R<2> and R<3> are independently hydrogen, alkyl, alkenyl or phenyl alkyl, or taken together with the adjacent nitrogen atom form a heterocyclic group optionally including one further heteroatom selected from oxygen and nitrogen, and which ring is optionally substituted by up to two alkyl groups; R<4> and R<5> are independently hydrogen, alkyl or halogen; provided that R<2> is hydrogen when R<1> is hydroxy; or a pharmaceutically-acceptable salt thereof, have been found to be very effective in the therapy of cardiac disorders, particularly cardiac arrythmias.
公开号:SU1015820A3
申请号:SU813229055
申请日:1981-01-15
公开日:1983-04-30
发明作者:Байант Лейсфилд Вильям；Ли Саймон Ричард
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

SP
00
iNd Found,% s C 78.43 H 8.11; N 8.59 9- (3 N-Benzil-N-isopropyl-aminopr (epil) -9-aminocarbonylfluorene. Ri p im 6 p 11. 9-J3- (2,6-Dimeti piperidineb propyl 3-9-cyanofluorene. 2, 6 Dimethyl-1- (3-chloropropyl) pipidine, HYDR9HL ori D. 2,6-Dimvtilylpiperidine Cyb9.5 g, 1.5 mol were reacted in aeote atmosphere with 3-Srompropanol (195 g, 1.4 mol ) in 800 MP of dry furan tetrahydr as a solvent, half of 2,6-dimethyl-1- (3-hydroxypropyl pipridine. This liquid L95.2 g, 0.55 mol) is then chlorinated with thionyl chloride (178.5 g, 1 , 5 mol) using chloroform (1 l) as a solvent and in the presence of gaseous HCU, getting named The product is in the form of gray crystals (67.8 g), mp (169-171 ° C.. (2, b-Dimethylpiperidino)) trans IZ-9-cyanofluorone. 9-Cyanofluorene (19.1 g, 0, 1 mol and sodium amide (g, 0.12 mol) are heated under reflux with dry toluene in a one liter, three flask for 2 hours, 2,6-dimethyl-1- (3-chloropropyl) piperidine (22.7 g, 0 , 12 mol) also in dry toluene is added to the flask and the mixture is heated under reflux overnight. The reaction mixture is cooled and water is added dropwise, then the mixture is poured into ice-water and extracted with diester. After further processing and recrystallization from Skelly B, light brown crystals of the title product are obtained (22.2 g), mp 78–81 ° C, ° C im 12 12. 9–3-igb-Dimetiopiperidino) propyl-9-aminocarbonylflyureon . the salt of maleic acid Nitrile 5.0 g) of Example 11 is added to a hundred-pound round-bottom cob. Sulfuric acid (90%, 20 g) is cooled and slowly added to neither the tride in the flask. The mixture is then heated on a steam cone for 45 minutes. The solution thus obtained. is added to ice water and alkalinized with aqueous sodium hydroxide (10%). This substance is then extracted with ethyl acetate and diethyl ether, and the extracts are washed with water. After drying over sodium sulfate, the amide thus obtained (5.4 g, mol) is introduced by reacting with maleic acid (L, 7 g, 0.015 mol) in ethyl acetate (150 sludge) and ethanol 125 ml) in a single-neck circle of a 500 ml flask. The recrystallized salt thus obtained is extracted from ethanol and ethyl acetate, yield 1.3 g, m.p. 182-184 ° C. Example 13. Ingredients Content, mg1 | 9- (3-IsopropylLaminopropyl) -9-aminocarbonylfluorene, hydrochloride20 Starch240 Saccharose240 These ingredients are thoroughly mixed with a lubricant, and the mixture is formed into tablets. Example 14. Formula suitable for intravenous administration, containing ingredients: 9- (3-And opropylaminopropyl J-9-aminocarbonylfluorene, hydrochloride, mg225 Isotonic. Physiological saline, mg450 10% aqueous glucose, ml 450 These ingredients are mixed to form a solution which can be infused into a patient suffering from arrhythmia. Derivatives of 9-aminoalkylfluorenes are useful as antiarrhythmic agents, as confirmed by biological tests. One of these analyzes involves the administration of a compound with non-arrhythmias. Natural biological activity of dogs suffering from experimentally-induced cardiac arrhythmia and monitoring its effect on bringing arrhythmia to a normal sinus rhythm and the duration of this process. In a typical test, by definition: the activity of the proposed compounds of one or more mongrel dogs of either sex anesthetize pentob. a sodium arbiter. A Butterfly Injection Needle, size 23, is placed (t in a radial vein for administration to a dog; a sufficient amount of ouabain (to induce; arrhythmia) and test compound. Each dog is constantly monitored during the experiment with an electrocardiogram readout. After . caused by ouabain arrhythmias continued for 30 minutes, compound i was injected with a needle. for Butterfly injections at a dose of 20 µg per kg body weight of the dog per 1 minute. If the arrhythmias are not conducted to the normal sinus rhythm within 10 minutes from the start of administration tested. compounds that are examined with the aid of an electrocardiogram, the degree of administration of the test compound is increased to 500 µg per kg per minute. The amount of compound tested is necessary to reduce arrhythmias.
to the normal rhythm of the sinus, register as a therapeutic dose. After the completion of the administration of the test compound, the dog's heart is checked by electrocardiogram removal until the arrhythmia appears again or during the maximum
a period of 2 hours, after which the experiment ends. The duration of a normal rhythm is recorded in minutes.
The table shows the results of experiments.
W “
N
/
AjR,
H
Isoprodil
and sn,
H
The compounds of formula (IJ can be used to treat cardiac arrhythmias in animals. The compounds are effective as antiarrhythmic agents when administered to an animal in the cardiovascular system. Parenteral administration of the compounds can be achieved by intraperitoneal, mobile or intravenous injection. Compounds can be administered orally in the form of tablets, capsules, elixirs, syrups, buccal hermetic preparations, etc. Possible pharmaceutical form of the preparation, which includes soy dynenie formula (.1) or its analogue, in which
120
104
80
. 18
is COj-R r where hydrogen is hydrogen or skyl with 1-4 carbon atoms of the genus, or its pharmaceutically acceptable salt in combination with a pharmaceutically acceptable carrier for it.
Aminoalkylfluorenes have good antiarrhythmic activity both in therapeutic terms, for example, when administered to animals suffering from arrhythmia and in need of treatment, and prophylactically when prescribed to animals suspected of developing arrhythmias and developing animals to protect them from developing or recurring | arrhythmias.

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING 9-AMYNOALKylFLUORENE DERIVATIVES OR THEIR PHARMACEUTALLY ACCEPTABLE SALTS (57) Method for the preparation of 9-aminoalkylfluorenes derivatives of the general formula
H where R-, - CONHj, η is an integer of 3,
R j and Rj are hydrogen, C ₁ -C 4 = alkyl, or taken together with the adjacent nitrogen atom form a piperidino group which can be substituted at the 2.6 Cf-Cq position. = alkyl
R ₄ , Rj is hydrogen.
or their pharmaceutically acceptable salts, characterized in that the hydrolysed compound of formula (D) wherein represents the cyano group in an acid medium at 100 ^e C with subsequent isolation of the desired product in the free form or in salt form.
_m SU, „, 1015820

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US1953379A| true| 1979-03-12|1979-03-12|

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