GB2271109A - Pharmaceutically active substituted alkylamine derivatives - Google Patents
Pharmaceutically active substituted alkylamine derivatives Download PDFInfo
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- GB2271109A GB2271109A GB9220601A GB9220601A GB2271109A GB 2271109 A GB2271109 A GB 2271109A GB 9220601 A GB9220601 A GB 9220601A GB 9220601 A GB9220601 A GB 9220601A GB 2271109 A GB2271109 A GB 2271109A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
Novel substituted alkylamine derivatives of the general formula <IMAGE> wherein X represents an oxygen atom, a sulfur atom or a group of the formula -NRb- in which Rb represents a hydrogen atom or an alkyl group; R1 represents an alkenyl group which may be substituted, an alkinyl group which may be substituted, an aryl group which may be substituted, or a heteroaryl group which may be substituted; R2 represents a hydrogen atom or an alkyl group; R3 represents a hydrogen atom, an alkyl group, haloalkyl group, an alkenyl group, an alkinyl group or a cycloalkyl group, R4 represents hydrogen, allyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, phenylcycloalkyl, trialkylsilyl, dialkylphenylsilyl, trifluoromethyl or alkoxycarbonyl, whereby alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyl may be substituted by alkoxy, alkylthio, hydroxy, halogen, cyano or a heterocyclic group and may contain a carbonyl group, R5 and R6 represent, independently from each other, hydrogen, halogen, cyano, trifluoromethyl, alkyl, alkoxy, hydroxy or alkylthio, whereby R3 may form together with the -CH2-group and nitrogen atom a group of formula <IMAGE> wherein m represents a number from 2 to 5, or R3 may form together with the nitrogen atom and the -CH2-group a group of formula <IMAGE> wherein x represents a number from 0 to 3, and nontoxic salts of these are useful against hypercholesterolemia, hyperlipemia and asteriosclerosis.
Description
New organic compounds, processes for production thereof and their use
This invention relates to novel substituted alkylamine derivatives. More specifically, it relates to substituted alkylamine derivatives and their salts which are useful as pharmaceuticals, particularly for the treatment and prevention of hypercholesterolemia, hyperlipemia and arteriosclerosis, processes for production thereof, and their use.
Arteriosclerosis is a degenerative arterial disease which has closely to do with aging and diet, and is regarded as the cause of coronary and cerebral arterial diseases, the principal cause of death in the present day. Arteriosclerosis begins in early ages as deposition of lipid on the endothelia of large vessels, and with age, its degree increases. it will finally show clinical symptoms as ischemic heart diseases such as myocardial Infarction and angina pectoris, cerebral arteriosclerosis such as cerebral infarction, and aneurism. It is known that the increase of various blood lipids is involved in this lipid deposition. In particular, the increase of blood cholesterol is the most prominent risk factor, and decreasing the blood cholesterol level to a normal value is the most effective therapeutic and prophylactic means against arteriosclerosis.It is said that in humans, more than 50 % of cholesterol is derived from de novo biosynthesis.
Nowadays lovastatin and pravastatin which are inhibitors of enzymes in the process of de novo biosynthesis are clinically used as hypocholesterolemic agents (see, for example, A.W. Alberts et al., Proc. Nati. Acad. Sci., vol. 77, page 3957, 1980; and Tsujita et al., Biochim.
Biophs. Acta, vol. 877, page 50, 986). However, since 3-hydroxymethyl glutaryi-coenzyme A reductase, a target enzyme of these inhibitors, is positioned In the early stage of the cholesterol biosynthesis pathway, the administration of these drugs will also inhlbit formation of dolichol and ubiquinone which are other biologicaliy important metabolites. Furthermore, it was reported that triparanol, an inhibitor of the later stage of the cholesterol biosynthesis pathway, becomes the cause of cataract due to the accumulation of desmosterol. Since squalene epoxidase is positioned in the middle stage of the cholesterol biosynthesis pathway, an inhibitor of this enzyme is expected to solve these problems and serve as a hypocholesterolemic agent with high safety.
It is a primary object of this invention to provide an hypolipemic agent, and a therapeutic and prophylactic agent for arteriosclerosis which is safer and better than conventional hypolipemic agents.
Thus, the present invention provides substituted alkylamine derivatives represented by the general formula
wherein X represents an oxygen atom, a sulfur atom or a group of the formula -NRb- in which Rb represents a hydrogen atom or a lower alkyl group; R1 represents a lower aikenyl group which may be substituted, a lower alkinyl group which may be substituted, an aryl group which may be substituted. or a heteroaryl group which may be substituted; R2 represents a hydrogen atom or a lower alkyl group;R3 represents a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkinyl group or a cycloalkyl group, R4 represents hydrogen, lower alkyl, lower aikenyl. lower alkinyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, phenylcycloalkyl, trialkyisilyl, dialkylphenyisilyl, trifluoromethyl or alkoxycarbonyl, whereby alkyl, alkenyl, alkyl, cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyi may be substituted by alkoxy, alkylthio, hydroxy, halogen, cyano or a heterocyclic group and may contain a carbonylgroup, R5 and R6 represent, independently from each other, hydrogen, halogen, cyano, trifluoromethyl, lower alkyl. lower alkoxy, hydroxy or lower alkylthio, whereby R3 may form together with the -CH2-group and nitrogen atom a group of formula
wherein m represents a number from 2 to 5, or R3 may form together with the nitrogen atom and the -CH2-group a group of formula
wherein x represents a number from 0 to 3, nontoxic salts of these, processes for production thereof, and the use thereof in the treatment of hypercholesterolemia, hyperlipemia and arteriosclerosis.
The term "lower", as used in the present specification and the appended claims to qualify a group or a compound, means that the group or compound so qualified has not more than 6, preferably not more than 4 carbon atoms.
The lower alkyl group may be, for example, a linear or branched alkyl group having 1 to 6 carbon atoms. The lower alkenyl group may be, for example, a linear or branched alkenyl group of 2 to 6 carbon atoms containing 1 or 2 double bonds in the carbon chain. The lower alkinyl group may be, for example, a linear or branched alkinyl group of 2 to 6 carbon atoms containing 1 or 2 triple bonds in the carbon chain.
The lower alkoxy group may be, for example, a linear or branched alkoxy group having 1 to 4 carbon atoms. The lower alkenyloxy group includes linear or branched alkenyloxy groups having 3 to 6 carbon atoms. Examples of the cycloalkyl groups are cycloalkyl groups having 3 to 7 carbon atoms.
Examples of the aryl group include monocyclic or polycyclic aromatic groups such as phenyl, naphthyl and tetrahydronaphthyl groups. The heterocyclic group may be, for example, 5- to 1 2-membered, preferably 5- or 6-membered, heterocyclic groups having 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring.
The halogen atoms may be, for example, fluorine, chlorine, bromine or iodine.
Examples of the substituents on the lower alkyl, lower alkinyl and cycloalkenyl groups which may be substituted include a hydroxyl group, halogen atoms, a cyano group, lower alkoxy groups, aryl groups and heterocyclic groups. The above alkenyl, alkinyl and cycloalkenyl groups may be substituted by 1 or 2 of these substituents.
Examples of the substituents in the aryl groups (or phenyl group) and heterocyclic groups which may be substituted include a hydroxyl group, halogen atoms, a cyano group, a formyl group, lower alkyl groups, lower haloalkyl groups, lower hydroxyalkyl groups, lower alkenyl groups, lower alkenyloxy groups, aryl groups and heterocyclic groups. The above aryl groups and heterocyclic groups may be substituted by 1 to 3 such substituents, preferably 1 or 2 such substituents.
The lower alkenyl group R1 which may be substituted is a linear or branched lower alkenyl group which may be substituted, for example, by a hydroxyl group, a halogen atom, a cyano group, a lower alkoxy group, an aryl group or a heterocyclic group. Preferably, it may be an unsubstituted lower alkenyl group.
Examples of especially preferred lower substituted alkenyl groups R1 include unsubstituted alkenyl groups of 3 to 5 carbon atoms.
The lower alkyl group R1 which may be substituted represents a lower alkinyl group which may be substituted, for example, by a hydroxyl group, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, an aryl group, or a heterocyclic group.
The aryl group R1 which may be substituted represents an aryl group which may be substituted, for example, by a hydroxyl group, a halogen atom, a cyano group, a formyl group, a lower alkyl group, a halogenaikyl group having 1 or 2 carbon atoms such as a trifluormethyl or 2.2,2-trifluoroethyl group, a hydroxyalkyl group having 1 or 2 carbon atoms such as a hydroxymethyl or 1-hydroxyethyl group, a lower alkenyl group, a lower alkoxy group, a linear or branched lower alkenyloxy group having 3 to 5 carbon atoms, an aryl group or a heterocyclic group.
The heteroaryl group R1 which may be substituted represents for example, a heteroaryl group which may be substituted by, for example, a hydroxyl group, a halogen atom, a cyano group, a formyl group, a lower alkyl group, a halogenoalkyl group having 1 or 2 carbon atoms, a hydroxyalkyl group having 1 or 2 carbon atoms, a lower alkenyl group, a lower alkoxy group, a lower alkenyloxy group, an aryl group or a heterocyclic group. Examples of preferred heteroaryl groups R1 include 5- to 1 2-membered, preferably 5- or 6-membered, unsubstituted aromatic heterocyclic groups containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms.
R2 is preferably a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms such as a methyl, ethyl, propyl or isopropyl group. The hydrogen atom is preferred.
R3 represents a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkinyl group or a cycloalkyl group, for example linear or branched lower alkyl groups having 1 to 5 carbon atoms, linear or branched lower alkenyl groups having 3 to 5 carbon atoms, linear or branched lower alkinyl groups having 3 to 5 carbon atoms and cycloalkyl groups having 3 to 5 carbon atoms. Methyl, ethyl, propyl, cyclopropyl. allyl and propargyl groups are preferred, and the methyl, ethyl and propyl groups are most preferred.
A preferred group of the compounds provided by this invention are substituted alkylamines of general formula I in which R1 represents an aryl or heteroaryl group which may be substituted; X represents an oxygen atom or an imino group; R2 represents a hydrogen atom; R3 represents an alkyl group having 1 to 5 carbon atoms, R4 represents a lower alkyl group or a phenylalkyl group, R5 and R5 represent hydrogen.
The above substituted alkylamine derivatives may exist in the form of an acid addition salt.
Examples of the acid addition salts are inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, perchlorates and phosphates, and organic acid salts such as p-toluenesulfonates, benzenesulfonates, methanesulfonates, oxalates, succinates, tartarates, citrates, fumarates and maleates. Preferably, they are nontoxic salts which are pharmaceutically acceptable. Furthermore, depending upon the embodiments of the substituents, the compounds of formula I provided by this invention may contain stereoisomers such as geometric isomers and optical isomers. The compounds of formula I of this invention include all of these stereoisomers and their mixtures.
The compounds of this invention may be produced by one of the following processes A, B, C and D.
Reaction Scheme
In the above formulae. B represents a leaving group, R'3 represents a lower alkyl group, a lower alkenyl group, a lower alkinyl group, a lower haloalkyl group or a cycloalkyl group and the rest of the substituents are as defined above.
The above processes A, B and C are alkylation of amines which are well known in the field of organic syntheses, and can therefore be carried out by using ordinary means known per se. These processes are carried out by using a solvent which does not adversely affect the reactions, and reacting compounds of formulae il and Ill in process A, compounds of formulae IV and V in process B and compounds of formulae la and Vl in process C in nearly equimolar proportions or using one of them in a slightly excessive proportion.Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; alcohols such as ethanol and isopropanol; dimethylformamide, acetone, acetonitrile and dimethyl sulfoxide, and mixtures of these. The reaction temperature is generally -200 C to 1500 C, preferably from room temperature to the boiling point of the solvent used.
The reaction time may be usually 5 minutes to 10 days, preferably 1 to 24 hours. Advantageously, the reactions are carried out in the presence of a base In order to carry them out smoothly. Examples of the base are alkali metal hydrides such as sodium hydride, lithium hydride and potassium hydride; alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate; and organic amines such as triethylamine and pyridine. The amount of the base used Is not critical, and can be varied over a broad range. Generally, it is nearly 1 mole, or slightly more, preferably 1 to 2 moles, per mole of the starting materials.
Process D is usually carried out in a solvent which does not adversely affect the reaction (such as tetrahydrofuran, dioxane, chloroform, benzene, acetone, dimethylformamide or dimethyl sulfoxide) by reacting compounds of of formulae VII and VIII in nearly equimolar proportions or using one of them in a slightly excessive molar proportion. The reaction conditions used at this time vary depending upon the starting compounds used. Generally, the reaction temperature is in the range of -700 C to 1000 C, preferably -200 C to 50 C, and the reaction time is 1 minute to 24 hours, preferably 30 minutes to 5 hours. Preferably, the reaction is carried out in the presence of a base. Examples of the base used at this time are inorganic bases such as sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate and organic bases such as pyridine, triethylamine and dimethylaminopyridine. The amount of the base used is not critical, and can be varied over a broad range. Generally, it is nearly 1 mole, or slightly more, preferably 1 to 2 moles, per mole of the starting materials. If the starting compounds contain reactive functional groups such as a hydroxyl or amino group in addition to the groups which are involved in the reaction, these reactive functional groups may, as required, be protected prior to the reaction, and the protected groups may be removed after the reaction.Protective groups which can be easily eliminated by hydrolysis under acidic or alkaline conditions may be used for this purpose. Examples of the protective groups are methoxymethyl, tetrahydropyranyl, trityl, dimethyl(tert.butyl)silyl, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl and tert.butoxycarbonyl groups.
The desired compounds of formula I obtained by the above processes in accordance with this invention can be isolated and purified by, for example, column chromatography, solvent extraction, precipitation and recrystallization, either alone or in combination. As required, the compound of formula I as a free base may be converted to its acid addition salt, or vice versa.
The step of converting the free base of the compound of formula l into its acid addition salt or the step of converting the acid addition salt to its free base can be carried out easily by ordinary methods using the corresponding acids or bases.
The leaving group represented by B may be, for example, a halogen atom such as a chlorine, bromine or iodine atom, or an organic sulfonyloxygroup such as a methanesulfonyloxy or p-toluenesulfonyloxy group.
The starting compounds used in processes A to D are known, or may be produced and obtained by the methods described in the literature, the general processes shown in the examples, or processes substantially in accordance with them.
The compounds of this invention represented by general formula I Inhibit the mammalian squalene epoxidase very selectively and strongly, and are expected to be useful as an hypolipemic agent or an antiarteriosclerotic agent. The following pharmacological test examples demonstrate this fact.
1. Squalene epoxidase inhibitory teat:
The rat squalene epoxidase was prepared by the method described in J. Biol. Chem., vol. 245, page 1670, 1970; ibid., vol. 250, page 1572, 1975.
The squalene epoxidase activity was assayed in accordance with the method described in
J. Biol. Chem., vol. 245, page 1670, 1970.
As a result, the 50 % inhibitory concentrations (IC50 values) of the compounds of this invention on squalene epoxidase were determined.
2. Inhibitory activity on cholesterol biosynthesis in cultured cells:
Human Hepatoma cells are obtained from the American Type Culture Collection (HepG2; ATCC HB 8065). Passing stocks of preconfluent monolayers are maintained in 75 cm2 flasks in Dulbecco's Modified Eagle Medium (DMEM) containing 10 % fetal bovine serum with 2 mM
L-glutamine, 0.1 mM non-essential amino acids, 100 Ulml penicillin and 100 sLg/ml streptomycin. For experiments, cells are released by trypsinization and seeded into 24-well plates at a density of 1x105 cells per well.After 72 hours, the growth medium is removed, the cells are rinsed with Dulbecco's phosphate buffered saline, and the medium is replaced with 1 mllwell of Defined Growth medium (DMEM supplemented with 0,1% Mito+Media supplement (Collaborative Research Inc., Bedford), 2 mM L-glutamlne, 0.1 mM non-essential amino acids, 100 U/ml penicillin and 100 ijg/ml streptomycin. After 24 hours, the medium is again replenished using Defined Growth medium, and the cells are incubated for an additional 24 hours.
On the day of the experiment, the growth medium is removed, the cells are rinsed with PBS, 0.25 ml of Labeling Medium (Defined Growth medium supplemented with 15% glycerol, 0.16 nM 3H-mevalonolactone and 0.2 % bovine serum albumin) are added, and the test compound is added in 2.5 lli of dimethyl sulfoxide. After 4 hours at 37 C the cells are rinsed with PBS and solubilized in 1 ml urea extraction buffer (8.33 M urea In 10 mM Tris-HCl, pH 7.8,1 mM EDTA). From the urea extract, 20 Crl are taken for protein analysis using the method of Bradford (Anal.Biochem. 72, 248-255 (1976)), 100 ul are taken for determination of total incorporation of label and 750 l are taken for extraction of neutral lipids. For neutral lipids, the 750 1ll urea extract is added to 750 ul acetone and mixed, and the mixture is extracted with 3 ml hexane. After removing a 100 Cll aliquot of the hexane extract for determination of total neutral lipid synthesis. the remaining portion is drIed under a stream of nitrogen gas, resuspended in chloroform containing 25 crag non-radioactive cholesterol and applied to a 20 x 20 cm plastic-backed 0.2 mm thick silica gel 60 thin layer chromatographic plate.After developing the plates twice in chloroform, the location of the cholesterol band is visualized using iodine vapor, and the cholesterol bands are cut out and counted. Test compound activity (ED50) is calculated as the concentration of compound giving 50 % Inhibition of cholesterol synthesis (dpm cholesterol per well) relative to control wells of cells.
3. Teat on inhibition of cholesterol biosynthesis in vivo:
Male SD rats, 5 weeks of age, were used in the in vivo test. The rats were kept for 9 days in an environment of reversed light cycle (i.e., dark between 6:00 a.m. and 6:00 p.m.). The rats were allowed to take a solid diet and water freely. The test drug was orally administered two hours before dark sixth hour when the cholesterol synthesis reached a maximum. The compounds were administered as a suspension in a 0,5 % aqueous solution of methyl cellulose or in a 0,5 % aqueous solution of methyl cellulose containing 5 % of dimethyl sulfoxide and 1 % Tween 80. The dose was 1 ml/100 g of body weight.
An equal volume of 0,5 % methyl cellulose was administered to a control group. One hour after administration of the test drug, C14 sodium acetate (56 mCi/mmole) was intraperitoneally administered to the rats in a dose of 201lCi/100 g of body weight. At dark sixth hour, a blood sample was obtained from the abdominal artery under ether anesthesia, and the plasma was separated by centrifugation.
Two milliliters of plasma was mixed with a 15 % methanoiic potassium hydroxide and saponified by heating at 750 C for 3 hours. The resulting sample was extracted with 2 ml of petroleum ether twice. The extracts were washed with 2 ml of distilled water, and finally evaporated under a nitrogen stream. The resulting residue was dissolved in a small amount of ethyl ether, and all the solution was spotted on a precoated silica gel TLC plate. The plate was developed with a solvent system composed of hexanelethyl etherlacetic acid (85/15/4). Color formation was carried out by iodine, and the radioactivity of the cholesterol portion was measured by a liquid scintillation counter.
The results were expressed in dpm of the resulting C14-cholesterol present in 1 ml of the plasma. The inhibition of cholesterol biosynthesis was calculated by comparing the amounts of C14-cholesterol biosynthesized in the test group and that in the control group.
The following examples illustrate the present invention, without limiting the scope.
Example 1: N-Ethyl-N-[3- (2-methylbenzyloxy) benzyl]-4- (2-phenyl-2-propyl) benzylami- ne (process D) 300 mg of N-ethyl-N-(3-hydroxybenzyl)-4-(2-phenyl-2-propyl)benzylamine are dissolved in 4 ml of a mixture of absolute tetrahydrofurane and absolute dimethylformamide (v/v=2/1) and 38 mg of 80 % sodiumhydride are added. After 30 minutes 185 mg of 2-methylbenzylbromide in 6 ml absolute dimethylformamide are added. The reaction mixture is stirred for 6 hours at room temperature, then poured onto 150 ml of water and extracted with ethylacetate. The crude product thus obtained is purified chromatographically on silicagel (hexan/ethylacetate = 4/1) to give the title compound as a colourless oil.
The following compounds may be obtained analogously. In the table the substituents have the following meaning: R2 = R5 = R6 = hydrogen
The substituent R4 is in the 4-position.
Ex. | R1 x A4 2 O -0- pH3 colouriess oil 3 v ÇL -O- CH3 CH3 5 H3 -0- H3 CHC- CH F 5 CH B 6CH3 CH3 -0- - N 7 g ~O~ ~ ~ n The starting materials may be obtained in the following way:
A) N-Ethyl-N-(3-hydroxybenzyl)-4-(2-phenyl-2-propyl)benzylamlne (process A) 1,3 g of 4-(2-phenyl-2-propyl)benzylbromide are added to a mixture of 0,7 9 of N-ethyl-3-hydroxybenzylamine and 2,5 g of potassium carbonate in 15 ml of absolute dimethylformamide and the reaction mixture is stirred over night at room temperature. The mixture is poured onto 200 ml of water and extracted with ethylacetate.The extract is drIed and after removing of
the solvents the crude product thus obtained is purified chromatographically on silicagel
(hexane/ethylacetate = 4/1) to give the title compound as a colourless oil.
B) N-Ethyl-N- (3-hydroxybenzyl)-4-t. butylbenzylamine Analogously as described under A). Colourless oil.
1H-NMR-Spectra
(CDCl3) Ex:
1 7.38-7.44 (m, 1H); 7.11-7.3 (m, 13H); 7.06 (br.s, 1H): 6.96 (d, J=7,5 Hz, 1H);
6.86 (dd, J=7,5+2Hz, 1 H); 5.02 (s, 2H); 3.53 (s, 4H); 2.49 (qua, J=7Hz. 2H); 2.37 (s, 3H); 1.66 (s, 6H); 1.05 (tr, J=7Hz, 3H).
2 7.53-7.61 (m, 2H); 7.07-7.43 (m, 16H); 6.98 (d, J=7,5Hz, 1H); 6.87 (dd, J=7,5+
2Hz, 1H); 5.22 (s, 2H); 3.53 (s, 4H); 2.49 (qua, J=7Hz, 2H); 1.66 (s, 6H); 1.05
(tr, J=7Hz, 3H).
3 7.04-7.4 (m, 16); 6.98 (d,j=7.5Hz, 1H); 6.87 (dd, J=2+7,5Hz, 1H); 5.2 (s,2H);
3.53 (s, 4H); 2.19 (qua, J=7Hz, 2H); 1.66 (s, 6H); 1.05 (tr, J=7Hz, 3H).
4 7.11-7.4 (m, 19H); 7.05-7.1 (m, 1H); 6.97 (d, J=7,5Hz, 1H); 6.82-6.88 (m, 1H);
5.0 (s, 2H); 3.53 (s, 4H); 2.49 (qua, J=7Hz, 2H): 1.68 (s, 6H); 1.66 (s, 6H);
1.04 (tr, J=7Hz, 3H).
5 7.23-7.4 (m, 4H); 7.17 (tr, J=8Hz, 1H); 6.9-6.95 (m, 2H); 6.7 (ddd,
J=8+2,5+2.5Hz, 1H); 3.56 (s, 2H); 3.53 (s, 2H); 2.51 (qus, J=7Hz, 2H); 1.32
(s, 9H); 1.08 (tr, J=7Hz. 3H).
6 7.93 (s, 1H); 7.77 (s, 1H); 7.6-7.67 (m, 1H); 7.41-7.51 (m, 2H); 7.39 (s, 1H);
7.27-7.35 (m, 4H); 7.22 (d, J=BHz, iH); 7.08-7.12 (m, 1H); 8.98 (d, J=7.5Hz,
1H); 6.87 (dd, J=2+7.5Hz, 1H); 5.11 (s, 2H); 3.54 (s, 4H); 2.5 (qua, J=7Hz, 2H);
1.3 (s, 9H); 1.05 (tr, J=7Hz, 3H).
7 7.58-7.36 (m, 10H); 7.08 (s, 1H); 6.99 (d, J=7.5Hz, 1H); 6.88 (dd, J=2+8Hz, 1H);
5.22 (s, 2H); 3.54 (s, 4H); 2.5 (qua, J=7Hz, 2H); 1.3 (s, 9H); 1.06 (tr. J=7Hz, 3H),
A 7.1-7.31 (m, 10H); 6.88-6.97 (m, 2H); 6.67-6.72 (m, 1H); 3.54 (s, 2H); 3.5
(s, 2H); 2.49 (qua, J=7Hz, 2H); 1.66 (s, 6H); 1.05 (tr, J=7Hz, 3H).
B 7.25-7.46 (m, 8H); 7.22 (tr, J=7,5Hz, 1H); .05-7.1 (m, 1H); 6.98 (d, J=7.5Hz.
1H); 6.82-6.89 (m, 1H); 5.04 (s, 2H); 3.56 (s,2H); 3.55 (s, 2H); 2.5 (qua, J=7Hz,
2H); 1.34 (s, 9H); 1.32 (s, 9H); 1.07 (tr, J=7Hz, 3H).
Claims (3)
1. Substituted alkylamine derivatives represented by the general formula
wherein X represents an oxygen atom, a sulfur atom or a group of the formula -NRb- in which Rb represents a hydrogen atom or a lower alkyl group; R1 represents a lower alkenyl group which may be substituted, a lower alkinyl group which may be substituted, an aryl group which may be substituted, or a heteroaryl group which may be substituted; A2 represents a hydrogen atom or a lower alkyl group;R3 represents a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkinyl group or a cycloalkyl group, R4 represents hydrogen, lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, phenylcycloalkyl, trialkylsilyl, dialkylphenylsilyl, trifluoromethyl or alkoxycarbonyl, whereby alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyl may be substituted by alkoxy, alkylthio, hydroxy, halogen, cyano or a heterocyclic group and may contain a carbonylgroup, Rs and A6 represent, independently from each other, hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, lower alkoxy, hydroxy or lower alkylthio, whereby R3 may form together with the -CH2-group and nitrogen atom a group of formula
wherein m represents a number from 2 to 5, or R3 may form together with the nitrogen atom and the -CH2-group a group of formula
wherein x represents a number from 0 to 3, and nontoxic salts of these.
2. A process for producing substituted alkylamine derivatives represented by the general formula
wherein X represents an oxygen atom, a sulfur atom or a group of the formula -NRb- in which Rb represents a hydrogen atom or a lower alkyl group; R1 represents a lower aikenyl group which may be substituted, a lower alkinyl group which may be substituted, an aryl group which may be substituted, or a heteroaryl group which may be substituted; A2 represents a hydrogen atom or a lower alkyl group;; A3 represents a hydrogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkenyl group, a lower alkinyl group or a cycloalkyl group, R4 represents hydrogen, lower alkyl, lower alkenyl, lower alkyl, cycloalkyl, cycloalkylalkyl, phenyl, phenylalkyl, phenylcycloalkyl, trialkylsilyl, dialkyiphenylsilyl, trifluoromethyl or alkoxy carbonyl, whereby alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyl may be substituted by alkoxy, alkylthio, hydroxy, halogen, cyano or a heterocyclic group and may contain a carbonylgroup, Rs and A6 represent, independently from each other, hydrogen, halogen, cyano, trifluoromethyl, lower alkyl, lower alkoxy, hydroxy or lower alkylthio, whereby R3 may form together with the -CH2-group and nitrogen atom a group of formula
wherein m represents a number from 2 to 5, or R3 may form together with the nitrogen atom and the -CH2-group a group of formula
wherein x represents a number from 0 to 3, and nontoxic salts of these, which comprises
a) reacting a compound of formula
or its properly protected derivative with a compound of formula
or b) reacting a compound of formula
or its properly protected derivative with a compound of formula
wherein the substituents have the same significance as defined in claim 1 and B represents a leaving group, or c) reacting a compound of formula
with a compound of formula
wherein the substituents have the same significance as defined In claim 1, and thereafter, as required, removing the protecting group and/or converting the resulting compound into a nontoxic salt.
3. A process for producing a substituted alkylamine of formula
and nontoxic salts thereof, which comprises reacting a compound of formula
or its properly protected derivative with a compound of formula B - A'3 VI wherin the substituents have the same significance as defined in claim 1 and R'S represents
a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, a lower alkinyl group or a cycloalkyl group, and thereafter, as required, removing the protecting group and/or converting the resulting compound into a nontoxic salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9220601A GB2271109A (en) | 1992-09-30 | 1992-09-30 | Pharmaceutically active substituted alkylamine derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9220601A GB2271109A (en) | 1992-09-30 | 1992-09-30 | Pharmaceutically active substituted alkylamine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9220601D0 GB9220601D0 (en) | 1992-11-11 |
| GB2271109A true GB2271109A (en) | 1994-04-06 |
Family
ID=10722739
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9220601A Withdrawn GB2271109A (en) | 1992-09-30 | 1992-09-30 | Pharmaceutically active substituted alkylamine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2271109A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5861496A (en) * | 1996-11-07 | 1999-01-19 | Incyte Pharmaceuticals, Inc. | Human squalene epoxidase |
-
1992
- 1992-09-30 GB GB9220601A patent/GB2271109A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5861496A (en) * | 1996-11-07 | 1999-01-19 | Incyte Pharmaceuticals, Inc. | Human squalene epoxidase |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9220601D0 (en) | 1992-11-11 |
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| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |