CA1207797A - Substituted 2,5-diaminopentanes, their preparation and drugs containing these compounds - Google Patents
Substituted 2,5-diaminopentanes, their preparation and drugs containing these compoundsInfo
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- CA1207797A CA1207797A CA000414272A CA414272A CA1207797A CA 1207797 A CA1207797 A CA 1207797A CA 000414272 A CA000414272 A CA 000414272A CA 414272 A CA414272 A CA 414272A CA 1207797 A CA1207797 A CA 1207797A
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- Prior art keywords
- pentane
- phenyl
- isopropyl
- methylamino
- hydrogen
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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
- C07C217/62—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 linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- Heart & Thoracic Surgery (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract of the Disclosure Substituted 1,5-diaminopen-tanes of the formula I
Description
77~97 _ ~ _ o,z, r)~5n/35~9 Subst;tuted 2~5-d;aminopentanes, the;r preparat;on and druqs containing these comDounds .
The present invent;on relates to noveL substituted 1,5-diaminopentanes, a process for their preparation and drugs containing these substances.
It 1s known that VerapamiL ;s a supraventricular antiarrhythmic drug and that one of the factors contri-buting to its action is an effect on ~he atrioventricular trans~;ss;on. $n addition, Verapamil has a powerful calGium-antagonistic action and hence has a hypotems;ve gffec~ (cf.: B4N. Singh, G. Elbrodt and C.l. Peter, Drugs 10~ 15 t1978~, 16~ 197).
We have ~ound that s~bst;tuted 1,5~d;am;nopentanes cf the formula I
~1 ~ R3 R ~ R7 N-C~}I2 CH2C~l2-N- Cx2 c~{2~9 where R1 and R2 are each hydrogen or C1-C6-alkyl, R3 ;s C1-C~z-aLkyl~ R4, R5, R6~ R7, R8 and R9 are each hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy or tri-fluoromethyl and R10 is hydrogen or methyl, and their salts with physiologically tolerated acids, possess act;ons which differ qual;tatively from that mer~ioned above.
?~ Su;table phys;ologically toLerated-acjds are .
- 1207 ~
~ 2 - ~.Z. 0050/35539 hydrochloric acid, ~ulfuric acid, phosphoric acid, acetic acidO malonic acid, succ;nic acicl, fumar;c acid, maleic acid, citric acid, tartaric acid, lactic acidO amidosul-fonic acid and oxalic acid.
lhe novel compounds possess an asymme~ric carbon atom and ~ay therefore also ocrur in the form of their a~tipodes.
In the formula I, R1 and R~ are each preferably C1-C4-alkyl, in particular methyl, R3 is preferably 1~ C1 C4-alkyl~ R4, R5, R6, R7, R8 and R9 are each preferably hydrogen or methyl and R1Q is, ;n particular, methyl.
The novel compounds can be prepared by a process in which a basically substituted phenylacetonitrile of the ~ormula II
~ C-CH C-I2CH ~N-C~ C~ ~ 8 II
R5 ~ R3 2 2 2 2 where R3 R4, R5, R6, R7, ~8, R9 and R10 have the above meanings~ is reduced and the resulting compound, which may, if desired, be first monoalkylated or dial-kylated, is, if appropriate, then converted into a salt
The present invent;on relates to noveL substituted 1,5-diaminopentanes, a process for their preparation and drugs containing these substances.
It 1s known that VerapamiL ;s a supraventricular antiarrhythmic drug and that one of the factors contri-buting to its action is an effect on ~he atrioventricular trans~;ss;on. $n addition, Verapamil has a powerful calGium-antagonistic action and hence has a hypotems;ve gffec~ (cf.: B4N. Singh, G. Elbrodt and C.l. Peter, Drugs 10~ 15 t1978~, 16~ 197).
We have ~ound that s~bst;tuted 1,5~d;am;nopentanes cf the formula I
~1 ~ R3 R ~ R7 N-C~}I2 CH2C~l2-N- Cx2 c~{2~9 where R1 and R2 are each hydrogen or C1-C6-alkyl, R3 ;s C1-C~z-aLkyl~ R4, R5, R6~ R7, R8 and R9 are each hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy or tri-fluoromethyl and R10 is hydrogen or methyl, and their salts with physiologically tolerated acids, possess act;ons which differ qual;tatively from that mer~ioned above.
?~ Su;table phys;ologically toLerated-acjds are .
- 1207 ~
~ 2 - ~.Z. 0050/35539 hydrochloric acid, ~ulfuric acid, phosphoric acid, acetic acidO malonic acid, succ;nic acicl, fumar;c acid, maleic acid, citric acid, tartaric acid, lactic acidO amidosul-fonic acid and oxalic acid.
lhe novel compounds possess an asymme~ric carbon atom and ~ay therefore also ocrur in the form of their a~tipodes.
In the formula I, R1 and R~ are each preferably C1-C4-alkyl, in particular methyl, R3 is preferably 1~ C1 C4-alkyl~ R4, R5, R6, R7, R8 and R9 are each preferably hydrogen or methyl and R1Q is, ;n particular, methyl.
The novel compounds can be prepared by a process in which a basically substituted phenylacetonitrile of the ~ormula II
~ C-CH C-I2CH ~N-C~ C~ ~ 8 II
R5 ~ R3 2 2 2 2 where R3 R4, R5, R6, R7, ~8, R9 and R10 have the above meanings~ is reduced and the resulting compound, which may, if desired, be first monoalkylated or dial-kylated, is, if appropriate, then converted into a salt
2~ with a physiolog;cally tolerated acid.
Reducing agents such as diborane or complex alu-minum hydrides, eg. l;thium aluminum hydride or sodium bis-(2-methoxyethoxy)-aluminum dihydride, are suitable for the reduction of the basically substituted phenylaceto-nitriles, part;cularly sui~able solvents being tetrahydro-- ~Z(~797
Reducing agents such as diborane or complex alu-minum hydrides, eg. l;thium aluminum hydride or sodium bis-(2-methoxyethoxy)-aluminum dihydride, are suitable for the reduction of the basically substituted phenylaceto-nitriles, part;cularly sui~able solvents being tetrahydro-- ~Z(~797
- 3 - O.Z. OOSO/35539 furan~ 1,2-d;methoxyethane, dioxane and ether. The reduc-tion is carr;ed out at an elevated ~emperature, preferably at the bo;l;ng poin~ of the solvent.
The nitri le group can be particularly readi~y reduced by catalytic hydrogenation us;ng a nickel conta;n;ng or cob~lt-conta;n-ng catalystO for example Raney cobalt, in the presence of ammon;a. Noble metal catalysts, eg. platinum oxide, pallad;um black, palladium/
charcoal, ruthen;um complexes or rhodium complexes, are a~so suitable~ The hydrogenation is carried out under a pressure of from 50 to 150 bar, prefer3bly under 80 bar~
and at from 20 to 150C, preferably 80C. Sui~able so~vents are lo~er alcohols and glacial acetic ac;d.
N monoalkylation ;s carried out by condensing the pr;mary amine ~ith an aldehyde or ketone, under con-d;t;ons of hydrogenat;on. The reaction can be particularly readily carried out using a nickel-containing or cobalt-containing catalyst, ~9. Raney nickel, but noble metal catalysts, eg. Pd~C or PtO2, are also suitableO Conden-2~ sat;on under conditions of hydrogenation ;s carried out under atmospheric pressure and at room temperature or slightly aboveO and good yields are obta;ned. The re-action ;s preferably carried out in a lower alcohol or glacial aceti G acid.
If aqueous formaldehyde solution ;s employed as the carbonyl component, condensat;on under condit;ons of hydrogenat;on results in N,N-dimethylation. The same com-pound may also be obtained by means of the Leuckart-Wallach method, using formaldehyde/formic acid.
.
3Z~ 7 ~ 4 - ~.Z. OO~0/35~33 The N-monoalkylation may also be ef-fected by re-action ~ h an acid halide or anhydride to give ~he N acyl compound~ which ;s then reduced w;th d;borane or l;th;um a~um;num hydr;de. Th;s method ;s preferred for monome-thylation or monoethylation. For this purpose, the pri--mary am;ne ;s con~erted ;nto the N~acyl compound using forma~acetic anhydr;de or acet;c anhydride, and the pro-duct is reduced by means of diborane or lithium aluminum hydr;de. Su;table solv~nts for th;s process are ether, tetrahydrofuran, d;oxane and dimethoxyethane. Mononethy-~a~ion may also be achieved by conversion ;nto the carba mate us;ng chloroform;c acid ester or diethoxy carbonate, fo~lo~ed by reduction of the produ~t.
; The compounds of the formula I can be separated into the;r ant;podes in a convent;onal manner. The anti podes may also be obta;ned ~hen ;nd;v;dual ;somers are used as starting materials.
In contrast to VerapamilO the novel compounds and their physiologicalLy tolerated addition salts with ac;ds 2n are substant;ally free of types of effect associated with ca~c;um antagonism (inhibition of atrioventricular ~rans~
mission, lowering of blood pressure)~ ;nstead~ the effects observed indi~ate powerful sodium antagon;sm.
They are ther~fore suitable for the pharmacotherapy of cardiac arrhythmias, in particular those of ventricular origin.
To determ;ne the antiarrhythmic activity, the sub-stances are administered orally to Sprague Dawley ratsy each weigh;ng 200-250 9~ and after 45 minutes the an;mals - 5 - ~.Z. ~ /3~39 are narcotized with sodium thiobutabarbi~aL (1aO.O mg/kgO
adm;n;stered ;ntraperitoneally). ~he arrhythmqgen;c sub-stance used is aconitine, ~h;ch ;s infused intravenously 60 ~inutes after administration of the substance ~dosage rate: 0.005 mg~kg x m;nute~ In the case of untreated animals ~N = SZ)O arrhythmias appear ;n the ECG after 2~74 0~07 minutesO and their onset can be delayed by ant;arrhythmic drugs~ the delay be;ng dependent on the dose~
IO The dose which prolongs the aconitine infus;on dura~ion by 50%, ie. the FD SOX, is determined from the l;near relationship between log dose (mg/kg) of test sub-s~ance and relative prolongation of aconitine inFusion - duration ~X~.
For further characterization of the substance, the anti-arrhythmic effect of the maximum tolerated dose is determined from the deci~al-geometric dosage progression tfactor ~ ~ used in the exper;ments.
In addition, the dose at wh;ch toxic symptoms ~0 tchanges ~n the initial ECG, cyanos;s or cramp) occur is determ;ned.
As a measure of the therapeutic index of the novel compounds, the quotient of the acute toxic dose and the anti arrhythmically effective dose (ED 50%) is determined.
The convent;onal ant;~arrhythm;c agent quin;dine ;s used as the comparative substance.
The compounds according to the invention tcf.
Table 1j have an anti-arrhythmic effect, on aconitine~
;nduced arrhythmia in rats, which is 1.3 ~Examples 23 and - 6 - () . Z . 0~)~0/3~539 32~ to 608 times (Example 11) greater than that of quin;-dine. A further advantage over quinidine is that the action on admin;strat;on of the h7ghest tolerated dose is greater ~c~. Table 2~. Qu;n;d;ne prolongs the dura.t;on of aconitine infus;on by a ma%;mum of 129X, ~hilst the com-pounds listed in Table 2 produce maximum increases of from 2Z4X (Example ZO) to 423% ~Example 37) and 499X (Example 30). In addition~ they possess a higher therapeu~lc index than quini~;ne. In the case o~ quinidine, toxiç symptoms occur ~hen only t1 t;mes the effective dose ;s adminis-tered, whereas the toxic doses of the novel subst3nces are from 13 (Example 37) to 42 times ~Example 30~ greater ~han the ant;-arrhythm;ca~ly effective doses.
~2~77~7 - 7 - 0.Z. 0~ /3~33 Aoti-arrhythmic effect on the rat, oral administra~ion Substance from Effective dose mg/kg Ex3mple No~ ED 50X1~ R~A~
~ .
6 21 ~ 6 2 .01 9 11.8 3.69 11 . 8 ~i . o9 11 6 ~ 42 o ~ 78 12 Z~!.5 1~93 12 12 ~ 9 3 . 37 14 14 " 3 3 .04 17 l ~ 2 .54 17 2~ . 1 1 .67 ~2~3 3-54 21 23~ ~.36 22 24.8 1~75 23 33.~ 1~29 24 17 ~0 2 . 56 27 21.5 . 2,02 28 11.6 3~75 11 ~0 3. g6 32 ~3~8 1~29 33 21~; 2~02 34 14,7 2~96 35 3 .02 5 . 42 36 8 ,Dor ~ ~02 37 7~9~ 5.44 38 27.3 1~57 o'.88 6~32 qu;n;dine 43~5 - 1~00 )dose (mg~kg~ which p~ongs the aconitine infusion durat;on by 50X.
2)R.A. = relat;ve act;v;ty, based on quinidine = 1.00 77~7 o, z O o!)50/35539 ~o ;Q ~
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~LLJ , 7~ 7 ~ 9 ~ O.Z. 0~0/35~39 The novel compounds may be adm;n;stered orally or parenteraL~y, ;n a conv~nt;onal mannerO
The dosage depends on tne age~ condition and ~e;gh~ of ~he patient an~ on the administration route. As a rule, the daily dose of act;ve compound is from about 0.2 to 20 mglkg of body ~eight for oral administration and from about 0.02 to 2.0 mg/kg of body we;ght for paren-tera~ adm;n;strat;on~ Normally, the da;~y dose 75 from 0.5 to 2 mg/kg ~hen used orally, and from OnO5 to 1~ 0.~5 mg/kg when used parenterally.
The nove~ compounds may be employed in the con-vent;onal solid or liquid pharmaceuticaL form, for example as tablets, film ta~lets, eapsules, powders, granu~es, coated tablets~ suppos;tor;es or solutions.
~hese are prepared in a conventional manner~ by compound;ng the active compounds with the conventional pharmaceutical auxiliaries, such as tablet binders, fillers, preserva-tives, tablet d;s;ntegrat;ng agents, flow regulators, plastic;zers, wett;ng agents, dispersants, emulsifiers, 2q solvents, retarders and/or antioxidants tcf. L.G. Goodman and A. G;lman: The Pharmacolog;cal Bas;s of Therapeut;cs).
The pharmaceutical products thus obta;ned normally contain from 0.1 to 99X by we;ght of the active compound~
EXAMPLES 1 to 8 1. 1-Amino-2~isopropyl-2-phenyl-5-C~phenethyL)-methyl-am;no~-pentane 33~.5 9 (1 mole) of 2,7-dimethyl-3-cyano-3,9-di-phenyl-7-azanonane are dissolved ;n 6 liters of methanol wh;ch had beforehand been saturated with ammon;a, nhi le - 10 - O.Z, ~ /35~3~
cold. The solution is hydrogenated in the presence of 200 g of methanol-moist Raney cobaLt in a 10 liter stirred autoclave at 80C and a hydrosen pressure of 1U1 bar. The reaction ;s complete after 3 hours. The m;x~
ture ;s cooled to room temperature, the catalyst is then fi~tered off under suction and washed with me~hanol, and the ~iltrate is evapo~ated to dryness. The 335 9 of resi-due ~hich rema;ns are dissol~ed in eth~nol, ethanolic oxalic acid is added~ and the product is recrystallized 1~ from ethanolO 450 9 t86%) of 1-amino-2-isopropyl 2-phenyl-5-rtphenethyl~-methylam;no~-pentane t13 are obta;ned as the dihydrogen oxalate of melting po;nt 136-138C. The dihydrochloride melts at 266-268C.
The following compounds are obtained by a similar procedure:
2. 1 Amino-~-isopropyl-2~3,4-dimethoxyphenyl)-5 ~t3,4-dimethoxyphenethyl~-methylamino~-pentane d;hydro-chloride, Mp = Z20-2Z4C, 3. 1-am;no-2-isopropyl-2-t3,4D5-~rime~hoxyphenyl-5~
2~ Ct3,4-d;methoxyphenethyl)-methylaminoJ-pentane di-hydrochloride, Mp = 196.5-198C
The nitri le group can be particularly readi~y reduced by catalytic hydrogenation us;ng a nickel conta;n;ng or cob~lt-conta;n-ng catalystO for example Raney cobalt, in the presence of ammon;a. Noble metal catalysts, eg. platinum oxide, pallad;um black, palladium/
charcoal, ruthen;um complexes or rhodium complexes, are a~so suitable~ The hydrogenation is carried out under a pressure of from 50 to 150 bar, prefer3bly under 80 bar~
and at from 20 to 150C, preferably 80C. Sui~able so~vents are lo~er alcohols and glacial acetic ac;d.
N monoalkylation ;s carried out by condensing the pr;mary amine ~ith an aldehyde or ketone, under con-d;t;ons of hydrogenat;on. The reaction can be particularly readily carried out using a nickel-containing or cobalt-containing catalyst, ~9. Raney nickel, but noble metal catalysts, eg. Pd~C or PtO2, are also suitableO Conden-2~ sat;on under conditions of hydrogenation ;s carried out under atmospheric pressure and at room temperature or slightly aboveO and good yields are obta;ned. The re-action ;s preferably carried out in a lower alcohol or glacial aceti G acid.
If aqueous formaldehyde solution ;s employed as the carbonyl component, condensat;on under condit;ons of hydrogenat;on results in N,N-dimethylation. The same com-pound may also be obtained by means of the Leuckart-Wallach method, using formaldehyde/formic acid.
.
3Z~ 7 ~ 4 - ~.Z. OO~0/35~33 The N-monoalkylation may also be ef-fected by re-action ~ h an acid halide or anhydride to give ~he N acyl compound~ which ;s then reduced w;th d;borane or l;th;um a~um;num hydr;de. Th;s method ;s preferred for monome-thylation or monoethylation. For this purpose, the pri--mary am;ne ;s con~erted ;nto the N~acyl compound using forma~acetic anhydr;de or acet;c anhydride, and the pro-duct is reduced by means of diborane or lithium aluminum hydr;de. Su;table solv~nts for th;s process are ether, tetrahydrofuran, d;oxane and dimethoxyethane. Mononethy-~a~ion may also be achieved by conversion ;nto the carba mate us;ng chloroform;c acid ester or diethoxy carbonate, fo~lo~ed by reduction of the produ~t.
; The compounds of the formula I can be separated into the;r ant;podes in a convent;onal manner. The anti podes may also be obta;ned ~hen ;nd;v;dual ;somers are used as starting materials.
In contrast to VerapamilO the novel compounds and their physiologicalLy tolerated addition salts with ac;ds 2n are substant;ally free of types of effect associated with ca~c;um antagonism (inhibition of atrioventricular ~rans~
mission, lowering of blood pressure)~ ;nstead~ the effects observed indi~ate powerful sodium antagon;sm.
They are ther~fore suitable for the pharmacotherapy of cardiac arrhythmias, in particular those of ventricular origin.
To determ;ne the antiarrhythmic activity, the sub-stances are administered orally to Sprague Dawley ratsy each weigh;ng 200-250 9~ and after 45 minutes the an;mals - 5 - ~.Z. ~ /3~39 are narcotized with sodium thiobutabarbi~aL (1aO.O mg/kgO
adm;n;stered ;ntraperitoneally). ~he arrhythmqgen;c sub-stance used is aconitine, ~h;ch ;s infused intravenously 60 ~inutes after administration of the substance ~dosage rate: 0.005 mg~kg x m;nute~ In the case of untreated animals ~N = SZ)O arrhythmias appear ;n the ECG after 2~74 0~07 minutesO and their onset can be delayed by ant;arrhythmic drugs~ the delay be;ng dependent on the dose~
IO The dose which prolongs the aconitine infus;on dura~ion by 50%, ie. the FD SOX, is determined from the l;near relationship between log dose (mg/kg) of test sub-s~ance and relative prolongation of aconitine inFusion - duration ~X~.
For further characterization of the substance, the anti-arrhythmic effect of the maximum tolerated dose is determined from the deci~al-geometric dosage progression tfactor ~ ~ used in the exper;ments.
In addition, the dose at wh;ch toxic symptoms ~0 tchanges ~n the initial ECG, cyanos;s or cramp) occur is determ;ned.
As a measure of the therapeutic index of the novel compounds, the quotient of the acute toxic dose and the anti arrhythmically effective dose (ED 50%) is determined.
The convent;onal ant;~arrhythm;c agent quin;dine ;s used as the comparative substance.
The compounds according to the invention tcf.
Table 1j have an anti-arrhythmic effect, on aconitine~
;nduced arrhythmia in rats, which is 1.3 ~Examples 23 and - 6 - () . Z . 0~)~0/3~539 32~ to 608 times (Example 11) greater than that of quin;-dine. A further advantage over quinidine is that the action on admin;strat;on of the h7ghest tolerated dose is greater ~c~. Table 2~. Qu;n;d;ne prolongs the dura.t;on of aconitine infus;on by a ma%;mum of 129X, ~hilst the com-pounds listed in Table 2 produce maximum increases of from 2Z4X (Example ZO) to 423% ~Example 37) and 499X (Example 30). In addition~ they possess a higher therapeu~lc index than quini~;ne. In the case o~ quinidine, toxiç symptoms occur ~hen only t1 t;mes the effective dose ;s adminis-tered, whereas the toxic doses of the novel subst3nces are from 13 (Example 37) to 42 times ~Example 30~ greater ~han the ant;-arrhythm;ca~ly effective doses.
~2~77~7 - 7 - 0.Z. 0~ /3~33 Aoti-arrhythmic effect on the rat, oral administra~ion Substance from Effective dose mg/kg Ex3mple No~ ED 50X1~ R~A~
~ .
6 21 ~ 6 2 .01 9 11.8 3.69 11 . 8 ~i . o9 11 6 ~ 42 o ~ 78 12 Z~!.5 1~93 12 12 ~ 9 3 . 37 14 14 " 3 3 .04 17 l ~ 2 .54 17 2~ . 1 1 .67 ~2~3 3-54 21 23~ ~.36 22 24.8 1~75 23 33.~ 1~29 24 17 ~0 2 . 56 27 21.5 . 2,02 28 11.6 3~75 11 ~0 3. g6 32 ~3~8 1~29 33 21~; 2~02 34 14,7 2~96 35 3 .02 5 . 42 36 8 ,Dor ~ ~02 37 7~9~ 5.44 38 27.3 1~57 o'.88 6~32 qu;n;dine 43~5 - 1~00 )dose (mg~kg~ which p~ongs the aconitine infusion durat;on by 50X.
2)R.A. = relat;ve act;v;ty, based on quinidine = 1.00 77~7 o, z O o!)50/35539 ~o ;Q ~
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~ x cr ~ r~
~LLJ , 7~ 7 ~ 9 ~ O.Z. 0~0/35~39 The novel compounds may be adm;n;stered orally or parenteraL~y, ;n a conv~nt;onal mannerO
The dosage depends on tne age~ condition and ~e;gh~ of ~he patient an~ on the administration route. As a rule, the daily dose of act;ve compound is from about 0.2 to 20 mglkg of body ~eight for oral administration and from about 0.02 to 2.0 mg/kg of body we;ght for paren-tera~ adm;n;strat;on~ Normally, the da;~y dose 75 from 0.5 to 2 mg/kg ~hen used orally, and from OnO5 to 1~ 0.~5 mg/kg when used parenterally.
The nove~ compounds may be employed in the con-vent;onal solid or liquid pharmaceuticaL form, for example as tablets, film ta~lets, eapsules, powders, granu~es, coated tablets~ suppos;tor;es or solutions.
~hese are prepared in a conventional manner~ by compound;ng the active compounds with the conventional pharmaceutical auxiliaries, such as tablet binders, fillers, preserva-tives, tablet d;s;ntegrat;ng agents, flow regulators, plastic;zers, wett;ng agents, dispersants, emulsifiers, 2q solvents, retarders and/or antioxidants tcf. L.G. Goodman and A. G;lman: The Pharmacolog;cal Bas;s of Therapeut;cs).
The pharmaceutical products thus obta;ned normally contain from 0.1 to 99X by we;ght of the active compound~
EXAMPLES 1 to 8 1. 1-Amino-2~isopropyl-2-phenyl-5-C~phenethyL)-methyl-am;no~-pentane 33~.5 9 (1 mole) of 2,7-dimethyl-3-cyano-3,9-di-phenyl-7-azanonane are dissolved ;n 6 liters of methanol wh;ch had beforehand been saturated with ammon;a, nhi le - 10 - O.Z, ~ /35~3~
cold. The solution is hydrogenated in the presence of 200 g of methanol-moist Raney cobaLt in a 10 liter stirred autoclave at 80C and a hydrosen pressure of 1U1 bar. The reaction ;s complete after 3 hours. The m;x~
ture ;s cooled to room temperature, the catalyst is then fi~tered off under suction and washed with me~hanol, and the ~iltrate is evapo~ated to dryness. The 335 9 of resi-due ~hich rema;ns are dissol~ed in eth~nol, ethanolic oxalic acid is added~ and the product is recrystallized 1~ from ethanolO 450 9 t86%) of 1-amino-2-isopropyl 2-phenyl-5-rtphenethyl~-methylam;no~-pentane t13 are obta;ned as the dihydrogen oxalate of melting po;nt 136-138C. The dihydrochloride melts at 266-268C.
The following compounds are obtained by a similar procedure:
2. 1 Amino-~-isopropyl-2~3,4-dimethoxyphenyl)-5 ~t3,4-dimethoxyphenethyl~-methylamino~-pentane d;hydro-chloride, Mp = Z20-2Z4C, 3. 1-am;no-2-isopropyl-2-t3,4D5-~rime~hoxyphenyl-5~
2~ Ct3,4-d;methoxyphenethyl)-methylaminoJ-pentane di-hydrochloride, Mp = 196.5-198C
4~ 1-amino-2-isopropyl-2-t3~trifluoromethylphenyl~-5-C(3,4-dimethoxyphenethyl3-methylamino~-pentane dihydro-chloride, Mp = 235-240C,
5. 1-amino-2-isopropyl-2-~3-trifluorome~hylphenyl)-5-tphenethyl~-methylamino3-pentane dihydrochloride, Mp = 252C,
6~ 1~amino~2-isopropyl-2~phenyl-5~C(phenethyl)-amino]=
pentane dihydrochloride, Mp = 225OC
pentane dihydrochloride, Mp = 225OC
7~7 ~ O.Z. ~50/3~539 7. 1-amino-2-isopropyL-2-(3-trifluoromethylphenyl)-5-~phenethyl~-3mino~-pentane d;hydrochloride, Mp ~
206 ~D
amino-2-(n-octyl) 2-phenyl-5-Ctphenethyl)-amino~
Bp. = 220-230C/0.01.
EXAMPLES 9 to 27 0.1 mole of a pr;mary 1,5~diaminopentane of the formula I twhere R1 and R~ are each H), obtained as des~
cribed in Example 1, and U.1 mole of aldehyde or ketone are dissoLved in 150 ml of methanol~ and hydrogenation is carried QUt at room temperature in ~he presence of 3 9 of 10X strength Pd/C until 1 equ;valent of hydrogen has been taken up.
The catalyst is fil~ered off under suction, the methanol ;s then removed under reduced pressure and the residue is pur;f;ed by salt formation and subsequent crystallization, or by chromatography.
The fo~lo~ing compounds are prepared ;n this manner:
9. 1-Ethylamino-2-;sopropyl-2-phenyl-5-L(phenethyl~-2n . methylamino~-pentane d;hydrochloride, Mp = 229-232C, 10. 1-tn-propyL~-amino-2-;sopropyl-Z-phenyl 5-C(phen-thyl)-methylam;no~-pentane d;hydrochloride, Mp =
Z23-Z25C, isopropylam;no-2-isopropyl-2-phenyl-5-Ctphenethyl~-methyLam;no~-pentane dihydrochloride~ Mp = 214-216C, 12. 1-(n-butyl)-am;no-2-isopropyl-2-phenyl~-Ctphenethyl)-methylamino~-pentane dihydrochloride, Mp ~ 120C, ~3. 1-(sec.-butyl)~amino-2-;sopropyl-2-phenyl-5-C~phen-~2~797 - 12 - 0.z~ 0~5'3553 ethy l) -methylamino~-pentane d;hydrochloride, Mp -164-166C, 14. 1-isobutylamino Z-isopropyl-2-phenyl-5-C(phenethyl~-methylamino~-pentane d;hydrochloride, Mp = 1Z0-13`5C, 15. 1-ethylam;no-2-isopropyl-2-~3,4-d;methoxyphenyl~-5-C~3~4-d;methoxyphenethyl)-methylamino~-pentane di-hydrochlorideO Mp = 207-208C, 16 1-~n-propyl~-amino-2-~sopropyl~2-~394-dimethoxy phenyl)-5-~t3,4-dimethoxyphenethyl)-methylamino~-pen-1~ tane dihydrochloride, Mp = Z28-230C, 70 1-isopropylamino-2-;sopropyl-2-~3,4-dimethoxyphenyl)-5-Ct3,4-d;methoxyphenethyl)-methylam;no~-pentane di-hydrochloride, Mp = 180-183C, 18r 1-~n-butyl)~amino-2-isopropyl-2-(3,4-dimethoxyphenyl)-5-~3,4-dimethoxyphenethyl)-methylamino~-pentane di-hydrochloride, Mp - 220-223C, 1$. 1-tsec.obutyll-amino-2~isopropyl-2-t3,4-dimethoxy-phenyl)-5-~(304-dimethoxyph~nethyl)-methyl3mino~-pentane dihydrochlor;de, Mp = 170-180C, ?0 20. 1-ethylamino-2-isopropyl-2-(3,4,5-trimethoxyphenyl~-S-C(3,4-dimethoxyphenethyl)-~ethylamino~-pentane di-hydrochloride~ Mp = Z05-208C, 21. 1-~n-propyl)-amino-2-isopropyl-2-(3,4,5-trimethoxy-phenyl~-5-C~3,4-dimethoxyphenethyL~-me~hylamino]-pen-- tane d;hydrochlor;de, Mp = 200-203C, 22. 1-;sopropylamino-2-isopropyl-2-~3,4,5-tr;methoxy-phenyl)-5-~t3,4-dimethoxyphenethyl)-methylamino] pen-tane dihy~rochloride, Mp = 207~210C, 23~ n-butylamino-2-isopropyl-2-~3~4,5-trimethoxyphenyl)-2~
- 13 - 0.Z. ~50/35~39 5-~3,4-dimethoxyphenethyl)-methylamino~-pentane di~
hydrochlor;de, Mp ~ 201-204C, 24. 1~sec.-butyl)-amino~2 isopropyl ~3,4~5-trimethoxy-phenyl~-5-C~3O4-dimethoxypheny~-methylamino]-pentane-dihydrochloride, Mp ~ 193-195C~
Z5. 1-isopropylam;no~2-;sopropyl-2-(3-tr;fluoromethyl~
phenyl~ C(3,4 d;methoxyphenethyl)~methylamino~-pentane dihydrochloride, Mp ~ 70Co 26. 1-isobutylamino~2-isopropyl-2-~3-tri~fluoromethyl-1~ phenyl)-5-~(3,4-d;methoxyphenethyL~omethylamino~-pen-tane dihydrochloride, Mp = 70C, 27~ 1-(n-butyl)-am;no 2-isopropyl-2-~4-chlorophenyl)-5-C~3~4~d;methoxyphenethyl)omethylamins]-pentane dihydro~
chloride~ Mp - 188C.
EXAMPLES 28 to 33 a) 0.035 mole of formylacetic anhydride is added dropwise to a solution of 0.033 mole of a 1,5-diam;nopen~
tane of the formula I twhere R1 and R2 are each H) in 200 ml of methylene chloride at 0-5C, while stirring.
After 20 minutes, the methylene chloride solution ;s uashed with SX strength potassium carbonate solution, and the organic phase is dried over potassium carbonate and then concentrated under reduced pressure from a water pump. The corresponding N-formyl compound is obtainedO
b) A solut;on of 0.03 mole of the N-formyl compound (cf. a)) in 50 ml of tetrahydrofuran is added dropwise, in the co~rse of 15 minutes at 40C, to a stirr~d suspen-sion of 10 9 of lithium aluminum hydride in Z00 ml 01 tetrahydrofuran. Thereafter, the mixture is heated at ~Z~7''~
- 14 - ~.Z. ~ /3~39 65C for a further 6 hours. After ~he mixture has cooled, it is hydrolyzed with a tetrahydrofuran/water m;xture and a 5X strength potassium carbonate solu~ion. The resulting ~hite precipitate is filtered off under suction and washed several times w;th tetrahydrofuran. ~he combined tetra-hydrofuran solutions are evaporated to dryness and the res;due ;s purified by salt formation or chromatography.
The following compounds are prepared in this manner:
1~ 28. 1-Methylam;no-2-phenyl-5 C~phenethyl)-methylamino~-pentane, colorless oil, 29. 1-methylam;no-2-methyl-2 phenyl-5-C(phenethyl)-methyl-am;no3-pentane, coLorless o;l, 30~ 1-methyla~;no-2-isopropyl-2-phenyl-5-~tphenethyl)-methylamino~-pentane dihydrochlorideO Mp = Z16-219C, 31. 1-methy~amino-2-(n-butyl~-Z-phenyl-5-~(phenethyl~-methylamino~-pentane, colorless oil, 37. 1Omethylam;no-2-isopropyl-2-t3,4-dimethoxyphenyl~-5-~(3,4-dimethoxyphenethyl)-methylam;no~-pentane d;hydro-chlor;de, Mp - 175-180C, 33. 1-methylamino-2-isopropyl-2-~3,4,5-~rimethoxyphenyl)-5~(3,4-dimethoxyphenethyl)-methylamino~-pentane di hydrochloride, Mp = 152-155C.
XAMPLES 34 to 40 0.023 mole of oxal;c acid, 0.0~6 mole of formal-dehyde t35% strength aqueous solution) and 3 9 of 10%
strength PdJC are added to a solution of 0 023 mole o~ a 1~5-diaminopentane of the formula I twhere R1 an~ R2 are each H) in 100 ml of methanol. The reaction solution is :~2(31~7~
- 15 - ~ . Z . 005(~/35~39 heated in a ~a~er hath to 40C, in the absence o~ ai r, and ;s hydrogenated under sl;ghtly superatmospher;c pressure until two equ;valents of hydrogen have been taken up. After 40 minutes, the catalyst ;s filter~d off under suct;on, the filtrate ;s concentrated under reduced pres-sure from a ~ater pump, and the residue is dissolved in 2ao ml of water~ The methylated amine is libera~ed by the addition o~ ammonia, and is extracted w;th ether. The ether solution is dried and concentrated, after which the 1~ b~se is obtained as a colorless o;l, ~hich is dissolved in ~thanoL and then precipitated as the dihydrochlor;de.
The follo~;ng compounds are prepared in th;s ma~ner: -34~ 1-Dimethylamino-2-phenyl 5-~(phenethyl)-methylamino]-pentane, coLorless oil, 35. 1-dimethylamino-2-methyl-2-phenyl-5-C(phenethyl)-~ethylamino]-pentane, colorless oil, 360 1-dimethylamino-2-(n-butyl)-2-phenyl-5~C(phenethyl)-methylamino~-pentane, colorless oil, 37. 1-dimethylamino-2-i~opropyl-Z~phenyl-~C(phenethyl~-methylamino~-pentane dihydrochloride, Mp ~ 19~-193C, 38. 1-dimethylamino-2-isopropyl-2-t3,4-dimethoxyphenyl)~
5-C(3,4-dimethoxyphenethyl)-methylamino~ pentane d;hydrochloride, Mp = 208-Z10C, 39. 1-dimethylamino-2-isopropyl 2-(3,4,5-trimethoxyphenyl)-5-C(3,4-dimethoxyphenethyl)-methylamino] pentane di-hydrochloride, Mp = 130C, 40. 1-dimethylamino-2-(n-dodecyl~-2-phenyl-5-C~phenethyl)-methylamino]-pentane, colorless oil.
7~ 7 - 16 - o.Z, ~o/3~539 1-Diethylamino-2-isopropyl-2~phenyl-5-Ctphene~hyl)Imethyl-ami no~ pen~ an e A solution of 7.9 9 tO.1 mole) of acetyl chloride is added dropwise to a solution of 3~.7 9 ~0.1 mole) of 1-ethylamino-2-;sopropyl-Z-phenyl~5-Ctphenethyl)-methyl-am;no~-pentane ~Example 9) and 1001 9 ~0.1 mole~ of tr;-ethy~amine in 150 mL of dry ether at 0C, ~hile stirring.
The reaction mixture is stirred for 3 hours at room tem-perature, the prec;p;tated triethylam;ne hydrochloride is fi lt~red off under suction, and the ether phase ;s ~ashed several times with ~ater and then dried ~;th potassium carbonate~ The ether is d;stilled off, and the acetyl compound is obtained as a colorless o;l~ in a yieLd of 95%.
The reduction of the acetyl compound is carried out by a procedure sim;lar to that described in Examples 28 to 37, using l;th;um aluminum hydride.
~ablets of the follow;ng compos;t;on are obta;ned ;n a co-nventional manner on a tabletting press:
40 mg of the substance from Example 37 2n 120 mg of corn starch 13~50 mg of geiatin 4i mg of lactose 22.5 mg of talc 2~25 mg of AerosilR echemically pure silica in the form of sub-microscopic particles) 6.75 mg of potato starch (as a 6% strength base) ~77 - 17 - ~Zo OO'iO/3~53 Coated tablets of the foLlowing compos;t;on are pre-pared ;n a conventiona~ manner:
20 mg of the substance from Example 37 60 mg of eore mi x~ure 60 mg of sugar-coating mixture Tha core mixture compl~;ses 9 parts of corn starch~, 3 parts of ~actose and 1 part of LuviskoLR VA 64 (60:40 copolymer of vinylpyrrolidone and vinyl acetate, cf.
Pharm. Ind. 1962, 586)~ The sugar~coating mixture com-1~ prises S parts o~ sugar, Z parts of corn ~tarch, 2 parts of calGium carbonate and 1 part of talc. The co3ted sab lets produced ;n this manner are then prov;ded with a further coat;ng ~hich ;s res;stant to ~astric juicesr 10 9 of the substance from Example 37 ~free base)are dissoLved in 5,000 ml of ~ater, NaCl being added, and the solution is brought to pH 6.0 with 1 N HCl. A blood-isotonic solution is thus obtained. The solution is 7ntroduced into ~mpoules, in an amount of S ml per ampouleO and the ampoules are sterilized.
206 ~D
amino-2-(n-octyl) 2-phenyl-5-Ctphenethyl)-amino~
Bp. = 220-230C/0.01.
EXAMPLES 9 to 27 0.1 mole of a pr;mary 1,5~diaminopentane of the formula I twhere R1 and R~ are each H), obtained as des~
cribed in Example 1, and U.1 mole of aldehyde or ketone are dissoLved in 150 ml of methanol~ and hydrogenation is carried QUt at room temperature in ~he presence of 3 9 of 10X strength Pd/C until 1 equ;valent of hydrogen has been taken up.
The catalyst is fil~ered off under suction, the methanol ;s then removed under reduced pressure and the residue is pur;f;ed by salt formation and subsequent crystallization, or by chromatography.
The fo~lo~ing compounds are prepared ;n this manner:
9. 1-Ethylamino-2-;sopropyl-2-phenyl-5-L(phenethyl~-2n . methylamino~-pentane d;hydrochloride, Mp = 229-232C, 10. 1-tn-propyL~-amino-2-;sopropyl-Z-phenyl 5-C(phen-thyl)-methylam;no~-pentane d;hydrochloride, Mp =
Z23-Z25C, isopropylam;no-2-isopropyl-2-phenyl-5-Ctphenethyl~-methyLam;no~-pentane dihydrochloride~ Mp = 214-216C, 12. 1-(n-butyl)-am;no-2-isopropyl-2-phenyl~-Ctphenethyl)-methylamino~-pentane dihydrochloride, Mp ~ 120C, ~3. 1-(sec.-butyl)~amino-2-;sopropyl-2-phenyl-5-C~phen-~2~797 - 12 - 0.z~ 0~5'3553 ethy l) -methylamino~-pentane d;hydrochloride, Mp -164-166C, 14. 1-isobutylamino Z-isopropyl-2-phenyl-5-C(phenethyl~-methylamino~-pentane d;hydrochloride, Mp = 1Z0-13`5C, 15. 1-ethylam;no-2-isopropyl-2-~3,4-d;methoxyphenyl~-5-C~3~4-d;methoxyphenethyl)-methylamino~-pentane di-hydrochlorideO Mp = 207-208C, 16 1-~n-propyl~-amino-2-~sopropyl~2-~394-dimethoxy phenyl)-5-~t3,4-dimethoxyphenethyl)-methylamino~-pen-1~ tane dihydrochloride, Mp = Z28-230C, 70 1-isopropylamino-2-;sopropyl-2-~3,4-dimethoxyphenyl)-5-Ct3,4-d;methoxyphenethyl)-methylam;no~-pentane di-hydrochloride, Mp = 180-183C, 18r 1-~n-butyl)~amino-2-isopropyl-2-(3,4-dimethoxyphenyl)-5-~3,4-dimethoxyphenethyl)-methylamino~-pentane di-hydrochloride, Mp - 220-223C, 1$. 1-tsec.obutyll-amino-2~isopropyl-2-t3,4-dimethoxy-phenyl)-5-~(304-dimethoxyph~nethyl)-methyl3mino~-pentane dihydrochlor;de, Mp = 170-180C, ?0 20. 1-ethylamino-2-isopropyl-2-(3,4,5-trimethoxyphenyl~-S-C(3,4-dimethoxyphenethyl)-~ethylamino~-pentane di-hydrochloride~ Mp = Z05-208C, 21. 1-~n-propyl)-amino-2-isopropyl-2-(3,4,5-trimethoxy-phenyl~-5-C~3,4-dimethoxyphenethyL~-me~hylamino]-pen-- tane d;hydrochlor;de, Mp = 200-203C, 22. 1-;sopropylamino-2-isopropyl-2-~3,4,5-tr;methoxy-phenyl)-5-~t3,4-dimethoxyphenethyl)-methylamino] pen-tane dihy~rochloride, Mp = 207~210C, 23~ n-butylamino-2-isopropyl-2-~3~4,5-trimethoxyphenyl)-2~
- 13 - 0.Z. ~50/35~39 5-~3,4-dimethoxyphenethyl)-methylamino~-pentane di~
hydrochlor;de, Mp ~ 201-204C, 24. 1~sec.-butyl)-amino~2 isopropyl ~3,4~5-trimethoxy-phenyl~-5-C~3O4-dimethoxypheny~-methylamino]-pentane-dihydrochloride, Mp ~ 193-195C~
Z5. 1-isopropylam;no~2-;sopropyl-2-(3-tr;fluoromethyl~
phenyl~ C(3,4 d;methoxyphenethyl)~methylamino~-pentane dihydrochloride, Mp ~ 70Co 26. 1-isobutylamino~2-isopropyl-2-~3-tri~fluoromethyl-1~ phenyl)-5-~(3,4-d;methoxyphenethyL~omethylamino~-pen-tane dihydrochloride, Mp = 70C, 27~ 1-(n-butyl)-am;no 2-isopropyl-2-~4-chlorophenyl)-5-C~3~4~d;methoxyphenethyl)omethylamins]-pentane dihydro~
chloride~ Mp - 188C.
EXAMPLES 28 to 33 a) 0.035 mole of formylacetic anhydride is added dropwise to a solution of 0.033 mole of a 1,5-diam;nopen~
tane of the formula I twhere R1 and R2 are each H) in 200 ml of methylene chloride at 0-5C, while stirring.
After 20 minutes, the methylene chloride solution ;s uashed with SX strength potassium carbonate solution, and the organic phase is dried over potassium carbonate and then concentrated under reduced pressure from a water pump. The corresponding N-formyl compound is obtainedO
b) A solut;on of 0.03 mole of the N-formyl compound (cf. a)) in 50 ml of tetrahydrofuran is added dropwise, in the co~rse of 15 minutes at 40C, to a stirr~d suspen-sion of 10 9 of lithium aluminum hydride in Z00 ml 01 tetrahydrofuran. Thereafter, the mixture is heated at ~Z~7''~
- 14 - ~.Z. ~ /3~39 65C for a further 6 hours. After ~he mixture has cooled, it is hydrolyzed with a tetrahydrofuran/water m;xture and a 5X strength potassium carbonate solu~ion. The resulting ~hite precipitate is filtered off under suction and washed several times w;th tetrahydrofuran. ~he combined tetra-hydrofuran solutions are evaporated to dryness and the res;due ;s purified by salt formation or chromatography.
The following compounds are prepared in this manner:
1~ 28. 1-Methylam;no-2-phenyl-5 C~phenethyl)-methylamino~-pentane, colorless oil, 29. 1-methylam;no-2-methyl-2 phenyl-5-C(phenethyl)-methyl-am;no3-pentane, coLorless o;l, 30~ 1-methyla~;no-2-isopropyl-2-phenyl-5-~tphenethyl)-methylamino~-pentane dihydrochlorideO Mp = Z16-219C, 31. 1-methy~amino-2-(n-butyl~-Z-phenyl-5-~(phenethyl~-methylamino~-pentane, colorless oil, 37. 1Omethylam;no-2-isopropyl-2-t3,4-dimethoxyphenyl~-5-~(3,4-dimethoxyphenethyl)-methylam;no~-pentane d;hydro-chlor;de, Mp - 175-180C, 33. 1-methylamino-2-isopropyl-2-~3,4,5-~rimethoxyphenyl)-5~(3,4-dimethoxyphenethyl)-methylamino~-pentane di hydrochloride, Mp = 152-155C.
XAMPLES 34 to 40 0.023 mole of oxal;c acid, 0.0~6 mole of formal-dehyde t35% strength aqueous solution) and 3 9 of 10%
strength PdJC are added to a solution of 0 023 mole o~ a 1~5-diaminopentane of the formula I twhere R1 an~ R2 are each H) in 100 ml of methanol. The reaction solution is :~2(31~7~
- 15 - ~ . Z . 005(~/35~39 heated in a ~a~er hath to 40C, in the absence o~ ai r, and ;s hydrogenated under sl;ghtly superatmospher;c pressure until two equ;valents of hydrogen have been taken up. After 40 minutes, the catalyst ;s filter~d off under suct;on, the filtrate ;s concentrated under reduced pres-sure from a ~ater pump, and the residue is dissolved in 2ao ml of water~ The methylated amine is libera~ed by the addition o~ ammonia, and is extracted w;th ether. The ether solution is dried and concentrated, after which the 1~ b~se is obtained as a colorless o;l, ~hich is dissolved in ~thanoL and then precipitated as the dihydrochlor;de.
The follo~;ng compounds are prepared in th;s ma~ner: -34~ 1-Dimethylamino-2-phenyl 5-~(phenethyl)-methylamino]-pentane, coLorless oil, 35. 1-dimethylamino-2-methyl-2-phenyl-5-C(phenethyl)-~ethylamino]-pentane, colorless oil, 360 1-dimethylamino-2-(n-butyl)-2-phenyl-5~C(phenethyl)-methylamino~-pentane, colorless oil, 37. 1-dimethylamino-2-i~opropyl-Z~phenyl-~C(phenethyl~-methylamino~-pentane dihydrochloride, Mp ~ 19~-193C, 38. 1-dimethylamino-2-isopropyl-2-t3,4-dimethoxyphenyl)~
5-C(3,4-dimethoxyphenethyl)-methylamino~ pentane d;hydrochloride, Mp = 208-Z10C, 39. 1-dimethylamino-2-isopropyl 2-(3,4,5-trimethoxyphenyl)-5-C(3,4-dimethoxyphenethyl)-methylamino] pentane di-hydrochloride, Mp = 130C, 40. 1-dimethylamino-2-(n-dodecyl~-2-phenyl-5-C~phenethyl)-methylamino]-pentane, colorless oil.
7~ 7 - 16 - o.Z, ~o/3~539 1-Diethylamino-2-isopropyl-2~phenyl-5-Ctphene~hyl)Imethyl-ami no~ pen~ an e A solution of 7.9 9 tO.1 mole) of acetyl chloride is added dropwise to a solution of 3~.7 9 ~0.1 mole) of 1-ethylamino-2-;sopropyl-Z-phenyl~5-Ctphenethyl)-methyl-am;no~-pentane ~Example 9) and 1001 9 ~0.1 mole~ of tr;-ethy~amine in 150 mL of dry ether at 0C, ~hile stirring.
The reaction mixture is stirred for 3 hours at room tem-perature, the prec;p;tated triethylam;ne hydrochloride is fi lt~red off under suction, and the ether phase ;s ~ashed several times with ~ater and then dried ~;th potassium carbonate~ The ether is d;stilled off, and the acetyl compound is obtained as a colorless o;l~ in a yieLd of 95%.
The reduction of the acetyl compound is carried out by a procedure sim;lar to that described in Examples 28 to 37, using l;th;um aluminum hydride.
~ablets of the follow;ng compos;t;on are obta;ned ;n a co-nventional manner on a tabletting press:
40 mg of the substance from Example 37 2n 120 mg of corn starch 13~50 mg of geiatin 4i mg of lactose 22.5 mg of talc 2~25 mg of AerosilR echemically pure silica in the form of sub-microscopic particles) 6.75 mg of potato starch (as a 6% strength base) ~77 - 17 - ~Zo OO'iO/3~53 Coated tablets of the foLlowing compos;t;on are pre-pared ;n a conventiona~ manner:
20 mg of the substance from Example 37 60 mg of eore mi x~ure 60 mg of sugar-coating mixture Tha core mixture compl~;ses 9 parts of corn starch~, 3 parts of ~actose and 1 part of LuviskoLR VA 64 (60:40 copolymer of vinylpyrrolidone and vinyl acetate, cf.
Pharm. Ind. 1962, 586)~ The sugar~coating mixture com-1~ prises S parts o~ sugar, Z parts of corn ~tarch, 2 parts of calGium carbonate and 1 part of talc. The co3ted sab lets produced ;n this manner are then prov;ded with a further coat;ng ~hich ;s res;stant to ~astric juicesr 10 9 of the substance from Example 37 ~free base)are dissoLved in 5,000 ml of ~ater, NaCl being added, and the solution is brought to pH 6.0 with 1 N HCl. A blood-isotonic solution is thus obtained. The solution is 7ntroduced into ~mpoules, in an amount of S ml per ampouleO and the ampoules are sterilized.
Claims
1. A process for the preparation of a substituted 1,5-diaminopentane of the formula(I) (I) where R1 and R2 are each hydrogen or C1-C6-aLkyl, R3 is C1-C12-alkyl, R4, R5, R6, R7, R8 and R9 are each hydrogen, halogen, C1-C4-alkyl, C1-C4-alkoxy or tri fluoromethyl and R10 is hydrogen or methyl, and its salts with physiologically tolerated acids, characterized in that a basically sustituted phenylacetonitrile of the formula (II) (II) where R3, R4, R5, R6, R7, R8, R9 and R10 have the above meanings, is reduced and the resulting compound, which may, if desired, be first monoalkylated or dial-kylated, is, if appropriate, then converted into a salt with a physiologically tolerated acid.
A compound of the formula(I) as defined in claim 1, and its salts with physiologically tolerated acids, whenever obtained by a process as defined in claim 1 or an obvious chemical equivalent thereof.
A compound of the formula(I) as defined in claim 1, and its salts with physiologically tolerated acids, whenever obtained by a process as defined in claim 1 or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813143356 DE3143356A1 (en) | 1981-11-02 | 1981-11-02 | SUBSTITUTED 1,5-DIAMINOPENTANES, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM |
| DEP3143356.1 | 1981-11-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1207797A true CA1207797A (en) | 1986-07-15 |
Family
ID=6145366
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000414272A Expired CA1207797A (en) | 1981-11-02 | 1982-10-27 | Substituted 2,5-diaminopentanes, their preparation and drugs containing these compounds |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0082266B1 (en) |
| JP (1) | JPS5888343A (en) |
| CA (1) | CA1207797A (en) |
| DE (2) | DE3143356A1 (en) |
| ZA (1) | ZA827957B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4968717A (en) * | 1986-01-31 | 1990-11-06 | Basf Aktiengesellschaft | Phenylacetonitriles which are substituted by basic groups, their preparation and drugs containing these substances |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3805225A1 (en) * | 1988-02-19 | 1989-08-31 | Basf Ag | NORMOPAMIL, ITS MANUFACTURE AND USE |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2438965A1 (en) * | 1974-08-14 | 1976-02-26 | Hoechst Ag | BASIC SUBSTITUTED 3,4-DIHYDRO2H-ISOCHINOLIN-1-THIONE AND METHOD FOR THEIR PRODUCTION |
-
1981
- 1981-11-02 DE DE19813143356 patent/DE3143356A1/en not_active Withdrawn
-
1982
- 1982-10-22 DE DE8282109743T patent/DE3261857D1/en not_active Expired
- 1982-10-22 EP EP82109743A patent/EP0082266B1/en not_active Expired
- 1982-10-27 CA CA000414272A patent/CA1207797A/en not_active Expired
- 1982-11-01 ZA ZA827957A patent/ZA827957B/en unknown
- 1982-11-02 JP JP57191993A patent/JPS5888343A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4968717A (en) * | 1986-01-31 | 1990-11-06 | Basf Aktiengesellschaft | Phenylacetonitriles which are substituted by basic groups, their preparation and drugs containing these substances |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3261857D1 (en) | 1985-02-21 |
| EP0082266B1 (en) | 1985-01-09 |
| ZA827957B (en) | 1983-09-28 |
| DE3143356A1 (en) | 1983-05-11 |
| JPS5888343A (en) | 1983-05-26 |
| EP0082266A1 (en) | 1983-06-29 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |