CH637370A5 - Racemic forms and optically active forms of 2-(4-biphenylyl)-N-(diethylaminoalkyl)-propionamide, salts thereof and relative preparation processes - Google Patents
Racemic forms and optically active forms of 2-(4-biphenylyl)-N-(diethylaminoalkyl)-propionamide, salts thereof and relative preparation processes Download PDFInfo
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- CH637370A5 CH637370A5 CH1216178A CH1216178A CH637370A5 CH 637370 A5 CH637370 A5 CH 637370A5 CH 1216178 A CH1216178 A CH 1216178A CH 1216178 A CH1216178 A CH 1216178A CH 637370 A5 CH637370 A5 CH 637370A5
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- propionamide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
Description
15 La presente invenzione riguarda nuovi composti ad azione spasmolitica migliorata. 15 The present invention relates to new compounds with improved spasmolytic action.
Tra i prodotti solitamente impiegati in terapia come spasmolitici, sì nota di frequente che l'azione di taluni di essi è limitata al tratto gastro-intestinale, Among the products usually used in therapy as spasmolytics, it is frequently known that the action of some of them is limited to the gastro-intestinal tract,
20 Quei prodotti che a seguito della somministrazione orale esplicano la loro azione anche su altri organi od apparati diversi dal tratto gastro-intestinale possiedono tuttavia effetti collaterali di tipo atropinosimile. 20 Those products which, following oral administration, also exert their action on other organs or systems other than the gastro-intestinal tract, nevertheless have side effects of the atropinosimile type.
È stato ora scoperto che i nuovi composti sia racemici 25 sia otticamente attivi, riferibili alla seguente formula generale I: It has now been discovered that the new racemic compounds 25 and optically active, referable to the following general formula I:
CH3 CH3
dove n=2 o 3 ed Et sta per C2H5 where n = 2 or 3 and Et stands for C2H5
ed i loro sali sono particolarmente adatti per uso orale e si 35 differenziano dai prodotti già noti per l'azione inibente la trasmissione dall'impulso nervoso alla fibra muscolare (attività parasimpaticolitica), per l'effetto inibitorio della contrazione della muscolatura liscia (attività miolitica diretta) e per i ridotti effetti collaterali a carico del sistema nervoso 40 centrale e periferico. and their salts are particularly suitable for oral use and differ from the products already known for their inhibiting action of transmission from the nerve impulse to the muscle fiber (parasympatholytic activity), for the inhibitory effect of smooth muscle contraction (myolytic activity direct) and for the reduced side effects of the central and peripheral nervous system 40.
È stato trovato che i nuovi composti corrispondenti alla formula generale I ed i loro sali sono particolarmente adatti per uso orale, e si differenziano dai prodotti già noti per la loro attività parasimpaticolitica e miolitica diretta e per 45 i loro ridotti effetti collaterali a carico del sistema nervoso centrale e periferico. It has been found that the new compounds corresponding to the general formula I and their salts are particularly suitable for oral use, and differ from the products already known for their direct parasympatholytic and myolytic activity and for their reduced side effects on the system. central and peripheral nervous.
È stato trovato che i nuovi composti corrispondenti alla formula generale I ed i loro sali sono particolarmente adatti per uso orale, e si differenziano dai prodotti già noti per la 50 loro attività parasimpaticolitica e miolitica diretta e per i loro ridotti effetti collaterali a carico del sistema nervoso centrale e periferico. It has been found that the new compounds corresponding to the general formula I and their salts are particularly suitable for oral use, and differ from the products already known for their direct parasympatholytic and myolytic activity and for their reduced system side effects. central and peripheral nervous.
Composti riferibili alla struttura I sono: 1. 2-(4-bifenilii)-N-(2-dietilaminoetil) propionamide; 55 2. 2-(4-bifenilil)-N-(3-dietilaminopropil) propionamide; Compounds referable to structure I are: 1. 2- (4-biphenyls) -N- (2-diethylaminoethyl) propionamide; 55 2. 2- (4-biphenyl) -N- (3-diethylaminopropyl) propionamide;
3. d 2-(4-bifenilil)-N-(2-dietilaminoetil) propionamide; 3. d 2- (4-biphenylyl) -N- (2-diethylaminoethyl) propionamide;
4. ] 2-(4-bifenilil-N-(2-dietilaminoetil) propionamide; 4.] 2- (4-biphenyl-N- (2-diethylaminoethyl) propionamide;
5. d 2-(4-bifenilil-N-(3-dietilaminopropil) propionamide; 5. d 2- (4-biphenyl-N- (3-diethylaminopropyl) propionamide;
6. 1 2-(4-bifenilil-N-(3-dietilaminopropil) propionamide. 6. 1 2- (4-biphenyl-N- (3-diethylaminopropyl) propionamide.
60 Sali farmaceuticamente accettabili dei suddetti composti sono come esempi non limitativi il cloruro, bromuro, joduro, fosfato, così come metil bromuro, metil joduro, etil bromuro, etil joduro. 60 Pharmaceutically acceptable salts of the above compounds are as non-limiting examples the chloride, bromide, iodide, phosphate, as well as methyl bromide, methyl iodide, ethyl bromide, ethyl iodide.
Composti della formula I possono essere preparati se-65 condo metodi noti, ed in particolare facendo reagire un derivato funzionale o dell'acido 2-(4-bifenili!) propionico con N,N-dietiletiIendiamina o N,N-dietil-l,3-propilendiamina in presenza di un adatto solvente. Come derivato funzionale Compounds of formula I can be prepared according to known methods, and in particular by reacting a functional derivative or of 2- (4-biphenyl!) Propionic acid with N, N-diethylethylendiamine or N, N-diethyl-1, 3-propylene diamine in the presence of a suitable solvent. As a functional derivative
3 3
637370 637370
della forma racemica o di una delle forme otticamente attive dell'acido 2-(4-bifenilil) propionico si può usare il cloruro o la corrispondente anidride, come pure un estere dell'acido stesso, ed in particolare un estere alchilico inferiore. Usando come reattivo il cloruro dell'acido, è preferibile condurre la reazione di condensazione con N,N-dietiletilendi-amina o con N,N-dietil-l,3-propilendiamina in presenza di una base. of the racemic form or of one of the optically active forms of 2- (4-biphenyl) propionic acid, chloride or the corresponding anhydride can be used, as well as an ester of the acid itself, and in particular a lower alkyl ester. Using the acid chloride as a reactive, it is preferable to conduct the condensation reaction with N, N-diethylethylenediamine or with N, N-diethyl-1, 3-propylenediamine in the presence of a base.
I composti 3, 4, 5, 6 possono anche essere ottenuti utilizzando i metodi descritti in letteratura come idonei per la risoluzione in antipodi ottici di forme racemiche di sostanze a carattere basico contenenti un atomo di carbonio asimmetrico a partire da di 2-(4-bifenilil)-N-(dietilamino alchil) propionamide. Compounds 3, 4, 5, 6 can also be obtained using the methods described in the literature as suitable for the resolution in optical antipodes of racemic forms of basic substances containing an asymmetrical carbon atom starting from 2- (4- biphenylyl) -N- (diethylamino alkyl) propionamide.
I sali dei composti di formula I sono anch'essi preparati secondo metodi noti. Gli alchilalogenoderivati sono preparati per alchilazione delle basi riferibili alla formula I, con agenti alchilanti quali alchil cloruro, alchil bromuro o alchil joduro in un solvente organico idoneo, quale diossano, acetone, etere etilico. The salts of the compounds of formula I are also prepared according to known methods. The alkyl halogen derivatives are prepared by alkylation of the bases referable to formula I, with alkylating agents such as alkyl chloride, alkyl bromide or alkyl iodide in a suitable organic solvent, such as dioxane, acetone, ethyl ether.
Esempio 1 Example 1
Preparazione del 2-(4-bifenilil)-N-(2-dietilamino etil) propionamide (Composto 1). Preparation of 2- (4-biphenyl) -N- (2-diethylamino ethyl) propionamide (Compound 1).
A g 11,6 di N,N-dietilaminoetilendiamina in 60 mi di benzene, si sgocciolano lentamente sotto agitazione g 24,4 di cloruro dell'acido 2-(4-bifenilil)-propionico sciolti in 60 mi di benzene. Dopo aver tenuto 1 h a ricadere, si concentra, si estrae con etere etilico ed acqua, si precipita con soda dalla soluzione acquosa; si cristallizza da esame: p.f. 67-68°C. I. R. (Nujol), v max (cm-1): 3340 (NH), 1640 (CO) N-NMR (CC14), 8 (ppm): 1 (t, 2 X CH3) 1,6 (d, CH3) 2,3-2,6 (m, 3 X CH2) 3,3 (q, CH2) 3,6 (q, CH) 7,2-7,5 (m, C6H4 e C6H5). At 11.6 g of N, N-diethylaminoethylenediamine in 60 ml of benzene, 24.4 g of 2- (4-biphenylyl) -propionic acid dissolved in 60 ml of benzene are slowly dripped under stirring. After keeping 1 hour in reflux, it is concentrated, extracted with ethyl ether and water, precipitated with soda from the aqueous solution; crystallizes from examination: m.p. 67-68 ° C. IR (Nujol), v max (cm-1): 3340 (NH), 1640 (CO) N-NMR (CC14), 8 (ppm): 1 (t, 2 X CH3) 1.6 (d, CH3) 2.3-2.6 (m, 3 X CH2) 3.3 (q, CH2) 3.6 (q, CH) 7.2-7.5 (m, C6H4 and C6H5).
Esempio 2 Example 2
Preparazione del 2-(4-bifenilil)-N-(3-dietilamino propil) propionamide (Composto 2). Preparation of 2- (4-biphenyl) -N- (3-diethylamino propyl) propionamide (Compound 2).
A g 13 di N,N-distilamino-l,3-propiIendiamina in 60 mi di benzene, si sgocciolano lentamente sotto agitazione g 24,4 di cloruro dell'acido 2-(4-bifenilil) propionico sciolti in 60 mi di benzene. Dopo aver tenuto 2 h a ricadere, si concentra, si estrae con etere etilico ed acqua, si precipita con soda dalla soluzione acquosa; si cristallizza da esano; p. f. 44-45°C. I. R. (Nujol), v max (cm-1): 3280 (NH), 1640 (CO) H-NMR (CDC13), 8 (ppm): 1,1 (t, 2 X CH3) 1,6-1,9 (m, CH3 a CH2) 2,4-2,7 (m, 3 X CH2) 3,5 (q, CH2) 3,8 (q, CH) 7,5-7,9 (m, C6H4 e C6H5). At 13 g of N, N-distilamino-1, 3-propiendiamine in 60 ml of benzene, 24.4 g of 2- (4-bisphenyl) propionic acid chloride dissolved in 60 ml of benzene are slowly dripped under stirring. After holding for 2 hours in reflux, it is concentrated, extracted with ethyl ether and water, precipitated with soda from the aqueous solution; crystallizes from hexane; p. f. 44-45 ° C. IR (Nujol), v max (cm-1): 3280 (NH), 1640 (CO) H-NMR (CDC13), 8 (ppm): 1.1 (t, 2 X CH3) 1.6-1, 9 (m, CH3 to CH2) 2.4-2.7 (m, 3 X CH2) 3.5 (q, CH2) 3.8 (q, CH) 7.5-7.9 (m, C6H4 and C6H5).
Esempio 3 Example 3
Preparazione del d 2-(4-bifenilil)-N-(2-dietilaminoetil) propionamide. (Composto 3). Preparation of d 2- (4-biphenyl) -N- (2-diethylaminoethyl) propionamide. (Compound 3).
A g 11,6 di N,N-dietiletilendiamina in 60 mi di benzene, si sgocciolano lentamente sotto agitazione g 24,4 di cloruro dell'acido d 2-(4-bifenilil)-propionico sciolti in 60 mi di benzene. Dopo aver tenuto 1 h a ricadere, si concentra, si estrae con etere etilico ed acqua, si precipita con soda della soluzione acquosa: si cristallizza da esano: p. f. 88-89°, [a]D20 = +7° (c = 2% in alcol etilico). I. R. (Nujol), max. (cm-1): 3340 (NH), 1640 (CO) N-NMR (CC14), (p.p.m): 1 (t, 2 X CH3) 1,6 (d, CH3) 2,3-2,6 (m, 3 X CH2) (q, CH2) 3,6 (q, CH) 7,2-7,5 (m, C6H4 e C6H5). At 11.6 g of N, N-diethylethylenediamine in 60 ml of benzene, 24.4 g of 2- (4-biphenylyl) -propionic acid chloride dissolved in 60 ml of benzene are slowly dripped under stirring. After keeping 1 hour in reflux, concentrate, extract with ethyl ether and water, precipitate with soda of the aqueous solution: crystallize from hexane: p. f. 88-89 °, [a] D20 = + 7 ° (c = 2% in ethyl alcohol). I. R. (Nujol), max. (cm-1): 3340 (NH), 1640 (CO) N-NMR (CC14), (ppm): 1 (t, 2 X CH3) 1.6 (d, CH3) 2.3-2.6 ( m, 3 X CH2) (q, CH2) 3.6 (q, CH) 7.2-7.5 (m, C6H4 and C6H5).
Esempio 4 Example 4
Preparazione del d 2-(4-bifenilil)-N-(3-dietilamino propil) propionamide. (Composto 5). Preparation of d 2- (4-biphenyl) -N- (3-diethylamino propyl) propionamide. (Compound 5).
A g 13 di N,N-dietil-l,3-propilendiamina in 60 mi di benzene, si sgocciolano lentamente sotto agitazione g 24,4 At 13 g of N, N-diethyl-1, 3-propylenediamine in 60 ml of benzene, slowly drain under stirring 24.4 g
di cloruro dell'acido d 2-(4-bifenilil) propionico sciolti in 60 mi di benzene. Dopo aver tenuto 2 h a ricadere, si concentra, si estrae con etere etilico ed acqua, si precipita con soda dalla soluzione acquosa: si cristallizza da esano: p. f. 51-53°C, [a]D20 = +17° (c = 2% in alcol etilitico). I. R. (Nujol), v max (cm-1): 3280 (NH), 1640 (CO) H-NMR (CDC13), S (ppm): 1,1 (t, 2 X CH3) 1,6-1,9 (m, CH3 e CH2) 2,4-2,7 (m, 3 X CH2) 3,5 (q, CH2) 3,8 (q, CH) 7,5-7,9 (m, C6H4 e C6H5). of 2- (4-biphenyl) propionic acid chloride dissolved in 60 ml of benzene. After holding 2 hours to reflux, concentrate, extract with ethyl ether and water, precipitate with soda from the aqueous solution: crystallize from hexane: p. f. 51-53 ° C, [a] D20 = + 17 ° (c = 2% in ethyl alcohol). IR (Nujol), v max (cm-1): 3280 (NH), 1640 (CO) H-NMR (CDC13), S (ppm): 1.1 (t, 2 X CH3) 1.6-1, 9 (m, CH3 and CH2) 2.4-2.7 (m, 3 X CH2) 3.5 (q, CH2) 3.8 (q, CH) 7.5-7.9 (m, C6H4 and C6H5).
Esempio 5 Example 5
Preparazione del 2-(4-bifeniliI)-N-(2-dietilmetilammoni--etil) propionamide bromuro. Preparation of 2- (4-biphenylI) -N- (2-diethylmethylammoni - ethyl) propionamide bromide.
In g 8 di 2-(4-bifenilil)-N-(2-dietilamino-etil) propionamide sciolti in 20 mi di acetone, si fanno gorgoliare g 2,5 di metile bromuro. Si filtra il precipitato e si cristallizza da alcool isopropilico: p. f. 161-163°C. I. R. (Nujol) v max (cm-1): 3150 (NH), 1650 (CO) H-NMR (CDCI3), 8 (ppm): 1,3 (t, 2 X CH3) 1,6 (d, CH3) 3,2 (s, CHj) 3,4-4,0 (m, 4 X CH2 e CH) 7,4-7,7 (m, C6H4 e C6H5). In 8 g of 2- (4-biphenyl) -N- (2-diethylamino-ethyl) propionamide dissolved in 20 ml of acetone, 2.5 g of methyl bromide are gorgolated. The precipitate is filtered and crystallized from isopropyl alcohol: p. f. 161-163 ° C. IR (Nujol) v max (cm-1): 3150 (NH), 1650 (CO) H-NMR (CDCI3), 8 (ppm): 1.3 (t, 2 X CH3) 1.6 (d, CH3 ) 3.2 (s, CHj) 3.4-4.0 (m, 4 X CH2 and CH) 7.4-7.7 (m, C6H4 and C6H5).
Esempio 6 Example 6
Preparazione del 2-(4-bifeniliI)-N-(3-dietilmetilammonio--propil) propionamide bromuro. Preparation of 2- (4-biphenylI) -N- (3-diethylmethylammonium - propyl) propionamide bromide.
In g 8,5 di 2-(4-bifenilil)-N-(3-dietilamino-propil) propionamide sciolti in 20 mi di acetone si fanno gorgogliare g 2,5 di metile bromuro. Si filtra il precipitato che viene cristallizzato da acetone/etere etilico: p. f. 116-118°C. I. R. (Nujol), v max (cm-1): 3150 (NH), 1645 (CO) H-NMR (CDC13), 8 (ppm): 1,25 (t, 2 X CH3), 1,55 (d, CH3), 1,8-2,3 (m, CH2) 3 (s, CH3) 3,1-3,7 (m, 4 X CH2) 3,7-4,2 (q, CH) (q, CH) 7,4-7,7 (m, C6H4 e C6H5). In 8.5 g of 2- (4-biphenyl) -N- (3-diethylamino-propyl) propionamide dissolved in 20 ml of acetone, 2.5 g of methyl bromide are bubbled. The precipitate is filtered and crystallized from acetone / ethyl ether: p. f. 116-118 ° C. IR (Nujol), v max (cm-1): 3150 (NH), 1645 (CO) H-NMR (CDC13), 8 (ppm): 1.25 (t, 2 X CH3), 1.55 (d , CH3), 1.8-2.3 (m, CH2) 3 (s, CH3) 3.1-3.7 (m, 4 X CH2) 3.7-4.2 (q, CH) (q , CH) 7.4-7.7 (m, C6H4 and C6H5).
Esempio 7 Example 7
Preparazione del 2-(4-bifeniIil)-N-(2-dietilmetilammonio-etil) propionamide joduro. Preparation of 2- (4-biphenyl) -N- (2-diethylmethylammonium-ethyl) propionamide iodide.
A g 8,0 di 2-(4-bifeniiil-N-(2-dietilaminopropiI) propionamide sciolti in 25 mi di alcool etilico si aggiungono g 4 di metile joduro. Si porta a secco sotto vuoto e si cristallizza da acetone: p. f. 132-134°C. I. R. (Nujol), v max (cnr1): 3200 (NH), 1655 (CO) H-NMR (CDC13), 8 (ppm): 1,3 (t, 2 X CH3) 1,6 (d, CH3) 3,1 (s, CH3) 3,3-4,0 (m, 4 X CH2 e CH) 7,4-7,65 (m, C6H5 e C6H4). 8.0 g of 2- (4-bifeniiil-N- (2-diethylaminopropiI) propionamide dissolved in 25 ml of ethyl alcohol are added with 4 g of methyl iodide, dried under vacuum and crystallized from acetone: mp 132 -134 ° CIR (Nujol), v max (cnr1): 3200 (NH), 1655 (CO) H-NMR (CDC13), 8 (ppm): 1.3 (t, 2 X CH3) 1.6 (d , CH3) 3.1 (s, CH3) 3.3-4.0 (m, 4 X CH2 and CH) 7.4-7.65 (m, C6H5 and C6H4).
Attività biologica Biological activity
L'attività miolitica è stata saggiata con il test che misura il transito del carbone nell'intenstino di topo, stimolato da BaCl2 secondo il metodo descritto da P.A.J. Janssen & A. Jageneau, J. Pharm. Pharmacol. 9, 381, 1957. Myolytic activity was tested with the test that measures the transit of coal in the mouse intensity, stimulated by BaCl2 according to the method described by P.A.J. Janssen & A. Jageneau, J. Pharm. Pharmacol. 9, 381, 1957.
L'attività parasimpaticolitica è stata saggiata nella cavia anestetizzata valutando l'effetto inibitorio dei prodotti sull'azione del carbachol a livello bronchiale secondo il metodo descritto da M. E. Rosenthale & A. Pervinis, Arch. Int. Pharmacodyn 1, 172, 1968 ed a livello cardiaco e pressorio, (vedi J. P. Long & C. Y. Chiou, J. Pharm. Sciences, 59, 133, 1970). The parasympatholytic activity was tested in anesthetized guinea pig by evaluating the inhibitory effect of the products on the action of carbachol at the bronchial level according to the method described by ME Rosenthale & A. Pervinis, Arch. Int. Pharmacodyn 1, 172, 1968 and at the level cardiac and blood pressure, (see JP Long & CY Chiou, J. Pharm. Sciences, 59, 133, 1970).
5 5
10 10
15 15
20 20
25 25
30 30
35 35
40 40
45 45
50 50
55 55
60 60
65 65
637370 637370
4 4
I risultati sono riportati nella tabella 1 che segue: The results are shown in table 1 below:
TABELLA 2 TABLE 2
TABELLA 1 TABLE 1
Composto Composed
Inibizione della stimolazione da cloruro di bario della peristalsi intestinale (test del carbone). Rapporto di potenza 0 Inhibition of barium chloride stimulation of intestinal peristalsis (carbon test). Power ratio 0
Cavia anestetizzata. Inibizione del seguente effetto indotto da carbachol ° (Rapporto di potenza) Anesthetized guinea pig. Inhibition of the following effect induced by carbachol ° (Power ratio)
Bronco- Ipoten- Bradi-costri- sione cardia zione Bronco- Hypen- Bradi-cardiac constriction
° I composti furono somministrati per via intraduodenale alla dose di 25 mg/kg. Il carbachol (5 [ig/kg) fu iniettato per via endovenosa prima e 40 minuti dopo la somministrazione dei prodotti. ° The compounds were administered intraduodenally at a dose of 25 mg / kg. Carbachol (5 [ig / kg) was injected intravenously before and 40 minutes after administration of the products.
1=2- (4-bifenilil)-N-(2-dietilaminoetil) acetamide 1 = 2- (4-biphenylyl) -N- (2-diethylaminoethyl) acetamide
2 = 2- (4-bifenilil)-N-(2-tietilaminoetil) propionamide 2 = 2- (4-biphenyl) -N- (2-thiethylaminoethyl) propionamide
3 = 2- (4-bifenilil)-N-(3-dietilaminopropil) propionamide 3 = 2- (4-biphenyl) -N- (3-diethylaminopropyl) propionamide
4 = d 2-(4-bifenilil-N-(2-dietilaminoetil) propionamide 4 = d 2- (4-biphenyl-N- (2-diethylaminoethyl) propionamide
5 = d 2(4-bifenilil)4-(3-dietilaminopropil) propionamide 5 = d 2 (4-biphenyl) 4- (3-diethylaminopropyl) propionamide
Attività anticolinergica centrale Central anticholinergic activity
5 Potenziamento degli effetti dell'Apomorfina secondo Sheel-Kriiger (a) 5 Enhancement of the effects of Apomorphine according to Sheel-Kriiger (a)
1 1
0,9 0.9
0,2 0.2
5 5
0,2 0.2
2 2
1,5 1.5
1 1
10 10
1,4 1.4
3 3
1,9 1.9
0,9 0.9
10 10
1,2 1.2
4 4
> 2,5 > 2.5
1,3 1.3
10 10
1,5 1.5
5 5
1,5 1.5
1,0 1.0
6 6
0,8 0.8
Diciclo- Diciclo-
mina mine
HCl HCl
1 1
1 1
1 1
1 1
Effetti centrali e periferici Central and peripheral effects
Inibizione degli effetti del-l'Ossotremorina (b) Inhibition of the effects of oxothremorin (b)
Composti compounds
Indice attività Activity index
Composti attività Indice io Compound Activities Index I.
15 15
Diciclomina HCl Dicyclomine HCl
1 1
Diciclomina HCl Dicyclomine HCl
1 1
2 (c) 2 (c)
0,5 0.5
2 (c) 2 (c)
0,2 0.2
Atropina solfato Atropine sulphate
1,3 1.3
Butilbromuro di Butylbromide of
scopolamina scopolamine
1,2 1.2
(a) (to)
Media degli effetti di 3 dosi (30-60-90 mg/kg/os) dei com-20 posti somministrati a topi femmine (17-25 g) 1 ora avanti l'Apomorfina (10 mg/-kg/c.c.). Si valuta l'intensità di masticamento per i prodotti ed il controllo (H2O) per un periodo di 40 minuti. Average of the effects of 3 doses (30-60-90 mg / kg / os) of the com-20 places administered to female mice (17-25 g) 1 hour before Apomorphine (10 mg / -kg / c.c.). The chewing intensity for the products and the control (H2O) is evaluated for a period of 40 minutes.
25 25
(b) (B)
Media degli effetti di 3 dosi (28,6-57,2-114,4 mg/kg/os) dei composti somministrati a topi maschi (18-25 g) 1 ora avanti l'Ossotremorina (0,5 mg/mg/s.c.). Si valuta l'effetto sulla lacrimazione, salivazione, diarrea e tremore rispetto al controllo (H2O) 15 min-30 min. 1 ora e 2 ore Average of the effects of 3 doses (28.6-57.2-114.4 mg / kg / os) of the compounds administered to male mice (18-25 g) 1 hour before oxothremorin (0.5 mg / mg / sc). We evaluate the effect on tearing, salivation, diarrhea and tremor with respect to control (H2O) 15 min-30 min. 1 hour and 2 hours
Da questi risultati si vede come la presenza di una struttura propionamidica sia rilevante per il miglioramento dell'attività. Infatti la già nota 2-(4-bifenilil)-N-(2-dietilamino-etil) acctamide [G. Cavallini, P. Ravenna, Farm. Sci. Tecn. 3, 648 (1948)] presenta un'attività parasimpaticolitica e miolitica diretta nettamente inferiore rispetto a quella mostrata dalla forma racemica e dalla forma destrogira della 2-(4-bi-fenilil)-N-(2-dietilaminoetil) propionamide. Quest'ultima inol tre, rispetto alla diciclomina, presenta un effetto inibitorio della contrazione della muscolatura liscia (attività miolitica diretta) di almeno 1,5 volte più marcata ed un'azione inibente la trasmissione dell'impulso nervoso alla fibra muscolare (attività parasimpaticolitica) da una a dieci volte più marcata. From these results it can be seen how the presence of a propionamide structure is relevant for the improvement of the activity. In fact the already known 2- (4-biphenyl) -N- (2-diethylamino-ethyl) acctamide [G. Cavallini, P. Ravenna, Farm. Sci. Tecn. 3, 648 (1948)] exhibits significantly lower parasympatholytic and direct myolytic activity than that shown by the racemic and dextrogyric form of 2- (4-bi-phenylyl) -N- (2-diethylaminoethyl) propionamide. The latter in addition, compared to dicyclomine, has an inhibitory effect of the contraction of the smooth muscle (direct myolytic activity) of at least 1.5 times more marked and an action inhibiting the transmission of the nerve impulse to the muscle fiber (parasympatholytic activity) one to ten times more pronounced.
Gli effetti collaterali atropinosimili sono stati studiati con il test dell'ossotremorina secondo il metodo descritto da Leslie G. Hayman G. Iresen J. D. & Smith S., Arch. Int. Pharmacodyn 197, 108, 1972, valutando gli effetti centrali (tremori) e periferici (salivazione, lacrimazione, diarrea) e con il test dell'apomorfina secondo il metodo descritto da J. Scheel-Krüger, Acta Pharmacol. Toxicol. 28, 1, 1970, valutando l'attività anticolinergica centrale. I dati sono ripor- 55 tati nella tabella 2. The atropinosimile side effects have been studied with the oxothremorin test according to the method described by Leslie G. Hayman G. Iresen JD & Smith S., Arch. Int. Pharmacodyn 197, 108, 1972, evaluating the central effects (tremors) and peripheral (salivation, lacrimation, diarrhea) and with the apomorphine test according to the method described by J. Scheel-Krüger, Acta Pharmacol. Toxicol. 28, 1, 1970, evaluating the central anticholinergic activity. The data are reported in table 2.
dall'Ossotremorina. (c) 2-(4-bifenilil)-N-(2-dietilaminoetil) propionamide. dall'Ossotremorina. (c) 2- (4-biphenyl) -N- (2-diethylaminoethyl) propionamide.
30 Da questa tabella 2 si può osservare che in confronto alla 2-(4-bifenilil)-N-(2-dietilaminoetil) propionamide, la diciclomina ed il butilbromuro di scopolamina presentano rispettivamente effetti centrali e periferici cinque o sei volte superiori. Per l'attività anticolinergica centrale, la diciclo-35 mina e l'atropina solfato presentano effetti circa due volte superiori rispetto alla 2-(4-bifenilil)-N-(2-dietiIaminoetil) propionamide. 30 From this table 2 it can be observed that in comparison with 2- (4-biphenyl) -N- (2-diethylaminoethyl) propionamide, dicyclomine and scopolamine butylbromide have respectively central and peripheral effects five or six times higher. Due to the central anticholinergic activity, dicyclo-35mine and atropine sulphate have effects about two times greater than 2- (4-biphenyl) -N- (2-dietsIaminoetil) propionamide.
Nessuno dei prodotti menzionati mostra proprietà anti-infiammatoria al test dell'edema da carragenina secondo il 40 metodo descritto da Winter C. A., Risley A. C. & Nuss G. W., Proc. Soc. Exp. Biol. Med. Ili, 544, 1962. None of the products mentioned shows anti-inflammatory properties on the carrageenan edema test according to the 40 method described by Winter C. A., Risley A. C. & Nuss G. W., Proc. Soc. Exp. Biol. Med. Ili, 544, 1962.
La presente invenzione inoltre prevede composizioni farmaceutiche comprendenti almeno un composto di formula I in associazione con un veicolante o eccipiente farmaceutico. 45 Le composizioni farmaceutiche possono essere presentate in adatte forme, per esempio per somministrazione orale, parenterale o suppositoria contenente in genere da 5 a 40 mg di sostanza attiva. Esempi di adatte forme di somministrazione includono tavolette, compresse, confetti, cap-50 sule, losanghe, dispersible powdes, sciroppi, elisir e supposte. Preferibilmente le composizioni sono presentate in forma unica di dosaggio. The present invention further provides pharmaceutical compositions comprising at least one compound of formula I in association with a carrier or pharmaceutical excipient. 45 The pharmaceutical compositions can be presented in suitable forms, for example for oral, parenteral or suppositorial administration generally containing from 5 to 40 mg of active substance. Examples of suitable forms of administration include tablets, tablets, sugared almonds, cap-50 gannets, lozenges, dispersible powdes, syrups, elixirs and suppositories. Preferably the compositions are presented in a single dosage form.
v v
Claims (16)
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IT964377A IT1090782B (en) | 1977-11-30 | 1977-11-30 | 2 4 BIPHENYLIL 2 DIETHYLAMIN ALCHYL PROPIONAMIDE ITS SALTS AND RELATED MANUFACTURING PROCEDURES |
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CH637370A5 true CH637370A5 (en) | 1983-07-29 |
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CH1216178A CH637370A5 (en) | 1977-11-30 | 1978-11-28 | Racemic forms and optically active forms of 2-(4-biphenylyl)-N-(diethylaminoalkyl)-propionamide, salts thereof and relative preparation processes |
Country Status (9)
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JP (1) | JPS5490157A (en) |
BE (1) | BE872403A (en) |
CA (1) | CA1118446A (en) |
CH (1) | CH637370A5 (en) |
DE (1) | DE2851416A1 (en) |
ES (1) | ES475533A1 (en) |
FR (1) | FR2410641A1 (en) |
IT (1) | IT1090782B (en) |
NL (1) | NL7811698A (en) |
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ITMI20012025A1 (en) * | 2001-09-28 | 2003-03-28 | Dompe Spa | QUATERNARY AMMONIUM SALTS OF OMEGA-AMINO ALKYLAMIDS OF R 2-ARY-PROPIONIC ACIDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US20090221703A1 (en) | 2006-07-09 | 2009-09-03 | Chongxi Yu | High penetration composition and uses thereof |
US20090238763A1 (en) | 2006-07-09 | 2009-09-24 | Chongxi Yu | High penetration compositions and uses thereof |
CN101506160A (en) * | 2006-08-08 | 2009-08-12 | 于崇曦 | Positively charged water-soluble prodrugs of aryl- and heteroarylacetic acids with very fast skin penetration rate |
AU2013206218B2 (en) * | 2006-08-15 | 2016-06-30 | Techfields Biochem Co. Ltd | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate |
JP5424880B2 (en) * | 2006-08-15 | 2014-02-26 | テックフィールズ バイオケム カンパニー リミテッド | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin permeability |
CN101687792B (en) | 2007-06-04 | 2016-03-02 | 于崇曦 | There is prodrug and the medicinal use thereof of the NSAID (non-steroidal anti-inflammatory drug) of fast skin and membranes penetration speed |
KR101946297B1 (en) | 2008-12-04 | 2019-02-11 | 충시 위 | High Penetration Compositions and Their Applications |
JP5940036B2 (en) * | 2013-10-08 | 2016-06-29 | テックフィールズ バイオケム カンパニー リミテッド | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin permeability |
JP6290947B2 (en) * | 2016-02-05 | 2018-03-07 | テックフィールズ バイオケム カンパニー リミテッド | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin permeability |
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FR1584547A (en) * | 1968-06-05 | 1969-12-26 | ||
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FR2119846A1 (en) * | 1970-12-28 | 1972-08-11 | Choay Sa | N,n-diethylaminoethylamide of para isobutyl phenylacetic - acid - antiinflammatory and analgesic |
US4145435A (en) * | 1976-11-12 | 1979-03-20 | The Upjohn Company | 2-aminocycloaliphatic amide compounds |
-
1977
- 1977-11-30 IT IT964377A patent/IT1090782B/en active
-
1978
- 1978-11-28 CH CH1216178A patent/CH637370A5/en not_active IP Right Cessation
- 1978-11-28 DE DE19782851416 patent/DE2851416A1/en active Granted
- 1978-11-29 ES ES475533A patent/ES475533A1/en not_active Expired
- 1978-11-29 NL NL7811698A patent/NL7811698A/en not_active Application Discontinuation
- 1978-11-30 FR FR7833889A patent/FR2410641A1/en active Granted
- 1978-11-30 BE BE192036A patent/BE872403A/en not_active IP Right Cessation
- 1978-11-30 JP JP14730778A patent/JPS5490157A/en active Granted
- 1978-11-30 CA CA000317175A patent/CA1118446A/en not_active Expired
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CA1118446A (en) | 1982-02-16 |
DE2851416A1 (en) | 1979-05-31 |
ES475533A1 (en) | 1980-01-16 |
IT1090782B (en) | 1985-06-26 |
JPS5490157A (en) | 1979-07-17 |
BE872403A (en) | 1979-03-16 |
JPS631286B2 (en) | 1988-01-12 |
FR2410641B1 (en) | 1983-04-15 |
NL7811698A (en) | 1979-06-01 |
DE2851416C2 (en) | 1989-02-23 |
FR2410641A1 (en) | 1979-06-29 |
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