CA1118446A - Racemic forms and optically active forms of 2-(4-biphenylyl)-n-(diethylamino alkyl) propionamide and salts thereof as well as processes for their production and use as spasmoltyic agents - Google Patents
Racemic forms and optically active forms of 2-(4-biphenylyl)-n-(diethylamino alkyl) propionamide and salts thereof as well as processes for their production and use as spasmoltyic agentsInfo
- Publication number
- CA1118446A CA1118446A CA000317175A CA317175A CA1118446A CA 1118446 A CA1118446 A CA 1118446A CA 000317175 A CA000317175 A CA 000317175A CA 317175 A CA317175 A CA 317175A CA 1118446 A CA1118446 A CA 1118446A
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- CA
- Canada
- Prior art keywords
- biphenyl
- propionamide
- ethyl
- diethyl
- bromide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
Abstract
2-(4-BIPHENYLYL)-N-(DIETHYLAMINO ALKYL) PROPIONAMIDE
AND SALTS THEREOF USED AS SPASMOLYTIC AGENTS
ABSTRACT OF THE DISCLOSURE
New compounds useful as spasmolytic agents are provided with the following formula:
AND SALTS THEREOF USED AS SPASMOLYTIC AGENTS
ABSTRACT OF THE DISCLOSURE
New compounds useful as spasmolytic agents are provided with the following formula:
Description
ill844G
BACK~RVUND OF THE INV~ ON
1. ~eld o~ the Invention '~!he present invention i9 concerned with new compounds ha~ g high ~pa~molytic a¢tion . ~ore particul0.rly, the inventio~l relates to certain pr~io~amld~ deri~rstiYe~ their pharmaceutically ac¢sptable ~alts and methoa~ of u~ th~se compound~
E~ 8pa8molyti.c agent~ in man and a~imal~.
BACK~RVUND OF THE INV~ ON
1. ~eld o~ the Invention '~!he present invention i9 concerned with new compounds ha~ g high ~pa~molytic a¢tion . ~ore particul0.rly, the inventio~l relates to certain pr~io~amld~ deri~rstiYe~ their pharmaceutically ac¢sptable ~alts and methoa~ of u~ th~se compound~
E~ 8pa8molyti.c agent~ in man and a~imal~.
2. Prior AFt Among the produots u~ually ~mployed i~ therapy a~ ~pa~molytlc, it i8 frequentl~r vb~erreà 1~hat the ~ction of 80~C o~ the~e known product~ 18 co~finsd to the ga~trointe~inal tract . 3ho8c product~ that after oral ~ ni~tration exert their aGtio~ also or~
organ~ and ~yst~m~ other tha~ th~ gastrointe~tinal tract, howe~er, have atrop~n~-like ~ide e~fects.
_MMAMY OF T~IE INVEN'~ION
It ha~ been ~ound that the new cRmpounds either rac~mio or opti~ally acti~e of the general ~ormula Is aH3 CH - CONH - (CH2) _ N/ ~I) n Et wherein n is 2 or 3~ and Et i8 the ethyl group, C2~ -9 and their non-toxlc, phRrmaceutically aceeptable 8alt5 are p~rticulsrly suitable for oral or parenteral use.
~k ~84~6 TheSe n~w com~oun~ and thelr salts d~ffer f~om the already kncwn products because: ¢a~ inhiblt the t~ansm~sslon o the ne~v~us impulse to the muscular fiber tParaSYmPatho~yt~ actlvLty); ~b) inhiblt the contractlon of the sm~oth mu~culature ~di~e~t myo~ytic activlty); and tc) have lower s~de effects on the central and pe~iphe~al nervou~ ~ystem.
It has be3n found that the new compounds cor~esponding to the general forn~la I and the~ nont~xic salts are partlcula~ly suitable for oral as well as parenteral use and differ rom the already kncwn products for their direct parasympathDlytic and myolytic actlvity and for their lcwer side effects on the central and peripheral nerv~us system. Specific examples of crmeowrLs related to the fo~mula I are:
1~ 2-t4-b~pbeny~-N-t2-dieth~la~lnoethyl) propLonamide; and 2) 2-~4-biph~ny)-N-~3~d-iethyla~ m apropyl) prop~onamide.
The bromide and iodide salts of 1) an~ 2) are especially useful as spasmolytic agents.
Pharmaceutically acceptable salts of the above mentioned comp~unds are, for instance, the non-boxic chloride, bromide, iodide, phosphate, and sulphate salts, as well as the methyl b~cmide/ methyl icdide, ethyl brcmide, eth~l iodide salts.
Ckmpounds of the fo~mula I are prepa~ed according to known methods.
In particular, these eompcunds are made by reaeting a functional derivative of 2-~4-biphenyl) prop~Qnie aeid wlth N,N dieth~lethylenediamine or N,N-diethyl -1,3-prc~ylenediamine in the presenee of a sultable solvent. As functional derivative o 2-~4-biphenyl) propionie acid the ehloride or the correspcnding anbydride o said aeid is very useul as well as an ester o bhe same acid and, in partieular, a lo~er alkyl ester such as the methyl esber of said acid.
Using the ehloride of the acid as reagent, it is preferable to perform the ecndensation reaetic~n with N,N-diethylethylenedia~lne or N,N-diethyl-1,3-pro~ylenediamine in the presenee of a base.
The salts o the compounds of the formula I are also prepared aecording to known me*hLds. The aLkylhalogen derivatives are prepared by aLkylation of the bases aeeording to fc~mula I, with aIkylat~ng agents such
organ~ and ~yst~m~ other tha~ th~ gastrointe~tinal tract, howe~er, have atrop~n~-like ~ide e~fects.
_MMAMY OF T~IE INVEN'~ION
It ha~ been ~ound that the new cRmpounds either rac~mio or opti~ally acti~e of the general ~ormula Is aH3 CH - CONH - (CH2) _ N/ ~I) n Et wherein n is 2 or 3~ and Et i8 the ethyl group, C2~ -9 and their non-toxlc, phRrmaceutically aceeptable 8alt5 are p~rticulsrly suitable for oral or parenteral use.
~k ~84~6 TheSe n~w com~oun~ and thelr salts d~ffer f~om the already kncwn products because: ¢a~ inhiblt the t~ansm~sslon o the ne~v~us impulse to the muscular fiber tParaSYmPatho~yt~ actlvLty); ~b) inhiblt the contractlon of the sm~oth mu~culature ~di~e~t myo~ytic activlty); and tc) have lower s~de effects on the central and pe~iphe~al nervou~ ~ystem.
It has be3n found that the new compounds cor~esponding to the general forn~la I and the~ nont~xic salts are partlcula~ly suitable for oral as well as parenteral use and differ rom the already kncwn products for their direct parasympathDlytic and myolytic actlvity and for their lcwer side effects on the central and peripheral nerv~us system. Specific examples of crmeowrLs related to the fo~mula I are:
1~ 2-t4-b~pbeny~-N-t2-dieth~la~lnoethyl) propLonamide; and 2) 2-~4-biph~ny)-N-~3~d-iethyla~ m apropyl) prop~onamide.
The bromide and iodide salts of 1) an~ 2) are especially useful as spasmolytic agents.
Pharmaceutically acceptable salts of the above mentioned comp~unds are, for instance, the non-boxic chloride, bromide, iodide, phosphate, and sulphate salts, as well as the methyl b~cmide/ methyl icdide, ethyl brcmide, eth~l iodide salts.
Ckmpounds of the fo~mula I are prepa~ed according to known methods.
In particular, these eompcunds are made by reaeting a functional derivative of 2-~4-biphenyl) prop~Qnie aeid wlth N,N dieth~lethylenediamine or N,N-diethyl -1,3-prc~ylenediamine in the presenee of a sultable solvent. As functional derivative o 2-~4-biphenyl) propionie acid the ehloride or the correspcnding anbydride o said aeid is very useul as well as an ester o bhe same acid and, in partieular, a lo~er alkyl ester such as the methyl esber of said acid.
Using the ehloride of the acid as reagent, it is preferable to perform the ecndensation reaetic~n with N,N-diethylethylenedia~lne or N,N-diethyl-1,3-pro~ylenediamine in the presenee of a base.
The salts o the compounds of the formula I are also prepared aecording to known me*hLds. The aLkylhalogen derivatives are prepared by aLkylation of the bases aeeording to fc~mula I, with aIkylat~ng agents such
- 3 -~184~G
asalkyl chloride, alkyl bromide or alkyl iodide in an organic low boiling solvent including, for example, dioxane, acetone, ethyl ether.
Example 1: Preparation of 2-(4-biphenyl)-N-(2-diethyl-amino ethyl) propionamide.
To 11.6 g of N,N-diethyl ethylenediamine in 60 ml of benzene are slowly added dropwise, with stirring, 24.4 g of 2-(4-biphenyl)-propionic acid chloride dissolved in 60 ml of benzene. After 1 hour refluxing, the mixture is concentrated, extracted with ethyl ether and water, and precipitation occurs from the aqueous solution with soda; crystallization of the desired product follows from hexane; melting point 67-68C.
I.R. (Nujol*), r max (cm 1): 3340 (NH), 1640 (CO)H-NMR (CC14), (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).
Example 2: Preparation of 2-(4-biphenyl)-N-(3-diethyl-aminopropyl) propionamide.
To 13 g of N,N-diethyl-1,3-propylenediamine in 60 ml of benzene are slowly added dropwise, with stirring, 24.4 g of 2-(4-biphenyl) propionic acid chloride dissolved in 60 ml of benzene. After 2 hours refluxing, the mixture is concentrated, extracted with ethyl ether and water; precipitation occurs with soda from the aqueous solution, crystallization of the desired product follows from hexane: m.p. 44-45C. I.R. (Nujol*), y max (cm ): 3280 (NH), 1640 (CO) H-NMR (CDC13), ~ (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).
Example 3: Preparation of 2-(4-biphenyl)-N-(2-diethyl-methylammonium-ethyl) propionamide bromide.
In 8 g of 2-(4-biphenyl)-N-(2-diethylamino-ethyl) propion-am:ide dissolved in 20 ml of acetone 2.5 g of methyl bromide are bubbled. The precipitate is filtered and crystallized from iso-* Trademarks
asalkyl chloride, alkyl bromide or alkyl iodide in an organic low boiling solvent including, for example, dioxane, acetone, ethyl ether.
Example 1: Preparation of 2-(4-biphenyl)-N-(2-diethyl-amino ethyl) propionamide.
To 11.6 g of N,N-diethyl ethylenediamine in 60 ml of benzene are slowly added dropwise, with stirring, 24.4 g of 2-(4-biphenyl)-propionic acid chloride dissolved in 60 ml of benzene. After 1 hour refluxing, the mixture is concentrated, extracted with ethyl ether and water, and precipitation occurs from the aqueous solution with soda; crystallization of the desired product follows from hexane; melting point 67-68C.
I.R. (Nujol*), r max (cm 1): 3340 (NH), 1640 (CO)H-NMR (CC14), (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).
Example 2: Preparation of 2-(4-biphenyl)-N-(3-diethyl-aminopropyl) propionamide.
To 13 g of N,N-diethyl-1,3-propylenediamine in 60 ml of benzene are slowly added dropwise, with stirring, 24.4 g of 2-(4-biphenyl) propionic acid chloride dissolved in 60 ml of benzene. After 2 hours refluxing, the mixture is concentrated, extracted with ethyl ether and water; precipitation occurs with soda from the aqueous solution, crystallization of the desired product follows from hexane: m.p. 44-45C. I.R. (Nujol*), y max (cm ): 3280 (NH), 1640 (CO) H-NMR (CDC13), ~ (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).
Example 3: Preparation of 2-(4-biphenyl)-N-(2-diethyl-methylammonium-ethyl) propionamide bromide.
In 8 g of 2-(4-biphenyl)-N-(2-diethylamino-ethyl) propion-am:ide dissolved in 20 ml of acetone 2.5 g of methyl bromide are bubbled. The precipitate is filtered and crystallized from iso-* Trademarks
-4-1~L184~6 propyl alcohol: m.p. 161-163 C. I.R. (Nujol*) y max (cm ):
3150 (NH), 1650 (CO) H-NMR (CDC13), ~ (ppm): 1.3 (t, 2 x CH3) 1.6 (d, CH3) 3.2 (s, CH3) 3.4-4.0 (m, 4 x CH2 and CH) 7.4-7.7 (m, C6H4 and C6H5) Example 4: Preparation of 2-(4-biphenylyl)-N-(3-diethyl-methyl-ammonium propyl) propionamide bromide.
In 8.5 g of 2-(4-biphenylyl)-N-(3-diethylamino-propyl) propionamide dissolved in 20 ml of acetone 2.5 g of methyl bromide are bubbled. The precipitate is filtered and crystal-lized from acetone/ethyl ether; the melting point of the desiredproduct is 116-118C and this product is characterized as follows:
I.R. (Nujol*), ~ max (cm 1): 3150 (NH), 1645 (CO) H-NMR (CDC13), (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) 7.4-7.7 (m, C6H4 6 5) Example 5: Preparation of 2-(4-biphenyl)-N-(2-diethyl-methyl-ammoniumethyl) propionamide iodide.
To 8.0 g of 2-(4-biphenyl)-N-(2-diethylamino-ethyl) pro-pionamide dissolved in 25 ml of ethyl alcohol 4 g of methyl io-dide are added. The mixture is dried under vacuum and crystall-ized from acetone: yielding the desired product whose melting point is 132-134C. This product has the following characteris-tic properties: I.R. (Nujol*) ~ max (cm ): 3200 (NH), 1655 (CO) H-NMR (CDC13), ~ (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).
Example 6: Biologic Activity: Use of Formula I compounds as spasmolytic agents in animals.
The potential myolytic activity of the compounds of the present invention was determined by measuring the transit of a charcoal meal in mouse intestine, stimulated by BaC12, according to P.A.J. Janssen and A. Jageneau, J. Pharm. Pharmacol. 9, 381, 1957.
* Trademarks B
1~184~6 ~ he potential parasympatholytic activity of the compounds of the present invention was tested by evaluating in the anesthet-ized guinea pig their antagonism toward the carbachol induced bronchoconstriction (according to M.E. Rosenthale and A. Pervinis, A ch. Int. Pharmacodyn. 1, 172, 1968), and bradycardia and hypo-tension (according to J.P. Long and C.Y. Chiou, J. Pharm. Sciences 59, 133, 1970).
The results are reported in the following Table 1.
-5a-34~
. l . I ~ _ 1 Y~ ~r ~1 ~
~ ~; ~ ,, ~,~
--r L L~
A~ -6-These results clearlv indicate that presence of the propionamide structure is required to better spasmolytic activity. In act the alrea~y kncwn 2-~4-biphenyl)-~-~2-daethylamLnoeth~vl) acetamide ~G. Cavallini, F.
Ravenna, Farm. Sci. ~ecn. 3, 648 ~1948) has a direct p æ asympatho~ytic and myolitic activity deinitely lower than that o 2-~4-biph~nyl)-N-~2-diethyl-aminoethyl) propiQnamide. Furthermo~e, this latter is 1.5 times as eective as dicyclcmine in antagonizing smooth muscle contraction ~d-irect myolytic effect) and 10 tLmes as effective as dicyclcmine in antagonizing the trans-mission o the nervcus impulses to the muscular fiber ~paras~mpathol~tic effect).
The atropinelike side effects o these ccmpounds have been studied with the oxDtremorane test accordang to the methcd described by Leslie G., Hayman G., Ireson J. D. and Smith S., Arch. Int. Pha~nacodyn. 197, 108, 1972, evaluating the central eects ~tremars) and peripheral efects ~salivation, lacrimation, diarrhea) and with the aFcmo~pbine test according to the method descri-ked by J. Scheel-K~ger, Acta Pha~macol. Toxicol. ~J 1~ 1970, evaluat mg the central antichli~er~ic activity. The data are reported in Table 2.
~, J~J
~ABLE 2 , ~ .
Central anticholmergac activity Central an~ Feripheral effects Potentiation of Inhibition of oxotremorine apcmorphine efects accordang effects ~b) to Scheel-Kr~ger ~a) . . . .
CompcNnds Activity index Compounds ALtivlty index .
Dicyclomine HCl 1 Dicyclomine HCl 1 _ 2 ~c) 0.5 2 ~c~ 0.2 , _ AtrcpLne sulpha~e 1.3 Scopola~ine 1.2 _ butyL b~onide ~a) Average effect of (b) Average effect of 3 3 doses ~30-60-90 mg/Kg/os) doses ~28.6-51.2-114.4 mg/Kg/os) o the ccnpound5 admLnistered o the caicurds administered to emale mice ~17-25 g) 1 hour to male mice ~18-25 g) 1 hour befo~e apomorphine ~10 mg/Xg/ before oxctremQLine ~0.5 s.c.). The gnawing intensaty mg/Kg/s.c.). The effect on is evaluated fo~ the products lacrimation, salivation, and the control ~H2O) cr a 40 diarrhea and tremor in comparison m m ute pe~iod. with contrc~s ~H~O) is evaluated in 15-30-60 and ~20 m m. after oxc,tremorine.
Compound 2 ~c) = 2-~4-biphen~1)-N-~2-diethy1aminoethy1) prc,pionamide ~1~34~
It is seen from Table 2 that m comparison with 2-~4-biphenyl)-N-~2-diethylaminoethyl) propionamlde, dicvclomlne and scopola~lne butyl bromlde have respectively 5 or 6 t~mes h~gher central and perlpheral side-effects. As to the central antlcholinergic activlty, dic~vclom me and atropine sulphate have about 2 times higher side-effects in relation to 2-~4-biphenyl)-N-~2-diethylaminoethyl) proplonamide.
None of the mentioned prodw ts exhibits antiphlogistic property as deteLmined by the carragee~an pa~ edema test according to W~nter, A.C., Risley, E.A., and Nuss, G.W., Proc. Soc~ Exp. Biol. Med. 111, 544, 1962.
The present invention further provides pharmaceutical compositions ccmprising at least one oompound of formula I in association with a pharma-ceutical carrier or excipient. The phaLmaceutical compositions may be presented in a orm su-it~ble, for example, for oral or parenteral or rectal administration in doses ranglng ~rom 5 to 40 mg o active ing~edients.
EXamples o suitable forms o administLation include, vials, tablets, coated tablets, capsules, lozenges, dispersible p~ders, syrups, elixirs and suppc~itories. Preerably the comFos~tions are presented in dosage unit form.
3150 (NH), 1650 (CO) H-NMR (CDC13), ~ (ppm): 1.3 (t, 2 x CH3) 1.6 (d, CH3) 3.2 (s, CH3) 3.4-4.0 (m, 4 x CH2 and CH) 7.4-7.7 (m, C6H4 and C6H5) Example 4: Preparation of 2-(4-biphenylyl)-N-(3-diethyl-methyl-ammonium propyl) propionamide bromide.
In 8.5 g of 2-(4-biphenylyl)-N-(3-diethylamino-propyl) propionamide dissolved in 20 ml of acetone 2.5 g of methyl bromide are bubbled. The precipitate is filtered and crystal-lized from acetone/ethyl ether; the melting point of the desiredproduct is 116-118C and this product is characterized as follows:
I.R. (Nujol*), ~ max (cm 1): 3150 (NH), 1645 (CO) H-NMR (CDC13), (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) 7.4-7.7 (m, C6H4 6 5) Example 5: Preparation of 2-(4-biphenyl)-N-(2-diethyl-methyl-ammoniumethyl) propionamide iodide.
To 8.0 g of 2-(4-biphenyl)-N-(2-diethylamino-ethyl) pro-pionamide dissolved in 25 ml of ethyl alcohol 4 g of methyl io-dide are added. The mixture is dried under vacuum and crystall-ized from acetone: yielding the desired product whose melting point is 132-134C. This product has the following characteris-tic properties: I.R. (Nujol*) ~ max (cm ): 3200 (NH), 1655 (CO) H-NMR (CDC13), ~ (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).
Example 6: Biologic Activity: Use of Formula I compounds as spasmolytic agents in animals.
The potential myolytic activity of the compounds of the present invention was determined by measuring the transit of a charcoal meal in mouse intestine, stimulated by BaC12, according to P.A.J. Janssen and A. Jageneau, J. Pharm. Pharmacol. 9, 381, 1957.
* Trademarks B
1~184~6 ~ he potential parasympatholytic activity of the compounds of the present invention was tested by evaluating in the anesthet-ized guinea pig their antagonism toward the carbachol induced bronchoconstriction (according to M.E. Rosenthale and A. Pervinis, A ch. Int. Pharmacodyn. 1, 172, 1968), and bradycardia and hypo-tension (according to J.P. Long and C.Y. Chiou, J. Pharm. Sciences 59, 133, 1970).
The results are reported in the following Table 1.
-5a-34~
. l . I ~ _ 1 Y~ ~r ~1 ~
~ ~; ~ ,, ~,~
--r L L~
A~ -6-These results clearlv indicate that presence of the propionamide structure is required to better spasmolytic activity. In act the alrea~y kncwn 2-~4-biphenyl)-~-~2-daethylamLnoeth~vl) acetamide ~G. Cavallini, F.
Ravenna, Farm. Sci. ~ecn. 3, 648 ~1948) has a direct p æ asympatho~ytic and myolitic activity deinitely lower than that o 2-~4-biph~nyl)-N-~2-diethyl-aminoethyl) propiQnamide. Furthermo~e, this latter is 1.5 times as eective as dicyclcmine in antagonizing smooth muscle contraction ~d-irect myolytic effect) and 10 tLmes as effective as dicyclcmine in antagonizing the trans-mission o the nervcus impulses to the muscular fiber ~paras~mpathol~tic effect).
The atropinelike side effects o these ccmpounds have been studied with the oxDtremorane test accordang to the methcd described by Leslie G., Hayman G., Ireson J. D. and Smith S., Arch. Int. Pha~nacodyn. 197, 108, 1972, evaluating the central eects ~tremars) and peripheral efects ~salivation, lacrimation, diarrhea) and with the aFcmo~pbine test according to the method descri-ked by J. Scheel-K~ger, Acta Pha~macol. Toxicol. ~J 1~ 1970, evaluat mg the central antichli~er~ic activity. The data are reported in Table 2.
~, J~J
~ABLE 2 , ~ .
Central anticholmergac activity Central an~ Feripheral effects Potentiation of Inhibition of oxotremorine apcmorphine efects accordang effects ~b) to Scheel-Kr~ger ~a) . . . .
CompcNnds Activity index Compounds ALtivlty index .
Dicyclomine HCl 1 Dicyclomine HCl 1 _ 2 ~c) 0.5 2 ~c~ 0.2 , _ AtrcpLne sulpha~e 1.3 Scopola~ine 1.2 _ butyL b~onide ~a) Average effect of (b) Average effect of 3 3 doses ~30-60-90 mg/Kg/os) doses ~28.6-51.2-114.4 mg/Kg/os) o the ccnpound5 admLnistered o the caicurds administered to emale mice ~17-25 g) 1 hour to male mice ~18-25 g) 1 hour befo~e apomorphine ~10 mg/Xg/ before oxctremQLine ~0.5 s.c.). The gnawing intensaty mg/Kg/s.c.). The effect on is evaluated fo~ the products lacrimation, salivation, and the control ~H2O) cr a 40 diarrhea and tremor in comparison m m ute pe~iod. with contrc~s ~H~O) is evaluated in 15-30-60 and ~20 m m. after oxc,tremorine.
Compound 2 ~c) = 2-~4-biphen~1)-N-~2-diethy1aminoethy1) prc,pionamide ~1~34~
It is seen from Table 2 that m comparison with 2-~4-biphenyl)-N-~2-diethylaminoethyl) propionamlde, dicvclomlne and scopola~lne butyl bromlde have respectively 5 or 6 t~mes h~gher central and perlpheral side-effects. As to the central antlcholinergic activlty, dic~vclom me and atropine sulphate have about 2 times higher side-effects in relation to 2-~4-biphenyl)-N-~2-diethylaminoethyl) proplonamide.
None of the mentioned prodw ts exhibits antiphlogistic property as deteLmined by the carragee~an pa~ edema test according to W~nter, A.C., Risley, E.A., and Nuss, G.W., Proc. Soc~ Exp. Biol. Med. 111, 544, 1962.
The present invention further provides pharmaceutical compositions ccmprising at least one oompound of formula I in association with a pharma-ceutical carrier or excipient. The phaLmaceutical compositions may be presented in a orm su-it~ble, for example, for oral or parenteral or rectal administration in doses ranglng ~rom 5 to 40 mg o active ing~edients.
EXamples o suitable forms o administLation include, vials, tablets, coated tablets, capsules, lozenges, dispersible p~ders, syrups, elixirs and suppc~itories. Preerably the comFos~tions are presented in dosage unit form.
Claims (15)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of biphenylpropionamides of the formula I
the pharmaceutically acceptable salts thereof, and the pharma-ceutically acceptable lower alkyl quaternary ammonium salts thereof, wherein n is 2 or 3 and Et represents a C2H5- group, which process comprises (i) reacting an acid chloride of the formula with a diamine of the formula ;
(ii) where a lower alkyl quaternary ammonium salt is desired, reacting a compound of formula I with an alkylating reagent;
and, if desired, converting the thus obtained product into a pharmaceutically acceptable acid addition salt.
the pharmaceutically acceptable salts thereof, and the pharma-ceutically acceptable lower alkyl quaternary ammonium salts thereof, wherein n is 2 or 3 and Et represents a C2H5- group, which process comprises (i) reacting an acid chloride of the formula with a diamine of the formula ;
(ii) where a lower alkyl quaternary ammonium salt is desired, reacting a compound of formula I with an alkylating reagent;
and, if desired, converting the thus obtained product into a pharmaceutically acceptable acid addition salt.
2. Process according to claim 1 wherein the compound of formula I is converted into a pharmaceutically acceptable quaternary ammonium salt by reaction with a lower alkyl halide.
3. Process according to claim 2 wherein the alkyl halide is chosen from methylbromide and methyliodide.
4. Biphenylpropionamides of the formula I in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
5. Quaternary ammonium pharmaceutically acceptable salts of a biphenylpropionamide as defined in claim 1, whenever pre-pared by the process of claims 1 or 2 or by an obvious chemical equivalent thereof.
6. Process for the preparation of 2-(4-biphenyl)-N-(2-diethyl-amino-ethyl)propionamide, which comprises reacting together 2-(4-biphenyl) -propionic acid chloride and N,N-diethyl ethylene diamine.
7. 2-(4-biphenyl)-N-(2-diethylaminoethyl)propionamide when-ever prepared by the process of claim 6 or by an obvious chemical equivalent thereof.
8. Process for the preparation of 2-(4-biphenyl)-N-(3-di-ethylaminopropyl)propionamide which comprises reacting together 2-(4-biphenyl)propionic acid chloride and N,N-diethyl propylene diamine.
9. 2-(4-Biphenyl)-N-(3-diethylaminopropyl)propionamide when-ever prepared by the process of claim 8 or by an obvious chemical equivalent thereof.
10. Process for the preparation of 2-(4-biphenyl)-N-(2-di-ethylmethyl ammonium ethyl)propionamide bromide which comprises reacting methyl bromide with 2-(4-biphenyl)-N-(2-diethylamino-ethyl)-propionamide.
11. 2-(4-biphenyl)-N-(2-diethylmethyl ammonium ethyl)propion-amide bromide whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
12. Process for the preparation of 2-(4-biphenyl)-N-(2-di-ethylmethyl ammonium ethyl)propionamide iodide which comprises reacting methyl iodide with 2-(4-biphenyl)-N-(2-diethylamino-ethyl)-propionamide.
13. 2-(4-biphenyl)-N-(2-diethylmethyl ammonium ethyl)propion-amide iodide whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
14. Process for the preparation of 2-(4-biphenyl)-N-(3-diethyl methyl ammonium propyl)propionamide bromide which comprises re-acting together methyl bromide and 2-(4-biphenyl)-N-(3-diethyl-amino propyl)propionamide.
15. 2-(4-biphenyl)-N-(3-diethyl methyl ammonium propyl)propion-amide bromide whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT9643A/77 | 1977-11-30 | ||
| IT964377A IT1090782B (en) | 1977-11-30 | 1977-11-30 | 2 4 BIPHENYLIL 2 DIETHYLAMIN ALCHYL PROPIONAMIDE ITS SALTS AND RELATED MANUFACTURING PROCEDURES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1118446A true CA1118446A (en) | 1982-02-16 |
Family
ID=11132874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000317175A Expired CA1118446A (en) | 1977-11-30 | 1978-11-30 | Racemic forms and optically active forms of 2-(4-biphenylyl)-n-(diethylamino alkyl) propionamide and salts thereof as well as processes for their production and use as spasmoltyic agents |
Country Status (9)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1584547A (en) * | 1968-06-05 | 1969-12-26 | ||
| FR1593024A (en) * | 1968-09-18 | 1970-05-25 | ||
| 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
Also Published As
| Publication number | Publication date |
|---|---|
| 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 |
| CH637370A5 (en) | 1983-07-29 |
| FR2410641A1 (en) | 1979-06-29 |
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