IE48012B1 - Soft anticholinergic agents exhibiting antisecretory activity - Google Patents
Soft anticholinergic agents exhibiting antisecretory activityInfo
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- IE48012B1 IE48012B1 IE2499/78A IE249978A IE48012B1 IE 48012 B1 IE48012 B1 IE 48012B1 IE 2499/78 A IE2499/78 A IE 2499/78A IE 249978 A IE249978 A IE 249978A IE 48012 B1 IE48012 B1 IE 48012B1
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- bromide
- acetoxymethyl
- cyclopentyl
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
Compounds of general formula I or II: are disclosed, wherein represents tertiary amine an unsaturated amine and R2, R3 and R4 (which may be the same or different, but at least two of them must be other than H and together they must contain at least five C-atoms) each represents hydrogen, C1-C8 alkyl or alkoxy, cycloalkyl cycloalkenyl, alkoxyalkyl, acyloxyalkyl, haloalkyl or carboxyalkyl each having up to 8 C atoms, alkenylphenyl having unto 8 C-atoms in the alkenyl moiety, aryl (optionally substituted by halogen, C1-C4 alkoxy, acyloxy, nitro, carboxyl or carboethoxy), -CH2, -CH2OCOR1 (wherein R1 is as defined below or -CH2ONO2), -OH, halogen, -OCOR1 (wherein R1 is as defined below) or - ONO2; or R2 is as hereinbefore defined and R3, R4 and the carbon atoms to which they are attached form a cyclo-alkyl group having up to 8 carbon atoms, or the groups represented by R2, R3 and R4 and the carbon atom to which they are attached form a fused polycarbocylic ring or a polyheterocyclic ring; and R1 is as defined by R2, R3 or R4; X is -O- or -S- and Y is halogen or another anion. The compounds possess anticholinergic anti- secretory activity, while exhibiting low toxicity following therapeutic application.
Description
The invention relates to anticholinergic agents exhibiting antisecretory activity and characterised as being soft in nature, meaning that they exhibit substantial anticholinergic antisecretory activity, while having low toxicity following therapeutic application.
Analagous prior art anticholinergic antisecretory agents, such as Banthine and Probanthine (registered trade marks), exhibit substantial anticholinergic antisecretory activity. However, in addition to maintaining such anticholinergic antisecretory activity, these compounds give rise to a number of toxic side effects, such as dizziness, blurred vision and dry mouth.
It has now been realised, through review of and experimentation with analogous compounds of the prior art, that all such compounds contained a 2-carbon linkage between the substituent corresponding to X in the'formula (I) below and the adjacent nitrogen atom of the amino moiety. Further experimentation led to the conclusion that, if one maintains a one carbon atom bridge between the X substituent and the adjacent nitrogen atom of the amino moiety on the overall molecule, substantial anticholinergic antisecretory activity is exhibited. Moreover, it has further been realised that the resulting compounds, due to the presence of this one carbon atom bridge, were subject to very easy hydrolytic and/or enzymatic cleavage, resulting in nontoxic and non-anticholinergic activity of the resulting by-products.
Therefore, with the invention, a select group of compounds have been developed which are highly active at peripheral receptor sites, such as the stomach wall and sweat glands, and yet essentially lack central anticholinergic activity due to their inability to penetrate the blood-brain barrier and because of their cleavage following entrance into general circulation.
The invention provides a quaternary ammonium salt in which one of the substituents of the quaternary nitrogen atom has the general formula I.
8 0 12 wherein:
X represents an oxygen or sulphur atom;
R2 represents a cycloalkyl group having up to 8 carbon atoms, a cycloalkenyl group having up to 8 carbon atoms, an alkenylphenyl group the alkenyl residue of which has up to 8 carbon atoms, a hydroxy group, a group of the formula ONO2, OCOR^ or CHjOCOR^ wherein Rj is as defined hereinbelow, a phenyl group, a naphthyl group, or a phenyl or naphthyl group substituted by one or more of a halogen atom, an alkoxy group having from 1 to 4 carbon atoms, an acyloxy group, a nitro group, a carboxy group or an ethoxycarbonyl group;
represents a halogen atom, or an alkyl, alkoxy, alkoxyalkyl, acyloxyalkyl, haloalkyl or carboxyalkyl group each of which has up to 8 carbon atoms, or any of the groups which R2 may represent;
R^ represents a hydrogen atom or any of the atoms or groups which R^ may represent; and 20 Rj represents any of the atoms or groups which R^ may represent; or
R2 and together with the carbon atom to which they are attached represent a cycloalkyl group having up to 8 carbon atoms, and X being as previously defined; or
4801
RgiRg, arm together with the carbon atom to which they are attached represent an adamantyl,
9,10-dihydroanthryl or phenylcyclopropyl group, R^ and X being as previously defined; with the proviso that
Rg, Rg and R4 together contain at least 5 carbon i.toms.
In the above formula, reference to 'halo' and 'halogen' in each occurrence denotes any suitable member of the halogen series, for example, chlorine, bromine or iodine; and reference to 'acyl' in the expression 1 acyloxyalkyl' and 'acyloxy' denotes any convenient earboacyl group, such as a forinyl, acetyl, propionyl, or bc-*nzoyl group.
The other three substituents of the quaternary nitrogen atom in the salts according to the invention may be chosen from a wide range of saturated and unsaturai.ed groups. The quaternary nitrogen atom may be part of a ring system.
Examples of unsaturated heterocyclic rings which may contain the quaternary nitrogen atom of a salt ?0 according to the invention are l-methyl-azirine, 1-methyl
-pyrrole, 1-methyl-imidazole, 1-methyl-pyrazole, pyridine pyrazine. pyrimidine, pyridazine, 2-methyl-isoindole, 3H-indole. quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, phenazine, isothiazole, isoxazole, 10-methy1-phenothiazine and furazan rings.
Saturated heterocyclic rings which may contain the quaternary nitrogen atom include
480 12 pyrrolidine, morpholine and quinuclidine.
Non cyclic substitutents include alkyl and alkoxyalkyl groups.
The quaternary ammonium salts according to the invention are preferably halides, methanesulphonates, fluorosulphates or tosylates.
The most preferred quaternary ammonium salts according to the invention are the triethylammonium, 1-methylmorpholinium, 1-methylpyrrolidinium,
3-methylimidazonium, 1,2-dimethylpyrrolidinium, quinuclidinium, 3-acetoxyquinuclidinium, 3-ethoxycarbonylpyridinium, tripropoxyethylammonium and 10-methylphenothiazinium chlorides in which R2 represents a phenyl group, R^ represents a cyclopropyl, cyclopentyl, cyclohexyl, cyclohex-2-enyl or ethyl group, and represents a hydrogen atom, or R2,R^ and together with the carbon atom to which they are attached represent an adamantyl group, and X represents an oxygen atom. These salts may be named as follows:
1. Ν -[d,J.-(2-Cyclopentyl-2-phepyl-acetoxymethylj]Ν,Ν,Ν-tri ethylammonium chloride.
2. 2-]d,l~(2-Cyclopentyl-2-phenyl -acetoxymethyl)] 1-methylmorpholinium chloride.
3. l-[d,l-(2-Cyclopentyl-2-phenyl-acetoxymethyl)] 1-methyl pyrroli di ni um chiori de.
4. l-[d,l-(2-Cyclopentyl-2-phenyl-acetoxymethyl)] 3-methylimidazonium chloride.
. l-jjj,l-(2-Cyclopentyl-2-phenyl-acetoxymethyl )]1.2- dimethylpyrrolidinium chloride.
6. l-y,l-(2-Cyclopentyl-2“phenyl-acetoxymethylj]quinuclidinium chloride.
7. 1 - &,1-(2-Cyclopentyl-2-pheny1-acetoxymethyl j] 3-acetoxyqui nucli di ni um chiori de.
8. 1 - [d»1- (2-Cyclopentyl -2-pheny 1 -acetoxymethyl )j 3-ethoxycarbonylpyri di ni um chiori de.
9. N- jj ,1- (2-Cycl opentyl -2-phenyl -acetoxymethyl )j Ν,Ν,Ν-tripropoxyetbylammonium chloride.
. 10- ^,1-(2-Cycl opentyl-2-phenyl-acetoxymethyl )j10-methylphenothiazinium chloride.
11. N-jj,1-(2-Cyclohexyl-2-phenyl-acetoxymethyl)]Ν,Ν,Ν-triethylammonium chloride.
12. l-[d.l-(2-Cyclohexyl-2-phenyl-acetoxymethyl)]1-methylmorpholinium chloride.
13. l-[^J-(2-Cyclohexyl-2-phenyl-acetoxyniethyl)] 1-methy1pyrroli di ni um chloride.
14. 1 - ,d, 1 - (2-Cycl ohexyl -2-phenyl -acetoxymethyl)] 3-methylimidazonium chloride.
. 1-(d,1-(2-Cyclohexyl-2-phenyl-acetoxymethylj]1.2- dimethyl pyrrol idi nium chloride.
16. l-[dJ-(2-Cyclohexyl-2-phenyl-acetoxymethyl)] quinuclidinium chloride.
17. 1-Qi,l-(2-Cyclohexyl-2-phenyl-acet°xymethyl)] 3-acetoxyquinuclidinium chloride.
18. 1-jji J-(2-Cycl°hexy 1-2-phenyl-acetoxymethylj]
3-ethoxycarbony 1 pyridiniuni chiori de.
19. N-jji J-(2-Cyclohexyl-2-phenyl-acetoxymathyl)] N,N,N-tripropoxyethylammoni um ch1ori de.
. !O-0dJ-( 2-Cyclohexyl-2-phenyl-acetoxymethyl)]
W -10-methylphenothiazinium chloride.
21. N-[ji,l_-(2-Phenyl-butyryloxymethylj] Ν,Ν,Ν-triethylammonium chloride.
22. l-j~dJ-(2-Phenyl-butyryloxymethylj] 1-methylmorpholinium chloride,
23. l-£d,J_-(2-Phenyl-butyryloxymethyli]1-methyl pyrrolidinium chloride.
24. 1 - jjd (2-Pheny 1- butyryl oxymethy 1 j] 3-methylimidazonium chloride.
. 1 £d J-(2-Phenyl-butyryl oxymethy! I] 20 1,2-dimethylpyrrolidinium chloride.
26. l-£d^J-(2-Phenyl-butyryloxymethyl j] quinuclidinium chloride.
27. 1 -[d J - (2-Pheny 1 -butyryl oxymethyl j] 3-acetoxyqui nucli di ni um chiori de.
28. 1-^jd,^-( 2-Phenyl-butyryl oxymethyl )j 3-ethoxycarbony1pyri di ni um ch1ori de.
29. N-J~d J-(2-Pheny 1 -butyryloxymethyl)] N,N,N-tripropoxyethylammoni um chiori de.
. 10-jjjJ_-(2-Phenyl-butyry'loxymethyl)] 30 10-methylphenothiazinium chloride.
48013
31. N-(Adamantyl-1-carboxymethyl )Ν,Ν,Ν-triethylammonium chloride.
32. 1-(Adamantyl-1-carboxymethyl)1-methylmorpholinium chloride.
33. 1-(Adamantyl-1-carboxymethyl)1-methylpyrrolidiniurn chloride.
34. l-(Adamantyl-l-carboxymethyl)3-methylimidazonium chloride.
. 1-(Adamantyl-1-carboxymethyl)1.2- dimethy1 pyrrolidiniurn chloride.
36. l-(Adamantyl-l-carboxymethyl)quinuclidinium chloride.
37. . l-(Adamantyl-l-carboxymethyl)3-acetoxyquinuclidinium chloride.
38. 1-(Adamantyl-1-carboxymethyl)3-ethoxycarbony1pyri di ni um chiori de.
39. N-(Adamantyl-1-carboxymethyl)N,N,N-tri propoxyethylammoni um chiori de.
40. 10-(Adamantyl-1-carboxymethyl)10-methyIphenothi azi ni um chlori de.
41. N-[d-(2-Cyclohex-2-enyl-2-phenyl-acetoxymethyl)jN,N,N-tri ethy1ammoni um ch1ori de.
42. l-fd-(2-Cyclohex-2-enyl-2-phenyl-acetoxymethyl )j1-methylmorpholinium chloride.
43. l-^d-(2-Cyclohex-2-enyl-2-phenyl-acetoxymethyl)]1-methylpyrrolidinium chloride.
44. l-ljb-^-Cyclohex^-enyl^-phenyl-acetoxymethyl j] 3-methylimidazonium chloride.
45. 1-[d-(2-Cyclohex-2-enyl-2-phenyl-acetoxymethy 1 j] 1.2- dimethylpyrrolidinium chloride.
4-80 12
46. 1 -[d- (2-Cycl ohex-2-eny 1 -2-phenyl -acetoxymethyl )J quinuclidinium chloride. 47. 1-d-(2-cyclohex-2-enyl-2-phenyl-acetoxymethyl)J3-acetoxyqui nucli di ni um chiori de. 48. 1 - Hd- (2-Cyclohex-2-enyl-2-phenyl-acetoxymethyl )1 3-ethoxycarbony1pyri di nium chiori de. 49. N-fd-(2-Cyclohex-2-enyl-2-phenyl-acetoxymethyl)] Ν,Ν,N-tri propoxyethy1ammoni um chiori de. 50. 10-p-(2-Cyclohex-2-enyl-2-phenyl-acetoxymethyl)] · 10-methy1phenothi azi ni um chiori de. 51. Ν-ΓΠ (2-Cycl opropyl -2-phenyl -acetoxymethyl fjΝ,Ν,Ν-triethyl ammonium chloride. 52. 1 -'l - (2-Cycl opropyl -2-phenyl -acetoxymethyl j] 1-methylmorpholinium chloride. 53. 1 -p - (2-Cyclopropyl-2-phenyl-acetoxymethylf]-1-methyl pyrroli di ni um chiori de. 54. 1 -fl - (2-Cycl opropyl -2-phenyl -acetoxymethyl )j 3-methylimidazonium chloride. 55. 1 -jj_- (2-Cycl opropyl -2-phenyl -acetoxymethyl)] 1,2-dimethy1 pyrrolidinium chloride. 56. 1 -Q- (2-Cy cl opropyl -2-phenyl -acetoxymethyl j] quinuclidinium chloride. 57. 1 -p - (2-Cycl opropy 1 -2-phenyl -acetoxymethy 1)] 3-acetoxyquinuclidinium chloride. 58. 1-f]-(2-Cyclopropyl-2-pheny1-acetoxymethylj] 3-ethoxyca rbony1 pyri di ni um ch1ori de. 59. N-[j_- (2-Cycl opropyl -2-phenyl -acetoxymethyl)] Ν,Ν,Ν-tri propoxyethylammonium chloride. 60. 10-p[-(2-Cycl opropyl-2-phenyl-acetoxymethyl)] 10-methy1phenothi azi ni um ch1ori de.
The invention further provides a process for the preparation of quaternary ammonium salts according to the invention, the process comprising condensing a halide of the general formula
R, O R
I 1 I c R, — C — C —X—CH—Halogen (II)
I R4 wherein RpR^R^R^ and X are as hereinbefore defined, with a tertiary amine. The reactants are generally used in approximately equimolecular proportions. The reaction may be conducted in the presence of an inert solvent such as chloroform, diethyl ether, acetonitrile or dichioromethane at a temperature of from room temperature to the reflux temperature of the solvent, for approximately 2 to 24 hours. Alternatively, the reaction can be conducted in the absence of a solvent by mixing the two reactants together and maintaining them at room temperature or between 20° to 70°C for 2 to hours. In either case, the crystalline salt formed can be purified by crystallization from an diethyl ether-ethanol mixture
The starting materials of formula (II) wherein X represents an oxygen atom can be prepared by reacting the corresponding aldehyde R^CHO with the appropriate acid halide of the general formula CR^R^R^.CO.halogen.
The starting materials of formula (II) wherein X represents a sulphur atom can be prepared by reacting the aldehyde R^CHO with a compound of the general formula CR2R3R4. CO.SH to afford the intermediate
R, — C — C — S — CH — OH
I R4 which can then be reacted with a phosphorus pentahalide to afford the desired starting material of formula (II) .
Yet another route to the starting materials c-f formula (II) proceeds by contacting a compound of the general formula CRjR^R^.CO.X.M wherein M represents a suitable metal ion such as sodium or potassium with a compound of the formula
Halogen - CHR^ - Halogen wherein the halogen atoms can be the same or different. When the halogen atoms are the same, a large excess of the ciihalo compound is employed. Another process for the preparation of the quaternary ammonium salts for the invention in which one of the substituents of the quaternary nitrogen atom is an alkyl group comprises quaternising a tertiary amine in which one of the substituents of the tertiaj'y nitrogen atom has the general formula I as defined hereinbefore with an alkyl halide. This process, which is also within the scope of the invention, can be conducted in an appropriate solvent such as acetonitrile or nitromethane.
The tertiary amines to bequarternised in such a process may be prepared by reacting a compound of the general formula .CO.X.M wherein M represents an alkali or alkaline earth or other suitable metal (for example sodium or potassium) with a tertiary amine in which one of the substituents of the tertiary nitrogen atom has the general formula Halogen - CHR^ in a suitable solvent such as dichloromethane or tetrahydrofuran. The last mentioned tertiary amines may be prepared by reacting two moles of any secondary amine (for example, a dialkylamine or a cyclic amine such as morpholine, piperidine, piperazine or imidazole) with an aldehyde of the formula R^CHO under basic conditions, followed by contacting the resultant
Rf substituted methylenediamine with a benzoyl halide in diethyl ether or tetrahydrofuran.
The quaternary ammonium salts obtained by the above described processes according to the invention are quaternary ammonium halides. When other salts are desired (for example, 5-sulphosalicylates or salts of the acid HRgSOg wherein Rg represents an alkyl group having from 1 to 20 carbon atoms, a phenyl or substituted phenyl group or a naphthyl group) any of the said processes may be followed by an ion exchange method.
Exchange of the gegen ion in the quaternary salt can be accomplished using an anion exchange resin. This procedure involves conversion of the quaternary salt to its hydroxide form and subsequent neutralization using the conjugate acid of the desired base. However, it has been found that a different and generally more convenient procedure can sometimes be employed for the exchange of gegen ions in the nuaternary salts. Xn this procedure a methanolic solution of the acid of the desired salt is reacted with the quaternary ammonium halide to produce a methyl halide and the desired quaternary ammonium salt. This method is described in A Convenient Method for an Ion Exchange in Quaternary Salts,
J.J.Kaminski, K.W. Knudsen and N.S. Bodor, Tetrahedron, Volume 34, pp. 28-57 (1978).
The invention is illustrated by the following Examples, in which all temperatures are expressed in °C.
EXAMPLE 1
PREPARATION OF THE SOFT ALKYLATING AGENTS
The following soft alkylating agents were prepared from the corresponding acyl halides and paraformaldehyde, by heating the equimolecular mixture of the two components to 90-100° in the presence of a catalytic amount of zinc chloride.
The crude products were purified and characterized as follows:
1. Chloromethyl d,1-(2-cyclopentyl-2-phenyl-acetate)
The crude product was chromatographed on florisil (100-200 mesh) (chloroform); ir (neat) 2920, 2840, 1750, 1450, 1315, 1190, 1110,
1025, 760 and 700 cm-1,- pmr (CDC13) 5,7.3 (s,5H),
.7 - 5.2 (m, 2H), 3.3 (d, 1H) and 3.0 - 0.8 (bin, 9H).
2. Chloromethyl d,l-(2-cyclohexyl-2-phenyl-acetate)
The crude product was chromatographed on florisil (100-200 mesh) (chloroform) and dried in vacuo to yield a white solid mp 53-4°; ir (KBr) 2910, 2840, 1740, 1490, 1435, 1350, 1280, 1250 1215, 1130, 1100, 1020, 1000, 770, 730, 710 and 690 cm 1; pmr (CDC13)5,7.3 (s, 5H) , 5.7 - 5.5 (m,2H),
3.3 (d, 1H) and 2.4 - 0.5 (bm, 11H).
Anal. Calcd for C1cHinclO : lb iy 2
C, 67.54; H, 7.18. Found: C, 67.40; H, 7.22.
3. Chloromethyl d,1-(2-phenylbutyrate)
The crude product was chromatographed on florisil (100-200 mesh) (chloroform) to yield a colourless liquid; bp 103-105°/!.8 mm; ir (neat)
2970, 1750, 1490, 1450, 1440, 1260, 1210, 1195,
1140, 1110, 1075, 1040, 1020, 740, 720 and 700 cm-1; pmr (CDClg) 6,7.2 (s,5H), 5.5 (s, 2H), 3.4 (t, IH),
2.5 - 1.4 (m, 2H) and 0.9 (t, 3H).
4. Chloromethyl d,l-(2-phenylprionate)
The crude product was chromatographed on florisil (100-200 mesh) (chloroform) to yield a colourless liquid; bp 101-105°/1.9 mm; ir (neat) 3050, 3020, 2970, 2930, 1750, 1490, 1450, 1140, 1100, 1080, 720 and 700 cm-1; pmr (CDClg) 6,7.2 (s, 5H), 5.6 (s, 2H), 3.8 (q, IH) and 1.5 (d, 3H).
. Chloromethyl adamantane-1-carboxylate
The crude product was chromatographed on florisil (100-200 mesh) (chloroform) to yield a colourless liquid; ir (neat) 2910, 2860, 1750, 1450,
1215, 1185, 1065, 750 and 710 cm-1,· pmr (CDClg)
6.5.7 (s, 2H) and 2.2 - 1.6 (m, 15H).
Anal. Calcd for cx5HxgclN2®2:
C, 61.12; H, 6.50; N, 9.50. Found: C, 60.94;
H, 6.76; N 9.37.
6. Chloromethyl thioacetate:
(1) Prepration of Hydroxymethylacetyl Sulphide
21.97 g (0.29 mole) thioacetic acid was deoxygenated with a nitrogen stream 15 min. Then
8.7 g (0.29 mol) paraformaldehyde was added and the mixture stirred and heated at 90°C for 3 hrs. At this time, all of the paraformaldehyde had gone into solution and the product was isolated by distillation. bp=60°C (10 mm); yield - 12.17 g (47% of theory); NMR 6,4.1 (HO-C, singlet) and
.1 (S-CH2-O, singlet).
(2) Preparation of Chloromethyl Thioacetate
To an ice-cooled solution of 24.3g (0.12 mole) phosphorus pentachloride in 250 ml anhydrous diethyl ether, under nitrogen and with stirring, was added 12.17 g (0.12 mole) hydroxymethylacetyl10 -sulphide, so slowly that the reaction temperature was never above 13°C. The reaction mixture was then allowed to warm to room temperature for 30 min.
The diethyl ether was next evaporated off and the residue set up for vacuum distillation of phosporus oxychloride and the CH^SCHjCl. Phosphorus o oxychloride distilled at 35 C at 15 mm and the product distilled at 32°C at 3 mm. Yield =
4.81 g (34% of theory). NMR: 6 2.4 (H^C=O, singlet); 6 4.95 (C1CH2S, singlet).
7. Chloromethyl 2-phehyl-thiopropionate
This compound was prepared according to procedures given above (6) from the corresponding thioacid .
EXAMPLE 2
N-/d,1- (2-Cyclopentyl-2-phenyl-acetoxymethyl)_7-Ν,Ν,Ν-triethylammonium chloride.
Anhydrous chloroform was prepared by distillation from phosphorous pentoxide prior to use. Triethylamine (2.5 cn?, 0.018 mole) was added to a stirred solution of chloromethyl d,1-(2-cyclopentyl-2-phenyl-acetate (4.8 g,
0.019 mole) in anhydrous chloroform (5 cm ).
The reaction vessel was sealed, placed in an oil bath and maintained at 75° overnight. On cooling to room temperature, anhydrous diethyl ether was added and the reaction triturated with diethyl ether until crystallization began. The solid was isolated by filtration under a nitrogen atmosphere and thoroughly washed with anhydrous diethyl ether. The product was dried in vacuo at 50°C over calcium sulphate to yield a white, hygroscopic solid mp 147-8° (5.3 g, 0.015 mole,
83%), ir (KBr) 1740 cm-1,· pmr (CDCip 6,7.3 (s, 5H) ,
.6 (s, 2H) and 3.6 - 0.8 (m, 25H).
Anal. Calcd for C20H32ClNO2: C, 67.87,- h,9.11; N, 3.96. Found: C, 67.63; H, 9.24; N, 3.95
Using the procedure described in this Example, the following quaternary ammonium salts were synthesized:
EXAMPLE 3
1-/3,1-(2-Cyclopentyl-2-phenyl-acetoxymethyl)/-1-methylmorpholinium chloride./ mp 166-8°; pmr (CDClj) 6,7.4 (s, 5H),
.8 (bs, 2H) and 4.4 - 0.6 (m, 21H).
8 012
EXAMPLE 4
N-/a,l-(2-Cyclohexyl-2-phenyl-acetoxymethy])7 -Ν,Ν,Ν-triethylammonium chloride_2 mp 128-9°; ir (KBr) 1740 cm-1; pmr (CDClg)
6,7.3 (s, 5H), 5.6 (s, 2H), 3.6 - 3.0 (m, 7H) and
2.7 - 0.7 (m, 20H)„
Anal. Calcd for c2iH34C1NO2: C, 68.55;
H, 9.31; N, 3.81. Found: C, 68.32; h, 9.54; N, 3.71.
EXAMPLE 5
1-/3,1-(2-Cyclopentyl-2-phenyl-acetoxymethyl)_7-llmethylpyrrolidinium chloride;
mp 144-5°; ir (KBr) 1740 cm-1; pmr (CDClg)
6,7.3 (s, 5H) , 5.7 (s, 2H) and 4.0 - 0.7 (m, 21H).
Anal. Calcd for clgH2gClNO2: C, 67.54;
H, 8.35; N, 4J4. Found: C, 67.76; H, 8.60; N, 4.02.
EXAMPLE 6
1-(Adamantane-l-carboxymethyl)-1-methylpyrrolidiniumchloride_ mp 181-2°; ir (KBr) 1730 cm-1; pmriCDClg)
6.5.7 (s, 2H), 4.1 - 3.7 (m, 4H), 3.5 (s, 3H), 2.6-2.2 (m, 4H) and 2.2 - 1.6 (m, 15H).
Anal. Calcd for C, „H C1NO_: C, 65.06; H, 8.99; 28 2
N, 4.46. Found: C, 64.95; H, 9,06; N, 4.27.
EXAMPLE 7
1-(Adamantane-l-carboxymethyl)-3-methylimidazonium chloride__ mp 158-164°. pr (KBr) 1730 cm-1; pmr (CDClg)
6,10.6 (m, IH), 8.0 (m, IH), 7.6 (m, IH), 6.3 (s, 2H),
4.2 (s, 3H) and 2.2 - 1.6 (m, 15H).
Anal. Cal cd C^g H23C1N2O2:
C, 61.83: H, 7.46; N, 9.01.
Found: C, 62.09; H, 7.76; N, 8.80.
EXAMPLE 8
-j~d ,2“ (2-Pheny1 -butyry loxymethyl )J-3-methyl 1 mi dazoni um chi ori de mp 89-94°; ir (KBr) 1740 cm~b pmr (COC13) δ, 10.5 (ra, IH), 8.0 (ra, IH), 7.5 (m, IH), 7.2 (s, 5H), 6.3 (s, 2H), 4.1 (s, 3H), 3.5 (t, IH), 2.0 (m, 2H) and 0.9 (t, 3H).
EXAMPLES 9 to 30
By following the above-described procedures and employing the appropriate generically and/or specifically described reactants and conditions, the following additional compounds are obtained:
The quaternary nitrogen atom, its other substituents and the anion of the salt.
Substituent of general formula I
ExampleR1R2R3R4 X 9 H Ph ά H 0 ?H3 Cl' .or f Μγ-Μ3Br 10 H Ph ό H 0 As example 9. 11 H Ph A H 0 As example 9. 12 H Ph A H 0 CHo zk C1°rBr'
The quaternary nitrogen atom, its other substituents and the anion of the salt.
Substituent of general formula I
ExampleR1 r2R3R4 X 13CH3 Ph ό H 0 + iyPr-N (Et)g Cl or Br 14* H (^2)4· Ph 0 As example 9 H Ph 0CH3 cf3 0 As example 9 :& H ό och3 cf3 0 As example 9 17* H r Ph 0 As example 9 ie* H PhZ 0+I^-CH3 Cl or Br 19 H Ph Ph ch3 0 As example 12 20 H Ph Ph ch3 0 As example 18 21 ch3 Ph Ph ch3 0 As example 18 22 ch3 Ph Ph ch3 0 Cl or Br
i !
The quaternary nitrogen atom, its other substitSubstituent of general formula I uents and the anion of the salt
In the above Table, Et represents an ethyl group,ph represents a phenyl group, i-Pr represents an isopropyl group, Ad represents an adamantyl group, * indicates that the moiety shown in the column is the entire CRgR^R^ group and + indicates that the moiety shown in the R^ column is the combined
R„ and R. substituent.
4
EXAMPLE 31
Pharmacological Studies (1) In vivo experiments for screening anticholinergic activity.
Adult cats were anesthetized by the intraperitoneal injection of a mixture of a-chloralose (80 mg/kg) and sodium pentobarbitone (6 mg/kg).
The animals were bilaterally vagotomized and artificially respired throughout the experiments.
Arterial blood pressure was recorded from a cannulated carotid artery using a Statham PD23 pressure transducer coupled to a Grass 7c inkwriting polygraph. Heart rate was routinely measured using either the arterial pulse
2o °n lead II ECG's to trigger a cardiotachometer (Grass
7P4). In all experiments drugs were injected intravenouslyinto a cannulated brachial vein.
Control responses were first obtained to a range of doses of acetylcholine. A dose producing
70-80% of the maximal vasodepressor response was then chosen and used throughout the rest of the experiment.
After constant control responses to acetylcholine had been obtained, a dose of the test drug was injected and 30 seconds later a response to acetylcholine was monitored. Responses to acetylcholine were then assessed at approximately 2-3 minute intervals. In this way, a measure of both the activity and duration of action of the test drug could be assessed.
The effects of a number of doses of each test compound were monitored in every animal.
After each test, responses to acetylcholine were allowed to return to control levels before the actions of higher doses were monitored.
For screening, each drug was made up in distilled water at a concentration of 10 mg/cm .
All of the quaternary salts were freely soluble in water. Each compound was administered over a dose range of 0.2 - 5.0 mg/kg.
(2) Estimation of Antagonist potency
Strips of guinea-pig whole ileum were set up in McEwen's solution, gassed with Carbogen (Og/COg 95:5), and maintained at 37° C in a 10 ml organ bath. A tension of lg was applied to the tissue, and cumulative concentration-response curves recorded to acetylcholine until constant responses were obtained.
A concentration of the antagonist was then added to the bath, and after allowing 15-20 minutes for equilibration, further concentration-effect curves to acetylcholine were established.
This procedure was then repeated using increasing concentrations of the antagonist.
Mean curves were plotted for the effects of acetylcholine alone, and for acetylcholine in the presence of the various antagonist concentrations. Antagonism was assessed from the dose ratios thus obtained.
The acetylcholine concentration was increased by adding aliquots from stock solutions of 0.1, 1, 10 and 100 pg/ml of acetylcholine.
The antagonist was dissolved in water to give a stock solution of 10~^ M concentration. This solution was then used in the bath to carry out antagonist studies at 10 1 M and 10 θ M concentrations.
RESULTS
48013
I. 1-{d,1-(2-Cyclopentyl-2-phenyl-acetoxymethyl)}-lmethylmorpholinium chloride.
(1) Acetylcholine antagonist effect on the cat blood pressure
a) Percent response to a dose of acetylcholine (0.05 ug/kg) compared to the same dose in the absence of antagonist.
480 12
Π. Ν-{d, 1-(2-Cyclohexyl-2-pheny1-acetoxymethyl)}
-Ν,Ν,Ν-triethyl ammonium chloride (1) Acetylcholine antagonist effect on the cat blood pressure.
Concentration •me! -f1) Activity ~~-)-1 1 2 4 5 8 10 Time £.4 x IO8 0 0 50 67 83 100 (min) % response 1 3 6 9 12 15 18 21 24 Time 5.4 x IO’7 (min) 0 0 0 0 43 60 78 93 100 % response
a) Percent response compared to the same dose in the absence of antagonist;
III. 1 -{d ,1 - (2-Cyclopentyl-2-phenyl-acetoxymethyl)}-lmethylpyrrolidinium chloride.
(Ί) Guinea-pig ileum - pAg = 8.8, atropine under similar conditions, pAg = 8.6 (2) Acetylcholine antagonist effect on the cat blood pressure
Concentration (mol kg1) Activity 5.4 x IO9 1 0 2 0 5 0 9 0 13 31 18 63 23 63 28 69 33 81 38 88 44 88 Time (min) % response3 5.4 x IO8 1 0 2 0 4 67 7 100 Time (min) K, response3
a) Percent response to a dose of acetylcholine (0.02 pgkg-1) compared to the same dose in the absence of antagonist.
8 0 12
Other quaternary ammonium salts according to the invention give substantially similar results on subjection to the foregoing biological studies.
The dose and dosage form administered, whether a single dose or a daily dose, will of course vary with the needs and size of the recipient. While the dosage administered is not subject to definite bounds, it will usually be an effective amount of the active drug to achieve its desired pharmacological and physiological effect, mainly, nonsecretion. For example, to inhibit gastric secretion, an oral dosage range of from 0.05 mg to 10 mg per Kg per day of body weight will suffice. When topically administered to inhibit passpiration, a 0.01% to 5% by weight application will normally suffice.
For oral administration, for example as a tablet or capsule, any of the compounds of the invention can be combined in an anticholinergic nonsecretory effective amount with any oral nontoxic pharmaceutically acceptable inert carrier such as lactose, starch (pharmaceutical grade), dicalcium phosphate,calcium sulphate, kaolin, mannitol and powdered sugar. Additionally, when needed, suitable binders, lubricants, disintergrating agents and colouring agents can also be included. Typical binders include starch, gelatin, sugars, such as acacia, sodium alginate, extract of Irish Moss, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene, glycol, ethylcellulose and waxes. Typical lubricants for use in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, and polyethylene glycol. Suitable disintergrators include starch, methylcellulose, agar, bentonite, cellulose, aglinic acid, guar gum, citris pulp, carboxymethylcellulose and sodium lauryl sulphate.. When desired, a conventional pharmaceutically acceptable dye can be incorporated. Any of the standard FD&C dyes is suitable.
Similarly, in a typical topical formulation for topical application, any of the compounds of the invention can be combined with any suitable topical vehicle safe for underarm application. The vehicle may be solid, liquid or aerosol. Vehicles serving the aforementioned purpose are readily found in REMINGTON'S PHARMACEUTICAL SCIENCES (Fourteenth Edition), 1970 and the text entitled, COSMETICS, SCIENCE AND TECHNOLOGY, H.D.
Goul den, et a), Interscience Publishers (1957), pp. 5, 717-31, 826-9, 1016, 1211, 1255 and 1266, respectively.
Claims (5)
1. A quaternary ammonium salt in which one of the substituents of the quaternary nitrogen atom has the general formula I as herein defined. 5 2. A trialkylammonium, trialkoxyammonium, pyrrolidinium, morpholinium, quinuclidinium, a2irinium, pyrronium, imidazonium, pyrazonium, pyridinium, pyrazinium, pyridazinium, pyrimidinium, isindonium, indonium, quinolinium,isoquinolinium, 10 phthalazinium, quinoxalinium, quinazolinium, phenazinium, isothiazonium, phenothiazinium, isoxazonium or furazanium salt according to claim 1.
2. 6. 1-/3,1-(2-Phenyl-2-cyclopentyl-acetoxymethyl)7-3-acetoxyquinuclidinium chloride or bromide. 27. l-/d,1-(2-Phenyl-2-cyclopentyl-acetoxymethyl)_/-3-ethoxycarbonylpyridinium chloride or bromide. 25 28. N-(9,10-Dihydro-anthracene-l-carboxymethyl)-Ν,Ν,Ν-triethylammonium chloride or bromide. 29. 1-(Adamantane-l-carboxymethyl)-3-.methylimadazonium bromide. 30. N-(Adamantane-l-carboxymethyl)-Ν,N,N-triethylammonium chloride or bromide. 311-(2-Phenyl-2-cyclopentyl-acetoxy Y7-benzyl)-N,N,N-triethylarimonium chloride or bromide. 32. 1-/3,1-(2-Pheny1-butyryloxymethyl^7-1,3-dimethyl-pyrrolidinium chloride or bromide. 33. N-/3,1-(2-Phenyl-propionylthiomethyl)7-N,Ν,N-triethylammonium chloride or bromide. 34. A process for the preparation of a quaternary ammonium salt according to claim 1, the process comprising condensing a halide of the general formula II as herein defined with a tertiary amine and, if the desired salt is not a halide, converting it to the desired salt by ion exchange using a methanolic solution of the acid of the desired salt or by basification followed by neutralisation with the acid of the desired salt. 35. A process according to claim 34 in which the condensation is effected in an inert solvent. 36. A process according to claim 35 in which the inert solvent is chloroform, diethyl ether, acetonitrile, or dichloromethane. 37. A process according to claim 35 or 36 in which the condensation is effected at a temperature of from .until i’nt tempei .iture to the reflux temperature of the inert solvent. 38. A process according to claim 34 in which the condensation is effected in the absence of a solvent. 39. A process according to claim 38 in which the condensation is effected at a temperature of from 20°C to 7O°C. 40. A process according to any of claims 34 to 39 in which the condensation is carried out for from 2 to 24 hours. 41. A process according to any of claims 34 to 40 in which the halide of the general formula II and the tertiary amine are employed in approximately equimolar proportions. 42. A process for the preparation of a quaternary ammonium salt according to claim 1 in which one of the substituents of the quaternary nitrogen atom is an alkyl group, the process comprising quaternising a tertiary amine in which one of the substituents of the tertiary nitrogen atom has the general formula I as defined herein with an alkyl halide and, if the desired salt is not a halide, converting it to the desired salt by ion exchange using a methanolic solution of the acid of the desired salt or by basification followed by neutralisation with the acid of the desired salt. 43. A process according to claim 42 carried out in acetonitrile or nitromethane as solvent. 44. A process for the preparation of a quaternary ammonium salt according to claim 1, the process being substantially as described herein with reference to any of Examples 2 to 30.
3. A quaternary ammonium halide, methanesulphonate, 15 fluorosulphate or tosylate according to claim 1 or claim 2.
4. A triethylammonium, 1-methylmorpholinium,
5. 45. A pharmaceutical composition comprising a quaternary ammonium salt according to any of claims 1 to 33 or prepared by a process according to any of claims 34 to 44 in admixture with a pharmaceutically acceptable diluent or carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86121077A | 1977-12-16 | 1977-12-16 |
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| IE782499L IE782499L (en) | 1979-06-16 |
| IE48012B1 true IE48012B1 (en) | 1984-09-05 |
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| IE2499/78A IE48012B1 (en) | 1977-12-16 | 1978-12-18 | Soft anticholinergic agents exhibiting antisecretory activity |
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| JP (1) | JPS5498711A (en) |
| AR (1) | AR222478A1 (en) |
| AT (1) | AT366380B (en) |
| AU (1) | AU531835B2 (en) |
| CA (1) | CA1102345A (en) |
| DE (1) | DE2854308A1 (en) |
| DK (1) | DK534178A (en) |
| ES (1) | ES476048A1 (en) |
| FR (1) | FR2422624A1 (en) |
| GB (1) | GB2010270B (en) |
| IE (1) | IE48012B1 (en) |
| IT (1) | IT1101735B (en) |
| NL (1) | NL7812257A (en) |
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| DE3045055A1 (en) * | 1980-11-29 | 1982-07-01 | Celamerck Gmbh & Co Kg, 6507 Ingelheim | HETEROCYCLIC COMPOUNDS |
| JPS5993075A (en) * | 1982-11-18 | 1984-05-29 | Shionogi & Co Ltd | Preparation of 1-phthalidyl-5-fluorouracil derivative |
| US5008111A (en) * | 1984-10-11 | 1991-04-16 | Schering Corporation | Physiological means of enhancing transdermal delivery of drugs |
| US4824676A (en) * | 1984-10-11 | 1989-04-25 | Schering Corporation | Physiological means of enhancing transdermal delivery of drugs |
| FR2703046B1 (en) * | 1993-03-26 | 1995-05-05 | Poudres & Explosifs Ste Nale | Process for the preparation of alpha-monohalogenated oxalates and haloglyoxalates and new alpha-monohalogenated oxalates and haloglyoxalates. |
| AUPN814496A0 (en) | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
| US5962505A (en) * | 1998-08-31 | 1999-10-05 | Bobrove; Arthur M. | Method for treating hot flashes in humans |
| US6433003B1 (en) | 1999-04-23 | 2002-08-13 | Arthur M. Bobrove | Method for treating hyperhidrosis in mammals |
| AR044134A1 (en) | 2003-05-02 | 2005-08-24 | Novartis Ag | DERIVATIVES OF QUINUCLIDINE, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS. |
| JP5401092B2 (en) | 2005-06-03 | 2014-01-29 | アクルックス・ディ・ディ・エス・プロプライエタリー・リミテッド | Methods and compositions for transdermal drug delivery |
| KR20080089461A (en) * | 2005-12-30 | 2008-10-06 | 랜박시 래보러터리스 리미티드 | Muscarinic receptor antagonists |
| EA019760B1 (en) | 2007-11-02 | 2014-06-30 | АКРУКС ДиДиЭс ПиТиУай ЭлТиДи | Transdermal delivery system, method for transdermal administration and method of preparing transdermal delivery system |
| CN110526864A (en) * | 2012-10-05 | 2019-12-03 | 斯菲拉制药私人有限公司 | New compound, its synthesis and application thereof |
| DE102013013397A1 (en) | 2013-08-13 | 2015-03-12 | Epinamics Gmbh | Aerosol dispenser for transdermal pharmaceutical compositions |
| CN110041264A (en) * | 2019-04-11 | 2019-07-23 | 贺州学院 | A kind of adamantyl glyoxaline ion liquid and preparation method thereof |
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| US3998815A (en) * | 1974-06-24 | 1976-12-21 | Interx Research Corporation | 1-hydrocarbonoyloxymethyl-3-carbamoyl or 3-carboethoxy-pyridinium salts |
-
1978
- 1978-11-29 DK DK534178A patent/DK534178A/en not_active Application Discontinuation
- 1978-12-12 IT IT30735/78A patent/IT1101735B/en active
- 1978-12-15 JP JP15601378A patent/JPS5498711A/en active Pending
- 1978-12-15 DE DE19782854308 patent/DE2854308A1/en not_active Withdrawn
- 1978-12-15 ES ES476048A patent/ES476048A1/en not_active Expired
- 1978-12-15 SE SE7812911A patent/SE436027B/en unknown
- 1978-12-15 AR AR274836A patent/AR222478A1/en active
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- 1978-12-18 AU AU42646/78A patent/AU531835B2/en not_active Expired
- 1978-12-18 CA CA318,112A patent/CA1102345A/en not_active Expired
- 1978-12-18 NL NL7812257A patent/NL7812257A/en not_active Application Discontinuation
- 1978-12-18 FR FR7835596A patent/FR2422624A1/en active Granted
- 1978-12-18 GB GB7848850A patent/GB2010270B/en not_active Expired
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| SE436027B (en) | 1984-11-05 |
| AU531835B2 (en) | 1983-09-08 |
| NO148776C (en) | 1983-12-14 |
| ATA901478A (en) | 1981-08-15 |
| FR2422624B1 (en) | 1983-10-14 |
| JPS5498711A (en) | 1979-08-03 |
| CA1102345A (en) | 1981-06-02 |
| NO784229L (en) | 1979-06-19 |
| NL7812257A (en) | 1979-06-19 |
| AU4264678A (en) | 1979-06-21 |
| IE782499L (en) | 1979-06-16 |
| DK534178A (en) | 1979-06-17 |
| IT7830735A0 (en) | 1978-12-12 |
| DE2854308A1 (en) | 1979-06-21 |
| GB2010270B (en) | 1982-10-20 |
| IT1101735B (en) | 1985-10-07 |
| SE7812911L (en) | 1979-06-17 |
| FR2422624A1 (en) | 1979-11-09 |
| GB2010270A (en) | 1979-06-27 |
| AT366380B (en) | 1982-04-13 |
| AR222478A1 (en) | 1981-05-29 |
| ES476048A1 (en) | 1979-11-01 |
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