IE871251L - Pyrrolidine derivatives - Google Patents
Pyrrolidine derivativesInfo
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- IE871251L IE871251L IE125187A IE125187A IE871251L IE 871251 L IE871251 L IE 871251L IE 125187 A IE125187 A IE 125187A IE 125187 A IE125187 A IE 125187A IE 871251 L IE871251 L IE 871251L
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Description
60229
- i -
The present invention relates to 5-[2-(pyrrolidin-1-yl)ethoxy]-p-cymene derivatives; it also relates to a process for the preparation of these derivatives and drugs in which the said derivatives are present.
The 5-[2-(pyrrolidin-l-yl)ethoxy]-p-cymene derivatives are the novel products of the formula:
(I)
in which R is selected from the group comprising H» OH, OCOCHg (acetoxy) and 0C0(CH^)nCH^> in which n is between 1 and 8 (1 and 8 being included in the definition of n), and the salts of the products of the formula (I) with pharmaceutically acceptable acids.
The process for the preparation of the compounds of the formula (I) consists, in a first stage, in reacting thymol with N-(2-chloroethy1)pyrrolidine hydrochloride; the reaction is performed by phase transfer in a liquid-liquid system in the presence of a catalyst (triethylbenzylammonium chloride)? this gives the product of the formula (I) in which R is H. The product of the formula (I) in which the group R is acetyl is prepared in a solvent, such as toluene, and in the presence of 70% perchloric acid, by reacting the product in which R = H with acetic anhydride.
The product of the formula (I) in which the group R is acetoxy is prepared by reacting an oxidizing agents such as m-chloroperbenzoic acids with the derivative of the formula (I) in which R is acetyl, the 5 said reaction being performed in a solvent (toluene) in the presence of an acid (trichloroacetic acid).
The product of the formula (I) in which the group R is a hydroxyl group is prepared by saponifying the product in which R is the acetoxy group with a 10 solution of sodium hydroxide*
Finallys the product of the formula (I) in which the group R is OCO^I^^CHg is prepared by esterifying the product in which R is OH with an acid chloride of the formulas
RC*
^Cl
The salts, for example the hydrochlorides, are obtained in a known manner by bringing a solution of the product of the formula (I) into contact with the acid in question (for example by bubbling hydrogen 20 chloride into a solution of the product of the formula
(I).
The present invention also relates to drugs which contain at least one product of the formula (I) as the active product; the said drugs can be useful 25 especially in the field of urology*
The non-limiting examples which follow illustrate the processes for the preparation of the products according to the invention.
EXAMPLE 1
Synthesis of 3-[2-(pyrrolidin-l-vl)ethoxv]-p-cymene hydrochloride (B 1007)
1 . Preparation of 3-f2-(pyrrolidin-l-yl)ethoxv 1-p-cymene
The following are introduced into a 4 liter
three-necked flask fitted with a condenser, a pneumatic stirrer and a thermometer:
150.2 g (1 mol) of thymol,
16.68 g of triethylbenzylammonium chloride, and 5 751 ml of sodium carbonate solution.
1495 ml of methylene chloride are added. The medium is stirred very vigorously.
The addition of 212.76 g of N-(2-chloroethyl)-pyrrolidine hydrochloride (1.25 mol) in 70,9 ml of water 10 causes the temperature to rise to 25°C.
The mixture is heated under reflux for 4 hours, with vigorous stirring.
After cooling to room temperature, the organic phase is left to separate out and the sodium carbonate 15 phase is extracted with 2 x 425 ml of methylene chloride*,
The combined organic phases are washed successively with 2 x 350 ml of acidified water (0.25% acetic acid) and then 2 x 700 ml of a saturated aqueous solution of sodium chloride until the washings are 20 neutral. They are then dried over sodium sulfate.
After filtration,, the solvent is driven off in vacuo.
This gives 259=57 g of an orange oil.
The crude product is purified by fractional dis-25 tillation in vacuo (under nitrogen).
184.7 g of a colorless oil are isolated. Boiling point under 0.1 mm Hgs 155-160°C? perchloric acid/ CH3C00H titer: 102.1%.
2. Preparation of the hydrochloride 30 24.73 g of this oil (0.1 mol) are dissolved in
400 ml of anhydrous ethyl ether. The solution is saturated with a stream of dry HC1 gas in an ice bath. The crystals formed are filtered off on a glass frits washed with anhydrous ethyl ether and then dried over 35 potassium hydroxide at 70°C.
This gives 25.12 g of beige crystals (yield of crude product = 88.6^).
After recrystallization from ethyl acetate, 22.22 g of slightly beige crystals are isolated.
The crystals obtained were subjected to elemental analysis (empirical formula C^^^CINO), which gave the following results:
calculated found c
67 .70
67 .69
H
9.23
9.25
N
4.93
4.83
CI
12.48
12.65
0
.63
.76
The crystals have a melting point m.p.^g of 15 157-158°C and their IR and NMR spectra are consistent with the proposed structure.
EXAMPLE 2
Synthesis of 2-acety1-5-[2-(pyrrolidin-1-y1)ethoxv]-p~ c ymene
The 3-[2-(pyrrolidin-l-yl)ethoxy]-p-cymene obtained according to process 1 of Example 1 is used as the starting material; this product was purified beforehand .
247.38 g (1 mol) of this product are dissolved 25 in 1600 ml of toluene and 863 ml of acetic anhydride in a 4 liter three-necked flask fitted with el condenser equipped with an f^SO^ trap, a thermometer and a dropping funnel. The mixture is stirred and 225.2 ml of 70% perchloric acid are then added dropwises the temperature 30 being kept below 45°C„
The mixture is stirred for 1 hour at room temperature and then poured into 760 ml of a saturated
aqueous solution of NaCl.
After cooling with an ice bath and rendering basic with sodium carbonate solution (pH; 12)s the organic phase is separated off and extraction is carried 5 out with 2 x 300 ml of methylene chloride. The organic phases are combined and washed with acidified water and a saturated aqueous solution of NaCl until the washings are neutral. They are dried over sodium sulfate and filtered and the solvent is driven off in vacuo. This 10 gives 297.3 g of a brown oil with a GC purity of 97% (yield of crude product > 100%).
The crude product is then purified by fractional distillation in vacuo (under nitrogen) .
196.14 g of a yellow oil are isolated. 15 The product obtained has a boiling point (under
0.4 mm Hg) of 149-153°C and a perchloric acid titer of 98.6% and its IR and NMR spectra are consistent with the proposed structure.
EXAMPLE 3
Synthesis of 2-acetoxy-5-[2-(pyrrolidin-l-yl)ethoxy]-p-cymene hydrochloride (B 1024)
1. Synthesis of 2-acetoxy--5-\2-(pyrrolidin-l-
vDethoxyl-p-cymene The purified oil obtained in Example 2 is used 25 as the starting material.
289.42 g (1 mol) of this product and 1650 ml of toluene are introduced into a 4 liter three-necked flask fitted with a condenser equipped with an f^SO^ trap, a thermometer and a pneumatic stirrer. 30 392.13 g (2.4 mol) of trifluoroacetic acid are added in portions, the temperature being kept below 15°C. 258.84 g (1.2 mol) of 80% m-chloroperbenzoic acid are then introduced.
The mixture is kept at 15°C for 24 h, with
stirring. It is then poured into 2130 ml of 5% aqueous ammonia.
The organic phase is separated off by decanta-tion. The aqueous phase is extracted with 2 times 890 ml 5 of toluene. The organic phases are combined and washed with 890 ml of acidified water and then 1180 ml of a saturated aqueous solution of NaCl until the washings are neutral. They are dried over sodium sulfate and filtered and the solvent is driven off in vacuo. 10 This gives 266.3 g of a brown oil with a GC
purity of 97.2% (yield of crude product = 87.2%).
2. Synthesis of the hydrochloride
.54 g (0.1 mol) of this crude oil are dissolved in 210 ml of anhydrous ethyl ether. A stream of dry 15 HC1 gas is bubbled into the solution, in an ice bath. The crystals formed are filtered off on a glass frit, washed with anhydrous ethyl ether and then dried over potassium hydroxide at 50°C in vacuo.
16.74 g of beige crystals are isolated (yield 20 of crude product = 49%).
After recrystallization from a 20/1 AcOEt/EtOH mixtures 11.31 g of light beige crystals are obtained.
The said crystals have a melting point m9p.„_.
K D
of 182-183°C and a perchloric acid titer of 100.8% and 25 their IR and NMR spectra are consistent with the proposed structure.
EXAMPLE 4
Synthesis of 2-hydroxy~5-[2-(pyrrolidin-l-yi)ethoxyj-p-cymene hydrochloride (B 1058)
The purified oil obtained after the first operation of Example 3 is used as the starting material.
.5 g (0.1 mol) of this oil and 110 ml of ethanol are introduced into a 500 ml conical flask fitted with a condenser and a magnetic stirrer.
- 7
110 ml of 1 N sodium hydroxide solution (0.11 mol) are added to this solution and the mixture is stirred for 24 h at room temperature. The ethanol is driven off in vacuo; the residue is taken up with 5 150 ml of water and extracted with 3 times 180 ml of methylene chloride.
The combined organic phases are washed with a saturated aqueous solution of sodium chloride until the washings are neutral. They are dried over sodium 10 sulfate and the solvent is driven off in vacuo. This gives 25.28 g of an orange oil (yield of crude product = 96%).
After crystallization from hot pentane and recrystallization from hexane, 21.54 g of white 15 crystals are isolated which have a melting point m.p.
K.U
of 86-87°C.
The product obtained was converted to a salt (hydrochloride) by the following procedure:
13.16 g (0.05 mol) of purified base are 20 dissolved in 200 ml of anhydrous ethyl ether, with stirring. After a stream of dry HC1 gas has been bubbled in, the crystals formed are isolated by filtration on a frit.
After washing with ethyl ether and drying in 25 vacuo at 50°C? 14„54 g of beige crystals are obtained (yield of crude product = 97%)„
After recrystallization from an AcOEt/EtOH mixture (2/1), 11.1 g of white crystals are isolated.
The said crystals have a melting point m.p.^g 30 of 147-148°C and their IR and NMR spectra are consistent with the proposed structure; elemental analysis of these crystals (empirical formula C^H^gClNO^) gave the following results;
calculated found c
64.09
64.08
H
8.74
8.78
N
4.67
4.65
CI
11.82
11.96
0
.67
.86
EXAMPLE 5
Preparation of an ester and its hydrochloride A - Synthesis of 2-butyryloxy-5-[2-(pyrrolid in-1 -y1)-10 ethoxy]-p-cymene (R = CH^-(Cl^ ))
The following are introduced, with stirring.
into a 500 ml three-necked flask fitted with a condenser, a pneumatic stirrer and a thermometer:
- 26.3 g (0.1 mol) of 2-hvdroxy-5-[2-(pyrrolidin-15 1-yl)ethoxy]-p-cymene,
- 200 ml of benzene and
- 10.6 g of triethylamine (0.105 mol). 11.2 g (0.105 mol) of butyryl chloride are added to this solution.
The reaction medium is heated at 50°C for 20
hour s .
The progress of the reaction is monitored by gas chromatographic analyses of the medium.
After cooling to room temperature, the reaction 25 mixture is poured into 350 ml of water.
The benzene phase is decanted and countercurrent extraction is carried out on the aqueous phase with 3 x 250 ml of benzene-
The combined benzene phases are washed with 30 water until the washings are neutral, and dried over sodium sulfate.
After filtration, the solvent is driven off in vacuo.
This gives 31.5 g qf a brown oil.
Yield of crude product GC purity
Perchloric acid titer TLC
94.5% 99.5% 94.3%
single spot
B - Synthesis of 2-butyryloxy-5-[2-(pyrrolidin-1-y1)-ethoxy]-p-cymene hydrochloride (B 1132)
16.67 g (0.05 mol) of this oil are dissolved in 180 ml of anhydrous ethyl ether. The solution is saturated with a stream of dry HC1 gas (in an ice bath) The crystals formed are filtered off9 washed with anhydrous ethyl ether and then dried over phosphorus pentoxide at 50°C.
This gives 12.18 g of beige crystals (yield of crude product = 65.8%).
After recrystallization from isopropanols 10.04 g of slightly beige crystals are isolated.
Yield after recrystallization = 54.3%
TBAH titer
AgNO^ titer GC purity
= 189-190°C = 97.8% = 97% = 99.8%
IR = consistent with the proposed structure NMR = consistent with the proposed structure Karl Fischer (water determination) = 0.2% TLC = single spot
The hydrochlorides mentioned in the summary table below were prepared by following the same procedu as in Example 5?
summary table
Code no.
n
Empirical formula (mw)
Yield %
m " p * kb °c (recryst. solvent)
b 1125
1
c19h30c1n03 (355.91)
51 . 2
177-178
b 1132
2
c20h32c1n03 (369.94)
54.3
189-190 (ipa)
b 1131
4
c22h36c1n03 (397.99)
50
156-157 (ipa)
b 1134
8
c26h44c1n03 (454.10)
45.4
148-149 (ipa)
The products according to the invention were studied for their toxicity and their pharmacological 15 properties.
1 » Toxicity
The following 50% lethal doses were obtained after oral administration (p.o.) and intravenous administration (i.v„) of the substances to mice, on The results obtained are collated in Table I.
TABLE I
Substance I
LD50 " m g/kg I
p . 0 .
i . v .
B 1007
330
75
B 1024
100
18
B 1058
80
17
B 1125
^ 300
ND*
B 1131
^ 550
ND*
B 1132
Si 500
ND*
B 1134
£=« 400
36
Thymoxamine
300
72.5
""ND : not determined
2. Pharmacological properties
2.1. - In vitro d-adrenolytic activity 15 This was studied on the ductus deferens of rats and on the urethra of rabbits.
Principle of the measurement:
Norepinephrine causes contractions of the isolated ductus deferens of rats and the isolated 20 urethra of rabbits. The presence of cC-blocking substances in a bath containing the organ antagonizes these contractions; the use of increasing concentrations of et-blocking substances makes it possible to calculate;
- the pA£ of the compounds on the ductus deferens 25 of rats, the PA2 being the negative logarithm of that molar concentration of the product in the presence of which the concentration of norepinephrine has to be doubled in order to obtain the same effect as in the absence of the product; and 30 - the pD!2 of the compounds on the urethra of rabbits, the pD^ being the negative logarithm of that
molar concentration of the product in the presence of which the contraction-inducing activity of norepinephrine is halved.
Results:
The results obtained are collated in Table II.
TABLE II
o{.-Blocking action towards nore
PRODUCT
pinephrine
on isolated ductus on isolated
deferens urethra
pA2
PD'2
B 1007
6.74
6.88
B 1024
6.98
6.38
B 1058
7.18
6»69
B 1125
7.14
6.25
B 1131
6.98
6.12
B 1132
7.35
6.0
B 1134
6.57
6.23
Thymox-
amine
7.25
7.03
These results show an interesting blocking activity for the products tested.
2.2. - In vivo adrenolytic activity 25 2.2.1. In rats
Principle of the measurement:
Norepinephrine injected intravenously in high doses causes the death of 100% of the animals within 15 minutes of being injected. The cause of death is 30 pulmonary edema due to the arterial hypertension induced by stimulation of the adrenergic receptors. The
oral administration of e£-adrenolytic substances beforehand enables the toxicity of norepinephrine to be reduced. The products are administered orally at times varying between 30 minutes and 6 hours before the intravenous injection (i»v») of norepinephrine (0.4 mg/ kg) -
Results:
The results obtained are collated in Table III.
TABLE III
PRODUCT
Dose p.o. mg/kg
% protection against death
Time of administration of the products before i . v .
B
1007
50
60
min
B
1024
70
min
B
1058
50
90
min
B
1125
60
min
B
1131
50
60
min
B
1132
50
90
min
B
1134
100
100
4
h
Thymox-araine
50
80
min
These results show that the products tested provide effective protection against the toxicity of 25 norepinephrine.
2 . 2.2 . In anesthetized rabbits The "in vivo" ^-blocking activity in terms of the urethral and vascular pressures in anesthetized rabbits was investigated by intravenous administration 30 of the products B 1007, B 1024, B 1058, B 1125 and B 1134.
Principle of the measurement;
The intravenous injection of norepinephrine causes a dose-dependent increase in the arterial and urethral pressures in rabbits. ©L-Blocking substances 5 injected intravenously antagonize these pressure increases as a function of dose. The 50% inhibitory dose (ID^q). defined as being the dose of product which causes a 50% decrease in the effects of norepinephrine on the arterial and urethral pressures, is calculated. 10 Results:
The results obtained are collated in Table IV.
TABLE IV
These results show that the products tested 25 antagonize the increase in urethral pressure at much lower doses than are necessary to antagonize the increase in arterial pressure.
2.2.3. Urethral specificity in anesthetized dogs The effect of products B 1007. B 10249 B 1125 30 and B 1134, injected intravenously, on the neurogenic urethral hypertension and the arterial pressure was
ID^q (mg/kg) with regard to
PRODUCT
arterial urethral
hypertension hypertension
B 1007
7.63
0.34
B 1024
4.14
0.23
B 1058
1.22
0.13
B 1125
.95
0.36
B 1134
6.17
0.48
Thymox-
amine
2.72
0.5
investigated on anesthetized dogs.
Principle of the measurement:
Electrical stimulation of the hypogastric nerve causes an increase in the urethral pressure by releasing
norepinephrine from the sympathetic fibers of the nerve.
c(.-Blocking substances antagonize these increases in urethral pressure as a function of dose and cause arterial hypotension through a blocking action on the vascular receptors.
The dose which causes a 50% inhibition of the effects of stimulation of the hypogastric nerve on the urethral pressure (ID,_q) and the dose which causes a 20% arterial hypotension (ED2q) are calculated-
Results;
The results obtained are collated in Table V«,
TABLE V
PRODUCT
Arterial hypotension
ED20 " mg/k8
Neurogenic urethral hypertension ID50 - mg/kg
B 1007
2
0.35
B 1024
8
0.07
B 1125
12
0.09
B 1134
0.11
Thymoxamine
0.27
0.09
These results show that the products tested antagonize the increase in urethral pressure induced by stimulation of the hypogastric nerve at doses very much lower than those which cause a hypotensive vascular effect.
The toxicological and pharmacological experiments show that the products according to the invention can be administered,, orally or by injection* as drugs in functional urethral pathologies dependent on a sympathetic mechanism.
Claims (11)
1, Novel products of the formula; CH R (I) -<ch2)2- n in which R is selected from the group comprising H, 0HS -0C0CHo and -0-C0-(CH„) -CH~S in which n is between 1 3 2' n 3 and 8f and the salts of the products of the formula (I) with pharmaceutically acceptable acids.
2. Novel products as claimed in claim 1, wherein n is selected from the group comprising 15 4 and 8.
3. A process for the preparation of the product of the formula (I) in which R is H? wherein thymol is reacted with N-(2-chloroethyl ) pyrrolidine hydrochloride.
4. A process for the preparation of the product of the formula (I) in which R is -O-COCH^s wherein the product of the formula (I) in which R is -COCH^, obtainable by reacting the product of the formula (I) in which R is H with acetic anhydride in the presence of perchloric acid, is reacted with m-chloroperbenzoic acid in the presence of an acid.
5. A process for the preparation of the product of the formula (I) in which R is OH;, wherein the product of the formula (I) in which R is -O-COCH^ is reacted with a solution of sodium carbonate.
6. A process for the preparation of esters of the formula (I)? wherein 2-hydroxv-5-[2-(pyrrolidin-1-v1)~ efchoxy]-p-cymene is reacted with an acid chloride of the formula: \ 'CI - 18 - in which R is CH^-CCI^) 9 n being between
7. Drugs having especially an el-blocking which contain at least one product of the or a salt of the said product* 1 and 8. activity formula 19 i 10 15
8. A compound of the formula (I) given and defined in claim 1 or a salt thereof with a pharmaceutically acceptable acid, which is any one of those specifically hereinbefore mentioned.
9. A process for the preparation of a compound of the formula (I) given and defined in claim 1 or a salt thereof with a pharmaceutically acceptable acid, substantially as hereinbefore described with particular reference to the accompanying Examples.
10» A compound of the formula (I) given and defined in claim 1 or a salt thereof with a pharmaceutically acceptable acid whenever prepared by a process claimed in any one of claims 3-6 or claim 9.
11. A drug according to claim 7, substantially as hereinbefore described. Dated this the 13th day of May,, 1987 F. R» KELLY & CO. BY; EXECUTIV] 21 Clyde Road, Ballsbridge, Dublin 4. AGENTS FOR THE APPLICANTS.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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IE125187A IE60229B1 (en) | 1987-05-13 | 1987-05-13 | 5-[2-(pyrrolidin-1-yl)ethoxy]-p-cymene derivatives, the process for the preparation of the said derivatives and drugs in which the said derivatives are present |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE125187A IE60229B1 (en) | 1987-05-13 | 1987-05-13 | 5-[2-(pyrrolidin-1-yl)ethoxy]-p-cymene derivatives, the process for the preparation of the said derivatives and drugs in which the said derivatives are present |
Publications (2)
Publication Number | Publication Date |
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IE871251L true IE871251L (en) | 1988-11-13 |
IE60229B1 IE60229B1 (en) | 1994-06-15 |
Family
ID=11024350
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IE125187A IE60229B1 (en) | 1987-05-13 | 1987-05-13 | 5-[2-(pyrrolidin-1-yl)ethoxy]-p-cymene derivatives, the process for the preparation of the said derivatives and drugs in which the said derivatives are present |
Country Status (1)
Country | Link |
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IE (1) | IE60229B1 (en) |
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1987
- 1987-05-13 IE IE125187A patent/IE60229B1/en not_active IP Right Cessation
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