IE42439B1 - , -diaryl- -(tert-amino)-propanols, processes for their preparation and pharmaceutical compositions containing them - Google Patents
, -diaryl- -(tert-amino)-propanols, processes for their preparation and pharmaceutical compositions containing themInfo
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- IE42439B1 IE42439B1 IE1613/75A IE161375A IE42439B1 IE 42439 B1 IE42439 B1 IE 42439B1 IE 1613/75 A IE1613/75 A IE 1613/75A IE 161375 A IE161375 A IE 161375A IE 42439 B1 IE42439 B1 IE 42439B1
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- methoxy
- propan
- diethyl ether
- piperidino
- methyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- 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
- C07D295/092—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 with aromatic radicals attached to the chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Cpds of formula (I) and their salts: (where R'1, R" are 1-6C opt. branched alkyl or together with the N atom form a 5- or 6-membered ring R1-R10 are each H, 1-6C opt. branched alkyl, 2-3C alkenyl, hydroxy, 1-4C alkoxy (2 adjacent gps together may form a 5 or 6-membered heterocyclic ring withone or two heteroatoms), benzyloxy or halo) are diuretics and saluretics which cause less potassium excretion than known cpds. Pharmacological tests comparing their activity with 2,4,7-triamino-6-phenyl pteridine and 6-chloro-3,4-dihydro,7-sulphanmoyl-2H-1,2,4-benzothiadiazine-1,1-- dioxide. (I) may be administered orally or parenterally with the usual vehicles.
Description
The present invention relates to derivatives of a,a -diaryl- β (tert-amino)-propano1s, processes for their preparation, and also to pharmaceutical compositions containing them.
α , a -Diaryl- β -(tert-amino)-propanols of the general formula:
?
are known, wherein R and R‘ are each independently a halogen atom, a benzyloxy radical, a lower alkyl or a lower alkoxy group and -N(CH2)n is a saturated Nheterocyclic radical., which is connected via the ring-stable nitrogen atom.
These compounds possess anti-tussive activity. The compounds of formula (I) may be prepared in known manner by the reaction of (a -tertiary amino)-ethyl aryl ketones with alkyl magnesium halides.
Surprisingly, compounds of the α, a-diaryl-β -(tert-ami no)-propanols having saluretic activity have now been found.
Accordingly, the present invention provides α , α-diaryl-β -(tert15 amino)-propanols of the general formula:
- 2 42439
in which R1 and R are each independently a straight or branched chain alkyl group having from 1 to 6 carbon atoms, or R' and R together with the nitrogen atom, form a 5- or 6-membered ring, and to are each independently a hydrogen or halogen atom, a straight or branched chain alkyl group having from to 6 carbon atoms, an alkenyl group having 2 or 3 carbon atoms, a hydroxy group, an alkoxy group having from 1-4 carbon atoms, or a benzyloxy group or wherein two adjacent substituents together form a 5- or 6-membered heterocyclic ring having one or two hetero-atoms and the other substituents are as defined above, provided that at least one of the rings A and B has more than one substituent group other than hydrogen attached thereto.
These multiple-substituted α,a-di aryl-β -(tert-ami no)-propanols of the formula (II) exhibit a diuretic and saluretic effect which differs from that of diuretics found commercially.
Medicaments which result in an increased discharge of urine and produce an increased elimination of sodium and chlorine ions via the kidneys (saluretics) are used for example in the treatment of oedema, in widely varying convalescent conditions and in the therapy of high-pressure conditions.
In addition to eliminating sodium and chloride, saluretics normally also effect at the same time an increase in the excretion of potassium. Such an effect is disadvantageous, since it carries with it the risk, particularly in tong-term therapy, of a potassium-depletion of the organism.
- 3 43439
Diuretics, in which this side effect is not found, are of particular interest. They are classified pharmacologically as aldosterone-antagonists or as pseudo-antialdosterones or anti-kaliuretic diuretics. Previously known examples of medicaments of this type are the aldosterone antagonist 4‘,5'dihydro-7 a -mercaptospiro-/_”androst-4-ene-17,2l-(3'H)-furan -3-one acetate which is from the group of spirolactones? and the antikaliuretic diuretics 2,4,7· tri ami no-6-1 phenyl-pteri di ne and N-ami di no-3,5-di ami no-6-chloropyrazi necarboxamide. However in patients, in which sodium is retained, these compounds generally only have a slight effect on the sodium elimination. For this reason they are generally only ised in combination with a powerful saluretic.
This procedure involves disadvantages since the effect of such a combination is frequently quantitatively impossible to anticipate. The effect will depend on the relationship between the primary disease and the simultaneous administration of the saluretic and anti-kaliuretic diuretic, and furthermore gives rise to problems in respect of the possible concurrence of side effects.
Furthermore, the previously known anti-kaliuretics may cause potassium congestion in the body, since because of their anti-kaliuretic action potassium is retained in the organism, if its elimination via the kidneys is not increased.
For these reasons, new diuretics have been sought which possess both anti-kaliuretic and saluretic activity.
As can be seen from the results of pharmacological tests which are summarised in the following tables, the compounds of the present invention increase the water and sodium chloride elimination beyond that obtained with 2,4,7-triamino-6-phenyl-pteridine, without inhibiting the elimination of potassium, and furthermore do not increase the excretion of potassium, such as is known with the conventional saluretics. It can be seen from Table 2 that the potassium values obtained using the compounds of the invention, by contrast with the reference compositions, are in the range which is considered to be normal.
It is also found that the novel compounds not only possess more favourable properties than 2,4,7-triamino-6-phenyl-pteridine, but that they to some extent also considerably surpass the effect of 6-chloro-3,4-dihydro-7sulphamoyl-2H-1,2,4-benzbthisdiazine-l,1-dioxide with respect to their diuretic and saluretic action. The following explanations are given with regard to
- 4 42439 the tables.
In order to test the saluretic efficiency of the compounds of the invention rats having a weight of 150 to 200 g were used. The animals were kept without food, but not without drinking water, for 15 hours before the beginning of the test. The test substances were administered to groups of four rats, of substantially equal weight, with a rigid stomach probe in a 1% methyl cellulose slime. The dose required per 100 g animal (unit dosage in umol/kg body weight) was contained in one ml.
Following the administration of the substance the rats were given ml 0.95( sodium chloride solution per 100 g body weight p.o. and placed in a diuresis funnel after manually emptying the bladder. Urine was collected for hours in an air-conditioned chamber at 24 ί 1°C and a relative air humidity of 50 - 5%. The diuretic effect of a particular dose was tested on at least two, but more frequently however on four to eight groups of rats. Two sodium chloride controls were also used for each test day.
At the end of the collecting periods the volumes of urine discharged per group were noted and the pH value and also the content of sodium, potassium (flame-photometrically) and chloride (measured argentometrically with the determination of the end point potentiometrically) were determined.
From the analysis results the quantities of Na+, K+ and Cl- eliminated were calculated in mol/lg body weight, and the values thus obtained compared with those of the control animals.
Means values and twice the standard deviation were calculated from the data for the sodium chloride controls, in order to determine the normal range. Then, for the values found with the test substances, the percentage variations from the average in respect of these parameters were calculated and tabulated.
In this connection, with the results given in Table 1, the upper limit of the normal range, which is defined as the mean value plus twice the standard deviation, was selected as the reference quantity for the variations, In this way relevant hyper-eliminations could clearly be recognised.
In Table 2, the mean percentage variations in potassium elimination after administration of the compounds in accordance with the invention are compared with the mean value of the potassium elimination in the case of the sodium chloride controls. At the same time the Na/K ratio is given which
- 5 provides conclusive evidence of the effective saluretic property. The larger quotient is, then the more sodium than potassium is eliminated in proportion. TABLE 1.
Influence on the elimination of water and sodium chloride
Substance Dose u mol/kg body wt. Mean percentage variation elimination (1) in the oral h2o Sodium Chloride T 1523 40 28.9 13.1 -5.1 80 39.6 28.2 14.2 T 1856 40 41.0 30.6 19.4 80 59.7 47.6 32.5 T 1857 40 52.0 54.8 32.9 80 56.5 54.6 36.0 T 1882 40 17.7 24.4 6,3 80 7.5 9.5 -4.4 T 2111 40 36.8 33.5 9.5 .80 33.8 37.1 23.4 T 2129 40 23.9 32.6 12.4 80 21.3 19.4 22.0 T 2152 40 22.9 22.7 11.6 80 22.6 20.4 5.6 T 2237 40 40.8 32.1 24.3 80 67.,9 59.8 57.1 T 2258 40 28.1 22.9 12.8 80 32.3 24.6 17.3 T 2259 40 46.5 28.7 94.0 80 76.6 59.8 109.7 T 2266 40 -12.9 -7.7 -13.2 80 19.7 19.4 12.2 T 2310 40 41.3 27.3 8.9 80 67.9 42.3 36.3 T 2350 40 24.1 15.5 2.6 80 49.8 40.5 21.2 2,4,7-triann no- - 40 -1.0 -4.0 -11.7 e-phenyl-pteridine 80 -2.0 '-0.2 -11.7 T 2378 40 6.7 6.7 -5.6 80 39.6 45.0 -20.4 T 2453 40 13.4 7.6 6.9 80 51.7 62.2 31.2 T 2455 40 39.8 31.3 21.4 80 62.4 55.8 34.8
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Table 1 continued
Influence on the elimination of water - and sodium chloride Substance Dose Mean percentage variation in the μ mol/kg body wt. elimination (1) oral h2o Sodium Chi ori de T 2458 40 30.9 40.4 16.9 80 83.8 84.2 59.0 T 2464 40 49.8 64.4 30.4 80 65.9 79.0 38.3 T 2481 40 3.0 -2.4 -7.5 80 34.1 43.8 20.0 T 2493 40 59.2 62.7 41.0 80 64.4 76.8 41.5
6-chloro-3,4-di hydro-7-sulphamoyl-2H-1,2 ,4-benzothi adi azi ne-1,1 -dioxi de, a typical saluretic, produced with a dose of 10 mol/kg body weight a maximum hyper-elimination amounting on an average for water to 19.9%, sodium 29.6% and chloride 17.3%.
FOOTNOTES . · -- ·«* (1) Deviations from the limits, defined by the average plus twice the standard deviation (x + 2s), of the control tests.
(2) Negative prefixes indicate that there is no hyper-elimination by comparison with the sodium chloride controls.
TABLE 2. Influence on the elimination of potassium Substance Dose Mean percentage Quotient μ mol/kg variation in the Na/K body wt. elimination of oral potassium (1) T 1523 40 25.5 5.35 80 13.3 6.72 T 1856 40 25.5 6.18 80 22.4 7.16 T 1857 40 30.6 7.04 80 29.6 7.09 T 1882 40 13.3 6.52 80 -12.2 7.41 T 2111 40 19.4 6.64 . 80 - 7.1 8.77
- 7 42439 1 Table 2 continued
Influence on the elimination of potassium
Substance Dose u mol/kg body wt. oral Mean percentage variation in the elimination of potassium (1) Quotient Na/K T 2129 40 12.3 7.02 80 35.7 5.23 T 2152 40 9.2 6.67 80 9.2 6.55 T 2237 40 13.3 6.93 80 19.4 7.95 T 2258 40 19.4 6.11 80 1.0 7.32 T 2259 40 19.4 6.40 80 38.8 6.84 T 2266 40 - 2.0 5.59 I 80 4.0 6.81 T 2310 40 14.3 6.62 80 - 2.0 8.64 T 2350 40 - 2.0 7.00 80 25.5 6.65 2,4,7-triamino- 40 -43.9 (*) 10.16 (** 6-phenyl-pteridi ne 80 -55.1 (*) 13.20 (**; T 2378 40 11.2 5.70-. 80 32.7 6.49 T 2453 40 - 2.0 6.52 80 + 0 9.63 T 2455 40 13.3 6.88 80 -23.5 12.93 T 2458 40 49.0+ 5.60 80 37.7 8.06 T 2464 40 9.2 8.94 80 - 1.0 10.74 T 2481 40 - 4.1 6.04 80 16.3 7.34 T 2493 40 . 35.7 7.74 80 34.7 7.88
With the maximum effective dose of 6-chloro-3,4-dihydro-7-> sulfamoyl-2H-1, 2,4,-benzothiadiazine-l,1-dioxide (10 mol/kg body wt.) in the case of pptassiun a hyper-elimination of 58.3% (*) was recorded. The Na/K ratio of the quantities eliminated was 4.86.
- 8 4 3-139
FOOTNOTES (*) Value lies outside the normal range.
(**) This extraordinarily high quotient can be explained in that the elimination of sodium remained unaffected while that of potassium was markedly reduced.
(1) In relation to the mean value of the K+ elimination of the controls.
(2) Negative prefixes indicate that there is no hyper-elimination in comparison with the sodium chloride controls.
Furthermore, the compounds in accordance with the invention differ advantageously from the hitherto known anti-kaliuretic diuretics with respect to their toxicity.
In Table 3 the mean lethal doses for mice, administered orally (LDgQ determination by the LICHTFIEL & WILCOXON method - J. Pharmacol. Exp. Ther. 96,99 (1949)) are compared.
TABLE 3. Comparison of toxicity in mice
Substance
LDgg mg/kg body Wt. oral, observation period 7 days, 95X confidence limit in brackets
3o
1523 > 3200 1856 2200 (1209 - 4004) 1857 3825 (2675 - 5470) 1882 3400 (2656 - 4352) 2111 4450 (3560 - 5563) 2129 > 3200 2152 2237 >6400 2258 >4500 2259 560 (444 - 706) 2266 >3200 2310 520 (361 - 749) 2350 > 4500
2,4,7-triamino-6phenyl-pteridine ca. 300 (1)
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Table 3 Comparison of toxicity in mice Substance N-Ami di no-3,5-di ami no- LD50 mg/kg body Wt. oral, observation period 7 days, 955! confidence limit in brackets 6-chloro-pyrazine- 70 (2) carboxamide T 2378 1600 T 2453 700 (569 - 841) T 2455 4550 T 2458 3200 T 2464 > 4550 T 2481 3775 (3341 - 4266) T 2493 3610 (2597 - 5018) (1) CLARKE, D: Identification of Drugs, p.581, London, PHarmaceutical Press, 1971. (2) ERHARD, G. and H. RUSCPIC (Hsg): Arzneimittel 2nd edn. Vol. 2, p. 351. Weinheim/Bergstr., Verlag Chemie. 1972.
2o The compounds of the present invention may be used in pharmaceutical compositions both in the free form and in the form of their salts. They may be administered orally or parenterally, in admixture with the usual pharmaceutical diluents or carriers used in human or veterinary medicine.
The carrier may be one or more inorganic or organic substance which are suitable for parenteral or oral administration and which do not react with the compounds of the invention. Examples of suitable carriers are water, vegetable oils, polyethylene glycols, gelatin, lactose, starch, magnesium stearate and talc.
For parenteral administration the compositions may be used in the 30 form of aqueous or oily solutions, suspensions, emulsions, implants or suppositories.
For oral administration tablets or dragees may also be used.
The new compounds listed below are compounds in accordance with the invention.
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1) 1-(4'Methoxy-2' me thy 1 -5' -i sopropy1 phenyl)-1-phenyl-2-pi peri di nopropan-1-ol .
2) 1-(4'-Methoxy-2'-methyl-51-tert-butyl phenyl)-1-phenyl-2-pyrroli di nopropan-1-ol .
3) 1-(21-Methoxy-3'-methyl-5'-tert-butyl phenyl)-1-phenyl-2-pi peri di nopropan-1 -ol.
4) 1-(4'-Methoxy-31,5'-di isopropyl phenyl)-l-(3,4-dimethoxyphenyl)-2piperi di no-propan-1-ol.
) 1-(21 -Methoxy-3' -methyl -51 -/3-methyl -pent-3-y1_/-1 -phenyl -210 pyrrolidino-propan-l-ol.
- 11 42439
6) 1 - (7'8‘ - Dimethylchroman - 6’ - yl) - 1 - phenyl
- 2 - piperidino - propan-l-ol.
7) 1 - (4' - Methoxy - 2',3’,5’,6' - tetramethyl phenyl)
- 1 - phenyl - 2 - piperidino-propan -l-ol.
8) 1 - (4' - Methoxy - 3',5' - di isopropyl phenyl) - 1 (4 - methoxyphenyl) - 2 - piperidino-propan-l-ol.
9) 1 - (4’ - Methoxy - 3',5' - diisopropylphenyl) - 1 (41· - ethoxyphenyl) - 2 - piperidino-propan-l-ol.
) 1 - (2‘ - Methoxy - 5‘ - tert - butylphenyl) - 1 phenyl - 2 - piperidino - propan - 1 - ol.
11) 1 -(41 - Methoxy - 3^51 - diisopropylphenyl) - 1 (4“ - methoxy - 3,5 - dimethyl phenyl) - 2 piperidino-propan -l-ol.
12) 1 - (4‘ - Ethoxy - 3* ,5' - diisopropylphenyl) - 1 (4 - methoxyphenyl) - 2 - piperidino-propan-l-ol.
13) 1 - (3‘ - Chloro - 6' - methoxy - 2' - methyl - 5' isopropy!phenyl) - 1 - phenyl - 2 - pyrrolidino-propan -l-ol.
14) 1 - (4',5' - Methylenedioxy - 2' - allylphenyl) - 1 (4“ - methoxyphenyl) - 2 - piperidino-propan-l-ol.
) 1 - (4' - Ethoxy - 3^51 - diisopropylphenyl) - 1 (4 - ethoxyphenyl) - 2 - piperidino-propan-l-ol.
16) 1 - (2' - Methoxy - 3' - methyl - 5' - tert - butylphenyl)
- 1 - {2 ,4*' - dimethoxyphenyl )-2-piperidino-propan-l-ol.
17) 1 - (2‘ - Methoxy - 3' - methyl - 5' - tert - butylphenyl)
- 1 - (2 - (or 4) hydroxy - 4 (or 2) - methoxyphenyT)
- 2 - piperidino-propan-l-ol.
18) 1 - (2‘- Methoxy - 3' - methyl - 5' - tert - butylphenyl)
- 1 - (3,4 - dimethoxyphenyl)-2-piperidino-propan-1-ol.
19) 1 - (21 - Methoxy - 5' - methylphenyl) - 1 - (4 - benzyloxy
- 3,5 - diisopropylphenyl)-2-piperidino-propan-l-ol.
) 1 - (3‘ - Chloro - 6' - methoxy - 5' - methylphenyl) - 1 - (4 methoxy - 3,5 - dimethyl phenyl) - 2 - (N - methyl - N - tertbutylamino) -propan-l-ol.
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The present invention also includes within its scope a process for the preparation of a compound of Formula (II) as hereinbefore defined which comprises a process for the preparation of an α,a -diaryl-8-(tert-amino)-propanol of the general formula:
as hereinbefore defined, which process comprises adding a compound of the general formula:
- 13 .42439 wherein R’ R, R6, R?, R®, R9 and are as hereinbefore defined, if desired, dissolved in diethyl ether, to a Grignard solution in diethyl ether, of magnesium and a compound of the general formula:
wherein r\ R2, R3, R4 and R9 are as hereinbefore defined but do not represent an alkenyl group containing 2 or 3 carbon atoms but may represent a dibromoalkyl group containing 2 or 3 carbon atoms in which the bromine atoms are on adjacent carbom atoms . and Hal is a halogen atom, optionally in the presence of 1,2 - dibromoethane, and thereafter treating the reaction mixture so obtained in order to isolate a compound of Formula II as hereinbefore defined.
The following Examples illustrate the preparation of compounds in accordance with the invention.
Example 1 ; (T 1523) g of α-piperidinopropiophenone were added to a
- 14 43439
Grignard solution of 4 g of magnesium and 40 g of 4-bromothymolmethylether in 200 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured on to ice, immediately acidified with hydrochloric acid and the crystals precipitated from the mixture were filtered off by suction.
The crystals were then washed with diethyl ether and were added, while still moist, to a mixture of concentrated ammonia solution and petroleum ether.
After brief agitation, the crystals dissolved. The petroleum ether extract was separated, dried with potash and then the petroleum ether was removed by evaporation. 23.7 g of l-(4'-methoxy-2'-methyl-5,-isopropylphenyl)-l-phenyl-2piperi di no-propan-1-ol, having a melting point of 134°C to 135°C were obtained.
Example 2 (T 1856) g of a -pyrrolidinopropiophenone were added to a Grignard solution of 7.3 g of magnesium, 38.5 g of 4-bromo-5-methyl-2-tert-butylanisole and 28.2 g of 1,2-dibromoethane in 300 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The crystals which precipitated from the water-ether mixture were filtered off by suction, washed with diethyl ether and added to a mixture of concentrated ammonia solution with diethyl ether. After brief agitation the crystals dissolved. The ether extract was separated, dried with potash and the ether was removed by evaporation. The remaining viscous brown oil was dissolved in a little isopropanol. After a short time,
28.2 g of l-(4'-methoxy-2'-methyl-5’-tert-butylphenyl)-l-phenyl-2-pyrrolidinopropan-l-ol, having a melting point of 112°C to 113°C, crystallized out. This product was recrystallized from isopropanol and then had a melting point of 113°C to 114°C.
Example 3 (T 1857) g of a -piperidinopropiophenone were added to a Grignard solution of 7.3 g of magnesium, 38.5 g of 6-bromo-2-methyl-4-tert-butylanisole and 28.2 g of 1,2-dibromethane in 300 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured on to ice and acidified with hydrochloric acid. The acidic aqueous solution and the oily intermediate layer were both separated, together made alkaline with a concentrated aqueous ammonia solution, and the base which separated therefrom was dissolved in diethyl ether.
- 15 42439
After evaporation of the diethyl ether, 26.5 g of a viscous brown oil were obtained from which, upon trituration or dilution with isopropanol, 21.5 g of 1-(21-methoxy-3'-methyl-5'-tert-butyl phenyl )-1-pheny 1-2-piperi di no-propanl-ol, having a melting point of 86°C to. 87°C, crystallized out. The product was recrystallized from isopropanol and then had a melting point of 87°C to 88°C.
Example 4 (T 1882) g of l-(3‘,4‘-dimethoxyphenyl)-2-piperidino-propan-l-one were added to a grignard solution of 7.3 g of magnesium, 40.6 g of 4-bromo-2,6diisopropylanisole and 28.2 g of 1,2-dibromoethane in 300 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous solution and the oily intermediate layer were both separated, together made alkaline with a concentrated aqueous anmonia solution and the base which precipitated therefrom was dissolved in diethyl ether. After drying the diethyl ether extract over potash and evaporation of the diethyl ether, 24.7 g of a yellowishbrown oil were obtained. On dilution with isopropanol, 14.8 g of crude 1-(41-methoxy-3',51-di i sopropylphenyl)-1 -(3,4-dimethoxyphenyl)-2-pi peri di nopropan-l-ol, having a melting point of 118°C to 119°C crystallized out.
After recrystallization from isopropanol the pure compound melted at 120 to 121°C.
Example 5 (T 2111)
7.5 g a-pyrrolidinopropiophenone were added to a Grignard solution, of 3.6 g of magnesium, 21.5 gof 2-methyl-4-(3-methy1pent-3-yl)-6-bromoanisole, 14.1 g of 1,2-dibromoethane and 200 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous solution and the oily intermediate layer were both separated, together made alkaline with a concentrated aqueous ammonia solution and the base which precipitated therefrom was dissolved in diethyl ether. After drying the diethyl ether extract over potash and evaporation of the diethyl ether, 14.8 g of a brown oil were obtained. On dilution with isopropanol, 8.3 g of crude l-(2‘-methOxy-3'-niethyl-5,-/_3methylpent-3-yl_7phenyl)-1-phenyl-2-pyrrolidino-propan-l-ol, having a melting point of 96°C to 97°C, were obtained. After recrystallization from
- 16 43439 isopropanol the compound melted at 97°C to 98°C.
Example 6 (T 2129) g of a -piperidinopropiophenone in 20 ml of ether were added to a Grignard solution of 5.4 g of magnesium, 26.5 g of 6-bromo-7,8-dimethylchromane and 20.7 g of 1,2-dibromoethane in 80 ml diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The crystals which precipitated from the mixture were filtered by suction. The crystals were mixed, while still moist, with a concentrated aqueous ammonia solution and the mixture was extracted with diethyl ether several times. After drying the combined diethyl ether extracts over potash and evaporation of the diethyl ether, an oil was obtained which crystallized out after a short time. After reerystallization from methanol 5.2 g of pure l-(7‘,8'-dimethylchroman-6'-y1)-l-pheny1-2-piperidinopropan-l-ol, having a melting point of 125°C to 128°C were obtained.
Example 7 (T 2152)
18.0 g of a -piperidinopropiophenone were added to a Grignard solution of 7.3 g magnesium, 36.4 g of 4-bromo-2,3,5,6-tetramethylanisole,
28.2 g of 1,2-dibromoethane and 300 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The acidic aqueous solution and the oily intermediate layer were both separated, together made alkaline with a concentrated aqueous ammonia solution and the base which precipitated therefrom was dissolved in ether. After evaporation of the diethyl ether, a brown oil was obtained.
On dilution with methanol, 10.5 g of l-(4'-methoxy-2‘,3',5',6'-tetramethylphenyl)-l-phenyl-2-piperidino-propan-l-ol, having a melting point of 148°C to 150°C, were obtained. After reerystallization from isopropanol, the pure compound melted at 151 °C to 152°C.
Example 8 (T 2237) g of p-methoxy- « -piperidino-propiophenone were added to a Grignard solution of 4.8 g of magnesium, 27.1 g of 4-bromo-2,6-diisopropylanisole, 18.8 g of 1,2-dibromoethane and 200 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The aqueous acidic solution and the oily
- 17 42439 intermediate layer were both separated, together made alkaline with concentrated aqueous ammonia solution and the base which separated therefrom was dissolved in ethyl ether. After evaporation of the diethyl ether, 18.2 g of a brown oil were obtained. On dilution with methanol, 12.9 g of l-(4'-methoxy-3‘,5'5 diisopropylphenyl)-l-(4-methoxyphenyl)-2-piperidino-propan-l-ol, having a melting point of 62 to 64°C, were obtained. After recrystallization the pure compound melted at 64°C to 65°C.
Example 9 (T 2258) g of p-ethoxy- a -piperidino-propiophenone were added to a )° Grignard solution of 4.8 g of magnesium, 27.1 g of 4-bromo-2,6-diisopropylanisole, 18.8 g of 1,2-dibromoethane and 200 ml of diethyl ether. After boiling for 4 hours under reflux, the mixture was poured onto ice and acidified with hydrochloric acid. The aqueous acidic layer and the oily intermediate layer, were both separated together made alkaline with a concentrated aqueous ammonia solution and extracted with diethyl ether several times. The combined diethyl ether extracts were dried over potash, the diethyl was evaporated therefrom and the residue was diluted with isopropanol. The resultant crude crystalline l-(4l-methoxy-3',5’-diisopropylphenyl)-(4-ethoxyphenyl)-2-piperidino-propan-l-ol had a melting point of 81°C to 83°C (8.5 g) and melted at 84°C to 85°C, after recrystallization from isopropanol.
Example 10 (T 2259) g of a -piperidino-propiophenone were added to a Grignard solution of 7.3 g of magnesium, 36.4 g of 2-bromo-4-tertiary-butylanisole,
28.2 g of 1,2-dibromoethane and 300 ml of diethyl ether. After boiling for hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The crystals, so precipitated, were filtered by suction, covered with a layer of diethyl ether and mixed with a concentrated aqueous ammonia solution until the crysrals dissolved upon stirring or agitating. After evaporation of the diethyl ether, 33.3 g of a partly crystalline compound were obtained and dissolved in the necessary quantity of hot methanol. Upon cooling, 25.8 g of l-(2'-methoxy-5,-tertiary-butylphenyl)-lphenyl-2-piperi dino-propan-1-ol having a melting point of 139 to 140°C crystallized out.
- 18 42439
Example Π (Τ 2266) g of l-(4'-methoxy-3' ,5'-dimethyl)-2-piperidino-propan-l-one were added to a Grignard solution of 4.8 g of magnesium, 27.1 g of 4-bromo2,6-diisopropylanisole, 18.8 g of 1,2-dibromoethane and 200 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The precipitated crystals were filtered by suction, covered with a layer of diethyl ether and mixed with a concentrated aqueous ammonia solution until all the crystals have dissolved upon agitation. The diethyl ether extract was separated and dried over potash. After evaporation of the diethyl ether 16.0 g of a partly crystalline compound were obtained. After recrystallization from isopropanol 10.0 g of l-(4'-methoxy-3',5'-diisopropylphenyl)-l-(4-methoxy-3,5''-dimethylphenyl)-2-piperidinopropan-l-ol having a melting point of 118 to 119°C were obtained.
Example 12 (T 2310) g of p-methoxy- a -piperidino-propiophenone were added to a Grignard solution, of 6.1 g of magnesium, 35,7 g of 4-bromo-2,6-diisopropylphenetole, 23.5 g of 1,2-dibromoethane and 200 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The aqueous acid solution and the oily intermediate layer were both separated together made alkaline with a concentrated aqueous amnonia solution and .the precipitated base was dissolved in diethyl ether. After evaporation of the diethyl ether, 21.7 g of a brown oil was obtained which was dissolved in a small amount of isopropanol and then immediately acidified with aqueous 70% perchloric acid. Upon dilution,
18.9 g of l-(4,-ethoxy-3',5'-diisopropylphenyl)-l-(4-methoxyphenyl)-2piperidino-propan-l-ol perchlorate precipitated which, after recrystallization from isopropanol, melted at 147°C to 148°C.
Example 13 (T 2350) g of a -pyrrolidino-propiophenone were added to a Grignard solution of 7.3 g of magnesium, 41,5 g of 4-chloro-6-bromo-thymol methyl ether,
28.2 g of 1,2-dibromoethane and 300 ml of diethyl ether. After boiling for 6 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. The precipitated crystals were filtered by suction,
- 19 43439 covered with a layer of diethyl ether and mixed with a concentrated aqueous ammonia solution until they dissolved upon agitation. The diethyl ether extract was separated and dried with potash. After evaporation of the diethyl ether 11.- g of l-(3‘-chloro-6'-methoxy-2'-methyl-5’-isopropylphenyl)1-phenyl-2-pyrrolidino-propan-1-ol having a crude m.p. of 108 to 109°C. After recrystallization from methanol the pure compound melted at 112°C to 113°C.
Example 14 (T 2378) g of p-methoxy- a -piperidino-propiophenone were added to a Grignard solution of 12.2 g of magnesium, 80.0 g of 2-(2,,3'-dibromopropyl)4,5-methylenedioxu-bromobenzene, 18.8 g of 1,2-dibromoethane and 300 ml of diethyl ether. After boiling for 6 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid. After a certain amount of time the precipitated dark oil partially crystallized. The crystals were filtered by suction, washed with diethyl ether and subsequently decomposed with a concentrated aqueous ammonia solution. The free base was dissolved in diethyl ether and diethyl ether extract was dried over potash. After evaporation of the diethyl ether, 4.8 of l-(4‘,5'-methylene dioxy-2'-allylphenyl)-l-(4methoxyphenyl)-2-piperidino-propan-l-ol, having a crude melting point of 117 to 130°C, were obtained. After treatment with activated carbon and recrystallis- . ation from isopropanol the pure compound had a melting point of 132 to 133.5°C.
Example 15 (T 2453) g of p-ethoxy- o -piperidino-propiophenone., dissolved in 100 ml of diethyl ether, were added to a Grignard solution of 7.3 g of magnesium,
42.8 g of 4-bromo-2,6-diisopropyl phenetole and 28.2 g of 1,2-dibromoethane in 100 ml of diethyl ether. After boiling for 4 hours under reflux, the reaction mixture was poured onto ice and the mixture acidified with hydrochloric acid. The oily intermediate layer and the aqueous acidic layer were both separated, together made alkaline with a concentrated aqueous ammonia solution and the base which precipitated therefrom was dissolved in ether. After drying over potash and evaporation of the diethyl ether, a brown oil remained (23 g) which was dissolved in 20 ml of isopropanol. The solution was acidified by drop-by-drop addition of aqueous 70 percent perchloric acid during which 17.4 g of l-^'-ethoxy-S1,5'-diisopropulphenyl)-(4 . -ethoxyphenyl)- 20 42439
2-piperidino-propan-l-ol perchlorate having a melting point of 160 to 161°C (decomposition), crystallized out. After recrystallization from isopropanol the pure perchlorate melted at 161-162°C. The free base was liberated from the perchlorate with dilute caustic soda solution dissolved in diethyl ether and dried over potash. After evaporation of the diethyl ether, l-(4'-ethoxy3‘,5'-di i sopropy1 phenyl)-1-(4-ethoxyphenyl)-2-pi peri di no-propan-1-ol was obtained as a colourless viscous oil (14.0 g). By adding a calculated quantity of aqueous hydrochloric acid, the free base could be converted into the corresponding hydrochloride which was chosen as the form for administration in the pharmacological tests.
Example 16 (T 2455) g of 2,4-dimethoxy- a -piperidino-propiophenone in 100 ml of diethyl ether were added to a Girgnard solution of 7.3 g of magnesium, 38.6 g of 6-bromo-2-methyl-4-tert. butyl anisole, 28.2 g of 1,2-dibromoethane and 200 ml of diethyl ether. After boiling for 6 hours under reflux, the reaction mixture was poured onto ice and acidified with hydrochloric acid.
The diethyl ether layer was separated and discarded whilst the aqueous acidic layer was made alkaline with a concentrated aqueous ammonia solution and was extracted several times with ether. The combined ether extracts were dried over potash and then the diethyl ether was evaporated. The residual brownish oil (13.4 g) crystallized on dilution with a little isopropanol. The pure 1(2‘-methoxy-3'-methyl-5'-tertiary-butyl phenyl)-l-(2,4-dimethoxyphenyl)-2piperidino-propan-l-ol, having a metling point of 133.5 to 135°C, was obtained after two recrystallisations from about 200 ml of isopropanol in each case.
Example 17 (T 2458) g of 2 (or 4) - methoxy-4-(or 2)-hydroxy- α -piperidinopropiophenone (obtained from 2,4-dimethoxy-propiophenone, which is a by-product from the preliminary stage of the production 2,4-dimethoxy- a -piperidinopropiophenone) dissolved in 100 ml of ether were added to a Grignard solution of 7.3 g of magnesium, 38,6 g of 6-bromo-2-methyl-4-tert.-butyl anisole, 28.2 g of 1,2-dibromoethane and 150 ml diethyl ether. The reaction mixture was boiled for 4 hours under reflux, was then poured onto ice and acidified with hydrochloric acid. The mixture was vigorously agitated and then the diethyl ether was separated. The separated ether layer was then thoroughly agitated several
- 21 times with semi-concentrated hydrochloric acid. The combined aqueous, hydrochloric acid extracts were then covered with a layer of 200 ml of diethyl ether and a concentrated aqueous ammonia solution was then added dropwise thereto until the pH-value of the mixture reached 8. The diethyl ether layer was then separated, the aqueous alkaline solution was extracted several times with diethyl ether and the combined ether extracts of the anmoniacal solution were dried over sodium sulphate. After evaporation of the diethyl ether 14.5 g of a brown oil remained. On dilution with a little isopropanol the oil crystallized out. The crystals (5.2 g having a crude melting point of 146 to 148°C) were filtered by suction and recrystallized several times from isopropanol. the melting point of the pure l-(2'-methoxy3‘-methyl-5‘-tertiary-butylphenyl)-2-(2 (or 4) - methoxy - 4 (or 2) hydroxyphenyl-2-piperidi no-propan-1-ol was then 153.5 to 155°C.
Example 18 (T 2464)
7.9 g of 3,4-dimethoxy- “ -piperidinopropiophenone, dissolved in 100 ml ether, were added to a Grignard solution of 7.3 g of magnesium,
38.6 g of 2-methyl-6-bromo-4-tertiary-butyl anisole, 28.2 g of 1,2-dibromoethane and 100 ml diethyl ether. The reaction mixture was heated to boiling for 4 hours under reflux and then poured onto ice. After acidification with hydrochloric acid and after stirring, three layers were formed. The upper diethyl ether layer was separated and discarded, the lower, aqueous layer and the oily central layer together were covered with a layer of fresh diethyl ether and, subsequently, were made alkaline with a concentrated aqueous ammonia solution. The diethyl ether layer above the alkaline solution was separated, dried with potash and evaporated. 13.4 g of a light-brown oil remained, which was dissolved in 100 ml of hot methanol. Upon cooling 8.3 g of l-(2'-methoxy-3'-methyl-5,-tertiary-butylphenyl)-l-(3l,,4“-dimethoxyphenyl)2-piperidinopropan-1-ol, having a melting point of 125 to 126°C, crystallized out. The melting point of the pure compound, after treatment with activated carbon and two recrystallizations from methanol, was 127 to 128°C.
- 22 42439 example 19 (Τ 24111)
6.0 g of 4-benzyloxy-3,5-diisopropyl- u -piperidinopropiophenono in 100 ml of diethyl ether were added to a Grignard solution of 7.3 g of magnesium
.2 g of 2-bromomethyl anisole, 28.2 g of 1,2-dibromoethane and 100 ml of diethyl ether. After boiling for 4 hours under reflux, the mixture was poured onto ice and acidified with hydrochloric acid. The resultant oily intermediate layer and the aqueous phase were both separated together mixed with diethyl ether and a concentrated aqueous ammonia solution and agitated thoroughly. The diethyl ether extract so obtained was separated, dried over potash and the ether evaporated. The residual brown oil (12.1 g) was dissolved in 40 ml of isopropanol and was acidified with saturated isopropanolic picric acid.
12.2 g of the pi crate, having a crude melting point of 95 to 100°C, crystallized out. After recrystallization from isopropanol, the pure picrate melted at to 101°C. The l-(2'-methoxy-5'-methylphenyl)-1-(4-benzyloxy-3'‘,511diisopropylphenyl)-2-piperi dino-propan-1-ol was obtained as a colourless oil by decomposition of the pure picrate with ethanolamine, in accordance with the directions of I.A. Kaye et al (J. Amer. Chem. Soc. 72, 5752 (1950)). By adding a calculated amount of aqueous hydrochloric acid, the free base could be converted into the corresponding hydrochloride which was chosen as the form for administration in the pharmacological tests.
Example 20 (T 2493) g of 5-methoxy-3,5-dimethyl- a -(N-methyl-N-tertiary butylamino)propiophenone in 100 ml of ether were added to a Grignard solution of 7.3 g of magnesium, 35.3 g of 6-bromo-4-chloro-2-methylanisole, 28.2 g of 1,2-dibromoethane and 100 ml diethyl ether. The mixture was boiled for 4 hours under reflux. Subsequently, the mixture was poured onto ice and acidified with hydrochloric acid. The resultant mixture was thoroughly agitated in a separating funnel, the diethyl ether layer being separated and discarded.
The aqueous layer and the oily intermediate layer together were rendered alkaline with an aqueous concentrated ammonia solution and were then extracted with diethyl ether. This diethyl ether extract was dried over potash and the ether was evaporated. 10.1 g of a brown alkaline oil remained which was dissolved in 20 ml of methanol and was mixed with a saturated methanolic picric acid solution until the solution reacted acidicly over the crystals
- 23 5
43439 precipitated therefrom. The resultant crude l-(6'-methoxy-5'-methyl-3'chlorophenyl)-l-(4-methoxy-3,5-dimethylphenyl)-2-(N-methyl-N-tertiarybutylamino)-propan-l-ol-picrate (9.4 g) had a melting point of 179 to 180°C. The pure picrate, which melted at -85 to 186°C after two recrystallizations from methanol, was decomposed with ethanolamine in accordance with the directions of I. A. Kaye et al (J. Amer. Chem. Soc. 72, 5752 (1950)).
The resultant colourless, oily l-iS'-chloro-e'-chloro^'-methoxy-S'-methylphenyl)-l-(4-methoxy-3u,5-dfmethylphenyl)-2-(N-methyl-N-tertiary-butylamino) propan-1-ol could be converted by the addition of a calculated quantity of aqueous hydrochloric acid, into the corresponding hydrochloride which was chosen as the form for administration in the pharmacological tests.
Claims (15)
1. A compound of the general formula:- 15 wherein R’ and R are each independently a straight or branched chain alkly group having from 1 to 6 carbon atoms, or R‘ and R together with the nitrogen atom form a 5- or 6-membered ring, and R^ and R^° are each independently a hydrogen or halogen atom, a straight or branched chain alkyl group having from 1 to 6 20 carbon atoms, an alkenyl group having 2 or 3 carbon atoms, a hydroxy group, an alkoxy group having from 1 to 4 carbon atoms or a benzyloxy group, or two adjacent substituents together ford a 5- or 6-membered heterocyclic ring having - 24 42439 one or two hetero atoms and the other substituents are as defined above, provided that at least one of the rings A and B has more than one substituent group other than hydrogen attached thereto. 2. - 2 - piperidino - propan - 1 - one to a Grignard solution of magnesium, 4-bromo-2,6-diisopropyl-anisole and 1,2-dibromoethane in diethyl ether and processing the liquid phase obtained from the reaction mixture. 28. A process for the preparation of 1-(2 1 -methoxy-3'-methyl-5'[3 - methyl - pent - 3 - yl]phenyl) - 1 - phenyl - 2 - pyrrolidino-prooan -l-ol as claimed in claim 23 which comprises adding a-pyrrolidinopropidphenone to a Grignard solution of magnesium, 2 - methyl -4-(3methyl - pent -3-yl) - 6-bromoanisole, 1,2-dibromoethane and diethyl ether and processing the liquid phase obtained from the reaction mixture. - 29 42439 29. A process for the preparation of l-iZ'jS'-dimethyl-chroman-e'-yl)l-phenyl-2-piperidino-propan-I-ol as claimed in Claim 23 which comprises adding a -piperidinopropiophenone in diethyl ether to a Grignard solution of magnesium, 6-bromo-7,8-dimethyl-chromane and 1,2-dibromoethane in diethyl ether and recovering the crystals precipitated from the reaction mixture. 30. A process for the preparation of l-(4'-methoXy-2‘,3',5',6'-tetramethylphenyl)-l-phenyl-2-piperidino-propan-l-ol as claimed in Claim 23 which comprises adding 31. A process for the preparation of l-(4'-niethoxy-3',5'-diisopropy1phenyl )-1-(4 11 -methoxyphenyl)-2-pi peri dino-propan-l-ol as claimed in Claim 23 which comprises adding p-methoxy- a -piperidino-propiophenone to a Grignard solution of magnesium, 4-br0mo-2,6-diisopropylanisole, 1,2-dibromoethane and diethyl ether and processing the liquid phase obtained from the reaction mixture. 32. A process for the preparation of l-(4'-methoxy-3',5‘-diisopropy1pheny1)l-(4 , '-ethoxyphenyl)-2-piperidino-propan-l-o1 as claimed in Claim 23 which comprises adding to ji-ethoxy- a -piperidino-propiophenone to a Grignard solution of magnesium, 4-bromo-2,6-diisopropylanisole, 1,2-dibromoethane and diethyl ether and processing the liquid phase obtained from the reaction mixture. 33. A process for the preparation of l-(2‘-methoxy-5'-tert-butylphenyl)1-phenyl-2-piperidino-propan-l-ol as claimed in Claim 23 which comprises adding a -piperidino-propiophenone to a Grignard solution of magnesium, 2-bromo-4tertlbutylanisole, 1,2-dibromoethane and diethyl ether and.recover!ng the crysrals precipitated from the reaction mixture. 34. A process for the preparation of l-(4'-methoxy-3 , ,5'-diisopropylphenyl)-l-(4-methoxy-3,5''-dimethylphenyl)-2-piperidino-propan-l-ol as claimed in Claim 23 which comprises adding 1-(4'-methoxy-3',5'-dimethylphenyl)-2-piperidino-propan-l-ol to a Grignard solution of magnesium, 4-bromo-2,6-diisopropylanisole, 1,2-dibromoethane and diethyl ether and recovering the crystals precipitated from the reaction mixture. 35. A process for the preparation of 1-(4 1 -ethoxy-3',5’-diisopropylpheny1)-l-(4-methoxyphenyl)-2-piperidino-propan-l-ol as claimed in Claim 23 which comprises adding p-methoxy- a -piperidino-propiophenone to a Grignard - 30 42439 solution of magnesium, 4-bromo-2,6-diisopropyl-phenetole,l,2-dibromoethane and diethyl ether and processing the liquid phase obtained from the reaction mixture. 36. A process for the manufacture of 1-(3 1 -chioro-6‘-methoxy-2'-methyl5'-isopropylphenyl)-l-phenyl-2-pyrrolidino-propan-l-ol as claimed in Claim 23 which comprises adding a -pyrrolidino-propiophenone to a Grignard solution of magnesium, 4-chloro-6-bromo-thymol methyl ether, 1,2-dibromoethane and diethyl ether and recovering the crystals precipitated from the reaction mixture. 37. A process for the preparation of l-(4‘,5'-methylenedioxy-2 1 -allylphenyl)-l-(4-methoxyphenyl)-2-piperidino-propan-l-ol as claimed in Claim 23 which comprises adding p-methoxy- a -piperidino-propiophenone to a Grignard solution of magnesium, 2-(2 1 ,3'-dibromopropyl)-4,5-methylenedioxy-bromobenzene, - 2 - pi peridino-propan-1-ol as claimed in claim 23 which comprises adding 1 - (3'»4' - dimethoxyphenyl) - 2 - piperidino - propan - 1 - ol as claimed in claim 23 which comprises adding α-piperidinopropiophenone to a Grignard solution of magnesium, 6-bromo-2-methyl - 4 tert - butylanisole and 1,2 - di bromoethane in diethyl ether and processing the liquid phase obtained from the reaction mixture. 27. A process for the preparation of 1-(4 1 - methoxy - 2 - pyrrolidino - propan - 1 - ol as claimed in claim 23 which comprises adding a - pyrrolidino - propiophenone to a Grignard solution of magnesium, 4-bromo-5-methyl-2-tertbutylanisole and 1,2 - di bromoethane in diethyl ether and recovering the crystals precipitated from the reaction mixture. 26. A process for the preparation of 1 - (2' - methoxy - 2' - methyl - 5' - tert - butyl phenyl) - 1 - phenyl - 2‘ - methyl - 5' - isopropyl phenyl) - 1 - phenyl - 2 piperidino - propan - 1· - o1 as claimed in claim 23 which comprises adding α-piperidinopropiophenone to a Grignard solution of magnesium and 4-bromo-thymol methyl ether in 15 diethyl ether and recovering the crystals precipitated from the reaction mixture. - 28 4 2.4 39 25. A process for the preparation of 1 - (4' - methoxy
2. 1-(4’-Methoxy-2'-methyl-5’isopropylphenyl)-1-phenyl-2-pi peri di no5 propan-1-ol. 3. - 3‘,5' - diisopropyl phenyl) - 1 - (3,4 - dimethoxyphenyl) - 3' - methyl - 5' - tert - butylphenyl) - 1 - phenyl
3. 1-(4 1 -Methoxy-2’-methyl-5'-tert-butyl phenyl )-1-phenyl-2-pyrroli di nopropan-l-ol .
4. 1-(2 1 -Methoxy-3 1 -methyl-5 1 -tert-butyl phenyl )-1-phenyl-2-pi peri di nopropan-l-ol . Ιθ 5. l-(4‘-Methoxy-3',5'-diisopropylphenyl)-l-(3,4-dimethoxyphenyl)2-piperi dino-propan-l-ol.
5. Active ingredient is a compound as claimed in any one of Claims 2 to 22 or Claim 45. 48. A pharmaceutical composition as claimed in Claim 46 or Claim 47 which is in the form of a solution suspension, emulsion, implant or suppository. 49. A pharmaceutical composition as claimed in Claim 46 or Claim 47 which is in the form of a tablet or dragee. 50. A method of treating a non-human mammal to increase the elimination of sodium and chlorine via the kidneys, which method comprises administering to the animal a diuretically effective amount of a compound as claimed in any one of Claims 1 to 22 or Claim 45, or of a pharmaceutical composition as claimed 5 2 or 3 carbon atoms in which the bromine atoms are on adjacent carbon atoms and Hal is a halogen atom, optionally in the presence of 1,2-dibromoethane, and thereafter treating the reaction mixture so obtained in order to isolate a compound of Formula II as defined in claim 1,
6. 1-(2‘-Methoxy-3 1 -methyl-5'-/”3-methyl-pent-3-y]7 phenyl )-1-phenyl2-pyrrolidino-propan-l-ol.
7. 1-(7 1 ,8'-Dimethylchroman-6'-y1)-1-phenyl-2-pi peri di no-propan15 Ί-οΙ.
8. 1-(4 1 -Methoxy-2',3',5',6'-tetramethylphenyl)-1-phenyl~2-piperidinopropan-l-ol.
9. 1-(4'-Methoxy-3',5'-di i sopropylphenyl)-1-(4-methoxyphenyl)-2piperi di no'propan-1-ol. 20 Ιθ- 1 - (4' -Methoxy-3', 5' -di isopropyl phenyl)-1 *- (4-ethoxyphenyl) -2piperi di no-propan-1-ol.
10. 24. A process for the preparation of 1-(4 1 - methoxy
11. 1-(2'-Methoxy-5'-tert-butyl phenyl)-1-phenyl-2-pi peri di no-propanl-ol. - 25 42439
12. 1 - (4 1 - Methoxy - 3',5' - diisopropylphenyl) - 1 (4 -methoxy - 3,5“ - dimethylphenyl) -2 - piperidino propan -l-ol.
13. 1 - (4‘ - Ethoxy - 3,5' - diisopropylphenyl) -1 (4 - methoxyphenyl) - 2 - piperidino-propan-1-ol.
14. 1 - (3‘ - Chloro - 6' - methoxy - 2' - methyl 5' - isopropylphenyl) - 1 - phenyl-2-pyrrolidino-propan-1-ol. 15. 1 - (4‘,5 1 - Methylene dioxy - 2' - allylphenyl) - 1 - (4 - methoxyphenyl) - 2-piperidino-propan-l-ol. 16. 1 - (4‘ - Ethoxy - 3',5‘ - diisopropylphenyl) - 1 (4“ - ethoxyphenyl) - 2 - piperidino-propan-1-ol. 17. 1 - (2 1 - Methoxy - 3' - methyl - 5' - tert - butyl phenyl)
15. In any one of Claims 46 to 49.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2508203A DE2508203C2 (en) | 1975-02-26 | 1975-02-26 | Use of polysubstituted α, α-diphenyl-β- (tert-amino) propanols in saluretic therapy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE42439L IE42439L (en) | 1976-08-26 |
| IE42439B1 true IE42439B1 (en) | 1980-08-13 |
Family
ID=5939810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1613/75A IE42439B1 (en) | 1975-02-26 | 1975-07-18 | , -diaryl- -(tert-amino)-propanols, processes for their preparation and pharmaceutical compositions containing them |
Country Status (14)
| Country | Link |
|---|---|
| CS (1) | CS194723B2 (en) |
| DE (1) | DE2508203C2 (en) |
| EG (1) | EG12529A (en) |
| FI (1) | FI752082A (en) |
| HU (1) | HU171369B (en) |
| IE (1) | IE42439B1 (en) |
| LU (1) | LU72953A1 (en) |
| MX (1) | MX3548E (en) |
| NO (1) | NO142908C (en) |
| NZ (1) | NZ178112A (en) |
| PL (1) | PL101806B1 (en) |
| RO (1) | RO70352A (en) |
| SU (2) | SU618035A3 (en) |
| YU (1) | YU182575A (en) |
-
1975
- 1975-02-26 DE DE2508203A patent/DE2508203C2/en not_active Expired
- 1975-06-17 YU YU01825/75A patent/YU182575A/en unknown
- 1975-07-10 NO NO752485A patent/NO142908C/en unknown
- 1975-07-10 LU LU72953A patent/LU72953A1/xx unknown
- 1975-07-11 HU HU75TE00000831A patent/HU171369B/en unknown
- 1975-07-15 NZ NZ178112A patent/NZ178112A/en unknown
- 1975-07-18 FI FI752082A patent/FI752082A/fi not_active Application Discontinuation
- 1975-07-18 IE IE1613/75A patent/IE42439B1/en unknown
- 1975-07-21 CS CS755150A patent/CS194723B2/en unknown
- 1975-07-21 RO RO7582915A patent/RO70352A/en unknown
- 1975-07-22 SU SU752159077A patent/SU618035A3/en active
- 1975-07-28 MX MX75100032U patent/MX3548E/en unknown
- 1975-08-13 PL PL1975182711A patent/PL101806B1/en unknown
-
1976
- 1976-02-25 EG EG111/76A patent/EG12529A/en active
- 1976-05-11 SU SU762355956A patent/SU614093A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| NZ178112A (en) | 1978-04-28 |
| LU72953A1 (en) | 1976-02-04 |
| MX3548E (en) | 1981-02-19 |
| EG12529A (en) | 1979-12-31 |
| FI752082A (en) | 1976-08-27 |
| NO142908B (en) | 1980-08-04 |
| SU618035A3 (en) | 1978-07-30 |
| HU171369B (en) | 1977-12-28 |
| NO142908C (en) | 1980-11-12 |
| DE2508203A1 (en) | 1976-09-09 |
| RO70352A (en) | 1982-02-26 |
| YU182575A (en) | 1982-02-28 |
| IE42439L (en) | 1976-08-26 |
| SU614093A1 (en) | 1978-07-05 |
| PL101806B1 (en) | 1979-02-28 |
| CS194723B2 (en) | 1979-12-31 |
| DE2508203C2 (en) | 1984-03-01 |
| NO752485L (en) | 1976-08-27 |
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