IE44298B1 - Piperazine derivatives - Google Patents
Piperazine derivativesInfo
- Publication number
- IE44298B1 IE44298B1 IE230876A IE230876A IE44298B1 IE 44298 B1 IE44298 B1 IE 44298B1 IE 230876 A IE230876 A IE 230876A IE 230876 A IE230876 A IE 230876A IE 44298 B1 IE44298 B1 IE 44298B1
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- IE
- Ireland
- Prior art keywords
- acid addition
- piperazine
- quaternary ammonium
- ethyl
- ammonium salts
- Prior art date
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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
- C07D295/088—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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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
1525166 Piperazine derivatives PARCOR 21 Oct 1976 [22 Oct 1975 30 July 1976] 43748/76 Heading C2C Novel compounds I:- in which R 1 is H, halogen, CF 3 , C 1-6 alkyl or C 1-6 alkoxy, R 2 is (a) C 5-8 cycloalkyl (optionally substituted by one or more alkyl groups), or (b) phenoxyalkyl, or (c) phenylalkyl, furylalkyl or thienylalkyl optionally substituted in the ring by 1 to 3 of halogen, C 1-6 alkyl, or C 1-6 alkoxy, or (c) the group -C(R 3 R 4 )-C#CH, in which each of R 3 and R 4 is H or C 1-6 alkyl or R 3 and R 4 , together with the adjacent C atom, represent a saturated 5-7 membered carbocyclic ring, and n is 2 or 3, and acid addition and quaternary ammonium salts thereof, are prepared by reacting a compound II: in which X is halogen, with a compound R 2 OH, followed, if desired, by converting a free base into an appropriate salt. Pharmaceutical compositions having analgesic, sedative and tranquillizing activity, for oral, parenteral or rectal administration, comprise one of the above novel compounds together with a pharmaceutical carrier.
Description
This invention relates to novel derivatives of piperazine, a process for their preparation and their use In human and veterinary medicine.
According to one feature of the present invention 5 there are provided compounds of the general formula
(I) [wherein R^ represents a hydrogen or halogen atom, or an alkyl or alkoxy group containing from 1 to 6 carbon atoms or a trifluoromethyl group; represents a cycloalkyl group containing from 5 to 8 carbon atoms or a phenylalkyl, furylalkyl or thienoalkyl group optionally mono-, di- or tri-substituted by halogen atoms, alkyl or alkoxy groups containing from 1 to 6 carbon atoms, or the group -C(RjR^)-CBCH (wherein R^ and R^, which may be the same or different, each represent a hydrogen atom or an alkyl group containing from 1 to 6 carbon atoms, or R^ and R^ together with the
I carbon atom to xvhich they are attached, represent a saturated 5- to 7-membered' carbocyclic ring); and n has
- 2 44298 the value 2 or 3] and acid addition or quaternary ammonium salts thereof.
In the compounds of general formula I as hereinbefore defined R^ is preferably a chlorine atom or a trifluoromethyl group and R2 is preferably a cyclohexyl, phenethyl or CiR^R^CsCH group (wherein and R^ are as hereinbefore defined).
The compounds of general formula I as hereinbefore defined exhibit interesting physiological properties including good tolerance upon administration. In particular, tests which we have conducted indicate that the compounds according to the invention exhibit analgesic, sedative and tranquillising activities.
By virtue of the anxiolytic, sedative and myorelaxant effects of the compounds according to the invention which we have tested, these compounds may be useful in the treatment of anxiety states. Thus, the said compounds may have applications in the treatment of both adults and children in practical psychopathology, neurology, rheumatology and psychiatry avoiding the side effects usually,associated with conventional medicaments for these uses. The rapid and prolonged
- 3 analgesic effect of tested compounds according to the invention indicates that the said compounds may be administered in the treatment of pain which is spasmodic, inflammatory or post-operative in origin.
Preferred compounds according to the invention by virtue of their especially favourable activity are:1-(2-Benzyloxy-ethyl)-4-m-chlorophenyl-piperazine and the acid addition or quaternary ammonium salts thereof;
1-p-Chlorophenyl-4-(3-c yclohexyloxy-propyl)10 piperazine and the acid addition or quaternary ammonium salts thereof;
l-p-Chloropheriyl-4-(2-cyclohexyloxy-ethyl)piperazine and the acid addition or quaternary ammonium salts thereof;
l-£-Chlorophenyl-4-(2-menthyloxy-ethyl)-piperazine and the acid addition or quaternary ammonium salts thereof;
l-(2-Benzyloxyethyl-ethyl)-4-]o-chlorophenylpiperazine and the acid addition or quaternary ammonium salts thereof;
1-(2-Benzyloxy-ethyl)-4-o-methoxyphenyl-piperazine and the acid addition or quaternary ammonium salts thereof;
- 4 44298 l-(2-£-Cb. lorobenzyioxy-ethyl)-4~g-chloro~phenylpiperazine and the acid addition or quaternary ammonium salts thereof;
l-£-Chlorophenyl-4-(3-£-methoxybenzyloxy-propyl)5 piperazine and the acid addition or quaternary ammonium salts thereof;
l-m-Chlorophenyl-4-[2-(3,4,5,-trimethoxybenzyloxy)-ethyl]-piperazine and the acid addition or quaternary ammonium salts· thereof;
l-o~Chlorophenyl-4-(2-phenethyloxy-ethyl)~ piperazine and the acid addition or quaternary ammonium salts thereof;
l-m-Chlorophenyl-4-(2-phenethyloxy-ethyl)-piperazine and the acid addition or quaternary ammonium salts thereof;
l“(2-Phenethyloxy-ethyl)-4-m-trifluoromethyl~ phenyl-piperazine and the acid addition or quaternary ammonium salts thereof;
l-(2-Phenethoxy-ethyl)-4-phenyl-piperazine and the acid addition or quaternary ammonium salts thereof;
1-(2-Phenethyloxy-ethyl)-4-£-tolyl-piperazine and the acid addition or quaternary ammonium salts thereof;
I-g-ChIorophenyl-4-[2-(2-furyl-methoxy)-ethyl]- 5 piperazine and the acid addition or quaternary ammonium salts thereof;
1-m-Chlorophenyl-4-[2-(2-thienyl)-ethoxyethyl)] piperazine and the acid addition or quaternary ammonium salts thereof;
l-(2-Benzyloxy-ethyl)-4-£-methoxyphenyl-pipera2ine . . and the acid addition or quaternary ammonium salts thereof;
l-tn-Chlorophenyl-4-(2-g-fluorobenzyloxy-ethyl)10 piperazine and the acid addition or quaternary ammonium salts thereof;
l-(2-jo-Chlorobenzyloxy-ethyl)-4“m-chlorophenylpiperazine and the acid addition or quaternary ammonium salts thereof;
l-m-Chlorophenyl-4-[2~(2-phenoxy-ethyloxy-ethyl]piperazine and the acid addition or quaternary ammonium salts thereof;
1-(2-p-Fluorobenzyloxy-ethyl)-4-o-methoxy-phenylpiperazine and the acid addition or quaternary ammonium salts thereof;
l-o-Chlorophpnyl-4-[2-(1,l-dimethyl-prcp-2-ynyl) oxyethyl]-piperazine and the acid addition or quaternary
- 6 I ι
ammonium salts thereof;
l-£-Chlorophenyl-4~[2-(1,1-dimethyl-prop~2~ynyl)oxyethyl] -piperazine and the acid addition or quaternary ammonium salts thereof;
l~m-Chlorophenyl-4-[2-(1,l-dimethyI-prop-2-ynyl)oxyethyl]-piperazine and the acid addition or quaternary ammonium salts thereof;
l-p-Chloromethyl-4-[3-(1,l-dimethyl~prop~2-ynyl)oxypropylj-piperazine and the acid addition or quaternary ammonium salts thereof;
l-[2-(1,l-dimethyl-prop-2-ynyl)oxy-ethyl]-4m-trifluoromethylphenyl-piperazine and the acid addition or quaternary ammonium salts thereof;
l-Phenyl-4-[2-(prop-2-ynyl)oxy-ethyl]-pipera2ine and the acid additinn or quaternary ammonium salts thereof;
1Chlorophenyl-4-[2-(l-e thyl-1-me thyl-prop-2-ynyl)oxy-ethyl]-piperazine and the acid addition or quaternary ammonium salts thereof;
l-£-Chlorophenyl-4-[3-(l,l-pentamethylene-prop-2ynyl)oxy-propyl]-piperazine and the acid addition or quaternary ammonium salt thereof;
- 7 1-Phenyl-4~L 2-(1-ethyl-prop-2-ynyl)oxy-ethyl]piperazine and the acid addition or quaternary ammonium salts thereof.
According to a further feature of the present 5 invention there is provided a process for the preparation of the compound of general formula I as[hereinbefore defined}which comprises reacting a .compound of formula xX'O~2,-'v (II>
h (wherein R^ is as hereinbefore defined and X represents a halogen atom) with an alcohol of formula
K2-0H (III) (wherein R2 is as hereinbefore defined).
This reaction is preferably effected in the presence of a concentrated aqueous solution of hydroxide, conveniently an aqueous solution of an alkali metal
I hydroxide, and advantageously a 10 to 60% sodium 3_5 hydroxide solution, preferably in a quantity of 50% by weight.
A process for preparing the starting compounds of formula II is described in Douglas C. KRIESEL and
- 8 44298
Ole GISVOLD, J. Pharm, Sci. 1957, 56 (3), 327 and Jacques BOURDAIS, Bull, Soc. Chim. Fr., 1968, (8), 3246.
This preparation process uses an original reaction in a heterogeneous medium with a phase transfer catalyst, 5 Catalysis is effected by means of quaternary ammonium salts A and B which are obtained by dimerisation and intramolecular cyclisation, respectively, of haloalkylpiperazines of formula (II),
These compounds A and B correspond 10 following formulae:
to the
-a
The two reagents (II) and (III) may be used in stoichiometric quantities but preferably an excess of the ί
- 9 I ί
E f
ί i ι
442S8 alcohol (III) is used.
The temperature of the reaction medium is preferably maintained at between 50° and 100°C,
The following non-restrictive examples are provided in order to show the preparation of the compounds according to the invention.
Example 1
Preparation of l-(2-benzyloxy-ethyl)-4-m-chlorophenylpiperazine hydrochloride[(derivative no. l)
PO A mixture of 10 g of sodium hydroxide pellets, g of water, 7 g of l-(2-chlorcethyl)-4-m-chlorophenylpiperazine and 5. 85 g of benzyl alcohol is heated to 100°C for 2 hours. The mixture is then diluted with water and extracted with ether. The ethereal extracts are washed with water, then 2N hydrochloric acid is added. The hydrochloride formed, which is Insoluble in both phases, is filtered, dried and recrystallised from an ethyl acetate/ethanol mixture. 6.4 g of white crystals are collected (yield 65%), m.p, 164°C, determined by the Kofler block.
Example 2
Preparation of l-p-c.hloropheny]-4-(3-cyclohexyloxypropyl)-piperazine dlhydrochloride,(derivative no, 2)
A mixture of 10 g of sodium hydroxide pellets,
g of water, 9 g of l-p-chlorophenyl-4-(3-chloropropyl)piperazine and 12 g of eyclohexanol is heated to 100°C for 6 hours. The mixture is diluted, acidifed and extracted with ether. The aqueous phase is made basic again and extracted with ether. The ethereal extracts are dried over sodium sulphate, then concentrated. A product is obtained in the form of an oil, which is converted into the hydrochloride. After recrystallisation from a mixture of ethyl acetate And ethanol, 4.δ g of white crystals are collected (yield 35%), tn.p. 188°C, determined by the Kofler block,
The following derivatives were obtained using the same method:
derivative 3: l-p-chlorophenyl-4-(2-cyclohexyl-oxyethyl)-piperazine, dihydrochloride,
Yield 32%;
t r white crystals, m.p, 190°C (dec.)
- il 1
4429 8
derivative 4: l-p-chlorophenyl-3- ( 2-menthyloxy-· ethyl)piperaz ine, dihydrochlor ide, yield 12%; white crystals, m.p. 172°C. 5 derivative 5: l-(2-benzyloxyethyl-ethyl)~4-p - chlorophenyl-piperazine white crystals, m.p, 110°C; yield 66%. derivative 6: l-(2-benzyloxy~ethyl)-4-o-methoxy-phenyl- 10 piperazine, dihydrochloride; yield 22%, white crystals, m.p. 142°C; derivative 7: 1-(2-p-chiorob enzyloxy-ethyl)-4-p- chlorophenyl-piperazine, dihydrochloride; yield 76%; white crystals, m.p. 172°C. derivative 8: l-p-chlorophenyl-4-(3-p-methoxy-benzyloxy- 15 propyl)piperazine; yield 10%; white crystals, m.p, 60°C. /
ί
I
29 8
derivative 9: l-m-chlorophenyl-4-[(3,4.5-trimethoxy)-2- benzyloxy-ethyl]-piperazine, dihydrochloride; yield 32%; white crystals, m.p, 144°C. derivative 10: l-orchlorophenyl-4-(2-phenethyloxy-ethyl)- 5 piperazine, dihydrochloride; yield 48%; white crystals, m.p. 112°C. derivative 11: l-rn~chlorophenyl-4-(2-phenylethyloxy~ ethyl)-piperazine, hydrochloride; yield 13%; white crystals, m.p. 124°C. in derivative 12: 1-(2-phenethyloxy-ethyl)-4-m~tri- fluoromethylphenyl-piperazine, hydrochloride; yield 38%; white crystals; m.p. 128°C. derivative 13: l-(2-phenethoxy-ethyl)-4-phenyl-piperazine, 15 dihydrochloride; yield 30%; white crystals,
m.p, -146°C.
- 13 4429
derivative 14: l-(2-phenethyloxy-ethyl)-4-p-tolyl- piperazine, dihydrochloride; yield 13%; white crystals, m.p, 156°C-160°C. derivative 15: l-p~chlorophenyl-4-[2-(2-furyl-methoxy)- 5 ethyl]-piperazine, dihydrochloride; yield 53%; cream-coloured crystals, m.p. =- 134°C. derivative 16: l-ni-chlorophenyl-4- [ 2- (2-thienyl) - ethoxyethyl]-piperazine, hydrochloride; 10 yield 28%; white crystals, m.p, 118°C. derivative 17: 1-(2-benzyloxy-0thyl)-4-p-methoxy-phenyl piperazine, dihydrochloride; white crystals, m.p. 164°C; yield 13%. derivative 18: 1-m.chlorophenyl-4-(2-p-fluoro-benzyloxy 15 ί ethyl)-piperazine, hydrochloride; pale yellow crystals, m.p, 182°C; yield 31%. / ·· 14 -
I derivative 19: 1-(2-p-chlorobenzyloxy-ethyl)-4-mrchlorophenyl-piperazine, hydrochloride; white crystals, m.p. 182°C; yield 68%.
derivative 20: 1-rn-chioropheny1-4 - [ 2 - (2-phenoxy5 ethyloxy)-ethyl]-piperazine, hydrochloride white crystals, m.p. 100°C; yield 30% derivative 21: 1-(2-p-fluorobenzyloxy-ethyl)-4-o-methoxyphenyl-piperazine, dihydrochloride white crystals m.p. 156-158°C; yield
46%.
Example 22 l-orchlorophenyl-4-[2-(1,l-dimethyl-prop,-2-ynyl)oxy-ethyl]piperazine
A vigourously stirred mixture of 100 g of sodium hydroxide pellets, 100 cc of water, 25 g (0,085 mol) of 1-(2-chloro-ethyl)-4-o-chlorophenyl-piperazine hydrochloride and 21,75 g (0,255 mol) of 2-methyl-3- 15 I but-2-ynol is reflux for 6 hours.
After cooling, it is diluted with water and extracted with ether, 6N hydrochloric acid is added to the organic extracts and they are then decanted.
The aqueous phase is made basic with soda and extracted with methylene chloride. The chloroethylenic extracts are washed with water, dried over sodium sulphate, filtered over a layer of silica and evaporated to dryness. The residual oil is converted into the hydrochloride: m.p. = 158°C (14.4 g; 49%).
The following were prepared by the same experimental method:
derivative 23 : l-p-chlorophenyl-4-[2-(l,1-dimethylpr op, - 2-yny 1) oxy- ethyl ] pip eraz ine;
base: white crystals; m.p, 85°C (isopropanol; yield 18%) derivative 24 : l-m'-chJ.orophenyl-2-[l, l-dimethyl-prop-2ynyl)oxy-ethyl]piperazine;
hydrochloride, hemihydrate: white crystals; m.p, 176°C (ethanol/water); yield 2S%
- 16 44298 derivative 25 : l-p-chloromethyl-3-[(i,1-dimethylprop-2-ynyl)oxy-propy1]-p iperazine;
dihydrochloride, hemihydrate; white crystals;
m.p, 168°C (ethanol/isopropanol);
yield 50% derivative 26 : 1~[2-(1,l-dimethyl-prop-2-ynyl)-oxyethyl]-4-mrtrifluoromethylphenylpiperazine;
hydrochloride, hydrate: white crystals;
m.p, 172°C (isopropanol) yield 38%.
derivative 27 : l-phenyl-4-[2-prop-2-ynyl)oxy-ethyl] piperazine;
base: m.p. 103°C (white crystals) derivative 28: l-prchlorophenyl-4-[2-(1-ethyl-lmethyl-prop -2-ynyl)oxy-ethyl]-piperazine;
hydrochloride, hydrate: m.p, 172°C, white crystals derivative 29 : l-prchlorophenyl-4-[3-(1,1-penta20 methylene-prop-2-ynyl )oxy-propyl] /
piperazine; '
- 17 4 4398 hydrochloride, hemihydrate: m.p. 165°C. , white crystals derivative 30 : l-phenyl-4-[2-(L-ethyl-pro-2-ynyl)oxyethyl]piperazine;
hydrochloride, hydrate: m.p. 183°C, white crystals
The results of the toxicological and pharmacological tests reported hereinafter show the good tolerance and interesting activities of the compounds, notably their analgesic, sedative and tranquillising activities.
Therefore, according to a further feature of the invention there are provided pharmaceutical compositions comprising as active ingredient, a compound of formula (I) or a pharmaceutically acceptable acid addition salt or ί
quaternary ammonium salt thereof in association with a pharmaceutical carrier or excipient,
TOXICOLOGICAL STUDY
The acute toxicity was determined, in the mouse, after administering by intravenous route a single dose of the products being tested, according to the method of
Miller and Tainter. .
/
As a guide, the LD3q/24 hrs/kg of body
- 18 weight is 45 mg for derivative no. 2, 51 mg for derivative no, 3, 45 mg for derivative no. 5, 38 mg for derivative no. 6, 31 mg for derivative no, 10, 70 mg for derivative no, 15, 108 mg for derivative no. 16, mg for derivative no 22, 47 mg for derivative no, 23 36 mg for derivative no, 25, 40 mg for derivative no, 26, 33 mg for derivative no, 28, 52 mg for derivative no, 29 and 29 mg for derivative 30,
The compounds of the invention did not cause any local or general reactions or any disturbances in the biological checks and macroscopic or microscopic examinations carried out on the test animals which were killed and on which autopses were performed, during the studies of the acute, chronic or retarded toxicity,
PHARMACOLOGICAL STUDY
1, Tranquillising and sedative effect
The tranquillising action of the compounds of the invention was studied by various methods, a) Behavioural study
This study was made using the method of SAMUEL IRWIN (Ph.D, Animal.· and clinical Pharmacology Technics in drug evaluation). The compounds of the invention
4429 8 are administered to mice by oral route in doses of 50 mg/kg. A study of the behaviour of the treated animals over the ensuing 4 hours and measurement of the different physiological parameters, temperature, cardiac and respiratory rate, demonstrate the sedative effect of the compounds ·of the invention, b) Action with regard to hypnotics
The products to be tested are administered to mice by oral route in a dosage of 50 mg/kg thirty minutes before the intraperitoneal injection of a solution of 300 mg of chloral in 20 ml of physiological serum, The number of mice which fall asleep, the time taken to fall asleep and the length of the sleep, compared with the control mice which are given only the injection of chloral. It is found that the compounds of the invention considerably potentialise the effect of chloral, particularly with regard to the length of sleep induced and the ’Wmbei» of mice which fall asleep. ,
c) Traction test
This test consists in suspending mice, which have been given 50 mg of the test derivative by oral
- 20 I route, from a wire by their front paws. The mice are considered to be tranquillised when, in thirty seconds, they do not manag« to raise themselves to the extent of placing at least one of their hind paws on the wire.
The animals are tested before the test and those which do net manage to raise themselves in a period of thirty seconds are eliminated. The tests show that 98% of the animals are tranquillised. d) 4 plate test (Boissier, Simon & Aron, Europ. J.
of Pharmacol, 4, 1968, 145-151)
The mouse placed in an enclosure containing 4 electrified plates is given an electric shock causing it to run away wildly each time it moves from one plate to
I another. After n electic shocks, the mouse does not move. It is considered that the degree of tranquillisation obtained is proportional to the number n of electric shocks which the treated mouse has received before it stays motionless in a corner.
Thus, it is found that, in a dosage of 50 mg/kg by oral route, the tested compoundsof the invention produce an average percentage increase in the number of electric shocks n of the order of 63% after 15 minutes, 66% after
- 21 44288 · minutes and 50% after 90 minutes.
The following table gives the results obtained with certain derivatives.
derivative percentage increase in number of shocks after 15 mins. after 30 mins. after 90 mins. 22 60 69 61 ' 23 55 67 52 24 62 65 54 25 51 63 53 : 26 64 65 58 27 62 67 55 28 ‘58 64 57 29 61 66 55 30 59 64 60 1
2. Analgesic activity
This activity was demonstrated using the test method of Koster, Anderson and de Beer (Fed. Proceed;
18, 1959, 412 1, 626), The intra-peritoneal injection of a dilute solution of acetic acid in mice causes / 2n characteristic repeated stretching movements under the
- 22 44398 effect of the pain. Administration of fche derivative of the invention by oral route thirty minutes before the injection of acetic acid leads to a reduction in the number of these movements in the following thirty minutes. In this way, the average number of stretching movements and the percentage analgesia obtained corresponding to the percentage reduction in the number of stretching movements compared with the controls.
The results are given in the following Table:
derivatives dosage administered percentage analgesia 2 100 mg/Kg 55 5 100 mg/Kg 71 9 100 mg/Kg 64 15 100 mg/Kg 48 15 16 100 mg/Kg 77 22 60 mg/Kg 74 23 60 mg/Kg 66 24 60 mg/Kg 68 25 60 mg/Kg 63 20 26 60 mg/Kg 57 27 /60 mg/Kg 70 28 60 mg/Kg 65 29 60 mg/Kg 62 30 60 mg/Kg /0 j
- 23 The results of this study show that all the tested compounds of the invention have sedative and tranquillising activities and that some of them also have analgesic effects. The preferred compounds are those of examples 2, 10, 13, 16, 22, 23 and 26,
The medicament of the invention may be presented for oral administration in the form of tablets, coated tablets, capsules, syrups and drops. For rectal administration it may also take the form of suppositories and for parenteral administration an injectable solution.
Each single dose of 25 to 2000 mg may advantageously contain from 10 to 250 mg of a derivative of formula (I), while the doses to be administered in 24 hours may vary from 10 to 750 mg, depending on the age of the patient and the gravity of the complaint being treated.
The following are non-restrictive pharmaceutical formulations of the medicament of the invention.
Example I : TABLETS derivative 4 or 22 0,100 g corn starch / 0.015 g lactose , 0,020 g
- 24 44288
talc 0,005 g magnesium stearate 0.005 g Example II : COATED TABLETS CORE derivative no, 7 0,075 g lactose 0,010 g maize starch 0. 005 g magnesium stearate 0.005 g COATING ethyl acetate 0.010 g patented blue trace white wax 0,005 g gum arabic 0,005 g yellow tartrazine trace levilite 0,010 g talc 0.005 g
sugar q.s. for 1 coated tablet
Example III : CAPSULES
derivative no, 12 or 26 0,125 g magnesium stearate 0,005 g talc , 0,003 g Example IV : DROPS derivative no, 12 o'r 27 3.00 g
flavoured excipient q.s, ad 60 ml
- 25 I
4420®
Example V : SUPPOSITORIES derivative no. 14 or 28 0.100 g semi-synthetic glycerides q.s, for 1 suppository Example VI : INJECTABLE AMPOULES derivative no, 16 or 30 0.100 g isotonic solvent q.s, ad 5 ml
Claims (4)
1. What we claim is:1, Compounds of the general formula / \
Ν N—(CH„) -0-R„ (I) v_y 2 ” 2 [wherein R^ represents a hydrogen or halogen atom,or
5 an alkyl or alkoxy group containing from 1 to 6 carbon atoms or a trifluoromethyl group; Rg represents a cycloalkyl group containing from 5 to 8 carbon atoms or a phenylalkyl, furylalkyl or thienoalkyl group optionally mono-, di- or tri-substituted hy halogen
10 atoms, alkyl or alkoxy groups containing from 1 to 6 carbon atoms, or the group -CiRgR^j-C^CH (wherein Rg and R^, which may be the same or .different, each represent a hydrogen atom or an alkyl group containing from 1 to 6 carbon atoms, or Rg and R^·together with the
15 carbon atom to which they are attached, represent a saturated 5- to 7-membered carbocyclic ring); and n has the value 2 or 3j and acid addition or quaternary f ammonium salts thereof.
27 (I)
2.
Compounds of the general formula
N-(CH 2 ) n -0-R 2
R.
(wherein R^ represents a hydrogen or halogen atom, or an alkyl or alkoxy group'containing up to 6 carbon atoms g or trifluoromethyl group;· R 2 represents a cycloalkyl group containing from 5 to 8 carbon atoms, or & phenylalkyl, furylalkyl or thienylalkyl group optionally mono-, di- or tri-substituted by halogen atoms, or alkyl or alkoxy groups containing up to 6 carbon atoms;
10 and n is 2 or 3) and acid addition or quaternary ammonium salts thereof.
3. Compounds of general formula I as claimed in either of claims 1 and 2, wherein R^ is a .chlorine atom or a trifluoromethyl group.
15 4. Compounds of general formula I as claimed in either of claims 2 or 3 wherein R 2 represents a cyclohexyl or phene,thyl group.
- 28 i
4. 4 298
5. Compounds of general formula I as claimed in either of claims 1 and 3, wherein Rg represents a C(R^R^)CsCH group (wherein Rg and are as defined in claim l).
6. 1-(2-Benzyloxy-ethyl)-4-m-chlorophenyl~pipexazine and the acid addition or quaternary’ammonium salts thereof.
7. , l-£-Chlorophenyl-4-(3-cyclohexyloxy-propyl)~ piperazine and the acid addition or quaternary ammonium salts thereof.
10
8. l-£-Chlorophenyl-4-(2-cyclohexyloxy-ethyl)piperazine and the acid addition or quaternary ammonium salts thereof.
9. , l-g-Chlorophenyl-4-(2-menthyloxy-ethyl)-piperazine and the acid addition or quaternary ammonium salts
15 thereof,
10. , l-(2-Benzyloxyethyl.-ethyl)-4-£-chlorophenylpiperazine and the acid addition or quaternary ammonium salts thereof.
11. , 1-(2-Benzyloxy-ethyl)-4-o-methoxyphenyl-piperazine 20 and the acid addition or quaternary ammonium salts thereof.
29
12. l-(2-£-Chlorobenzyloxy-ethyl)-4-£-chloro-phenylpiperazine and the acid addition or quaternary ammonium salts thereof.
13. l-jo-Chlorophenyl-4-(3-£-methoxybenzyloxy-propy1)piperazine and the acid addition or quaternary ammonium salts thereof,
14. l-m-Chlorophenyl-4-[2-(3,4,5,-trimethoxybenzyloxy)-ethyl]-piperazine and the acid addition or quaternary ammonium salts thereof,
15. l-_o-Chlorophenyl-4-(2-phenethyloxy-ethyl)piperazine and the acid addition or quaternary ammonium salts thereof.
16. l-m-Chlorophenyl-4-(2-phenethyloxy-ethyl)-piperazine and the acid addition or quaternary ammonium salts thereof. yi. l-(2-Phenefchyloxy-ethyl)-4-m-tri£luoromethyl“ phenyl-piperazine and the acid addition or quaternary ammonium salts thereof.
17. 18, l-(2-Phenethoxy-ethyl)-4-phenyl-piperazine and the acid addition or quaternary ammonium salts thereof,
18. 19. l-(2-Phenethyloxy-ethyl)-4-p-tolyl-piperazine and the acid addition or quaternary ammonium salts thereof. Z l-g-Chlorophenyl-4-[2-(2-furyl-methoxy)-ethyl]20.
- 30 I
I piperazine and the acid addition or quaternary ammonium salts thereof.
21, l-m-Chlorophenyl-4-[2-(2-thienyl)- ethoxyethyl)] piperazine and the acid addition or quaternary ammonium
5 salts thereof.
22, 1-(2-BenzyIoxy-ethyl)-4-£-methoxyphenyl-piperazine and the acid addition or quaternary ammonium salts thereof
23, l-m-Chlorophenylr4-(2-p-fluorobenzyloxy-ethyl)piperazine and the acid addition or quaternary ammonium salts thereof,
24, 1-(2-£-Chiorob ?nzyloxy-ethy1)-4-m-chlorophenylpiperazine and the acid addition or quaternary ammonium salts thereof,
15 25. l-m-Chlorophenyl“4-[2-(2-phenoxy-ethyloxy-ethyl]piperazine and the acid addition or quaternary ammonium salts thereof.
26, 1-(2-p-Fluorobenzyloxy-ethyl)-4-o-methoxy-phenylpiperazine and the acid additjnn or quaternary ammonium
19. 20 salts thereof,
27. l-o-Chlorophenyl-4-[2-(1,l-dimethyl-prop-2-ynyl)-oxy·
I ethyl]-piperazine and the acid addition or quaternary
- 31 4439 ammonium salts thereof:
28. l-£-Chlorophenyl-4-[2-(1,l-dimethyl-prop-2-ynyl)oxyethyl] -piperazine and the acid addition or quaternary ammonium salts thereof.
5 29. .l-m-’Chlorophenyl-4-[2-(1,l-dimethyl-prop-2-ynyl)oxyethyl] -piperazine and the acid addition or quaternary ammonium salts thereof.
30. l-£-Chloromethyl-4-[3-(l,l-dimethyl-prop-2-ynyl)oxypropyl] -piperazine and the acid addition or quaternary
10 ammonium salts thereof.
31 l-[2-(l,l-dimethyl-prop-2-ynyl)oxy-ethyl]-4m-trifluoromethylphenyl-piperazine and the acid addition or quaternary ammonium salts thereof,
32. l-Phenyl-4~[2-(prop-2-ynyl)oxy-ethyl]-piperazine
15 and the acid additinn pr quaternary ammonium salts thereof,
33. l-£-Chlorophenyl-4-[2-(l-ethyl-l-methyl-prop-2-ynyl) oxy-ethyl]-piperazine and the acid addition or quaternary ammonium salts thereof, •20 34, l-£-Chlorophenyl-4“[3-(l,l-pentamethylene-prop-2ynyl)oxy-propyl]-piperazine and the acid addition or quaternary ammonium salt thereof;
i ί - 32 i
35, 1-Phenyl -4-(. 2-( 1-ethyl-prop-2-ynyl) oxy- ethyl] piperazine and the salts thereof.
36, A process for the preparation of compounds of general formula I as claimed in claim 1, which
5 comprises reacting a compound of formula
(Π) (wherein X represents a halogen atom and R^ is as defined in claim 1) with a compound of formula I^-OH (wherein is as defined in claim 1),
10 37, A process as claimed in claim 36 wherein the <
reaction is effected using a compound of formula II wherein X represents a chlorine atom,
38. A process as claimed in claim 36 wherein the reaction is effected using a compound of formula II
15 wherein R, represents a cycloalkyi group containing from 5 to 8 carbon atoms,
39, A process as claimed in claim 36 wherein the reaction is effected in an aqueous hydroxide solution.
- 33 1
4Φ2 9 8
40, A process as claimed in claim 39 wherein the hydroxide comprises an alkali metal hydroxide.
41, .. A process as claimed in any of claims 3S to 40 wherein the reaction is effected in the presence of a g stoichiomatric excess of the compound of formula III,
42, A process as claimed in any of claims 36 to 41 wherein the reaction is effected at a temperature between
50 and 100°C.
43., A process as claimed in any of claims 36 to ,42 10 which comprises converting the compound of formula I as defined in claim 1 produced into ah acid addition or quaternary ammonium salt thereof.
44, A process for the preparation of compounds of general formula I as defined in claim 1 substantially
15 as herein described,
45, A process for the preparation of compounds of general formula I as defined in claim 1 substantially as herein described in any of Examples 1 to 3 ,
45 Compounds of general formula I as defined * s 1 in claim 1 whenever prepared by a process as claimed in any of claims 36 to 45.
I
4 4 298
47. Pharmaceutical compositions comprising as active ingredient a compound of formula I as defined in claim 1 or an acid addition or quaternary ammonium salt thereof, in association with a pharmaceutical carrier or excipient.
48. Compositions as claimed in claim 47 m a form suitable for oral, rectal or parenteral administration, .49, Compositions as^claimed in claim 48 in the form of tablets, capsules, coated tablets, syrups; drops, suppositories and solutions,
50, Compositions as claimed in any of claims 47 to 49 in dosage unit form.
51, Compositions as claimed in claim 50 wherein each dosage unit comprises 25 to 2000 mg of the said active ingredient,
52, Compositions as claimed in claim 50 wherein each dosage unit comprises 10 to 250 mg of the said active ingredient,
53, Pharmaceutical compositions as claimed in any of claims 47 to 52 substantially as herein described.
54, Pharmaceutical compositions as claimed in any of claims 4?> to 52 substantially as herein described in any of Examples I to VI.
55. Compounds of general formula 1 as herein specifically disclosed with the exception of those claimed in claim 6 to 35,
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7532273A FR2328469A1 (en) | 1975-10-22 | 1975-10-22 | Phenyl-piperazine sedatives, muscle relaxants and tranquillisers - some having analgesic activity |
| FR7623364A FR2359611A2 (en) | 1976-07-30 | 1976-07-30 | Phenyl-piperazine sedatives, muscle relaxants and tranquillisers - some having analgesic activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE44298L IE44298L (en) | 1977-04-22 |
| IE44298B1 true IE44298B1 (en) | 1981-10-07 |
Family
ID=26219113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE230876A IE44298B1 (en) | 1975-10-22 | 1976-10-20 | Piperazine derivatives |
Country Status (7)
| Country | Link |
|---|---|
| DE (1) | DE2647918A1 (en) |
| DK (1) | DK145043C (en) |
| ES (1) | ES452491A1 (en) |
| GB (1) | GB1525166A (en) |
| IE (1) | IE44298B1 (en) |
| LU (1) | LU76038A1 (en) |
| NL (1) | NL7611568A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10161644A1 (en) * | 2001-12-14 | 2003-06-26 | Gruenenthal Gmbh | New N,N'-disubstituted piperazine derivatives are noradrenaline reuptake inhibitors, useful e.g. for the treatment of arrhythmia, emesis, diarrhea, inflammation or especially depression or pain |
-
1976
- 1976-10-18 ES ES452491A patent/ES452491A1/en not_active Expired
- 1976-10-20 IE IE230876A patent/IE44298B1/en unknown
- 1976-10-20 NL NL7611568A patent/NL7611568A/en not_active Application Discontinuation
- 1976-10-20 LU LU76038A patent/LU76038A1/xx unknown
- 1976-10-20 DK DK472376A patent/DK145043C/en active
- 1976-10-21 GB GB4374876A patent/GB1525166A/en not_active Expired
- 1976-10-22 DE DE19762647918 patent/DE2647918A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| GB1525166A (en) | 1978-09-20 |
| NL7611568A (en) | 1977-04-26 |
| DK472376A (en) | 1977-04-23 |
| DK145043C (en) | 1983-01-17 |
| DE2647918A1 (en) | 1977-04-28 |
| DK145043B (en) | 1982-08-09 |
| IE44298L (en) | 1977-04-22 |
| LU76038A1 (en) | 1977-05-16 |
| ES452491A1 (en) | 1977-12-16 |
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