IE43222B1 - Piperazine derivatives - Google Patents

Abstract

1490507 Piperazine derivatives PARCOR 6 April 1976 [7 April 1975] 13923/76 Heading C2C Novel compounds of formula where R 1 is halogen, alkyl, alkoxy or trifluoromethyl, and either R 2 and R 3 together complete a 4- to 8-membered saturated heterocyclic ring which may contain an oxygen or nitrogen atom as a second hetero atom, or R 2 is H and R 3 is cycloalkyl, and salts thereof, are prepared by reacting with B, wherein A is H and B is Hal(CH 2 ) 3 NR 2 R 3 or A is -(CH 2 ) 3 Hal and B is HNR 2 R 3 , or by condensing a cycloalkanone with an appropriate amine and reducing the resulting imine. Pharmaceutical compositions comprising the above novel compounds have hypocholesterolaemic, anti-inflammatory and analgesic activity.

Description

Tl:· pre· .enI invenlίοη reliit.es Lo now piperazino lerivatives, processes for the preparation thereof and pharmaceutical compositions containing the same.

The invention provides piperazine derivatives of the formula: 'N - (CH2)3 - N Rn z. *3 wherein is a halogen atom or an alkyl, trif ludrornFtliyi group, and either R^ and alkoxy or together Ipwith the nitrogen, atom to which, they are attached form a If- to 8-roeinbercd saturated heterocyclic ring which may contain an oxygen or nitrogen atom as a second hoteroatom, or R2 is a hydrogen atom and R^ is a cycloalkyl group; and the salts thereof.

In general, the alkyl and cycloalkyl groups presouL in these compounds arc lower groups containing rip l.o J2 carbon atom;. The alkyl radicals preferably lave'up to 6 carbon ί toms and the cycloalkyl radicals Erom 5 to S carbon aljms.

Preferably, ihe saturated heterocyclic group is pyrrdTirfin -l-yl8 piperidino, morpholino or azetidinrl-yl The salts of the compounds of the invention include thv pharmaceutically acceptable addition salts with Inorg.-.nic or organic acids and the quaternary ammonium salts.

The compound;; of the invention may be prepared by condensing a phonylpiperazine of formula: Ri with a reagent B, wherein; A is hydrogen when B is X - (Ci^)^ A is -(CH ) - X when B is H - Nf z 3 1 Rn or X being a halogen atom; or, only when R^ is hydrogen, A is - (Cl^^Nl^ when B is R = 0, R^ being the divalent group derived from by removing a hydrogen from the first carbon atom; the condensation being followed in the latter case by reduction cf the imine initially obtained.

Thus, the three methods used in the process ac ording Ic the invention are: 1, Condensation of 4-aryl-pipc-razines and 3-halogeno-propylatnines, e.g. according to the following equation: 232 h this reaction, an organic solvent such as dimethylformamide butanol can advantageously be used. It is desirable to work the presence of an acid binding agent'for hydrochloric acid formed ing the reaction, such as for example potassium carbonate.

As catalyst, small quantities of potassium iodide be used.

Condensing an amine and a 3~(4-arylpiperazini1-y'I)-’l>ro-propant e.g. according to the following equation: rcacLion conditions a e the same, as in the previous od.

Condensing a 3-(4-arylpiperazin-l-yi) propyl amine . an aldehyde or ketone, then reducing the imine obtained eans of a reducing agent such as sodium borohydride, e.g. rding to the following equation: V )--- Ν Ν -CH,-CH9-CH9-NH9 + 0=R, -—) ' ' 2 2 2 ' // \\ Na ΒΗ Γ~\ \ // \\--ν jsj -CH2Cii2-C‘I2“NH-R3R1 This method can only be used for the derivatives wherein the 5 group R / 2 -N 'x is The processes for preparing 4-aryl-piperazines, 3-(4-aryl-piperaz,ino)~l-chloro-propancsand 3-(4-aryl-piperazino) -propylamines respectively, can be found in the following publications: P.C, Jain et al., J, Med. Chem 1967, 10,812; C.B. Pollard, W.M. Lautcr and N.O Nessle, J. Org. Chem, 1.959, 26,764; S, Ha>ao (Miles Lab.), U.S. Patent. No. 3,005,821.

The salts and quaternary ammonium derivatives are 15 pr. pared by well known ci nventional methods.

The following, examples illustrate the preparation of the compounds according to the invention. 22 Example 1 Preparation of l-(3-cyclohexylami.no-propyl)-4p-tolyl-pipcrazine ;y Lhe 3rd method.

A solution containing 11.6 g of l-(3-amino-pr^pyl)i-p-tolyl-piperazine, 5 g or cyclohexanone and 50 mg of j-toluenesulphonic acid in 100 mi of benzene is refluxed 'or 4 hours in an apparatus which enables the water formed luring the reaction to be removed.

The reaction mixture is then evaporated and the esidue is taken up in ethanol. 2.5 g of sodium borohydride re added to the solution obtained. After 2 hours' stirring at ambient temperature, the mixture is evaporate! ind then taken up in dilute hydrochloric acid.

The- solution obtained is washed with methylene .hloride, then made alkaline by the addition of sodium arbonate. It is then extracted with chloroform. The rganic fractions are combined and evaporated. The oil bt.ained is treated with a solution of hydrochloric acid n ethanol to form the hydrochloride of the desired product, which is filtered and recrystallised from ethanol. A white powder is thus obtained, with a melting point of 202°C, determined by the Koff'ier block (total yield 45%). Examplc 2 Preparation of 4-p-chlorophcnyl-l-(3-pipcridinopropyl)-piptrazine _ by the 2nd i ethod.

A mixture of 100 ml of n-butanol, 15 g of 4j)-chlorophti /1-1-(3-chIoro-propyl)-pjperazinc, 5 g of piper id in.?, 7 g of potassium carbonate and 300 mg of potassium iodide is refluxed overnight. The solvent is then evaporated and the residue is taken up in chloroform and filtered. Then the filtrate is concentrated to pra/idc an oil, which is treated with a solution of hydrochloric acid in ethanol. The precipitated hydrochloride is filtired and again recrystallised from ’thanol. A slightly pink powder is obtained with a nelting point of 250°C, with decomposition, determined by the Kofflcr block (total yield 51%).

Example 2(a) Preparation of the derivative of Example 2 (or 3223 derivative 2) by the 1st method.

A mixture, of 100 ml of dimethyl formamide, 7.9 g of N-p-chlorophenyl piperazine, 8 g of l-(3-chloro-propyl)oiperidine liydrochlori.de, 12 g of poLassium carbonate md 600 mg of potassium iodide is heated to 30°C for ?4 hours. After filtration, the hydrochloride of the lesired product is precipitated by adding a solution of lydrochloric. acid in ethanol. After filtration and 'ecrystalli.iation from ethanol, a slightly pink powder is btaincd, with, a melting poi.nt of 250 °C (with decomposition) eterinined by the Koffler block (total yield 55a).

The following compounds were prepared by analogous sthods: Ixamplc 3 1-(3-cyclohexylamino-propyl)-4-(p-chlorophenyl)iperazine trihydrochloride (-^ = C1-; -NR2R3 = -NH-/ \) M.p. = 250^0. xample 4 4-(o-chlorophenyl)-1-(3-cyclohexylamino)-propyliperazi ne trihydrochlorlde (-βχ = Cl -NR2R3 = “NH campl p 5 1- (p -chlorophc nyl) -4- ( 3-pyrr olidin-i -yl) propy Ί .pcrazine dihvdrochloride 3 2 32 (Rj - Cl; -NR R = -N ) -M.p. = 200°C / (decomposition) Example 6 f l-(p-inethoxyphcnyl)-4-(3-pyrrolidin-1-yl-ppopyl) p ipera z ine t-rihyd rochloride (decomposition) Examp1< _7 l-(p-chlorophenyl)-4-(3-morpholino-propyl)/--\ piperazine ditnaleate (-R., -- C1-; -NR„E., = -N 0) 1 23 \_7 M.p. = 195°C.

The results of the toxicological and pharmacological tests reported hereinafter demonstrate the interesting activities of the derivatives according to the invention, particularly their hypocholesterolaemic, anti-inflammatory and analgesic properties.

The invention therefore also relates Lo a pharmaceutical composition (having in particular, hypocholesterolaeinic, anti-inflammatory and analgesic activities) comprising as active principle a compound according to the invention or a pharmaceutically acceptable acid addition salt or quaternary ammonium derivative thereof, 3333 together with a physiologically acceptable carrier.

The derivatives referred to below are numbered in accordance with the above Examples.

TOXICOLOGICAL STUDY This demonstrated the low toxicity and good tolerance of the derivatives of the invention.

As a guide, the LD^q/24 hoir· s/kg of body weight, determined by the method of Miller and Tainter, by intravenous route in mice is 25 mg for derivative no, 1, mg for derivative no. 2, 41 mg for derivative no. 3·, mg for derivative no. 4, 66 mg for derivative no. 5, mg for derivative no. 6 and 100 mg for derivative no. 7 These experiments showed that, throughout the acute, chronic or retarded toxicity vests, the derivatives of the invention did not cause any local or general reaction or any disturbances in the biological checks carried out at regular intervals in the test animals, or any anomalies in the macroscopic or microscopic examinations of the animals which were killed and on which autopsies were performed, PHARMACOLOGICAL STUDY 1. Hypocholesterolaemic activity This experiment demonstrated the clear hypocholesterolaemic and normolipaemic activity of the 43232 compounds cf the invention. It was carried out using two method:;. a) Test using propyl thiouracil (RANMEY and Coil,, J, Pharmacol, Exper, Therap., 1963, 142, 132-136), g Propyl thiouracil administered to adult rats has the property of making them hypercholestcrolaemic; the cholesterol level in the plasma rises by about 15% under these conditions. The tests are carried out on different latches of rats, the control batch being giver. only propyl thiouracil, while the other treated batches are also given a compound of the invention, orally, in a dosage of 10 mg/kg.

On the 11th day of the experiment, blood samples are taken and the free cholesterol and total cholesterol are estimated. It is observed that the cholesterol levels in the treated animals are significantly reduced as compared to the cor.Lrol animals.

The results obtained for certain derivatives are given in the following table: 3222 i’rt e choJ (.•.Lerol g/1 Total chol.esLc-roi g/1 Control '0.21 0.82 Derivative no, 2 0.13 0.62 Derivative no. 3 0.16 0.55 Derivative no. 4 0.15 0.53 Derivative no. 5 0.12 0.50 Derivative no, 7 0,13 0.57 Thi-se lesults are confirmed by the following test: 3) This study was carried out on rabbits kept on a lyperc.holestevolaemic diet. The rabbits are divided into >atches of 40 animals; the control batch (A) receives no :reatmcnc, whereas the treated batches are given a compound of the invention. Thus, derivative 0. 1 is administered to the animals in batch B, derivative o. 3 to those in'batch C and derivative no. 5 to those n batch D, by oral route, daily,iria dosage of 10 mg/kg, n the first day of the experiment and then every 15 days or a period of 75 days, biological tests are carried out ι all the animals whereby the various elements which idicate dyslipacmia are determined: total cholesterol (T), 4 3 2 2 2 esterified cholesterol (E), free cholesterol (L), esterification ratio (Γ,/ϊ), Kunkel phenol test (Kl), Kunkel phenol, test (K2), Burstcin test with dextranc (B) and scrum lipids (LS).

At the end of the experiment, all the animals are killed and autopsies are performed on them; macroscopic examinations of their livers and aortas are then carried out, and the fatty infiltrations of the liver are marked, in size, from 0 to 3 and the aortic atheromatous lesions are marked, in intensity, from 0 to 4.

The results, representing the average values determined with each batch, are assembled in the following Tables: ' 1st Day Batches Ί E L E/T Kl 1~ K2 B LS A 0,54 0. 23 0. 26 0.51 7.9 12.3 10.3 2,06 B 0.55 0.28 0.27 0.50 8.2 13.7 11.1 1.95 C 0.57 0.23 0.29 0.49 8.1 12,6 10.9 2.1 1 D 0. 52 0. 27 0. 25 0. 51 8.1 13. 2 10.6 1.98 3222 30tn Pay Batches T E L E/T Kl K2 B LS Λ :·. 29 1,46 0.83 0.63 21,6 31.5 26.6 3.89 B '':.47· 0.92 •0.55 0.62 18. 6 25.4 21,2 2.91 C 1.45 0.91 . 0.54 0,62 18.8 25.0 21.1 2.85 D 1.51 0.96 0. 55 0.63 18.5 25.2 21.2 2.88 7 5 th. Lay z ,. - Batches T E L E/T Kl K2 B LS A ..:h 67 ' • 2; 27'H1.40 0.61 43.3 ’ 66. 5 51.8 5.19 B 2.92 1.80 1.12 0.66 33.1 41,9 35.8 4.03 C 2.92 1.78 1.14 0.60 32.8 41.8 35.9 4.1 D : 2.95 1.83 1.12 0,62 32.9 50.0 35.6 3.97 Batches fatty infiltrations of tho liver l aortic atheromatous lesions A 2.7 3.4 B 0.9 1.4 C 1.0 1.2 D 1.2 1.4 43323 2. Ant i-inf lair?.! ory activity This activity was studied using two methods: a) Method using 3oc.alised carrageenin-induced oedema A 1% carrageenin solution (0.1 ml) is injected g into Lhe metatarsal flexors of the right hind paw of the rat at time 0. The animals in the treated batch are also given by oral route, 10 mg/kg of the test derivative, one hour be lore, then at the same time as the injection of the phlogogenic a;.ent, then one hour and 2¾ hours θ afterwards, respectiv. ly. The measurements taken with a Roch micrometer at tine 0, then 1 hour, 2 hours, 3 hours and 5 hour, after administration of the carrageenin make it possible to determine, .as a function of time, the percentage anti-inflammatory activity compared with the control batch.

The results, with regard to derivative, no. are given in the following table: 3222 Percentage anti-inflammatory activity After 1 hr J 2 hrs | 3 hrs 5 hrs1 ί I 1 erivative no 37 ) Method using generalised ovalbumin oedema The rat is given a simultaneous intraperitoneal ijection of 1 ml of ovalbumin and 0,5 ml of a 1% aqueous )luLiou of Ivans blue. Moreover, 50 mg of the test derivative 'c administered orally to the animals of the Lest batches ie hour before and at the same time as the injection of albumin. The intensity of the phenomenon thus induced is ven a mark from 1 to 5, depending on the progression of the flammaLory syndrome. Thus, the average oedematous intensity 1 the percentage reduction in the oedematous reaction, npared with the control, are determined.

The results are given in the following table: - 16 43222 Percentage reduction n oedematons reaction 2nd hour 3rd hour derivative no. 6 55 68 3, Analgesic actlvitv This activity was demonstrated using the method of KOSTER, ANDERSON AND DE BEER (Fed. Proceed., 18, 1959. 412, 1.626).

The intraperitoneal injection of a dilute solution of acetic acid-causes, in mice, repeated characteristic stretching movements under the effect of the pain. The oral administration of a dosage of 50 mg/kg of the test derivative, thirty minutes before the injection of acetic acid, reduces the number of movements in the next 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, are determined.

The results show that the average percentage of analgesia obtained is 65% for derivative no. 1, 72% for - 17 43222 derivative ne. 2, 61% lor derivative no, h and 69% for derivative no, 5.

Tlie toxicological and pharmacological studies reported above show that the compounds of the invention are well tolerated and have hypocholesterolaemic, anti-inflammatory and analgesic activities.

The compounds according to the invention may be presented for oral administration in the form of tablets, coated tablets, capsules, drops or syrup. for rectal idministration, it may be presented in the form of suppositories and for parenteral administration in the orm of an injectable solution.

Each single dose advantageously contains from 0.010 g o 0.300 g of active principle, while- the doses to be dministereil per day may vary from 0.010 g to 1 g of active rinciple.

Some pharmaceutical formulations of the compounds ccording to the invention are given hereinafter, >y way of example: - 18 43222 Example 1\ TABLETS derivative no. 2 0.100 g magnesium stearate 0,005 g talc 0.005 g dried ίecula 0.0J0 g corn starch 0.010 g magnesium hydroxide 1 0.010 g Example B COATED TABLETS derivative no. 1 0.075 g fecula 0.010 g starch 0.025 g stearic acid 0.005 g lactose 0.020 g magnesium stearate 0.010 g polyvidone 0.020 g shellac 0.005 g gum arabic 0.005 g levilite 0.002 g white wax 0.002 g Core Coating indigo blue traces suSar q.s. for 1 coated tablet 22 Example C CAPSULES lerivative no. 3 0.150 g nagnosiuni stearate 0.005 g stearic acid 0.005 g ale 0.003 g lerivative no. 7 Example D SYRUP 2.000 g sweetened, flavoured •xcipient............ q.s. for 100 ml Example E SUPPOSITORIES erivative no. I 0,100 g «mi-synthetic triglycerides.....q.s. for 1 suppository Example E INJECTABLE SOLUTION srivative no, 5 0.050 g sotonic soli tion _ q.s. for 3 ml 3233 Our tests reported above indicate that the active compounds normalise the cholesterol and lipids levels in .the blood by regularising their metabolism and thus effectively protect the organism from vascular complaints of atherosclerotic origin and their cardiac, cerebral or peripheral complications. Owing to their anti-inflammatory and analgesic activities, they enable inflammatory conditions to be combated effectively, whatever their aetiology, and produce rapid and prolonged sedation of the pain which usually accompanies the inf laminati on. 21'

Claims (9)

1. CLAIMS:1. Piperazine derivatives of the formula: N - (CH 2 ) 3 - ir wherein R, is a halogen atom or an alkyl, alkoxy or trifluoro-iethyl group, and either R.., and R o together with the nitrogen atom to which they are attached form a 4- Lo S-in-'miberetl saturated heterocyclic ring whicli may contain an oxygen or nitrogen aLom ax a second hcteroatoi;, or R^ is a hydrogen atom and is a cycloalkyJ group; and the salts thereof.

2. A compound as claimed in claim 1, wherein the alkyl, and cycloalkyl groups contain up to 12 carbon atoms.

3. A compound as claimed in claim 1 Or claim 2 wherein -NR R represents a pyrrolidin-l-yl, piperidino or CO. morpholino group.

4. l-(3-Gyclohexylamino~propyl)-4-p-tolyl-piperazine; 4-p-chlorophenyl-l-(3-piperidino-propyl)-piperazine; l-(3-eyclohexylamino-propyl)-4-p-chloropheny122 piperazine; 4-o-chlorophenyl-l-(3-cyclohexylamino-propyl)i'iperaz.ine; l-p-chloiophe/iyl-4-(3-pyrrolidin-l»yl-prooyl)piperazine; l-p-methoxyphenyl-4-(3-pyrrolidin-l-yl-nrof»yl)piperazine; and 1-p-cb loropheny1-4-(3-morpholino-propyl) 5. Piperazine; c.:,d the salls thereof.

5. A process for the preparation of a compound as claimed in any one of the preceding claims, comprising condensing a phenyl piperazine of formula: with a reagent B, wherein: A is hydrogen when B is X-(CH 2 ) 3 N or Λ is -(C!I ,).,-)1 when B is H-N X being a halogen atom; or,only when S 2 is hydrogen, A is -(αΐ 2 ) 3 Ν!1 2 when B is R /( -0, R^ being the divalent group derived from R^ by removing a hydrogen from the first carbon atom; the condensation being followed in this latter case by reduction of the imine initially obtained. - 23 15 3222

6. , Λ process as claimed in claim 5 and substantially as desc.ril-ed herein with reference to any one of Examples 1 to 7.

7. A compound as claimed in claim 1 when produced by a process as claimed in claim 5 or claim 6.

8. A pharmaceutical composition comprising a compound ; s claimed in any one of claims 1 to 4 together with a physiologically acceptable carrier.

9. A pharmaceutical composition substantially as described herein in any one of Examples A - F.