IE832488L - Phenyl-(3-aminopropyl)-ketone derivatives. - Google Patents

Abstract

1. Claims for the contracting state AT Use of the (2,4,6-trimethoxyphenyl)-3-(hexamethyleneiminopropyl)-ketone having the following structural formula see diagramm : EP0110748,P6,F1 and its non toxic addition salts, for the manufacture of a medicine. 1. Claims for the contracting states BE, CH, DE, FR, GB, IT, LI, LU, NL, SE, The (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone having the following structural formula see diagramm : EP0110748,P7,F1 and its addition salts.

Description

t» I US 2 Thi; present invent ion relates an industrial products In nnve I derivatives of plienyl-f.l-flminopropy] )-ketone, namely ( 2 ,4 , <>-trimethoxypheny 1 )-(3-hexamethylene-iminopropy1)-ketone and its addition salts. It relates 5 also to the use in therapeutics and the process of preparing these novel products.

It is known that there has already been described in the past a certain number of deriv;»tives of the (alkoxy-and hydroxy-phenyl )-(aminoalky1)-ketone type. See for 10 this purpose French Patents Nos. 1,4"^,2S6 and 5636M and the ai't-icle of A. IJOUCKERI.E et al., Chiroie Therapeut. i que 3 (\o 4), 256-25'), (1968), on the one hand, British Patents No. 1,078,'>7 5 and No. 1,115,992, on the other hand, and 1 inally USP No. 0,395,0.10, on the other hand. 15 It is known that the above-indicated derivatives of the (alkoxy- and hydroxy-phenyl)-(aminoalkyI)-ketone typo have been presented as anti-inflammatory, antalgic, antipyretic, antispasmodic, tranquilizing agents, peripheral vasodilators or bradycardiac agents• 20 Finally it is known, particularly from French Patent Xi>. 2 404 003, that there is no structure-activity relationship within the family of (alkoxy- and hydroxy-phenyl )-( am i noa 1 ky I ) -ketones , the pharmacological effects ieing modified or disappearing according to the nature 25 of the substi tncnts of the phenyl group, the nature of the amino group and finally the nature of the alkyl group present between the CO group and the amino group.

It has just been found surprisingly that (2,4,6-t.r- i methoxypheny 1) - ( 3-hexaraethylene iminopropy 1 ) -ketone, 30 which is included in the family of the (alkoxyphenyl)-(3-aininopropyI)-ketones envisaged in the description 3 <>r t he aforc.su id U.S. Patent No. 3,895,030, without being specifically exemplified, has, with its addition salts, pharmacological properties interesting in therapeutics and not obvious taking into account tho teaching S ol tin- prior art.

In particular, it was not obvious from the l each ins of U.S. Patent No. 3,^95,030 which describes part icularly (i) (2,4,6-trimothoxyphonyI)-(3-pyrrolidino-propy I .(-ketone hydrochloride a product marketed under 10 the name "F0NZYLANE" ^International Common Name : BUFLOMEDIL HYDROCHLORIDE) and having Code No. LL 1656] which is a rcfi-rcnco peripheral vasodilator agent, and (ii) (2,4,6-trimethoxypheny1)-(3-piperidinopropy1)-ketone hydrochloride £codc So. LL 1647J which is essentially an antispasmodic 15 a;>ent, that (2,4,6-trimethoxvphenyl)-(3-hexamethylene-iminopropyI)-ketone hydrochloride [[Code So. CRL 41080 according to the invention is more effective than LL 1656 is a vasodilator and bradycardiac agent, and devoid of ant-1 spasmoili c effect unlike LL 1647. In brief, there 20 is no sti-ucture-activity relationship when one passes Iront the pyrrolidino derivative to the piperidino derivative and then to the hexamethyleneimino derivative.

The novel derivatives of phenyl-(3-aminopropyl)-ketone according to the invention are 25 (i.) ( 2,4,6-tr imethoxypheny .1 )-(3-hexamethylene- inino-propyl)-ketone which has the formula _JCH3 yC0-(CH2)3 -l/ ^ (1) oca3 and, 30 (ii) its addition salts.

By addition salts, is meant here, on the one hand, the acid addition salts obtained by the reaction 4 of t hi- free base of formula I with inorganic arid organic acids, and, on the other hand, ammonium salts. Among the acids usable to salify the base of formula T, mdy hi- merit. i oned particularly hydrochloric, hydrobromic, S arctic, formic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic, tartaric aspartic, glutamic, methanesulfonic and p-toluenesulfonic acids. Among the compounds enabling ammonium salts to ht> obtained, may be mentioned particularly ""d CICH^. 10 The acid addition salts are the preferred salts, (2,4,6-t r i met lioxy pheny I ) - ( 3-hexumethy I enoim i nopropy 1) -ketone liyd rochlor ide being particularly interesting therapeutic-a 1 J v .

The base of formula I may be prepared by a 1 1 mi't.hod known in itself by the application of conventional reaction mechanisms. The proccss which is recommended according to the invention comprises : a) the reaction of hexamethy1eneimine with 4 eh I or-o-bu ty roil i ( r i I e, l.hen •jo b) the reaction of 4-hexamethyleni'imino- butyronitri1« so obtained with 1 , 3 > 5-triinethoxybenzene in the presence of a flow of HCl gas at a temperature of between -5°C and 0°C for at least 2 hours in an anhydrous solvent (particularly scleeted trom among the 2 i group consisting of bonzene, toluene, chlorobcnzene ;ind tlieir mixtures), then the subjection of the ketimini-derivative thus obtained to a hydrolysis reaction for at least 0.5 hours at the reflux temperature of the reaction med i urn. ,;(l Advantageously, the reaction of stage a) will be carried out. from 2 moles or hexamethy leneiminc for-1 mole of 4-chJorobutyronitrile in the presence of an aromatic hydrocarbon such as benzene or toluene, for at least 0.4 hours at the reflux temperature of the reaction 35 medium; and the reaction ot stage b) between 4-bexamethy1-erieimino-butyronitrile and 1,3,5-trimethoxybenzene will be carried out under stoichiometric conditions in chloro- s lienzone. the ketimine derivative formed being then hydro-ly/.fd without being isolated. (2,4,G-Trimethoxyphenyl)-(3-hexamethyleneimino-propyI(-ketone and its salts are agents useful in the 5 treatment of disorders of the cardiovascular system; they act as vasodi Lator and bradycardiac agents intravenously and i ntradimdcna I I y. According to the invention, then- is recommended a therapeutic composition which i.s characterized in that it comprises, in association 10 with a physiologically acceptable excipient, at least one compound selected f rom (2,4,6-trimethoxypheny1)-(3-hexamethyleneiminopropyl)-ketone and its non-toxic addition salts. In such a composition, the active ingredient is present, of course, I j in .< pharmaceiit. i ca 1 ly effective amount.

Other advantages and features of the invention will be better understood on reading the description which follow.-, (i) <>l" an example of the preparation which is in no way limiting but given purely by way of illustra-2(i (ion, and (ii) results of pharmacological tests which have been carried out. i'K I'P ARATTON' Preparation of ( 2_j 4_. 6-trimethoxypheny l_)-(J?-hexaraethyJ.enej i-n i noprouy l_)-ketone_ hydrochloride (Code No. CRI. 41 080). 25 a) 4-HexamethyIeneimino-butyronitri1e Into a solution under reflux of 50 g (0.505 mole) of hexamethylcneimine in 80 ml of benzene, are run in 15 min 26.1 g (0.252 mole) of 4-chlorobutyronitrile. The reflux is continued 4h, the cold reaction medium 30 taken up with diethyl ether, the precipitate removed by filtration and the filtrate taken to dryness. The residue so obtained was purified by distillation under reduced pressure to give 29.3 g (yield 70$) of 4-hexamethyl-eneimino-butyronitrile which is in the form of a colorless s nil. Ill'/ _ - I2ft"c: (6-7 mm llg corresponding approxi- (i- 7 mm HK in.it i-I y I <1 ^(l<)-',>33 pascals). bl CKL 41 080 ^ A current of dry HC1 qaz is passed 5 for 1. 5li bi'twn -5°C and 0"C into a solution of 16.8 g (('.JO mole?) of 1 ,3. S-tri methoxybenzene and 16.6 g (0.10 ■no It-) of 4-he xanif thyleneimino-butyron i t r i 1 c in solution in llj ml of anhydrous chlorobenzene. The suspension is left in the cold between 0°C and + 4°C overnight and the 10 reaction medium is extracted with water. The aqueous phase is taken to reflux for lh, it is made alkaline with concentrated sodium hydroxide and the precipitate extracted with diethyl ether to give 29.8 g of a pale yellow oil. This oil is treated in diethyl ether with 15 hydrochloric rthanol. After purification of the precipitate by crystallization in the mixture ethyl acetate-isopropanol (8:7) v/v, 10.5 g (yield from stage b is obtained : 52 . 5'";. global, yield: 38.75;') of CRL 41 080 in the form of a water-soluble white powder. ^inst (Kofi or) I50°C. 20 Below are summarized the results of the pharmaco logical tests which were undertaken with CRL 41 080. I - VASODILATOR PROPER?TES OF CRL 41 080 A - l" 1-HOK A L_ V ASODIL AT0R_ ACT I ON _ INTR AV LN OUS L Y Two dogs (average weight 12.4 kg) anesthetized 2S with pentobarbital received CRL 41 080 intravenously, in perfusion of 6 min, at successive doses of twicc 1 mg/kg, then 2 and 4 >"g/kg every 60 min. For comparison, these animals received at the end of the test a perfusion of 6 nitf/kg I.V. of a known reference product, the aforesaid ">0 LL 16 56.

It is observed that CRL 41 080 does not modify the blood pressure nor the heart rate; the femoral flow rate increases during the period of the perfusion from I mg/kg, the effcct is reproducible and increases moderately .5 5 with the dose. LL 1656, at the dose of 6 mg/kg, increases the femoral flow rate less than 1 mg/kg of CRL 41 080. 7 II VASODILATOR ACTION I NTRADUODENALI.Y lour dogs (uvcragc weight 15-7 kg) anesthetized with nembutal received CRL 41 080 intraduodenally, at the successive doses of 0.5 mg/kg» 1 mg/kg, 2-5 mg/kg 5 and 5 m/sf/kg; three of these dogs then received 10 mg/kg of CKL 41 080. The blood pressure, the heart rate, the femoral artery flow rate, the vertebral artery flow rate, tin* rectal and skin temperatures were measured. ;It. was observed that CRL 41 OHO distinctly 0 increased the femoral flow rate from the dose of 5 rag/kRJ this effect lasted more than one hour. In addition, it seems that the vertebral flow rate was reduced, but this effect was not statistically significant. ;C - DURATION 01 VASODILATORACTION ;5 Three dogs (average weight 11.1 kg) received ;CRL 41 080 intraduodenal ly at the dose of 5 mg/kg at two t lines (period between the two administr.itions: 00 min) then 6 mg/kg I.D. of LL 1656 and, 2 hours later, a further ndm i n i strat ion of ng/kg T.D. of CRL 4* 0S0. 0 It was observed that CRL 41 080 increased the femoral flow rate at 5 mg/kg I.D.; this effect was a maximum at 30 min, lost half its intensity at 60 min and disappeared at 120 min; the other parameters measured were not modified. A second administration of 5 mg/kg ry of CRL 41 080 had a more intense effect on the femoral flow rate, the effect was a maximum at 30 min, then gradually decceased, hut was still present at 120 min. An administration of 0 mg/kg l.D. of LL 1656 resulted in an increase in I he femoral flow rate of average intensity, slow to 0 deve I op and t hen the maximum of the effect was obtained at 120 min. This kinetics of action of LL 1656 intraduodenal ly is not the usual kinetics (maximum of the effect at 30 or 60 min and gradual disappearance then of the latter); it may be thought that the prior administration 5 of CRL 41 080 modifies the action of LL 1656. An additional dose of 5 i.ig/kg l.D. of 41 080 does not further increase the femora i flow rate but results in a hypotension and 0 and a bradycardia. In these dogs, the CRL 41 OSO does not diminish the? vertebral flow rate.

II - CONCLUSION Results of the tests sunraarized above establish S that CRL 41 080 is a peripheral vasodilator (particularly a femoral vasodilator) and a particularly interesting bradycard i ac agent. CRL 41 080 is more active as a vasodilator than LL 16J6, its pyrrolidino homo log, and does not have the antispasmodic properties of its piperidino 10 homo log.

II - COMPARATIVE TESTS There are collected in Tables I and IX below the results of the additional tests which were undertaken -to compare the CRL 41 080 according to the invention 1 <; with its pyrrolidino (l.L 1656) and piperidino (LL 1647) homo logs described in USP No. 3>895,030 mentioned above.

Table I relates to the toxicity in the male mouse, on the one hand, and the minimum dose inducing in the anesthetized dog a distinct femoral vasodilator 20 effect, on the other hand. The LD-S0 I.V. was determined on batches of 10 male mice; the minimum vasodilator dose was determined on a batch of 5 dogs serving as controls with respect to themselves and each receiving a dose of I lie product, to be tested every 2.5 hours. :! 5 'fable II relal-es to the variations in the ,-irte- rlal blood pressures (systolic, diastolic, differential and average), the heart rate and the femoral artery blood flow. These variations were determined intravenously en the same aforementioned batch of 5 anesthetized dogs. V) Jn the course of clinical assays, good results in r.ian were obtained by administering CRL Al 080 orally (three capsules daily each containing 100 mg of active .ingredient) and by injection (I.V. route or I.N. route, one ampoule of 5 ml per day containing 40 mg of active 35 principle in a physiological saline Solution). a TABl.F. T Product.

LD-50 I.V. mouse mlnimum dt in the anc dog a feme dilat I.V. ise inducing :sthetized >ral vaso->r effect l.D.

CRL 41 OSO (a) 96+3 rag/kg 1 mg/kg 5 mg/kg LL 1656 (b)(c) 60 + 2.2 nig/kg 5 mg/kg 6 mg/kg LL 1647 (c) 68+4 mg/kg 5 mg/kg (d) Not.i-s (a) product, .according to the invention (b) reference peripheral vasodilator fc) described in USP No. 3,895,030 (d) no vasodilator effect l.D.

TABLE II Cardiovascular Properties in the Anesthetized Dog Product Dose Variation 0.25h after administration (mg/kg I.V.) Systolic Diastolic Differential Average Heart Femoral B.P.

B.P.

B.P.

B.P.

Rate Flow Rate LL 1656 6 - 10 - 12 + I - 12 0 + 27(a) 1 0 - 3 - 9 - 4 + 1 + 20(b) CRL 41 080 2 + 2 - 1 + IS 0 + 3 + 39 4 - 2 - 1 - 5 - 1 - 6 + 82 Notes (a) : + 32% at the 6th minute ; (b) : + 51% at the 6th minute.

Claims (10)

11

1. CI.A IMS ketone of the formula or an addition salt thereof.

2. (2,4,6-Trimethoxyphenyl)-(3-hexamethyleneiminopropyl )-k<-toiif hydrochloride.

3. A therapc-utical composition comprising, in .'ihsocintion with a physiologically acceptable excipient, .i pharmaceutical1y pffective amount of (2,4,6—trimethoxyphenyl)-(3-hexanethyleneiminopropyl)-ketone or a non-toxic addition salt thereof. i. A therapeutical composition according to Claim ?•,, coiiipr i s i n;i (2,4, 6-trimcthoxyphenyl ) - ( 3-hexainethy tenc-i i nopropy I )-ki:tono liyilroclil or ido.

4. ?. A process for preparing ( 2 , 4 , 6-trimethoxypheny I ) - ( 3-licxainotfiy 1 cnoiiuinopropy 1)-ketone in which 4-hexamcthyl-enoimino-ljutyronitril.e is formed, its k«timine derivative is obtained by reaction with 1,3,5-trimethoxybenzenn, and said ki.-t i mine derivative is hydrolyzed, said process compr i s i ti;\ a) reacting 2 males of hexamethylcneimine with 1 mo] of 4-chlorobutyronitrile, in the presence of an aromatic solvent for at least 4 hours at tz

5. (.III- refills t.cnipor.itiin- of the react, i.011 medium, then b) reacting X mole of 4-hexamet.liy leneim i no- butyronitrile thus obtained with 1 mole of 1,3,5-trimethoxy-bcnzciie in the presence of a HC1 gas stream, at a temperature 5 of between -5°C and 0°C, for at least 2 hours, in an anhydrous solvent , then hydrnly/.ing the corresponding ketimine derivative thus obtained for at la-ist 0.1 hours at the reflux temperature of the reaction medium.

6. A proocss according to Claim 5, herein in step a) the aromatic hydrocarbon is benzene or toluene and in step b) the anhydrous solvent 10 is selected from benzene, toluene, chlorotoluene or a mixture thereof.

7. (2,4,6^riitethojiypheny 1)-(3-hexanethyleneimLnopropyl)-ketone of the formula I given and defined in Claim 1 or an addition salt thereof, . which is specifically hereinbefore mentioned.

8. A process'for preparing (2,4,6-trimethoi^pheny 1)-(3-hexarrcthylene-15 iminopropy 1) -ketone of the formula I given and defined in Claim .1 or an iddition salt thereof, substantially as hereinbefore described and exemplified.

9. (2,4,6-Trimethoxyph€3^yl)~(3-hexamethyleneiminopropyl) -ketone of the formula I given and defined in Claim 1 or an addition salt thereof, 20 whenever prepared by a process claimed in a preceding claim.

10. A therapeutical composition according to Claim 3, substantially as hereinbefore described. F. R. KELLY 8 CO., AGENTS FOR THE APPLICANTS.