CA1183853A - (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)- keton and its acid salts, use thereof in therapeutics and method for preparing same - Google Patents
(2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)- keton and its acid salts, use thereof in therapeutics and method for preparing sameInfo
- Publication number
- CA1183853A CA1183853A CA000400489A CA400489A CA1183853A CA 1183853 A CA1183853 A CA 1183853A CA 000400489 A CA000400489 A CA 000400489A CA 400489 A CA400489 A CA 400489A CA 1183853 A CA1183853 A CA 1183853A
- Authority
- CA
- Canada
- Prior art keywords
- dimethoxy
- ketone
- hydroxyphenyl
- piperidinopropyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 title claims description 9
- MVDBGZOSRSXNHU-UHFFFAOYSA-N 1-(4-hydroxy-2,6-dimethoxyphenyl)-4-piperidin-1-ylbutan-1-one Chemical class COC1=CC(O)=CC(OC)=C1C(=O)CCCN1CCCCC1 MVDBGZOSRSXNHU-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000003814 drug Substances 0.000 title abstract description 3
- 239000002253 acid Chemical class 0.000 title description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 239000012429 reaction media Substances 0.000 claims description 5
- 150000004658 ketimines Chemical class 0.000 claims description 3
- ZNDKGZTXFLTQKE-UHFFFAOYSA-N 2-piperidin-1-ylbutanenitrile Chemical compound CCC(C#N)N1CCCCC1 ZNDKGZTXFLTQKE-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- XQDNFAMOIPNVES-UHFFFAOYSA-N 3,5-Dimethoxyphenol Chemical compound COC1=CC(O)=CC(OC)=C1 XQDNFAMOIPNVES-UHFFFAOYSA-N 0.000 claims 1
- 239000000810 peripheral vasodilating agent Substances 0.000 abstract description 8
- 229960002116 peripheral vasodilator Drugs 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 206010051814 Eschar Diseases 0.000 abstract description 3
- 231100000333 eschar Toxicity 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 210000001105 femoral artery Anatomy 0.000 description 4
- 229940124549 vasodilator Drugs 0.000 description 4
- 239000003071 vasodilator agent Substances 0.000 description 4
- -1 (2,6-dimethoxy-4-hydroxy-phenyl)- Chemical class 0.000 description 3
- ZDPACSAHMZADFZ-UHFFFAOYSA-N 1-[3-(2,4,6-Trimethoxybenzoyl)propyl]pyrrolidinium chloride Chemical compound [Cl-].COC1=CC(OC)=CC(OC)=C1C(=O)CCC[NH+]1CCCC1 ZDPACSAHMZADFZ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 230000004872 arterial blood pressure Effects 0.000 description 3
- 239000006229 carbon black Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000002921 anti-spasmodic effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GHPYJLCQYMAXGG-WCCKRBBISA-N (2R)-2-amino-3-(2-boronoethylsulfanyl)propanoic acid hydrochloride Chemical compound Cl.N[C@@H](CSCCB(O)O)C(O)=O GHPYJLCQYMAXGG-WCCKRBBISA-N 0.000 description 1
- IXFSQRBBMWQMRF-UHFFFAOYSA-N 1,7-dipyrrolidin-1-ylheptan-4-one Chemical compound C1CCCN1CCCC(=O)CCCN1CCCC1 IXFSQRBBMWQMRF-UHFFFAOYSA-N 0.000 description 1
- XZICCHYGIANPTF-UHFFFAOYSA-N 1-(2,4-dihydroxy-6-methoxyphenyl)-4-pyrrolidin-1-ylbutan-1-one Chemical class COC1=CC(O)=CC(O)=C1C(=O)CCCN1CCCC1 XZICCHYGIANPTF-UHFFFAOYSA-N 0.000 description 1
- 101100080971 Caenorhabditis elegans cps-6 gene Proteins 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000000146 antalgic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- 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
- C07D295/10—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 doubly bound oxygen or sulphur atoms
- C07D295/104—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 doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/108—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 doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates, as new indus-trial products, to the (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts.
These products are useful in therapeutics as peripheral vasodilator agents, particularly in the treatment of eschars.
The present invention relates, as new indus-trial products, to the (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts.
These products are useful in therapeutics as peripheral vasodilator agents, particularly in the treatment of eschars.
Description
~3~1~3 The present inven-tion relates, as new indus-trial products belon~in~ to the f~nily of the (alkoxy~
and hydroxy--phenyl)-(3-~ninopropyl-ketones, to the (2,6-dimethoxy-4-hydroxy-phenyl)-~3-piperidinopropyl)-ketone and to its addition salts~ It also relates tothe use thereof in therapeutics and to their method for preparation.
It is known that a certain number of com-pounds of the (alkoxy- and hydroxy phenyl)~(aminoalkyl)-10 ketone type has already been described and proposed intherapeutics in the past. In particular, - Freneh Patent No. l 492 256, French Patent (BSM) No.
5636~ and the article by ~. BOUCHERLE et al, Chimie ~ peutique, _ (No.4), 255-259 (1968), disclose the ~2,4,6-trimethoxyphenyl)-(2-piperidinoethyl)-ketone and (2~4,6-trimethoxyphenyl)-~2-(4-methylpiperidino)-ethyl/-ketone, whlch present essentially anti-inflam-matory, antalgic and antipyretic effects;
- British Patent No. 1 115 992 discloses the (2,4-20 dimethoxyphenyl~--(piperidinomethy].)-ketone and ~2,4,6-trimethoxyphenyl-/ (4-methylpiperidino)-methyl7-ketone, which present essentially antispasmodic and tranquilli-zing ef~ects; and - British Patent No. 1 325 192 discloses the hydro-chloride o~ (2,4-6-trihydroxyphenyl)-(3-piperidino-propyl)-ketone (Code No. LL 1647~ , which presents essentially antispasmodic effects and which is useful in the treatment of renal colics, and the hydrochloride o~
(2,4l6-trimethoxyphenyl)-(3-pyrrolidinopropyl)-ketone (Code No~ L~ 1656), which is a reference peripheral vasodllator a~ent, which has formed the subject matter of a publlcation by DEBRAY et al., Th~rapie, 30, 259-266 (1975~ and which is marketed in the pharmacy under khe name o:E FONZ~LANE (Common In-ternational Name: HYDRO-C~LORIDE OF BUFLQ~DIL).
Finally, French Patent No. 78 26464 discloses 3l3~3 -that the replacement of one or more OCH3 groups of the L,L 1656 mentioned above, by one or moxe OH groups has unforeseeable consequences as far as the possible peri-pheral vasodilator properties of the resulting products are concerned. In fact, French ~atent No. 78 26464 shows that there is no structure-activity relationship in said OCH3/OH replacement: if the (2,4,6- tri-Iydro~- phen~ (3-pyrrolidinopropyl)-ketone and (2, 4-dimethoxy-6-hydroxyphenyl)-(3-pyrrolidinopropyl)-10 ketone are peripheral vasodilator agents as advantageousas the LL I656, on the contrary, the (2,6-dihydroxy-4-methoxyphenyl)- or (2,4-dihydroxy-6-methoxyphenyl)-(3-pyrrolidinopropyl)-ketone derivative and the (2,6-dimethoxy-4-hydroxy-phenyl)-(3-pyrrolidinopropyl)-15 ketone derivative have no peripheral vasodilator effects.
It has been unexpectedly found that the (2,6-dimethoxy-4-hyclroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts are, as peripheral vasodilator agents, (i) more efficient than the similar products 20 of the piperidino type and (ii) at least as advantageous as the LL 1656 mentioned above.
A novel derivative belonging to the family of the (alkoxy- and hydroxy-phenyl)-(3-aminopropyl)-ketones according to the invention is characterised in that it is selected from the ~roup constituted by (i) the (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidino-propyl)-ke~one of formula:
HO~ CO-(CH2)3-N ~ (I) O~H3 and (ii) its addition salts.
30Addition salts are understood here to mean ~3~353 the acid addition salts (obtained by reaction of the Eree base of formula (I) with a mineral or oryanic acid) and the ammoni~m salts. Among the acids which may be used for salifying the base of formula (I), particular mention may be made of hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, oxalic, iuma~ic, maleic, succinic, benzoic, cinnamic, mandelic, citric, lactic, malic, tar-tric, aspartic, p-toluenesulfonic and methanesulfonic acids. Among the compounds enabling ammonium salts to be lO obtained, particular mention may be made of IC~13 and ClCH3. The acid addition salts are generally preferred to the ammonium salts.
The preferred product according to the inven-- tion is the hydrochloride of (2,6-dimethoxy-4-hydroxy-phenyl)-(3-piperidinopropyl)-ketone.
The free base of formula (I) may be prepared according to a method, known per se, by application of conventional reaction mechanisms. ~he method proposed according to the lnvention consists in stoichiometrical-ly reacting the l,5-dimethoxy-3-hydroxy-benzene of formula:
~ OCH3 HO ~
with ths piperidinobutyronitrile of formula:
( 2)3 N ~ (III) i.n the presence oE AlCl3 and by passing a HCl ~as stream through the reaction medium for at least 2 hours at a temperature of 10-20C, then in hydrolyzing the ketimine derivative thus Pormed and which corresponds to the ~ormula:
HO ~ C-(=NH)-(CH2)3-N ~ (IV) to ob-tain the compound of formula (I).
In this method, the reac-tion of II with III
is ad~antageously carried out in chlorobenzene, using 1 mole of II, 1 mole of III and 1 mole of AlC13~ It is not necessary to isolate the ketimine derivative IV:
hydrolysis thereof is effected directly in the reac-tion medium resulting rom the reaction of II with III
by introducing ice into said reaction medium. The resultant aqueous phase is collected by decantation, thensub;ected to boiling for at least 30 mins. in the presence of carbon black.
According to the invention, a therapeutical composition is also proposed, which is particularly useful in the trea~nent of vascular diseases, in parti-cular the treatment of eschars, and which is charac-terised in that it contains, in association w~th a physiologically acceptable excipient, the free base of formula (I) or one of its non-toxic addition salts. Of 2Q course, such a therapeut~cal compositicn will include a pharmaceutically effective peripheral vasodilator-active ingredient.
Other advantages and characteristics of the invention will be more readily understood on reading the following examples of preparation given solely by way of non-limiting illustration.
reparation I
Obtaining of the hydrochloride of (2,6-dimethoxy-4-hydrox~pheily~ 3 piperi i_opropyl)-ketone 3~3~3 ~OC~13 HO~ CO-(CH2)3-N ~ , HCl (Example l; Code No. CRL 40746) 30.8 g (0.2 mole) oE 1,5-dimethoxy-3-hydroxy~
benzene, 34 g (0.2 mole) of piperidinobu-tyronitrile - 5 and 200 ml of chloro~enzene are in-troduced into a three-necked flask provided with stirring means; 28 c~ (0.2 mole) of aluminium chloride are then added slowly, then, maintaining the temperature between 14 and 20C, an anhydrous HC1 gas stream is passed through the resultant 10 reaction medium, with stirring, Eor 4.25 hrs. It is-left to stand at 4C for 20 hours then thrown on ice (to hy~rolyze -the ketimine hydrochloride which has formed~
and the lower aqueous phase is decanted and boiled in the presence of CXA black for 1 hour. It is filtered hot and the ~other liquor is cooled. A crystallized product and an oil are obtained. (After isolation and treatment, the oil will give the CRL 40747 (cf. Preparation II
hereinbelow). The crystallized product is filtered, washed over filter with ice water to free it of the oil which accompanies it. By recrystallization in water, a crystallized hydrate is obtained, yellow in colour, which, a~ter trtturation in ethanol, gives 21 g (yield 31~) of CRL 40746 in the form o~ a white crystalline powder, soluble in water. Inst.m.p.=214-215C (wi-th decomposi-tion)Preparation II
-Obtainin~ of the hydrochloride oE (2,4-dimeth_ XY-6~-hyc1roxyphe,1yl)-(3-plperidinopropyl1-ketone 113CO - ~ - CO-(CH2)3-N ~ , HCl OH (comparative Ex.CPl,Code No.CRL 40747) 5~
The oil which decants in preparation I herein-above, after hydrolysis of -the keti~,ine hydrochloride IV
then bo ilin~ of th~ a~ueous phase in the presence of carbon black, is extracted with chloroform.
The chloroform phase ls dried over Na2S04 in the pre-sence of carbon black. ~he solvent is evaporated and a rough po~der , yellow in colour, is obtained, which is recrystallized from the isopropanol-water mixture (100:2) v/v. 18.2 g (yield 26.6%) of CRL 40 747 is obtained, 10 in the form of a crystalline powder, pale cream in colour, very soluble in ~ater. Inst.m.p.=131-183C (~ith decom-position).
Part of the results of the tests undertaken on animals have been summarized hereinafter, and more par-15 ticularly those of the comparative tests relative to the products mentioned in Table I hereinafter, namely CRL
40 746 (Example 1), its structural analogues (CPl-CP6) and a reference peripheral vasodilator product which is LI. 1656 (CP7) mentioned above.
The peripheral vasodilator properties were studied in the male dog anaesthetized with nembutal (6 animals per dose and per product). The products to be compared are adminis-~red in solution in physiological serum i~ a volume of 6 ml/animal by the intravenous route (perfusion of 1 ml/min) and in a volume of 10 ml/
animal by the intrad~odenal route. With respect to the con-trols (the same animals receiving only the physio-logical serum), three pararneters are measured: the average arterial pressure (expressed in mm Hg; 1 mm Hg corresponds ko 1.333224 x 102 Pa), the cardiac frequen~
cy (expressed in beats/minu-te) and the Elow rate of the femoral artery (expressed in ml/min). The variations of these pararneters expressed in percen-tages, with respect to the controls are given in Tables II (intravenous administration) and III (intraduodenal administration) her~inafte:r.
Peripheral vasodilation ls translated under these circumstances by an increase in the flow rate of the femoral artery. Accord:ing to the present conditions of operation, a product is said to be a peripheral vasodilator agent if the flow rate o~
the femoral artery increases by at least 30% by intra venous administration, on the one hand, and by intra-duodenal adminstration on the other hand, without the variation in the arterial pressure bein~ greater 10 than -~10 or less than -10~.
The res~lts of Tables II and III hereinafter demonstrate the interest of CRL 40746 as perip~ral vaso-dilator. In fact, this product is, on the one hand, as active as the reference product CP7 (LL 1656) and, on the other hand, more effective than its analogues of the piperidino type such as, in particular, its isomer CPl (CRL 40747) and its homolo~ue CP2 (LL 1647) which p~sents a trihydroxylated phenyl' group.
More precisely, the CRL 40746 according to 20 the invent~on, administered by IV route and by ID route increases the flow rate of the femoral artery (varia-tion always greater than +30~), whilst its isomer CPl is (i) very weakly va'sodilato~ by the IV route (varla-tion always less than + 30~, but of the order of +20 to ~22~) and (ii) has hardly any vasodilator effect by ID route (it hasl rathermore, an antihypertensive eff~ct as it reduces the arterial pressure by more than 10~), and its trihydroxylated homologue CP2 which is vasodilator by IV route (from the dose of ~ mg/kg as indicated in British Paten-t No. 1 325 192 mentioned above), has virtually no vasodilator effect by ID route (variation of the flow rate of the ~'emoral artery by ID route -~17% with antihypertensive effect~
In cllnic, the C~L 40746 has given good re-sul-ts in human beings in the treatment of eschars.
3~
~' o o __ _ , ~ ,c C C
¢ o C~ o o , o .~ , U ~,J~ O ~D
cl CJ ;) ;) ~ Cl a 1~ U~
C~. Cl. ~ ,C~ h Cl~ t~.Q. ~ ~ ~ ~ c~. cn ~.o Cn ._ ._ . _ , ~Icr.
ti C ___, __ ~~ t~ 1 ri Z Z ' ~ ¢~ _ ~r~ O ~ O ~ ~ a 5 u '5 ~i 5 O ~ O ~ ~ I W555 ', rl _ O 5 0 ~ ~ 5'5~5 0 O ~ r~ I I I I u~ ~ D, g cu ~ _ _ (~
Ca'' ~10 5 ~ _ _ _ ~
3~3 T A B L E _I I
t~ariatit)n_r)t C i~` L~ IE~S . ftel ~llt~a~/ellCLI~:;
~ I r . i ~, t :L ~. ~ i r? r 1 i I I t I: r ~ s ~ l i Z F G Ci O C
_~ ~ Variations in ~
Prod-lct CC~de No. Dose 7~rtr ria~ I 11G~ Iai.~ Of cardi Ic ~, r ~ e e ~ r e ~f enl o ~ .,1 a r te ~y f r r- q ~ rl r: y ¦
Ex~p1s 1CP~L 40746 1,5 + ' + 3'. ~ 2 CP1 CRL 40747 1, S + 2 -r 20 + 5 CP2 I.L, 1647 1,5 + 1 + 10 - 2 CP3 _ 1~5 + 3 + i3 - 1 CP4 _ 1,5 - 2 ~ 3 - 2 CP5 _ 1,5 - 1 - 5 + 1 CP6 _ 1~5 + 1 + 7 + 3 . L-L 1656 1,5 + 33 _ _ Examp1~ 1 CRL 40746 3 + 5 + 35 + 3 CP1CRl. 40747 3 - 12 + 22 ~ 2 CP2 LL 1647 3 + 1 -~ 18 + 3 CP3 _ 3 - 2 -t 8 - 6 CP4 _ 3 - 5 + 2 +1 CP5 _ 3 _ ~ - 8 ~ 3 CP6 _ 3 ~ 1 + 5 ~ 2 .
CP7 LL 1656 3 - 2 + 36 + 6 . _ .
Example 1 CRL 40746 6 t 5 + 41 + 3 CP1 CRL 40747 6 - 18 + 22 ~ 15 CP2 LL 1647 6 + ~ + 34 + 3 CP3 _ 6 + 5 + 3 - 1 CP4 _ 6 + 1 -1- 2 ~ 1 CPS _ 6 ~ 2 - 3 -~ 2 CP6 _ 6 ~ 8 + 2 + 1 CP7 LL 165fi 6 - 2 + 39 ~_ 3~ii3 T A B L E _ I I I
Variation r~f ~ e ;~lrc~ &tarr .~ter intr~duod~nal ~,di~ c l . c:-~Jan in t~le ùn~,r ~ eti~ .a~, _ -- - ----L ~ aria-tions in ~/0 - ' ~~
Prod uc t r r~ c~ e ~O . D os e _ _ m,/!;g Artr-eL-ial. t`lG~ ra-lC af CaIoiac _ ~- r ~ C ~ I ) r ;- I ~ 1 u ~ r ~ r ~ r ~ C ~rr Ex ,mp1e 1 CRL 40746 20 ~ ~ 83 _ 5 CPl CRL 40747 20 - 15 ~ 10 - 2 CP2 LL 1647 2 0 - 12 + 17 - 1 CP3 _ 20 - 8 - 5 - 2 CP4 _ 20 - 1 - 2 + 3 CP5 _ 20 0 ~ 2 ~ 1 CP6 _ 20 + 6 + 1 ~4 CP 7 LL 16 5 6 2 0 __ + 84 ~k 5
and hydroxy--phenyl)-(3-~ninopropyl-ketones, to the (2,6-dimethoxy-4-hydroxy-phenyl)-~3-piperidinopropyl)-ketone and to its addition salts~ It also relates tothe use thereof in therapeutics and to their method for preparation.
It is known that a certain number of com-pounds of the (alkoxy- and hydroxy phenyl)~(aminoalkyl)-10 ketone type has already been described and proposed intherapeutics in the past. In particular, - Freneh Patent No. l 492 256, French Patent (BSM) No.
5636~ and the article by ~. BOUCHERLE et al, Chimie ~ peutique, _ (No.4), 255-259 (1968), disclose the ~2,4,6-trimethoxyphenyl)-(2-piperidinoethyl)-ketone and (2~4,6-trimethoxyphenyl)-~2-(4-methylpiperidino)-ethyl/-ketone, whlch present essentially anti-inflam-matory, antalgic and antipyretic effects;
- British Patent No. 1 115 992 discloses the (2,4-20 dimethoxyphenyl~--(piperidinomethy].)-ketone and ~2,4,6-trimethoxyphenyl-/ (4-methylpiperidino)-methyl7-ketone, which present essentially antispasmodic and tranquilli-zing ef~ects; and - British Patent No. 1 325 192 discloses the hydro-chloride o~ (2,4-6-trihydroxyphenyl)-(3-piperidino-propyl)-ketone (Code No. LL 1647~ , which presents essentially antispasmodic effects and which is useful in the treatment of renal colics, and the hydrochloride o~
(2,4l6-trimethoxyphenyl)-(3-pyrrolidinopropyl)-ketone (Code No~ L~ 1656), which is a reference peripheral vasodllator a~ent, which has formed the subject matter of a publlcation by DEBRAY et al., Th~rapie, 30, 259-266 (1975~ and which is marketed in the pharmacy under khe name o:E FONZ~LANE (Common In-ternational Name: HYDRO-C~LORIDE OF BUFLQ~DIL).
Finally, French Patent No. 78 26464 discloses 3l3~3 -that the replacement of one or more OCH3 groups of the L,L 1656 mentioned above, by one or moxe OH groups has unforeseeable consequences as far as the possible peri-pheral vasodilator properties of the resulting products are concerned. In fact, French ~atent No. 78 26464 shows that there is no structure-activity relationship in said OCH3/OH replacement: if the (2,4,6- tri-Iydro~- phen~ (3-pyrrolidinopropyl)-ketone and (2, 4-dimethoxy-6-hydroxyphenyl)-(3-pyrrolidinopropyl)-10 ketone are peripheral vasodilator agents as advantageousas the LL I656, on the contrary, the (2,6-dihydroxy-4-methoxyphenyl)- or (2,4-dihydroxy-6-methoxyphenyl)-(3-pyrrolidinopropyl)-ketone derivative and the (2,6-dimethoxy-4-hydroxy-phenyl)-(3-pyrrolidinopropyl)-15 ketone derivative have no peripheral vasodilator effects.
It has been unexpectedly found that the (2,6-dimethoxy-4-hyclroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts are, as peripheral vasodilator agents, (i) more efficient than the similar products 20 of the piperidino type and (ii) at least as advantageous as the LL 1656 mentioned above.
A novel derivative belonging to the family of the (alkoxy- and hydroxy-phenyl)-(3-aminopropyl)-ketones according to the invention is characterised in that it is selected from the ~roup constituted by (i) the (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidino-propyl)-ke~one of formula:
HO~ CO-(CH2)3-N ~ (I) O~H3 and (ii) its addition salts.
30Addition salts are understood here to mean ~3~353 the acid addition salts (obtained by reaction of the Eree base of formula (I) with a mineral or oryanic acid) and the ammoni~m salts. Among the acids which may be used for salifying the base of formula (I), particular mention may be made of hydrochloric, hydrobromic, nitric, sulfuric, acetic, propionic, oxalic, iuma~ic, maleic, succinic, benzoic, cinnamic, mandelic, citric, lactic, malic, tar-tric, aspartic, p-toluenesulfonic and methanesulfonic acids. Among the compounds enabling ammonium salts to be lO obtained, particular mention may be made of IC~13 and ClCH3. The acid addition salts are generally preferred to the ammonium salts.
The preferred product according to the inven-- tion is the hydrochloride of (2,6-dimethoxy-4-hydroxy-phenyl)-(3-piperidinopropyl)-ketone.
The free base of formula (I) may be prepared according to a method, known per se, by application of conventional reaction mechanisms. ~he method proposed according to the lnvention consists in stoichiometrical-ly reacting the l,5-dimethoxy-3-hydroxy-benzene of formula:
~ OCH3 HO ~
with ths piperidinobutyronitrile of formula:
( 2)3 N ~ (III) i.n the presence oE AlCl3 and by passing a HCl ~as stream through the reaction medium for at least 2 hours at a temperature of 10-20C, then in hydrolyzing the ketimine derivative thus Pormed and which corresponds to the ~ormula:
HO ~ C-(=NH)-(CH2)3-N ~ (IV) to ob-tain the compound of formula (I).
In this method, the reac-tion of II with III
is ad~antageously carried out in chlorobenzene, using 1 mole of II, 1 mole of III and 1 mole of AlC13~ It is not necessary to isolate the ketimine derivative IV:
hydrolysis thereof is effected directly in the reac-tion medium resulting rom the reaction of II with III
by introducing ice into said reaction medium. The resultant aqueous phase is collected by decantation, thensub;ected to boiling for at least 30 mins. in the presence of carbon black.
According to the invention, a therapeutical composition is also proposed, which is particularly useful in the trea~nent of vascular diseases, in parti-cular the treatment of eschars, and which is charac-terised in that it contains, in association w~th a physiologically acceptable excipient, the free base of formula (I) or one of its non-toxic addition salts. Of 2Q course, such a therapeut~cal compositicn will include a pharmaceutically effective peripheral vasodilator-active ingredient.
Other advantages and characteristics of the invention will be more readily understood on reading the following examples of preparation given solely by way of non-limiting illustration.
reparation I
Obtaining of the hydrochloride of (2,6-dimethoxy-4-hydrox~pheily~ 3 piperi i_opropyl)-ketone 3~3~3 ~OC~13 HO~ CO-(CH2)3-N ~ , HCl (Example l; Code No. CRL 40746) 30.8 g (0.2 mole) oE 1,5-dimethoxy-3-hydroxy~
benzene, 34 g (0.2 mole) of piperidinobu-tyronitrile - 5 and 200 ml of chloro~enzene are in-troduced into a three-necked flask provided with stirring means; 28 c~ (0.2 mole) of aluminium chloride are then added slowly, then, maintaining the temperature between 14 and 20C, an anhydrous HC1 gas stream is passed through the resultant 10 reaction medium, with stirring, Eor 4.25 hrs. It is-left to stand at 4C for 20 hours then thrown on ice (to hy~rolyze -the ketimine hydrochloride which has formed~
and the lower aqueous phase is decanted and boiled in the presence of CXA black for 1 hour. It is filtered hot and the ~other liquor is cooled. A crystallized product and an oil are obtained. (After isolation and treatment, the oil will give the CRL 40747 (cf. Preparation II
hereinbelow). The crystallized product is filtered, washed over filter with ice water to free it of the oil which accompanies it. By recrystallization in water, a crystallized hydrate is obtained, yellow in colour, which, a~ter trtturation in ethanol, gives 21 g (yield 31~) of CRL 40746 in the form o~ a white crystalline powder, soluble in water. Inst.m.p.=214-215C (wi-th decomposi-tion)Preparation II
-Obtainin~ of the hydrochloride oE (2,4-dimeth_ XY-6~-hyc1roxyphe,1yl)-(3-plperidinopropyl1-ketone 113CO - ~ - CO-(CH2)3-N ~ , HCl OH (comparative Ex.CPl,Code No.CRL 40747) 5~
The oil which decants in preparation I herein-above, after hydrolysis of -the keti~,ine hydrochloride IV
then bo ilin~ of th~ a~ueous phase in the presence of carbon black, is extracted with chloroform.
The chloroform phase ls dried over Na2S04 in the pre-sence of carbon black. ~he solvent is evaporated and a rough po~der , yellow in colour, is obtained, which is recrystallized from the isopropanol-water mixture (100:2) v/v. 18.2 g (yield 26.6%) of CRL 40 747 is obtained, 10 in the form of a crystalline powder, pale cream in colour, very soluble in ~ater. Inst.m.p.=131-183C (~ith decom-position).
Part of the results of the tests undertaken on animals have been summarized hereinafter, and more par-15 ticularly those of the comparative tests relative to the products mentioned in Table I hereinafter, namely CRL
40 746 (Example 1), its structural analogues (CPl-CP6) and a reference peripheral vasodilator product which is LI. 1656 (CP7) mentioned above.
The peripheral vasodilator properties were studied in the male dog anaesthetized with nembutal (6 animals per dose and per product). The products to be compared are adminis-~red in solution in physiological serum i~ a volume of 6 ml/animal by the intravenous route (perfusion of 1 ml/min) and in a volume of 10 ml/
animal by the intrad~odenal route. With respect to the con-trols (the same animals receiving only the physio-logical serum), three pararneters are measured: the average arterial pressure (expressed in mm Hg; 1 mm Hg corresponds ko 1.333224 x 102 Pa), the cardiac frequen~
cy (expressed in beats/minu-te) and the Elow rate of the femoral artery (expressed in ml/min). The variations of these pararneters expressed in percen-tages, with respect to the controls are given in Tables II (intravenous administration) and III (intraduodenal administration) her~inafte:r.
Peripheral vasodilation ls translated under these circumstances by an increase in the flow rate of the femoral artery. Accord:ing to the present conditions of operation, a product is said to be a peripheral vasodilator agent if the flow rate o~
the femoral artery increases by at least 30% by intra venous administration, on the one hand, and by intra-duodenal adminstration on the other hand, without the variation in the arterial pressure bein~ greater 10 than -~10 or less than -10~.
The res~lts of Tables II and III hereinafter demonstrate the interest of CRL 40746 as perip~ral vaso-dilator. In fact, this product is, on the one hand, as active as the reference product CP7 (LL 1656) and, on the other hand, more effective than its analogues of the piperidino type such as, in particular, its isomer CPl (CRL 40747) and its homolo~ue CP2 (LL 1647) which p~sents a trihydroxylated phenyl' group.
More precisely, the CRL 40746 according to 20 the invent~on, administered by IV route and by ID route increases the flow rate of the femoral artery (varia-tion always greater than +30~), whilst its isomer CPl is (i) very weakly va'sodilato~ by the IV route (varla-tion always less than + 30~, but of the order of +20 to ~22~) and (ii) has hardly any vasodilator effect by ID route (it hasl rathermore, an antihypertensive eff~ct as it reduces the arterial pressure by more than 10~), and its trihydroxylated homologue CP2 which is vasodilator by IV route (from the dose of ~ mg/kg as indicated in British Paten-t No. 1 325 192 mentioned above), has virtually no vasodilator effect by ID route (variation of the flow rate of the ~'emoral artery by ID route -~17% with antihypertensive effect~
In cllnic, the C~L 40746 has given good re-sul-ts in human beings in the treatment of eschars.
3~
~' o o __ _ , ~ ,c C C
¢ o C~ o o , o .~ , U ~,J~ O ~D
cl CJ ;) ;) ~ Cl a 1~ U~
C~. Cl. ~ ,C~ h Cl~ t~.Q. ~ ~ ~ ~ c~. cn ~.o Cn ._ ._ . _ , ~Icr.
ti C ___, __ ~~ t~ 1 ri Z Z ' ~ ¢~ _ ~r~ O ~ O ~ ~ a 5 u '5 ~i 5 O ~ O ~ ~ I W555 ', rl _ O 5 0 ~ ~ 5'5~5 0 O ~ r~ I I I I u~ ~ D, g cu ~ _ _ (~
Ca'' ~10 5 ~ _ _ _ ~
3~3 T A B L E _I I
t~ariatit)n_r)t C i~` L~ IE~S . ftel ~llt~a~/ellCLI~:;
~ I r . i ~, t :L ~. ~ i r? r 1 i I I t I: r ~ s ~ l i Z F G Ci O C
_~ ~ Variations in ~
Prod-lct CC~de No. Dose 7~rtr ria~ I 11G~ Iai.~ Of cardi Ic ~, r ~ e e ~ r e ~f enl o ~ .,1 a r te ~y f r r- q ~ rl r: y ¦
Ex~p1s 1CP~L 40746 1,5 + ' + 3'. ~ 2 CP1 CRL 40747 1, S + 2 -r 20 + 5 CP2 I.L, 1647 1,5 + 1 + 10 - 2 CP3 _ 1~5 + 3 + i3 - 1 CP4 _ 1,5 - 2 ~ 3 - 2 CP5 _ 1,5 - 1 - 5 + 1 CP6 _ 1~5 + 1 + 7 + 3 . L-L 1656 1,5 + 33 _ _ Examp1~ 1 CRL 40746 3 + 5 + 35 + 3 CP1CRl. 40747 3 - 12 + 22 ~ 2 CP2 LL 1647 3 + 1 -~ 18 + 3 CP3 _ 3 - 2 -t 8 - 6 CP4 _ 3 - 5 + 2 +1 CP5 _ 3 _ ~ - 8 ~ 3 CP6 _ 3 ~ 1 + 5 ~ 2 .
CP7 LL 1656 3 - 2 + 36 + 6 . _ .
Example 1 CRL 40746 6 t 5 + 41 + 3 CP1 CRL 40747 6 - 18 + 22 ~ 15 CP2 LL 1647 6 + ~ + 34 + 3 CP3 _ 6 + 5 + 3 - 1 CP4 _ 6 + 1 -1- 2 ~ 1 CPS _ 6 ~ 2 - 3 -~ 2 CP6 _ 6 ~ 8 + 2 + 1 CP7 LL 165fi 6 - 2 + 39 ~_ 3~ii3 T A B L E _ I I I
Variation r~f ~ e ;~lrc~ &tarr .~ter intr~duod~nal ~,di~ c l . c:-~Jan in t~le ùn~,r ~ eti~ .a~, _ -- - ----L ~ aria-tions in ~/0 - ' ~~
Prod uc t r r~ c~ e ~O . D os e _ _ m,/!;g Artr-eL-ial. t`lG~ ra-lC af CaIoiac _ ~- r ~ C ~ I ) r ;- I ~ 1 u ~ r ~ r ~ r ~ C ~rr Ex ,mp1e 1 CRL 40746 20 ~ ~ 83 _ 5 CPl CRL 40747 20 - 15 ~ 10 - 2 CP2 LL 1647 2 0 - 12 + 17 - 1 CP3 _ 20 - 8 - 5 - 2 CP4 _ 20 - 1 - 2 + 3 CP5 _ 20 0 ~ 2 ~ 1 CP6 _ 20 + 6 + 1 ~4 CP 7 LL 16 5 6 2 0 __ + 84 ~k 5
Claims (4)
- The embodiments of the invention in which an exclusive property of privilege is claimed, are defined as follows:
l. A method for preparing 2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)-ketone and its addition salts which comprises stoichiometrically reacting 1,5-dimethoxy-3-hydroxybenzene of the formula:
with piperidinobutyronitrile of the formula in the presence of AlCl3 and by passing through the reaction medium a HCl gas stream for at least 2 hours, at 10-20°C, then hydrolyzing the ketimine derivative thus formed and which corresponds to the formula and if desired converting the product to an addition salt. - 2. A method according to claim 1 including converting the product with hydrochlorine and to the hydrochloride addition salt.
- 3. (2,6-dimethoxy-4-hydroxyphenyl)-(3-piper-idinopropyl)- ketone and its addition salts, when prepared by the process of claim 1 or any obvious chemical equivalent thereof.
- 4. (2,6-dimethoxy-4-hydroxyphenyl)-(3-piper-idinopropyl)-ketone hydrochloride, when prepared by the process of claim 2 or any obvious chemical equivalent thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8107597A FR2504136A1 (en) | 1981-04-15 | 1981-04-15 | (2,6-DIMETHOXY-4-HYDROXYPHENYL) - (3-PIPERIDINOPROPYL) -CETONE AND ITS ADDITION SALTS, THERAPEUTIC USE AND PREPARATION METHOD |
FR8107597 | 1981-04-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1183853A true CA1183853A (en) | 1985-03-12 |
Family
ID=9257449
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000400489A Expired CA1183853A (en) | 1981-04-15 | 1982-04-05 | (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)- keton and its acid salts, use thereof in therapeutics and method for preparing same |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP0063075B1 (en) |
JP (1) | JPS57181073A (en) |
AT (1) | ATE8258T1 (en) |
CA (1) | CA1183853A (en) |
DE (1) | DE3260320D1 (en) |
DK (1) | DK156002C (en) |
ES (1) | ES511431A0 (en) |
FR (1) | FR2504136A1 (en) |
GR (1) | GR75918B (en) |
IE (1) | IE52871B1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4755522A (en) * | 1986-04-28 | 1988-07-05 | Laboratoire L. Lafon | Derivatives of N-[3-(2,4,6-trimethoxybenzoyl)propyl]piperidine, and their use in therapeutics |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2534912B1 (en) * | 1982-10-26 | 1985-06-28 | Lafon Labor | NOVEL (2,4,6-TRIMETHOXYPHENYL) - (3-PIPERIDINOPROPYL) -CETONE DERIVATIVES, USE IN THERAPEUTICS AND METHOD OF PREPARATION |
JP2569940Y2 (en) * | 1992-02-14 | 1998-04-28 | 株式会社ヨシコー | Friction clutch |
EP0700383B1 (en) * | 1993-05-26 | 1998-09-23 | Syntex (U.S.A.) Inc. | Novel 1-phenylalkanone 5-ht 4? receptor ligands |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2092133B1 (en) * | 1970-05-06 | 1974-03-22 | Orsymonde | |
FR2134218A1 (en) * | 1971-04-27 | 1972-12-08 | Penciolelli Madeleine | Phloroglucinol aminoketones - vasodilators and antispasmodics |
FR2404003A1 (en) * | 1977-09-26 | 1979-04-20 | Lafon Labor | NEW DERIVATIVES OF PHLOROGLUCINOL, THEIR PROCESS FOR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS |
GB2004883B (en) * | 1977-09-26 | 1982-03-17 | Lafon Labor | Phloroglucinol derivatives their method of preparation and their use as pharmaceuticals |
-
1981
- 1981-04-15 FR FR8107597A patent/FR2504136A1/en active Granted
-
1982
- 1982-03-29 IE IE742/82A patent/IE52871B1/en unknown
- 1982-03-30 AT AT82400577T patent/ATE8258T1/en not_active IP Right Cessation
- 1982-03-30 EP EP82400577A patent/EP0063075B1/en not_active Expired
- 1982-03-30 DE DE8282400577T patent/DE3260320D1/en not_active Expired
- 1982-04-05 CA CA000400489A patent/CA1183853A/en not_active Expired
- 1982-04-06 GR GR67826A patent/GR75918B/el unknown
- 1982-04-14 ES ES511431A patent/ES511431A0/en active Granted
- 1982-04-14 DK DK167782A patent/DK156002C/en not_active IP Right Cessation
- 1982-04-14 JP JP57063198A patent/JPS57181073A/en active Granted
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4755522A (en) * | 1986-04-28 | 1988-07-05 | Laboratoire L. Lafon | Derivatives of N-[3-(2,4,6-trimethoxybenzoyl)propyl]piperidine, and their use in therapeutics |
Also Published As
Publication number | Publication date |
---|---|
EP0063075B1 (en) | 1984-07-04 |
JPS57181073A (en) | 1982-11-08 |
DK156002C (en) | 1989-11-06 |
DK156002B (en) | 1989-06-12 |
JPH039112B2 (en) | 1991-02-07 |
ATE8258T1 (en) | 1984-07-15 |
IE52871B1 (en) | 1988-03-30 |
ES8304105A1 (en) | 1983-02-16 |
IE820742L (en) | 1982-10-15 |
DK167782A (en) | 1982-10-16 |
GR75918B (en) | 1984-08-02 |
FR2504136A1 (en) | 1982-10-22 |
DE3260320D1 (en) | 1984-08-09 |
ES511431A0 (en) | 1983-02-16 |
FR2504136B1 (en) | 1984-02-10 |
EP0063075A1 (en) | 1982-10-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0159566B1 (en) | Novel piperazine derivatives, processes for production thereof, and pharmaceutical compositions comprising said compounds as active ingredient | |
IE48368B1 (en) | Imidazole derivatives | |
CA1183853A (en) | (2,6-dimethoxy-4-hydroxyphenyl)-(3-piperidinopropyl)- keton and its acid salts, use thereof in therapeutics and method for preparing same | |
EP0097340B1 (en) | Piperazine derivatives, a process for preparing them and pharmaceutical compositions | |
US4605672A (en) | Diethylaminoalkoxybenzhydrol derivatives, process for their preparation and pharmaceutical compositions containing them | |
HU211134A9 (en) | Butynylamine derivatives and their production | |
JPH0316952B2 (en) | ||
US4551465A (en) | Piperidine derivatives and pharmaceutical compositions containing them | |
DE2819896A1 (en) | CHROME DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THE SAME | |
US4206217A (en) | 3-[4-(1,3-Diazacycloalken-2-yl)-phenyl]-1,2-benzisothiazoles, their manufacture, and drugs containing these compounds | |
US4568765A (en) | Isoprenylamine derivatives | |
CA1212944A (en) | Phenyl-(3-aminopropyl)-ketone derivatives | |
US5118682A (en) | P-hydroxy phenone derivatives and the use thereof | |
EP0110747B1 (en) | (2,4,6-trimethoxyphenyl)-(3-piperidinopropyl)-ketone derivatives, their therapeutical use and preparation process | |
CA1293731C (en) | Derivatives of n-¬3-(2,4,6-trimethoxybenzoyl) propyl| piperidine, their preparation processes and their use in therapeutics | |
CA1085847A (en) | Piperazine derivatives, a process for their preparation and their applications | |
IE54987B1 (en) | Benzhydrylsulfinylethylamine derivatives | |
US5274000A (en) | Benzofuran and benzothiophene derivatives, anti-hyperuricemia agents | |
KR20010020378A (en) | Processes for Preparing Benzothiophenes | |
HU178272B (en) | Process for preparing new piperazino-methane-imino derivatives | |
DE2121996B2 (en) | Dibasic ethers of 2,6- and 2,7-dihydroxyanthraquinones of manufacture and pharmaceutical preparation | |
FI78913C (en) | FOERFARANDE FOER FRAMSTAELLNING AV NYA, TERAPEUTISKT ANVAENDBARA 1- (AMINOALKOXIFENYL) -1-PHENYLPROPANOLER. | |
EP0066919B1 (en) | 4-alkyl-thiophenyl-ethanolamines, having an activity on the cerebral circulation, the blood platelet-aggregation and the lipemia | |
PT78281B (en) | 2-aminoethyl-pyridine or -pyrazine derivatives | |
DE1620128A1 (en) | Process for the preparation of new organic amides |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MKEC | Expiry (correction) | ||
MKEX | Expiry |