CA1212944A - Phenyl-(3-aminopropyl)-ketone derivatives - Google Patents
Phenyl-(3-aminopropyl)-ketone derivativesInfo
- Publication number
- CA1212944A CA1212944A CA000439563A CA439563A CA1212944A CA 1212944 A CA1212944 A CA 1212944A CA 000439563 A CA000439563 A CA 000439563A CA 439563 A CA439563 A CA 439563A CA 1212944 A CA1212944 A CA 1212944A
- Authority
- CA
- Canada
- Prior art keywords
- ketone
- trimethoxyphenyl
- group
- reacting
- hexamethyleneiminopropyl
- 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
- YVZLEAGJRDBABM-UHFFFAOYSA-N 4-amino-1-phenylbutan-1-one Chemical class NCCCC(=O)C1=CC=CC=C1 YVZLEAGJRDBABM-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- SOKKYQNPGLERHO-UHFFFAOYSA-N 4-(azepan-1-yl)-1-(2,4,6-trimethoxyphenyl)butan-1-one Chemical compound COC1=CC(OC)=CC(OC)=C1C(=O)CCCN1CCCCCC1 SOKKYQNPGLERHO-UHFFFAOYSA-N 0.000 claims abstract description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 claims description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012429 reaction media Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- -1 1,3,5-trimenthoxybenzene Chemical compound 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 150000004658 ketimines Chemical class 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- OQPSAQBHEQYYMJ-UHFFFAOYSA-N 4-(azepan-1-yl)butanenitrile Chemical compound N#CCCCN1CCCCCC1 OQPSAQBHEQYYMJ-UHFFFAOYSA-N 0.000 claims description 5
- ZFCFBWSVQWGOJJ-UHFFFAOYSA-N 4-chlorobutanenitrile Chemical compound ClCCCC#N ZFCFBWSVQWGOJJ-UHFFFAOYSA-N 0.000 claims description 5
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 5
- VUKSFISGFOJLPO-UHFFFAOYSA-N 4-(azepan-1-yl)-1-(2,4,6-trimethoxyphenyl)butan-1-one hydrochloride Chemical compound Cl.COC1=CC(OC)=CC(OC)=C1C(=O)CCCN1CCCCCC1 VUKSFISGFOJLPO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 239000003849 aromatic solvent Substances 0.000 claims 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 2
- 229940124549 vasodilator Drugs 0.000 abstract description 9
- 239000003071 vasodilator agent Substances 0.000 abstract description 9
- 239000003795 chemical substances by application Substances 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 3
- 230000036471 bradycardia Effects 0.000 abstract description 2
- 208000006218 bradycardia Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 210000000748 cardiovascular system Anatomy 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 12
- 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 9
- 241000282472 Canis lupus familiaris Species 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- 230000002921 anti-spasmodic effect Effects 0.000 description 4
- 239000000810 peripheral vasodilating agent Substances 0.000 description 4
- 229960002116 peripheral vasodilator Drugs 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 3
- 230000000059 bradycardiac effect Effects 0.000 description 3
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 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 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- POLIOTNRLQFNRU-UHFFFAOYSA-N 4-piperidin-1-yl-1-(2,4,6-trimethoxyphenyl)butan-1-one;hydrochloride Chemical compound Cl.COC1=CC(OC)=CC(OC)=C1C(=O)CCCN1CCCCC1 POLIOTNRLQFNRU-UHFFFAOYSA-N 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 101100112336 Homo sapiens CASP5 gene Proteins 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100273286 Mus musculus Casp4 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000146 antalgic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000002585 base Substances 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
- 230000017531 blood circulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 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
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- ANFZRGMDGDYNGA-UHFFFAOYSA-N ethyl acetate;propan-2-ol Chemical compound CC(C)O.CCOC(C)=O ANFZRGMDGDYNGA-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
-
- 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
- A61P9/12—Antihypertensives
-
- 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
- C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A B S T R A C T
The present invention relates to new phenyl-(3-amino-propyl)-ketone derivatives, namely (2, 4, 6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone and its addition salts.
The invention also relates to the method for preparing these new derivatives and to their use in therapeutics for the treatment of disorders of the cardiovascular system as vasodilator and bradycardia agents intraveniously and intraduodenially.
The present invention relates to new phenyl-(3-amino-propyl)-ketone derivatives, namely (2, 4, 6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone and its addition salts.
The invention also relates to the method for preparing these new derivatives and to their use in therapeutics for the treatment of disorders of the cardiovascular system as vasodilator and bradycardia agents intraveniously and intraduodenially.
Description
~ ) - lZ~:9~L
PHE~YL-(3-A~IINOPROPYL)-~ETONE DERIVATIVES
B~CKGROUND OF THE INVENTION
The present invention relates as industrial products to novel derivatives of phenyl-(3-aminopropyl)-ketone, namely (2,4,6-trimethGxyphenyl)-(3-hexamethylene-iminopropyl)-ketone and its addition salts. It relates also to the use in therapeutics and the process of preparing these novel products.
_ It is known that therz has already been described in the past a certain number of deri~atives of the (alkoxy-and hydroxy-phenyl)-(aminoalkyl)-ketone type. See for this purpose French Patents Nos. 1,492,256 and 5636M
and the article of A. BOUCHERLE et al., Chimie Therapeutique 3 (No ~), 256-259, (1968), on the one hand, British Patents No. 1,078,975 and No. 1,115,992, on the other hand, and finally USP No. 3,895,030, on the other hand.
It is known that the above-indicated derivatives of the (alkoxy- and hydroxy-phenyl)-(aminoalkyl~-ketone type have been presented as anti-inflammatory, antalgic, anti~yretic, antispasmodic, tranquilizing agents, peripheral vasodilators or bradycardiac agents.
- Finally it is known, particularly from French Patent ~o. 2 404 003 that there is no structur~-activity relationship within the family of (alkoxy- and hydroxy-phenyl)-(aminoalkyl)-ketones, the pharmacological effects being modified or disappearing according to the nature of the substituents of the pheDyl group, the nature o~
the amino group and ~inally the nature of the alkyl group present between the CO group and the amino group.
GENERAL DESCRIPTION OF THE INVENTION
It has just been found surprisiDgly that (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone, which is included in the family o~ the (alkoxyphenyl)-(3-aminopropyl)-~etones envisaged in the description 294~
of the aforesaid American Patent No. 3,39j,030, without being specifically exemplified, has, with its addition salts, pharmacological properties interesting in thera-peutics and not obvious taking into account the teaching S o~ the prior art.
In particular, it was not obvious from the teaching of American Patent No. 3,895,030 which describes particularly (i1 (2,4,~-trimethoxyphenyl)-(3-pyrrolidino-propyl~-ketone hydrochloride a product marketed under the name "FO~ZYLANE" [International Common Name : BUFLO~IEDIL
HYDROCHLORIDE) and having Code No. LL 16j6~ which is a reference peripheral vasodilator agent, and (ii) (2,4,6-trimethoxyphenyl)-(3-piperidinopropyl)-ketone hydrochloride [Code No. LL 1647~ which is essentially an antispasmodic l; agent, that (2,4,6-trimethoxyphenyl)-(3-hexamethylene-iminopropyl)-ketone hydrochloride ~Code No. CRL 41080 according to the invention is more ef~ective than LL 1656 as a vasodilator and bradycardiac agent, and deYoid o~
antispasmodic effect unlike LL 1647. In brief, there ?O is no structure-activity relRtionship when one passes from the pyrrolidino derivative to the piperidino derivative and then to the hexamethyleneimino derivati~e.
The novel derivatives of phenyl-(3-aminopropyl)-ketone according to the invention are characterized in 25 that they are selected from the group consisting of (i) (2,4,6-trimethoxyphenyl)-{3-hexamethylene-imino-propyl)-ketone which has the developed ~ormula ~C~l3 C~O- ~ -CO~tCH~)3-N 3 (1) ~l3 and, (ii~ its addition salts.
9y addition salts, is meant here, on the one 35 hand, the acid addition salts obtained by the reaction .
~ ) -of the free base of formula I with inorganic and organic acids, and, on the other hand, ammonium salts. Among the acids usable to salify the bass of formula I, may be mentioned particularly hydrochloric, hydrobromic, acetic, formic, propionic, oxalic, fumaric, maleic, suc-cinic, benzoic, cinnamic, mandelic, citric, malic, tartaric aspartic~ ~lutamic~ methanesul~onic, p-toluenesulfonic acids. Among the compounds enabling ammonium salts to be obtained, may be mentioned particularly ICH3 and ClCH3.
The acid addition salts are the preferred salts, (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride being particularly interesting therapeutic-ally.
The base of formula I may be prepared by a method known in itself by the application of conventional reaction mechanisms. The process which is recommended according to the invention comprises :
a) the reaction of hexamethyleneimine with 4-chloro-butyronitrile, then b) the reaction of 4-hexamethyleneimino-butyronitrile so obtained with 1,3,5-trimethoxybenzene in the presence of a flow of HCl gas at a temperature comprised between 5C and 0C for at least 2h in an anhydrous solvent (particularly selected rrom among the group consisting of benzene, toluene, chlorobenzene and their mixtures), then the -subjection of the ketimine derivative thus obtained to a hydrolysis reaction for at least O.Sh at the reflux temperature of the reaction medium.
Advantageously, the reaction of stage a) ~ill be carried out from 2 moles or hexamethyleneimine for 1 mole of 4-chlorobutyronitrile in the pre~ence of an aromatic hydrocarbon such as benzene or toluene, for at least 4h at the reflux temperature of the reaction medium; and the reaction or stage b) between 4-hexamethyl-eneimi`no-butyronitrile and 1,3,5-trimethoxybenzene will be carried out under stoichiometric conditions in chloro-:
.... ~ ... ~
~Z3L~
benzene, the ketimine derivative formed being then hydro-lyzed l~ithout being isolated.
(2,4,6-trimethoxyphenyl)-(3-hexamethyleneimino-propyl)-ketone and its salts are agents useful in the treatment of disorders of the cardiovascular ~ystem;
they act as vasodilator and brady~ardiac agents intraven-ously and intraduodenally. According to the invention, there is recommended a therapeutic composition which is characterized in that it comprises, in association with a physiologically acceptable excipient, at least one compound se~ected from among the group constituted by (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl~-ketone and its non-toxic additior salts. In such a composition, the actiYe ingredient takes part. of course, in a pharmaceutically effective amount.
Other advanta~es and features o~ the invention will be better understood on reading the description which follows (i) of an example of the preparation which i5 in no way limiting but given purely by way of illustra-tion, and (ii) results of pharmacological tests whichhave been carried out.
DESCRIPTIO~ OF PREFERRED EMBODIMENTS
PREPARATIO~
Preparation of (2~4~6-trimethoxyphen~])-(3~hexameth~1ene-____________________ _ ___________ _________________s_ _____ iminopropyl)-ketone hydrochlor~de (Code No. CRL 41 o80).
a) 4-He~amethyleneimino-butyronitrile ___________________________________ Into a solution under reflux of 50 g (~.505 mole) of hexamethyleneimine in 80 ml of ben~ene, are run in 15 min 26.1 g (0.252 mole) of 4-chlorobutyronitrile.
The reflux is continued 4h, the cold reaction medium 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 giYe 29.3 g (yield 70%) of 4-hexamethyl-eneimino-butyronitrile which is in the ~orm of a colorless .~
,, ~z~9~L~
s oil. BP6 7 m Hg = 126C (6-7 mm Hg corresponding approxi-mately to 800-933 p~scals).
b) CRL 4t 080 A current of dry HCl gaz is passed for 2.Sh between -5C and 0C into a solution of 16.8 g (0~10 mole) of 1,3,5-trimethoxybenzene and 16.6 g (0.10 mole) of 4-hexamethyleneimino-butyronitrile in solution in 115 ml of anhydrous chlorobenzene. The suspension is left in the cold between 0C and +4C overnight and the reaction medium is extracted with water. The aqueous phase is take~ to re~lux for lh3 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 hydrochloric ethanol. After puri~ication of the precipitate by crystallization in the mixture ethyl acetate-isopropanol (8:7)v/v, 19.5 ~tyield from stage b is obtained:~2.5~-, global yield: 38.75~o) of CRL 41 o80 in the form of a water-soluble white powder. MPinSt (Kofler~ = 150C.
Belo~Y are summarized the results of the pharmaco-logical tests which were undertaken with CRL 41 080.
I - VASODILATOR PROPERTIES OF CRL 41 o80 , A - EE~IORAL VASODILATOR ACTION INTRAVENOUSLY
Two dogs (average weight 12.4 kg) anesthetized with pentobarbital received CRL 41 o80 intravenously, in perfusion of 6 min, at successive doses of twice 1 mg/kg, then 2 and 4 mg/kg every 60 min. For comparison, these animals received at the end of the test a perfusion of 6 mg/kg I.V. of a known reference product, the aforesaid LL 1656.
It is observed that CRL 41 o80 does not modify the blood pressure nor the heart rate; the -femoral flow rate increases during the period of the perfusion from 1 mg/kg, the effect is reproducible and increases moderately with the dose. LL 1656, at the dose of 6 mg/kg, increases the femoral flow rate l0ss than 1 mg/kg of CRL 41 080.
9~L
B - VA.~ODILATOR ACTION INTRADUODENALLY
_________________________._______ Four dogs (average weight 15.7 kg) anesthetized with nembutal received CRL 41 o80 intraduodenally, at the successive doses of 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg and 5 mg/kg; three of these dogs then received 10 mg/kg of CRL 41 OSO. The blood pressure, the heart rate, the femoral artery flol-~ rate~ the Yertebral artery flow rate, the rectal and skin temperatures were measured.
It was obserYed that CRL 41 o80 distinctly increased the femoral flow rate from the dose of 5 mg/kg;
this effect lasted more than one hour. In addition, it seems that the ~ertebral flow rate was reduced, but this effect was not statistically significant.
C - DURATION 0~ V~SODILATOR ACTION
______________________________ Three dogs (average weight 11.1 kg) received CRL 41 o80 intraduodenally at the dose of 5 mg/kg at two ti~es (period between the two administrations: 90 min~
then 6 mg/~g l.D. of LL 1656 and, 2 hours later, a further administration of 5 mg/kg I.D. of CRL 41 080.
It was observed that CRL 41 080 increased the femoral flow rate at 5 mg/kg I.D.3 this effect was a maximum at 30 min 3 lost hal~ its intensity at 60 ~in and disappeared at 120 min; the other parameters measured were not modified. A second administration of 5 mO/kg of CRL 41 o80 had a more intense effect on the fe~oral flow rate, the effect was a ma~imum at 30 min, then gradual-ly decreased, but was still present at 120 min. An adminis-tration of 6 mg/kg I.D. of LL 1656 resulted in an insrease in the femoral flow rate of average intensity, slow to develop and then the maximum of the effect was obtained at 120 min. This cinetics of action of LL 1656 intraduo-denally is not the usual cinetics (maximum of the effect at 30 or 60 min and gradual disappearance then of the latter); it may be thought that the prior administration of CRL 41 o80 modifi~s the action of LL 1656. An additional dose of S mg/kg I.D. of 41 080 does not further increase the femoral flow rate but results in a hypotension and , -: ~2~
and a bradycardia. In these dogs, the CRL 41 080 does not diminish the vertebral flow rate.
D - CO~CLUSI0~
__________ Results of the tests summarized above establish that CRL 41 080 is a peripheral vasodilator (particularly a femoral vasodilator) and a particularly interesting bradycardiac agent. CRL 41 o80 is more active as a ~aso-dilator than LL 1656, its pyrrolidino homolog, and does not have the antispasmodic properties of its piperidino homolo~.
II - CO~IPARATIVE TESTS
There are colleoted in Tables I and II below the results of the additional tests which were under-taken to compare the CRL 41 o80 sccording to the invention with its pyrroli~ino (LL 16~6) and piperidino (LL 1647) homologs 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 vasodila~or effeet, on the other hand. The LD-50 I.V. was determined on batches of 10 male mice; the minimum vasodilator dose was determined on a batch of S dogs serving as controls with respect to themselves and each receiving a doae of the product to be tested every 2.5 hours.
Table II relates to the variations in the arte-rial blood pressures (systolic, diastolic, dif~erential and average~, the heart rate and the femoral artery blood flow. These Yariations were determined intravenously on the same aforementioned batch o~ 5 anesthetized dogs.
In the course of clinieal assays, good results in ~an were obtained by ad~inistering CRL 41 080 orally ~three capsules daily each containing 100 mg of aotive ingredient) and by injection (I~Vo route or I.M. route, one ~mpoule of 5 ml per day containing 40 mg of aotive principle in a physiological sallne ~olution).
~ 294~
TABLE I
minimum dose inducing Product LD-50 I.V. in the anesthetized mouse dog a Pemoral vaso-dilator effect I~Va I.D.
. . .
CRL 41 o80 (a) 96 + 3 mg/kg 1 mg/kg 5 ~g/~
. , , _. ~
LL 1656 (b)(c) 60 + 2.2 mg/kg5 mg/kg 6 mglkg :.
LL ~6~47 (c) 68 + 4 mg/kg 5 mg/kg (d) , - . ~ . - .
Notes (a) product according to the invention (b) re~erence peripheral vasodilator -(c~ descri~ed in USP No. 3,895jO30 (d) no vasodilator effect I.D.
. ~ , , , ,, . .
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PHE~YL-(3-A~IINOPROPYL)-~ETONE DERIVATIVES
B~CKGROUND OF THE INVENTION
The present invention relates as industrial products to novel derivatives of phenyl-(3-aminopropyl)-ketone, namely (2,4,6-trimethGxyphenyl)-(3-hexamethylene-iminopropyl)-ketone and its addition salts. It relates also to the use in therapeutics and the process of preparing these novel products.
_ It is known that therz has already been described in the past a certain number of deri~atives of the (alkoxy-and hydroxy-phenyl)-(aminoalkyl)-ketone type. See for this purpose French Patents Nos. 1,492,256 and 5636M
and the article of A. BOUCHERLE et al., Chimie Therapeutique 3 (No ~), 256-259, (1968), on the one hand, British Patents No. 1,078,975 and No. 1,115,992, on the other hand, and finally USP No. 3,895,030, on the other hand.
It is known that the above-indicated derivatives of the (alkoxy- and hydroxy-phenyl)-(aminoalkyl~-ketone type have been presented as anti-inflammatory, antalgic, anti~yretic, antispasmodic, tranquilizing agents, peripheral vasodilators or bradycardiac agents.
- Finally it is known, particularly from French Patent ~o. 2 404 003 that there is no structur~-activity relationship within the family of (alkoxy- and hydroxy-phenyl)-(aminoalkyl)-ketones, the pharmacological effects being modified or disappearing according to the nature of the substituents of the pheDyl group, the nature o~
the amino group and ~inally the nature of the alkyl group present between the CO group and the amino group.
GENERAL DESCRIPTION OF THE INVENTION
It has just been found surprisiDgly that (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone, which is included in the family o~ the (alkoxyphenyl)-(3-aminopropyl)-~etones envisaged in the description 294~
of the aforesaid American Patent No. 3,39j,030, without being specifically exemplified, has, with its addition salts, pharmacological properties interesting in thera-peutics and not obvious taking into account the teaching S o~ the prior art.
In particular, it was not obvious from the teaching of American Patent No. 3,895,030 which describes particularly (i1 (2,4,~-trimethoxyphenyl)-(3-pyrrolidino-propyl~-ketone hydrochloride a product marketed under the name "FO~ZYLANE" [International Common Name : BUFLO~IEDIL
HYDROCHLORIDE) and having Code No. LL 16j6~ which is a reference peripheral vasodilator agent, and (ii) (2,4,6-trimethoxyphenyl)-(3-piperidinopropyl)-ketone hydrochloride [Code No. LL 1647~ which is essentially an antispasmodic l; agent, that (2,4,6-trimethoxyphenyl)-(3-hexamethylene-iminopropyl)-ketone hydrochloride ~Code No. CRL 41080 according to the invention is more ef~ective than LL 1656 as a vasodilator and bradycardiac agent, and deYoid o~
antispasmodic effect unlike LL 1647. In brief, there ?O is no structure-activity relRtionship when one passes from the pyrrolidino derivative to the piperidino derivative and then to the hexamethyleneimino derivati~e.
The novel derivatives of phenyl-(3-aminopropyl)-ketone according to the invention are characterized in 25 that they are selected from the group consisting of (i) (2,4,6-trimethoxyphenyl)-{3-hexamethylene-imino-propyl)-ketone which has the developed ~ormula ~C~l3 C~O- ~ -CO~tCH~)3-N 3 (1) ~l3 and, (ii~ its addition salts.
9y addition salts, is meant here, on the one 35 hand, the acid addition salts obtained by the reaction .
~ ) -of the free base of formula I with inorganic and organic acids, and, on the other hand, ammonium salts. Among the acids usable to salify the bass of formula I, may be mentioned particularly hydrochloric, hydrobromic, acetic, formic, propionic, oxalic, fumaric, maleic, suc-cinic, benzoic, cinnamic, mandelic, citric, malic, tartaric aspartic~ ~lutamic~ methanesul~onic, p-toluenesulfonic acids. Among the compounds enabling ammonium salts to be obtained, may be mentioned particularly ICH3 and ClCH3.
The acid addition salts are the preferred salts, (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride being particularly interesting therapeutic-ally.
The base of formula I may be prepared by a method known in itself by the application of conventional reaction mechanisms. The process which is recommended according to the invention comprises :
a) the reaction of hexamethyleneimine with 4-chloro-butyronitrile, then b) the reaction of 4-hexamethyleneimino-butyronitrile so obtained with 1,3,5-trimethoxybenzene in the presence of a flow of HCl gas at a temperature comprised between 5C and 0C for at least 2h in an anhydrous solvent (particularly selected rrom among the group consisting of benzene, toluene, chlorobenzene and their mixtures), then the -subjection of the ketimine derivative thus obtained to a hydrolysis reaction for at least O.Sh at the reflux temperature of the reaction medium.
Advantageously, the reaction of stage a) ~ill be carried out from 2 moles or hexamethyleneimine for 1 mole of 4-chlorobutyronitrile in the pre~ence of an aromatic hydrocarbon such as benzene or toluene, for at least 4h at the reflux temperature of the reaction medium; and the reaction or stage b) between 4-hexamethyl-eneimi`no-butyronitrile and 1,3,5-trimethoxybenzene will be carried out under stoichiometric conditions in chloro-:
.... ~ ... ~
~Z3L~
benzene, the ketimine derivative formed being then hydro-lyzed l~ithout being isolated.
(2,4,6-trimethoxyphenyl)-(3-hexamethyleneimino-propyl)-ketone and its salts are agents useful in the treatment of disorders of the cardiovascular ~ystem;
they act as vasodilator and brady~ardiac agents intraven-ously and intraduodenally. According to the invention, there is recommended a therapeutic composition which is characterized in that it comprises, in association with a physiologically acceptable excipient, at least one compound se~ected from among the group constituted by (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl~-ketone and its non-toxic additior salts. In such a composition, the actiYe ingredient takes part. of course, in a pharmaceutically effective amount.
Other advanta~es and features o~ the invention will be better understood on reading the description which follows (i) of an example of the preparation which i5 in no way limiting but given purely by way of illustra-tion, and (ii) results of pharmacological tests whichhave been carried out.
DESCRIPTIO~ OF PREFERRED EMBODIMENTS
PREPARATIO~
Preparation of (2~4~6-trimethoxyphen~])-(3~hexameth~1ene-____________________ _ ___________ _________________s_ _____ iminopropyl)-ketone hydrochlor~de (Code No. CRL 41 o80).
a) 4-He~amethyleneimino-butyronitrile ___________________________________ Into a solution under reflux of 50 g (~.505 mole) of hexamethyleneimine in 80 ml of ben~ene, are run in 15 min 26.1 g (0.252 mole) of 4-chlorobutyronitrile.
The reflux is continued 4h, the cold reaction medium 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 giYe 29.3 g (yield 70%) of 4-hexamethyl-eneimino-butyronitrile which is in the ~orm of a colorless .~
,, ~z~9~L~
s oil. BP6 7 m Hg = 126C (6-7 mm Hg corresponding approxi-mately to 800-933 p~scals).
b) CRL 4t 080 A current of dry HCl gaz is passed for 2.Sh between -5C and 0C into a solution of 16.8 g (0~10 mole) of 1,3,5-trimethoxybenzene and 16.6 g (0.10 mole) of 4-hexamethyleneimino-butyronitrile in solution in 115 ml of anhydrous chlorobenzene. The suspension is left in the cold between 0C and +4C overnight and the reaction medium is extracted with water. The aqueous phase is take~ to re~lux for lh3 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 hydrochloric ethanol. After puri~ication of the precipitate by crystallization in the mixture ethyl acetate-isopropanol (8:7)v/v, 19.5 ~tyield from stage b is obtained:~2.5~-, global yield: 38.75~o) of CRL 41 o80 in the form of a water-soluble white powder. MPinSt (Kofler~ = 150C.
Belo~Y are summarized the results of the pharmaco-logical tests which were undertaken with CRL 41 080.
I - VASODILATOR PROPERTIES OF CRL 41 o80 , A - EE~IORAL VASODILATOR ACTION INTRAVENOUSLY
Two dogs (average weight 12.4 kg) anesthetized with pentobarbital received CRL 41 o80 intravenously, in perfusion of 6 min, at successive doses of twice 1 mg/kg, then 2 and 4 mg/kg every 60 min. For comparison, these animals received at the end of the test a perfusion of 6 mg/kg I.V. of a known reference product, the aforesaid LL 1656.
It is observed that CRL 41 o80 does not modify the blood pressure nor the heart rate; the -femoral flow rate increases during the period of the perfusion from 1 mg/kg, the effect is reproducible and increases moderately with the dose. LL 1656, at the dose of 6 mg/kg, increases the femoral flow rate l0ss than 1 mg/kg of CRL 41 080.
9~L
B - VA.~ODILATOR ACTION INTRADUODENALLY
_________________________._______ Four dogs (average weight 15.7 kg) anesthetized with nembutal received CRL 41 o80 intraduodenally, at the successive doses of 0.5 mg/kg, 1 mg/kg, 2.5 mg/kg and 5 mg/kg; three of these dogs then received 10 mg/kg of CRL 41 OSO. The blood pressure, the heart rate, the femoral artery flol-~ rate~ the Yertebral artery flow rate, the rectal and skin temperatures were measured.
It was obserYed that CRL 41 o80 distinctly increased the femoral flow rate from the dose of 5 mg/kg;
this effect lasted more than one hour. In addition, it seems that the ~ertebral flow rate was reduced, but this effect was not statistically significant.
C - DURATION 0~ V~SODILATOR ACTION
______________________________ Three dogs (average weight 11.1 kg) received CRL 41 o80 intraduodenally at the dose of 5 mg/kg at two ti~es (period between the two administrations: 90 min~
then 6 mg/~g l.D. of LL 1656 and, 2 hours later, a further administration of 5 mg/kg I.D. of CRL 41 080.
It was observed that CRL 41 080 increased the femoral flow rate at 5 mg/kg I.D.3 this effect was a maximum at 30 min 3 lost hal~ its intensity at 60 ~in and disappeared at 120 min; the other parameters measured were not modified. A second administration of 5 mO/kg of CRL 41 o80 had a more intense effect on the fe~oral flow rate, the effect was a ma~imum at 30 min, then gradual-ly decreased, but was still present at 120 min. An adminis-tration of 6 mg/kg I.D. of LL 1656 resulted in an insrease in the femoral flow rate of average intensity, slow to develop and then the maximum of the effect was obtained at 120 min. This cinetics of action of LL 1656 intraduo-denally is not the usual cinetics (maximum of the effect at 30 or 60 min and gradual disappearance then of the latter); it may be thought that the prior administration of CRL 41 o80 modifi~s the action of LL 1656. An additional dose of S mg/kg I.D. of 41 080 does not further increase the femoral flow rate but results in a hypotension and , -: ~2~
and a bradycardia. In these dogs, the CRL 41 080 does not diminish the vertebral flow rate.
D - CO~CLUSI0~
__________ Results of the tests summarized above establish that CRL 41 080 is a peripheral vasodilator (particularly a femoral vasodilator) and a particularly interesting bradycardiac agent. CRL 41 o80 is more active as a ~aso-dilator than LL 1656, its pyrrolidino homolog, and does not have the antispasmodic properties of its piperidino homolo~.
II - CO~IPARATIVE TESTS
There are colleoted in Tables I and II below the results of the additional tests which were under-taken to compare the CRL 41 o80 sccording to the invention with its pyrroli~ino (LL 16~6) and piperidino (LL 1647) homologs 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 vasodila~or effeet, on the other hand. The LD-50 I.V. was determined on batches of 10 male mice; the minimum vasodilator dose was determined on a batch of S dogs serving as controls with respect to themselves and each receiving a doae of the product to be tested every 2.5 hours.
Table II relates to the variations in the arte-rial blood pressures (systolic, diastolic, dif~erential and average~, the heart rate and the femoral artery blood flow. These Yariations were determined intravenously on the same aforementioned batch o~ 5 anesthetized dogs.
In the course of clinieal assays, good results in ~an were obtained by ad~inistering CRL 41 080 orally ~three capsules daily each containing 100 mg of aotive ingredient) and by injection (I~Vo route or I.M. route, one ~mpoule of 5 ml per day containing 40 mg of aotive principle in a physiological sallne ~olution).
~ 294~
TABLE I
minimum dose inducing Product LD-50 I.V. in the anesthetized mouse dog a Pemoral vaso-dilator effect I~Va I.D.
. . .
CRL 41 o80 (a) 96 + 3 mg/kg 1 mg/kg 5 ~g/~
. , , _. ~
LL 1656 (b)(c) 60 + 2.2 mg/kg5 mg/kg 6 mglkg :.
LL ~6~47 (c) 68 + 4 mg/kg 5 mg/kg (d) , - . ~ . - .
Notes (a) product according to the invention (b) re~erence peripheral vasodilator -(c~ descri~ed in USP No. 3,895jO30 (d) no vasodilator effect I.D.
. ~ , , , ,, . .
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. ~ O ~ ~ ~
,~ i 0~
~ . ~, ~ v ~ ~t ~ 1 E O ~ ~ a . o ~ 8~ ~
~ , o ~ `?:i
Claims (6)
1. A method for preparing (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone in which 4-hexamethyleneimino-butyronitrile is formed, its ketimine derivative is obtained by reaction with 1,3,5-trimenthoxybenzene, and said ketimine derivative is hydrolyzed, said method comprising a) reacting 2 mols of hexamethyleneimine with 1 mol of 4-chlorobutyronitrile, in the presence of an aromatic solvent selected from the group consisting of benzene and toluene, for at least 4h at the reflux temperature of the reaction medium, then b) reacting 1 mole of 4-hexamethyleneimino-butyronitrile thus obtained with 1 mol of 1,3,5-trimethoxybenzene in the presence of HC1 gas stream, at a temperature comprised between -5°C and 0°C, for at least 2h, in an anhydrous solvent selected from the group consisting of benzene, toluene, chlorobenzene and mixtures thereof, then hydrolyzing the corresponding ketimine derivative thus obtained for at least 0.5 h at the reflux temperature of the reaction medium.
2. (2,4,6-trimethoxyphenyl)-(3-hexmethylenimino-propyl)-ketone when produced by the method of claim 1, and addition salts thereof.
3. A pharmaceutically effective amount of a phenyl-(3-aminopropyl)-ketone derivative which is selected from the group consisting of the (2,4,6-trimethoxyphenyl)-(3-hexamethylene-iminopropyl)-ketone and its non-toxic addition salts when produced by the method of claim 1.
4 A method for preparing (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride comprising a) reacting 2 mols of hexamethyleneimine with 1 mol of 4-chlorobutyronitrile, in the presence of an aromatic solvent selected from the group consisting of benzene and toluene, for at least 4h at the reflux temperature of the reaction medium, then b) reacting 1 mole of 4-hexamethyleneimino-butryronitrile thus obtained with 1 mol of 1,3,5-trimethoxybenzene in the presence of HC1 gas stream, at a temperature comprised between -5°C and 0°C, for at least 2h, in an anhydrous solvent selected from the group consisting of benzene, toluene, chlorobenzene and mixtures thereof, then hydrolyzing the corresponding ketimine derivative thus obtained for at least 0.5h at the reflux temperature of the reaction medium, and then c) reacting the product of step b) with hydrochloric acid.
5. (2,4,6-trimethoxyphenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride when produced by the method of claim 4.
6. A pharmaceutically effective amount (2,4,5-trimethoxy-phenyl)-(3-hexamethyleneiminopropyl)-ketone hydrochloride when produced by the method of claim 4.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8217937A FR2534916B1 (en) | 1982-10-26 | 1982-10-26 | NOVEL PHENYL- (3-AMINOPROPYL) -CETONE DERIVATIVES, USE IN THERAPEUTICS AND PREPARATION METHOD |
FR82.17.937 | 1982-10-26 |
Publications (1)
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CA1212944A true CA1212944A (en) | 1986-10-21 |
Family
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CA000439563A Expired CA1212944A (en) | 1982-10-26 | 1983-10-24 | Phenyl-(3-aminopropyl)-ketone derivatives |
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EP (1) | EP0110748B1 (en) |
JP (1) | JPS5995283A (en) |
AT (1) | ATE26712T1 (en) |
AU (1) | AU556589B2 (en) |
CA (1) | CA1212944A (en) |
DE (1) | DE3371077D1 (en) |
DK (1) | DK156003C (en) |
ES (1) | ES8406069A1 (en) |
FR (1) | FR2534916B1 (en) |
GR (1) | GR79617B (en) |
IE (1) | IE56129B1 (en) |
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FR2584715B1 (en) * | 1985-07-10 | 1987-10-09 | Lafon Labor | PHENYL- (3-HEXAMETHYLENEIMINOPROPYL) -CETONE, PROCESS FOR PREPARATION AND THERAPEUTIC USE |
TW248554B (en) * | 1993-05-26 | 1995-06-01 | Syntex Inc |
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FR2101045A1 (en) * | 1970-08-12 | 1972-03-31 | Penciolelli Madeleine | Omega-dialkylamino-1-(2,4,6-trialkoxy phenyl) alkan-1-ones - with vasodilator and spasmolytic activity |
FR2134218A1 (en) * | 1971-04-27 | 1972-12-08 | Penciolelli Madeleine | Phloroglucinol aminoketones - vasodilators and antispasmodics |
-
1982
- 1982-10-26 FR FR8217937A patent/FR2534916B1/en not_active Expired
-
1983
- 1983-10-18 GR GR72730A patent/GR79617B/el unknown
- 1983-10-24 CA CA000439563A patent/CA1212944A/en not_active Expired
- 1983-10-24 IE IE2488/83A patent/IE56129B1/en not_active IP Right Cessation
- 1983-10-25 ES ES526736A patent/ES8406069A1/en not_active Expired
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- 1983-10-25 AU AU20568/83A patent/AU556589B2/en not_active Ceased
- 1983-10-25 DK DK489283A patent/DK156003C/en not_active IP Right Cessation
- 1983-10-25 DE DE8383402070T patent/DE3371077D1/en not_active Expired
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DK156003C (en) | 1989-11-13 |
EP0110748B1 (en) | 1987-04-22 |
ATE26712T1 (en) | 1987-05-15 |
AU2056883A (en) | 1984-05-03 |
EP0110748A1 (en) | 1984-06-13 |
FR2534916B1 (en) | 1985-11-22 |
DE3371077D1 (en) | 1987-05-27 |
AU556589B2 (en) | 1986-11-13 |
DK156003B (en) | 1989-06-12 |
IE832488L (en) | 1984-04-26 |
FR2534916A1 (en) | 1984-04-27 |
JPS5995283A (en) | 1984-06-01 |
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ES8406069A1 (en) | 1984-07-01 |
IE56129B1 (en) | 1991-04-24 |
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