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EP0346367A1 - Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie - Google Patents

Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie

Info

Publication number
EP0346367A1
EP0346367A1 EP88901794A EP88901794A EP0346367A1 EP 0346367 A1 EP0346367 A1 EP 0346367A1 EP 88901794 A EP88901794 A EP 88901794A EP 88901794 A EP88901794 A EP 88901794A EP 0346367 A1 EP0346367 A1 EP 0346367A1
Authority
EP
European Patent Office
Prior art keywords
methyl
hydroxy
group
formula
methoxy
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.)
Withdrawn
Application number
EP88901794A
Other languages
German (de)
English (en)
Inventor
Rudolf Albrecht
Klaus Schöllkopf
Manfred Lehmann
Gertrud SCHRÖDER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0346367A1 publication Critical patent/EP0346367A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/82—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Aryl- and aryloxy-substituted tert-alkylene amines processes for their preparation and their pharmaceutical use
  • the present invention relates to aryl-substituted tert-alkylene amines, processes for their preparation and their therapeutic use in cardiovascular diseases.
  • substituted butyrophenones of the structure below have a broad therapeutic application as neuroleptics (M.E. Wolff (Ed.), Burger's Medicinal Chemistry, 4th Edition, Part III, J. Wiley, New York, 1981, p. 859).
  • EP 29 707 claims similar compounds of the following structure with hypotensive activity
  • EP 154 959 describes piperazine compounds
  • R V called alkoxy, which have a calcium-antagonistic and hypotensive effect.
  • the invention thus relates
  • R is an alkyl group with 1-6 carbon atoms or all of the rest are heterocyclic
  • A the radicals carbonyl, hydroxymethylene, C 2 -C 4 -acyloxy-methylene,
  • Z is hydrogen, 2-fluorine, 6-fluorine, 2-chlorine, 5-chlorine, 2-methyl or
  • R 1 is hydroxy or C 2 -C 4 -acyloxy if R 2 is hydroxy, C 2 -C 4 -acyloxy, amino or NHR 3 , NH-CHO or NH-CO-NH 2 ,
  • R 2 is hydroxy or C 2 -C 4 acyloxy when R 1 is hydroxy, C 2 -C 4 acyloxy, amino or NHR 3 ,
  • R 3 alkyl with 1-4 C atoms, 4-methoxybenzyl, acetyl, methylsulfonyl or trifluoromethylsulfonyl, or
  • R 4 as hydrogen, methoxycarbonyl or ethoxycarbonyl, and their acid addition salts with physiologically compatible acids.
  • R as an alkyl group with 1-6 C atoms means a saturated straight-chain or branched-chain hydrocarbon residue such as e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl etc.
  • residues with 1-4 C atoms are preferred.
  • R 3 as C 1 -C 4 alkyl means the radicals already mentioned for R.
  • Inorganic or organic acids are suitable as physiologically acceptable acids.
  • hydrogen halide preferably HCl or HBr
  • organic acids acetic acid and maleic acid.
  • the new compounds are preferably used as salts.
  • the vasodilatory effect of the compounds according to the invention was measured in vitro. Isolated rings of the rabbit lienalis artery in a Krebs-Ringer solution flushed with O 2 and CO 2 are contracted with noradrenaline before the start of the experiment. The test substances are added cumulatively in the concentration range from 10 -7 to 10 -5 mol / 1. It becomes the dilator effect caused by the test substances by the decrease of the
  • Table 1 summarizes the test results of a representative selection of the compounds of the formula I according to the invention in comparison with the comparison substance buflomedil (the numbers represent mean values from 4-8 measurements). This results in an up to 5 times stronger relaxing effect for the new compounds.
  • the compounds can find therapeutic uses in all indications in which vascular dilation is desired, such as circulatory disorders, hypertension, heart failure or coronary heart disease.
  • the compounds according to the invention are therefore suitable as antihypertensives.
  • the compounds according to the invention are brought into the form of a pharmaceutical preparation according to galenical methods known per se which, in addition to the active ingredient, are particularly suitable organic or inorganic inert carrier materials, such as e.g. May contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, polyalkylene glycols etc.
  • the pharmaceutical preparations can be in solid form, e.g. as tablets, Drag ⁇ es suppositories, capsules or in liquid form, e.g. present as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.
  • the dosage is 50 to 1000 mg per day.
  • the compounds of the formula I are prepared in a manner known per se by a) an aryl-substituted alkyl halide or tosylate of the formula II,
  • n 2-4 and A 'is carbonyl, dimethoxymethylene or oxygen, R 6 is tosyloxy, chlorine or bromine and R' 1 is methoxy or benzyloxy, R 2 'is methoxy, benzyloxy or methylsulfonamido, Z 'hydrogen and Z' and R 2 together mean the group -CH 2 -CO-NH- in 2,3-position of the benzene ring, optionally after prior protection of the carbonyl group in A 'with an amine of the formula III
  • n and R have the meanings already mentioned and R 7 is a carboxyl radical or a cyano group, in the presence of polyphosphoric acid or AlCl 3 , c) a benzene derivative of the formula VII
  • R 1 ''' is hydrogen, methoxy or benzyloxy
  • R 8 is an aldehyde or cyano group, with a Grignard reagent of the formula VIII,
  • n and R have the meanings already mentioned and X 'represents chlorine or bromine, or d) 3,4-dimethoxyacetophenone is reacted with an amine of the formula III and formaldehyde and, if appropriate, the compounds I obtained according to a) -d), an ether cleavage, reduction of the carbonyl group in A, oxidation of the OH group in A, a LiAlH 4 reduction , subject to an acylation or Umamidierung or in the case of free NH 2 groups with potassium cyanate or with alkylating agents.
  • the reactions according to a) are carried out either in polar solvents, e.g. Butanol, methyl ethyl ketone, dimethylformamide, or without solvent at temperatures between 20 ° C and
  • the reactions according to b) are carried out in pure polyphosphoric acid or in inert solvents such as methylene chloride, benzene, toluene at temperatures from 20 ° C. to 150 ° C. and reaction times from 0.5 to 48 hours.
  • the reactions according to c) are carried out in a solvent typical of the Grignard reaction, such as diethyl ether, tetrahydrofuran, at temperatures from 0 ° C. to the boiling point of the solvent with reaction times of 10 minutes to 48 hours.
  • a solvent typical of the Grignard reaction such as diethyl ether, tetrahydrofuran
  • the reactions according to d) are preferably carried out in an alcohol, e.g. Ethanol, in the presence of a mineral acid, e.g. Hydrochloric acid, at temperatures from 25 ° C to the boiling point of the solvent with reaction times of 0.25 to 48 hours.
  • an alcohol e.g. Ethanol
  • a mineral acid e.g. Hydrochloric acid
  • the Grignard reagent is prepared from 1.46 g of magnesium and 10.5 g of 1- (3-chloropropyl) -4-methyl-piperidine in 25 ml of tetrahydrofuran. A solution of 9.6 g of 3,4-dibenzyloxybenzaldehyde in 50 ml of tetrahydrofuran is added dropwise to this solution while cooling with ice, and the mixture is then boiled for 3 hours.
  • Example 7a 12.4 g of 3,4-dimethoxy-acetophenone are reacted analogously to Example 7a).
  • the hydrochloride obtained is treated with aqueous sodium bicarbonate solution, 11.6 g of 3 ', 4'-dimethoxy-3- (4-methyl-piperidino) propiophenone of melting point 72-74 ° C. being obtained.
  • a Grignard solution is prepared in tetrahydrofuran from 0.13 g of magnesium and 0.93 g of 1- (3-chloropropyl) -4-methyl-piperidine.
  • a solution of 0.50 g of 4,5-dimethoxy-2-fluoro-benzonitrile in tetrahydrofuran is added dropwise with cooling and the mixture is then boiled under reflux for 2.5 hours.
  • the product is recrystallized from petroleum ether.
  • 0.45 g of 4- (4-methyl-piperidino) -2'-fluoro-4 ', 5'-dimethoxy-butyrophenone are obtained.
  • reaction solution is poured onto ice, the precipitate is filtered off with suction, washed with saturated sodium hydrogen carbonate solution and then with ethyl acetate, 150 mg of 7-hydroxy- 4- [4- (4-methyl-1-piperidyl) -butyryl] -indole-2-carboxylic acid ethyl ester, hydrochloride from the decomposition point 235-236 ° C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Des alkylénamines tert. à substitution aryle ont la formule (I), dans laquelle R est un groupe alkyle ayant entre 1 et 6 atomes de C, ou l'ensemble de résidu (a) représente les résidus hétérocycliques (b), (c), (d), (e) ou (f), où R5 est hydrogène, méthyle, phényle, 4 - chlorphénol ou 4-fluorbenzoyle, n = 2 - 4, A représente les résidus carbonyle, hydroxyméthylène, C2-C4-acyloxyméthylène, méthylène ou oxygène, Z représente hydrogène, 2-fluor, 6-fluor, 2-chlore, 5-chlore, 2-méthyle ou 6-méthyle, R1 représente hydroxy ou C2-C4-acyloxy, lorsque R2 est hydroxy, C2-C4-acyloxy, amino ou NHR3, NH-CHO ou NH-CHO-NH2, R2 est hydroxy ou C2-C4-acyloxy, lorsque R1 est hydroxy, C2-C4-acyloxy, amino ou NHR3, R3 est alkyle ayant entre 1 et 4 atomes de C, 4-méthoxybenzyle, acétyle, méthylsulfonyle ou trifluorméthylsulfonyle, ou le résidu (g) forme par cyclisation de R2 et de Z les groupes bicycliques (h), (i), (j), (k) ou (l), où R4 est hydrogène, méthoxycarbonyle ou éthoxycarbonyle. L'invention concerne également les sels d'addition d'acides de ces alkylénamines comportant des acides physiologiquement compatibles, leur procédé de production et leur utilisation en pharmacie.
EP88901794A 1987-02-25 1988-02-23 Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie Withdrawn EP0346367A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3706585 1987-02-25
DE19873706585 DE3706585A1 (de) 1987-02-25 1987-02-25 Aryl- und aryloxy-substituierte tert.-alkylenamine, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung

Publications (1)

Publication Number Publication Date
EP0346367A1 true EP0346367A1 (fr) 1989-12-20

Family

ID=6322048

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88901794A Withdrawn EP0346367A1 (fr) 1987-02-25 1988-02-23 Alkylenamine tert. a substitution aryle et aryloxyle, leur procede de production et leur utilisation en pharmacie

Country Status (4)

Country Link
EP (1) EP0346367A1 (fr)
JP (1) JPH02502376A (fr)
DE (1) DE3706585A1 (fr)
WO (1) WO1988006580A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07506104A (ja) * 1992-04-24 1995-07-06 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー カルシウムチャネル拮抗物質として有用なｎ−アリールオキシ（チオ）アルキルーアザシクロアルカン
KR950704284A (ko) * 1992-12-22 1995-11-17 데이비드 로버츠 칼슘 채널 길항제로서의 피페리딘 유도체(Piperidine Derivatives as Calcium Channel Antagonists)
US6528529B1 (en) * 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
AU2003252259A1 (en) * 2002-07-26 2004-02-16 Nihon Nohyaku Co., Ltd. Novel haloalkylsulfonanilide derivatives, herbicides and usage thereof
JP2004107323A (ja) * 2002-07-26 2004-04-08 Nippon Nohyaku Co Ltd 新規なハロアルキルスルホンアニリド誘導体及び除草剤並びにその使用方法
US7786140B2 (en) * 2003-09-25 2010-08-31 Shionogi & Co., Ltd. Piperidine derivative having NMDA receptor antagonistic activity
JP2009126785A (ja) * 2007-11-19 2009-06-11 Mitsubishi Gas Chem Co Inc ２−ヨード−３，４−ジメトキシベンゾニトリルの製造方法
JP2009126784A (ja) * 2007-11-19 2009-06-11 Mitsubishi Gas Chem Co Inc ２−ヨード−３，４−ジメトキシベンゾニトリルの製造方法。

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3317538A (en) * 1965-10-22 1967-05-02 American Home Prod 4, 4'-diamino-butyrophenones
DE1618010A1 (de) * 1967-06-15 1970-11-05 Thomae Gmbh Dr K Verfahren zur Herstellung von neuen Aminoketonen
GB1262965A (en) * 1969-03-21 1972-02-09 Ferrosan As Butyrophenones
SE7807408L (sv) * 1978-06-30 1979-12-31 Haessle Ab Hjertaktiva foreningar
US4353900A (en) * 1981-10-19 1982-10-12 Syntex (U.S.A.) Inc. 9-(Arylalkyl or aroylalkyl)-1-oxa-4,9-diazaspiro(5.5)undecan-3-ones
US4613598A (en) * 1984-03-13 1986-09-23 Mitsubishi Chemical Industries Limited Piperazine derivatives and their acid addition salts

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8806580A1 *

Also Published As

Publication number Publication date
JPH02502376A (ja) 1990-08-02
WO1988006580A1 (fr) 1988-09-07
DE3706585A1 (de) 1988-09-08

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