EP0525023A1 - Nouveaux esters de pyridine - Google Patents

Nouveaux esters de pyridine

Info

Publication number
EP0525023A1
EP0525023A1 EP91907715A EP91907715A EP0525023A1 EP 0525023 A1 EP0525023 A1 EP 0525023A1 EP 91907715 A EP91907715 A EP 91907715A EP 91907715 A EP91907715 A EP 91907715A EP 0525023 A1 EP0525023 A1 EP 0525023A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compounds
formula
hydrogen
alkoxy
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Withdrawn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
EP91907715A
Other languages
German (de)
English (en)
Inventor
Wolf-Rüdiger Ulrich
Dieter Flockerzi
Peter Zimmermann
Kurt Klemm
Karl Sanders
Rainer Boer
Hildegard Boss
Klaus-Dieter Beller
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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 Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Publication of EP0525023A1 publication Critical patent/EP0525023A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to new pyridine esters, processes for their preparation, their use and medicaments containing them.
  • the compounds according to the invention are used in the pharmaceutical industry for the production of medicaments.
  • the invention relates to new pyridine esters of the formula I.
  • R1 is hydrogen or 1-6C-alkyl
  • R2 is hydrogen, 1-6C-alkyl or together with R3 2-3C-alkylene,
  • R3 is 1-4C-alkyl, 1-4C-alkoxy, 3-5C-alkoxyalkyl, 3-5C-alkoxyalkoxy or together with R2 is 2-3C-alkylene,
  • R4 denotes phenyl substituted by R41 and R42
  • R41 is hydrogen, hydroxy, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-1-4C-alkylamino,
  • R42 is hydrogen, hydroxy, halogen, nitro, cyano, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or partially substituted by fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-1-4C-alkylamino,
  • E1 means oxygen (0) or imino (NH)
  • n 1 or 2
  • n the number 1 or 2
  • A1 means 2-4C-alkylene
  • A2 is 2-4C-alkylene or 2C-alkyleneoxy-2C-alkylene
  • R7 is hydrogen (H) or aryl
  • R8 means aryl
  • R7 and R8 together denote diarylmethylene
  • R9 means diaryl-1-4C-alkyl
  • R10 means aryl-1-4C-alkyl
  • R11 and R12 are the same or different and have the meaning hydrogen (H), 1-4C-alkyl, 1-4C-alkoxy, halogen, hydroxy, trifluoromethyl or together methylenedioxy,
  • 1-6C-alkyl is straight-chain or branched and means, for example, a hexyl, neopentyl, isopentyl, butyl, i-butyl, sec.-butyl, t-butyl, propyl, isopropyl or in particular ethyl or methyl radical.
  • 2-3C-Alkylene is ethylene or propylene, so that R2 and R3, if they together have this meaning, together with the carbonyl group form a 5- or 6-ring fused to the dihydropyridine ring.
  • 1-4C-alkyl is straight-chain or branched and means, for example, a butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl or in particular methyl radical.
  • 1-4C-alkoxy contains one of the 1-4C-alkyl radicals mentioned above.
  • Preferred 1-4C-alkoxy radicals R41, R42, R11 and R12 are the methoxy and the ethoxy radical.
  • Preferred 1-4C-alkoxy radicals R3 are the isopropoxy and the t-butoxy radical.
  • 3-5C-alkoxyalkyl is, for example, a methoxyethyl, ethoxyethyl, propoxyethyl or ethoxymethyl radical.
  • 3-5C-alkoxyalkoxy stands for example for a methoxyethoxy, ethoxyethoxy or propoxyethoxy radical.
  • Halogen in the sense of the invention means bromine, fluorine and especially chlorine.
  • 1-4C-Alkoxy which is wholly or partly substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or in particular difluoromethoxy.
  • 1-4C-alkoxycarbonyl contains one of the 1-4C-alkoxy radicals mentioned above.
  • 2-5C-acyl contains one of the 1-4C-alkyl radicals mentioned above.
  • the acetyl radical is preferred.
  • mono- or di -1-4C-alkylamino contains one or two of the 1-4C-alkyl radicals mentioned above. Di-1-4C-alkylamino is preferred, and here in particular dimethyl-, diethyl- or diisopropylamino.
  • Straight-chain or branched 1-5C-alkylene is, for example, methylene
  • 2-4C-alkylene stands for ethylene (-CH 2 -CH 2 -), trimethylene (-CH 2 -CH 2 -CH 2 -) and tetramethylene (-CH 2 -CH 2 -CH 2 -CH 2 -), whereby Ethylene is preferred.
  • 2C-Alkyleneoxy-2C-alkylene stands for ethylene which is substituted by ethyl enoxy (-CH 2 -CH 2 -O-CH 2 -CH 2 -).
  • Aryl represents phenyl substituted by R11 and R12.
  • aryl radicals which may be mentioned are: phenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-methylphenyl, 3-chloro-4-methylphenyl, 3,4-dichlorophenyl, 3,6-dichlorophenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,4-methylenedioxyphenyl, 2- Trifluoromethylphenyl and 3-trifluoromethylphenyl.
  • Diaryl-1-4C-alkyl is 1-4C-alkyl which is substituted by two aryl radicals. Diaryl-1-4C-alkyl is especially diphenylmethyl (benzhydryl), or substituted benzhydryl, e.g. 4,4'-difluorobenzhydryl, 4,4'-dimethylbenzhydryl, 4,4'-dimethoxybenzhydryl or 4,4'Dichlorbenzhydryl.
  • Aryl-1-4C-alkyl stands for 1-4C-alkyl which is substituted by aryl.
  • aryl-1-4C-alkyl radicals 4-methylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 1-phenethyl, 2-phenylethyl, 3-phenylpropyl,
  • Suitable as such are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate, maleate, laurate, malate, fumarate, succinate Oxalate, tartrate, amsonate, metembonate, stearate, tosilate, 2-hydroxy-3-naphthoate, 3-hydroxy-2-naphthoate or mesilate.
  • water-soluble and water-insoluble acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulfosalicylate
  • the invention relates to compounds of the formula I in which
  • R1 1 -6C-alkyl means
  • R2 means 3-4C-alkyl
  • R3 denotes 1 -4C-alkyl or branched-chain 3-4C-alkoxy
  • R4 denotes phenyl substituted by R41 and R42
  • R41 means hydrogen, chlorine or nitro
  • R42 means hydrogen or chlorine
  • E2 means ethylene or propylene
  • R7 is hydrogen or phenyl
  • R8 is phenyl
  • R7 and R8 together mean diphenylmethylene
  • R10 means benzyl or 4-chlorobenzyl
  • the invention preferably relates to compounds of the formula I in which R1 is 1-4C-alkyl,
  • R2 is 1-4C-alkyl
  • R3 denotes 1-4C-alkyl or branched-chain 3-4C-alkoxy
  • R4 means 3-nitrophenyl
  • E2 means ethylene or propylene
  • R8-CH 2 -CH 2 - means
  • R8 means phenyl
  • the invention further relates to a process for the preparation of the compounds of the formula I and their salts.
  • the process is characterized in that compounds of the formula II
  • R1, R2, R3, R4, R5, R6, E1 and E2 have the meanings given above.
  • the oxidation is carried out in a manner known per se to those skilled in the art in inert solvents such as dichloromethane at temperatures between 0 ° and 200 ° C, preferably between 0 ° and 50 ° C.
  • inert solvents such as dichloromethane
  • inorganic and organic oxidizing agents such as, for example, manganese dioxide, nitric acid, chromium (VI) oxide or alkali dichromate, nitrogen oxides, chloranil, tetracyanobenzoquinone or anodic oxidation in the presence of a suitable electrolyte system are suitable.
  • EP-A-176956, EP-A-138505, EP-A-242829, EP-A-314038 or DE-OS 3627742 are known or they can be produced in an analogous manner.
  • the compounds of the formula I and their salts have valuable properties which make them commercially usable. They are primarily antineoplastic agents with interesting cytostatic activity. They can be used in the treatment of tumor diseases, for example to reduce or prevent metastasis and tumor growth in mammals. They can not only be used in combination with other cytostatics to overcome the so-called 'drug resistance' or 'multidrug resistance'. Rather, due to their antineoplastic properties, they are per se suitable for treating tumors that are considered resistant to therapy.
  • the low calcium channel blocking activity of compounds of formula I comes from the comparatively small influence of these compounds on the cardiovascular system, e.g. on blood pressure and heart rate, expressed.
  • This weak cardiovascular activity of compounds of the formula I and their salts permits their use in human medicine as potent agents for inhibiting tumor growth and preventing metastasis, since they can be administered in therapeutically effective doses without the risk of undesirable side effects on the cardiovascular system.
  • Another object of the invention is therefore a method for the treatment of mammals, especially humans, who are suffering from one of the diseases mentioned.
  • the method is characterized in that the diseased individual is administered a therapeutically effective and pharmacologically acceptable amount of one or more compounds of the formula I and / or their pharmacologically acceptable salts.
  • the invention also relates to the compounds of the formula I and their pharmacologically tolerable salts for use in the treatment of the diseases mentioned.
  • the invention also encompasses the use of compounds of the formula I and their pharmacologically tolerable salts in the production of medicaments which are used to combat the diseases mentioned.
  • the invention further relates to medicaments which contain one or more compounds of the general formula I and / or their pharmacologically tolerable salts.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulators, defoamers, taste correctors, preservatives, solubilizers, colorants or, in particular, permeation promoters and complexing agents (eg cyclodextrins) can be used.
  • the active substances can be administered rectally, by inhalation, parenterally (perlingually, intravenously, percutaneously) or orally.
  • the active ingredient (s) when given orally in a daily dose of about 0.5 to 30 mg / kg body weight, if desired in the form of several, preferably 1 to 4, single doses to achieve the desired result administer.
  • similar or generally lower doses in particular when the active compounds are administered intravenously can be used.
  • the pharmaceutical preparations can also contain one or more other pharmacologically active constituents of other groups of medicaments.
  • the treatment with the medicaments according to the invention can be combined with the administration of other cytostatics with different activity spectra. It can also be expedient to carry out the treatment on the principle of cyclic cytostatic therapy. A recovery phase is inserted after each treatment. It makes use of the experience that healthy tissue in most organs regenerates faster than malignant tissue.
  • the respective cell suspension - ZR-75 or Amnion - (50,000 cells / ml in RIMEN + 10% FCS + insulin) is incubated in culture dishes in an incubator for 24 h. After this time the cells have grown, the medium is aspirated and replaced by new medium without (control) or with test substance.
  • the medium used for the measurement of the substance effects (RIMEN) contains 2% estrogen-free FCS (estrogen-free by dextran / activated carbon treatment) and no insulin.
  • the cell lines are treated with test substance for 6 days each. The medium is replaced after 72 hours. After 6 days of substance incubation, cell growth is quantified by determining the DNA content according to BURTON (J. Steroid Biochem. 20, 1083-1088, 1984).
  • the compound inhibits 2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid 3-methyl-5- [3- (4,4-diphenyl-1-piperidinyl) propyl] ester cell proliferation with an IC 50 value of 0.4 ⁇ M (ZR-75) or 1.5 ⁇ M (Amnion).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des esters de pyridine ayant la formule (I), dans laquelle les substituants et les symboles ont les notations données dans la description, constituent de nouvelles substances ayant des propriétés pharmacologiques intéressantes.
EP91907715A 1990-04-10 1991-04-08 Nouveaux esters de pyridine Withdrawn EP0525023A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH122390 1990-04-10
CH1223/90 1990-04-10

Publications (1)

Publication Number Publication Date
EP0525023A1 true EP0525023A1 (fr) 1993-02-03

Family

ID=4205372

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91907715A Withdrawn EP0525023A1 (fr) 1990-04-10 1991-04-08 Nouveaux esters de pyridine

Country Status (4)

Country Link
EP (1) EP0525023A1 (fr)
JP (1) JPH05506027A (fr)
AU (1) AU7652391A (fr)
WO (1) WO1991015485A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5352684A (en) * 1990-04-10 1994-10-04 Byk Gulden Lomberg Chemische Fabrik Gmbh Pyridines as medicaments
DE4220616C2 (de) * 1992-06-24 1994-12-22 Byk Gulden Lomberg Chem Fab Dexniguldipin zur intravenösen Verabreichung
US5455253A (en) * 1992-10-20 1995-10-03 Zeneca Limited Heterocyclic derivatives
DE19624659A1 (de) 1996-06-20 1998-01-08 Klinge Co Chem Pharm Fab Neue Pyridylalken- und Pyridylalkinsäureamide
DE19624668A1 (de) * 1996-06-20 1998-02-19 Klinge Co Chem Pharm Fab Verwendung von Pyridylalkan-, Pyridylalken- bzw. Pyridylalkinsäureamiden
DE19624704A1 (de) * 1996-06-20 1998-01-08 Klinge Co Chem Pharm Fab Neue Pyridylalkansäureamide
US6451816B1 (en) 1997-06-20 2002-09-17 Klinge Pharma Gmbh Use of pyridyl alkane, pyridyl alkene and/or pyridyl alkine acid amides in the treatment of tumors or for immunosuppression
US6903118B1 (en) 1997-12-17 2005-06-07 Klinge Pharma Gmbh Piperazinyl-substituted pyridylalkane, alkene and alkine carboxamides
DE19756235A1 (de) * 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue piperidinylsubstituierte Pyridylalkan- alken- und -alkincarbonsäureamide
DE19756212A1 (de) * 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue, mit einem cyclischen Imid substituierte Pyridylalkan-, alken- und -alkincarbonsäureamide
DE19756261A1 (de) 1997-12-17 1999-07-01 Klinge Co Chem Pharm Fab Neue arylsubstituierte Pyridylalkan-, alken- und alkincarbonsäureamide
EP1031564A1 (fr) 1999-02-26 2000-08-30 Klinge Pharma GmbH Inhibiteurs de la formation du nicotinamide mononucléotide et leur utilisation dans le traitement du cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE107284T1 (de) * 1984-09-28 1994-07-15 Byk Gulden Lomberg Chem Fab Neue diarylverbindungen.
FI880990A7 (fi) * 1987-03-05 1988-09-06 Yamanouchi Pharma Co Ltd Pyridinderivat, deras framstaellning, dessa innehaollande aemnen foer att skoeta och foerebygga leverskador, och metod foer att skoeta och foerebygga leverskador genom att anvaenda dessa aemnen.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9115485A1 *

Also Published As

Publication number Publication date
WO1991015485A1 (fr) 1991-10-17
JPH05506027A (ja) 1993-09-02
AU7652391A (en) 1991-10-30

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