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WO2001074778A1 - (1-adamantylamino)pyridines et procede de preparation associe - Google Patents

(1-adamantylamino)pyridines et procede de preparation associe Download PDF

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Publication number
WO2001074778A1
WO2001074778A1 PCT/PL2001/000029 PL0100029W WO0174778A1 WO 2001074778 A1 WO2001074778 A1 WO 2001074778A1 PL 0100029 W PL0100029 W PL 0100029W WO 0174778 A1 WO0174778 A1 WO 0174778A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
amino
group
adamantylamino
substituents
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.)
Ceased
Application number
PCT/PL2001/000029
Other languages
English (en)
Inventor
Zygmunt Kazimierczuk
Witold Lasek
Agata Sikorska
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.)
FUNDACJA ROZWOJU DIAGNOSTYKI I TERAPII
Original Assignee
FUNDACJA ROZWOJU DIAGNOSTYKI I TERAPII
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 FUNDACJA ROZWOJU DIAGNOSTYKI I TERAPII filed Critical FUNDACJA ROZWOJU DIAGNOSTYKI I TERAPII
Priority to AU2001248926A priority Critical patent/AU2001248926A1/en
Publication of WO2001074778A1 publication Critical patent/WO2001074778A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • An object of the invention are new (1-adamantylamino) ⁇ pyridines, salts thereof with inorganic and organic acids and method of their preparation.
  • New (1 -adamantylamino )-pyridines of formula 2 are substituted at heterocydic ring by alkyl groups or by halogen atoms. Many derivatives of adamantane exhibit biological activity.
  • the most known compounds of this group are derivatives of 1 -adamantane (amantidine, rimantidine and tromantidine) used as antiviral drugs or in therapy of Parkinson's disease [W.L. Davies et al., Science, 144, 862, (1964), R. S. Schwab et al., J. Am. Med. Assoc, 208, 1168 (1969)].
  • Selected adamantyl esters of phthalimide substituted by amino acids inhibit growth of various bacteria strains to an extent that is comparable to activity of some antibiotics [A.Orzeszko, J. Stefa ⁇ ska, B. Starosciak, Z. Kazimierczuk, Acta Biochim. Polon., paper in press].
  • Tumour necrosis factor - TNF- ⁇ is a cytokine exhibiting antineoplastic and immunomodulating properties. From a structural point of view it is identical with cachectin secreted by macrophages in the course of neoplastic processes and infection [B. Beutler et al., Nature, 320, 584, 1986].
  • Factors that stimulate secretion of TNF- ⁇ by macrophages are bacterial endotoxins of lipopolysaccharides (LPS) type. Recently, it has been found that also chemical compounds, such as e.g.
  • 5,6- dimethylxanthenone-4-acetic acid can stimulate secretion of TNF- ⁇ within a tumour [W. R. Joseph et al., Cancer Res. 59, 633, (1999] and this can possibly constitute a new targeted method of treatment of some tumours, e.g. solid tumours.
  • (I-Adamantylamino)pyridine derivatives and salts thereof constituting an object of the present invention exhibit considerable activity as substances that cause an increase in production of tumour necrosis factor of alpha-type (TNF- ⁇ ) in some cell lines.
  • New compounds stimulating TNF- ⁇ production that we have synthesized can constitute a promising group of drugs to be used for topical treatment of neoplastic solid tumours.
  • substituents Ri , R 2 , R 3 , R 4 or R5 denote adamantylamino group, hydrogen atom, methyl group or halogen atom, the compound of formula 2 containing one adamantylamino group and a substituent or substituents being methyl groups or halogen atoms at a position different from an ortho-position to the amino group.
  • the new compounds are: 2-(1 -adamantylamino)pyridine, 3-(1 -adamantylamino)pyridine,
  • Another important aspect of the invention is a method of preparation of new (l-adamantylamino)pyridines of formula 2,
  • substituents R-i, R 2 , R3, R4 or R5 denote adamantylamino group, hydrogen atom, methyl group or halogen atom, the compound of formula 2 containing one adamantylamino group and a substituent or substituents being methyl groups or halogen atoms at a position different from an ortho-position to the amino group, consisting in that, a pyridine derivative of formula 1 ,
  • R ⁇ R 2 , R3, R4 or R5 denote an amino group, a hydrogen atom, a methyl group or a halogen atom, the molecule of formula 1 containing one amino group and a substituent or substituents being methyl groups or halogen atoms at a position different from an ortho-position to the amino group, is subjected to reaction with 1 -adamantanol at elevated temperature in an acid solution, to yield a product of formula 2, wherein substituents R ⁇ R 2 ,R3, R4 or R 5 are as defined above, the compound of formula 2 containing one adamantylamino group and a substituent or substituents being methyl groups or halogen atoms at a position different from an ortho-position to the amino group, and the product of formula 2 is isolated and converted by a known method into a salt, preferably hydrochloride.
  • trifluoracetic acid or ortophosphoric acid is used to provide an acid reaction solution, the ortophosphoric acid being used at concentration of 85-100%, preferably 90%.
  • the reaction is carried out at elevated temperature, within the range of 90-120°C, preferably at boiling temperature of trifluoroacetic acid.
  • the final new (l-adamantylamino)pyridines are isolated from a reaction mixture by diluting reaction mixture with water and adjusting it to pH 7.0-14.0.
  • adamantylation of an exocyclic amino group of pyrimidine derivatives results from formation of an adamantyl carbocation from 1 -adamantanol in a trifluoroacetic acid solution at elevated temperature.
  • reaction does not take place e.g. in case of aniline, where the amino group in an acid solution is protonated.
  • a successful course of the reaction of aminopyridines with the adamantyl carbocation is conditioned by the fact that it is a nitrogen atom of the heterocydic ring which is subjected to protonation and not the amino group, which captures carbocations, to yield (l-adamantylamino)pyridine derivatives as final products.
  • the new compounds exhibit activity stimulating production of tumour necrosis factor - TNF- ⁇ and can constitute a promising group of drugs for topical treatment of neoplastic solid tumours.
  • the present invention covers pharmaceutical or veterinary compositions comprising at least one compound defined by formula 2 as a single active substance used or in combination with a pharmaceutically acceptable and compatible carrier and an excipient.
  • pharmaceutical composition is meant as a mixture of an active substance combined with a pharmaceutically acceptable and compatible carrier and an excipient, to be used for treatment of humans and animals.
  • the compounds of formula 2 can be formulated as an ointment or a cream or in another form comprising the compound of formula 2 suspended in a liquid or solid carrier, used for preparation of such pharmaceutical forms.
  • a liquid or solid carrier used for preparation of such pharmaceutical forms.
  • An addition of particular carriers to provide protection of an active substance from its decomposition or oxidation is also possible.
  • compounds of formula 2 can be formulated as injections or infusion solutions into a tumour.
  • the pharmaceutical form has to be sterile and a liquid should enable a use of syringe.
  • Another possible form is a dry pharmaceutical composition to be diluted or suspended prior to administration in an injection liquid containing e.g. liquid polyethylene glycol, propylene glycol, glycerol or the like.
  • prolonged absorption of an injection composition can be achieved through a use of known compounds delaying absorption and/or sustaining release, such as aluminium monostearate and gelatine.
  • a unit dose can contain e.g. a main active ingredient in an amount from about 0.1 to about 500 mg, preferably from about 0.1 to about 250 mg per day.
  • chemical reagents were from Aldrich (apart from solvents). Column chromatography was performed on silica gel 60H (Merck). Analytical thin-layer chromatography was performed on aluminium plates with silica gel 60F254 (Merck). Melting points were determined with a use of Gallenkamp-5 apparatus in glass capillaries. UV spectra were measured on Kontron-Uvikon-940 spectrophotometer. NMR spectra (ppm) were measured on Varian-Gemini-200 MHz spectrometer.

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

Abstract

L'invention concerne des (1-adamantylamino)pyridines de formule (2), dans laquelle le substituants R1, R2, R3, R4 ou R5 représentent des groupes adamantylamino, un atome d'hydrogène, un groupe méthyle ou un atome d'halogène, la molécule de la formule (2) contenant un groupe adamantylamino et un substituant ou des substituants étant des groupes méthyles ou des atomes d'halogènes à une position différente d'une position ortho par rapport au groupe amino. L'invention concerne aussi le procédé de préparation de ces composés. Des études ont montré que ces composés stimulent la sécrétion du TNF-α dans certaines populations cellulaires néoplastiques.
PCT/PL2001/000029 2000-04-04 2001-04-03 (1-adamantylamino)pyridines et procede de preparation associe Ceased WO2001074778A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001248926A AU2001248926A1 (en) 2000-04-04 2001-04-03 (1-adamantylamino)pyridines and method of their preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL339418A PL207853B1 (pl) 2000-04-04 2000-04-04 Nowe (1-adamantyloamino)pirydyny, sposób ich wytwarzania i zastosowanie medyczne
PLP.339418 2000-04-04

Publications (1)

Publication Number Publication Date
WO2001074778A1 true WO2001074778A1 (fr) 2001-10-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/PL2001/000029 Ceased WO2001074778A1 (fr) 2000-04-04 2001-04-03 (1-adamantylamino)pyridines et procede de preparation associe

Country Status (3)

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AU (1) AU2001248926A1 (fr)
PL (1) PL207853B1 (fr)
WO (1) WO2001074778A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2058661A1 (de) * 1970-11-28 1972-06-08 Goldschmidt Ag Th Biocides Adamantylaminderivat
WO1991002725A1 (fr) * 1989-08-25 1991-06-07 Syntheses Et Recherches Derives de la 5-amino-1,2,3,4-tetrahydro-acridine et applications comme medicaments
WO1999032448A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Compose de pyridine et de pyridazine substituees et leurs utilisations pharmaceutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2058661A1 (de) * 1970-11-28 1972-06-08 Goldschmidt Ag Th Biocides Adamantylaminderivat
WO1991002725A1 (fr) * 1989-08-25 1991-06-07 Syntheses Et Recherches Derives de la 5-amino-1,2,3,4-tetrahydro-acridine et applications comme medicaments
WO1999032448A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Compose de pyridine et de pyridazine substituees et leurs utilisations pharmaceutiques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ABRAMOVITCH, R. A. ET AL: "Direct acylamination of pyridine 1-oxides", J. ORG. CHEM. (1974), 39(13), 1795-801, XP001008199 *
CHEMICAL ABSTRACTS, vol. 71, no. 3, 21 July 1969, Columbus, Ohio, US; abstract no. 12643, STEPANOV, F. N. ET AL: "Adamantane and its derivatives. XVIII. Reaction of 1-bromoadamantane with amines" XP002173268 *
MORTON, COLIN ET AL: "Control of metal/ligand stoichiometry and structure in aminopyridinato complexes of zirconium: N-alkyl is better than trimethylsilyl", CHEM. COMMUN. (CAMBRIDGE) (2000), (21), 2099-2100, XP001008221 *
ZH. ORG. KHIM. (1969), 5(3), 537-41 *

Also Published As

Publication number Publication date
PL207853B1 (pl) 2011-02-28
PL339418A1 (en) 2001-10-08
AU2001248926A1 (en) 2001-10-15

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