EP0745082A1 - Derives substitues de 1,3,8-triaza-spiro(4,5)-decan-4-one utiles comme progeniteurs de produits pharmaceutiques - Google Patents

Derives substitues de 1,3,8-triaza-spiro(4,5)-decan-4-one utiles comme progeniteurs de produits pharmaceutiques

Info

Publication number
EP0745082A1
EP0745082A1 EP95908935A EP95908935A EP0745082A1 EP 0745082 A1 EP0745082 A1 EP 0745082A1 EP 95908935 A EP95908935 A EP 95908935A EP 95908935 A EP95908935 A EP 95908935A EP 0745082 A1 EP0745082 A1 EP 0745082A1
Authority
EP
European Patent Office
Prior art keywords
compounds
formula
independently
same
integer
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Withdrawn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
EP95908935A
Other languages
German (de)
English (en)
Inventor
Wolfgang Brandau
Samuel Samnick
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.)
CIS Bio International SA
Original Assignee
CIS Bio International SA
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 CIS Bio International SA filed Critical CIS Bio International SA
Publication of EP0745082A1 publication Critical patent/EP0745082A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • the invention relates to substituted 1,3,8-triazaspiro (4,5) -decan-4-one derivatives as precursors for the production of neuroleptics, analgesics and radioactively labeled pharmaceuticals, a process for their use Manufacture and its use in nuclear medicine.
  • the term neurolepsy refers to a characteristic psychophysiological process of retuning, which, if intellectual abilities are retained, includes a reduction in emotional excitability, a reduction in driving, spontaneous movements and expressive motor skills. Neuroleptics can cause hallucinations,
  • neuroleptics are not only used therapeutically, but, after appropriate labeling, for imaging diagnostics.
  • Receptor systems or metabolic processes can be made visible.
  • the methods currently used are divided into two groups. On the one hand there are the processes with which space-demanding processes are mapped. This includes in particular X-rays, ultrasound and computer tomography (CT).
  • CT computer tomography
  • the NMR diagnosis based on the resonance of atomic nuclei in the magnetic field can also be classified here.
  • nuclides that can be used in nuclear medicine or NMR diagnostics must meet narrowly defined criteria, among other things with regard to the type of radiation and the physical half-life. Depending on the particular question, the following nuclides are used: 1 1 C, 13 N, 15 O, 18 F, 123 I, 124 I, 125 I, 131 I, 75 Br, 77 Br, 99m Tc, 68 Ga, 67 Ga, 1 1 1 In, 1 13m In, 186 Re, 188 Re, 62 Cu, 64 Cu, 67 Cu, 153 Gd or other stable gadolinium isotopes.
  • the isotopes iodine-123 and technetium-99m are of outstanding importance in nuclear medicine. Due to their favorable physical half-lives ( 99m Tc: 6.02 h, 123 I: 13.3 h) and their optimal ⁇ energies ( 99m Tc: 140 keV, 123 I: 159 keV), they have in single-photon emission tomography (Single Photon Emission Tomography, SPECT) found the most widespread.
  • radionuclide iodine in the form of iodallyl, iodoalkyl or iodaryl Introduce groups to an appropriate precursor of the radiopharmaceutical.
  • iodine radiopharmaceuticals have been described in recent years, with which certain metabolic processes and receptor systems of the human organism can be visualized. The achieved in these areas
  • PET positron emission tomography
  • Metabolic processes as well as the receptor density or the concentration distribution of a chemical substance can be quantified without intervention on the living organism.
  • R 1 and R 2 are the same or different and
  • R 3 H - (CH 2 ) a -CH 3 , -CONR'R ", -OR ', -SO 3 R', -OCOR ', -SO 2 NR'R",
  • p-Hydroxyphenyl, N-piperidinyl, N-piperazinyl or N-morpholinyl, and a and b independently of one another are an integer from 0 to 20, preferably from 0 to 10.
  • R 3 is preferably H, F, Cl, Br or I and -OR ', where R' is -CCH 2 ) b CH 3 .
  • a and b are preferably independently an integer from 0 to 5, preferably from 0 to 2.
  • R 1 and R 2 are the same and are hydrogen or - (CH 2 ) a -CH 3
  • R is hydrogen, - (CH 2 ) a -C 6 H 4 -R 3 or - (CH 2 ) b - (CO) -C 6 H 4 -R 3 and
  • R 4 is hydrogen, - (CH 2 ) a -CH 3 or - (CH 2 ) b - (CO) - (C 6 H 4 -R 3 ), where a and b are independently 0 or 1 and
  • R 3 is hydrogen, fluorine, chlorine, bromine or iodine.
  • Formula I Formula II where X is a nucleophilic leaving group, in particular chlorine, bromine or tosylate and R 4 is a radical mentioned for R, one or more carbon atoms in these radicals being replaced by 1 1 C-carbon or one or more nitrogen atoms by 13 N-nitrogen are replaced or one or more oxygen atoms are replaced by 15 O-oxygen or one or more halogen atoms of a halogen type F, Cl, Br or I are replaced by a corresponding radioactive isotope or a radical of the formula III which contains at least one 99 m Chelated Tc isotope means
  • W, X, Y and Z independently of one another denote N or S,
  • R 10 and R 20 together each represent double-bonded O or S and / or
  • R 10 , R 20 , R 30 , R 40 , R 5 and R 6 are the same or different and
  • R 'and R are the same or different and H, - (CH 2 ) b CH 3 , phenyl, p-hydroxyphenyl, N-piperidinyl, N-piperazinyl or N-morpholinyl,
  • n, o and p each independently represent 0, 1 or 2 and
  • a and b are each independently an integer from 0 to 20, preferably from 0 to 10,
  • Preferred chelating agents of formula III are those in which
  • R 10 and R 20 together represent a double bonded oxygen
  • R 10 , R 20 , R 30 , R 40 , R 5 and R 6 are the same or different and
  • V denotes -H, -COCH 3 , -COC 6 H 5 or -CH 2 -C 6 H 5 , m, n, o and p are identical and 0, 1 or 2 and
  • a and b are identical and represent an integer from 0 to 5.
  • Very particularly preferred chelating agents of the formula III are those in which m, n, o and p are identical and are 1 or 2, preferably 1.
  • R 10 and R 20 are each hydrogen or R 10 and R 20 together form a double bond O, provided that with the neighboring X or W a carbonylamido structure
  • R 30 together with R 40 means - (CH 2 ) a -CH 3 , where a is an integer from 0 to 5 and
  • R 5 and R 6 independently of one another are hydrogen or - (CH 2 ) a -CH 3 , where a is an integer from 0 to 5.
  • R 3 is H, -CONR'R ", OR ', -SO 3 R', F, Cl, Br, I or -NR'R", where a and b are independently 0 or 1 and
  • R 4 contains only a single radioactive isotope of one of the specified elements. 123 I or 1 1 C is particularly preferred here, provided that R 4 is a radical of Formula III means is preferred as the radioactive isotope 99m-Tc. Finally, R 4 is particularly preferably a radical of the formula III.
  • the invention further relates to a compound of the formula II which can be prepared by a process in which a compound of the formula I is reacted with R 4 X.
  • the invention relates to the use of a compound of the general formula II as a neuroleptic, as an analgesic or generally as a pharmaceutical in nuclear medicine.
  • the invention also relates to a diagnostic agent containing a compound of general formula II for use in nuclear medicine.
  • Scheme 4 shows an example of the course of the reaction of a compound of the general formula I which is alkylated at position 2. The synthesis is described in Example 3.
  • Scheme 5 shows the course of the reaction to produce 8- [3- (4-fluorobenzoyl) propyl] -1, 3,8-triazaspiro [4,5] decan-4-one (J), while examples of the reaction of compounds of the general formula I for the general formula II can be found in scheme 6.
  • the syntheses themselves are described in Examples 4, 5, 6 and 7.
  • the direct reaction of a compound of the general formula I with, for example, I 1 1 CH 3 provides a positron-emitting compound for possible use in positron emission tomography (PET).
  • the compound L is a precursor for metal complexation such as 99m Tc, while the compound M is a bromine-iodine-exchangeable molecule for eventual SPECT use.
  • Such a bromine [ 123 l] iodine exchange reaction is shown in Scheme 7.
  • IR [cm -1 ]: 3207, 1701 (NH, C O of amide), 3080, 1490 (aryl), 2940-2880 (CH 3 , CH 2 ).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des composés ayant la formule générale (I) sont utiles comme progéniteurs de nouveaux produits pharmaceutiques. Ces produits pharmaceutiques sont utilisés comme agents neuroleptiques ou analgésiques ou comme produits pharmaceutiques en médecine nucléaire.
EP95908935A 1994-02-18 1995-02-13 Derives substitues de 1,3,8-triaza-spiro(4,5)-decan-4-one utiles comme progeniteurs de produits pharmaceutiques Withdrawn EP0745082A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4405178 1994-02-18
DE19944405178 DE4405178A1 (de) 1994-02-18 1994-02-18 Substituierte 1,3,8-Triaza-spiro(4,5)-decan-4-on-Derivate als Vorstufen zur Herstellung von Pharmazeutika
PCT/EP1995/000513 WO1995022544A2 (fr) 1994-02-18 1995-02-13 Derives substitues de 1,3,8-triaza-spiro(4,5)-decan-4-one utiles comme progeniteurs de produits pharmaceutiques

Publications (1)

Publication Number Publication Date
EP0745082A1 true EP0745082A1 (fr) 1996-12-04

Family

ID=6510551

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95908935A Withdrawn EP0745082A1 (fr) 1994-02-18 1995-02-13 Derives substitues de 1,3,8-triaza-spiro(4,5)-decan-4-one utiles comme progeniteurs de produits pharmaceutiques

Country Status (3)

Country Link
EP (1) EP0745082A1 (fr)
DE (1) DE4405178A1 (fr)
WO (1) WO1995022544A2 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2226058C (fr) * 1997-01-30 2008-01-29 F. Hoffmann-La Roche Ag Derives de substitution en 8 de 1,3,8-triazaspiro[4.5]decan-4-one
EP1087770A4 (fr) 1998-06-15 2001-11-14 Merck & Co Inc Inhibiteurs de prenyl-proteine transferase
MXPA06005748A (es) * 2003-12-02 2006-08-17 Pfizer Prod Inc Procedimiento para convertir cetonas heterociclicas en compuestos heterociclos amido-sustituidos.
DE102005038141A1 (de) * 2005-08-12 2007-02-15 Grünenthal GmbH Substituierte 8-(3-Aminopropyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-on-Derivate

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3155669A (en) * 1962-06-22 1964-11-03 Res Lab Dr C Janssen N V 2, 4, 8-triaza-spiro (4, 5) dec-2-enes
JPS49133380A (fr) * 1973-04-25 1974-12-21
WO1989010759A1 (fr) * 1988-04-29 1989-11-16 Mallinckrodt, Inc. Agents chelateurs de diaminedithiol pour substances radiopharmaceutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9522544A3 *

Also Published As

Publication number Publication date
WO1995022544A2 (fr) 1995-08-24
DE4405178A1 (de) 1995-08-24
WO1995022544A3 (fr) 1996-09-26

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