WO1995022544A2 - Substituierte 1,3,8-triaza-spiro(4,5)-decan-4-on-derivate als vorstufen zur herstellung von pharmazeutika - Google Patents
Substituierte 1,3,8-triaza-spiro(4,5)-decan-4-on-derivate als vorstufen zur herstellung von pharmazeutika Download PDFInfo
- Publication number
- WO1995022544A2 WO1995022544A2 PCT/EP1995/000513 EP9500513W WO9522544A2 WO 1995022544 A2 WO1995022544 A2 WO 1995022544A2 EP 9500513 W EP9500513 W EP 9500513W WO 9522544 A2 WO9522544 A2 WO 9522544A2
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- WO
- WIPO (PCT)
- Prior art keywords
- compounds
- formula
- independently
- same
- integer
- Prior art date
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- 0 *C(NC12CCN(*)CC1)N(*)C2=O Chemical compound *C(NC12CCN(*)CC1)N(*)C2=O 0.000 description 2
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 ).
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- 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
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95908935A EP0745082A1 (de) | 1994-02-18 | 1995-02-13 | Substituierte 1,3,8-triaza-spiro(4,5)-decan-4-on-derivate als vorstufen zur herstellung von pharmazeutika |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
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 |
DEP4405178.6 | 1994-02-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1995022544A2 true WO1995022544A2 (de) | 1995-08-24 |
WO1995022544A3 WO1995022544A3 (de) | 1996-09-26 |
Family
ID=6510551
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1995/000513 WO1995022544A2 (de) | 1994-02-18 | 1995-02-13 | Substituierte 1,3,8-triaza-spiro(4,5)-decan-4-on-derivate als vorstufen zur herstellung von pharmazeutika |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0745082A1 (de) |
DE (1) | DE4405178A1 (de) |
WO (1) | WO1995022544A2 (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6071925A (en) * | 1997-01-30 | 2000-06-06 | Hoffmann-La Roche Inc. | 1,3,8-triazaspiro[4,5]decan-4-one derivatives |
US6172076B1 (en) | 1998-06-15 | 2001-01-09 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007513141A (ja) * | 2003-12-02 | 2007-05-24 | ファイザー・プロダクツ・インク | ヘテロ環式ケトンをアミド置換ヘテロ環に変換する方法 |
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 |
Citations (2)
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 |
WO1989010759A1 (en) * | 1988-04-29 | 1989-11-16 | Mallinckrodt, Inc. | Diaminedithiol chelating agents for radiopharmaceuticals |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS49133380A (de) * | 1973-04-25 | 1974-12-21 |
-
1994
- 1994-02-18 DE DE19944405178 patent/DE4405178A1/de not_active Withdrawn
-
1995
- 1995-02-13 WO PCT/EP1995/000513 patent/WO1995022544A2/de not_active Application Discontinuation
- 1995-02-13 EP EP95908935A patent/EP0745082A1/de not_active Withdrawn
Patent Citations (2)
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 |
WO1989010759A1 (en) * | 1988-04-29 | 1989-11-16 | Mallinckrodt, Inc. | Diaminedithiol chelating agents for radiopharmaceuticals |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 85, no. 13, 27.September 1976 Columbus, Ohio, US; abstract no. 94399s, Seite 641; & JP-A-75 160 269 (SUMITOMO CHEMICAL CO., LTD.) 25.Dezember 1975 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6071925A (en) * | 1997-01-30 | 2000-06-06 | Hoffmann-La Roche Inc. | 1,3,8-triazaspiro[4,5]decan-4-one derivatives |
US6172076B1 (en) | 1998-06-15 | 2001-01-09 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
Also Published As
Publication number | Publication date |
---|---|
EP0745082A1 (de) | 1996-12-04 |
WO1995022544A3 (de) | 1996-09-26 |
DE4405178A1 (de) | 1995-08-24 |
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