WO1995006053A1 - Derive de bismuth tris(phenyle substitue) - Google Patents
Derive de bismuth tris(phenyle substitue) Download PDFInfo
- Publication number
- WO1995006053A1 WO1995006053A1 PCT/JP1994/001381 JP9401381W WO9506053A1 WO 1995006053 A1 WO1995006053 A1 WO 1995006053A1 JP 9401381 W JP9401381 W JP 9401381W WO 9506053 A1 WO9506053 A1 WO 9506053A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbon atoms
- alkyl group
- hydrogen atom
- group
- atom
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/94—Bismuth compounds
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S424/00—Drug, bio-affecting and body treating compositions
- Y10S424/90—In vivo diagnostic or in vivo test agent which contains an additional ingredient to reduce the toxicity or side effects of the active ingredient
Definitions
- the present invention relates to a novel substituted trifunal bismuth derivative having excellent radioimaging ability, a pharmaceutically acceptable salt thereof where possible, a method for producing the same, and a medical test agent composition containing the same as a component. Things.
- radiography using X-rays has long been widely used as a medical technique for diagnosing or examining various diseases.
- some systems such as the vasculature, urinary tract, bile ducts, gallbladder, or cerebrospinal cavity, rarely require a contrast agent to further improve the resolution.
- angiography is almost indispensable in the diagnosis of various vascular lesions mainly in tissues such as the four legs and the brain, and medical needs are increasing.
- 2,4,6-triodebenzoic acid derivatives represented by iopamidol, iohexol, and ioxaglate are all used as angiographic agents. Diagnostic situations where drugs are needed are also increasing.
- these injections have high osmotic pressure compared to blood osmotic pressure, such as hot sensation and pain at the time of injection, as well as nausea, vomiting, and rash, which are considered to be peculiar to eodo compounds.
- side effects are regarded as a problem
- a compound in which more iodine atoms are introduced in one molecule can be devised, but there are actually many practical issues due to factors such as chemical instability and difficulty in production. it is conceivable that.
- a compound containing an atom whose atomic nucleus is larger than that of an iodine atom is expected to exhibit a higher contrast ability in accordance with the radiation shielding power.
- factors such as increased chemical instability, difficulty in production, and toxicity associated with the increase in the size of nuclei are significant when these compounds are actually put into practical use as contrast agents. Will be an issue.
- Bismuth is the atom with atomic number 83, and its atomic radius is about 1.5 times as large as iodine.
- triflunibismuths A notable advantage of triflunibismuths is that higher contrast is expected at shorter wavelengths around O.lA. This is supported by the fact that the mass absorption coefficient of bismuth in ⁇ and ⁇ is 0.345, which is larger than the value of iodine of 0.136, and has high X-ray shielding ability (Chemical Handbook).
- the tris (substituted phenyl) bismuth derivative and the pharmaceutically acceptable salt of the present invention which are different from any of the compounds disclosed in References (a) to (c), All are compounds that are rich in chemical stability and biological stability ⁇ i ', and are also excellent in X-ray imaging ability. Especially, a hydroxyl group is added at the ⁇ -terminal of the substituent on the benzene ring.
- the water-soluble tris (substituted phenyl) bismuth derivatives and pharmaceutically acceptable salts have high X-ray contrast ability, so that the side effects of iodine, which is a problem with conventional drugs, can be avoided.
- the present invention was found to be a safe and highly useful vascular system, urinary tract, and bile duct.
- the present invention provides a compound represented by the general formula (I)
- X 1 is YLNWR 2 [ ⁇ 1 is - S0 2 - or
- R 1 and R 2 are each independently a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or A-Z (A is a carbon atom having 2 or more carbon atoms which may be branched and has a total carbon number of 2 to 6 represents an alkylene chain; Z represents OR 3 (R 3 represents SiR 4 R 5 R 6 (R 4 , R 5 and R 6 each independently represent an alkyl group having 1 to 4 carbon atoms or a fuynyl group) ), A hydrogen atom or an alkyl group having 1 to 4 carbon atoms.) Or NR 7 R 8 (R 7 and R 8 each independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.) However, R 1 and R 2 are not hydrogen atoms at the same time. ] R 7
- R 9 represents an alkyl group having 1 to 4 carbon atoms, R 7 is the same as described above.
- Y 2 -A-Z Y 2 is an oxygen atom, -S (0) n- (n is 0 or 2 ) Or one N—
- X 2 and X 3 each independently represent a hydrogen atom or each of the above substituents represented by X 1 . ⁇
- the present invention relates to a tris (substituted fuunyl) bismuth derivative represented by the formula (I), a pharmaceutically acceptable salt thereof where possible, a method for producing the same and a medical test composition containing these as components.
- X 1 is- (R 1 and R 2 each independently represent a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group or a butyl group.
- N- alkyl represented by N- alkyl) - to N, N- dialkyl - sulfamoyl group or a - or shows a force Rubamoiru group, SO ⁇ - ⁇ '- ⁇ ' , SO ⁇ NR ⁇ iA'-Z'), S0 2 N (A, -Z,) (A "-Z"), -C (0) NH (A, -Z,), -C (0) NR x, (A'-Z ') or -C (0) N (A, -Z,) (A "-Z")
- CR 1 ' represents the alkyl group described above, and Z and Z "each independently represent a trimethylsilyloxy group, a triethylsilyloxy group, a t -Silyloxy groups such as -butyl-dimethylsilyloxy group, t-butyl-diphenylsilyloxy group, hydroxyl group, methoxy group
- X 2 and X 3 each independently include a hydrogen atom or each of the substituents described above for X 1 .
- the compound of the formula (I) of the present invention which has high water solubility, is a preferable compound which can be used as a contrast agent in a wide range of dosage forms, including an angiographic agent used as an injection which has recently been required for medical treatment.
- II 1 and R 2 are each independently an alkyl group having 1 to 4 carbon atoms or AZ 1
- A is an alkylene group having 2 to 6 carbon atoms which may be branched with 2 or more carbon atoms.
- Z 1 represents OR 3 (R 3 represents SiR 4 R 5 R 6 (Il 4 , R 5 and R 6 each independently represent an alkyl group having 1 to 4 carbon atoms or a phenyl group)),.
- R 7 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms
- R 9 represents an alkyl group having 1 to 4 carbon atoms.
- X 2 and X 3 each independently represent a hydrogen atom or X 1
- Each of which is a tris (substituted phenyl) bismuth derivative of the general formula (I) and, where possible, pharmaceutically acceptable salts thereof.
- n means normal, i-iso, sec means secondary, t means tertiary, Me means methyl group, Et means ethyl group, Pr means propyl group, and Bu means butyl group.
- the tris (substituted phenyl) bismuth derivative of the general formula (I) of the compound of the present invention and a pharmaceutically acceptable salt thereof where possible can be produced, for example, by a method represented by the following reaction formula.
- M is MgX '(X' is iodine, shows a bromine atom or a chlorine atom.) Or a lithium atom, alkali metal such as Na Application Benefits um atoms X represents a chlorine atom or a bromine atom.
- the production method according to the reaction formula (1) comprises the steps of reacting a substituted phenyl metal reactive derivative represented by the general formula () and a trihalobismuth conjugate represented by the general formula ( ⁇ ) with an inert solvent. This is a method for producing one ( ⁇ ) compound of the present invention by a medium reaction.
- the molar ratio of the starting materials is usually 3 to 10 times, preferably 3.3 to 5 times, the amount of the substituted phenyl metal reactive derivative of the general formula ( ⁇ ) based on the trihalobismuth compound of the general formula ( ⁇ ). It is sufficient to use about twice the molar amount.
- the reaction temperature is usually from -40'C when using a substituted phenylmagnesium halide to the boiling point of the solvent used in the reaction, or from -78'C to 40 when using a substituted phenyl alkali metal salt.
- the range up to can be adopted.
- ether solvents such as ethyl ether, tetrahydrofuran, 1,4-dioxane, diisopropyl ether and the like or a mixed solvent thereof are substituted phenyl alcohols.
- metal salts in addition to the above ether solvents, mixed solvent systems with amide solvents such as ⁇ , ⁇ -dimethylformamide, ⁇ -methylpyrrolidone, and ether solvents are sometimes used. .
- the substituted phenyl metal reactive derivative represented by the general formula ( ⁇ ) can be produced, for example, by using a known production method of the following reaction schemes ( ⁇ ⁇ ) and ( ⁇ ) or a known organic reaction. it can.
- 3 ⁇ 4T represents an alkali metal salt such as a lithium atom and a sodium atom, and X 1 , X 2 and X 3 are the same as described above.
- the reaction scheme ( ⁇ ) uses a starting phenol derivative represented by the general formula ( ⁇ -1) as a starting material and reacts it with magnesium or ⁇ -butyl lithium, sec-butyl lithium, butyl By reacting an alkali metal base such as lithium, phenyllithium, and sodium amide to effect a substitution reaction between a halogen atom and a metal atom, a substituted phenylmagnesium halide derivative represented by the general formula ( ⁇ ) and This is a method for producing a substituted funyl alkali metal salt derivative.
- an alkali metal base such as lithium, phenyllithium, and sodium amide
- the reaction temperature at which these substituted phenyl metal reactive derivatives are formed is from -30 ° C to the boiling point of the solvent for substituted phenylmagnesium halide derivatives, and-for substituted phenylalkali metal salt derivatives. Normally, the range from 78'C to O'C can be set.
- Reaction Scheme (B) has the general formula ( ⁇ -2) with a phenyl derivative represented by the ortho hydrogen atoms Al Chikarari metal atom substituent X 1 which is reacted with Al force Li metal base as a starting material To produce a substituted phenyl alkali metal salt derivative represented by the general formula Ota).
- This route is expressed by the general formula ( ⁇ -1) in terms of raw material production.
- This production method provides a significant method especially when it is difficult to produce a raw material having a halogen atom X at the ortho position of the substituent X 1 .
- reaction conditions such as the alkali metal base, the solvent, and the temperature used in this method may be set in accordance with the conditions for forming the substituted phenylalkali metal salt derivative in the above-mentioned reaction scheme (A), in particular.
- R 2a represents a A'-Z a (A 'is an alkylene chain having a total carbon number of 2 to 6 may be branched chain length carbon atoms is 2 or more, Z a is OSiR 4 R3 ⁇ 4 6 (R 4, R 5 ⁇ Pi R 6 have the same.) to the, Y 1 and R 1 have the same meanings as defined above.] or Y 2 -AZ a (Y 2, a and Z a have the same.) to the, X 2 and X 3 are the same as above.
- M, + indicates a ⁇ Le kill group RWRUR RWN + dl 10, R 11 , R 12 and R 13 having 1 to 4 carbon atoms independently. ), Alkali metal ions or pyridinium ions.
- X la represents each substituent corresponding to 18 is a hydroxyl group both the ends of the substituent, X 2, and X 3, the functional terminal Z site by a substituent corresponding to X 2, X 3, respectively
- the substituents which may be excluded from the silyloxy group are shown below. ⁇
- a desilylation reaction is carried out by treating a tris ( ⁇ - ⁇ -silyloxyalkylalkylene-substituted phenyl) bismuth derivative represented by the general formula (la) with a fluoride-type compound or an acid catalyst.
- a fluoride-type compound or an acid catalyst represented by the general formula (Ia,)
- Fluoride ion-type compounds used in the above reaction include tetraalkylammonium fluorides such as tetra- ⁇ -butylammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, futsudani Examples thereof include alkali metal fluoride salts such as cesium or pyridine hydrofluoride.
- the molar ratio of the present fluoride ion type compound to the raw material (la) can be appropriately set according to the number of silyloxy groups contained in (la).
- (la) contains a plurality of silyloxy groups
- a compound in which all the silyl groups have been eliminated is usually desired by using a slight excess of the fluoride compound over the equivalent number of the silyl groups. It is enough.
- any solvent may be used as long as it does not participate in the reaction, and it can be selected widely.
- the reaction temperature is -40. It often progresses relatively quickly under mild conditions of C to room temperature.
- the desilylation reaction using an acid catalyst is particularly preferably used when the desilylation reaction of (la) containing a trialkylsilyl silyloxy group is performed.
- an organic solvent can be appropriately added to assist the dissolution of the raw material (la).
- Examples of the acid catalyst that can be used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid, organic acids such as acetic acid and citric acid, sulfonic acid derivatives such as P-toluenesulfonic acid, pyridinium P-toluenesulfonic acid, and acidic acids. Is used.
- the solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, and can be selected widely.
- the solubility of compound (la) and compound (Ia,) differ greatly, when a polar solvent and a non-polar solvent are combined, for example, a mixed solvent of ethanol and dichloromethane is used, This is preferable because the compound (Ia,) precipitates and is taken out as crystals.
- the reaction temperature can usually be set between -10'C and the boiling point of the solvent.
- the method for isolating and purifying the compound of the general formula (Ia,) of the compound of the present invention includes various chromatography methods using recrystallization or silica gel, liquid chromatography, and the like. In some cases, methods such as ion exchange chromatography and affinity chromatography are effective.
- Examples of the dosage form of the tris (substituted phenyl) bismuth derivative of the general formula (I) of the present invention and a pharmaceutically acceptable salt thereof include parenteral administration by injection or the like, tablets, capsules, capsules, Oral administration by granules, pills, emulsions, suspensions and the like can be mentioned.
- the above-mentioned pharmaceutical composition containing the compound of the present invention contains 1 to 99.5%, preferably 5 to 95%, of the compound of the present invention based on the weight of the whole composition.
- the conjugates of the present invention are formulated for administration by conventional pharmaceutical means.
- Compound No. 6 was dissolved in physiological saline for injection to a concentration of 28.5 w / v% to prepare an administration solution.
- the compound of the present invention has excellent radioimaging ability, and in particular, can exhibit sufficient imaging ability in a water-soluble compound.
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69426933T DE69426933D1 (de) | 1993-08-23 | 1994-08-22 | Tris(substituiertes phenyl)wismut derivat |
US08/596,371 US5730953A (en) | 1993-08-23 | 1994-08-22 | Tris(substituted phenyl) bismuth derivatives |
AU74677/94A AU7467794A (en) | 1993-08-23 | 1994-08-22 | Tris(substituted phenyl)bismuth derivative |
EP94924399A EP0716091B1 (en) | 1993-08-23 | 1994-08-22 | Tris(substituted phenyl)bismuth derivative |
CA002170155A CA2170155A1 (en) | 1993-08-23 | 1994-08-22 | Tris(substituted phenyl)bismuth derivatives |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20797093 | 1993-08-23 | ||
JP5/207970 | 1993-08-23 | ||
JP6/166619 | 1994-07-19 | ||
JP16661994A JP3668983B2 (ja) | 1993-08-23 | 1994-07-19 | トリス(置換フェニル)ビスマス誘導体 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995006053A1 true WO1995006053A1 (fr) | 1995-03-02 |
Family
ID=26490913
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1994/001381 WO1995006053A1 (fr) | 1993-08-23 | 1994-08-22 | Derive de bismuth tris(phenyle substitue) |
Country Status (7)
Country | Link |
---|---|
US (1) | US5730953A (ja) |
EP (1) | EP0716091B1 (ja) |
JP (1) | JP3668983B2 (ja) |
AU (1) | AU7467794A (ja) |
CA (1) | CA2170155A1 (ja) |
DE (1) | DE69426933D1 (ja) |
WO (1) | WO1995006053A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996022994A1 (en) * | 1995-01-26 | 1996-08-01 | Nycomed Imaging A/S | Bismuth compounds |
US5817289A (en) * | 1995-01-26 | 1998-10-06 | Nycomed Imaging As | Non-cluster type bismuth compounds |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU4188196A (en) * | 1994-12-22 | 1996-07-10 | Nissan Chemical Industries Ltd. | Organobismuth derivatives and process for producing the same |
DE19635419C1 (de) * | 1996-08-23 | 1998-08-20 | Schering Ag | Wismutdendrimere und ihre Verwendung als Röntgenkontrastmittel |
SG108945A1 (en) * | 2003-01-20 | 2005-02-28 | Sumitomo Chemical Co | Metal compound, and catalyst component and catalyst for addition polymerization, and process for producing addition polymer |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04154622A (ja) * | 1990-10-16 | 1992-05-27 | Sumitomo Metal Mining Co Ltd | 白色酸化ビスマス組成物の製造方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0387348A4 (en) * | 1988-09-12 | 1992-07-08 | Johannes Smid | Homogeneous radiopaque polymer-organobismuth composites |
JPH06128508A (ja) * | 1992-10-16 | 1994-05-10 | Nitto Kasei Co Ltd | 海棲生物付着防止塗料 |
FR2715401B1 (fr) * | 1994-01-26 | 1996-04-05 | Inst Francais Du Petrole | Nouveaux composés sulfonés du bismuth, leur préparation et leur utilisation notamment pour la préparation de produits colloidaux surbasés, eux-mêmes utilisables comme additifs pour lubrifiants. |
-
1994
- 1994-07-19 JP JP16661994A patent/JP3668983B2/ja not_active Expired - Fee Related
- 1994-08-22 EP EP94924399A patent/EP0716091B1/en not_active Expired - Lifetime
- 1994-08-22 CA CA002170155A patent/CA2170155A1/en not_active Abandoned
- 1994-08-22 WO PCT/JP1994/001381 patent/WO1995006053A1/ja active IP Right Grant
- 1994-08-22 US US08/596,371 patent/US5730953A/en not_active Expired - Fee Related
- 1994-08-22 AU AU74677/94A patent/AU7467794A/en not_active Abandoned
- 1994-08-22 DE DE69426933T patent/DE69426933D1/de not_active Expired - Lifetime
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH04154622A (ja) * | 1990-10-16 | 1992-05-27 | Sumitomo Metal Mining Co Ltd | 白色酸化ビスマス組成物の製造方法 |
Non-Patent Citations (4)
Title |
---|
J. CHEM. SOC., CHEM. COMMUN., Vol. 16, p. 1143-1144, (1992). * |
J. COORD. CHEM., Vol. 12, No. 1, p. 53-57, (1982). * |
See also references of EP0716091A4 * |
VESTN. LENINGRAD. UNIV., Fiz., Khim., Vol. 4, p. 113-116, (1971). * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996022994A1 (en) * | 1995-01-26 | 1996-08-01 | Nycomed Imaging A/S | Bismuth compounds |
US5817289A (en) * | 1995-01-26 | 1998-10-06 | Nycomed Imaging As | Non-cluster type bismuth compounds |
US6117412A (en) * | 1995-01-26 | 2000-09-12 | Nycomed Imaging As | Non-cluster type bismuth compounds |
US6303101B1 (en) | 1995-01-26 | 2001-10-16 | Nycomed Imaging As | Bismuth compounds |
Also Published As
Publication number | Publication date |
---|---|
AU7467794A (en) | 1995-03-21 |
CA2170155A1 (en) | 1995-03-02 |
JP3668983B2 (ja) | 2005-07-06 |
EP0716091A4 (en) | 1997-01-15 |
EP0716091B1 (en) | 2001-03-21 |
DE69426933D1 (de) | 2001-04-26 |
US5730953A (en) | 1998-03-24 |
JPH07112993A (ja) | 1995-05-02 |
EP0716091A1 (en) | 1996-06-12 |
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