KR960706467A - Aryl Halide Substituted Metallic Complexes, Pharmaceuticals Containing These Complexes, Their Use for Diagnostic Purposes, and Methods for Preparing the Complexes and Pharmaceuticals ) - Google Patents

Aryl Halide Substituted Metallic Complexes, Pharmaceuticals Containing These Complexes, Their Use for Diagnostic Purposes, and Methods for Preparing the Complexes and Pharmaceuticals ) Download PDF

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KR960706467A
KR960706467A KR1019960702895A KR19960702895A KR960706467A KR 960706467 A KR960706467 A KR 960706467A KR 1019960702895 A KR1019960702895 A KR 1019960702895A KR 19960702895 A KR19960702895 A KR 19960702895A KR 960706467 A KR960706467 A KR 960706467A
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halogen
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베르너 크라우스
프란쯔 칼 마이어
볼프-뤼디거 프레쓰
가브리엘 슈만-지암피에리
마카엘 바우어
빌리히 헤리베르트 슈미트
페터 마레스키
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클로제 · 우베 하르트만
쉐링 악티엔게젤샤프트
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Abstract

본 발명은 원자 번호가 12, 13, 20∼31, 39∼42, 44∼50 도는 57∼83인 원소의 이온 1종 이상 및 하기 일반식(Ⅰ)의 할로겐 함유 착물화 리간드(식 중, R1, R2, R3, Z1, Z2, Z3, U1, U1', U2, V1, V2또는 V3는 상이한 의미를 가짐)을 함유하는 신균한 금속 착물, 이들 착물을 함유하는 약제, NMR 진단법 및(또는) 진단적 방사선 의학, 특히 간의 진단적 방사성 의학에 있어서의 이들의 용도는 물론 이들 착물 및 제제의 제조 방법에 관한 것이다.The present invention relates to at least one ion of an element having an atomic number of 12, 13, 20 to 31, 39 to 42, 44 to 50 or 57 to 83, and a halogen-containing complexing ligand of the general formula (I) Fungal metal complexes containing 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 , U 1 , U 1 ′, U 2 , V 1 , V 2 or V 3 have different meanings, these Their use in medicaments containing complexes, NMR diagnostics and / or diagnostic radiopharmaceuticals, in particular liver radiopharmaceuticals, as well as methods of making these complexes and preparations.

Description

아릴 할라이드 치환된 금속 착물, 이를 함유하는 약제, 진단상의 그의 용도 및 이 착물 및 약제의 제조방법(Aryl Halide Substituted Metallic Complexes, Pharmaceuticals Containing These Complexes, Their Use for Diagnostic Purposes, and Methods for Preparing the Complexes and Pharmaceuticals)Aryl Halide Substituted Metallic Complexes, Pharmaceuticals Containing These Complexes, Their Use for Diagnostic Purposes, and Methods for Preparing the Complexes and Pharmaceuticals )

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is an open matter, no full text was included.

Claims (11)

원자 번호가 12, 13, 20∼31, 39∼42, 44∼50 도는 57∼83인 원소의 이온 1종 이상 및 하기 일반식(Ⅰ)의 할로겐 함유 착물화 리간드를 함유하는 금속 착물.A metal complex containing at least one ion of an element having an atomic number of 12, 13, 20 to 31, 39 to 42, 44 to 50 or 57 to 83 and a halogen-containing complexing ligand of the following general formula (I). 식 중, R1은 수소 원자, 카르복실산, 라디칼, 직쇄 또는 분지쇄 C1-C15알킬 라디칼, C6-C15아릴 라디칼 또는 C7-C15아르알킬 라디칼을 나타내며, 이는 1-5 히드록시기 및(또는) 1-2 카르복시기에 의해 임의 치환되고(되거나) 1-4 산소 원자에 의해 간섭되거나, 또는 R'은 하기 일반식(Ⅱ) 또는 (Ⅲ)의 라디칼을 나타내며;Wherein R 1 represents a hydrogen atom, a carboxylic acid, a radical, a straight or branched C 1 -C 15 alkyl radical, a C 6 -C 15 aryl radical or a C 7 -C 15 aralkyl radical, which is 1-5 Optionally substituted by a hydroxy group and / or a 1-2 carboxy group and / or interrupted by 1-4 oxygen atoms, or R 'represents a radical of the following general formula (II) or (III); -CO-NR4R5(Ⅱ)-CO-NR 4 R 5 (II) -CH2-NR6-CO-R7Ⅲ)-CH 2 -NR 6 -CO-R 7 III) [식 중, R4및 R5는 서로 독립적으로 수소 원자, 직쇄 또는 분지쇄 C1-C15알킬 라디칼, C6-C15아릴 라디칼 또는 C7-C15아르알킬 라디칼(이는 1-5 히드록시기, 1-2 카르복시기 및(또는) 1-4 산소원자를 임의로 함유함)을 나타내거나, 또는 여기서 R4및 R5과 함께 질소 원자를 혼입하여 산소 원자, 아실화된 또 다른 질소 원자 또는 술폰닐기를 임의로 함유하며 1-3 히드록시기로 임의 치환된 5 내지 6원 고리를 형성하며, R6는 수소 원자, 직쇄 또는 분지쇄 C1-C15알킬 라디칼, C6-C15아릴 라디칼 또는 C7-C15아르알킬 라디칼(이는 1-5 히드록시기, 1-2 카르복시기 및(또는) 1-4 산소 원자를 임의로 함유함)을 나타내거나, 또는 여기서 R6및 R7과 함께 질소 원자 및 카르보닐기를 혼힙하여, 산소 원자, 아실화된 또 다른 질소 원자 또는 술포닐기를 임의로 함유하며 1-3 히드록시기로 임의 치환된 5 내지 6원 고리를 형성하며, R7은 수소 원자, 직쇄 또는 분지쇄 C1-C15알킬 라디칼, C6-C15아릴 라디칼 또는 C7-C15아르알킬 라디칼(1-2 히드록시기 또는 카르복시기를 임의로 함유함)을 나타내거나, 또는 여기서 R7및 R6과 함께 질소 원자 카르보닐기를 혼합하여 산소 원자, 아실화된 또 다른 질소 원자 또는 술포닐기를 임의로 함유하며 1-3 히드록시기로 임의 치환된 5 내지 6원 고리를 형성함] R2 및 R3는 서로 독립적으로, 수소 원자, C1-C15알킬 라디킬, C6-C15아릴 라디칼 또는 C7-C15아르알킬 라디칼(1-5 히드록시기에 의해 임의 치환된(되거나) 1-4 산소 원자에 의해 간섭됨)을 나타내거나, 또는 함게 트리메틸렌 또는 테트라메틸렌기를 형성하거나, 또는 U1(U2)의 의미를 가지며; Z1, Z2및 Z3는 서로 독립적으로 히드록시기 또는 라디칼 -NR17-U1'(여기서, R17은 수소 원자, 메틸 또는 메톡시에틸기를 나타냄)을 나타내며; U1, U1', U2, V1, V2및 V3는 각각 독립적으로 수소 원자 또는 하기 일반식 (Ⅳ)의 할로겐화 방향족 라디칼을 나타낸다.[Wherein R 4 and R 5 independently of one another are a hydrogen atom, a straight or branched C 1 -C 15 alkyl radical, a C 6 -C 15 aryl radical or a C 7 -C 15 aralkyl radical (which is a 1-5 hydroxy group , Optionally containing 1-2 carboxyl groups and / or 1-4 oxygen atoms, or incorporating a nitrogen atom together with R 4 and R 5 to form an oxygen atom, another acylated nitrogen atom or sulfonyl Forms a 5-6 membered ring optionally containing a group and optionally substituted with 1-3 hydroxy groups, R 6 is a hydrogen atom, a straight or branched C 1 -C 15 alkyl radical, a C 6 -C 15 aryl radical or a C 7- Or represent a C 15 aralkyl radical, which optionally contains 1-5 hydroxy groups, 1-2 carboxyl groups and / or 1-4 oxygen atoms, or wherein R 6 and R 7 together with a nitrogen atom and a carbonyl group Optionally containing an oxygen atom, another acylated nitrogen atom or a sulfonyl group Said 1-3 and optionally form a substituted 5 to 6 membered ring with a hydroxy group, R 7 is a hydrogen atom, a straight or branched chain C 1 -C 15 alkyl radicals, C 6 -C 15 aryl radical or a C 7 -C 15 ahreu Represents an alkyl radical (optionally containing 1-2 hydroxy groups or carboxyl groups) or wherein it optionally contains an oxygen atom, another acylated nitrogen atom or a sulfonyl group by mixing a nitrogen atom carbonyl group with R 7 and R 6 ; Forms a 5 to 6 membered ring optionally substituted with 1-3 hydroxy groups] R 2 and R 3, independently of one another, represent a hydrogen atom, a C 1 -C 15 alkyl radical, a C 6 -C 15 aryl radical or a C 7 -C 15 Represent an aralkyl radical (optionally substituted by 1-5 hydroxy groups (or) and interrupted by 1-4 oxygen atoms), or together form a trimethylene or tetramethylene group, or mean U 1 (U 2 ) Has; Z 1 , Z 2 and Z 3 independently of one another represent a hydroxy group or a radical —NR 17 —U 1 ′ where R 17 represents a hydrogen atom, methyl or methoxyethyl group; U 1 , U 1 ′, U 2 , V 1 , V 2 and V 3 each independently represent a hydrogen atom or a halogenated aromatic radical of the following general formula (IV). [식 중, R8및 R9는 서로 독립적으로, -NR6-CO-R7기 및(또는) C1-C15알킬 라디칼, C6-C15아릴 라디칼 또는 C7-C15아르알킬 라디칼을 제외한 R1에 지시한 의미를 가지며, R10및 R11은 서로 독립적으로, 하로겐 원자 또는 수소 원자를 나타내며, X는 할로겐 원자 또는 하기 일반식 (Ⅴ)의 가교 형태 교차결합을 나타내며, Y는 R9또는 하기 일반식(Ⅴ)의 가교 형태 교차결합을 나타내며,[Wherein R 8 and R 9 are independently of each other, a -NR 6 -CO-R 7 group and / or a C 1 -C 15 alkyl radical, a C 6 -C 15 aryl radical or a C 7 -C 15 aralkyl Has the meanings indicated in R 1 excluding radicals, R 10 and R 11 independently of one another represent a halogen atom or a hydrogen atom, X represents a halogen atom or a crosslinked form crosslink of general formula (V), Y represents a crosslinked form crosslink of R 9 or the following general formula (V), (α)-(CH2)p-(C6H4)n-(L)m-R12-(β) (Ⅴ)(α)-(CH 2 ) p- (C 6 H 4 ) n- (L) m -R 12- (β) (V) (여기서, m, n 및 p는 서로 독립적으로 0 또는 1의 수를 나타내며, L은 산소 원자, 황 원자, C1-C4알킬렌 라디칼, ＞S=O, ＞SO2또는 R4가 상기 의미를 갖는 ＞NR4을 나타내고, R12는 직접 결합, 카르보닐, 카르복실, -CO-NR18, -NR18-CO-, -NH-CS- 또는 CS-NH기(여기서, R18은 수소 원자, 직쇄 또는 분지쇄 C1-C15알킬 라디킬, C6-C15아릴 라디칼 또는 C7-C15아르알킬 라디칼을 나타내며, 이는 1-4 히드록시기 또는 1-2 카르복시기 및(또는) 1-2 산소 원자를 임의로 함유함)를 나타내거나, 또는 여기서 R12는 카르보닐기 및(또는) 아미노기를 임의로 함유하는 직쇄 또는 분지쇄 C1-C4알킬렌 라디칼을 나타내며, 여기서 (α) 위치는 디에틸렌트리아민 골격에 연결되고, (β) 위치는 할로겐화 방향족 화합물에 연결됨) 여기서 X가 할로겐인 경우, Y는 일반식 (Ⅴ)의 가교 형태 교차결합을 나타내고, X가 일반식 (Ⅴ)의 가교 형태 교차결합을 나타내고 라디칼, R2, R3, Z1, Z2, Z3, U1, U2, V1, V2또는 V3중 적어도 하나가 일반식 (Ⅳ)의 라디칼을 나타내거나 이를 함유하는 경우, Y는 R9을 나타내며, 상기 원소의 금속 이온을 착물화하는데 필요하지 않은 임의의 유리 카르복시기는 무기 및(또는) 유기 염기 또는 아미노산의 염으로서 존재한, 단, R8및(또는) R9이 아릴 라디칼을 함유하고(하거나); 치환체 R2, R3, U1, U2, V1, V2또는 V3중 적어도 하나가 수소 원자가 아닌 경우에만 Z1및(또는) Z2는 완전히 치환된 일반식 (Ⅳ)의 방향족 화합물을 함유하지 않고(않거나); 모든 치환체 R2, R3, U1, U2, V1, V2또는 V3가 수소를 나타내면 라디칼 R8, R9, R10또는 R11중 적어도 하나가 수소 원자를 나타내고(내거나), R8및(또는) R9이 직접 결합하지 않은 카르복실산을 함유하는 라디칼을 나타낸다는 것 중 적어도 하나의 전제를 가짐].Wherein m, n and p represent, independently of one another, a number of 0 or 1, L represents an oxygen atom, a sulfur atom, a C 1 -C 4 alkylene radical,> S = O,> SO 2 or R 4 > NR 4 having a meaning, R 12 is a direct bond, carbonyl, carboxyl, -CO-NR 18 , -NR 18 -CO-, -NH-CS- or CS-NH group wherein R 18 is Hydrogen atom, straight or branched C 1 -C 15 alkyl radical, C 6 -C 15 aryl radical or C 7 -C 15 aralkyl radical, which represents a 1-4 hydroxy group or 1-2 carboxyl group and / or 1 Optionally contains -2 oxygen atoms, or wherein R 12 represents a straight or branched C 1 -C 4 alkylene radical optionally containing a carbonyl group and / or an amino group, wherein the (α) position is di Linked to an ethylenetriamine backbone, and the (β) position is linked to a halogenated aromatic compound, where X is a halogen, Y is a crosslinked form of Formula (V) Represents a crosslink, X represents a crosslinked form crosslink of formula (V) and represents a radical, R 2 , R 3 , Z 1 , Z 2 , Z 3 , U 1 , U 2 , V 1 , V 2 or V 3 When at least one of represents or contains a radical of the general formula (IV), Y represents R 9 , and any free carboxyl group which is not necessary to complex the metal ions of the element is an inorganic and / or organic base. Or present as a salt of an amino acid, provided that R 8 and / or R 9 contain an aryl radical; Z 1 and / or Z 2 are fully substituted aromatic compounds of general formula (IV) only when at least one of substituents R 2 , R 3 , U 1 , U 2 , V 1 , V 2 or V 3 is not a hydrogen atom Contains no or; If all substituents R 2 , R 3 , U 1 , U 2 , V 1 , V 2 or V 3 represent hydrogen, at least one of the radicals R 8 , R 9 , R 10 or R 11 represents (or represents) a hydrogen atom, Having at least one premise that R 8 and / or R 9 represents a radical containing a carboxylic acid which is not directly bonded. 제1항에 있어서, Z1, Z2및 Z3가 히드록시기인 것을 특징으로 하는 할로겐 함유 금속 착물.The halogen-containing metal complex of claim 1 wherein Z 1 , Z 2 and Z 3 are hydroxy groups. 제1 또는 2항에 있어서, R8, R9, R10또는 R11라디칼 중 적어도 하나가 수소 원자인 할로겐 함유 금속 착물.3. The halogen containing metal complex of claim 1 or 2 wherein at least one of the R 8 , R 9 , R 10 or R 11 radicals is a hydrogen atom. 제1 내지 3항 중 어느 한 항에 있어서, U1이 하기 일반식 (Ⅵ)의 라디칼을 나타내는 할로겐 함유 금속 착물.The halogen-containing metal complex according to any one of claims 1 to 3, wherein U 1 represents a radical of the following general formula (VI). 제1 내지 4항 중 어느 한 항에 있어서, 금속 이온으로서 가돌리늄 이온을 함유하는 할로겐 함유 금속 착물.The halogen-containing metal complex according to any one of claims 1 to 4, which contains gadolinium ions as metal ions. 제1 내지 4항 중 어느 한 항에 있어서, 홀로겐 원자(들)로서 요오드를 함유하는 할로겐 함유 금속 착물.The halogen-containing metal complex according to any one of claims 1 to 4, which contains iodine as the hologen atom (s). 제1항에 있어서, 3,6,9-트리아자-3,6,9-트리스-(카르복시메틸)-4-[4-(2,4,6-트리요오도벤질옥시)-벤질]-운데칸디오산의 이나트륨염의 가돌리늄 착물인 화합물.3,6,9-triaza-3,6,9-tris- (carboxymethyl) -4- [4- (2,4,6-triiodobenzyloxy) -benzyl]- A compound that is a gadolinium complex of disodium salt of undecanedioic acid. 임의로 생약에 통상 사용되는 첨가제와 함께 제1항에 따른 화합물 적어도 하나를 함유하는 진단용 제제.A diagnostic preparation, optionally comprising at least one compound according to claim 1 together with additives commonly used in herbal medicines. NMR 진단법 및(또는) 진단적 방사선 의학용 제제의 제조에 있어서 1종 이상의 금속 착물의 용도.Use of at least one metal complex in the preparation of NMR diagnostics and / or diagnostic radiomedical preparations. 간의 진단적 방사선 의학용 제제의 제조에 있어서 1종 이상의 금속 착물의 용도.Use of at least one metal complex in the preparation of a diagnostic radiomedical preparation for liver. 물에 용해된 착염을 생약에 통상 사용하는 첨가제 및 안정화제와 함께 장내 또는 비경구투여에 적당한 형태로 만들어, 착염이 1 내지 1500mmOL/ℓ의 농도로 존재하는 제1 내지 6항 중 어느 한 항에 따른 제제의 제조 방법.The complex salt dissolved in water, together with additives and stabilizers commonly used in herbal medicines, is made into a form suitable for enteral or parenteral administration, so that the complex salt is present in a concentration of 1 to 1500 mmOL / L. Method for the preparation of the preparation according to the invention. ※ 참고사항 : 최초출원 내용에 의하여 공개되는 것임.※ Note: This is to be disclosed by the original application.
KR1019960702895A 1993-12-03 1994-11-26 Aryl Halide Substituted Metallic Complexes, Pharmaceuticals Containing These Complexes, Their Use for Diagnostic Purposes, and Methods for Preparing the Complexes and Pharmaceuticals ) KR960706467A (en)

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