KR930702967A - Anticoagulant Properties of Macrocyclic Compounds and Treatment Methods Using the Same - Google Patents

Anticoagulant Properties of Macrocyclic Compounds and Treatment Methods Using the Same

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Publication number
KR930702967A
KR930702967A KR1019930702267A KR930702267A KR930702967A KR 930702967 A KR930702967 A KR 930702967A KR 1019930702267 A KR1019930702267 A KR 1019930702267A KR 930702267 A KR930702267 A KR 930702267A KR 930702967 A KR930702967 A KR 930702967A
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KR
South Korea
Prior art keywords
composition
sulfonic acid
group
acid
ring
Prior art date
Application number
KR1019930702267A
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Korean (ko)
Inventor
엠. 황 코우
엠. 키 유
리우 수-윙
시. 리 토마스
초이 윌리암
첸 젠
Original Assignee
프랭크 쿵
제네랩스 테크놀로지스, 인코포레이티드
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Publication date
Priority claimed from US07/647,720 external-priority patent/US5196452A/en
Priority claimed from US07/647,469 external-priority patent/US5166173A/en
Application filed by 프랭크 쿵, 제네랩스 테크놀로지스, 인코포레이티드 filed Critical 프랭크 쿵
Publication of KR930702967A publication Critical patent/KR930702967A/en

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    • C07F9/3882—Arylalkanephosphonic acids

Abstract

본 발명은 인간을 대상으로 혈액 응고를 억제하는데에 사용하기 위한 약제 조성물에 관한 것이다. 이 조성물은 고리-결합 브릿지 연결에 의해 서로 연결되고 아릴 서브유닛의 비-브릿지 원자상에 치환된 술폰산 유도 치환기를 함유하는 아릴 고리 서브유닛으로 구성된 마크로고리 회합물을 포함한다. 마크로고리 화합물은 약제학적으로 허용할 수 있는 담체중에서 운반된다. 본 발명은 또한 신규의 마크로고리 화합물에 관한 것이다.The present invention relates to pharmaceutical compositions for use in inhibiting blood clotting in humans. The composition includes macrocyclic associations consisting of aryl ring subunits containing sulfonic acid derived substituents linked to each other by ring-bond bridge linkages and substituted on non-bridge atoms of the aryl subunits. The macrocyclic compound is carried in a pharmaceutically acceptable carrier. The invention also relates to novel macrocyclic compounds.

Description

마크로고리 화합물의 항응고 특성 및 그것을 이용한 치료방법Anticoagulant Properties of Macrocyclic Compounds and Treatment Methods Using the Same

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

제1도는 본 발명에 사용하기 위한 나프탈렌 서브유닛으로 구성된 마크로고리 화합물의 일반구조이고, 제2A도 및 제2B도는 n=4 이고 서브유닛이 크로모트로프산인, 제1도의 구조의 비산화형태(2A)및 부분적 산화형태(2B)이고, 제 3A도 및 제3B도는 제2A도에 도시한 것과 같은 마크로 고리 화합물의 2가지 일반적 합성 방법을 도해한 것이다.FIG. 1 is a general structure of macrocyclic compounds composed of naphthalene subunits for use in the present invention, and FIGS. 2A and 2B are n = 4 and the non-oxidized form of the structure of FIG. 2A) and partially oxidized form (2B), FIGS. 3A and 3B illustrate two general methods of synthesizing macrocyclic compounds as shown in FIG. 2A.

Claims (17)

마크로고리의 골격을 만드는 연결된 원자들의 연소 사슬을 형성하는 고리-결합 브릿지 연결에 의해 연결되고, 아릴 서브 유닛에 대해 비-골격 원자들상에 술폰산 유도 치환기를 함유하는 아릴 고리 서브유닛으로 구성된 마크로고리 화합물, 및 펩티드를 운반하는 약제학적으로 허용될수 있는 담체로 이루어진, 인간을 대상으로 응고를 억제하는데에 효과적인 약제 조성물.Macrocycles consisting of aryl ring subunits containing sulfonic acid derived substituents on non-skeleton atoms for aryl subunits, linked by ring-bond bridge linkages forming the combustion chain of linked atoms making up the skeleton of the macrocycle A pharmaceutical composition effective in inhibiting coagulation in a human, comprising a compound, and a pharmaceutically acceptable carrier that carries the peptide. 제1항에 있어서, 술폰산 유도 치환기가 술폰산, 술폰산염, 술핀산, 술핀산염, 술폰 및 술폰아미드로 구성된 군으로 부터 선택됨을 특징으로 하는 조성물.The composition of claim 1 wherein the sulfonic acid derived substituent is selected from the group consisting of sulfonic acid, sulfonic acid salts, sulfinic acid, sulfinates, sulfones and sulfonamides. 제1항에 있어서, 아릴 고리 서브유닛, (a)1-및 8-위치 극성기 및 3- 및 6-위치 술폰산 -유도 치환기를 갖는 나프탈렌 서브유닛, (b)1-위치 극성기 및 4-위치 술폰산 유도기를 갖는 페닐 서브유닛 (c)(a)와 (b)의 혼합물로 구성된 군으로부터 선택되며, 여기에서 1개의 나프탈렌 또는 페닐기의 2번 고리-탄소위치와, 인접 나프탈렌기의 7번 고리-탄소기 또는 인접 페닐기의 6번 고리-탄소 위치 사이에 브릿지 연결이 있음을 특징으로 하는 조성물.The naphthalene subunit of claim 1, wherein the aryl ring subunit has a (a) 1- and 8-position polar group and a 3- and 6-position sulfonic acid-derived substituent, (b) a 1-position polar group and a 4-position sulfonic acid Selected from the group consisting of a mixture of phenyl subunits (c) (a) and (b) having an inducer, wherein the ring 2 -carbon position of one naphthalene or phenyl group and the ring 7 of the adjacent naphthalene group A composition characterized in that there is a bridge link between the 6 ring-carbon position of a group or adjacent phenyl group. 제3항에 있어서, 마크로고리 화합물이 하기식의 형태를 가짐을 특징으로 하는 조성물.The composition according to claim 3, wherein the macrocyclic compound has the form of the following formula. 상기식에서, R2는 술폰산, 술폰산염, 술핀산, 술핀산염, 술폰 또는 술폰아미드이고, R1은 OH, =O, 알킬 또는 에테르, 에스테르, 또는 산 또는 이들의 혼합물이고, R4는 ＞CHR″ 또는 ＞CR″이며, 여기에서 R″는 H또는 카르복실산기이며, n은 4,6또는 8이다.Wherein R 2 is sulfonic acid, sulfonate, sulfinic acid, sulfinate, sulfone or sulfonamide, R 1 is OH, = 0, alkyl or ether, ester, or acid or mixtures thereof, and R 4 is> CHR Or ″ CR ″, where R ″ is H or a carboxylic acid group, and n is 4, 6 or 8. 제4항에 있어서, R2가 술폰산 또는 술폰산염임을 특징으로 하는 조성물.The composition of claim 4 wherein R 2 is sulfonic acid or sulfonate. 제4항에 있어서, R2가 알킬 술폰 또는 SO2NHR이며, 여기에서 NHR은 NH2, NHOH 또는 아미노산임을 특징으로 하는 조성물.5. The composition of claim 4, wherein R 2 is alkyl sulfone or SO 2 NHR, wherein NHR is NH 2 , NHOH or an amino acid. 제3항에 있어서, 화합물이 하기식의 형태를 가짐을 특징으로 하는 조성물.The composition of claim 3 wherein the compound has the form of: 상기식에서, R2는 술폰산, 술폰산염, 술핀산, 술핀산염, 술폰 또는 술폰아미드이고, R1은 OH, =O, 알킬 또는 에테르, 에스테르, 또는 산 또는 이들의 혼합물이고, R4는 ＞CHR″ 또는 ＞CR″이며, 여기에서 R″는 H또는 카르복실산기이며, n은 4,6또는 8이다.Wherein R 2 is sulfonic acid, sulfonate, sulfinic acid, sulfinate, sulfone or sulfonamide, R 1 is OH, = 0, alkyl or ether, ester, or acid or mixtures thereof, and R 4 is> CHR Or ″ CR ″, where R ″ is H or a carboxylic acid group, and n is 4, 6 or 8. 제7항에 있어서, R1이 -OCOCH3, -SO3C6H4CH3, -COOH 및 OMe로 구성된 군으로부터 선택됨을 특징으로 하는 조성물.8. The composition of claim 7, wherein R 1 is selected from the group consisting of -OCOCH 3 , -SO 3 C 6 H 4 CH 3 , -COOH and OMe. 제7항에 있어서, R2가 알킬술폰 또는 SO2NHR 이며, 여기에서 NHR은 NH2, NHOH 또는 아미노산임을 특징으로 하는 조성물.8. The composition of claim 7, wherein R 2 is alkylsulfone or SO 2 NHR, wherein NHR is NH 2 , NHOH or amino acid. 제7항에 있어서, R1기중 일부가 =O임을 특징으로 하는 조성물,The composition of claim 7, wherein some of the R 1 groups are ═O, 제1항에 있어서, 조성물이 경구 투여 후에, 약 10내지 100㎍/㎖의 화합물의 최대 혈액 농도를 생성시키도록 제제됨을 특징으로 하는 조성물.The composition of claim 1, wherein the composition is formulated to produce a maximum blood concentration of the compound of about 10 to 100 μg / ml after oral administration. 알킬 술폰 및 SO2NHR 형태(NHR은 NH2, NHOH 또는 아미노산임)의 술폰아미드로 구성된 군으로부터 선택된 6개 이상의 규칙적으로 일정 간격으로 있는 술폰산 유도 치환기로 구성된 생체에 적합한 마크로고리 중합체, 및 펩티드를 운반하는 약제학적으로 허용될 수 있는 담체로 이루어진, 인간을 대상으로 혈액응고를 억제하는 데에 효과적인 약제 조성물.Biocompatible macrocyclic polymers composed of at least six regularly spaced sulfonic acid derived substituents selected from the group consisting of alkyl sulfone and SO 2 NHR form (NHR is NH 2 , NHOH or amino acid), and peptides; A pharmaceutical composition effective in inhibiting blood coagulation in a human, comprising a pharmaceutically acceptable carrier for carrying. 제12항에 있어서, 중합체가 마크로고리의 골격을 만드는 연결된 원자들의 연결 사슬을 형성하는 고리-결합 브릿지 연결에 이해 연결되고, 아릴 서브유닛 비-골격 원자들상에 술폰산 유도 치환기를 함유하는 아릴 고리 서브 유닛으로 구성된 마크로고리 화합물임을 특징으로 하는 조성물.13. An aryl ring according to claim 12, wherein the polymer is linked to a ring-bonded bridge linkage forming a linking chain of linked atoms that make up the backbone of the macrocycle, and contains sulfonic acid derived substituents on the aryl subunit non-skeleton atoms. A composition characterized in that the macrocyclic compound composed of subunits. 제13항에 있어서, 마크로고리 화합물이 1개의 술폰산 유도 치환기를 각각 함유하는 6개 이상의 페닐 고리 서브유닛으로 구성됨을 특징으로 하는 조성물.The composition of claim 13, wherein the macrocyclic compound consists of at least six phenyl ring subunits each containing one sulfonic acid derived substituent. 하기식의 형태를 갖는 마크로유리 화합물.Macro glass compound which has a form of a following formula. 상기식에서, R2는 술폰산, 술폰산염, 술핀산, 술핀산염, 술폰 또는 술폰아미드이고, R1은 =0 또는 -OH, 알킬 또는 아릴 에테르, 에스테르, 또는 산, 또는 이들의 혼합물이고, R4는 ＞CHR″ 및 ＞CR″ 이며, 여기에서 R″는 H 또는 카르복실산이고 n=4,6 또는 8이다.Wherein R 2 is sulfonic acid, sulfonate, sulfinic acid, sulfinate, sulfone or sulfonamide, R 1 is = 0 or -OH, alkyl or aryl ether, ester, or acid, or mixtures thereof, and R 4 Is> CHR "and>CR", where R "is H or carboxylic acid and n = 4,6 or 8. 제15항에 있어서, R1이 -OCOCH3, -SO3C6H4CH3, -COOH 또는 OMe로 구성된 군으로부터 선택됨을 특징으로 하는 화합물.The compound of claim 15, wherein R 1 is selected from the group consisting of —OCOCH 3 , —SO 3 C 6 H 4 CH 3 , —COOH, or OMe. 재15항에 있어서, R2가 알킬 술폰 또는 SO2NHR이며, 여기에서 NHR은 NH2, NHOH또는 아미노산임을 특징으로 하는 화합물.The compound of claim 15, wherein R 2 is alkyl sulfone or SO 2 NHR, wherein NHR is NH 2 , NHOH or an amino acid. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
KR1019930702267A 1991-01-29 1992-01-21 Anticoagulant Properties of Macrocyclic Compounds and Treatment Methods Using the Same KR930702967A (en)

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US07/647,720 US5196452A (en) 1991-01-29 1991-01-29 Macrocyclic anti-viral compound and method
US07/647,469 US5166173A (en) 1991-01-29 1991-01-29 Method of treating herpes simplex virus infection
US07/647,720 1991-01-29
US07/647.469 1991-01-29
US79213591A 1991-11-13 1991-11-13
US07/792,135 1991-11-13
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