KR850000846B1 - 아미노산 유도체의 제조방법 - Google Patents
아미노산 유도체의 제조방법 Download PDFInfo
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- KR850000846B1 KR850000846B1 KR1019840002123A KR840002123A KR850000846B1 KR 850000846 B1 KR850000846 B1 KR 850000846B1 KR 1019840002123 A KR1019840002123 A KR 1019840002123A KR 840002123 A KR840002123 A KR 840002123A KR 850000846 B1 KR850000846 B1 KR 850000846B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- 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
- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/80—Antihypertensive peptides
Abstract
내용 없음.
Description
본 발명은 전환 효소억제제 및 항고혈압제로서 유용한 다음 일반식(1)의 카복시알킬 디펩티드 및 그의 유도체를 제조하는 방법에 관한 것이다.
식중, R 및 R6는 동일 또는 상이하며, 히드록시, 저급알콕시, 저급알켄옥시, 디저급알킬아미노 저급알콕시(디메틸아미노에톡시), 아실아미노저급알콕시(아세틸아미노에톡시), 아실옥시 저급알콕시(피발로일옥시메톡시), 페녹시같은 아릴옥시, 벤질옥시같은 아르저급알콕시, 치환기가 메틸, 할로 또는 메톡시인 치환아릴옥시 또는 치환아르저급알콕시, 아미노, 저급아미노, 디저급알킬아미노, 히드록시아미노, 벤질아미노와 같은 아르저급알킬아미노이며,
R1은 수소, 분지 및 싸이클 및 불포화(아릴같은) 알킬기를 내포하는 C1-20의 알킬 ; 치환기가 할로, 히드록시, 아미노, 디저급알킬아미노, 아세트아미도 및 벤즈 아미도 같은 아실아미노, 아릴아미노, 구아니디노, 이미다졸릴, 인돌릴, 메르갚토, 저급알킬티오, 페닐티오 같은 아릴티오, 카복시 또는 카복스 아미도, 카보저급알콕시일 수 있는 치환저급알킬 ; 페닐 또는 나프틸같은 아릴 ; 치환기가 저급알킬, 저급알콕시 또는 할로인 페닐같은 치환아릴 ; 벤질, 스티릴 또는 인돌릴 에틸같은 아르저급알킬, 아르저급알케닐 헤테로아르 저급알킬 또는 헤테로아르저급알케닐 ; 치환기가 할로, 디할로, 저급알킬, 히드록시, 저급알콕시, 아미노, 아미노메틸, 아실아미노(아세틸아미노 또는 벤조일아미노), 디저급 알킬아미노, 저급알킬아미노, 카복실, 할로저급알킬, 시아노 또는 설폰아미도인 치환아르저급알킬, 치환아르저급알케닐, 치환헤테로아르저급알킬 또는 치환헤테로 아르저급알케닐 ; 아미노 또는 아실아미노(아세틸아미노 또는 벤조일 아미노)에 의하여 알킬부분이 치환된 아르저급 알킬 또는 헤테로아르저급 알킬이고 ;
R2및 R7은 동일하거나 상이하며, 수소 또는 저급알킬이다.
R3는 수소, 저급알킬, 페닐저급알킬, 아미노메틸페닐저급알킬, 히드록시페닐저급알킬, 히드록시 저급알킬, 아실아미노저급알킬(벤조일아미노저급알킬, 아세틸아미노저급알킬 같은), 아미노저급알킬, 디메틸아미노저급알킬, 할로저급알킬, 구아니디노저급알킬, 이미다졸릴저급알킬, 인돌릴저급알킬, 메르갚토저급알킬 또는 저급 알킬티오 저급알킬이고,
R4는 수소 또는 저급알킬이고,
R5는 수소, 저급알킬, 페닐, 페닐저급알킬, 히드록시페닐저급알킬, 히드록시저급알킬, 아미노저급알킬 구아니디노저급알킬, 이미다졸릴저급알킬, 인돌릴저급알킬, 메르갚토저급알킬 또는저급알킬티오 저급알킬이며,
R4및 R5는 함께 결합되어 C2-4의 알킬렌가교, C2-3및 하나의 황원자를 갖는 알킬렌가교, 이중결합을 함유하는 C3-4의 알킬렌가교 또는 히드록시, 저급알콕시, 저급알킬 또는 디저급알킬로 치환된 상술한 바와같은 알킬렌가교를 형성할 수 있다.
별도로 표시하지 않는한 저급알킬 또는 저급알케닐기는 예컨대 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, t-부틸, 펜틸, 이소펜틸, 헥실 또는 비닐, 아릴, 부테닐과 같은 C1-6의 직쇄 및 분지쇄 탄화수소기이다. 또 아랄킬은 그의 알킬부분에 C1-4를 가지며, 예컨대 벤질, P-메톡시벤질등을 포함한다. 할로는 염소, 불소, 옥소 또는 브롬을 의미한다. 별도로 표시하지 않는한 아릴은 페닐 또는 나프틸이다. 헤테로아릴기에는 예컨대 피리딜, 푸릴, 인돌릴, 벤즈테이닐, 이미다졸릴 및 티아졸릴이 있다.
R1, R3및 R5치환 저급알킬 부분을 예시하면 다음과 같다.
R4및 R5는 이들이 부착되는 탄소 및 질소원자로 결합될 때 하나의 황원자 또는 이중결합을 함유할 수 있는 4-6원환을 형성한다. 바람직한 환(ring)으로서는 다음과 같은 것이었다.
식중, [Y는 CH2, S또는 CHOCH3이다.]
일반식(1)의 바람직한 화합물은 다음과 같은 것들이다.
즉, R는 히드록시, 저급알콕시, 저급알켄옥시, 아르저급알킬옥시, 디저급알킬 아미노저급알콕시, 아실아미노 저급알콕시, 치환기가메틸, 할로 또는 메톡시인 아실옥시 저급알콕시이고,
R6는 히드록시 또는 아미노이며,
R7및 R2은 수소이고,
R3는 저급알킬 또는 아미노저급 알킬이며,
R4및 R5는 결합하여 Y가 CH2, S 또는 CHOCH3인 상술한 바와같은 바람직한 환을 형성하고,
R1는 상술한 바과같은 것이다.
또한 일반식(1)의 더욱 바람직한 화합물은 다음과 같은 것들이다.
R1이 C-8의 알킬,
알킬기가 C1-4이며 치환기는 아미노, 아릴티오, 아릴옥시 또는 아릴아미노인 치환저급알킬이고, 알킬부분이 페네틸 또는 인돌릴에틸과 같은 C1-3알랄킬 또는 헤테로아랄킬이거나 알킬기가 C1-3를 가지며, 치환기가 할로, 디할로, 아미노, 아미노알킬, 히드록시, 저급알콕시 또는 저급알킬인 치환아르저급알킬(페닐저급알킬 또는 나프틸저급알킬) 및 치환헤테로 아르저급알킬인 것이다.
일반식(1)의 가장 바람직한 화합물은 다음과 같은 것들이다.
R는 히드록시 또는 저급 알콕시이며,
R6는 히드록시이고,
R7및 R2는 수소이며,
R3는 메틸 또는 아미노저급알킬이고,
R4및 R5는 탄소 및 질소원자로 결합하여 프롤린, 4-티아프롤린 또는 4-메톡시프롤린을 형성하며,
R1는 C1-8의 알킬.
알킬기가 C1-4를 가지며, 치환기가 아미노, 아릴티오 또는 아릴옥시인 치환저급알킬, 알킬부분이 페네틸 또는 인돌릴에틸 같은 C1-3를 갖는 아랄킬이거나 아킬기가 C1-3를 가지며, 치환기가 할로, 디할로, 아미노, 아미노알킬, 히드록시, 저급알콕시 또는 저급아랄킬(페닐저급아킬 또는 나프릴 저급알킬) 및 치환헤테로 아랄킬인 것이다.
바람직한 화합물, 더욱 바람직한 화합물, 가장 바람직한 화합물은 제약상 인정되는 것의 염을 또한 포함한다.
일반식(1)의 생성물 및 바람직한 아군(亞群)은 1종 또는 그 이상의 방법에 의해 그리고 하기식들로 표시되는 부차적 경로에 의해 제조되는 것일 수 있다.
본 기술분야에 숙련된 사람에게는 명백하여, 실시예에 증명되어 있는 바와같이, 아미노, 카복시, 메르갚토등과 같이 축합에 포함되지 안는 반응성기는 커플링 반응(coupling reaction)전에 펩티드 화학에서의 표준방법에 의하여 보호된 다음 소망하는 생성물을 얻기위해 탈보호된다.
방법 1, 경로 1 (R2=H)
케토산(또는 에스테르, 아미도 또는 히드록사민산) (2)를 수용액(중성에 가까운 것이 바람직함), 또는 적당한 유기용매(예컨대 CH3CN)에서 나트륨시아노보로하이드라이드의 존재하에 디펩타이드(3)와 축합시켜 일반식(1) (R2=H)를 얻는다. 이와는 달리, 중간 쉬프(Schiff) 염기, 에나민 또는 아미놀을 예컨대 탄소상의 10% 팔라듐 또는 라니니켈의 존재하에 수소로 촉매적으로 환원시켜 일반식(1)을 얻을 수 있다. 형성되는 디아스테레오머 생성물의 비율은 촉매의 선택에 의하여 변할수 있다.
R 및 R6가 알콕시 또는 벤질옥시등과 같은 카복시보호기인 경우, 이들을 가수분해 또는 수첨과 같은 공지된 방법에 의하여 R 및/또는 R6가 히드록시인 일반식(1)로 전환시킬 수 있다. 이것은 상기의 상태가 존재하는 다음 방법 전부에 해당한다.
또한 일반식(2)를 동일한 조건하에서 아미노산(4)과 축합시켜 아미노산(5)을 얻을 수 있다.
이어서 공지방법으로 아미노산 유도체(6)와 커플링시켜 일반식(1)을 얻는다. 공지방법은 커플링 반응중에 예컨대 N-포르밀, N-t-부톡시카보닐 및 N-카보벤질옥시기에 의하여 반응성기를 보호한다음 탈보호하여 일반식(1)을 제조하는 것을 포함한다. 더우기, R기능은 벤질, 에틸 또는 t-부틸같은 제거가능한 에스테르기를 포함할 수 있다. 본 합성경로에서 축합제는 디사이클로 헥실카보디이미드(DCC) 또는 디페닐포스포릴아시드(DPPA)와 같은 펩티드화학에서 전형적으로 유용한 것들이며, 또한 일반식(5)는 1-히드록시벤조트리아졸로부터 유도된 것과 같은 활성에스테르의 중간물질을 경유하여 활성화시킬 수도 있다.
아미노산(또는 에스테르, 아미드 또는 하이드록사민산)(7)을 경로 1에 대하여 기술한 조건하에서 케톤(8)과 축합시켜 일반식(1)을 얻는다.
또한 (7)을 케토산(9)과 축합시켜 단계적인 방법으로 아미노산(10)을 얻을수 있다.
경로에서 상술한 바와같은 공지방법에 의하여 (10)을 아미노산유도체(6)와 축합시켜 일반식(1)을 얻을 수 있다.
α-아미노 치환기를 갖는 R의 특수 경우에 있어서, 카보닐 아미노기는 β-락탐 기능으로서 편리하게 보호될 수 있다.
식중, X는 염소, 브롬, 요오드 또는 알킬 설포닐옥시 또는 아릴설포닐옥시
디펩타이드(3)를 물 또는 유기용매중의 염기성 조건하에서 적당한 α-할로산(에스테르 또는 아미드) 또는 α-설포닐옥시산(에스테르 또는 아미드)으로 알킬화시킨다.
다음의 단계 방법으로 합성을 수행할 수 있다.
식중, X=Cl, Br, I, 알킬설포닐옥시 또는 아릴설포닐옥시
아미노산(4)을 염기성조건하에서 α-할로산(에스테르 또는 아미드) 또는 α-설포닐옥시산(에스테르 또는 아미드)으로 알킬화시켜 화합물(10)을 얻는다. 이것을 경로 1에서 기술한 표준방법에 의하여 아미노산(에스테르 또는 아미드) (6)과 축합시켜 일반식(1)을 얻는다.
벤질에스테르 (1) (R6가 벤질옥시이고, R가 알콕시인 경우)의 환원 분리에 의하여 R가 알콕시이고, R6가 히드록시인 일반식(1)의 화합물이 얻어지고, R6가 알콕시이고, R가 벤질옥시인 경우에는 R6가 히드록시이고, R6가 알콕시인 일반식(1)의 화합물이 얻어진다.
식중, X=Cl, Br, I, 알킬설포닐옥시 또는 아릴설포닐옥시
아미노산 또는 유도체(7)를 염기성조건하에서 물 또는 기타 용매에서 적당히 치환된 α-할로아세틸 또는 α-설포닐 옥시아세틸 아미노(12)으로 알킬화시켜 일반식(1)을 얻는다.
또한, 단계적방식으로 아미노산 에스테르(7)를 치환 α-할로아세트산 또는 α-설포닐 옥시아세트산(13)으로 축합시켜 중간생성물(10)을 얻은다음, 방법경로 1에 기술한 공지방법에 의하여 생성물(10)을 아미노산(6) 또는 유도체와 결합시켜 일반식(1)을 얻는다.
필요에 따라 보호기를 공지방법에 의하여 제거할 수도 있다.
본 명세서에 기술되어 있는 상술한 공정에 요하는 출발물질은 문헌에 공지되어 있거나 또는 공지 출발물질로부터 공지방법에 의하여 제조할 수 있다.
일반식(1)의 생성물에서, R1, R3및 R5가 부착되는 탄소원자는 비대칭일 수 있다. 따라서, 화합물은 디아스테레오머형태 또는 그의 혼합물로서 존재한다. 상술한 합성은 출발물질로서 라세미체, 에난티오머 또는 디아스테레오머를 사용할 수 있다. 디아스테레오머 생성물이 합성공정으로 부터 얻어지는 경우, 디아스테레오머 생성물을 통상의 크로마토그래피방법 또는 분별결정화 방법에 의하여 분리할 수 있다. 일반적으로, 아미노산-부분 구조, 즉 일반식(1)의및는 S-배열이 바람직하다.
본 발명의 화합물은 각종 무기 및 유기산염을 생성하고 또한 발명의 범위내에서 염기를 생성한다. 이와같은 염은 암모늄염, 나트륨 및 칼륨염과 같은 알카리금속염, 칼슘 및 마그네슘염과 같은 알카리토금속염, 예컨대 디사이클로헥실아민염, N-메틸-D-글루카민등의 유기염기를 갖는 염, 아르기닌 및 리신등과 같은 아미노산을 갖는 염을 포함한다. 또한 예컨대 HCl, HBr, H2SO4, H3PO4, 메탄설폰산, 톨루엔설폰산, 말레인산, 푸말산, 캄포설폰산같은 유기산 및 무기산과의 염을 제조할 수도 있다. 기타의 염도 유용하나, 예컨대 생성물을 분리 또는 정제하는 동안 무독성이 생리학적으로 인정되는 염이 바람직하다.
염은, 용매 또는 매질(염이 불용성인)중에서 또는 물과 같은 용매(진공내에서 제거될 수 있는)중에서 유리산이나 유리염기 상태의 생성물을 1당량 또는 그이상의 당량의 염기 또는 산과 반응시키는 것에 의해, 또는 냉동 건조시키는 것에 의해 또는 적당한 이온교환 수지상에 존재하는 염의 양이온을 기타 양이온으로 교환하는 것에 의해 통상적인 방법으로 생성될 수 있다.
본 발명의 화합물은 안지오텐신 전환효소를 억제하며 따라서 데카펩티드 안지오텐신(Ⅰ)이 안지오텐신(Ⅱ)(Ⅱ)으로의 전환을 억제한다. 안지오텐신(Ⅱ)은 유효한 혈압증진 물질이다. 따라서 혈압강하는 특히 고혈압이 안지오텐신(Ⅱ)과 관계되어 있는 동물 또는 인간에 있어서 그의 생합성을 억제함으로서 일어날 수 있다. 더우기 전환효소는 혈관확장인자물질, 브라디키닌을 감성시킨다. 따라서 안지오텐신 전환효소의 억제제는 또한 브라디키닌의 상승작용에 의하여 혈압을 저하시킨다. 안지오텐신 전환효소의 억제제는 각종 동물에 있어서 효과적인 항고혈압제이며, 예컨대 신장혈관, 악성종양 및 고혈압환자에 있어서 임상적으로 유용하다. [예컨대 D. W. Cushman과 그의동료, 생화학 제16권, 제5484항(1977)참조].
전환효소억제제의 평가는 시험관내의 효소억제 분석에 의하여 이루어진다. 예컨대 유용한 방법은 카보벤질옥시페닐 알타닐히스 리디닐로이신의 가수분해를 측정하는 Y. piqillud, A. Reinharz및 M. Roth, Biochem, Biophy. Acta, 206, 136 (1970)의 방법이다. 생체내에서의 평가는 예컨대 J. R. Weeks 및 J .A. Jones, Proc, Soc, Exp,5Biol, Med, 104, 646 (1960)의 기술에 다라 안지오텐신(Ⅰ)으로 공격된 상압성의 쥐에서 또는 S. Koletky등, Proc, Soc, Exp, Biol, Med, 125, 96 (1067)의 기술에 의한 고-레닌 쥐모델에서 실시할 수 있다.
따라서 본 발명의 화합물은 인간을 포함한 고혈압동물의 치료에 있어서 항고혈압제로서 유용하며, 경구투여용으로 정제, 캅셀제 또는 엑릭시르와 같은 조제로 또는 비경구 투여용으로 무균용액제 또는 현택액제로 처방하여 혈압을 감소시키는 데 이용될 수 있다. 본 발명의 화합물은 일반적으로 여러회에 걸쳐 환자 1인당 5-500mg로 환자(동물 또는 인간)에게 투여할 수 있으며, 총 1일투여량은 5-2000mg이다. 용량은 본 기술분야에 숙련된자이면 알 수 있는 바와같이 병의 경중, 환자의 체중 및 당업자가 인정하는 기타인자에 따른다.
또한 본 발명의 화합물은 기타 이뇨제 또는 항고혈압제와 함계 투여할 수 있다. 전형적으로 이들은 1일용량당 1단위가 최소한도로 추천되는 임상용량의 1/5로부터 단독으로 투여되는 질병(entities)단위에 대한 최대한도를 추천되는 레벨까지의 범위에서 조합된다. 이들 조합을 구체적으로 표시하며 1일당 15-200mg범위내에서 임상적으로 유효한 본 발명의 항고혈압 제1종을 1일당 복용범위에서, 하기하는 항고혈압제 및 이뇨제와 함께 1일당 3-200mg 수준 범위로 유효하게 병용할 수 있다 : 히드로클로로티아지드(10-200mg), 클로로티아지드(125-2000mg) 에타크린산(15-200mg), 아밀로라이드(5-20mg), 프로세마이드(5-80mg), 프로파놀올(20-480mg), 티몰올(5-50mg) 및 메틸도파(65-2000mg). 이외에 히드로클로로티아지드(15-50mg)+아밀로라이드(65-2000mg). +본 발명의 전환효소 억제제(15-200mg) 또는 히드로클로로티아지드(5-20mg)+티몰올(3-200mg)+본 발명의 전환효소억제제(15-200mg)+3중 약제의 병용이 고혈압환자에 있어서 혈압을 억제하는데 유효한 조합이다. 상술한 복용범위는 매일분할 투여할 수 있도록 필요에 따라 단위주성분으로 조절할 수 있다. 또한 본 기술분야에 숙련된 자이면 알 수 있는 바와같이 투여량은 질병의 경중, 환자의 체중 및 당업자가 인정하는 기타요인에 따라 달라진다.
상술한 혼합물은 하기하는 바와같이 제약조성물로 재형화된다.
일반식(1)의 화합물 또는 생리학적으로 허용되는 염(약 10-500mg)은 생리학적으로 허용되는 부형제, 담체, 결합제, 방부제, 안정제, 향미제와 함께 일반적으로 제약실시에 요구되는 단위용량 형태로혼합된다. 이들 조성물 또는 제제에서 활성물질의 양은 지시된 범위로 적당한 투여량이 얻어지는 그러한 양이다.
정제, 캅셀등에 혼합할 수 있는 보조제의 예로서는 다음과 같은 것이 있다. 즉, 트라가간트검, 아카시아, 옥수수전분 또는 젤라틴 같은 결합제 ; 미세 결정성 셀루로스같은 부형제 ; 옥수수 전분, 예비 젤라틴화전분알긴산등과 같은 봉해제 ; 스테아린산마그네슘 같은 윤활제 ; 슈크로우스, 락토스 또는 사카린같은 감미제 ; 박하윈터그린 또는 버찌같은 향미제, 복용단위형태가 캅셀인 경우, 상술한 형태의 물질 이외에 지방유 같은 액체담체를 함유할 수 있다. 각종 기타물질이 복용단위의 물리적 형태를 변형시키지 않는한 코팅제로서 존재할 수 있다. 예컨대 정제는 쉘락, 설탕 또는 이들 양자로 코팅할 수 있다. 시럽 또는 에릭시르(elixir)는 활성 화합물, 감미제로서 슈크로우스, 방부제로서 메틸 및 프로필라라벤스, 염료 및 버찌 또는 오렌지향 같은 향미제를 함유할 수 있다.
주사용 무균조성물은 통상의 제약적 방법에 따라 활성물질을 주사용물, 참기름, 야자유, 낙하생유, 면실유등과 같은 천연식물유 같은 부형제 또는 에틸올레이트등과 같은 합성지방부형제에 용해시키거나 또는 현탁시켜 제형화할 수 있다.
완충제, 방부제, 산화방지제를 필요에 따라 혼합할 수 있다.
다음의 실시에는 본 발명을 구체적으로 예시한 것으로서 특히 바람직한 예로 구성되어 있다. 이들 실시예의 바람직한 디아스테레오머는 컬럼크로마토그래피 또는 분별경정에 의하여 분리된다.
[실시예]
N-(1-카복시-1-메틸에틸)-L-알라닐-L-프롤린
7.7g의 2-브로모이소브티르산 벤질 에스테르, 2.4g의 L-알라닐-프롤린-L-t-부틸에스테르 및 7.0g의산화은을 40ml의 벤젠중에서 결합시킨다. 24시간 환류시킨 다음 7.7g의 브로모에스테르 및 7.0g의 산화은을 더 가한 다음 24시간 더 환류시켰다. 냉각시키고, 여과하고, 용매를 제거한다음 통상의 크로마토그래피공정에 의하여 생성물의 디에스테르를 분리하였다. 트리플루오로아세트산내의 t-부틸에스테르기 및 벤질기를 통상 방법으로 수첨 분해하여 제거한결과 소기의 유리산이 얻어졌다.
Claims (1)
- 다음 일반식(7)의 아민을 일반식(8)의 케톤과 반응시켜 일반식(1)의 화합물을 제조하는 방법 :식중, R 및 R6은 서로 동일하거나 다른 하이드록시, 저급알콕시, 저급알켄옥시, 디저급알킬 아미노 저급알콕시, 아실아미노저급알콕시, 아실옥시저급알콕시, 아릴옥시, 아르저급 알킬옥시, 치환된 아릴옥시 또는 치환된 아르저급알콕시(치환기는 메틸, 할로겐 또는 메톡시), 아미노, 저급알킬아미노, 디저급알킬 아미노, 아르저급알킬아미노 또는 하이드록시 아미노이고, R1은 수소, 분지된 환식의 불포화된 알킬기를 포함하는 1-20개까지의 알킬, (치환기가 할로, 하이드록시, 저급알콕시, 아릴옥시, 아미노, 저급알킬아미노, 디저급알킬아미노, 아실아미노, 아릴아미노, 구아니디노, 이미다졸릴, 인돌릴, 메르캅토, 저급알킬티오, 아릴티오, 카복시, 카복스아미노, 카보저급알콕시임)치환 저급알킬, 페닐(치환기가 저급알킬, 저급알콕시 또는 할로임) 치환페닐, 아르저급알킬 또는 헤테로아르저급알킬, 아르저급알케닐 또는 헤테로아르저급알케닐, 치환아르저급알킬, 치환헤데로아르저급알킬, (치환기가 할로 또는 디할로, 저급알킬, 하이드록시, 저급알콕시, 아미노, 아미노메틸, 아실아미노, 디저급알킬아미노, 저급알킬아미노, 카복시할로저급알킬, 시아노 님) 치환아르저급알케닐 또는 치환헤테로아르 저급알케닐 또는 아미노또는아실아미노에 의해 알킬부분이 치환된 아르저급알킬 또는 헤테로아르저급알킬이며, R2는 저급알킬이고, R7은 수소 및 저급알킬이며, R3가 수소, 저급알킬, 페닐저급알킬, 아미노메틸페닐저급알킬, 하이드록시페닐저급알킬, 하이드록시저급알킬, 아세틸아미노저급알킬, 아실아미노저급알킬, 아미노저급알킬, 디메틸아미노저급알킬, 할로저급알킬, 구아니디노저급알킬, 이미다졸릴저급알킬, 인돌릴저급알킬, 메르캅토저급 알킬및저급알킬티오저급알킬이며, R4는 수소 또는 저급알킬이고, R5는 수소, 저급알킬, 페닐, 페닐저급알킬, 하이드록시페닐저급알킬, 하이드록시저급알킬, 아미노저급알킬, 구아니디노저급알킬, 이미다졸릴저급알킬, 인돌릴저급알킬, 메르캅토저급알킬 또는 저급알킬티오저급알킬이며, R4및 R5는 함께 결합하여 2-4개 탄소원자로 된 알킬렌가교, 2-3개의 탄소원자와 한개의 황원자로 된 알킬렌가교, 이중결합을 포함하는 3-4개 탄소원자의 알킬렌가교 또는 하이드록시, 저급알콕시 또는 저급알킬로 치환된 상기와 같은 알킬렌가교를 형성할 수 있다.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US96824978A | 1978-12-11 | 1978-12-11 | |
KR7904273A KR850000847B1 (ko) | 1978-12-11 | 1979-12-11 | 아미노산 유도체의 제조방법 |
US968249 | 1992-10-29 |
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Application Number | Title | Priority Date | Filing Date |
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KR7904273A Division KR850000847B1 (ko) | 1978-12-11 | 1979-12-11 | 아미노산 유도체의 제조방법 |
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KR840005084A KR840005084A (ko) | 1984-11-03 |
KR850000846B1 true KR850000846B1 (ko) | 1985-06-17 |
Family
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Application Number | Title | Priority Date | Filing Date |
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KR7904273A KR850000847B1 (ko) | 1978-12-11 | 1979-12-11 | 아미노산 유도체의 제조방법 |
KR1019840000192A KR840005083A (ko) | 1978-12-11 | 1984-01-17 | 항고혈압제로서 유용한 아미노산유도체의 제조방법 |
KR1019840002123A KR850000846B1 (ko) | 1978-12-11 | 1984-04-21 | 아미노산 유도체의 제조방법 |
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KR7904273A KR850000847B1 (ko) | 1978-12-11 | 1979-12-11 | 아미노산 유도체의 제조방법 |
KR1019840000192A KR840005083A (ko) | 1978-12-11 | 1984-01-17 | 항고혈압제로서 유용한 아미노산유도체의 제조방법 |
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EP (1) | EP0012401B1 (ko) |
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BG (6) | BG39294A3 (ko) |
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Families Citing this family (386)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL58849A (en) * | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
US4595675A (en) * | 1979-09-19 | 1986-06-17 | Hoechst Aktiengesellschaft | Bicyclic α-iminocarboxylic acid compounds having hypotensive activity |
US4508729A (en) * | 1979-12-07 | 1985-04-02 | Adir | Substituted iminodiacids, their preparation and pharmaceutical compositions containing them |
FR2503155A2 (fr) * | 1980-10-02 | 1982-10-08 | Science Union & Cie | Nouveaux imino diacides substitues, leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme |
US4616031A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
US4616029A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydromdole-2-carboxylic acids as antihypertensives |
US4616030A (en) * | 1979-12-07 | 1986-10-07 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
US4644008A (en) * | 1979-12-07 | 1987-02-17 | Adir | Perhydroindole-2-carboxylic acids as antihypertensives |
JPS5683483A (en) * | 1979-12-13 | 1981-07-08 | Santen Pharmaceut Co Ltd | Thiazolidine compound |
IE52663B1 (en) * | 1980-04-02 | 1988-01-20 | Warner Lambert Co | Substituted acyl derivatives of octahydro-1h-indole-2-carboxylic acids |
US4350704A (en) * | 1980-10-06 | 1982-09-21 | Warner-Lambert Company | Substituted acyl derivatives of octahydro-1H-indole-2-carboxylic acids |
FR2480747A1 (fr) * | 1980-04-17 | 1981-10-23 | Roques Bernard | Derives d'acides amines et leur application therapeutique |
PT73522B (en) * | 1980-08-18 | 1983-07-14 | Merck & Co Inc | Process for preparing substituted caprylolactam derivatives as antihypertensives |
GR74635B (ko) * | 1980-08-18 | 1984-06-29 | Merck & Co Inc | |
IL63540A0 (en) * | 1980-08-18 | 1981-11-30 | Merck & Co Inc | Substituted enantholactam derivatives as antihypertensives |
GR75019B (ko) * | 1980-09-17 | 1984-07-12 | Univ Miami | |
US4344949A (en) * | 1980-10-03 | 1982-08-17 | Warner-Lambert Company | Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids |
GR75775B (ko) * | 1980-10-06 | 1984-08-02 | Merck & Co Inc | |
EP0050800B2 (en) * | 1980-10-23 | 1995-06-07 | Schering Corporation | Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them |
ZA817261B (en) * | 1980-10-23 | 1982-09-29 | Schering Corp | Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them |
US4296110A (en) * | 1980-10-28 | 1981-10-20 | E. I. Du Pont De Nemours And Company | Antihypertensive I-substituted cyclic lactam-2-carboxylic acids |
AU543804B2 (en) * | 1980-10-31 | 1985-05-02 | Takeda Chemical Industries Ltd. | Amides having bicyclic substituents on nitrogen |
GB2086390B (en) * | 1980-11-03 | 1984-06-06 | Ciba Geigy Ag | 1-carboxy-azaalkanoylindoline-2-carboxylic acids process for their manufacture pharmaceutical preparations containing these compounds and their therapeutic application |
US4462943A (en) * | 1980-11-24 | 1984-07-31 | E. R. Squibb & Sons, Inc. | Carboxyalkyl amino acid derivatives of various substituted prolines |
US4906615A (en) * | 1980-12-18 | 1990-03-06 | Schering Corporation | Substituted dipeptides as inhibitors of enkephalinases |
IE53315B1 (en) * | 1980-12-18 | 1988-10-12 | Schering Corp | Substituted dipeptides,processes for their preparation and pharmaceutical compositions containing them and their use in the inhibition of enkephalinase |
CY1406A (en) * | 1980-12-18 | 1988-04-22 | Schering Corp | Substituted dipeptides, processes for their preparation and pharmaceutical compositions containing them and their use in the inhibition of enkephalinase |
EP0057998B1 (en) * | 1981-01-23 | 1984-08-08 | Takeda Chemical Industries, Ltd. | Alicyclic compounds, their production and use |
US4532342A (en) * | 1981-02-20 | 1985-07-30 | Warner-Lambert Company | N-substituted amino acids as intermediates in the preparation of acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids |
EP0059966B1 (en) * | 1981-03-09 | 1986-08-13 | Merck & Co. Inc. | Substituted thiazolidine carboxylic acid analogs and derivatives as antihypertensives |
US4512979A (en) * | 1981-03-23 | 1985-04-23 | Merck & Co., Inc. | Dipeptides containing thialysine and related amino acids as antihypertensives |
US4820729A (en) * | 1981-03-30 | 1989-04-11 | Rorer Pharmaceutical Corporation | N-substituted-amido-amino acids |
AU556932B2 (en) * | 1981-03-30 | 1986-11-27 | Usv Pharmaceutical Corp. | Dipetide with heterocyclic groiup |
US4510322A (en) * | 1981-07-13 | 1985-04-09 | Merck & Co., Inc. | Indacrinone having enhanced uricosuric |
US4454292A (en) * | 1981-07-20 | 1984-06-12 | American Home Products Corporation | N-[2-Substituted-1-oxoalkyl]-2,3-dihydro-1H-indole-2-carboxylic acid derivatives |
US4454291A (en) * | 1981-07-20 | 1984-06-12 | American Home Products Corporation | N-(2-Substituted-1-oxoalkyl)-2,3-dihydro-1H-indole-2-carboxylic acid derivatives |
CS226907B1 (en) * | 1981-08-07 | 1984-04-16 | Kasafirek Evzen | Alkylamides of carboxyalkanoylpeptides |
US4766110A (en) * | 1981-08-21 | 1988-08-23 | Ryan James W | Novel complex amido and imido derivatives of carboxyalkyl peptides |
ZA826022B (en) * | 1981-08-21 | 1983-08-31 | Univ Miami | Novel complex amido and imido derivatives of carboxyalkyl peptides and thioethers and ethers of peptides |
DE3226768A1 (de) * | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | Derivate der cis, endo-2-azabicyclo-(3.3.0)-octan-3-carbonsaeure, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung |
EP0079522B1 (en) * | 1981-11-09 | 1986-05-07 | Merck & Co. Inc. | N-carboxymethyl(amidino)lysyl-proline antihypertensive agents |
EP0079521A1 (en) * | 1981-11-09 | 1983-05-25 | Merck & Co. Inc. | Process for preparation of carboxyalkyldipeptide derivatives |
US4410520A (en) * | 1981-11-09 | 1983-10-18 | Ciba-Geigy Corporation | 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids |
EP0081094A1 (en) * | 1981-11-12 | 1983-06-15 | Merck & Co. Inc. | Substituted omega-amino-carboxymethyldipeptide antihypertensive agents |
EP0080822A1 (en) * | 1981-11-27 | 1983-06-08 | Beecham Group Plc | Anti-hypertensive prolinol-based peptides |
US4503043A (en) * | 1981-12-07 | 1985-03-05 | Warner-Lambert Company | Substituted acyl derivatives of octahydro-1H-isoindole-1-carboxylic acids |
GR78413B (ko) * | 1981-12-29 | 1984-09-27 | Hoechst Ag | |
US4555502A (en) * | 1982-09-30 | 1985-11-26 | Merck & Co., Inc. | Aminoacyl-containing dipeptide derivatives useful as antihypertensives |
EP0083923B1 (en) * | 1982-01-11 | 1988-10-19 | Merck & Co. Inc. | Aminoacyl-containing dipeptide derivatives useful as antihypertensives |
JPS58126851A (ja) * | 1982-01-11 | 1983-07-28 | メルク エンド カムパニー インコーポレーテッド | 抗高血圧剤として有用なアミノアシル含有ジペプチド誘導体 |
IE54551B1 (en) * | 1982-01-22 | 1989-11-22 | Ici Plc | Amide derivatives |
US4665087A (en) * | 1982-02-22 | 1987-05-12 | Ciba-Geigy Corporation | 1-(carbamyl, thiocarbamyl, and iminocarbamyl)-indoline derivatives |
DE3360065D1 (en) * | 1982-03-08 | 1985-03-28 | Schering Corp | Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them |
US4410807A (en) * | 1982-03-26 | 1983-10-18 | Kay Industries, Inc. | Regulating device for polyphase electrical circuits |
DE3211397A1 (de) * | 1982-03-27 | 1983-11-10 | Hoechst Ag, 6230 Frankfurt | Spiro (4.(3+n))-2-aza-3-carbonsaeure-derivate, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung |
DE3211676A1 (de) * | 1982-03-30 | 1983-10-06 | Hoechst Ag | Neue derivate von cycloalka (c) pyrrol-carbonsaeuren, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung sowie neue cycloalka (c) pyrrol-carbonsaeuren als zwischenstufen und verfahren zu deren herstellung |
JPS58188847A (ja) * | 1982-04-26 | 1983-11-04 | Takeda Chem Ind Ltd | ペプチド誘導体 |
US4681886A (en) * | 1982-04-30 | 1987-07-21 | E. R. Squibb & Sons, Inc. | Substituted 4-phenoxy or 4-phenylthio prolines |
US4555503A (en) * | 1982-05-05 | 1985-11-26 | Merck & Co., Inc. | N2 -(Substituted)carboxymethyl-N6 -(substituted)-lysyl-and αε-aminoalkyl)glycyl amino acid antihypertensive agents |
US4483850A (en) * | 1982-05-10 | 1984-11-20 | Merck & Co., Inc. | N-Terminal substituted oligopeptide converting enzyme inhibitors |
NZ204130A (en) * | 1982-05-12 | 1986-03-14 | Hoffmann La Roche | Bicyclic heterocyclic compounds and pharmaceutical compositions |
GB2128984B (en) * | 1982-05-12 | 1985-05-22 | Hoffmann La Roche | Diaza-bicyclic compounds |
AU563196B2 (en) * | 1982-05-18 | 1987-07-02 | Smithkline Beckman Corporation | Peptide prodrug transport system |
JPS6058233B2 (ja) * | 1982-05-24 | 1985-12-19 | 田辺製薬株式会社 | 2−オキソイミダゾリジン誘導体及びその製法 |
US4442030A (en) * | 1982-06-07 | 1984-04-10 | Merck & Co., Inc. | Process for preparing carboxyalkyl dipeptides |
EP0103077B1 (en) * | 1982-06-17 | 1988-05-18 | Schering Corporation | Substituted dipeptides, methods for their production, pharmaceutical compositions containing them, method for making such pharmaceutical compositions |
US4442089A (en) * | 1982-07-06 | 1984-04-10 | E. R. Squibb & Sons, Inc. | Method for treating glaucoma with topical or systemic ACE inhibitor compositions |
EP0099709A3 (en) * | 1982-07-19 | 1985-11-13 | Imperial Chemical Industries Plc | Amide derivatives |
US4473575A (en) * | 1982-07-19 | 1984-09-25 | Ciba-Geigy Corporation | 3-Amino-(1)-benzazepin-2-one-1-alkanoic acids |
IL69136A0 (en) * | 1982-07-19 | 1983-10-31 | Squibb & Sons Inc | Substituted peptide compounds |
US4470973A (en) * | 1982-07-19 | 1984-09-11 | E. R. Squibb & Sons, Inc. | Substituted peptide compounds |
US4736066A (en) * | 1982-07-19 | 1988-04-05 | E. R. Squibb & Sons, Inc. | Intermediate for substituted peptide compounds |
US4661515A (en) * | 1982-07-21 | 1987-04-28 | Usv Pharmaceutical Corporation | Compounds having angiotensin converting enzyme inhibitory activity and diuretic activity |
US4742067A (en) * | 1982-07-22 | 1988-05-03 | E. R. Squibb & Sons, Inc. | Acylalkylaminocarbonyl substituted amino and imino acid compounds |
US4621092A (en) * | 1982-07-22 | 1986-11-04 | E. R. Squibb & Sons, Inc. | Substituted proline compounds, composition and method of use |
US4487716A (en) * | 1982-08-23 | 1984-12-11 | American Home Products Corporation | N-(1-Carboxy-3-phenylpropyl)-dipeptides |
US4439364A (en) * | 1982-09-01 | 1984-03-27 | E. I. Du Pont De Nemours & Company | Process for preparing antihypertensive 1-substituted cyclic lactam-2-carboxylic acids and their derivatives |
US4866173A (en) * | 1982-09-22 | 1989-09-12 | Rorer Pharmaceutical Corporation | Therapeutic substituted semicarbazides |
US4500713A (en) * | 1982-09-23 | 1985-02-19 | Usv Pharmaceutical Corporation | Therapeutic dipeptides |
US4634716A (en) * | 1982-09-30 | 1987-01-06 | Merck & Co., Inc. | Substituted N-carboxymethyl-aminoacylaminoalkanoic acids useful as antihypertensive agents |
US4642315A (en) * | 1982-11-18 | 1987-02-10 | E. R. Squibb & Sons, Inc. | Carboxy and substituted carboxy alkanoyl and cycloalkanoyl peptides |
US4587234A (en) * | 1982-11-18 | 1986-05-06 | E. R. Squibb & Sons, Inc. | Carboxy and substituted carboxy alkanoyl and cycloalkanoyl peptides |
US4499079A (en) * | 1982-11-18 | 1985-02-12 | E. R. Squibb & Sons, Inc. | Carboxy and substituted carboxy alkanoyl and cycloalkanoyl peptides |
US4482544A (en) * | 1982-11-29 | 1984-11-13 | Usv Pharmaceutical Corporation | Compounds for treating hypertension |
US4456595A (en) * | 1982-12-06 | 1984-06-26 | E. R. Squibb & Sons, Inc. | Carboxy and substituted carboxy aroly peptides |
US4826812A (en) * | 1982-12-27 | 1989-05-02 | Schering Corporation | Antiglaucoma agent |
US4496541A (en) * | 1983-01-12 | 1985-01-29 | Usv Pharmaceutical Corporation | Compounds for treating hypertension |
DE3300774A1 (de) * | 1983-01-12 | 1984-07-12 | Hoechst Ag, 6230 Frankfurt | Neue spirocyclische aminosaeuren, verfahren zu ihrer herstellung, diese enthaltende mittel und deren verwendung sowie neue spirocyclische aminosaeuren als zwischenprodukte und verfahren zu deren herstellung |
DE3302125A1 (de) * | 1983-01-22 | 1984-07-26 | Boehringer Ingelheim KG, 6507 Ingelheim | Aminosaeure-derivate, verfahren zu ihrer herstellung und verwendung |
EP0115091A1 (en) * | 1983-01-27 | 1984-08-08 | ENI-Ente Nazionale Idrocarburi | N-carboxyacyl derivatives of cyclic amino acids, useful as antihypertensives |
US5175306A (en) * | 1983-01-31 | 1992-12-29 | Hoechst Aktiengesellschaft | Process for the resolution of racemates of optically active bicyclic imino-α-carboxylic esters |
US4659711A (en) * | 1983-01-31 | 1987-04-21 | Usv Pharmaceutical Corporation | 1,2,3,4-Tetrahydrophthalazine and hexahydropyridazine compounds for treating hypertension |
US4711884A (en) * | 1983-02-28 | 1987-12-08 | E. R. Squibb & Sons, Inc. | Thiazine and thiazepine containing compounds |
US4596791A (en) * | 1983-03-16 | 1986-06-24 | Usv Pharmaceutical Corp. | Compounds for treating hypertension |
US4666906A (en) * | 1983-03-16 | 1987-05-19 | Usv Pharmaceutical Corporation | Compounds for treating hypertension |
US4481191A (en) * | 1983-03-30 | 1984-11-06 | The Regents Of The University Of California | Method for controlling blood pressure |
GB8311286D0 (en) * | 1983-04-26 | 1983-06-02 | Searle & Co | Carboxyalkyl peptide derivatives |
US4585758A (en) * | 1983-05-20 | 1986-04-29 | Usv Pharmaceutical Corp. | Angiotensin-converting enzyme inhibitors |
AU2859984A (en) * | 1983-05-23 | 1984-11-29 | Usv Pharmaceutical Corp. | Compounds for treating hypertension |
US4574079A (en) * | 1983-05-27 | 1986-03-04 | Gavras Haralambos P | Radiolabeled angiotensin converting enzyme inhibitors for radiolabeling mammalian organ sites |
US4840772A (en) * | 1983-06-02 | 1989-06-20 | Schering Corporation | Antiglaucoma compositions and methods |
US4783444A (en) * | 1984-09-17 | 1988-11-08 | Schering Corporation | Antiglaucoma compositions and methods |
US4584285A (en) * | 1983-06-02 | 1986-04-22 | Schering Corporation | Antihypertensive agents |
US4472384A (en) * | 1983-06-15 | 1984-09-18 | Merck & Co., Inc. | Antihypertensive composition |
US4514391A (en) * | 1983-07-21 | 1985-04-30 | E. R. Squibb & Sons, Inc. | Hydroxy substituted peptide compounds |
DE3333455A1 (de) * | 1983-09-16 | 1985-04-11 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung n-alkylierter dipeptide und deren estern |
DE3333454A1 (de) * | 1983-09-16 | 1985-04-11 | Hoechst Ag, 6230 Frankfurt | Verfahren zur herstellung von n-alkylierten dipeptiden und deren estern |
EP0137746A3 (en) * | 1983-09-22 | 1986-01-08 | FISONS plc | Nitrogen substituted angiotensin converting enzyme inhibitors |
US4642355A (en) * | 1984-02-24 | 1987-02-10 | Otsuka Pharmaceutical Factory, Inc. | Proline derivatives |
JPS61501565A (ja) * | 1984-03-01 | 1986-07-31 | ア−ク,バ−ノン | 脊椎動物の高血圧治療方法 |
FI850948L (fi) * | 1984-03-12 | 1985-09-13 | Pfizer | Renin inhibitorer som innehaoller statin eller dess derivat. |
US4536501A (en) * | 1984-03-30 | 1985-08-20 | E. R. Squibb & Sons, Inc. | Substituted 4-phenoxy or 4-phenylthio prolines |
US5684016A (en) * | 1984-04-12 | 1997-11-04 | Hoechst Aktiengesellschaft | Method of treating cardiac insufficiency |
US4568666A (en) * | 1984-10-18 | 1986-02-04 | G. D. Searle & Co. | Carboxylalkyl peptide derivatives |
DE3413710A1 (de) * | 1984-04-12 | 1985-10-24 | Hoechst Ag, 6230 Frankfurt | Verfahren zur behandlung der herzinsuffizienz |
DE3482590D1 (de) | 1984-04-12 | 1990-08-02 | Searle & Co | Carboxyalkyl-peptid-derivate. |
US4500518A (en) * | 1984-04-19 | 1985-02-19 | E. R. Squibb & Sons, Inc. | Amino thiol dipeptides |
US4558150A (en) * | 1984-04-19 | 1985-12-10 | E. R. Squibb & Sons, Inc. | Intermediates for preparing amino thiol dipeptides |
AU569789B2 (en) * | 1984-05-03 | 1988-02-18 | Brigham And Women's Hospital | A.c.e. inhibitors to treat renal diseases |
US4558037A (en) * | 1984-06-04 | 1985-12-10 | Merck & Co., Inc. | Cardiovascular composition |
EP0168769A3 (en) * | 1984-07-16 | 1989-02-08 | Merck & Co. Inc. | Process for preparing carboxyalkyl dipeptides |
US4801721A (en) * | 1984-08-16 | 1989-01-31 | Ryan James W | Stereospecific synthesis of carboxyalkyl peptides |
USH642H (en) | 1984-08-20 | 1989-06-06 | E. R. Squibb & Sons, Inc. | Substituted urido amino and imino acids and esters |
US4626545A (en) * | 1984-08-27 | 1986-12-02 | Merck & Co., Inc. | Amino acid derivatives as enzyme inhibitors |
DE3431541A1 (de) * | 1984-08-28 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | Cis,endo-2-azabicycloalkan-3-carbonsaeure-derivate, verfahren zu deren herstellung, deren verwendung sowie zwischenprodukte bei deren herstellung |
GB8422165D0 (en) * | 1984-09-01 | 1984-10-03 | Wellcome Found | Compounds |
US4746676A (en) * | 1984-09-12 | 1988-05-24 | Rorer Pharmaceutical Corporation | Carboxyalkyl dipeptide compounds |
IT1176983B (it) * | 1984-10-16 | 1987-08-26 | Zambon Spa | Dipeptidi ad attivita' farmacologica |
DE3437917A1 (de) * | 1984-10-17 | 1986-04-17 | Bayer Ag, 5090 Leverkusen | Kombination von dihydropyridinen mit ace-hemmern sowie ihre verwendung in arzneimitteln |
FR2575163B1 (fr) * | 1984-12-20 | 1987-03-20 | Sanofi Sa | Tri- et tetrapeptides reduits inhibiteurs de la secretion gastrique, procede d'obtention et compositions pharmaceutiques les contenant |
EP0187037A3 (en) * | 1984-12-21 | 1988-03-23 | Takeda Chemical Industries, Ltd. | Piperidine derivatives, their production and use |
CS250699B2 (en) * | 1984-12-21 | 1987-05-14 | Pfizer | Method of octahydro-6-azaindole's depetidic derivatives production |
US4762821A (en) * | 1985-03-22 | 1988-08-09 | Syntex (U.S.A.) Inc. | N',N"-dialkylguanidino dipeptides |
CN86101850A (zh) * | 1985-03-22 | 1987-02-04 | 森得克斯(美国)有限公司 | N,n′-二烷基胍基二肽的制造方法与用途 |
US4873342A (en) * | 1985-04-16 | 1989-10-10 | Suntory Limited | Dipeptide derivative and synthesis and use thereof |
ES8604609A1 (es) * | 1985-07-02 | 1986-02-01 | Uriach & Cia Sa J | Procedimiento para la obtencion de la 1-(n-(1(r,s)-(etoxi- carbonil)-3-fenilpropil)-l-alanil)-l-prolina |
ATE72431T1 (de) | 1985-08-31 | 1992-02-15 | Fisons Plc | 5-gliedrige heterocyclische angiotensinumwandlungsenzym-inhibitoren. |
DE3532036A1 (de) * | 1985-09-09 | 1987-03-26 | Hoechst Ag | Pharmazeutische zubereitung zur behandlung des bluthochdrucks |
US5256687A (en) * | 1985-09-09 | 1993-10-26 | Hoechst Aktiengesellschaft | Pharmaceutical composition for the treatment of high blood pressure |
US5231080A (en) * | 1985-10-15 | 1993-07-27 | Hoechst Aktiengesellschaft | Method for the treatment of atherosclerosis, thrombosis, and peripheral vessel disease |
GB2182938B (en) * | 1985-11-13 | 1989-11-08 | Otsuka Pharma Co Ltd | Antihypertensive proline peptides |
JPH0653757B2 (ja) * | 1985-12-06 | 1994-07-20 | 味の素株式会社 | プロリン誘導体の芳香族スルホン酸塩 |
JPH0662671B2 (ja) * | 1986-01-17 | 1994-08-17 | 株式会社大塚製薬工場 | プロリン誘導体 |
US4771037A (en) * | 1986-01-21 | 1988-09-13 | Ici Americas Inc. | N-carboxyalkyl compounds |
FI870871A (fi) * | 1986-02-28 | 1987-08-29 | Wellcome Found | Foerfarande foer framstaellning av nya terapeutiskt anvaendbara peptidderivat. |
FI870872A (fi) * | 1986-02-28 | 1987-08-29 | Wellcome Found | Nya foereningar. |
ATE90076T1 (de) | 1986-03-27 | 1993-06-15 | Merck Frosst Canada Inc | Tetrahydrocarbazole ester. |
US5231084A (en) * | 1986-03-27 | 1993-07-27 | Hoechst Aktiengesellschaft | Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfuncitons |
US4738850A (en) * | 1986-05-27 | 1988-04-19 | E. R. Squibb & Sons, Inc. | Controlled release formulation and method |
US4749688A (en) * | 1986-06-20 | 1988-06-07 | Schering Corporation | Use of neutral metalloendopeptidase inhibitors in the treatment of hypertension |
EP0254032A3 (en) | 1986-06-20 | 1990-09-05 | Schering Corporation | Neutral metalloendopeptidase inhibitors in the treatment of hypertension |
EP0566157A1 (en) | 1986-06-20 | 1993-10-20 | Schering Corporation | Neutral metalloendopeptidase inhibitors in the treatment of hypertension |
AT395012B (de) * | 1986-06-27 | 1992-08-25 | Richter Gedeon Vegyeszet | Verfahren zur herstellung von n-(1(s)|thoxycarbonyl-3-phenyl-propyl)-(s)-alanyl-(s)prolin und von dessen saeureadditionssalzen |
DE3627613A1 (de) * | 1986-08-14 | 1988-02-18 | Merck Patent Gmbh | Pharmazeutische zubereitung |
DE3774975D1 (de) * | 1986-09-10 | 1992-01-16 | Syntex Inc | Selektive amidinierung von diaminen. |
US5948939A (en) * | 1986-09-10 | 1999-09-07 | Syntex (U.S.A.) Inc. | Selective amidination of diamines |
DE3633496A1 (de) * | 1986-10-02 | 1988-04-14 | Hoechst Ag | Kombination von angiotensin-converting-enzyme-hemmern mit calciumantagonisten sowie deren verwendung in arzneimitteln |
DE3639879A1 (de) * | 1986-11-21 | 1988-06-01 | Hoechst Ag | Verfahren zur herstellung von mono-, bi- und tricyclischen aminosaeuren, zwischenprodukte dieses verfahrens sowie ein verfahren zu deren herstellung |
JPH075633B2 (ja) * | 1987-02-19 | 1995-01-25 | アサヒビール株式会社 | アミノ酸誘導体その製造方法及び血圧降下剤 |
CA1313724C (en) * | 1987-02-19 | 1993-02-16 | Shizuo Saito | Aminoacid derivatives as antihypertensives |
US4837354A (en) * | 1987-02-26 | 1989-06-06 | Merrell Dow Pharmaceuticals Inc. | Process for making and isolating (R)-2-hydroxy-4-phenylbutyric acid and esters |
US5262436A (en) * | 1987-03-27 | 1993-11-16 | Schering Corporation | Acylamino acid antihypertensives in the treatment of congestive heart failure |
JPH0657707B2 (ja) * | 1987-05-25 | 1994-08-03 | 吉富製薬株式会社 | ピペリジン化合物 |
CA1337400C (en) * | 1987-06-08 | 1995-10-24 | Norma G. Delaney | Inhibitors of neutral endopeptidase |
DE3722007A1 (de) * | 1987-07-03 | 1989-01-12 | Hoechst Ag | Verfahren zur herstellung bicyclischer aminocarbonsaeuren, zwischenprodukte dieses verfahrens und deren verwendung |
FR2619813B1 (fr) * | 1987-08-28 | 1991-05-03 | Adir | Nouveaux derives de l'acide aza - 2 bicyclooctane carboxylique - 3, leurs procedes de preparation et les compositions pharmaceutiques qui les contiennent |
USH734H (en) | 1988-03-07 | 1990-02-06 | E. R. Squibb & Sons, Inc. | Method for inhibiting onset of or treating migraine headaches employing an ACE inhibitor |
DE3739690A1 (de) * | 1987-11-24 | 1989-06-08 | Hoechst Ag | Stabilisierte arzneistoffe, verfahren zu ihrer herstellung sowie stabile arzneizubereitungen |
US5110927A (en) * | 1987-12-31 | 1992-05-05 | The United States Of America As Represented By The Department Of Health And Human Services | Prazosin analog with increased selectivity and duration of action |
DE3803225A1 (de) * | 1988-02-04 | 1989-08-17 | Hoechst Ag | Aminosaeureamide mit psychotroper wirkung, verfahren zu ihrer herstellung, sie enthaltende mittel und deren verwendung |
US5136044A (en) * | 1988-04-04 | 1992-08-04 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | N2 -carboxy-3-phenylpropyl)-l-lysine derivative and process of producing lysinolpril using the compound |
IL90189A0 (en) * | 1988-06-01 | 1989-12-15 | Squibb & Sons Inc | Pharmaceutical compositions containing a benzazepine-type calcium channel blocker |
GB8827308D0 (en) * | 1988-11-23 | 1988-12-29 | British Bio Technology | Compounds |
GB8827305D0 (en) * | 1988-11-23 | 1988-12-29 | British Bio Technology | Compounds |
SE506179C2 (sv) * | 1989-01-23 | 1997-11-17 | Ciba Geigy Ag | Farmaceutisk lågkomposition av benazepril och ett tiaziddiuretikum |
ZA902661B (en) * | 1989-04-10 | 1991-01-30 | Schering Corp | Mercapto-acyl amino acids |
DE3915236A1 (de) * | 1989-05-10 | 1990-11-15 | Merck Patent Gmbh | Pharmazeutische zubereitung |
FI94339C (fi) | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
US5110799A (en) * | 1989-07-28 | 1992-05-05 | Merck & Co., Inc. | Antiherpetic agents |
DE3926606A1 (de) * | 1989-08-11 | 1991-02-14 | Hoechst Ag | Verfahren zur behandlung der cardialen sowie der vasculaeren hypertrophie und hyperplasie |
GB8919251D0 (en) * | 1989-08-24 | 1989-10-04 | British Bio Technology | Compounds |
US5212165A (en) * | 1989-10-23 | 1993-05-18 | E. R. Squibb & Sons, Inc. | Method for rehabilitating the vasorelaxant action of the coronary arteries impaired through atherosclerosis or hypercholesterolemia employing an ace inhibitor |
EP0502075A1 (en) * | 1989-11-21 | 1992-09-09 | Schering Corporation | Carboxyalkylcarbonyl aminoacid endopeptidase inhibitors |
US5407960A (en) * | 1989-12-22 | 1995-04-18 | Schering Corporation | Mercaptocycloacyl aminoacid endopeptidase inhibitors |
US5075302A (en) * | 1990-03-09 | 1991-12-24 | Schering Corporation | Mercaptoacyl aminolactam endopeptidase inhibitors |
BR9106438A (pt) * | 1990-05-11 | 1993-05-18 | Pfizer | Composicoes terapeuticas sinergisticas e processos |
US5821232A (en) * | 1990-05-11 | 1998-10-13 | Pfizer Inc. | Synergistic therapeutic compositions and methods |
US5166143A (en) * | 1990-05-31 | 1992-11-24 | E. R. Squibb & Sons, Inc. | Method for preventing onset of restenosis after angioplasty employing an ace inhibitor |
US6300361B1 (en) | 1990-07-25 | 2001-10-09 | Novartis Ag | Stabilized pharmaceutical compositions comprising acid donors |
US5173506A (en) * | 1990-08-16 | 1992-12-22 | Schering Corporation | N-(mercaptoalkyl)ureas and carbamates |
TW197945B (ko) * | 1990-11-27 | 1993-01-11 | Hoechst Ag | |
EP0490379A3 (de) * | 1990-12-13 | 1992-06-24 | BERLIN-CHEMIE Aktiengesellschaft | Diaminosäurederivate und pharmazeutische Zusammensetzungen |
US5124152A (en) * | 1991-01-07 | 1992-06-23 | Fisons Corporation | Parenteral formulation of metolazone |
GB9102635D0 (en) * | 1991-02-07 | 1991-03-27 | British Bio Technology | Compounds |
US5530161A (en) * | 1991-07-08 | 1996-06-25 | British Bio-Technology Limited | Hydroxamic acid based collagenase inhibitors |
US5977160A (en) * | 1992-04-10 | 1999-11-02 | Brigham And Women's Hospital, Inc. | Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims |
US5972990A (en) * | 1992-04-10 | 1999-10-26 | Brigham And Women's Hospital, Inc. | Methods for reducing risk of repeat myocardial infarction and increasing survival in heart attack victims |
US5552397A (en) * | 1992-05-18 | 1996-09-03 | E. R. Squibb & Sons, Inc. | Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase |
US5504080A (en) * | 1992-10-28 | 1996-04-02 | Bristol-Myers Squibb Co. | Benzo-fused lactams |
US5589499A (en) * | 1992-11-25 | 1996-12-31 | Weth; Gosbert | Dopaminergic agents for the treatment of cerebral and peripheral blood flow disorders |
US5455353A (en) * | 1993-03-24 | 1995-10-03 | Hoffmann-La Roche Inc. | 4-(benzyl-2-oxo-oxazolidin-5 ylmethyl)N tertbutyl-decahydroisoquinoline-3-carboxamides |
US5654294A (en) * | 1993-05-13 | 1997-08-05 | Bristol-Myers Squibb | Spiro lactam dual action inhibitors |
US5508272A (en) * | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
ATE198551T1 (de) * | 1993-07-15 | 2001-01-15 | Hoffmann La Roche | Pharmazeutische kombination, die einen hemmer des renin-angiotensin-systems und einen endothelin- antagonisten enthält |
US5362727A (en) * | 1993-07-26 | 1994-11-08 | Bristol-Myers Squibb | Substituted azepino[2,1-a]isoquinoline compounds |
US5525723A (en) * | 1993-11-18 | 1996-06-11 | Bristol-Myers Squibb Co. | Compounds containing a fused multiple ring lactam |
WO1995026188A1 (en) * | 1994-03-29 | 1995-10-05 | Merck & Co., Inc. | Treatment of atherosclerosis with angiotensin ii receptor blocking imidazoles |
AU2394795A (en) * | 1994-04-28 | 1995-11-29 | Du Pont Merck Pharmaceutical Company, The | Hydroxamic acid and amino acid derivatives and their use as anti-arthritic agents |
US5616775A (en) * | 1994-05-05 | 1997-04-01 | Bristol-Myers Squibb Co. | Process for preparing homocystein analogs useful as intermediates for compounds containing a fused bicyclic ring |
AU2942495A (en) * | 1994-07-13 | 1996-02-16 | Lek Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. | Process for the preparation of compounds having ace inhibitory action as well as novel compounds useful as starting materials or intermediates in said process |
CA2128199C (en) * | 1994-07-15 | 1997-02-04 | Bernard Charles Sherman | Stable solid pharmaceutical compositions containing enalapril maleate |
US5601801A (en) * | 1994-08-02 | 1997-02-11 | Merck Frosst Canada, Inc. | Radiolabelled angiotensin converting enzyme inhibitors |
CN1065860C (zh) * | 1994-08-27 | 2001-05-16 | 王隶书 | 提取盐酸甜菜碱工艺 |
DE4431530C2 (de) * | 1994-09-03 | 2002-01-31 | Degussa | Verfahren zur Herstellung von 2-[3(S)-Amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isochinolin-3(S)-carboxamid |
US5587375A (en) * | 1995-02-17 | 1996-12-24 | Bristol-Myers Squibb Company | Azepinone compounds useful in the inhibition of ACE and NEP |
EA000736B1 (ru) | 1995-04-11 | 2000-02-28 | Мерк Энд Ко., Инк. | Способ получения дипептидов |
US5877313A (en) | 1995-05-17 | 1999-03-02 | Bristol-Myers Squibb | Benzo-fused azepinone and piperidinone compounds useful in the inhibition of ACE and NEP |
US7056935B2 (en) | 1995-06-07 | 2006-06-06 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
US5650408A (en) * | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
US20020042377A1 (en) * | 1995-06-07 | 2002-04-11 | Steiner Joseph P. | Rotamase enzyme activity inhibitors |
US5859031A (en) | 1995-06-07 | 1999-01-12 | Gpi Nil Holdings, Inc. | Small molecule inhibitors of rotamase enzyme activity |
US5635504A (en) * | 1995-06-07 | 1997-06-03 | Bristol-Myers Squibb Co. | Diazepine containing dual action inhibitors |
CN1053437C (zh) * | 1995-07-19 | 2000-06-14 | 五洲药厂 | 赖诺普利合成方法 |
US5573780A (en) * | 1995-08-04 | 1996-11-12 | Apotex Usa Inc. | Stable solid formulation of enalapril salt and process for preparation thereof |
US5550127A (en) * | 1995-09-07 | 1996-08-27 | Pantano; James A. | Method of treatment for eiph in racing stock |
AU702718B2 (en) * | 1995-09-15 | 1999-03-04 | Merck & Co., Inc. | Method for analyzing isomers of enalapril and enalaprilat |
US5670655A (en) * | 1995-09-15 | 1997-09-23 | Merck & Co. Inc. | Method for analyzing isomers of enalapril and enalaprilat |
US5801197A (en) * | 1995-10-31 | 1998-09-01 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
ES2175437T3 (es) * | 1996-06-24 | 2002-11-16 | Merck & Co Inc | Composicion de enalapril y losartan. |
CA2182258C (en) * | 1996-07-29 | 2001-04-17 | K.S. Keshava Murthy | Sodium enalapril complex and the use thereof to make sodium enalapril |
US5801187A (en) * | 1996-09-25 | 1998-09-01 | Gpi-Nil Holdings, Inc. | Heterocyclic esters and amides |
US6218424B1 (en) | 1996-09-25 | 2001-04-17 | Gpi Nil Holdings, Inc. | Heterocyclic ketone and thioester compounds and uses |
US5786378A (en) * | 1996-09-25 | 1998-07-28 | Gpi Nil Holdings, Inc. | Heterocyclic thioesters |
US6187796B1 (en) | 1998-06-03 | 2001-02-13 | Gpi Nil Holdings, Inc. | Sulfone hair growth compositions and uses |
US5945441A (en) | 1997-06-04 | 1999-08-31 | Gpi Nil Holdings, Inc. | Pyrrolidine carboxylate hair revitalizing agents |
US6274602B1 (en) | 1998-06-03 | 2001-08-14 | Gpi Nil Holdings, Inc. | Heterocyclic thioester and ketone hair growth compositions and uses |
US6271244B1 (en) | 1998-06-03 | 2001-08-07 | Gpi Nil Holdings, Inc. | N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses |
US20010049381A1 (en) | 1997-06-04 | 2001-12-06 | Gpl Nil Holdings, Inc., | Pyrrolidine derivative hair growth compositions and uses |
US6187784B1 (en) | 1998-06-03 | 2001-02-13 | Gpi Nil Holdings, Inc. | Pipecolic acid derivative hair growth compositions and uses |
US7378506B2 (en) * | 1997-07-21 | 2008-05-27 | Ohio University | Synthetic genes for plant gums and other hydroxyproline-rich glycoproteins |
US6570062B1 (en) * | 1997-07-21 | 2003-05-27 | Ohio University | Synthetic genes for plant gums and other hydroxyproline-rich glycoproteins |
US6548642B1 (en) * | 1997-07-21 | 2003-04-15 | Ohio University | Synthetic genes for plant gums |
US6639050B1 (en) * | 1997-07-21 | 2003-10-28 | Ohio University | Synthetic genes for plant gums and other hydroxyproline-rich glycoproteins |
IN184759B (ko) | 1997-07-22 | 2000-09-23 | Kaneka Corp | |
IT1299341B1 (it) * | 1998-02-09 | 2000-03-16 | Pfc Italiana Srl | Processo per la produzione di alcossicarbonildipeptidi intermedi nella sintesi del lisinopril. |
US6296871B1 (en) | 1998-04-12 | 2001-10-02 | Ranbaxy Laboratories Limited | Stable solid pharmaceutical compositions containing enalapril maleate |
AU770459B2 (en) | 1998-06-03 | 2004-02-19 | Gpi Nil Holdings, Inc. | Heterocyclic ester and amide hair growth compositions and uses |
JP2002516904A (ja) | 1998-06-03 | 2002-06-11 | ジーピーアイ ニル ホールディングス インコーポレイテッド | N−複素環式カルボン酸またはカルボン酸等配電子体のn−結合スルホンアミド |
US6429215B1 (en) | 1998-06-03 | 2002-08-06 | Gpi Nil Holdings, Inc. | N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses |
US6172087B1 (en) | 1998-06-03 | 2001-01-09 | Gpi Nil Holding, Inc. | N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses |
US6331537B1 (en) | 1998-06-03 | 2001-12-18 | Gpi Nil Holdings, Inc. | Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds |
HUP0102260A3 (en) * | 1998-06-05 | 2002-12-28 | Warner Lambert Co | Stabilization of compositions containing ace inhibitors using magnesium oxide |
WO2000005247A1 (fr) * | 1998-07-21 | 2000-02-03 | Kaneka Corporation | Procede de cristallisation d'un sel d'acide maleique de n-(1(s)-ethoxycarbonyl-3-phenylpropyl)-l-alanyl-l-proline |
US6339101B1 (en) | 1998-08-14 | 2002-01-15 | Gpi Nil Holdings, Inc. | N-linked sulfonamides of N-heterocyclic carboxylic acids or isosteres for vision and memory disorders |
US6218423B1 (en) | 1998-08-14 | 2001-04-17 | Gpi Nil Holdings, Inc. | Pyrrolidine derivatives for vision and memory disorders |
US6384056B1 (en) | 1998-08-14 | 2002-05-07 | Gpi Nil Holdings, Inc. | Heterocyclic thioesters or ketones for vision and memory disorders |
US6395758B1 (en) | 1998-08-14 | 2002-05-28 | Gpi Nil Holdings, Inc. | Small molecule carbamates or ureas for vision and memory disorders |
US6506788B1 (en) | 1998-08-14 | 2003-01-14 | Gpi Nil Holdings, Inc. | N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders |
US6333340B1 (en) | 1998-08-14 | 2001-12-25 | Gpi Nil Holdings, Inc. | Small molecule sulfonamides for vision and memory disorders |
US6337340B1 (en) | 1998-08-14 | 2002-01-08 | Gpi Nil Holdings, Inc. | Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders |
US6335348B1 (en) | 1998-08-14 | 2002-01-01 | Gpi Nil Holdings, Inc. | Nitrogen-containing linear and azepinyl/ compositions and uses for vision and memory disorders |
US6399648B1 (en) | 1998-08-14 | 2002-06-04 | Gpi Nil Holdings, Inc. | N-oxides of heterocyclic ester, amide, thioester, or ketone for vision and memory disorders |
US6376517B1 (en) | 1998-08-14 | 2002-04-23 | Gpi Nil Holdings, Inc. | Pipecolic acid derivatives for vision and memory disorders |
US7338976B1 (en) | 1998-08-14 | 2008-03-04 | Gpi Nil Holdings, Inc. | Heterocyclic esters or amides for vision and memory disorders |
US6191144B1 (en) | 1998-08-17 | 2001-02-20 | Warner-Lambert Company | Method of using angiotensin converting enzyme inhibitor to stimulate angiogenesis |
US6462072B1 (en) | 1998-09-21 | 2002-10-08 | Gpi Nil Holdings, Inc. | Cyclic ester or amide derivatives |
CN1320160A (zh) * | 1998-09-25 | 2001-10-31 | 格利科克斯有限公司 | 果糖胺氧化酶测定的方法和材料 |
CN1324234A (zh) * | 1998-09-25 | 2001-11-28 | 格利科克斯有限公司 | 果糖胺氧化酶,拮抗剂和抑制剂 |
NZ333206A (en) | 1998-12-08 | 2000-07-28 | Bernard Charles Sherman | Solid pharmaceutical compositions comprising a stable magnesium salt of quinapril that acts as a ACE (Angiotensin Converting Enzyme) inhibitor |
US6048874A (en) * | 1999-01-26 | 2000-04-11 | Medeva Pharmaceuticals Manufacturing, Inc. | Parenteral metolazone formulations |
US6555139B2 (en) | 1999-06-28 | 2003-04-29 | Wockhardt Europe Limited | Preparation of micron-size pharmaceutical particles by microfluidization |
AU7604400A (en) * | 1999-09-21 | 2001-04-24 | Emory University | Methods and compositions for treating platelet-related disorders using mpl pathway inhibitory agents |
US20030113330A1 (en) * | 1999-11-08 | 2003-06-19 | Uhal Bruce D. | Methods for treating pulmonary fibrosis |
US6569456B2 (en) | 2000-01-13 | 2003-05-27 | Osmotica Corp. | Osmotic device containing diltiazem and an ACE inhibitor or diuretic |
CA2398995C (en) | 2000-02-04 | 2014-09-23 | Children's Hospital Research Foundation | Lipid hydrolysis therapy for atherosclerosis and related diseases |
US6635277B2 (en) | 2000-04-12 | 2003-10-21 | Wockhardt Limited | Composition for pulsatile delivery of diltiazem and process of manufacture |
ES2375268T3 (es) | 2000-12-14 | 2012-02-28 | The Brigham And Women's Hospital, Inc. | Marcadores inflamatorios para la detección y prevención de diabetes mellitus. |
US6458769B1 (en) | 2001-06-25 | 2002-10-01 | Astrazeneca Ab | Amorphous compound |
US6462174B1 (en) | 2001-06-25 | 2002-10-08 | Astrazeneca Ab | Amorphous compound |
US6627760B1 (en) | 2001-06-25 | 2003-09-30 | Astrazeneca Ab | Amorphous compound |
EP1443919A4 (en) * | 2001-11-16 | 2006-03-22 | Bristol Myers Squibb Co | DOUBLE INHIBITORS OF THE FATTY ACID BINDING PROTEIN OF THE ADIPOCYTES AND THE FATTY ACID BINDING PROTEIN OF KERATINOCYTES |
SI21101A (sl) * | 2001-11-26 | 2003-06-30 | LEK farmacevtska dru�ba d.d. | Koncentriranje vodnih frakcij lisinoprila z reverzno osmozo |
US20030215526A1 (en) * | 2002-03-08 | 2003-11-20 | Scott Stofik | Stable formulations of angiotensin converting enzyme (ACE) inhibitors |
DK1487431T3 (da) | 2002-03-08 | 2012-08-20 | Philera New Zealand Ltd | Forebyggelse og/eller behandling af cardiovaskulær sygdom og/eller dermed associeret hjertefejl |
HUE039881T2 (hu) | 2002-05-09 | 2019-02-28 | Brigham & Womens Hospital Inc | 1L1RL-1, mint egy kardiovaszkuláris betegség-marker |
EP1513868B1 (en) * | 2002-06-19 | 2006-08-09 | EOS Eczacibasi Ozgun Kimyasal Urunler Sanayi Ve Ti Caret A.S. | Process for the production of lisinopril |
EA200500234A1 (ru) | 2002-08-19 | 2005-08-25 | Пфайзер Продактс Инк. | Комбинированная терапия гиперпролиферативных болезней |
JP2006503014A (ja) * | 2002-08-20 | 2006-01-26 | プロテミックス コーポレイション リミティド | 剤形及び関連する治療法 |
CA2498757A1 (en) * | 2002-09-11 | 2004-03-25 | Toaeiyo Ltd. | Proline ester and preparation containing the same for percutaneous administration |
US20040110241A1 (en) * | 2002-12-06 | 2004-06-10 | Segal Mark S. | Materials and methods for monitoring vascular endothelial function |
US20070218139A1 (en) * | 2002-12-20 | 2007-09-20 | Smith Thomas J | High Pressure Compaction For Pharmaceutical Formulations |
CL2004000366A1 (es) * | 2003-02-26 | 2005-01-07 | Pharmacia Corp Sa Organizada B | USO DE UNA COMBINACION DE UN COMPUESTO DERIVADO DE PIRAZOL INHIBIDOR DE QUINASA p38, Y UN INHIBIDOR DE ACE PARA TRATAR DISFUNCION RENAL, ENFERMEDAD CARDIOVASCULAR Y VASCULAR, RETINOPATIA, NEUROPATIA, EDEMA, DISFUNCION ENDOTELIAL O INSULINOPATIA. |
CL2004000544A1 (es) * | 2003-03-18 | 2005-01-28 | Pharmacia Corp Sa Organizada B | Uso de una combinacion farmaceutica, de un antagonista del receptor de aldosterona y un inhibidor de endopeptidasa neutral, util para el tratamiento y prevencion de una condicion patologica relacionada con hipertension, disfuncion renal, insulinopati |
US20060252120A1 (en) * | 2003-05-09 | 2006-11-09 | Kieliszewski Marcia J | Synthetic genes for plant gums and other hydroxyproline-rich glycoproteins |
US7923467B2 (en) | 2003-05-30 | 2011-04-12 | Ranbaxy Laboratories, Inc. | Substituted pyrrole derivatives and their use as HMG-CO inhibitors |
US7459474B2 (en) * | 2003-06-11 | 2008-12-02 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor and method |
US20040265238A1 (en) * | 2003-06-27 | 2004-12-30 | Imtiaz Chaudry | Inhalable formulations for treating pulmonary hypertension and methods of using same |
US20060089374A1 (en) * | 2003-07-17 | 2006-04-27 | Glenn Cornett | Enantiomeric compositions of cicletanine, alone and in combination with other agents, for the treatment of disease |
GB2419529B (en) * | 2003-07-17 | 2008-01-09 | Cotherix Inc | Combination therapies for treatment of hypertension and complications in patients with diabetes or metabolic syndrome |
US20050037063A1 (en) * | 2003-07-21 | 2005-02-17 | Bolton Anthony E. | Combined therapies |
EP1663184A2 (en) | 2003-08-29 | 2006-06-07 | The Brigham And Women's Hospital, Inc. | Hydantoin derivatives as inhibitors of cellular necrosis |
US7371759B2 (en) * | 2003-09-25 | 2008-05-13 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
US20050153885A1 (en) * | 2003-10-08 | 2005-07-14 | Yun Anthony J. | Treatment of conditions through modulation of the autonomic nervous system |
US7420059B2 (en) * | 2003-11-20 | 2008-09-02 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
ES2381551T3 (es) | 2003-12-05 | 2012-05-29 | The Cleveland Clinic Foundation | Marcadores de riesgo para enfermedad cardiovascular |
CA2550505A1 (en) * | 2003-12-19 | 2005-06-30 | Protemix Corporation Limited | Copper antagonist compounds |
WO2005069845A2 (en) * | 2004-01-14 | 2005-08-04 | Ohio University | Methods of producing peptides/proteins in plants and peptides/proteins produced thereby |
WO2005110015A2 (en) * | 2004-04-19 | 2005-11-24 | Ohio University | Cross-linkable glycoproteins and methods of making the same |
US7803838B2 (en) * | 2004-06-04 | 2010-09-28 | Forest Laboratories Holdings Limited | Compositions comprising nebivolol |
EP1778618B1 (en) | 2004-07-19 | 2013-12-25 | PhilERA New Zealand Limited | Synthesis of triethylenetetramines |
WO2006042192A2 (en) | 2004-10-06 | 2006-04-20 | The Brigham And Womens's Hospital, Inc. | Relevance of achieved levels of markers of systemic inflammation following treatment |
EP1848424B1 (en) * | 2005-01-31 | 2017-04-05 | Mylan Laboratories, Inc | Pharmaceutical composition comprising hydroxylated nebivolol |
ZA200710880B (en) * | 2005-05-27 | 2009-06-24 | Univ Cape Town | Angiotensin I-converting enzyme (ace) inhibitors |
CA2610694A1 (en) | 2005-05-31 | 2006-12-07 | Mylan Laboratories, Inc. | Compositions comrising nebivolol |
US20080242834A1 (en) * | 2005-07-08 | 2008-10-02 | Ohio University | Methods of Predicting Hyp-Glycosylation Sites For Proteins Expressed and Secreted in Plant Cells, and Related Methods and Products |
US20090297496A1 (en) * | 2005-09-08 | 2009-12-03 | Childrens Hospital Medical Center | Lysosomal Acid Lipase Therapy for NAFLD and Related Diseases |
US8119358B2 (en) | 2005-10-11 | 2012-02-21 | Tethys Bioscience, Inc. | Diabetes-related biomarkers and methods of use thereof |
US7741317B2 (en) | 2005-10-21 | 2010-06-22 | Bristol-Myers Squibb Company | LXR modulators |
WO2007054896A1 (en) | 2005-11-08 | 2007-05-18 | Ranbaxy Laboratories Limited | Process for (3r, 5r)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [(4-hydroxy methyl phenyl amino) carbonyl]-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid hemi calcium salt |
US7888376B2 (en) | 2005-11-23 | 2011-02-15 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
US7592461B2 (en) | 2005-12-21 | 2009-09-22 | Bristol-Myers Squibb Company | Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof |
CA2634473A1 (en) * | 2006-02-17 | 2007-08-30 | Nitromed, Inc. | Methods using hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate |
JP5412273B2 (ja) * | 2006-03-21 | 2014-02-12 | アミリン・ファーマシューティカルズ,リミテッド・ライアビリティ・カンパニー | ペプチド−ぺプチダーゼ阻害剤及びその使用 |
US20070238770A1 (en) * | 2006-04-05 | 2007-10-11 | Bristol-Myers Squibb Company | Process for preparing novel crystalline forms of peliglitazar, novel stable forms produced therein and formulations |
WO2007146229A2 (en) | 2006-06-07 | 2007-12-21 | Tethys Bioscience, Inc. | Markers associated with arteriovascular events and methods of use thereof |
EP2089355A2 (en) | 2006-11-01 | 2009-08-19 | Brystol-Myers Squibb Company | Modulators of glucocorticoid receptor, ap-1, and/or nf- kappa b activity and use thereof |
CN101573340A (zh) | 2006-11-01 | 2009-11-04 | 百时美施贵宝公司 | 糖皮质激素受体AP-1和/或NF-κB活性的调节剂及其用途 |
ES2382009T3 (es) | 2006-12-01 | 2012-06-04 | Bristol-Myers Squibb Company | Derivados de N-((3-bencil)-2,2-(bis-fenil-)-propan-1-amina como inhibidores de CETP para el tratamiento de aterosclerosis y enfermedades cardiovasculares |
EP2541254B1 (en) | 2007-04-18 | 2014-11-12 | Health Diagnostic Laboratory, Inc. | Diabetes-related biomarkers and methods of use thereof |
MX2009013293A (es) | 2007-06-04 | 2010-02-15 | Synergy Pharmaceuticals Inc | Agonistas de guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos. |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
WO2009042922A2 (en) * | 2007-09-27 | 2009-04-02 | Amylin Pharmaceuticals, Inc. | Peptide-peptidase inhibitor conjugates and methods of making and using same |
CA2705097A1 (en) * | 2007-11-07 | 2009-05-14 | Janssen Pharmaceutica N.V. | Combination therapy comprising angiotensin converting enzyme inhibitors and vasopressin receptor antagonists |
US7828840B2 (en) * | 2007-11-15 | 2010-11-09 | Med Institute, Inc. | Medical devices and methods for local delivery of angiotensin II type 2 receptor antagonists |
ES2627848T3 (es) | 2008-06-04 | 2017-07-31 | Synergy Pharmaceuticals Inc. | Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos |
GB2462022B (en) | 2008-06-16 | 2011-05-25 | Biovascular Inc | Controlled release compositions of agents that reduce circulating levels of platelets and methods thereof |
JP2011528375A (ja) | 2008-07-16 | 2011-11-17 | シナジー ファーマシューティカルズ インコーポレイテッド | 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト |
SI23149A (sl) | 2009-09-21 | 2011-03-31 | Silverstone Pharma | Nove benzatinske soli ACE inhibitorjev, postopek za njihovo pripravo in njihova uporaba za zdravljenje kardiovaskularnih bolezni |
US8119817B2 (en) * | 2009-09-29 | 2012-02-21 | Degussa-Huels Ag | Process for separating the diastereomers of RSS-and SSS-N- α [1-carboxy-3-phenylpropyl] lysylproline |
US20110190807A1 (en) | 2010-02-01 | 2011-08-04 | The Hospital For Sick Children | Remote ischemic conditioning for treatment and prevention of restenosis |
SG10201502031XA (en) | 2010-03-31 | 2015-05-28 | Hospital For Sick Children | Use of remote ischemic conditioning to improve outcome after myocardial infarction |
EP2555692A2 (en) | 2010-04-08 | 2013-02-13 | The Hospital For Sick Children | Use of remote ischemic conditioning for traumatic injury |
WO2011161223A2 (en) | 2010-06-23 | 2011-12-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical oral dosage forms comprising lercanidipine and enalapril and their pharmaceutically acceptable salts |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
CN105061314A (zh) | 2010-12-15 | 2015-11-18 | 施万生物制药研发Ip有限责任公司 | 脑啡肽酶抑制剂 |
CA2819153A1 (en) | 2010-12-15 | 2012-06-21 | Theravance, Inc. | Neprilysin inhibitors |
SI2654729T1 (sl) | 2010-12-24 | 2016-08-31 | Krka, D.D., Novo Mesto | Homogene farmacevtske oralne dozirne oblike, ki obsegajo lerkanidipin in enalapril ali njune farmacevtsko sprejemljive soli skupaj z organsko kislino |
WO2012154249A1 (en) | 2011-02-17 | 2012-11-15 | Theravance, Inc. | Substituted aminobutyric derivatives as neprilysin inhibitors |
JP5959065B2 (ja) | 2011-02-17 | 2016-08-02 | セラヴァンス バイオファーマ アール&ディー アイピー, エルエルシー | ネプリライシン阻害剤としての置換アミノ酪酸誘導体 |
CN103596928B (zh) | 2011-05-31 | 2017-02-15 | 施万生物制药研发Ip有限责任公司 | 脑啡肽酶抑制剂 |
CN103748070B (zh) | 2011-05-31 | 2015-06-24 | 施万生物制药研发Ip有限责任公司 | 脑啡肽酶抑制剂 |
EP2714660B1 (en) | 2011-05-31 | 2018-09-26 | Theravance Biopharma R&D IP, LLC | Neprilysin inhibitors |
EP3173093B1 (en) | 2011-07-18 | 2018-12-05 | Critical Care Diagnostics, Inc. | Methods of treating cardiovascular diseases and predicting the efficacy of exercise therapy |
AU2012303683B2 (en) | 2011-08-26 | 2016-09-08 | Wockhardt Limited | Methods for treating cardiovascular disorders |
TWI560172B (en) | 2011-11-02 | 2016-12-01 | Theravance Biopharma R&D Ip Llc | Neprilysin inhibitors |
EP2855458B1 (en) | 2012-05-11 | 2018-08-08 | Reset Therapeutics, Inc. | Carbazole-containing sulfonamides as cryptochrome modulators |
WO2013181332A1 (en) | 2012-05-31 | 2013-12-05 | Theravance, Inc. | Nitric oxide donor neprilysin inhibitors |
AU2013271537B2 (en) | 2012-06-08 | 2017-05-11 | Theravance Biopharma R&D Ip, Llc | Neprilysin inhibitors |
ES2710932T3 (es) | 2012-06-08 | 2019-04-29 | Theravance Biopharma R&D Ip Llc | Inhibidores de neprilisina |
AU2013296803B2 (en) | 2012-08-01 | 2018-03-08 | Eric Ostertag | Free flowing, frozen compositions comprising a therapeutic agent |
RS55797B1 (sr) | 2012-08-08 | 2017-08-31 | Theravance Biopharma R&D Ip Llc | Inhibitori neprilizina |
US8568747B1 (en) | 2012-10-05 | 2013-10-29 | Silvergate Pharmaceuticals, Inc. | Enalapril compositions |
LT2964616T (lt) | 2013-03-05 | 2017-07-25 | Theravance Biopharma R&D Ip, Llc | Neprilizino inhibitoriai |
AU2014235209B2 (en) | 2013-03-15 | 2018-06-14 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonists combined with other drugs |
JP2016514671A (ja) | 2013-03-15 | 2016-05-23 | シナジー ファーマシューティカルズ インコーポレイテッド | グアニル酸シクラーゼのアゴニストおよびその使用 |
EP2968276A4 (en) | 2013-03-15 | 2017-02-15 | President and Fellows of Harvard College | Hybrid necroptosis inhibitors |
JP6230691B2 (ja) | 2013-03-21 | 2017-11-15 | ユープラシア ファーマシューティカルズ ユーエスエー エルエルシーEupraxia Pharmaceuticals Usa Llc | 関節の炎症およびそれに関連する疼痛を治療するための注射用持続放出組成物およびその使用方法 |
BR112015026513A2 (pt) | 2013-04-17 | 2017-07-25 | Pfizer | derivados de n-piperidin-3-ilbenzamida para tratar as doenças cardiovasculares |
KR102272746B1 (ko) | 2013-06-05 | 2021-07-08 | 보슈 헬스 아일랜드 리미티드 | 구아닐레이트 사이클라제 c의 초순수 작용제, 및 이의 제조 및 사용 방법 |
US9593113B2 (en) | 2013-08-22 | 2017-03-14 | Bristol-Myers Squibb Company | Imide and acylurea derivatives as modulators of the glucocorticoid receptor |
AU2015210983B2 (en) | 2014-01-30 | 2018-10-04 | Theravance Biopharma R&D Ip, Llc | Neprilysin inhibitors |
US9585882B2 (en) | 2014-01-30 | 2017-03-07 | Theravance Biopharma R&D Ip, Llc | Neprilysin inhibitors |
TWI690521B (zh) | 2014-04-07 | 2020-04-11 | 美商同步製藥公司 | 作為隱花色素調節劑之含有咔唑之醯胺類、胺基甲酸酯類及脲類 |
HUE041705T2 (hu) | 2014-07-31 | 2019-05-28 | Pharmathen Sa | Enalaprilt tartalmazó, szájban diszpergálódó film készítmény magas vérnyomás kezelésére gyermek populációban |
WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
SG11201706308RA (en) | 2015-02-11 | 2017-09-28 | Theravance Biopharma R&D Ip Llc | (2s,4r)-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid as neprilysin inhibitor |
PL3259255T3 (pl) | 2015-02-19 | 2021-07-26 | Theravance Biopharma R&D Ip, Llc | Kwas (2R,4R)-5-(5'-chloro-2'-fluorobifenyl-4-ilo)-2-hydroksy-4-[(5-metylooksazolo-2-karbonylo)amino]pentanowy |
MX2018005035A (es) | 2015-10-27 | 2018-09-06 | Eupraxia Pharmaceuticals Inc | Formulaciones de liberacion sostenida de anestesicos locales. |
US9463183B1 (en) | 2015-10-30 | 2016-10-11 | Silvergate Pharmaceuticals, Inc. | Lisinopril formulations |
MX2018010727A (es) | 2016-03-08 | 2019-01-24 | Theravance Biopharma R&D Ip Llc | Acido (2s,4r)-5-(5'-cloro-2'-fluoro-[1,1'-bifenil]-4-il)-2-(etoxim etil)-4-(3-hidroxiisoxazol-5-carboxamido)-2-metilpentanoico cristalino, y sus usos. |
US9669008B1 (en) | 2016-03-18 | 2017-06-06 | Silvergate Pharmaceuticals, Inc. | Enalapril formulations |
WO2018097999A1 (en) * | 2016-11-23 | 2018-05-31 | The Regents Of The University Of California | Compositions and methods for modulating protease activity |
US11046729B2 (en) | 2017-10-26 | 2021-06-29 | Southern Research Institute | Dipeptide analogs as TGF-beta inhibitors |
CN109734775A (zh) * | 2018-12-31 | 2019-05-10 | 辰欣药业股份有限公司 | 一种马来酸依那普利的精制方法 |
MA54261A (fr) | 2019-01-18 | 2022-04-27 | Astrazeneca Ab | Inhibiteurs de pcsk9 et leurs procédés d'utilisation |
GB2595203A (en) | 2020-03-03 | 2021-11-24 | Alkaloid Ad Skopje | Formulation |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2256445C3 (de) * | 1972-11-17 | 1981-11-05 | Hoechst Ag, 6000 Frankfurt | Heptapeptide, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Präparate |
IL58849A (en) * | 1978-12-11 | 1983-03-31 | Merck & Co Inc | Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them |
-
1979
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- 1979-12-10 SU SU792851802A patent/SU1287756A3/ru active
- 1979-12-10 DE DE1993175005 patent/DE19375005I2/de active Active
- 1979-12-10 BG BG8568627A patent/BG39467A3/xx unknown
- 1979-12-10 BG BG8568626A patent/BG39466A3/xx unknown
- 1979-12-11 ES ES486786A patent/ES8101540A1/es not_active Expired
- 1979-12-11 KR KR7904273A patent/KR850000847B1/ko active
- 1979-12-11 JP JP15986979A patent/JPS5581845A/ja active Granted
- 1979-12-11 CS CS798645A patent/CS237311B2/cs unknown
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1980
- 1980-08-14 ES ES494300A patent/ES8106134A1/es not_active Expired
- 1980-08-29 PH PH24512A patent/PH24268A/en unknown
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1981
- 1981-02-17 US US06/235,335 patent/US4374829A/en not_active Expired - Lifetime
- 1981-09-22 AR AR286844A patent/AR231971A1/es active
-
1982
- 1982-09-27 US US06/423,916 patent/US4472380A/en not_active Expired - Lifetime
- 1982-11-17 YU YU2567/82A patent/YU43533B/xx unknown
- 1982-11-17 YU YU2566/82A patent/YU43532B/xx unknown
-
1984
- 1984-01-17 KR KR1019840000192A patent/KR840005083A/ko not_active IP Right Cessation
- 1984-04-21 KR KR1019840002123A patent/KR850000846B1/ko not_active IP Right Cessation
-
1986
- 1986-09-16 CA CA000518335A patent/CA1300313C/en not_active Expired - Lifetime
- 1986-09-16 CA CA000518334A patent/CA1275349C/en not_active Expired - Lifetime
-
1987
- 1987-04-09 HK HK274/87A patent/HK27487A/xx not_active IP Right Cessation
-
1988
- 1988-09-07 CA CA000576716A patent/CA1276559C/en not_active Expired - Lifetime
-
1989
- 1989-09-13 JP JP1238329A patent/JPH02131430A/ja active Granted
- 1989-09-13 JP JP1238330A patent/JPH02131496A/ja active Granted
-
1993
- 1993-02-09 NL NL930008C patent/NL930008I2/nl unknown
- 1993-02-09 NL NL930007C patent/NL930007I2/nl unknown
- 1993-02-09 NL NL930006C patent/NL930006I2/nl unknown
-
1995
- 1995-08-02 NO NO1995007C patent/NO1995007I1/no unknown
-
1996
- 1996-02-23 NO NO1996004C patent/NO1996004I1/no unknown
-
1997
- 1997-06-19 NL NL970022C patent/NL970022I1/nl unknown
- 1997-11-19 LU LU90173C patent/LU90173I2/fr unknown
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