公开(公告)号：US5422341A

公开(公告)日：1995-06-06

申请号：US103490

申请日：1993-08-06

申请人： Mark J. Macielag ,  Ramalinga Dharanipragada ,  James R. Florance ,  Mary S. Marvin ,  Alphonse Galdes

发明人： Mark J. Macielag ,  Ramalinga Dharanipragada ,  James R. Florance ,  Mary S. Marvin ,  Alphonse Galdes

IPC分类号： C07K7/04 ,  A61K38/00 ,  A61P3/00 ,  A61P3/02 ,  C07K14/575 ,  C07K14/63 ,  C07K5/00 ,  C07K7/00 ,  C07K17/00

CPC分类号： C07K14/63 ,  A61K38/00

摘要： This invention pertains to polypeptides, other than motilin, having gastrointestinal motor stimulating activity and represented by the formula: ##STR1## wherein A and D are lipophilic aliphatic or alicyclic amino acids; B is L-proline or L-alanine; E is an aromatic, lipophilic aliphatic, or alicyclic amino acid; F is an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine, L-glutamic acid, or L-alanine; J is a direct bond or is selected from, inter alia Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu (SEQ ID NO:2) or Z-Leu-Gln-Glu-Lys (SEQ ID NO:3), wherein Z is, inter alia, arginine, D-arginine, D-homoarginine, or D-lysine, and further wherein the amino acids represented by A, D, E and F are L-stereoisomers; R.sub.1 is lower-alkyl or allyl; R.sub.2 is hydrogen, lower-alkyl, propargyl, or allyl; R.sub.3 is hydrogen, lower-alkyl, and allyl; R.sub.4 is lower-alkyl, cycloalkyl, heteroaryl, unsubstituted aryl, and aryl substituted by halogen, hydroxy, or lower-alkoxy; R.sub.5 is --CH.sub.2 CONH.sub.2, aminoalkyl, or guanidinoalkyl; R.sub.6 is --COOH or --CONH.sub.2 ; and m is 0 or 1, and the asymmetric carbon represented by * may be D or L configuration, with certain specified provisos.

摘要翻译： 本发明涉及具有胃肠运动刺激活性并由下式表示的除胃动素以外的多肽：其中A和D是亲脂性脂族或脂环族氨基酸; B是L-脯氨酸或L-丙氨酸; E是芳族，亲脂性脂族或脂环族氨基酸; F是芳族或杂芳族氨基酸; G是甘氨酸或D-丙氨酸; H是L-谷氨酸或L-谷氨酰胺; 我是L-谷氨酰胺，L-谷氨酸或L-丙氨酸; J是直接键或选自Z，Z-Leu，Z-Leu-Gln，Z-Leu-Gln-Glu（SEQ ID NO：2）或Z-Leu-Gln-Glu-Lys（SEQ 其中Z特别是精氨酸，D-精氨酸，D-高精氨酸或D-赖氨酸，其中由A，D，E和F表示的氨基酸是L-立体异构体; R1是低级烷基或烯丙基; R2是氢，低级烷基，炔丙基或烯丙基; R3是氢，低级烷基和烯丙基; R4是低级烷基，环烷基，杂芳基，未取代的芳基和被卤素，羟基或低级烷氧基取代的芳基; R5是-CH2CONH2，氨基烷基或胍基烷基; R6是-COOH或-CONH 2; 并且m为0或1，并且由*表示的不对称碳可以是D或L构型，具有特定的条件。

公开(公告)号：US5470830A

公开(公告)日：1995-11-28

申请号：US103489

申请日：1993-08-06

申请人： Mark J. Macielag ,  Ramalinga Dharanipragada ,  Mary S. Marvin

发明人： Mark J. Macielag ,  Ramalinga Dharanipragada ,  Mary S. Marvin

IPC分类号： C07K7/04 ,  A61K38/00 ,  A61P1/00 ,  C07K14/575 ,  C07K14/63 ,  C07K5/00 ,  C07K7/00 ,  C07K17/00

CPC分类号： C07K14/63 ,  A61K38/00

摘要： This invention pertains to polypeptides having gastrointestinal motor inhibitory activity represented by the formula: ##STR1## including optically active isomeric forms and the pharmaceutically acceptable acid addition salts thereof wherein A is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; B is selected from the group consisting of L and D aromatic, heteroaromatic, lipophilic aliphatic, and alicyclic amino acids; D is the L-stereoisomer of a lipophilic aliphatic or alicyclic amino acid; E is the L-stereoisomer of an aromatic, aliphatic, or alicyclic amino acid; F is the L-stereoisomer of an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine, L-glutamic acid, or L-alanine; J is a direct bond between I and group --NH-- or is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-Gln-Glu (SEQ ID NO:2), Z-Leu-Gln-Glu-Lys (SEQ ID NO:3), Zleu-Gln-Glu-Lys-Glu (SEQ ID NO:4), Z-Leu-Gln-Glu-Lys-Glu-Arg (SEQ ID NO:5), ZLeu-Gln-Glu-Lys-Glu-Arg-Asn (SEQ ID NO:6), Z-Leu-Gln-Glu-Lys-Glu-Arg-AsnLys (SEQ ID NO:7), and Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly (SEQ ID NO:8), wherein Z is selected from the group consisting of arginine, D-arginine, D-homoarginine, D-lysine, D-ornithine, D-2,4-diaminobutyric acid, D-glutamine, D-asparagine, and D-alanine; R.sub.1 and R.sub.2 are independently hydrogen or lower alkyl; R.sub.3 is selected from the group consisting of lower-alkyl, cycloalkyl, substituted and unsubstituted aryl, and heteroaryl, wherein the aryl group may be substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and lower-alkoxy; R.sub.4 is selected from the group consisting of --CH.sub.2 CONH.sub.2, aminoalkyl groups containing from 1 to 3 carbon atoms, and guanidinoalkyl groups containing 2 or 3 carbon atoms; R.sub.5 is --COOH or --CONH.sub.2 ; and the symbol * represents an asymmetric carbon atom which may be in the D or L configuration, and each lower-alkyl group contains from 1 to 4 carbon atoms, with the proviso that R.sub.4 is --CH.sub.2 CONH.sub.2 only when J is Z-Leu or Z-Leu-Gln-Glu-Lys-Glu-Arg-Asn-Lys-Gly (SEQ ID NO:8).

公开(公告)号：US5734012A

公开(公告)日：1998-03-31

申请号：US648644

申请日：1996-05-16

申请人： Ramalinga Dharanipragada ,  Mark J. Macielag ,  Jung Kim-Dettelback ,  James Florance

发明人： Ramalinga Dharanipragada ,  Mark J. Macielag ,  Jung Kim-Dettelback ,  James Florance

IPC分类号： A61K38/00 ,  A61P1/00 ,  C07K14/63 ,  C07K5/12 ,  C07K7/00 ,  C07K7/08

CPC分类号： C07K14/63 ,  A61K38/00

摘要： This invention pertains to cyclic polypeptides having gastrointestinal motor stimulating activity which may be represented by formula (1): ##STR1## including optically active isomeric forms and the pharmaceutically acceptable acid addition salts thereof, wherein groups A and D are linked to from a cyclic structure; and R.sub.1 is lower alkyl; R.sub.2 is hydrogen or lower alkyl; R.sub.3 is hydrogen or lower alkyl; R.sub.4 is phenyl or substituted phenyl, wherein the phenyl group may be substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and lower alkoxy; R.sub.5 is --OH or --NH.sub.2 ; A is selected from the group consisting of L-glutamic acid, L-aspartic acid, L-lysine, L-ornithine, and L-2,4-diaminobutyric acid; B is L-alanine or L-glutamine; C is L-arginine or D-arginine; D is selected from the group consisting of L-lysine, L-ornithine, L-2,4-diaminobutyric acid, L-glutamic acid, and L-aspartic acid; E is a direct bond between group D and group R.sub.5 or is L-lysine or D-lysine; m is 0 or 1; the symbol * represents an asymmetric carbon atom which may be in the D or L configuration, with the proviso that: (a) when A is L-glutamic acid or L-aspartic acid, D is L-lysine, L-ornithine, or L-2,4-diaminobutyric acid; and (b) when A is L-lysine, L-ornithine, or L-2,4-diaminobutyric acid, D is L-glutamic acid or L-aspartic acid. This invention also pertains to methods for using the novel cyclic polypeptides.

摘要翻译： 本发明涉及具有胃肠运动刺激活性的环状多肽，其可以由式（1）表示：（1）包括旋光异构体形式及其药学上可接受的酸加成盐，其中基团A和D与 循环结构; 且R 1为低级烷基; R2是氢或低级烷基; R3是氢或低级烷基; R4是苯基或取代的苯基，其中苯基可以被一个或多个选自卤素，羟基和低级烷氧基的取代基取代; R5是-OH或-NH2; A选自L-谷氨酸，L-天冬氨酸，L-赖氨酸，L-鸟氨酸和L-2,4-二氨基丁酸; B是L-丙氨酸或L-谷氨酰胺; C是L-精氨酸或D-精氨酸; D选自L-赖氨酸，L-鸟氨酸，L-2,4-二氨基丁酸，L-谷氨酸和L-天冬氨酸; E是D组和R5组之间的直接键，或是L-赖氨酸或D-赖氨酸; m为0或1; 符号*表示可以是D或L构型的不对称碳原子，条件是：（a）当A是L-谷氨酸或L-天冬氨酸时，D是L-赖氨酸，L-鸟氨酸或 L-2,4-二氨基丁酸; 和（b）当A是L-赖氨酸，L-鸟氨酸或L-2,4-二氨基丁酸时，D是L-谷氨酸或L-天冬氨酸。 本发明还涉及使用新型环状多肽的方法。

公开(公告)号：US20070254937A1

公开(公告)日：2007-11-01

申请号：US11368566

申请日：2006-03-06

申请人： John Jurcak ,  Matthieu Barrague ,  Timothy Gillespy ,  Michael Edwards ,  Kwon Musick ,  Philip Weintraub ,  Yan Du ,  Ramalinga Dharanipragada ,  Ashfaq Parkar

发明人： John Jurcak ,  Matthieu Barrague ,  Timothy Gillespy ,  Michael Edwards ,  Kwon Musick ,  Philip Weintraub ,  Yan Du ,  Ramalinga Dharanipragada ,  Ashfaq Parkar

IPC分类号： A61K31/415 ,  C07D231/54

CPC分类号： C07D495/04

摘要： Thienopyrazoles of formula I, their preparation, pharmaceutical compositions comprising these compounds, and their pharmaceutical uses in the treatment of disease states capable of being modulated by the inhibition of the protein kinases, in particular interleukin-2 inducible tyrosine kinase (ITK).

摘要翻译： 式I的噻吩并吡唑类，其制备方法，包含这些化合物的药物组合物及其在治疗能够通过抑制蛋白激酶（特别是白细胞介素-2诱导型酪氨酸激酶（ITK））调节的疾病状态的药物用途。

公开(公告)号：US20050054729A1

公开(公告)日：2005-03-10

申请号：US10920395

申请日：2004-08-18

申请人： Paulus Wohlfart ,  Teri Suzuki ,  Ramalinga Dharanipragada ,  Alena Safarova ,  Armin Walser ,  Hartmut Strobel

发明人： Paulus Wohlfart ,  Teri Suzuki ,  Ramalinga Dharanipragada ,  Alena Safarova ,  Armin Walser ,  Hartmut Strobel

IPC分类号： A61K31/00 ,  A61K31/166 ,  A61K31/66 ,  A61P1/16 ,  A61P5/48 ,  A61P7/02 ,  A61P9/00 ,  A61P9/04 ,  A61P9/06 ,  A61P9/10 ,  A61P9/12 ,  A61P11/06 ,  A61P13/12 ,  A61P15/10 ,  A61P19/10 ,  A61P25/28 ,  A61P27/06 ,  A61P43/00 ,  C07C233/65 ,  A61K31/165

CPC分类号： C07C233/65 ,  A61K31/166 ,  C07C2602/08

摘要： The present invention relates to the method of stimulating the expression of endothelial NO-synthase in a mammal, which method comprises administering a physiologically active amount of 4-fluoro-N-indan-2-yl benzamide according to the formula (I) to the said mammal. The compound (I) can be used for the therapy and prophylaxis of cardiovascular diseases like stable and unstable angina pectoris, Prinzmetal angina (spasm), acute coronary syndrome, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease PAOD, atherosclerosis, restenosis, endothelial damage after PTCA, essential hypertension, pulmonary hypertension, secondary hypertension, renovascular chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, and the lowering of cardiovascular risk of postmenopausal women or after intake of contraceptives, the therapy and prophylaxis of diabetes and diabetes complications (nephropathy, retinopathy), angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of the liver, restricted memory performance or a restricted ability to learn.

摘要翻译： 本发明涉及刺激哺乳动物内皮细胞NO合成酶表达的方法，该方法包括将生理活性量的式（I）的4-氟-N-茚满-2-基苯甲酰胺给予 哺乳动物说 化合物（I）可用于治疗和预防心血管疾病如稳定和不稳定型心绞痛，Prinzmetal心绞痛（痉挛），急性冠状动脉综合征，心力衰竭，心肌梗死，中风，血栓形成，外周动脉闭塞性疾病PAOD，动脉粥样硬化 ，PTCA后再狭窄，内皮损伤，原发性高血压，肺动脉高压，继发性高血压，肾血管性慢性肾小球肾炎，勃起功能障碍，室性心律失常，绝经后妇女心血管危险降低或避孕药物摄入后，糖尿病和糖尿病的治疗和预防 并发症（肾病，视网膜病变），血管生成，哮喘支气管炎，慢性肾功能衰竭，肝硬化，限制性记忆能力或受限的学习能力。