Combination of rotational atherothrombectomy and Paclitaxel-coated angioplasty for femoropopliteal occlusion.

OBJECTIVE: The rotational atherothrombectomy with Straub Rotarex(®) is a safe and efficient treatment of acute/subactute vascular occlusions. The purpose of this study was to evaluate the benefit of paclitaxel-coated angioplasty after rotational atherothrombectomy over an observation period of six months. MATERIALS AND METHODS: Overall, 29 patients were treated with the Rotarex catheter in combination with paclitaxel-coated angioplasty. All patients had acute/subacute and chronic occlusions of the superficial femoral artery (SFA) and/or popliteal arteries. The ankle-brachial index (ABI) was detected before the intervention, after the procedure, and after six months. Also clinical examination and ultrasound scans were done in the observation period. RESULTS: There were no technical failures. The ABI shows a significant increase from 0.52 ± 0.17 to 0.91 ± 0.25 in the follow-up. By ultrasound examination, there were found two (6.9%) restenoses during the follow-up. There was one dissection during the intervention (3.5%). CONCLUSION: The rotational atherothrombectomy in combination with paclitaxel-coated angioplasty might be an effective and safe method with a promising low rate of restenosis at six months.

Solitary breast cancer metastasis to the esophagus - a multimodal diagnostic approach.

We present a case of late breast cancer metastasis over 15 years since the initial diagnosis which was highly unusual because of its solitary aspect with no other evidence of the disease and its uncommon localization in the esophagus. With a history of breast cancer, several differential diagnoses for suspicious space-occupying masses need to be considered, like radiation-induced cancer or multiple neoplasm. A multimodal diagnostic approach can lead to the correct diagnosis. Endoscopy, endoscopic ultrasound (EUS) including EUS-guided fine-needle aspiration (FNA), CT and PET/CT findings are provided.

3-Amidinophenylalanine-based inhibitors of urokinase.

Synthesis and anti-uPA activity of a series of Nalpha-triisopropyl-phenylsulfonyl-protected 3-amidinophenylalanine amides are described. We have explored SAR around the C-terminal amide part for inhibition of uPA, plasmin and trypsin. Modification of the amide part has been found to affect potency but not selectivity. With a Ki of 0.41 microM 2r-L is one of the most potent uPA inhibitors described so far. The X-ray crystal structure of 2r-L was solved in complex with trypsin, superimposed with uPA and the results suggest an unique binding mode of this inhibitor type.

Synthesis and structure-activity relationships of potent thrombin inhibitors: piperazides of 3-amidinophenylalanine.

Thrombin is the key enzyme in the blood coagulation system, and inhibitors of its proteolytic activity are of therapeutic interest since they are potential anticoagulants. The most potent inhibitor of the benzamidine type is N alpha-[(2-naphthylsulfonyl)glycyl]-4-amidinophenylalanylpiperid ide (NAPAP). However, NAPAP and other benzamidine derivatives do not show favorable pharmacological properties; above all, they have very low systemic bioavailability after oral administration. The goal of designing new compounds was to obtain potent inhibitors with improved pharmacokinetic properties. Piperazide derivatives of 3-amidinophenylalanine as the key building block were synthesized. The piperazine moiety opened the possibility to introduce quite different substituents on the second nitrogen using common synthetic procedures. Some of the newly synthesized compounds are potent inhibitors of thrombin and offer an approach to study structure-function relationships for inhibition of thrombin and related enzymes and for the improvement of their pharmacokinetic properties.

Structure-activity relationships of inhibitors derived from 3-amidinophenylalanine.

Thrombin is the key enzyme in coagulation and its inhibitors are of therapeutic interest since they are potential anticoagulants. The most potent inhibitor of the benzamidine type is N alpha-(2-naphthylsulfonyl-glycyl)-4-amidinophenylalanine piperidide (NAPAP). However, NAPAP and other substances designed so far do not fulfill the pharmacological requirements. The goal of designing new compounds was to obtain potent inhibitors with improved pharmacokinetic properties, such as absorption after oral application and a sustained elimination. Novel derivatives of 3-amidinophenylalanine as key building block were synthesized. The amidino moiety and both the N alpha- and the C-terminal substituents were widely varied. Some of the newly synthesized compounds are potent inhibitors of thrombin and exert improved pharmacokinetic properties.

Novel plasma kallikrein inhibitors of the benzamidine type.

Besides guanidino compounds and amines structurally related to arginine and lysine, compounds with an amidino moiety are inhibitors of trypsin-like enzymes. However, in most cases ordinary benzamidine derivatives are not selective inhibitors. Relatively selective inhibitors of some enzymes were found among amino acids containing a benzamidine moiety at the side chain. For example, derivatives of phenyl-alpha-aminobutyric acid with one or two amidino moieties such as the 4'-amidinoanilide of N alpha-[4-amidinophenylsulfonyl]-phenyl-alpha- aminobutyric acid are potent and selective inhibitors of plasma kallikrein (Ki = 0.15 microM). Using N alpha-arylsulfonylated 3-amidinophenylalanine as the key building block, novel inhibitors of plasma kallikrein were developed. Several esters and amides of the nipecotic acid derivative were synthesized which inhibit plasma kallikrein competitively with Ki values between 0.1 and 1.0 microM. The compounds prolonged aPTT in micromolar concentration, indicating an inhibition of the intrinsic coagulation pathway.

[Synthesis of 4-methyl-6-phenyl-thieno(2,3-d)pyrimidines with a formamidino- or oxalamidocarbonic acid residue with antianaphylactic activity]. / Synthese von 4-Methyl-6-phenyl-thieno[2,3-d]pyrimidinen mit Formamidin- bzw. Oxalsäureamidrest mit antianaphylaktischer Wirkung.

3-Amino-4-methyl-6-phenyl-thieno[2,3-d]pyrimidine-2-carbonic acid alkylesters 1a, b were hydrolyzed to the potassium salt of the carbonic acid 2. Cyclization of 2 with acetanhydride yielded the tricyclic 1,3-oxazinone derivative 4. This compound reacted with pyrrolidine by different conditions of reaction to give the bisamide 7, the acetamidino carbonic acid 5 and their decarboxylated product 6. Compound 1a yielded with Vilsmeier reagents the formamidino compound 3. 3-Amino-thieno[2,3-d]pyrimidin-2-carbonitrile gave under different conditions of reaction with oxalic acid diethylester or with oxalic acid ethylester chloride the tetracyclic 4-methoxy-9-methyl-7-phenyl-thieno[2,3-d:4,5-d']dipyrimidine-2-car bonic acid methylester 10 or the N-(2-cyano-4-methyl-6-phenyl-thieno[2,3-d]pyrimid-3-yl)oxalamid ic ethylester 12. These compounds were hydrolyzed to give the carbonic acids 11 and 13. Some of the synthesized substances showed an antianaphylactic activity.

[Synthesis of 11-aryl-7,8,9,10-tetrahydro-1,2,3-triazino-(4',5':4,5)-thienol- -(2,3-b)-quinolines with antianaphylactic action]. / Synthese von 11-Acyl-7,8,9,10-tetrahydro-1,2,3-triazino[4',5':4,5]- thienol[2,3-b]chinolinen mit antianaphylaktischer Wirkung.

Title compounds of structure B with an oxo function in position 4 of the triazine ring were synthesized by reaction of the aminocarboxamides A with sodium nitrite in acetic acid. Aminocarbonitriles of structure H yielded with sodium nitrite in acetic acid and hydrochloric acid the 4-chloro derivatives I. These compounds gave with N-nucleophiles, methoxide or thiourea the substances J. Tetracyclic compounds with a hydroxyethyl or a piperidinoethyl residue in position 3 in the triazine ring (E, G) were also prepared. Some of the investigated compounds showed an antianaphylactic activity.

[Synthesis of new pyrido-(3',2':4,5)-thieno-(3,2-d)-1,2,3-triazine derivatives as antianaphylactics]. / Synthese neuer Pyrido[3',2':4,5]thieno[3,2-d]1,2,3-triazin-Derivate als Antianaphylaktika.

Some new pyrido[3',2':4,5]thieno[3,2-d]1,2,3-triazine-4(3H)-ones (C) were synthesized from 2-thioxo-1,2-dihydro-3-carbonitriles (A) via the 3-amino-thieno[2,3-b]pyridine-2-carboxamides (B). Substances of structure A were converted to 3-amino-thieno[2,3-b]pyridine-2-carbonitriles (G) which yielded the desired 4-amino substituted compounds I via the tricyclic 4-chloro-pyrido[3',2':4:5]thieno[3,2-d]1,2,3-triazines (H) by the reaction with N-nucleophiles. Some of the investigated compounds showed a respectable antianaphylactic activity.

[Synthesis of thieno(2,3-b)pyridines with oxalamidic acid or an oxalamidic alkylester residues and of 4-alkoxy-pyrido(3',2':4,5)thieno(3,2-d)pyridine-2-carboxylic acid derivates]. / Synthese von Thieno(2,3-)pyridinen mit Oxalamidsäure- bzw. Oxalamidsäurealkylester-Rest und von 4-Alkoxy-pyrido(3',2':4,5)thieno(3,2-d)pyrimidin-2-carbons]aure-Derivat en

N-(2-Alkoxycarbonyl-thieno[2,3-b]pyrid-3-yl)oxalamide acid alkylester B were synthesized by the reaction of 3-amino-2-carboxylic esters A with oxalic acid diethylester in presence of sodium alkoxides. The 3-amino-2-cyano-thieno[2,3-b]pyridines C yielded under the same conditions via the N-(2-cyano-thieno[2,3-b]pyrid-3-yl)oxalamidic acid alkylesters D/1-D/4 the 4-alkoxy-pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-2-carboxylic acid alkylesters E/1-E/8. The compounds D/1, D/2 and E/1-E/5 were hydrolyzed to give the corresponding carboxylic acids. The 3-amino-furo[2,3-b]pyridine-2-carboxylic acid ethylester H reacted with oxalic ethylester chloride to give the oxalamide ethylester I. The synthesized substances showed an antinaphylactic activity.

[Synthesis of N-(2-carboxy-thieno(2,3-b)pyridin-3-yl)-formamidines corresponding alkyl esters with antianaphylactic activity]. / Synthese von N-(2-Carboxy-thieno[2,3-b]pyridin-3-yl)-formamidinen und entsprechender Alkylester mit antianaphylaktischer Wirkung.

A lot of N-(2-carboxy-thieno[2,3-b]pyridin-3-yl)formamidines especially in form of their amine salts--were synthesized by reaction of 3-amino-thieno[2,3-b]pyridine-2-carboxylic acids with dimethylformamide/phosphoroxide chloride or by reaction of 4-oxo-4H-pyrido[3',2':4,5]thieno[3,2-d]1,3- oxazines with amines. Carboxylic acid alkylesters of this structure were yielded from 3-amino-thieno[2,3-b]pyridine-2-carbonic acid alkylesters by reaction with dimethylformamide/phosphoroxide chloride or with N-formyl-piperidine or N-formyl-morpholine and phosphoroxide chloride. The compounds showed antianaphylactic activity.

[Synthesis of N-(2-carboxy-thieno(2,3-b)pyridin-3-yl)amidines by means of reaction of 4-oxo-4H-pyrido(3',2':4,5)thieno(3,2-d)-1,3-oxazines with primary aliphatic amines]. / Synthese von N-(2-carboxy-thieno(2,3-b)pyridin-3-yl)amidinen durch Reaktion von 4-Oxo-4H-pyrido(3',2':4,5)thieno(3,2-d)-1,3-oxazinen mit primären aliphatischen Aminen.

The title compounds were synthesized by the reaction of tricyclic compounds of structure B with primary aliphatic amines under different conditions and useful isolation methods in good yields. These compounds showed an acceptable antianaphylactic activity.

[Synthesis of N-(2-carboxy-thieno(2,3-b)pyridin-3-yl)-amidines by the reaction with 4-oxo-4H-pyrido(3',2':4,5)-thieno(3,2-d)-1,3-oxazines with secondary cycloaliphatic amines]. / Synthese von N-(2-Carboxy-thieno[2,3-b]pyridin-3-yl)amidenen durch Umsetzung von 4-Oxo-4H-pyrido[3',2':4,5]thieno[3,2-d]1,3-oxazinen mit sekundären cycloaliphatischen Aminen.

4-Oxo-4H-pyrido[3',2':4,5]thieno[3,2-d]1,3-oxazines react with secondary cycloaliphatic amines to give besides the expected bisamides the amine salts of N-(2-carboxy-thieno[2,3-b]pyridine-3-yl)amidines. These compounds showed inhibitory activity against different lipoxygenases, but a small chemical stability.

Interactions of thrombin with benzamidine-based inhibitors.

Trypsin and trypsin-like enzymes cleave C-terminal bonds of the basic amino acids Arg and Lys. Inhibitors of these enzymes have been found not only among Arg and Lys derivatives but also with structurally related benzamidines. Especially cyclic amides of 4-amidinophenylalanine were found to be inhibitors of thrombin. The most potent selective thrombin inhibitor of these type is N alpha-(beta-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidine. From the X-ray crystal structures of thrombin and trypsin-inhibitor complexes the thrombin complexes formed with inhibitors derived from amidinophenylalanine have been modeled. These models allow valuable predictions to design inhibitors of improved selection and binding properties. Most recently, also the X-ray crystal structures of complexes of inhibitors with bovine thrombin have been solved.

Inhibition of glandular and plasma kallikrein by benzamidine derivatives.

Besides guanidino compounds and amines structurally related to arginine and lysine, compounds with other cationic groups are inhibitors of trypsin-like serine proteinases. Particularly aromatic ring structures with an amidino moiety have high affinity for these enzymes. In most cases ordinary benzamidine derivatives are no selective inhibitors, however, among derivatives of N alpha-arylsulfonyl-omega-amidinophenyl-alpha-amino-alkylcarboxylic acids selective competitive inhibitors of several enzymes were found. Amides of phenyl-alpha-aminobutyric acid containing an amidino moiety are inhibitors of plasma kallikrein. The p-amidinoanilide of 2-tosylamino-4-phenylbutyric acid inhibits selectively plasma kallikrein with a Ki of 0.70 mumol/l. In contrast, potent and selective inhibitors of glandular kallikrein were hardly found among benzamidines.

Inhibition of chymotrypsin and pancreatic elastase by 4H-3,1-benzoxazin-4-ones.

Eight 3,1-Benzoxazin-4-ones have been used to inactivate chymotrypsin and pancreatic elastase. Whereas 6,7-dimethoxy substitution only slightly decreased the acylation rate constant, the deacylation reaction was nearly unaffected. Bulky alkoxy groups in position 2 of the heterocyclic moiety were shown to increase enormously the acylation rate of chymotrypsin, but not that of elastase.

Synthetic inhibitors of bovine factor Xa and thrombin comparison of their anticoagulant efficiency.

New derivatives of benzamidine (N alpha-arylsulfonylamino-acylated derivatives of 3-amidinophenylalanine) were found to be potent inhibitors of bovine factor Xa (F Xa). The methyl and ethyl esters of N alpha-Tos-Gly- and N alpha-beta Nas-Gly-substituted 3-amidinophenylalanine, inhibited F Xa more effectively (Ki values near 0.5 mumol/l) than thrombin (Ki about 50 mumol/l). Reinvestigation of inhibition of F Xa by bis-benzamidines showed that compounds containing a cycloheptanone linking bridge are tight-binding inhibitors of F Xa (Ki in the 10 nmol/l range). The use of these inhibitors enabled us to clarify whether inhibition of F Xa or inhibition of thrombin is more efficient in anticoagulation. The thrombin inhibitors and not the potent F Xa inhibitors proved to be particularly effective in anticoagulation in vitro.