Bernhard Kutscher

D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures

The anticonvulsant activity of the novel drug D-23129 (N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester) was evaluated in animal models of epileptic seizures. D-23129 was active after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests at nontoxic doses. The compound was active against electrically induced seizures (MES, ED50 rat p.o. = 2.87 mg/kg), against seizures induced chemically by pentylenetetrazole (s.c. PTZ, ED50 mouse p.o. = 13.5 mg/kg), picrotoxin and N-methyl-D-aspartate (NMDA) and in a genetic animal model, the DBA/2 mouse. It was not active against seizures induced by bicuculline and strychnine. Motor impairment, evaluated with the rotarod test and by observation in the open field, was minimal at doses showing anticonvulsant activity. D-23129 was very effective in elevating the threshold for electrically and chemically induced seizures. Considering the dose increasing the MES threshold by 50% (TID50 mouse i.p. = 1.6 mg/kg; TID50 rat i.p. = 0.72 mg/kg) and the TD50 obtained in the rotarod test, the protective index of D-23129 is better than that of valproate and phenytoin. During 14 days chronic oral treatment with 15 mg/kg, no development of tolerance was observed. D-23129 thus presents an orally active, safe, broad spectrum anticonvulsant agent, which is structurally unrelated to anticonvulsants currently used. We expect that D-23129 will improve the treatment of refractory seizures in humans.

BENZODIAZA-, BENZOXAZA-, AND BENZODIOXAPHOSPHORINONES - FORMATION, REACTIVITY, STRUCTURE, AND BIOLOGICAL ACTIVITY

Abstract Although diverse phosphorus-containing heterocycles had been synthe-sized during the late nineteenth century already, work was still sparse in this area as recently as 1950[1,2]. The realization, around 1950, of the importance of phosphorus-containing substances in biological processes resulted in intense activity in preparative organophosphorus chemistry, and in an upsurge of research on structural and mechanistic problems [3–6].

1,5-Disubstituted indazol-3-ols with anti-inflammatory activity

A series of new indazol‐3‐ol derivatives was synthesized. Some of these compounds exhibit interesting anti‐inflammatory activities in various models of inflammation. 5‐Methoxy‐1‐[quinoline‐2‐yl‐methoxy)‐benzyl]‐1H‐indazol‐3‐ol (27) strongly inhibits the oxidation of arachidonic acid to 5‐hydroperoxyeicosatetraenoic acid catalyzed by 5‐lipoxygenase (IC50 = 44 nM). 27 also inhibits the contraction of sensitized guinea pig tracheal segments (IC50 = 2.9 μM). In guinea pigs treated with 27 (1 mg/kg i.p.) 2 h before antigen provocation, there was a marked inhibition (47%) of the antigen‐induced airway eosinophilia. After topical application of 1 μg/ear 27 inhibits the arachidonic acid induced mouse ear edema (41%).

Synthesis of dolastatin 15 mimetic peptoids

Eight peptoids have been synthesized as peptidomimetics of the cytostatic Dolastatin 15, a depsipeptide isolated from the Indian sea hare Dolabella auricularia. The compounds have been tested against several human cancer cell lines and did not show any cytostatic properties.

Degradation Products of Cyclophosphamide Synthesis and Structural studies

Abstract The degradation of cyclophosphamide in neutral or slightly acidic aqueous solution starts with an intramolecular alkylation leading to an intermediary bicyclic compound which hydrolyses immediately and exclusively to a nine-membered heterocycle. Subsequent acid-catalyzed hydrolysis of the P-N-bond leads to a phosphoric acid monoester. In strongly acidic solutions (1 N HC1) cyclophosphamide decomposes exclusively to bis(2-chloroethyl)-amine and to the corresponding phosphoric acid monoester H2N(CH2)3OP(O)(OH)2. In solid samples of cyclophosphamide, heated up to its melting point, the first pathway predominates over the second one. The structures of the phosphorus compounds were established by 1H and 31P NMR spectroscopy, and synthesis. The structure of the bicyclic compound 2 is confirmed by a single crystal X-ray diffraction study which allows an explanation for the selective and immediate hydrolysis with formation of a nine-membered heterocycle and for the absence of the isomer with a six-member...

New LHRH antagonists with enhanced biological activity: Preclinical and clinical results

Gonadorelin (GnRH, LHRH) analogs are indispensable drugs for the clinical treatment of sex-hormone dependent tumors, such as breast, ovary and prostate cancer. LHRH agonists and antagonists have also been utilized in various artificial reproduction techniques and have been investigated as potential contraceptives in humans [1]. Over 25 years, thousands of analogs of LHRH, both agonists and antagonists, have been synthesized and evaluated for potential therapeutic benefit. Agonists, e.g. Leuprolide or Goserelin, are well established in medical treatment. They stimulate, initially and for several days, the release of LH and FSH prior to downregulation of the LHRH receptor, causing transiently rising levels of sexual steroid hormones testosterone and estradiol. Third generation antagonists like Cetrorelix, Abarelix, or Ganirelix are under investigation in clinical studies. Cetrorelix itself has been characterized as a safe and potent LHRH antagonist, based on results in a variety of models. Clinical studies indicate that Cetrorelix is a highly effective gonadotropineand subsequently sexsteroid-suppressing agent. Therefore, Cetrorelix has potential for treatment of hormone dependent cancers as well as for non-malignant applications in which a suppression or control of gonadotropins and sex-steroids is desired [2]. The advantage of Cetrorelix is that it inhibits LH and testosterone from the beginning of administration and thereby avoids the agonist-induced “flare up effect.” Treatment of prostatic carcinoma and pre-menopausal mammary carcinoma are primary applications. Endometriosis and benign prostate hyperplasia (BPH) also represent also attractive applications for the LHRH antagonist. Cetrorelix (Cetrotide®) has been approved in 1999 by EU authorities for marketing within the European Union for controlled ovulation stimulation for assisted reproduction (COS/ART).

A New Method of Preparation of Ifosfamide and Cyclophosphamide; Synthesis of Side Products

Abstract This study focusses on the preparation of ifosfamide (1; R1=CH2CH2Cl, R2=NHCH2CH2Cl) and cyclophosphamide (2 R1=H, R2=N(CH2CH2Cl)2), standard drugs in tumor therapy, in order to avoid the alkylating educts like 2-chloroethylamine by introducing chlorine in the final reaction step. The reaction of the trimethylsilyl compounds (3; R1=CH2CH2Cl, R2=NHCH2CH20SiMe3) and (4; R1=H, R2=N(CH2CH20SiMe3)2), respectively, with 2-chloro- 1,3,5-trimethyl-1,3,5-triaza-σ3λ3-2-phosphoM-4,6-dione, followed by chlorination of the resulting product with sulphuryl chloride, furnished the cytotoxic drugs (1) and (2) [l].

Highly Diastereoselective Synthesis of Anomeric β-O-Glycopyranosyl σ3λ3-and σ4λ5-Phosphorus Compounds

Abstract A new method for the highly stereoselective synthesis of β-O-σ3λ3 and σ4λ4 phosphorus-substituted 2,3,4,6-tetrabcnzylglucose is presented. The β-diastereoselective synthesis of the carbohydrates containing σ3λ3 and σ4λ5 phosphorus groups could be accomplished via two main synthetic routes. The first involves the addition of the σ3λ3-phosphorus derivative 3 to the 2,3,4,6-tetrabenylglucose derivative 1 (αβ = 1:l) in toluene and triethylamine as a catalyst to provide the σ3λ3 phosphorus derivative 4 with practically 100% β-diastereoselectivity.