Synthesis of Some New Derivatives of Thiazolo[4,3-b]- and Thiazolo[2,3-b] quinazolone

The new 5H-thiazolo[4,3-b]quinazoline-3,5(1H)-diones 3, 4a–c, 5a–c and 5H-thiazolo[2,3-b]quinazoline-3,5(2H)-diones 9a–c, 11a–c were prepared by reaction of anthranilic acid with the 2-thiazolidinone-4-thione derivatives 1b, 6a–c, 7a–c and the 5-substituted 2-(alkylmercapto)-2-thiazolin-4-ones 8a-c, 10a-c , respectively.     

Benzopyrano[4,3-b]-1,5-benzodiazepines (author's transl)

Benzopyrano[4,3-b]-1,5-benzodiazepines¹⁾ By reaction with an acidic ion exchanger the benzopyrano[4,3-b]-1,5-benzodiazepines 5c – f are obtained from the (o-hydroxyphenyl)(dimethylamino)methylen-1,5-benzodiazepines 4c – f . The o-hydroxyphenyl-1,5-benzodiazepines 3a – d react with acid halides to the O-acyl derivatives 14a–f . With acetic anhydride the N,O-diacetyl derivatives 13a–c are obtained, which can be hydrolysed to the N-acetyl derivatives 15a–b .     

Zur Synthese von [1,2,5]-Triazepino-[3,4,5-jk]- und Pyrazino[3,2,1-jk]carbazol-Derivaten

Synthesis of [1,2,5]-Triazepino[3,4,5-jk]- and Pyrazino[3,2,1-jk]carbazole Derivatives Reaction of the enaminone 2 and p-benzoquinone (1) yields the carbazole 3 , which is used as precursor for the title compounds after methylation to 5b or acetylation to 5a . The nitrones 7a, b are formed from 5a, b and hydroxylamine. The structures of 7a, b are proved by reduction to 9 and 10 and rearrangement to 12 and 13 . The carbazole 5b reacts with hydrazine to yield the [1,2,5]-triazepinocarbazole 8a . The structure of 8a was determined by acetylation to 8b and spectroscopy.     

Synthese von 2,2a,3,4-Tetrahydro[1,2-d]benz[b]-1,4-oxazin-2,4-dionen, 2. Mitt.

Synthesis of 2,2a,3,4,-Tetrahydro[1,2d]benz[b]-1,4-oxazine-2,4-diones, II The diasteromeric 3-amino-β-lactams 7 and 8 were obtained from the azides 5 and 6 and the phthalimido derivatives 9 and 12 . Compound 9 was synthesized directly from 2 by means of phthalimidoacetyl chloride/triethylamine, whereas 12 is accessible from 11 only by the Mitsunobu reaction. Acylation of 7 or 8 (to 13 or 14 ) is followed by hydrolysis of the ester function (to 15 or 16 ) and debenzylation to yield 17 or 18 which are lactonized to 19 or 20 by the action of DCC.     

Synthese von 5H-Pyrido[2,3-c]-2-benzazepinen

Synthesis of 5H-Pyrido[2,3-c]-2-benzazepines The title compounds can be obtained by two differend ways: Ring closure of 2-benzazepine enaminonitrile 1 and the C₂-building blocks 2, 7 and 8 gives rise to the title compounds 6, 9 and 10 . - The second way starts with Wolff-Kishner-reduction of the 2-amino-3-benzoylpyridines 16a,b to the 2-amino-3-benzylpyridines 18a,b . Benzoylation of 18a,b leads to the dibenzoylated compounds 20 and 21 , respectively, which can be transformed to the monobenzoylated pyridines 22 resp. 23 . Applying the Bischler-Napieralski-reaction on 22a,b and 23a,b leads to the 5H-pyrido[2,3-c]-2-benzazepines 24a,b and 25a,b . By means of ¹H-, ¹³C- and ¹⁵N-NMR-data it is demonstrated that ethyl benzoylcyanacetimidate ( 12a ) exists as benzoylketene-O,N-acetal 12a AE .     

Novel Antiinflammatory Analgesics: 3-(2-/4-Pyridylethyl)-Benzoxazolinone and Oxazolo[4,5-β]pyridin-2-one Derivatives

Twenty-two new 3-[2-(2-and/or 4-pyridyl)ethyl]benzoxazolinone and oxazolo[4,5-b]pyridin-2-one derivatives have been synthesized by reacting 2-and/or 4-vinylpyridine and appropriate benzoxazolinones and oxazolo[4,5-b]pyridine-2-one. Their chemical structures have been proven by IR, ¹H-NMR, ¹³C-NMR, mass spectroscopy, and elemental analysis. The analgesic activities of these compounds were investigated by a modified Koster′s Test. Test results revealed that, at 100 mg/kg dose level, most of the compounds showed significant analgesic activities when compared to aspirin. Therefore the compounds were screened for their antiinflammatory activities using the carrageenan hind paw edema test. Compounds 1, 7, 10, 11, 12, 13, 15, 18, 20, 21 were found more active than indomethacine. In gastric ulceration studies gastrointestinal bleeding was not observed at 100 mg/kg dose level in compounds 1 and 2 .     

Synthesis of isotope‐labeled HSP90 inhibitor: [13CD3] and [14C]‐TAK‐459

[¹³CD₃]‐TAK‐459 (1A), an HSP90 inhibitor, was synthesized from [¹³CD₃]‐sodium methoxide in three steps in an overall yield of 29%. The key intermediate [¹³CD₃]‐2‐methoxy‐6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)pyridine was synthesized in two steps from 2,6‐dibromopyridine and stable isotope‐labeled sodium methoxide. [¹⁴C]‐TAK‐459 (1B) was synthesized from [¹⁴C(U)]‐guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [¹⁴C]‐(R)‐2‐amino‐7‐(2‐bromo‐4‐fluorophenyl)‐4‐methyl‐7,8‐dihydropyrido[4,3‐d]pyrimidin‐5(6H)‐one, was prepared by microwave‐assisted condensation.     

Untersuchungen an 1,3-Dicarbonylverbindungen, 14. Mitt. 4-Oxo-4H-[1]benzofuro[3,2-b]pyrane und 4-Oxo-4H[1]benzothieno-[3,2-b]pyrane

1,3-Dicarbonyl Compounds, XIV: 4-Oxo-4H-[1]benzofuro[3,2-b]pyranes and 4-Oxo-4H-[1]benzothieno[3,2-b]pyranes The 1,3-dicarbonyl compounds 1 condense with dialkyl oxalates to form the 1,3,5,6-tetracarbonyl compounds 2 , which hydrolize under mildly alkaline conditions to give the ketocarboxylic acids 3 . Compounds 2 and 3 cyclize on heating with alcohols, saturated with HCl, to yield the alkyl 4-pyrone-2-carboxylates 4 . The acids 5 , obtained from 4 , decarboxylate on heating with quinoline/copper to give the heterocycles 6 . Compound 6b is also obtained from 1b by reaction with N,N-dimethylformamide dimethyl acetal (DMFDMA) and treatment with acid of the product 8b , whereas 1a and DMFDMA give the derivative 7a . Compounds 4 were characterized in the form of their amides 10 . The pyrylium salts 11 were obtained from 6 by reaction with dimethyl sulfate/HClO₄. Compounds 4 and 6 are converted to the thiocarbonyl compounds 12 and 13 by reaction with P₄S₁₀. Condensation of 2 with triethyl orthoformate/acetic anhydride yields the alkyl 4-pyrone-3-ketocarboxylates 14 . Compound 15b , formed by hydrolysis from 14b, afforded the 4-pyrone-3-carboxylic acid 16b by oxidative decarbonylation.     

Synthesis of [3H], [13C215N] and [14C]Sch 66336 (Sarasar™)

[³H]Sch 66336 was prepared at a specific activity of 1.35 Ci/mmol by Ru(Ph₃P)₃Cl₂ catalysed exchange with tritiated water. [¹³CN]Sch 66336 was synthesized from potassium [¹³C]cyanide and [¹³C¹⁵N₂]urea in 29% overall yield from potassium [¹³C]cyanide. [¹⁴C]Sch 66336 was synthesized from potassium [¹⁴C]cyanide in 31% yield. A second synthesis, from N‐Boc‐4‐hydroxy[¹⁴C]piperidine, gave [¹⁴C]Sch 66336 labelled in a different site in 19% overall yield. Copyright © 2004 John Wiley & Sons, Ltd.     

Isochino[3,2-a]phthalazin-5,8-dione

Isoquino[3,2-a]phthalazine-5,8-diones Deoxybenzoin-2,2′-dicarboxylic acid (1) reacts with the hydrazines 4a-d to yield the phthalazinones 8a-d . Heating of 8a in acetic anhydride leads to the isoquino[3,2-a]phthalazinone 9a , which can also be prepared from 2 and 4a via the O, N-acetal 13 . From 1 and 1,2-dimethylhydrazine (4e) the spiro-compound 14 is formed.     

Synthese und pharmakologische Prüfung von 2- und 3-substituierten Pyrano[2,3-b]indolonen

Synthesis and Pharmacological Test of 2- and 3-Substituted Pyrano[2,3-b]indolones . The condensation of oxindole (3a) with ethyl 2-methylacetoacetate (6b) leads to the propionyloxindole 4 . With the acetal esters 6f, 6g and 6h and the cyclic β-ketoesters 12, 13 and 14 the reaction results in the 3-acyloxindoles 7f, 7c , and 7d or 7h and 15a, 15b, 15c . These can be cyclised to the 2- and 3-substituted pyrano[2,3-b]indolones 16a–16c and 17a–17c .     

Synthesis and Biological Activity of New [1,3]Thiazolo[4,5-d]pyridazin-4(5H)-ones

A series of novel 2-(N-pyrrolidino, N-piperidino or N-morpholino)-7-phenyl(α-furoyl or α-thienyl)-[1,3]thiazolo[4,5-d]pyridazinones 10a–c, 14–16a,b was synthesized in 78–87% yields via the reaction of methyl 5-benzoyl(α-furoyl or α-thienyl)-2-aminosubstituted-thiazol-4-carboxylates 9a–c, 13a–e with hydrazine. These new compounds have been tested for their in vivo analgesic and anti-inflammatory activities. All compounds have been characterized by ¹H-NMR, ¹³C-NMR spectroscopy, and liquid chromatography–mass spectrometry.     

2-Amino-2′-[18F]fluorobenzhydrols,intermediates for the synthesis of [2′-18F]-1,4-benzodiazepine-2-ones

A method for synthesizing ¹⁸F-labelled 2-amino-2′-fluorobenzhydrols under nocarrier-added conditions for use as radiolabelled intermediates in the synthesis of[2′-¹⁸F]-1,4-benzodiazepine-2-ones is presented. Anilinodichloroborane reagents were formed by the reaction of boron trichloride with 4-chloro-N-methylaniline, 6a , 4-nitro-N-methylaniline, 6b , 4-nitro-N-ethylaniline, 6c , and 4-chloro-N-(2,2,2-trifluoroethyl)aniline, 6d . 2-[¹⁸F]Fluorobenzaldehyde, 5 , synthesized in 55–70% yields by the nucleophilic aromatic substitution of 2-nitrobenzaldehyde with the Kryptofix/K⁺ complex of [¹⁸F]F⁻, was subsequently reacted with the anilinodichloroborane coupling reagents with aromatic substitution occurring ortho to the amino group. The resulting 2-amino-2′-[¹⁸F]fluorobenzhydrols, 7a - 7d , were produced in conversions of 60–95% with reaction time ⩽ 10 min at room temperature or 60°C, depending on the aniline used. The total synthesis time, including evaporation of the target water, was 60–65 min. The total radiochemical conversions were of the order of 50–65% for 7a - 7c and 35–45% for 7d , decay-corrected and based on [¹⁸F]F⁻.     

Synthesis characterization and biological evaluation of some alkoxyphthalimide derivatives of 3-(4-substituted phenyl)-6,6-diphenyl-3,3a-dihydro-2H-imidazo[2,1-b]pyrazolo[3,4-d][1,3]thiazol-7(6H)-one

A series of 2-N-ethoxyphthalimido 3-(4-substitutedphenyl)-6,6-diphenyl-3,3a-dihydro-2H-imidazo[2,1-b]pyrazolo[3,4-d][1,3]thiazol-7(6H)-one(7a–e) and 4-(4-substituted phenyl)-2-(N-ethoxyphthalimido amino)-7,7-diphenylimidazo[2′,1′:2,3][1,3]thiazolo[4,5-d] pyrimidin-8(7H)-one (9a–e) have been designed and synthesized starting from thiohydentoin (1). The structure of all synthesized compounds has been established by IR, ¹H NMR, ¹³C NMR and mass studies. These compounds have been screened for antimicrobial activities in order to evaluate the possibility of the derivatives to be used as potential chemotherapeutic agents.     

Anellierte Thiopyrone, 4. Mitt.1): Indeno[1,2-b]-, Indolo[3,2,-b]-, [1]Benzofuro[3,2-b]- und [1]Benzothieno[3,2-b]thiopyrone

Fused Thiopyrones, IV: Indeno[1,2-b]-, Indolo[3,2-b]-, [1]Benzofuro[3,2-b]-, and [1]Benzothieno[3,2-b]thiopyrones The thiopyrones 2 are obtained from the corresponding thiopyranones 1 by dehydration with tritylperchlorate or SeO₂. Treatment of the benzofurane 2d with m-chloroperbenzoic acid (mCPBA) yields the thiopyrone-S, S-dioxide 3d. Starting from the benzothienothiopyrone 2e only one product, the thiophene-sulfone 3e , can be isolated.     

Metabolism of the carcinogen 7-methylbenz[c]-acridine in the rat

1. The biliary excretion of radioactivity by adult Wistar rats given i.v. 7-methyl-[7-¹⁴C]benz[c]acridine(¹⁴C-7-MBAC) and [methyl-³H]-7-methylbenz[c]acridine (³H-7-MBAC) (2 mg/kg) was 61% and 48%, respectively, in males in six hours. Females excreted 33% of a 2 mg/kg dose of ³H-7-MBAC in the same time-period.

2. For male rats, the urinary and faecal excretions were about 10% and 61% of the dose of ¹⁴C-7-MBAC, respectively, in seven days. No enterohepatic circulation could be demonstrated in control male rats.

3. The biliary excretion of radioactivity by phenobarbital- and 3-methylcholanthrene-induced male rats given ¹⁴C-7-MBAC was similar to or greater than that of control male rats.

4. The organo-soluble biliary metabolites after β-glucuronidase/arylsulphatase hydrolysis were separated by h.p.l.c., and quantitative metabolite distributions were obtained for induced and control rats by comparison with metabolite standards.

5. The mutagenicity of bilt from carcinogen-dosed control rats was greater than that of equivalent bile from carcinogen-dosed 3-methylcholanthrene-pretreated animals.     

Reaktionen von 2-Amino-imidazo[2,1-b]-1,3,4-thiadiazolen mit Dicarbonsäureestern in Polyphosphorsäure (PPA)

Reactions of 2-Aminoimidazo[2,1-b]-1,3,4-thiazoles with Ethyl Dicarboxylates in Polyphosphoric Acid (PPA) The 2-amino-6-arylimidazo[2,1-b]-1,3,4-thiadiazoles 1d,e cyclise on heating in polyphosphoric acid (PPA) with ethyl malonate or ethyl diethylmalonate to yield the 2-aryl-6,8-dioxodihydro-6H-imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-a] pyrimidines 3d,e or the 7,7-diethyl compounds 4d,e . Compounds 1a – f cyclise in PPA with ethyl succinate or ethyl phthalate to yield the 6-aryl-2-succinimido- or 6-aryl-2-phthalimido-imidazo[2,1-b]-1,3,4-thiadiazoles 5a, b, d-f and 6a – f . Compounds 1d,e were condensed with ethyl oxalate to yield the 2-(ethoxycarbonyl-formylamino)-6-arylimidazo[2,1-b]-1,3,4-thiadiazoles 7d,e. Ethyl levulinate with 1d,e in PPA probably forms 6-aryl-2-(2-methyl-5-oxo-Δ³-pyrrolino)imidazo [2,1-b]-1,3,4-thiadiazoles.     

Differentiation of the structural features of melanotropins important for biological potency and prolonged activity in vitro

Several α-melanotropin (α-MSH) analogues have been synthesized and tested for their melanotropin activities in order to determine the functional importance of certain amino acids near the primary active sequence of α-MSH, H-(Glu)-His-Phe-Arg-Trp-Gly-OH, on the biological activities of the hormone. In particular, we have examined the importance of the 4 and 11 positions in conjunction with the substitution of l -Phe in position 7 by d -Phe on potency and prolonged activity of the hormone. In the frog (Rana pipiens) skin system the relative potencies were found to be: [Nle⁴, d -Phe⁷]-α-MSH (60) > α-MSH (1.0) > Ac-[Nle⁴, d -Phe⁷]-α-MSH_4–11-NH₂ (0.16) > Ac-[Nle⁴, d -Phe⁷]-α-MSH_4–10-NH₂ (0.02) · Ac-[d -Phe⁷]-α-MSH_5–11-NH₂ (0.01) > Ac-[Nle⁴]-α-MSH_4–10-NH₂ (0.002) = Ac-[Nle⁴]-α-MSH_4–11-NH₂ > Ac-α-MSH_4–10-NH₂ (0.0003) · Ac-α-MSH_5–11-NH₂ (0.0002). On the other hand the relative potencies on the lizard (Anolis carolinensis) skin system were found to be: Ac-[Nle⁴, d -Phe⁷]-α-MSH_4–10-NH₂ (10) · Ac-[Nle⁴, d -Phe⁷]-α-MSH_4–11-NH₂ (8.0) · Ac-[Nle⁴, d -Phe⁷]-α-MSH (5.0) > α-MSH (1.0) = Ac-[Nle⁴]-α-MSH_4–11-NH₂ = Ac-[d -Phe⁷]-α-MSH_5–11-NH₂ > Ac-[Nle⁴]-α-MSH_4–10-NH₂ (0.06) > Ac-α-MSH_5–11-NH₂ (0.01) > Ac-α-MSH_4–10-NH₂ (0.004). Detailed analyses of these data suggest species-dependent differences in the stereostructural relationships of the residues in the 4, 7, and 11 positions for melanotropic potency in vitro. Particularly noteworthy is the observation that the 4–11 fragment analogue Ac-[Nle⁴]-α-MSH_4–11-NH₂ is equipotent to α-MSH in the lizard assay system, suggesting that the 1–3, 12, and 13 residues of α-MSH are not involved in the binding or transduction in this system. Examination of the ability of these α-melanotropin analogues to effect sustained biological activity (prolongation) following removal of exogenous peptide from the bioassay medium showed striking differences in the two systems. On the lizard skin assay, only [Nle⁴, d -Phe⁷]-α-MSH, Ac-[Nle⁴, d -Phe⁷]-α-MSH_4–11-NH₂ and Ac-[Nle⁴, d -Phe⁷]-α-MSH_4–10-NH₂ effect marked prolonged melanotropic activity as compared to α-MSH. In contrast, on the frog skin assay, only [Nle⁴, d -Phe⁷]-α-MSH, Ac-[Nle⁴, d -Phe⁷]-α-MSH_4–11-NH₂, Ac-α-MSH_5–11-NH₂, and Ac-[Nle⁴]-α-MSH_4–10-NH₂ exhibited significant prolonged activity. These results demonstrate that relative potency and prolongation of melanotropic activity are not directly related, but rather are the manifestation of different, species-dependent structural and topographical requirements for peptide-receptor interactions related to binding and signal transduction.     

A gram‐scale synthesis of [3,4‐13C2,1α,7‐2H2]cortisone

A gram‐scale synthesis of [3,4‐¹³C₂,1α,7‐²H₂]cortisone from prednisone was developed. The deuterium atom at the C‐1 position was introduced through a regioselective and stereoselective deuteration of the 1,2‐double bond of the 1,4‐diene‐3‐one using Wilkinson's catalyst. After the oxidative cleavage of the A‐ring, two carbon‐13 atoms were introduced via acetylation of an A‐ring enol lactone with [1,2‐¹³C₂]acetyl chloride. The steroidal A‐ring was then reconstructed to incorporate the carbon‐13 atoms into the C‐3 and C‐4 positions. The deuterium atom at C‐7 was introduced through a regioselective deuteration of the 6,7‐double bond of a 4,6‐diene‐3‐one intermediate using palladium on strontium carbonate. The M + 4 stable isotope labeled cortisone was thus prepared in ca. 4% overall yield. In addition, [3,4‐¹³C₂,1α,7‐²H₂]‐11‐dehydrocorticosterone, [3,4‐¹³C₂,1α,7‐²H₂]cortisol, and [3,4‐¹³C₂,1α,7‐²H₂]corticosterone were also prepared. Copyright © 2011 John Wiley & Sons, Ltd.     

Biological and conformational studies of [Val4]morphiceptin and [D-Val4]morphiceptin analogs incorporating cis-2-aminocyclopentane carboxylic acid as a peptidomimetic for proline

We report the synthesis, biological activity, and conformational analysis of tetrapeptide analogs related to [Val⁴] morphiceptin and [d -Val⁴]morphiceptin in which the proline at the second position has been replaced with cw-2-aminocyclopentane carboxylic acid (cis-2-Ac⁵c). Since the cis-2-Ac⁵c residue contains a normal amide, only the trans form has been observed about the amide bond between the first and second residues. The cis-2-Ac⁵c is a β amino acid with two chiral centers resulting in two possible configurational isomers, namely (1s, 2R) and (1R, 2S) forms. The analogs containing the (1s, 2R)-Ac⁵c residue show activity at the μ-receptor but are inactive at the δ-receptor, resulting in a high selectivity for the μ-receptor. The (1R, 2S)-Ac⁵c containing analogs are completely inactive at both the μ- and δ-receptors. The conformational analysis indicates that the separation of the aromatic rings of the tyrosine and phenylalanine residues, as expressed by the center-to-center distance, is 10.1-12.7 Å for the preferred conformations of the bioactive analogs containing the (1S, 2R)-Ac⁵c residue while a range of 4.8-7.0 Å is observed for the preferred conformations of the inactive analogs with the (1R, 2S)-Ac⁵c residue. A comparison of the findings from the conformational analysis and biological assays establishes the fact that a relatively large separation of the two aromatic side chains is required for the μ-opioid receptor activity of these molecules. Since the tetrapeptide amides studied in this investigation show similar biological profiles to those of the morphiceptin-related analogs, we have compared the preferred conformations estimated for the cis-2-Ac⁵c containing analogs with those of morphiceptin. One of the low energy conformations calculated for morphiceptin with the cis form about the tyrosine and proline residues has considerable topological similarity with the bioactive analogs containing the (1S, 2R)-Ac⁵c residue, indicating that the cis from about these two residues is required for the biological activity of the morphiceptin-related analogs containing the proline at the second position.