Chemotherapeutic agents. XVI [1]. Synthesis of Pyrimidines and fused pyrimidines as leishmanicides

Various mono and bicyclic pyrimidine analogs ( 3–15 ) were prepared as leishmanicides from 6-aryl-4-chloro-2-methylthiopyrimidine-5-carbonitrile ( 2 ), obtained from the halogenation of 6-aryl-3,4-dihydro-2-methylthio-4-oxopyrimidine-6-carbonitrile ( 1 ).     

Amino-thieno[2,3–c]pyrazole und Amino-thieno[2,3–b]pyrrole

Amino-thieno[2,3–c]pyrazoles and Amino-thieno[2,3–b]pyrroles The synthesis of thieno[2,3–c]pyrazoles and thieno[2,3–b]pyrroles is described. From the dithioliumsalt ( 1 ) and potassium hydroxide the potassium-(2,2-dicyan-1-methylthio-ethen-1-yl)-thiolate ( 2 ) is formed. This reacts with hydrazine hydrate to form the 3-amino-5-thioxo-pyrazol-4-carbonitrile ( 3 ) S-Alkylation with α-chlorocarbonyl compounds yielding ( 6a–c ) leads via Thorpe-Ziegler-cyclization to 3,4-diamino-thieno[2,3–c]pyrazoles ( 9 ) if the position 1 is alkylated ( 8 ). Acetyl acetone yields 2-mercapto-pyrazolo[1,5–a]pyrimidine ( 5 ). After S-alkylation ( 10a–d ) are immediately cyclized to thieno [2′,3′:3,4]pyrazolo[1,5-a]pyrimidine ( 11a–d ). The ketone ( 6a ) can be cyclized to the pyrazolo [5,1–b]thiazole ( 12 ). 3 reacts with oxalyl chloride to form the 2,3-dioxo-6-thioxo-imidazo[1,2-b]pyrazole ( 13 ) of which S-phenacyl derivative ( 14 ) because the NH-proton cannot be cyclized. The 5-amino-3,4-dicyano-pyrrol-2-thiolate ( 16 ) shows the analogous behaviour. The S-alkylation is followed by cyclization, and 3,5-diamino-thieno[2,3–b]pyrroles ( 18a–b ) arise. Reaction of 5-amino-2-alkylthio-pyrrol-3,5-dicarbonitrile ( 17 ) with acetyl acetone provides pyrrolo[1,2-a]pyrimidine ( 20a–c ) which can be cyclized to form thieno[3′,2′:4,6]pyrimidines ( 21a–c ) very easily.     

Orthoamide. LI. Push-Pull-Butadiene und Heterocyclen aus CH2-aciden Verbindungen und Orthoamiden von Alkincarbonsäuren

Orthoamides. LI. Push-Pull-Butadienes and Heterocycles from Alkyne Carboxylic Acid Orthoamides and CH₂-acidic Compounds The acetylides 4b, 4f react with N,N,N′,N′,N″,N″-hexamethylguanidiniumchloride ( 5 ) to give the orthoamides 6b, 6f , resp. From CH₂-acidic compounds and the orthoamides 6a, c, e can be obtained the push-pull-substituted butadienes 8a–8aj . The 2,3,5-trimethyl-thiadiazolium salt 9 does not condense with 6e , as other CH₂-acidic compounds do, instead the vinylogous guanidinium salt 10a is produced. On heating, the ketenaminals 8d, aa cyclize to give the pyridone-carbonitriles 11a, b , resp. From 4-amino-coumarins 12 and the orthocarboxylic acid amideacetals 13a, b and the ketenaminal 16 resp., the amidines 14a–c and the heterocyclic compounds 15a–c resp., are formed. The enamines 17a–c, 19a, b react with the orthoamides 6a–f to give the pyridine derivatives 18a–1, 20a–h and 21a, b , resp. Analogously, from 6-aminouracil 22 and 6a, b, e, f are formed the pure 7-dimethylaminopyrido[2,3-d] pyrimidines 23a, b or mixtures of compounds 23c, d and the isomeric 4-dimethylamino-pyrido[2,3-d]pyrimidines 24a, b resp., which can be separated via their salts 25a,b/26a,b . The heterocyclic compounds 30a–d, 32a,b can be prepared from the pyrazole derivatives 28, 31 resp. and the orthoamides 6a–f .     

Synthesis of some new spiroheterocyclic pyrylium salts related to 1-oxa-4-thiaspiro[4.4] nonan-2-one and/or [4.5]decan-2-one as antimicrobial agents

1-Oxa-4-thiaspiro[4.4]nonan-2-one ( 1a ) and/or 1-oxa-4-thiaspiro[4.5] decan-2-one ( 1b ) were reacted with aniline and/or p-chloroaniline to afford the corresponding spirothiazolidinones ( 2a–d ). Reaction of 2a–d with chalcones gave 2-(α – paracylbenzyl)-4-aryl-1-thia-4-azaspiro[4.4]nonan-3-one and 2-(α-aracylbenzyl)-4-aryl-1-thia-4-azaspiro[4.5]decan-3-one ( 3a–p ) respectively. Compounds 3a–p were reacted with acetic anhydride and perchloric acid to yield the spiropyrano[2,3-d]thiazol[4]ium perchlorate derivatives 4a–p . The structures of the synthesized compounds were elucidated by elemental and spectroscopic ( IR and ¹H-NMR) analysis. All the prepared compounds were tested for their antimicrobial activities in comparison with tetracyclic as a reference compound.     

5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-芳磺酸酯新型化合物的合成及生物活性

三唑类化合物具有广泛的生物活性。以2-羟基-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶为原料,在缚酸剂存在下,于室温分别和苯磺酰氯、对甲苯磺酰氯进行酯化反应,合成了两个新型的5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-芳磺酸酯化合物a和b。产物经质谱、红外光谱、核磁共振谱确证。初步生物活性表明,该化合物具有一定的杀菌活性和除草活性,其中a有较高除草活性,而b对禾本科植物有较好的促进生长活性。     

Orthoamide. L. Beiträge zur Chemie von Propiolaldehydaminalen – Synthesen und Umsetzungen zu Push–Pull-substituierten Buta-1,3-dienen,Cyclobutanen sowie vinylogen Amidiniumsalzen und 1,2,3-Triazolen

Orthoamides. L. Contribution to the Chemistry of Propiolaldehydaminales – Synthesis and Transformations to Push–Pull-substituted Buta-1,3-dienes, Cyclobutanes, Vinylogous Amidinium Salts and 1,2,3-Triazoles Tert-butylaminalester 5 reacts with terminal alkynes to give aminals of substituted propiolaldehydes 3c, d . The aminal 3a is accessible from N,N,N′,N′-tetramethylformamidinium chloride (7b) and sodium acetylide. The aminals 3b,c can also be prepared from bis(dimethylamino)acetonitrile 8 and terminal alkynes in the presence of sodium hydride. The nitrile 8 is also useful for the preparation of the bis-aminal of acetylenedialdehyde 6 . The aminal 3e can be transaminated by heating with secondary amines to give the aminals 3f–i . The aminals 3a–i react with strong CH₂-acidic compounds (pK_a between 9 and 14) to give the 1-dialkylamino-1,3-butadienes 10 . The isomeric 1-dialkylamino-butadienes 18 can be obtained from the condensation of the CH-acidic cinnamic acid derivatives 19 with dimethylformamidedimethylacetal. CH and NH-acidic compounds as cyanacetamide react with the aminals 3c,e exclusively with the acidic methylene group to produce the enamines 10h,t . The acylformamidine 21 can be obtained from 10t and tert-butylaminalester 5 . The pyridone 22 is accessible from the condensation product 10h by thermal cyclization. The pyrido[2,3-d]pyrimidine 26 is formed in the reaction of the 6-amino-uracile 23 with the aminal 3a . In an unexpected reaction the 1,2-bis(cyano-dialkylaminomethylene)-cyclobutanes 28a–d result from the action of trimethylsilylcyanide on the aminals 3e–h . The corresponding reaction with trimethylsilylisothiocyanate affords the vinylogous amidinium thiocyanates 34a, b . In the reaction of trimethylsilylazide and the aminals 3 are produced the 4-(dialkylaminomethylene)-4H-1,2,3-triazoles 38 .     

A Series of 18F‐Labelled Pyridinylphenyl Amides as Subtype‐Selective Radioligands for the Dopamine D3 Receptor

Synthesis, biological activity, and structure–selectivity relationship (SSR) studies of a novel series of potential dopamine D3 receptor radioligands as imaging agents for positron emission tomography (PET) are reported. Considering a structurally diverse library of D3 ligands, SSR studies were performed for a new series of fluorinated pyridinylphenyl amides using CoMFA and CoMSIA methods. The in vitro D3 affinities of the predicted series of biphenyl amide ligands 9 a – d revealed single‐digit to sub‐nanomolar potencies (K_i=0.52–1.6 nM ), displaying excellent D3 selectivity over the D2 subtype of 110‐ to 210‐fold for the test compounds 9 a – c . Radiofluorination by nucleophilic substitution of Br or NO₂ by ¹⁸F led to radiochemical yields of 66–92 % for [¹⁸F] 9 a – d . However, the specific activities of [¹⁸F] 9 b and [¹⁸F] 9 d were insufficient, rendering their use for in vivo studies impossible. Biodistribution studies of [¹⁸F] 9 a and [¹⁸F] 9 c using rat brain autoradiography revealed accumulation in the ventricles, thus indicating insufficient biokinetic properties of [¹⁸F] 9 a and [¹⁸F] 9 c for D3 receptor imaging in vivo.     

Synthesis and antimicrobial activity of certain novel monomethine cyanine dyes

A series of novel monomethine cyanine dyes were synthesized by using 3-methyl-5-substituted-1-phenyl-pyrano[2,3-c]pyrazole derivatives 2a–c. Reaction of equimolar ratios of 2a–c with 2(4)-methyl heterocyclic quaternary salts afforded the corresponding monomethine cyanines 3a–c. Reaction of compound 5 with 2(4)-methyl heterocyclic quaternary salts gives monomethine 6a–c. Condensation reaction of equimolar ratios of compounds 7 and 9a,b with 2(4)-methyl heterocyclic quaternary salts afforded the corresponding monomethine cyanines 8a–c and 10a,b respectively. The new synthesized monomethine cyanine dyes were identified by elemental analyses, IR, ¹H-NMR and Ms spectral data. The electronic absorption spectra in ethanolic solution of novel monomethine cyanine dyes were measured and the antimicrobial activity of some selected monomethine cyanine dyes was discussed.     

A New Entry for Short and Regioselective Synthesis of [1,2,4]Triazolo[4,3‐b][1,2,4]‐triazin‐7(1H)‐ones

Reaction of benzenediazonium chloride with active [1,2,4]triazin‐3‐ylthio‐methylene compounds 3 afforded the azo coupling products 5 , which yielded [1,2,4]triazolo[4,3‐b][1,2,4]triazin‐7(1H)‐ones 8 upon treatment with sodium ethoxide in ethanol. The latter products 8 were characterized on the basis of alternate synthesis and spectral data. The mechanism of formation of 8 and the regiochemistry of the studied reactions are discussed.     

6-Substituted pyrrolo[3,4-c]pyrazoles: an improved class of CDK2 inhibitors

We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma.     

4,6-二甲氧基嘧啶衍生物的合成及生物活性测定

以4,6-二甲氧基-2-甲基磺酰基嘧啶为起始原料,采用中间体衍生化方法,合成了三类嘧啶类化合物.应用氢核磁共振、红外和元素分析验证了所合成化合物的结构.生物活性测试结果显示大部分化合物具有杀菌活性,其中化合物8在25 mg/L质量浓度下对水稻稻瘟病的抑制率达100%,化合物10c在400 mg/L质量浓度下对黄瓜霜霉病具有100%的防效.部分化合物具有一定的除草活性.     

A New Access to Piperidino-cyclopiperidinecarboxamides – constrained analogues of a pharmaceutical used diaminic building block

6-Piperidino-3-azabicyclo[3.1.0]hexane-6-carboxamide diastereomers 1a and 2a represent conformationally rigid analogues of 3a which is a building block in some pharmaceutical compounds. A new access to these compounds 1a and 2a was found via the cleavage of bicyclic N,N-acetal 6 with hydrocyanic acid as the stereodetermining step. Reaction of derivatives 1a and 2a with bromodiphenyl-butyronitrile 14 gave cyclopiritramide isomers 1c and 2c , respectively. Qualitative preliminary investigations showed different affinities of 1c and 2c to the opiate-μ receptor. These results were discussed on the basis of an X-ray structural analysis of cyclopiritramide isomer 2c . 1-Benzylcyclopiperidine derivatives 1d and 2d were used as model systems for studying the conformation of cyclopiritramide isomer 1c and 2c , respectively.     

Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry – Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

Recent advances in the field of ring‐expansion chemistry, involving 1‐azoniabicyclo[n.1.0]alkane scaffolds (bicyclic aziridinium ions) as key transient intermediates, have made it possible to efficiently construct a broad variety of medium‐ and large‐sized functionalized nitrogen‐containing heterocycles. In this tutorial review, a comprehensive survey of all pathways leading to the generation of 1‐azoniabicyclo[n.1.0]alkanes is provided, as well as a discussion on their subsequent ring expansions to relevant azaheterocycles governed by ring size, substitution pattern, and/or nature of applied nucleophiles.

     

Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E2 Production: Increasing Aqueous Solubility

Water solubility is one of the key features of potential therapeutic agents. In order to enhance the low water solubility of the parent 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine, a potent inhibitor of prostaglandin E₂ (PGE₂) production, we synthesized and evaluated a new series of derivatives in which the butyl group at the C5 position of the pyrimidine ring was replaced with a less lipophilic substituent, preferably with a hydrophilic aliphatic moiety. Except for the 5-cyanopyrimidine derivative, all target compounds exhibited increased (2.7–87-fold) water solubility relative to the parent compound. Although nontoxic in mouse peritoneal cells, the prepared compounds were either equipotent or weaker inhibitors of PGE₂ production than the parent compound. The most promising compound from the series was found to be the 5-(2,5,8,11-tetraoxadodecyl)pyrimidine derivative (with three polyethylene glycol units at the C5 position), which exhibited 32-fold higher water solubility and only slightly weaker inhibitory activity (22 % of remaining PGE₂ production) compared with the parent compound (15 % of remaining PGE₂ production).     

Synthesis, Structure of Nitrogen-Containing Phosphinogold(I) Ferrocenes. In vitro Activity against Bladder and Colon Carcinoma Cell Lines

The gold salt [(tht)AuCl] was reacted with [1-N,N-dimethylaminométhyl-2-diphenylphosphino]ferrocene (1) forming the bimetallic derivative 4. The reaction of methyl iodide and tetramethylammonium bromide on the chloride 4 produced the ammonium salt 5 and the bromide 6 respectively. New aminophosphines 2 and 3, which represent two of the rare phosphorylated metallocenes containing P(III)-N bond have also been coordinated to gold(I) to form 7 and 8. The presence of the ethoxy group in 7 provides evidence for the lability of one nitrogen-phosphorus bond. The X-ray structure of compounds 4 and 7 have been established. Both crystallize in space group P2₁/c, monoclinic, with a = 11.095(2) Å, b = 12.030(3) Å, c = 17.763(4) Å, β= 94.02(2)∘, Z = 4 for 4 and a = 14.863(3) Å, b = 8.036(5)Å, c = 18.062(5)Å, β =101.64(1)°, Z = 4 for 7. ¹⁹⁷Au Mössbauer data are in good agreement with those for other linear P-Au-Cl containing complexes. The compounds were evaluated for in vitro anti-tumour activity against two human tumours. Differential cytotoxicity was observed with activity comparable to cisplatin, with the exception of one compound which was significantly more cytotoxic.     

Reaction of CH-acidic compounds with thiacumulenes and alkylation with dihaloalkanes

Dithiocarboxylation of CH-acidic compounds 1 and stepwise alkylation of primarily formed dithiolates 2 yielded ketene dithioacetals 5a,b or methylenebis(dithiocarbonates) 12a–c. Reaction of 5a,b with nucleophiles afforded thiophene 7 and dithioacetals 8, 9a,b, 11, respectively. 1,3-Thiazetidines 14a,c,e and thiazolidines 14b,d,f were prepared by thiocarbamoylation of 1b,c,e and subsequent alkylation with dihaloalkanes.     

Reactions with the Arylhydrazones of some α-cyanoketones

Ethereal diazomethane reacts with the arylhydrazones of mesoxalic acid dinitrile 1a–c and of ethyl α-cyanoglyoxalate 2b, d–g to yield the methylarylhydrazones 3a–c and 4a–e respectively. Treatment of 4b–e with phenylmagnesium bromide results in the formation of the imino derivatives 5a–d . Whereas 2a–g react with phenylhydrazine to yield the aminopyrazoles 8a–g , the hydrazides 10a, b are formed on treatment of 4c, e with hydrazine hydrate. 1a–c react with hydrazine hydrate and with phenylhydrazine to yield 3-amino-4-arylhydrazono-5-imino-2-pyrazoline derivatives 11a–f 11a, b react with acrylonitrile to yield 3-amino-1(β-cyanoethyl)-4-arylhydrazono-5-imino-2-pyrazoline derivatives 12a, b which can be readily cyclised to the pyrazolo[3,2-b]pyrimidine derivatives 13a, b by the action of hot acetic acid.     

On the Reaction of Nitrilium Salts with Heterocyclic Nitrones

Nitrilium hexachloroantimonates 1a – c react with pyridine N-oxides 2a , d , f , j , m , o to afford bicyclic 2,3-dihydropyridinium salts 5a – p . The constitution of 5f was secured by an X-ray crystallographic analysis. Compounds 5 proved to be thermally labile (23–82°C) rearranging to 2-acylamino- pyridinium salts 6a , f – i or decomposing to tars. The benzimidazole-3-oxide 7 reacts with nitrilium salts 1a , b to 2-acylaminobenzimidazoles 9a , b . The experimental results as well as AM1 calculations support a mechanism for the reaction of nitrilium cations with heterocyclic nitrones, which has originally been suggested by Abramovitch [25, 26].     

Synthesis and Antimicrobial Evaluation of Some Novel Bis-α,β-Unsaturated Ketones,Nicotinonitrile, 1,2-Dihydropyridine-3-carbonitrile,Fused Thieno[2,3-b]pyridine and Pyrazolo[3,4-b]pyridine Derivatives

The title compounds were prepared by reaction of 1,1′-(5-methyl-1-phenyl-1H-pyrazole-3,4-diyl)diethanone (1) with different aromatic aldehydes 2a–c, namely Furfural (2a), 4-chlorobenzaldehyde (2b) and 4-methoxybenzaldhyde (2c) to yield the corresponding α,β-unsaturated ketones 3a–c. Compound 3 was reacted with malononitrile, 2-cyanoacetamide or 2-cyanothioacetamide yielded the corresponding bis[2-amino-6-(aryl)nicotinonitrile] 4a–c, bis[6-(2-aryl)-2-oxo-1,2-dihydropyridine-3-carbonitrile] 5a–c or bis[6-(2-aryl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile] 6a,b, respectively. The reaction of compound 6a with each of 2-chloro-N-(4-bromophenyl) acetamide (7a), chloroacetamide (7b) in ethanolic sodium ethoxide solution at room temperature to give the corresponding 4,4′-(5-methyl-1-phenyl-1H-pyrazole-3,4-diyl)bis-6-(2-furyl)thieno[2,3-b]pyridine-2-carboxamide] derivatives 9a,b. While compound 6a reacted with hydrazine hydrate yielded the 4,4′-(5-methyl-1-phenyl-1H-pyrazole-3,4-diyl)bis[6-(2-furyl)-1H-pyrazolo[3,4-b]pyridin-3-amine] 11. The structures of the products were elucidated based on their spectral properties, elemental analyses and, wherever possible, by alternate synthesis. Antimicrobial evaluation of the products was carried out.