Thieno pyrimidine-2,4-diones

The thieno[3,2-d]pyrimidine-2,4-diones were prepared as shown in Scheme 237, and their silyl derivatives were coupled with various acetoxy-methyl ethers in the presence of stannic chloride to give diseco (type 2.1), triseco (type 3.1), and pentaseco benzyl derivatives of type 5.1 nucleosides (94JHC305). 

Townsend and coworkers (80JCS(P1)1853) prepared several ribofuranosyl nucleosides of the thieno[2,3-d]pyrimidine ring system by condensation of the silylated base with l-O-acetyl-2,3,5-tri-0-benzoyl-j3-D-ribofuranose in 1,2-dichloroethane in the presence of tin(IV) chloride (Scheme 101). These nucleosides are analogs of cytidine. Uridine analogs have been prepared from thieno[2,3-rf]pyrimidine-2,4-diones. 

The bis(trimethylisilyl) derivatives 271 resulting from the reaction of thieno[3,2-with hexamethyldisilazane (HMDS) and a catalytic amount of ammonium sulfate were condensed with 1-0-acetyl-2,3,5-tri-0-benzoyl-/3-D-ribofuranose in the presence of stannic chloride to furnish, after treatment with methanolic ammonia, the l-(/3-D-ribofuranosyl)thieno[3,2,-d]pyrimidine-2,4-diones 272 and 3-(/3-d-ribofuranosyl)thieno[3,2-d]pyrimidine-2,4-diones 273. 

The same experimental procedure was used for further N-alkylation reactions of 2,4-bis(trimethylsilyloxo)thieno[3,2-d]pyrimidine-2,4-diones 271. Thus, reaction of 271 with 2-acetoxyethyl acetoxymethyl ether, 2-(acetoxymethoxy)propane-l,3-dibenzoate, and benzyloxymethyl acetate gave the respective 1- and 3-alkylated derivatives 274 and 275, 276 and 277, and 278 and 279 (90MI1 94JHC305 94MI2, 94MI3). ... 

Several thieno[3,2-d]pyrimidine-2,4-diones 267 were evaluated in vitro for their ability to inhibit enzymatic activity on partially purified bovine lens aldose reductase. A high level of in vitro activity was demonstrated (ICjo 10"6 to 4 x 10 8 M) (91JMC1492 93MI1). 

Ogawa et al. (93MI1) obtained 3-(4-bromo-2-fluorobenzyl)thieno[3,4-d]pyrimidine-2(lH),4-dione 303 from o-aminoester 292 (R = Et) in two steps. The latter was reacted gradually from 5°C to 70°C with trichloro-... 

Two synthetic routes for 3-[4-[4-(2-methoxyphenyl)piperazin-l-yl]butyl]-thieno[3,4-d]pyrimidine-2,4-dione 316 were described by Russell et al. (90JHC1761). Carbamate 310a, prepared by treating a mixture of amine hydrochloride 309 and ethyl chloroformate with dilute sodium hydroxide, was reacted with 4-[(2-methoxyphenyl)piperazin-l-yl]butanamine 313 in the presence of trimethylaluminum/toluene. The yield of 316 was a modest 20%. However, when bromobutyl urea 314 was heated with l-(2-methoxyphenyl)piperazine hydrochloride 315 in the presence of sodium bicarbonate and sodium iodide in propan-2-ol, compound 316 was obtained in 84% yield. The first route was also used to synthesize thieno[3,4-d]py-rimidine-2,4-dione 312 in 36% yield from 310a and 4-(2-methoxyphenyl)-1-piperazinethanamine 311. 

Several compounds with various substituents on the piperazine ring of 311, or instead with a substituted piperidine ring, have been patented [89JAP(K)213284]. Thieno[3,4-d]pyrimidin-2,4-dione 318 was synthesized in 91% yield from bromopentyl urea 317 and l-(2-methoxyphenyl)pipera-zine hydrochloride 315 using the second method. In a more recent publication (92SC3221) the same authors report the cyclization of the amide 319 into the thieno[3,4-d]pyrimidine-2(l//),4-dione 320 using methanolic sodium hydroxide. 

Heating carbamate 310a with ethanolamine gave 3-(2-hydroxyethyl) thieno[3,4-d]pyrimidine-2(l//),4(3//)-dione 333a. The 3-(2-hydroxypro-... 

The hydroxy group of l-(2-hydroxyethyl)thieno[3,4-d]pyrimidine-2,4(3//)-dione 344 was chlorinated with thionyl chloride in a mixture of pyridine and chloroform, or mesylated with methanesulfonyl chloride in pyridine. No ring chlorination was observed under these conditions. The resulting l-(2-chloro or 2-methanesulfonylethyl) derivative 365 was cyclized to l,2-dihydrooxazolo[2,3-6]thieno[3,4-d]pyrimidin-5-one 366 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (89H985). A similar transformation of 3-(2-hydroxyethyl)thieno[3,4-d]pyrimidine-2(l//),4-diones 333a,b into the 3-(2-chloroethyl) derivatives 367 with thionyl chloride occurred in chlo-... 

Substituted thieno[3,4-d]pyrimidine-2(l//),4-diones 306 and 312 were alkylated at position 1 with alkyl halides, in DMF, DMSO or THF, in the presence of sodium hydride (87USP4670560 88JMC1786 90JHC1761 91 Mil). The alkylation of compound 303 with ethyl bromoacetate in DMF in the presence of sodium hydride produced derivative 381 (93MI1). Alkylation of N-3-protected thieno[3,4-d]pyrimidine 320 with l-bromo-2-chloroethane in dimethyl sulfoxide containing sodium hydride, afforded 1 -(2-chloroethyl)-3-(2,4-dime thoxyphenylmethyl)thieno [3,4-d] pyrimidine-... 

Thieno[3,4-d]pyrimidine-2(l//),4-dione 312 exhibited potent oral antihypertensive activity in spontaneously hypertensive rats (SHR) with a 0.21 mg/kg dose required for reducing systolic blood pressure (SBP) by 50 mm Hg (ED50sbp)- The ED50 value is 10.4 mg/kg (88JMC1786). 

A method for inhibiting IL-2 transcription using thieno[2,3d]pyrimidine-2,4(lH,3H)-dione derivatives for the treatment of skin-related disorders is described. 

Preparation of l-(2-methylpropyl)-6-(l-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(lH,3H)-dione... 

Table 1 Selected thieno[2,3-d]pyrimidine-2,4( 1 H,3H)-dione derivatives and their corresponding physical data. When evaluated for their effectiveness as IL-2 inhibitors using the human mixed lymphocyte reaction assay, all experimental agents had IC50 values less than 1 x 10 6M...

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