Discovery of a Thieno[2,3-d]pyrimidine-2,4-dione Bearing a p-Methoxyureidophenyl Moiety at the 6-Position: A Highly Potent and Orally Bioavailable Non-Peptide Antagonist for the Human Luteinizing Hormone-Releasing Hormone Receptor was written by Sasaki, Satoshi;Cho, Nobuo;Nara, Yoshi;Harada, Masataka;Endo, Satoshi;Suzuki, Nobuhiro;Furuya, Shuichi;Fujino, Masahiko. And the article was included in Journal of Medicinal Chemistry in 2003.Computed Properties of C7H5ClF2 This article mentions the following:
We have previously disclosed the first potent and orally effective non-peptide antagonist for the human LH-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475. Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (I: TAK-013). Compound I showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC50) values of 0.1 and 0.06 nM, resp. Oral administration of I caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, mol. modeling studies indicate that the unique methoxyurea side chain of I preferentially forms an intramol. hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramol. hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of I in monkeys. On the basis of its profile, compound I has been selected as a candidate for clin. trials and it is expected that it will provide a new class of potential therapeutic agents for the clin. treatment of a variety of sex-hormone-dependent diseases. In the experiment, the researchers used many compounds, for example, 2-(Chloromethyl)-1,3-difluorobenzene (cas: 697-73-4Computed Properties of C7H5ClF2).
2-(Chloromethyl)-1,3-difluorobenzene (cas: 697-73-4) belongs to organic chlorides. Chlorination modifies the physical properties of hydrocarbons in several ways. These compounds are typically denser than water due to the higher atomic weight of chlorine versus hydrogen. Alkyl chlorides are versatile building blocks in organic chemistry. While alkyl bromides and iodides are more reactive, alkyl chlorides tend to be less expensive and more readily available.Computed Properties of C7H5ClF2
Referemce:
Chloride – Wikipedia,
Chlorides – an overview | ScienceDirect Topics