Thiophens of Pharmacological Interest

In the field of analgesics, thienomorphans have been synthesized as well as some 6-(2-thenoyl)benzoxazolinones and some thiophen derivatives of 3,8-diazabicyclo[3,2,l]octane. In the field of anti-inflammatory agents, a 

Hisano, M. Ichikawa, A. Nakagawa, and M. Tsuji, Chem. and Pharm. Bull. Japan), 1975, 23, 1910. 

Some aminobenzoic acid diuretics containing the thiophen ring have also been studied. The syntheses and lipid-lowering properties of (203) and (204) have been described. 3-j8-(2-Thienyl-alanine-8-lysine)vasopressine has been synthesized by the solution technique. A comparison of the bioavailability of [2,5- C]thiophen after oral and rectal administration in mice has been reported. The nitro-reduction of carcinogenic 5-nitro-thiophens by rat-tissues has been studied. Thiophen-ring-containing compounds with antiradiation, antidepressant, antiparasitic, antibacterial, - antiviral, and broncho-dilator activity have been studied. A thia-steroid, 14,15-dehydro-A-nor-3-thiaequilenin, has been synthesized. In connection with studies on the syn- 

Thuillier, J. Laforest, B. Cariou, P. Bessin, J. Bonnet, and J. Thuillier, Chim. TMrap., 1974, 9, 625. 

DafgSrd, S. Gronowitz, G. Bondesson, O. Magnusson, and N. E. Stjernstrom, Acta Pharm. Suecica, 1974, 11, 309. 

and NOj. The 4-N-oxide of (225) has also been obtained. C-Annelated thieno-l,4-diazepines (227) have been similarly prepared. The derivative (226 R = 2-Et, R = o-Cl) is probably 

Semisynthetic penicillins containing side-chains related to those in oxacillin and cloxacillin, such as (229)—(232), and to ampicillin, such as (233), have been prepared. In connection with studies on the synthesis and chemistry of cephalosporin antibiotics, thiophen-2-acetic acid is used as side-chain. -  

The compounds (234) have been synthesized as analogues of the antibiotic capillin. New 2-nitrothiophen derivatives having antimicrobial 

Nakanishi, T. Tsumagari, Y. Takigawa, S. Shuto, T. Kenjo, and T. Fukuda, Arzneim.-Forsch., 1972, 22, 1905. 

Szarvasi, L. Fontaine, and A. Betbeder-Matibet, J. Medicin. Chetn., 1973, 16, 281. 

Thiophens of Pharmacological Interest.—Since the beginning of the 1950 s, when thiophen became commercially available at a reasonable price, there has been continued interest in the preparation of pharmacologically active thiophen derivatives. Attempts were often made to prepare analogues of pharmacologically active benzene derivatives, applying the principle of isosterism. This approach has only had limited success. During recent years, however, thiophen derivatives with superior activity have been found, and increased activity may be noted in this field. 

New anthelmintic agents which are already in use in veterinary medicine have been found in two cyclic amidine derivatives, pyrantel tartrate (Banminth, Strongid) (269) and morantel tartrate (Banminth II) (270). For references concerning their evaluation in sheep, cattle, pigs, horses, dogs, and man see Ref. 260. These compounds are most probably prepared by condensation of the appropriate thiophen aldehyde with 1,4,5,6-tetra-hydro-l,2-dimethylpyrimidine. Extensive investigations on structure- 

Schauer, M. Japelj, M. Globokar, M. Oklobdiija, A. PovSe, and V. Sunjid,/. Medicin, Chem., 1970, 13, 159. 

Vejdelek, M. Rajsner, E. Svatek, J. Holubek, and M. Protiva, Collect. Czech. Chem. Commun.. 1979, 44, 3604. 

Dihydrothienocoumarins that have analgesic activity without anti-inflammatory activity have been synthesized. Compounds of type (154), with antibacterial, antifungal, and other activities, have been synthesized. Some NN N -trisubstituted guanidines that contain thiophen rings and have anti-inflammatory properties have been synthesized. Nitrosation of methapyrilene in vitro has been studied. 

Starting from (155), 3-carboxyceph-3-enes have been prepared.Thiophen-2-acetic and thiophen-2-carboxylic acid derivatives have been used 

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Thiophens of Pharmacological Interest. - There has been an almost explosive development in the number of papers and patents in this field, and the space that is available allows only a very brief summary. However, most references will be included, for the benefit of those interested in this field. 

B. Compounds of Pharmacological Interest During recent years a certain slackening in interest in the preparation of thiophenes for pharmacological studies can be noticed. As an excellent review on the biological activity of thiophenes has recently been published, the latest developments in this field will only briefly be sketched. 

The usefulness of the Gewald reaction for the synthesis of 2-amino-3-carbonyl-substituted thiophens has been amply demonstrated during the past two years (c/. ref. 6fl). These thiophens are very useful starting materials for complex condensed systems of pharmacological interest. I.r. and n.m.r. studies showed some anomalies which were interpreted in terms of electron delocalization in the enaminocarbonyl structure. From cyanoacetamide, benzylacetone, and sulphur, the thiophen (9) was obtained. 3-Aryl-substituted derivatives such as (10) were obtained from the appropriate aryl methyl ketone, ethyl cyanoacetate, and sulphur. It has been claimed that (11) is obtained from the reaction of acetoacetic acid anilide with malononitrile and sulphur. This hardly seems to be correct, as (12) is the product expected in the Gewald reaction. It was found that 2-amino-3-ethoxycarbonyl-thiophens (13) react with sodium ethoxide in ethanol, pre-... 

Interest in dithienylalkanes of potential pharmacological importance was aroused by the discovery that some 3-dialkylamino-l,l-bis(2-thienyl)but-l-enes possess analgesic activity.116 Compounds 91, termed thiambutenes, are prepared by dehydration of carbinols of general formula 92. Considerable variations in the substituents have been made in the search for greater activity and for a reduction in undesirable side effects often, these variants have both analgesic and antitussive properties. Substances with obvious structural similarities to 91 and 92, namely, the thiophene analog of methadone (93) and of isomethadone, have also been prepared.63,107... 

Pyrimidine-fused Systems.—The Gewald synthesis of thiophen analogues of anthranilic acid has opened the synthetic route to pyrimidine-fused thiophens. The interest in this field is mainly due to the potential pharmacological properties of these systems. Condensation of (603) with forma-mide at 200 °C yields (604). Similarly, (605) was prepared from 3-amino-2-methoxycarbonylthiophen or from its formamide derivative. Derivatives of (604) were also obtained by cyclization of the 2-amino-3-carboxamide... 

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