title: Synthesis of novel trifluoromethyl-substituted spiro-[chromeno[4,3-d]pyrimidine-5,1'-cycloalkanes], and evaluation of their analgesic effects in a mouse pain model.
abstract: Herein we report the synthesis of twelve 2,5-substituted 4-(trifluoromethyl)-spirochromeno[4,3-d]pyrimidines (7-10), as well as an evaluation of their analgesic effect in a mouse pain model. The nine new chromeno[4,3-d]pyrimidines (7-9) were synthesized from the cyclocondensation reactions of three 2,2,2-trifluoro-1-(4-methoxyspiro[chromene-2,1'-cycloalkane]-3-yl)ethanones (3) containing 5-, 6- and 7-membered spirocycloalkanes, with some well-known amidine salts (4-6) [NH2CR(NH)]-in which R=Me, Ph, and NH2-at yields of 60-95%. Subsequently, three new 2-(pyrrol-1-yl)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (10) were obtained through a Clauson-Kaas reaction between the respective 2-(amino)-4-(trifluoromethyl)-chromeno[4,3-d]pyrimidines (9) and 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation showed that these 4-(trifluoromethyl)chromeno[4,3-d]pyrimidines (100mg/kg, p.o.) and Ketoprofen (100mg/kg, p.o.) significantly reduced capsaicin-induced spontaneous nociception. Moreover, the 2-pyrrolyl-spirocyclohexane derivative 10b (100 and 300mg/kg, p.o.) had an anti-allodynic effect comparable to Ketoprofen (100 and 300mg/kg, p.o.) in the arthritic pain model, without causing locomotor alterations in the mice. These results suggest that the compound 10b is a promising molecule for new analgesic drugs in the treatment of pathological pain, such as in arthritis.
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil. Electronic address: helio.bonacorso@ufsm.br.
authors.forename: Helio G
authors.initials: HG
authors.lastname: Bonacorso
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil.
authors.forename: Wilian C
authors.initials: WC
authors.lastname: Rosa
authors.affiliation: Laboratório de Neurotoxicidade e Psicofarmacologia, Departamento de Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Oliveira
authors.affiliation: Laboratório de Neurotoxicidade e Psicofarmacologia, Departamento de Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil.
authors.forename: Indiara
authors.initials: I
authors.lastname: Brusco
authors.affiliation: Laboratório de Neurotoxicidade e Psicofarmacologia, Departamento de Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil.
authors.forename: Evelyne S
authors.initials: ES
authors.lastname: Brum
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil.
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Rodrigues
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil.
authors.forename: Clarissa P
authors.initials: CP
authors.lastname: Frizzo
authors.affiliation: Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil.
authors.forename: Nilo
authors.initials: N
authors.lastname: Zanatta
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D001578:Benzopyrans / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D002211:Capsaicin; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007660:Ketoprofen / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*
chemical_list: C000621525:2-(1H-pyrrol-1-yl)-4-(trifluoromethyl)spiro(chromeno(4,3-d)pyrimidine-5,1'-cyclohexane); D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D006575:Heterocyclic Compounds, 3-Ring; D011743:Pyrimidines; D013141:Spiro Compounds; D007660:Ketoprofen; D002211:Capsaicin
keywords: Analgesic effects; Arthritic pain; Chromeno[4,3-d]pyrimidines; Spiro compounds; Trifluoromethyl