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At least 19 recordsLinked to original sources
PubMed1983

1H-2-benzopyran-1-one derivatives, microbial products with pharmacological activity. Relationship between structure and activity in 6-[[1(S)-(3(S),4- dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]-amino]-4(S), 5(S)-dihydroxy-6-oxo-3(S)-ammoniohexanoate.

In order to investigate the structural requirements for gastroprotective activity in 6-[[1(S)-(3(S),4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-4(S),5(S)-dihydroxy 6-oxo-3(S)-ammoniohexanoate [AI-77-B, 1], a product of Bacillus pumilus AI-77, nine derivatives were prepared and then tested for protective activity against stress-induced ulcers in rats. Neither the chromophore, [1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]ammonium chloride (2), nor the side-chain moiety, 4-amino-2,3-dihydroxyhexanedioic acid (4), as separate fragments alone showed any significant activity. Hydrolysis of the lactone ring of the 1H-2-benzopyran-1-one skeleton, to give 6-[[1-(2-carboxy-3-hydroxyphenyl)-2-hydroxy-5-methylhex-3-yl]amino]-4, 5-dihydroxy-6-oxo-3-ammoniohexanoate (5), led to a considerable decrease in activity. The formation of a gamma-lactone ring in the side chain, 4-[1-hydroxy-2-[[1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl) -3-methylbutyl]-amino]-2-oxoethyl]butan-4-olid-3-yl]ammonium chloride (6), resulted in a small decrease in activity. Selective acetylation at the primary amine position of 6, to give 4-[1-hydroxy-2- [[1-(3,4-dihydro-8- hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-2-oxoethyl]-3- (acetylamino)butan-4-olide (7), led to a considerable decrease in activity. Both di- and triacetylated derivatives of 6, 4-[1-acetoxy-2 -[[1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl] amino]-2-oxoethyl]-3-(acetylamino)butan-4-olide (8) and 4-[1-acetoxy-2- [[1-(3,4- dihydro-8-acetoxy-1-oxo-1H-2-benzopyran-3-yl)-3-methylbutyl]amino]-2- oxoethyl]-3-(acetylamino)butan-4-olide (9), were inactive. Selective methylation of the phenolic hydroxyl group of to give 1, 6-[[1-(3,4-dihydro-8-methoxy-1-oxo-1H-2-benzopyran-3-yl) -3-methylbutyl]amino]-4,5-dihydroxy-6-oxo-3-ammoniohexanoate (15), resulted in a small decrease in activity. On the other hand, conversion of the carboxyl group of the side chain to an amide, to give [6-[[1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)- 3-methylbutyl]amino]-4,5-dihydroxy-6-oxo-3-hexanamido]ammonium chloride (10), caused a considerable increase in both activity and toxicity. The findings showed that modifications at the position of the amino acid moiety of 1 significantly influenced the activity and that the 1H-2-benzopyran-1-one skeleton was also required for activity to occur.

Animals↗
PubMed1990

Relaxant activity of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans on guinea pig isolated trachealis.

A series of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans related to the potassium channel activator cromakalim have been prepared and evaluated for their relaxant activity in guinea pig isolated tracheal spirals. Several analogues show enhanced relaxant activity relative to cromakalim in this preparation and the rank order of potency for those substituents investigated at C-6 was CF3 greater than CN greater than C2H5 greater than aza greater than or equal to CH3. One compound, trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-7-(trifluor omethyl)-2H- 1-benzopyran-3-ol (24), was resolved into its two enantiomers and the activity was shown to reside essentially in the (+)-isomer, adding further support to the suggestion that the smooth muscle receptor for these potassium channel activators is stereoselective.

Amides↗
PubMed1996

3-amino-3,4-dihydro-2H-1-benzopyran derivatives as 5-HT1A receptor ligands and potential anxiolytic agents. 2. Synthesis and quantitative structure-activity relationship studies of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans].

In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.

Animals↗
PubMed2002

Prevention of lipopolysaccharide-induced apoptosis by (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine, a benzopyran analog, in endothelial cells.

This study describes the antiapoptotic action of (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378), a novel benzopyran analog, in human umbilical vein endothelial cells (HUVECs) in comparison with its acetylated metabolite, (2S,3S,4R)-N"-cyano-N-(6-acetylamino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31612), and with alpha-tocopherol. Exposure of HUVECs to lipopolysaccharide (LPS) (1 microg/ml) induced time- and concentration-dependent cytotoxicity and oligonucleosomal DNA fragmentation. KR-31378, KR-31612, and alpha-tocopherol potently suppressed LPS-induced cell death in association with significant reduction in the intracellular reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha) that are stimulated by LPS. KR-31378 more effectively protected HUVECs from LPS-induced DNA fragmentation and was more effective in peroxyl radical scavenging than alpha-tocopherol. Incubation with LPS markedly decreased the Bcl-2 level, which was totally reversed by KR-31378 and to a lesser degree by KR-31612 and by alpha-tocopherol. In contrast, the greatly increased Bax protein and cytochrome c release stimulated by LPS were markedly suppressed by KR-31378 and by KR-31612, and to a lesser degree by alpha-tocopherol. Taken together, KR-31378 strongly inhibited cell death in HUVECs in association with antiapoptotic effects, which were accompanied by up-regulation of Bcl-2 protein expression and down-regulation of Bax protein and suppression of cytochrome c release. KR-31378 also showed the properties to scavenge the intracellular ROS and peroxyl radicals, and to reduce the TNF-alpha production induced by LPS.

Apoptosis↗
PubMed1992

Differential effects of endothelin-1 on the vasorelaxant properties of benzopyran and non-benzopyran potassium channel openers.

1. The effects of endothelin-1 (ET-1) on the vasorelaxant properties of structurally different potassium channel openers (PCOs), BRL-38227, Ro 31-6930, SDZ PCO 400, EMD-52692, RP-49356 and pinacidil, were studied. 2. All PCOs evoked concentration-related relaxations of ET-1 (10 nM) or KCl (20 mM) contracted rat isolated aortic rings denuded of endothelium. BRL-38227, EMD 52692, SDZ PCO 400 and Ro 31-6930 were 11-42 times less potent in relaxing contractions to ET-1 than KCl. In contrast, this differential potency was not observed with RP-49356 or pinacidil. 3. BRL-38227 (0.06-3.0 microM), RP-49356 (0.3-3.0 microM) and pinacidil (0.3-3.0 microM) displaced KCl concentration-response curves to the right of controls, without modifying the maximum response. A subcontractile concentration of ET-1 (0.1 nM) prevented the inhibitory effects of low concentrations of BRL-38227 (0.06-0.1 microM) on KCl responses, but failed to modify those to RP-49356, pinacidil or high concentrations of BRL-38227 (0.3-3.0 microM). The inhibitory effects of BRL-38227 (0.1 microM) were also not changed by ET-3 (1.0 nM) or angiotensin II (0.1 nM). 4. In anaesthetized spontaneously hypertensive rats (SHR), cumulative bolus intravenous administrations of BRL-38227 (1-1000 micrograms kg-1, i.v.), Ro 31-6930 (1-1000 micrograms kg-1, i.v.), RP-49356 (10-1000 micrograms kg-1, i.v.) or nitrendipine (0.1-30 micrograms kg-1, i.v.) produced dose-dependent falls in diastolic blood pressure (DBP).ET-1 (i.v.) evoked a transient fall in DBP (1 pg kg- = 58 + 1 mmHg) which returnedto pre-administration levels within 4 min.5. Pretreatment of anaesthetized SHR with ET-l (1 pg kg-', i.v.) significantly increased the ED,5 (dose to evoke a 15% fall in DBP) values for BRL-38227 and Ro 31-6930. However, ET-l failed to modify the ED,5 values for RP-49356 or nitrendipine. The ED50 values for all of the vasodilators studied were not modified by ET-1.6. Infusion of BRL-38227 (2 pgkg-'min-', i.v.) or RP-49356 (4 pgkg-'min', i.v.) to anaesthetized SHR evoked dose-related falls in DBP, with a corresponding increase in descending aortic blood flow (DABF) and a decrease in total lower body vascular resistance (TLBVR). Pretreatment with ET-1 (1 ptg kg-', i.v.) significantly attenuated the decreases in DBP and TLBVR observed with low doses of BRL-38227, but not RP-49356 or high doses of BRL-38227. In contrast, ET-3 (3 pig kg-, i.v.) failed to modify the effects of BRL-38227 on DBP or TLBVR.7. In conscious SHR, the fall in DBP to BRL-38227 (30 pgkg-', p.o.) was significantly reduced following ET-1 (1 pig kg-', i.a.) treatment. ET-1 (1 pg kg-', i.a.) pretreatment, however, failed to modify the decrease in DBP induced by an equieffective oral dose of RP-49356 (1001pgkg-1).8. In conclusion, ET-1 selectively attenuated the vasorelaxant effects of the potassium channel opener,BRL-38227 and other substituted benzopyrans. The results are compatible with the hypothesis that benzopyran PCOs and ET-1 have affinity for a site that does not recognise RP-49356 or pinacidil. Thus,ET-l can differentiate between structurally unrelated potassium channel openers. The cardiovascular effects of some, but not all, PCOs might be radically modified in the clinical setting by elevated endogenous levels of ET-1 associated with certain diseased states.

Animals↗
PubMed2002

Neuroprotective effect of (2S,3S,4R)-N"-cyano-N-(6-amino-3, 4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378), a benzopyran analog, against focal ischemic brain damage in rats.

This study shows the preventive effect of KR-31378 [(2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine] against cerebral infarct via antioxidant and antiapoptotic actions evoked by subjecting rats to 2 h of occlusion of the left middle cerebral artery followed by 24 h of reperfusion. The brain infarct zone in the cortex and striatum of the left hemisphere was consistently identified in the cortex and striatum of the left hemisphere. The infarct area was significantly reduced after three intraperitoneal administrations of 10, 30, or 50 mg/kg KR-31378 at 5 min, 4 h, and 8 h after the completion of 2 h of ischemia. Treatment with KR-31378 (30 or 50 mg/kg) significantly reduced the increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells as well as strongly suppressed the laddered feature of DNA fragmentation in the lateral cortical tissue corresponding to the penumbra. The findings of samples from penumbral zone, which showed markedly reduced Bcl-2 protein level and increased Bax protein and cytochrome c release, were wholly reversed by treatment with KR-31378. In conclusion, postischemic treatment with KR-31378 provided significant levels of cortical neuroprotection in association with inhibition of apoptotic cell death through the up-regulation of Bcl-2 expression, and the down-regulation of Bax protein and cytochrome c release.

Animals↗
PubMed2006

7-Hydroxy-6-methoxy-3-[(2-oxo-2H-1-benzopyran-7-yl)oxy]-2H-1-benzopyran-2-one.

The title compound, daphnoretin, C19H12O7, was isolated from the leaves of Stellera chamaejasme L. Two independent molecules are present in the asymmetric unit, with similar conformations. Each of the independent molecules is composed of two chromene systems connected by an ether bridge. The dihedral angles between the mean planes of the two chromene systems are 86.9 (2) and 81.9 (3) degrees. Molecules form chains via hydrogen bonds and adjacent chains are parallel to each other.

Coumarins↗
PubMed1993

Synthesis of potential metabolites of ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-1-propenyl] benzoate.

Potential metabolites of ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-1-propenyl] benzoate were synthesized. The new compounds include ethyl 3-[3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl]crotonate, 3-[3,4-dihydro-4,4-dimethyl-1H-1-benzopyran-6-yl]crotonic acid, 3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-carboxylic acid, 4-[3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl]delta 2-butenolide, ethyl (E)-4-[3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-3-hydroxy-1- propenyl]benzoate, ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-2-propenal] benzoate, and ethyl (E)-4-[2-(3,4-dihydro-4,4-dimethyl-2H-1-benzopyran-6-yl)-2-propenoic+ ++ acid]benzoate. Stereospecific oxidizing reagents and/or conditions were developed for these sensitive systems and include the use of SeO2, Clorox bleach, activated MnO2, and NaClO2 in the presence of resorcinol as a chlorine scavenger.

Benzopyrans↗
PubMed1990

Structure-activity relationship of antiestrogens. Studies on 2,3-diaryl-1-benzopyrans.

A series of 2,3-diaryl-1-benzopyran analogues substituted at position 4 of 2-phenyl with a hydroxy or pyrrolidinoethoxy residue were synthesized as models for (E)-triarylpropenones constrained in the s-trans conformation. The prototypes, belonging to five chemical series, were evaluated for their estrogen receptor affinity and for estrogen agonist-antagonist activities. The 4H-1-benzopyran-4-one, the 2,3-dihydro-4H-1-benzopyran-4-one, the 4H-1-benzopyran, and the 2,3-dihydro-1-benzopyran derivatives were found to be inactive or only marginally activate as receptor ligands or estrogen agonists-antagonists. In the 2H-1-benzopyran category the parent phenol was also inactive whereas the basic ethers 16 and 26 were modest receptor ligands while being quite active as antiestrogens. In a comparative study the benzopyran 16 was found to be more effective antiestrogen than tamoxifen while being as effective as LY-117018. The benzopyrans have thus emerged as a new class of potent antiestrogens.

Animals↗
PubMed2005

Benzopyrans from Curvularia sp., an endophytic fungus associated with Ocotea corymbosa (Lauraceae).

An isolate of Curvularia sp. was obtained from the leaves of Ocotea corymbosa, a native plant of the Brazilian Cerrado. The ethyl acetate extract from culture of this fungus afforded two benzopyran derivatives: (2'S)-2-(propan-2'-ol)-5-hydroxy-benzopyran-4-one (2) and 2,3-dihydro-2-methyl-benzopyran-4,5-diol (4); and two known benzopyrans: 2-methyl-5-methoxy-benzopyran-4-one (1) and (2R)-2,3-dihydro-2-methyl-5-methoxy-benzopyran-4-one (3). The structures of 2 and 4 were established on the basis of comprehensive spectroscopic analysis, mainly using 1D and 2D NMR experiments. The benzopyrans 1 and 2 showed weak in vitro antifungal activity against Cladosporium sphaerospermum and C. cladosporioides. Analyses of the biological activities were also carried out on HeLa (human cervix tumor) and CHO (Chinese hamster ovary) cells, aiming to evaluate their potential effects on mammalian cell line proliferation. Results from both cell lines indicated that compound 2 was able to induce cell proliferation: 70% on HeLa cells and 25% on CHO cells.

Animals↗
PubMed2004

Regio- and diastereoselective insertion of allenes into stable oxapalladacycles with a metal-bonded stereogenic carbon. preparation of contiguously substituted 3,4-dihydro-2H-1-benzopyrans.

Insertion of monosubstituted allenes into stable oxapalladacycle I was studied. The aim of this work was to define steric and electronic parameters of allenes that would allow for a regio- and diastereoselective synthesis of 2,3-disubstituted 3,4-dihydro-2H-1-benzopyrans, which could not be prepared via related catalytic protocols. Allenes with electron-donating alkyl substituents R sterically unencumbered at the C-3 and C-4 carbons reacted with palladacycles I to afford benzopyrans IV in good yields (45-81%), exclusively as cis diastereomers. Less than 10% of the regioisomeric benzopyrans V was detected in the crude reaction mixtures. Methoxy 1,2-propadiene afforded benzopyran IV in 98% yield as the trans diastereomer in 92% de. In contrast, allenes with electron-withdrawing substituents yielded benzopyrans V with an E double bond exclusively. Nonracemic palladacycles featuring a palladium-bonded stereogenic carbon as the only element of asymmetry underwent the allene insertion with 63-93% retention of the stereochemical information, providing benzopyrans IV or V in 40-47% ee. These results demonstrated that O-bonded palladium enolates did not operate as predominant intermediates in the insertion process. The study highlights the configurational stability of carbon-bonded palladium ester enolates, especially notable in systems lacking chiral nonracemic auxiliary ligands.

Alkadienes↗
PubMed2002

[Synthesis and vasorelaxant activities of benzopyran-4-one hydrazone derivatives].

AIM: In search of more potent, less toxic and selective potassium channel openers. METHODS: According to the structure-activity relationships of benzopyran compounds and the features of structures of aprikalim, dofetilide and nifekalant, twenty benzopyran-4-one hydrazone derivatives have been designed and synthesized from 4-cyanophenos through acetylation, Fries rearrangment, cyclization, hydrazone, substitution reaction and so on. The compounds were tested for their vasorelaxant activity in low (30 mmol.L-1) and high (80 mmol.L-1) KCl-induced contraction of rat aorta to identify potential potassium channel openers in vitro. RESULTS: Three series of twenty benzopyran-4-one hydrazone derivatives, nominated N-aminoacetyl-(6-cyano-3,4-dihydrospiro [2H-1-benzopyran-2,1'-cyclohexane]-4)-one hydrazone (I), 2-(6-cyano-3, 4-dihydro-2H-1-benzopyran-4-ylene) hydrazinethiocarboxamide derivatives (II) and N-(2-arylethyl) aminoacetyl-(6-cyano-3,4-dihydro-2H-1-benzopyran)-4-one hydrazone (III), have been synthesized. They (I1-9, II1-4 and III1-7) are new compounds. Their chemical structures were determined by IR, 1HNMR, MS and elemental analysis. The vasorelaxant effects of those novel compounds indicated that some of the compounds have vasorelaxant activities at 1 x 10(-6) mol.L-1. CONCLUSION: The vasorelaxant activities of compounds I9, III2 and III5 in inhibiting low KCl-induced vasocontraction at 1 x 10(-6) mol.L-1 are less potent than the reference compound emakalim. However they are more potent than emakalim to inhibition high concentration KCl-induced vasocontraction at 1 x 10(-5) mol.L-1. It is worthy of further study.

Animals↗
PubMed1996

Cardioselective antiischemic ATP-sensitive potassium channel openers. 4. Structure-activity studies on benzopyranylcyanoguanidines: replacement of the benzopyran portion.

The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac selective antiischemic ATP-sensitive potassium channel (KATP) opener (4) are described. Systematic modification of the benzopyran ring of 4 resulted in the discovery of a structurally simpler acyclic analog (8) with slightly lower antiischemic potency than the lead compound 4. Further structure-activity studies on the acyclic analog 8 provided the 2-phenoxy-3-pyridylurea analog 18 with improved antiischemic potency and selectivity compared to the benzopyran-based compound 4. These data demonstrate that the benzopyran ring of 4 and its congeners is not mandatory for antiischemic activity and cardiac selectivity. The results described in this paper also show that, as for the benzopyran class of compounds, the structure-activity relationships for the antiischemic and vasorelaxant activities of KATP openers are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve KATP opening as their cardioprotective effects are abolished by pretreatment with the KATP blocker glyburide.

Adenosine Triphosphate↗
PubMed1996

Synthesis and selective coronary vasodilatory activity of 3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: novel potassium channel openers.

A variety of compounds having a benzopyran such as levcromakalim generally exhibit potent antihypertensive activity. During extensive investigations aimed toward identifying K+ channel openers having selective coronary vasodilation without potent hypotensive and tachycardiac effects, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol derivatives modified at positions 2, 4, and 6 in the benzopyran ring. Initially, compounds having two methoxymethyl groups at position 2 were found to show a selective effect on coronary blood flow (CoBF) relative to mean arterial pressure (MAP) in anesthetized dogs. To find more potent vasodilators, various benzopyran derivatives modified at position 4 were synthesized and structure-activity relationships were examined by evaluation of the extent and duration of the increase in CoBF in anesthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyridazin-3-yl)amino group at position 4, in addition to the two methoxymethyl groups at position 2, were found to be more potent and to have an improved duration of action. Among these compounds, JTV-506, (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxopyridaz in-3-yl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity for its effect. Administration of this compound (0.03 mg/kg, p.o.) elicited an increase of CoBF without a change of systemic blood pressure and heart rate (HR) in conscious dogs. Further evaluation was performed with respect to (i) the selectivity of its action on the coronary artery versus the aorta and (ii) its effects on MAP, HR, and electrocardiographic ST elevation. As a result, JTV-506 was selected as a potent and selective coronary vasodilator with various pharmacological features favoring clinical development.

Animals↗
PubMed1993

Synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers.

A series of novel spirocyclic benzopyran imidazolones were synthesized as rigid analogues of cromakalim. These compounds cause a dose-dependent membrane hyperpolarization of A10 rat aorta cells. This hyperpolarization was blocked by pretreatment with glyburide, indicating that the spirocyclic benzopyran imidazolones were acting by increasing the open probability of ATP-sensitive potassium channels in A10 cells. Representative compounds also showed potent in vivo activity as hypotensive agents in normotensive rats. Many of the compounds described are much more potent than cromakalim both in vitro and in vivo, with one of the most potent compounds being 2,3-dihydro-2,2-dimethyl-6-nitro-2'-(propylamino)spiro[4H-1-benzopyran- 4,4'-[4H]imidazol]-5'(1'H)-one (5r). It is concluded that the N1' nitrogen of the imidazolone is an effective substitute for the carbonyl oxygen of cromakalim. The rigid spirocyclic ring fusion holds this nitrogen in an optimum orientation relative to the benzopyran ring.

Animals↗