WO2014003694A1

WO2014003694A1 - Synthesis of thiosemicarbazides and triazoles derived from etodolac

Info

Publication number: WO2014003694A1
Application number: PCT/TR2012/000109
Authority: WO
Inventors: S. Guniz KUCUKGUZEL; Pelin SUZGUN
Original assignee: Individual
Current assignee: Individual
Priority date: 2012-06-25
Filing date: 2012-06-25
Publication date: 2014-01-03
Anticipated expiration: 2014-12-25
Also published as: EP2864334B1; EP2864334A1

Description

DESCRIPTION

SYNTHESIS OF THIOSEMICARBAZIDES AND TRIAZOLES DERIVED FROM ETODOLAC

FIELD OF THE INVENTION

Etodolac (i?,S -2-[l,8-diethyl-l ,3,4-tetrahydrapyrano[3,4-&]indol-l-yl]acetic acid is a non-steroidal antiinflammatory drug which has antitumor activities reported in the literature. In light of this, etodolac was chosen as as a starting compound to synthesize thiosemicarbazides and 1,2,4-triazoles, as etodolac contains carboxylic acid group with the structure of pyrano[3,4-£]indole. Characterization of the compounds synthesized from etodolac, were performed by the help of elemental analysis, UV, FT-IR, 'H-NMR, ¹³C-NMR and HR-MS spectral data while the purities of them were proved with TLC. BACKGROUND OF THE INVENTION

Etodolac (i?,S)-2-[l ,8-diethyl-l ,3,4-tetrahydrapyrano[3,4- )]indol-l-yl]acetic acid is a nonsteroidal antiinflammatory agent with analgesic and antipyretic properties. Etodolac has a stronger inhibitory effect on cyclooxygenase-2 (COX-2) activation. Its mechanism of action is through inhibition of COX with reduction in the synthesis of prostaglandins and other mediators of inflammation and pain. Prostaglandins are thought to play an important role in the proliferation of prostate cancer and are highly expressed in prostate cancer tissue. COX-2 inhibitors such as etodolac, suppress proliferation, induce apoptosis in prostate cancer cells and have no effect in normal prostate stromal cells. Thiosemicarbazides are interesting compounds with essential structural features responsible for various biological activities. Basic cyclisation of thiosemicarbazides yields in 1,2,4-triazoles, which also display a wide range of interesting biological activities. For instance, the search for more effective and less toxic antitumoral drugs, led to the discovery of 1,2,4-triazoles derivatives having antitumoral activity.

Compounds, containing the pyrano[3,4-6]indole scaffold have been reported to exhibit anti-hepatitis C virus (HCV) NS5B polymerase activity. HCV NS5B RNA polymerase has crucial role for replicating the viral RNA genome and is a key target for the development of anti-HCV drugs. Gopalsamy et al. recently identified a novel series of l,3,4,9-tetrahydrapyrano[3,4-&]indole derivatives as potent and selective HCV NS5B inhibitors.

These observations led us to synthesize etodolac derivatives and to investigate their possible anticancer and anti-HCV activities. Structure of the synthesized compounds were confirmed using UV, FT-IR, 'H-NMR, ¹³C-NMR and HR-MS spectral data besides elemental analysis and TLC. DETAILED DESCRIPTION OF THE INVENTION

In this study, (i?,S)-2-[l ,8-diethyl-l ,3,4-tetrahydrapyrano[3,4-6]indol-l-yl]acetic acid (etodolac) that possess analgesic, antipyretic and antiinflammatory activity was chosen as the starting compound to design thiosemicarbazides and l,2,4-triazole-3-thiones derivatives.

We synthesized methyl (l ,8-diethyl-l ,3,4,9-tetrahydropirano[3,4-i>]indol-l -yl) acetate

SGK196 and 2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4- ⁾]indol-l -yl)acetohydrazide SGK197 in our laboratory. SGK 197 and alkyl/aryl isothiocyanates were heated in ethanol to yield original l-[2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-i]indol-l-yl)acetyl]-4-alkyl/aryl thiosemicarbazides [SGK224-230, SGK313]. Alkaline cyclisation of the etodolac thiosemicarbazides using sodium hydroxide afforded the corresponding 5-[(l,8-diethyl- l,3,4,9-tetrahydropyrano[3,4-b]indol-l -yl)methyl]-4-substituted-2,4-dihydro-3H-l,2,4- triazole-3-thiones [SGK238-244, SGK315]. Synthetic route to compounds [SGK224-230, SGK313] and [SGK238-244, SGK315] are shown in Scheme 1. Purity of the synthesized compounds in this study was confirmed by thin layer chromatography and elemental analysis. Characterization of these compounds synthesized from etodolac, were performed by the help of FT-IR, Ή-NMR, ¹³C-NMR and HR-MS spectral data.

In the invention, the isothiocyanates which were used in the stage of obtaining [SGK224-230, SGK313] from [SGK197] are selected from the group including preferably methylisothiocyanate, ethylisothiocyanate, propylisothiocyanate, butylisothiocyanate, benzylisothiocyanate, allyl isothiocyanate, phenyl isothiocyanate and cyclohexylisothiocyanate.

[SGK238-244, SGK 31S]

Scheme 1

Synthesis of methyl (l,8-diethyl-l,3,4,9-tetrahydropirano[3,4-b]indol-l-yl) acetate [SGK 196] (TR 2012/07059)

Etodolac (0.01 mol) and methanol (16 niL) refluxed for 3 h in a few drops of concentrated sulfuric acid. The contents of the flask were subsequently cooled and neutralized by using NaHC03 (5%). The resulting precipitate was filtered, dried and recrystallized twice from ethanol.

Compound [SGK 196]: Yield 66%, m.p. 127-130 °C (rap. 128-130 °C [13, 14] ). IR ( maks, cm^"1): 3379 (NH), 1705 (C=0). *H NMR (400 MHz, DMSO-d₆) δ ppm: 0.83 (3H, t, - CH2-CH3 at Ci); 1.37 (3H, t, -CH₂-CH₃ at C₈); 1.98-2.18 (2H, m, -CH2-CH3 at Ci); 2.73-3.04 (6H, m, -CH2-CH3 at C₈, -CH₂-COOCH₃ at Ci and -CH₂ at C₄); 3.72 (3H, s, -COOCH3); 3.94-4.06 (2H, m, -CH₂ at C₃); 7.01 (1H, d, C₇-H, J=6.8 Hz); 7.06 (1H, t, C₆-H); 7.36 (1H, d, C₅-H, J=7.2 Hz); 9.06 (s, 1H, indole N-H). ¹³C NMR (100 MHz) (DMSO-d TMS) δ ppm: 8.26 (C-12); 14.92 (C-10); 22.34 (C-9); 24.18 (C-4); 31.18 (C-l l); 42.93 (C-13); 5 L68 (- COOCH3); 60.43 (C-3); 75.82 (C-l); 107.83 (C-4a); 115.88 (C-5); 119.32 (C-6); 120.15 (C- 7); 126.47 (C-5a); 127.03 (C-8); 135.01 (C-la); 136.28 (C-8a); 170.52 (C=0). Analysis for C18H23NO3 (301.380). Calcd: C, 71.73; H, 7.69; N, 4.65%. Found: C, 70.85; H, 7.24; N, 4.75%.

Synthesis of 2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)acetohydrazide [SGK 197] (TR 2012/07059)

To methanolic solution of compound [SGK 196] (20 mL, 0.01 mol) was added hydrazine-hydrate (80%, 7 mL) and refluxed for 3 h. The reaction mixture was then cooled, diluted with water and allowed to stand overnight. The precipitated solid was washed with water, dried and recrystallized twice from petroleum ether.

Compound [SGK 197]: Yield 80%, m.p. 186-188 °C. IR (v_max, cm^"1): 3354, 3310 (NH), 1651 (C=0). ^l NMR (400 MHz, DMSO-d*) δ ppm: 0.62 (3H, t, -CH₂-CH.3 at Ci); 1.26 (3H, t, -CH₂-CH3 at C₈); 2.00-2.07 (2H, m, -CH CH₃ at Ci); 2.58-2.86 (6H, m, CH₂- CONHNH₂, -CH2-CH3 at C₈ and -CH₂ at C₄); 3.91-3.97 (2H, m, -CH₂ at C₃); 4.27 (2H, b.s., NH-NH₂); 6.87-7.24 (3H, m, Ar-H); 8.94 (1H, s, NHNH₂); 10.55 (s, 1H, indole N-H). ¹³C- NMR(100 MHz) (DMSO-d TMS) δ ppm: 8.29 (C-12); 14.84 (C-10); 22.42 (C-9); 24.22 (C- 4); 30.85 (C-l ); 42.65 (C-13); 60.29 (C-3); 75.79 (C-l); 107.40 (C-4a); 115.88 (C-6); 119.18 (C-5); 120.06 (C-7); 126.57 (C-5a); 126.94 (C-8); 134.88 (C-l a); 137.32 (C-8a); 169.21 (C=0). Analysis for C17H23N3O2 (301.383). Calcd: C, 67.75; H, 7.69; N, 13.94%>. Found: C, 67.33; H, 6.95; N, 13.73%. Etodolac methyl ester has been previously reported in the literature. This compound which was not original was synthesized using a different method in this study. Etodolac hydrazide, SGK 197 was first reported in this study. In the ^!H NMR spectra of 2-(l,8-diethyl- l,3,4,9-tetrahydropyrano[3,4-6]indole-l-yl) acetohydrazide SGK 197,- singlet signals derived from hydrazide structure appeared at 4.27 ppm (-NHNH₂) and 8.94 ppm (-NHNH₂) showing the integration for two protons and one proton, respectively.

Synthesis of l^-iljS-diethyl-l^^^-tetrahydropyranofS^-bJindol-l-y^acetylJ-^-alkyl/aryl thiosemicarbazides [SGK224-230, SGK313] A solution of 0.01 mol of 2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-6]indole-l- yl)acetohydrazide [SGK197] and equimolar amount of appropriate isothiocyanate in 20 mL of etanol was heated under reflux for 2 h. The precipitate obtained was filtered-off, washed with water and cleaned twice with boiling etanol.

The FT-IR spectra of etodolac thiosemicarbazide derivatives displayed C=0 bands at 1674-1688 cm^"1 and C=S bands at 1 188-1217 cm^"1 In the ^-NMR spectra, all protons were observed accordingly to the expected chemical shift and integral values. For the thiosemicarbazides, the signals of the proton linked to N*,N² and N⁴ nitrogens were shown at 10.48-10.55, 9.58-9.96 and 7.03-9.08 ppm, respectively. In addition, NH protons of compound SGK 225 was observed to exchange with D₂0 in the spectrum. All the other aliphatic and aromatic protons were observed at expected regions. In the ¹³C-NMR spectra of selected prototype compounds SGK 224 and SGK 225, hydrazide C=0 were observed at 170.21 and 168.95 ppm, respectively. The peaks resonated at 183.79 and 170.52 ppm in the ¹³C-NMR spectra of these compounds, assigned for C=S, confirming thione form of thiosemicarbazides The EI-MS of the selected compound SGK 225 displayed molecular ion at m/z 419 which confirmed its molecular weight. The major fragmentation pattern involved the cleavage of the CONH-NH-CS bonds of amide. Synthesis of 5-[(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)methyl]-4-substituted -2,4-dihydro-3H-l,2,4-triazole-3-thiones [SGK238-244, SGK315]

A solution of 0.01 mol compounds SGK224-230, SGK313 in 2N sodium hydroxide solution (25 mL) was heated under reflux for 4 h. After cooling to room temperature, concentrated hydrochloric acid was added. The precipitate was filtered and washed several times with distilled water. The compounds were recrystallized from ethanol.

Alkaline cyclisation of etodolac thiosemicarbazides [SGK224-230, SGK313] using sodium hydroxide afforded the corresponding 5-[(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4- b]indol-l-yl)methyl]-4-substituted-2,4-dihydro-3H-l,2,4-triazole-3-thiones [SGK238-244, SGK315]. Etodolac triazoles were characterized by their melting points and spectral data. Formation of triazoles [SGK238-244, SGK315] was confirmed by IR spectroscopy, the existence of triazoles in thione form was also confirmed by the absence of SH stretching in the characteristic region of 2550 cm^-1 and presence of C=S stretching in the region of 1215- 1262 cm^"1. The cyclization of thiosemicarbazides [SGK224-230, SGK313] to the products [SGK238-244, SGK315] was indicated in the IR spectra by appearance of a single absorption for NH and disapperance of the carbonyl absorption. The formation of triazole was confirmed in 'H-NMR spectra by the apperance of only one relatively broad NH proton signal in the region of 13.38-13.82 ppm, whereas S-H proton at 1.0-3.7 ppm was not detected and so their thionic form was proved. Triazole NH resonances were observed to be shifted to downfield because of strong intermolecular hydrogen bonding as previously reported. Remaining chemical shifts were also recorded at expected values. The ^,3C NMR spectra of compounds SGK239, SGK243 and SGK244 which were chosen as prototypes, verified the proposed l,2,4-triazole-3-thione structure. In ¹³C-NMR spectra, the absence of the signal for C=0 and apperance of the signal for C=N respectively, 148.83, 150.46 and 154.31 ppm also confirmed the formation of the 1 ,2,4-triazoles. The -C=S form is present also in dimethyl sulfoxide, as suggested by the respective ¹³C-NMR spectral data. The presence of the signals at 165.70, 167.82 and 170.66 ppm respectively for selected compounds, characteristic for the C=S group, indicated that these compounds from the 1,2,4-triazole class existed in solution predominantly in the thione form. High resolution mass spectra (HR-MS) confirmed the molecular weights, empirical formulae of compounds, SGK238, SGK243, SGK244 and 1,2,4-triazoles and fragments, with less than 5 mmu bias between calculated and experimental m/z values of either molecular or fragment ions. Fragmentation pattern for all etodolac 1,2,4- triazoles supported the proposed structures. The fragment ion peaks especially [M-N₂]⁺, [M- HCNS]⁺ , [M-RNCSf and [M-S] ⁺ are the diagnostic peaks for 1,2,4-triazoles rings.

The invention which was mentioned here is essentially the synthetic method for l -[2- (l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l -yl)acetyl]-4-alkyl/arylthiosemicarbazide [SGK224-230, SGK313] compounds and it is characterised in that 2-(l,8-diethyl-l,3,4,9- tetrahydropyrano[3,4- >]indole-l -yI)acetohydrazide [SGK197] is synthesised by substituted isothiocyanates with at least 60-97% yield and it is a synthetic method for 5-[(l,8-diethyl- l,3,4,9-tetrahydropyrano[3,4-b]indole-l-yl)methyl]-4-substituted-2,4-dihydro-3H-l,2,4- triazole-3-thione [SGK238-244, SGK315] compounds and it is also characterised in that it is synthesised by the reaction of l-[2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indole-l- yl)acetyl]-4-alkyl/arylthiosemicarbazide [SGK224-230, SGK313] compounds in the alkaline medium with at least 50-80% yield. In addition, the invention which was mentioned here consists of the synthesis of the following compounds and it is also not limited to them;

SGK224 l-[2-(l ,8-diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)acetyl]-4-methyl thiosemicarbazide

SGK225 l-[2-(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)acetyl]-4-ethyl thiosemicarbazide

SGK226 l-[2-(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indole-l-yl)acetyl]-4-propyl thiosemicarbazide

SGK227 l-[2-(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)acetyl]-4-butyl thiosemicarbazide

SGK228 l-[2-(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l -yl)acetyl]-4-benzyl thiosemicarbazide

SGK229 l -[2-(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indole-l -yl)acetyl]-4-allyl thiosemicarbazide

SGK230 l-[2-(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)acetyl]-4-phenyl thiosemicarbazide

SGK313 l -[2-(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)acetyl]-4-cyclohexyl thiosemicarbazide

SGK238 5-[(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)methyl]-4-methyl-2,4- dihydro-3H-l,2,4-triazole-3-thione

SGK239 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l -yl) methyl]-4-ethyl-2,4- dihydro-3H-l,2,4-triazole-3-thione

SGK240 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l -yl)methyl]-4-propyl-2,4- dihydro-3H-l,2,4-triazole-3-thione

SGK241 5-[(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)methyl]-4-butyl-2,4- dihydro-3H-1.2,4-triazole-3-thione

SGK242 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)methyl]-4-benzyl-2,4- dihydro-3H- 1 ,2,4-triazole-3-thione

SGK243 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)methyl]-4-allyl-2,4- dihydro-3H-l,2,4-triazole-3-thione

SGK244 5-[(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l-yl)methyl]-4-phenyl-2,4- dihydro-3H-l,2,4-triazole-3-thione

SGK315 5-[(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-b]indol-l -yl)methyl]-4-cyclohexyl- 2,4-dihydro-3H-l,2,4-triazole-3-thione

Table 3

Ar Yield Molecular M.W. M.p. HR-MS (ΕΓ)

Comp

(%) Formula (g/mol) (°C ) Calculated/Found (m/z)

356.1670/356.1663 (M ) (C,₉H₂₄N₄OS); 341.1441/341.0010; 328.1609/328.1317; 324.1950/324.1943 (C₁₉H₂₄N₄0);

297.1841/297.9783; 281.1581/281.1633;

SGK238 -CH₃ 71 C₁₉H₂₄N₄OS 356.485 227-229

279.1372/279.1453; 269.1648/269.9906; 268.1576/268.1513; 243.1623/243.1576; 229.1466/229.1409; 228.1382/228.1345 (C,₅H₁₈NO); 227.1310/227.1298

370.1827/370.1821(M⁺ (C₂₀H₂₆N₄OS); 341.1682/341.1605; 341.1441/341.1382

C₂₀H₂₆N₄OS

SGK239 -CH₂CH₃ 82 370.512 159-160 (C₁₈H₂₁N₄OS); 229.1466/ 229.1399;

228.1382/228.1389 (C₁₅H₁₈NO);

227.1310/227.1399

384.1984/384.1990 (NT) (C₂₁H_2gN₄OS); 355.1839/355.1574; 355.1587/355.1574;

SGK240 -CH₂CH₂CH₃ 82 C₂₄H₂₈N₄OS 384.538 138-140 324.2070/324.9914; 229.1466/229.1416;

228.1382/228.1369 (C₁₅H₁₈NO);

227.1310/227.1302

398.2140/398.2113 (M ) (C₂₂H₃₀N₄OS); 397.2057/397.2112; 369.1995/369.1689; 369.1743/369.1689; 229.1466/229.1439;

C₂₂H₃oN₄OS

SGK241 -CH₂CH₂CH₂CH₃ 78 398.565 186-188 228.1382/228.1374 (d₅Hi₈NO);

227.1310/227.1292

COMPOUNDS

Claims

1. The synthesis method for l -[2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-¾]indole-l - yl)acetyl]-4-alkyl/arylthiosemicarbazide [SGK224-230, SGK313] compounds and it is characterised in that 2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-6]indole-l -yl) acetohydrazide [SGK197] is synthesised by the reaction of substituted isothiocyanates in an ethanolic medium.

2. The synthesis process according to claim 1, it is characterised in that l -[2-(l ,8-diethyI- l,3,4,9-tetrahydropyrano[3,4-^]indole-l-yl)acetyl]-4-alkyl/aryl thiosemicarbazides [SGK224-230, SGK313] are synthesised with at least 60-97% yield.

3. A compound of l-[2-(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-&]indole-l -yl)acetyl]- 4-methyl thiosemicarbazide.

4. A compound of l-[2-(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-^]indole-l-yl)acetyl]- 4-ethyl thiosemicarbazide.

5. A compound of l-[2-(l ,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-6]indole-l -yl)acetyl]- 4-propyl thiosemicarbazide.

6. A compound of l-[2-(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-0]indole-l-yl)acetyl]- 4-butyl thiosemicarbazide.

7. A compound of l-[2-(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-i]indole-l -yl)acetyl]- 4-benzyl thiosemicarbazide.

8. A compound of l-[2-(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-6]indole-l -yl)acetyl]- 4-allyl thiosemicarbazide.

9. A compound of l-[2-(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-¾]indole-l -yl)acetyl]- 4-phenyl thiosemicarbazide.

10. A compound of l-[2-(l ,8-Diethyl-l,3,4,9-tetrahydropyTano[3,4-0]indole-l -yl)acetyl]- 4-cyclohexyl thiosemicarbazide.

11. The synthesis method for 5-[(l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-i)]indole-l- yl)methyl]-4-substituted-2,4-dihydro-3H-l,2,4-triazole-3-thione compounds [SG 238-244, SGK315] and it is characterised in that it is synthesised by the reaction of 1- [2-(l ,8-diethyl- 1 ,3 ,4,9-tetrahydropyrano[3,4-6]indole- 1 -yl)acetyl]-4-alkyl/aryl thiosemicarbazide compounds [SGK224-230, SGK313] in the alkaline medium followed by neutralization with acid.

12. The synthesis process according to claim 1 1, it is characterised in that 5-[(l ,8-diethyl- 1 ,3 ,4,9-tetrahydropyrano[3,4-&]indole-l -yl)methyl]-4-substituted-2,4-dihydro-3H- l,2,4-triazole-3-thione compounds [SGK238-244, SGK315] are synthesised with at least 50-80% yield.

13. A compound of 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-6]indol-l-yl)methyl]-4- methyl-2,4-dihydro-3H-l,2,4-triazole-3-thione.

14. A compound of 5-[(l,8-Diethyl-l ,3,4,9-tetrahydropyrano[3,4-6]indol-l-yl) methyl]-4- ethyl-2,4-dihydro-3H-l,2,4-triazole-3-thione.

15. A compound of 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-6]indol-l-yl)methyl]-4- propyl-2,4-dihydro-3H- 1 ,2,4-triazole-3-thione.

16. A compound of 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-&]indol-l-yl)methyl]-4- butyl-2,4-dihydro-3H-l,2,4-triazole-3-thione.

17. A compound of 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-*]indol-l-yl)methyl]-4- benzyl-2,4-dihydro-3H-l,2,4-triazole-3-thione.

18. A compound of 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-&]indol-l-yl)methyl]-4- allyl-2,4-dihydro-3H-l,2,4-triazole-3-thione.

19. A compound of 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-*]indol-l-yl)methyl]-4- phenyl-2,4-dihydro-3H-l,2,4-triazole-3-thione.

20. A compound of 5-[(l,8-Diethyl-l,3,4,9-tetrahydropyrano[3,4-¾]indol-l-yl)methyl]-4- cyclohexyl-2,4-dihydro-3H-l,2,4-triazole-3-thione.