Composition of 1,3,4-selenadiazole containing compounds with pharmacological activity

Abstract

The invention belongs to the field of biomedical research involving the 1,3,4-selenyldiazo derivatives that have cell protective activity. Because there are not so many heterocyclic selenium compounds, we synthesized a new type of selenium analog of BPTES. As the isoacceptor of BPTES, the compounds have antitumor activity, anti-oxidation and cell protection function. Currently many drugs contain the thiodiazo motif, so synthesis of selenyldiazo functional group could further optimize these drugs and are important in new drug development and application.

Claims

1. A 1, 3, 4-selenadiazole compound, represented by a general formula as follows: ##STR00080## wherein: R.sub.7, R.sub.8, R.sub.9, X are selected as follows: TABLE-US-00003 R.sub.7 R.sub.8 R.sub.9 X —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se.

2. A pharmaceutical composition containing the 1, 3, 4-selenadiazole compound of claim 1 and/or a pharmaceutically acceptable salt of the 1, 3, 4-selenadiazole compound and a pharmaceutically accepted carrier.

3. A 1, 3, 4-selenadiazole compound, selected from the group consisting of: ##STR00094##

4. A 1, 3, 4-selenadiazole compound, selected from the group consisting of: ##STR00095##

5. A method of applying the 1, 3, 4-selenadiazole compound of claim 1, for cancer therapeutics such as liver cancer and pancreatic cancer.

6. The method of claim 5 wherein the method is used in combination with at least one selected from the group consisting of rapamycin, FK506, bacteriocin D, adriamycin, paclitaxel, mitomycin, gemcitabine, 5 fluorouracil, pinocanoic acid, and their derivatives.

Description

DESCRIPTION OF DRAWINGS

(1) This application has 1 illustration:

(2) FIG. 1. Schematic diagram of the antioxidant activity of related compounds in the present invention.

EXAMPLES

(3) Without special notice, the terminology used in this invention has the following general implications:

(4) The sign [ ] indicates that the contents in [ ] can be omitted or removed. After omitting or removing, the groups on both sides of [ ] can be directly connected by chemical bonds.

(5) The term “halogen” or “halogen atom” means a halogen substituent, the fluorine (—F), the chlorine group (—Cl), the bromine group (—Br) or the iodine group (—I); the term “halogen” is replaced by the halogen substituent.

(6) The term “alkyl” refers to the straight chain, branched alkyl chain or cycloalkyl. The “alkyl” is refers to both single ended free alkyl bond such as but not limited to: methyl, ethyl, propyl, isopropyl, butyl, primary/secondary/tertiary butyl, cyclopropyl, methyl cyclopropyl, and cyclobutyl et al, but also include alky that meet the bond valence theory with two or more than two alkyl, refer to but not limited to: —CH.sub.2—, —(CH.sub.2).sub.2—, —(CH.sub.2).sub.3—, —(CH.sub.2).sub.4—, —C(CH.sub.3) (CH.sub.2).sub.2—.

(7) The term “cyclic hydrocarbons” refers to a ring of at least 3 carbons or with functional group substitutions; in the absence of any opposite meaning, any of the carbon atom can be substituted by another hetero atom containing group to form a new group or a functional group.

(8) The term “heterocyclic ring” refers to a ring contains at least 2 carbons and other hetero atoms or functional groups.

(9) The term “selen” refers to the

(10) ##STR00020##
group containing molecular, or with additional group or functional group which is referred as selen derivatives.

(11) The term “oxyalkyl” refers to the substituent can include different alkyl, for example but not limited to all kind of straight chain, branched alkyl chain or cycloalkyl alkyl, similar to that is described for “the alkyl” above.

(12) The term “substitution” refers to the substitution of a hydrogen atom by other functional groups or substituents.

(13) The term “nitrophenyll” refers to at least 2 hydrogen atoms on the benzene are replaced by nitro, hydrogen atoms are substituted by the unknown can choose, for example, but not limited to, a para and ortho.

(14) The term “aromatic” refers to aromatic ring with substituents; no other specific, the aromatic ring could either carbocyclic aryl, or heterocyclic aryl including but not limited to N, S and O atoms; can be monocyclic aryl; can also be fused ring aryl, or polycyclic aryl ring and non fused aryl ring substituents.

(15) The term “heterocyclic” or “aromatic heterocyclic ring” refers to functional groups or substituents derived from the aromatic rings of N, S, O, or other atoms, which vary in quantity.

(16) The term “amide” refers to a functional group or substituent containing an amide bond —CONH—.

(17) The term “carbonyl” refers to a functional group or substituent containing the C═O double bond.

(18) The term “Ether” refers to a functional group or group containing —O—.

(19) The term “ester” refers to a functional group or group containing —COO—, or its derivatives.

(20) The term “silane” refers to a compound or derivative of the Si—H bond.

(21) The term “sulfur ether” refers to a compound containing the same R, wherein R—S—R is an alkyl group.

(22) The term “phosphoric acid group” refers to a functional group or substituent containing —PO4, —HPO4, or —H2PO4.

(23) The term “sulfinyl” refers to a functional group or substituent containing —S═O—.

(24) The term “sulfonyl” refers to a functional group or substituent containing —S(═O).sub.2.

(25) The term “amino acid” refers to a group of functional groups or substituents that contain both amino and carboxyl groups.

(26) The present invention is further illustrated by the following examples.

Example 1

5-(2-bromoethyl)-N-phenyl-1,3,4-selenadiazol-2-amine (Compound 1)

(27) ##STR00021##

(28) m/z 332 (100%, M+H.sup.+)

(29) .sup.1H NMR (500 MHz,) δ 10.37 (s, 1H), 7.65-7.53 (m, 2H), 7.35 (d, J=9.0 Hz, 2H), 6.99 (dt, J=7.4, 3.7 Hz, 1H), 3.6 (t, J=6.5 Hz, 2H), 3.38-3.29 (t, J=6.5 Hz, 2H)

(30) To further explore the reaction conditions on the yield of reaction, a group of reactants in different reaction conditions were explored, the specific reaction data are as follows:

(31) TABLE-US-00001 Reactant 3- Catalyzer Benzamide Bromopropionic Oil of Phosphorus Procceding No. Selenide(ml) acid(mmol) vitriol(ml) oxychloride(ml) Temp. (° C.) Time (h) Crude yield (%) 1 44 37 14 100-120 2  8% 2 44 37 15 100-140 2 3 44 37 15 120-126 4 14% 4 44 37 15 100-110 7 10% 5 44 37 15 100-130 3  2% 6 44 37 15 110-120 3 17% 7 44 37 15 120  1.5  3% 8 44 37 15 115-125 3  3% 9 44 37 15 115-120 5.5  1% 10 44 37 15 115-120 3 27% 11 44 37 15 115  3 23% 12 44 37 15 80 2 53% 13 44 37 15  90-100 2.5 45% 14 44 37 15 90 2.5 36% 15 44 37 15 80-85 5 26% 16 44 37 15 101-107 1 30% 17 44 37 15 81.3-84.0 1 39% 18 44 37 15   80-84.8 2 22% 19 44 37 15 100-110 1 12% 20 44 37 15 <110  2 19% 21 22 19 6 75-80 3 24% 22 176 148 60 80 1 47% 23 22 19 3 75-80 3 45% 24 44 37 15 90 1 30% 25 44 37 15 100-80  1.5 25% 26 44 37 15 90-70 1.5 42% 27 44 37 15 80-60 1.5 35% 28 44 37 10 60-50 1.5 80% 29 53 30 8 50-40 1.5 50% 30 44 37 5 10 100-85  3 45% 31 44 37 18 90-70 3 85% 32 44 37 15 80-60 3 95% 33 220 185 75 60-50 3 84% 34 44 37 15 60-40 6 85%

(32) A variety of different reactants and the reaction equation are listed as follows. Emphasized here is that the reaction conditions are essentially the same: selenyl urea carboxylic acid or cyanide compounds (0.2˜4 mmol), and 5 ml POCl.sub.3 are mixed and reacted at 50 to 80° C. for 0.5˜12 h, normal workup to yield selenyldiazo 40-95%; The methods are applicable to other listed compounds in the claim.

5-(2-bromoethyl)-N-(pyridin-3-yl)-1,3,4-selenadiazol-2-amine (Compound 2)

(33) ##STR00022##

(34) m/z 333 (100%, M+H.sup.+)

(35) .sup.1H NMR (500 MHz,) δ 10 (s, 1H), 8.9 (s, 1H), 8.1 (d, J=9.0 Hz, 2H), 7.3 m, 1H), 3.6 (t, J=6.5 Hz, 2H), 3.38-3.29 (t, J=6.5 Hz, 2H)

5-(2-chloroethyl)-N-phenyl-1,3,4-selenadiazol-2-amine (Compound 3)

(36) ##STR00023##

(37) Mp: 109-110° C.

(38) m/z 288 (100%, M+H.sup.+)

(39) .sup.1H NMR (500 MHz,) δ 10.37 (s, 1H), 7.65-7.53 (m, 2H), 7.35 (d, J=9.0 Hz, 2H), 6.99 (dt, J=7.4, 3.7 Hz, 1H), 3.96 (t, J=6.5 Hz, 2H), 3.38 (t, J=6.5 Hz, 2H)

N-benzyl-5-(2-chloroethyl)-1,3,4-selenadiazol-2-amine (Compound 4)

(40) ##STR00024##

(41) Mp: 109-110° C.

(42) m/z 302 (100%, M+H.sup.+)

(43) .sup.1H NMR (500 MHz,) δ9 (1H), 7.65-7.53 (m, 2H), 7.35 (d, J=9.0 Hz, 2H), 6.99 (dt, J=7.4, 3.7 Hz, 1H), 3.96 (m, J=6.5 Hz, 4H), 3.38-3.29 (t, J=6.5 Hz, 2H)

5-(2-chloroethyl)-N-phenethyl-1,3,4-selenadiazol-2-amine (Compound 5)

(44) ##STR00025##

(45) Mp: 109-110° C.

(46) m/z 316 (100%, M+H.sup.+)

(47) .sup.1H NMR (500 MHz,) δ 9 (1H), 7.65-7.53 (m, 2H), 7.35 (d, J=9.0 Hz, 2H), 6.99 (dt, J=7.4, 3.710 Hz, 1H), 3.6 (m, J=6.5 Hz, 4H), 3.38-3.29 (t, J=6.5 Hz, 4H)

4-(2-((5-(2-chloroethyl)-1,3,4-selenadiazol-2-yl)amino)ethyl)-1,2-phenylene diacetate (Compound 6)

(48) ##STR00026##

(49) Mp: 109-110° C.

(50) m/z 316 (100%, M+H.sup.+)

(51) .sup.1H NMR (500 MHz,) δ 9 (1H), 7.65-7.53 (m, 3H), 3.6 (m, J=6.5 Hz, 4H), 3.38-3.29 (t, J=6.5 Hz, 4H), 2.4 (s, 6H)

1-((5-(phenylamino)-1,3,4-selenadiazol-2-yl)methyl)guanidine (Compound 7)

(52) ##STR00027##

(53) Mp: 109-110° C.

(54) m/z 296 (100%, M+H.sup.+)

(55) .sup.1H NMR (500 MHz,) δ 10.6 (1H), 7.65-7.53 (m, 2H), 7.35 (d, J=9.0 Hz, 2H), 6.99 (dt, J=7.4, 3.7 Hz, 1H), 3.2 (2H)

5,5′-(thiobis(ethane-2,1-diyl))bis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 8)

(56) ##STR00028##

(57) Mp=172-174° C., m/z 534.4 (100%, M+H.sup.+)

(58) .sup.1H NMR (500 MHz, DMSO-d6) δ 10.37 (d, J=70.4 Hz, 2H), 7.65-7.53 (m, 4H), 7.35 (d, J=9.010 Hz, 4H), 6.99 (dt, J=7.4, 3.7 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 3.06 (t, J=7.2 Hz, 2H), 2.88 (dt, J=27.2, 7.2 Hz, 4H)

N5,N5′-diphenyl-[2,2′-bi(1,3,4-selenadiazole)]-5,5′-diamine (Compound 9)

(59) ##STR00029##

(60) m/z 447 (100%, M+H.sup.+)

(61) .sup.1H NMR (500 MHz,) δ 10.26 (s, 2H), 7.58 (dd, J=30.9, 7.6 Hz, 4H), 7.33 (t, J=7.9 Hz, 4H), 6.99 (t, J=7.3 Hz, 2H)

5,5′-methylenebis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 10)

(62) ##STR00030##

(63) Mp=130-132° C.

(64) m/z 461 (100%, M+H.sup.+)

(65) .sup.1H NMR (500 MHz,) δ 10.15 (s, 2H), 7.51 (d, J=8.0 Hz, 4H), 7.24-7.17 (m, 4H), 6.90 (t, J=5.6 Hz, 2H), 3.45-3.35 (s, 2H)

5,5′-(ethane-1,2-diyl)bis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 11)

(66) ##STR00031##

(67) Mp=160-161° C.

(68) m/z 475 (100%, M+H.sup.+)

(69) .sup.1H NMR (500 MHz,) δ 10.25 (s, 2H), 7.61 (d, J=8.0 Hz, 4H), 7.34-7.27 (m, 4H), 6.98 (t, J=5.610 Hz, 2H), 1.32-1.20 (m, 4H)

5,5′-(propane-1,3-diyl)bis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 12)

(70) ##STR00032##

(71) Mp: 198-201° C.

(72) m/z 489 (100%, M+H.sup.+)

(73) .sup.1H NMR (500 MHz,) δ 9.97 (s, 2H), 7.62 (d, J=8.0 Hz, 4H), 7.33 (t, J=7.5 Hz, 4H), 6.99 (t, J=7.0 Hz, 2H), 3.02 (t, J=7.2 Hz, 4H), 2.15-2.07 (m, 2H)

5,5′-(butane-1,3-diyl)bis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 13)

(74) ##STR00033##

(75) Mp=205-208° C.

(76) m/z 503 (100%, M+H.sup.+)

(77) .sup.1H NMR (500 MHz,) δ 10.35 (s, 2H), 7.61 (d, J=7.9 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.33 (t, J=7.6 Hz, 4H), 6.99 (t, J=6.9 Hz, 2H), 3.40 2.96-2.79 (m, 4H), 1.77-1.67 (m, 4H)

5,5′-(pentane-1,5-diyl)bis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 14)

(78) ##STR00034##

(79) Mp=165-171° C.

(80) m/z 517 (100%, M+H.sup.+)

(81) .sup.1H NMR (500 MHz,) δ 10.34 (s, 2H), 7.61 (d, J=7.8 Hz, 4H), 7.32 (t, J=7.9 Hz, 4H), 6.98 (t, J=7.3 Hz, 2H), 2.91-2.77 (t, J=7.4 Hz, 4H), 1.77-1.67 (m, 4H), 1.51-1.40 (m, 2H)

methyl 4-(5-(phenylamino)-1,3,4-selenadiazol-2-yl)butanoate (Compound 15)

(82) ##STR00035##

(83) m/z 325 (100%, M+H.sup.+).

(84) .sup.1H NMR (500 MHz,) δ 10.34 (s, 1H), 7.61 (d, J=7.8 Hz, 2H), 7.32 (t, J=7.9 Hz, 2H), 6.98 (t, J=157.3 Hz, 1H), 3.65 (s, 3H), 2.32 (t, J=7.2 Hz, 2H), 1.9 (m, 2H), 1.5 (t, J=7.2 Hz, 2H)

2-((5-(5-(phenylamino)-1,3,4-selenadiazol-2-yl)pentyl)carbamoyl)phenyl acetate (Compound 16)

(85) ##STR00036##

(86) m/z 472 (100%, M+H.sup.+)

(87) .sup.1H NMR (500 MHz,) δ 10.34 (s, 1H), 7.61-6.98 (m, 9H), 2.4 (s, 3H), 3.18-1.3 (m, 10H),

N-(5-(5-(phenylamino)-1,3,4-selenadiazol-2-yl)pentyl)benzamide (Compound 17)

(88) ##STR00037##

(89) m/z 428 (100%, M+H.sup.+)

(90) .sup.1H NMR (500 MHz,) δ 10.34 (s, 1H), 7.61-6.98 (m, 10H), 3.19-1.3 (m, 10),

tert-butyl(5-(5-(naphthalen-2-ylamino)-1,3,4-selenadiazol-2-yl)pentyl)carbamate (Compound 18)

(91) ##STR00038##

(92) m/z 460 (100%, M+H.sup.+)

(93) .sup.1H NMR (500 MHz,) δ 10.34 (s, 1H), 7.61-6.98 (m, 7H), 3.18-1.3 (m, 10H), 1.4 (s, 9H).

tert-butyl(5-(5-((2,4-dinitrophenyl)amino)-1,3,4-selenadiazol-2-yl)pentyl)carbamate (Compound 19)

(94) ##STR00039##

(95) m/z 500 (100%, M+H.sup.+)

(96) .sup.1H NMR (500 MHz,) δ 10.34 (s, 1H), 8.5-6.98 (m, 3H), 3.18-1.3 (m, 10H), 1.4 (s, 9H).

tert-butyl(5-(5-((2-fluorophenyl)amino)-1,3,4-selenadiazol-2-yl)pentyl)carbamate (Compound 20)

(97) ##STR00040##

(98) m/z 428 (100%, M+H.sup.+)

(99) .sup.1H NMR (500 MHz) δ 10.34 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.59 (m, 211), 7.46 (m, 1H), 7.37 (d, J=8.0, 1H), 3.18-1.3 (m, 10H), 1.4 (s, 9H).

tert-butyl(5-(5-((3-((11-oxidanyl)-15-methyl)phenyl)amino)-1,4-selenadiazol-2-yl)pentyl)carbamate (Compound 21)

(100) ##STR00041##

(101) m/z 440 (100%, M+H.sup.+)

(102) .sup.1H NMR (500 MHz) δ 10.34 (s, 1H), 8.06 (s, J=7.8 Hz, 1H), 7.59 (m, 2H), 7.46 (d, J=8.0, 1H), 7.37 (d, J=8.0, 1H), 3.8 (s, 3H), 3.18-1.3 (m, 10H), 1.4 (s, 9H).

tert-butyl (5-(5-((4-(trifluoromethyl)phenyl)amino)-1,3,4-selenadiazol-2-yl)pentyl)carbamate (Compound 22)

(103) ##STR00042##

(104) m/z 478 (100%, M+H.sup.+)

(105) .sup.1H NMR (500 MHz) δ 10.34 (s, 1H), 8.06 (d, J=7.8 Hz, 2H), 7.59 (m, 1H), 7.46 (d, J=7.8, 2H), 3.18-1.3 (m, 10H), 1.4 (s, 9H).

tert-butyl 2-(5-(phenylamino)-1,3,4-selenadiazol-2-yl)pyrrolidine-1-carboxylate (Compound 23)

(106) ##STR00043##

(107) m/z 394 (100%, M+H.sup.+)

(108) .sup.1H NMR (500 MHz) δ 10.34 (s, 1H), 8.06 (d, J=7.8 Hz, 2H), 7.59-7.46 (m, 3H), 3.4 (m, 3H), 1.7-1.5 (m, 4H), 1.4 (s, 9H).

tert-butyl (2-phenyl-1-(5-(phenylamino)-1,3,4-selenadiazol-2-yl)ethyl)carbamate (Compound 24)

(109) ##STR00044##

(110) m/z 444 (100%, M+H.sup.+)

(111) .sup.1H NMR (500 MHz) δ 10.34 (s, 1H), 8.06 (m, J=7.8 Hz, 4H), 7.59-7.46 m, 7H), 4-3.2 (m, 3H), 1.4 (s, 9H).

tert-butyl(1-(5-(phenylamino)-1,3,4-selenadiazol-2-yl)-2-(4-((trimethylsilyl)oxy)phenyl)ethyl)carbamate (Compound 25)

(112) ##STR00045##

(113) m/z 532 (100%, M+H.sup.+)

(114) .sup.1H NMR (500 MHz) δ 10.34 (s, 1H), 8.06 (m, J=7.8 Hz, 4H), 7.59-7.46 (m, 6H), 4-3.2 (m, 3H), 101.4 (s, 9H), 0.2 (s, 9H)

tert-butyl(2-(4H-imidazol-5-yl)-1-(5-(phenylamino)-1,3,4-selenadiazol-2-yl)ethyl)carbamate (Compound 26)

(115) ##STR00046##

(116) m/z 434 (100%, M+H.sup.+)

(117) .sup.1H NMR (500 MHz) δ 10.34 (s, 1H), 8.06 (m, J=7.8 Hz, 5H), 7.59-7.46 (m, 3H), 4-3 (m, 3H), 1.4 (s, 9H)

5,5′-(1,3-phenylene)bis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 27)

(118) ##STR00047##

(119) m/z 523 (100%, M+H.sup.+)

(120) .sup.1H NMR (500 MHz) δ 9.97 (s, 2H), 8.4 (s, 1H), 8.1 (d, J=7.5, 2H), 7.62 (m, 5H), 7.33 (t, J=7.5 Hz, 4H), 6.99 (t, J=7.0 Hz, 2H)

5,5′-(1,2-phenylene)bis(N-phenyl-1,3,4-selenadiazol-2-amine) (Compound 28)

(121) ##STR00048##

(122) m/z 523 (100%, M+H.sup.+)

(123) .sup.1H NMR (500 MHz) δ 9.97 (s, 2H), 8.1 (d, J=7.5, 2H), 7.62 (m, 6H), 7.33 (t, J=7.5 Hz, 4H), 6.9910 (t, J=7.0 Hz, 2H)

(124) The 1,3,4-selenadiazole containing compounds described above showed antioxidant activity and protect PC12 cells (1000 per well) under anaerobic condition or in the presence of hydrogen peroxide. As shown in FIG. 1, 1,3,4-selenadiazole compounds (10000 nM) could protect and support cell growth under anaerobic condition for 3 days, whereas in the no compound control, cells did not survive.

Example 2

(125) Further studies have shown that the selenadiazole containing KGA allosteric inhibitors have strong KGA inhibition (IC50<100 nM) and anti-tumor activity (IC50<100 nM for inhibiting A 549 lung cancer cells). The molecular structure of specific compounds is described as follows:

2.1 N-(6-(4-(5-(3-oxobenzo[d][1,2]selenazol-2(3H)-yl)-1,3,4-selenadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

(126) ##STR00049##

(127) LRMS: m/z=682 [M+H].sup.+

2.2 N-(5-(4-(6-(2-(3-oxobenzo[d][1,2]selenazol-2(3H)-yl)acetamido)pyridazin-3-yl)butyl)-1,3,4-selenadiazol-2-yl)picolinamide

(128) ##STR00050##

(129) LRMS: m/z=642 [M+H].sup.+

2.3 N-(6-(4-(5-(3-(pyridin-2-yl)ureido)-1,3,4-selenadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

(130) ##STR00051##

(131) LRMS: m/z=620 [M+H].sup.+

2.4 N-(6-(4-(5-(3-(pyridin-3-yl)ureido)-1,3,4-selenadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

(132) ##STR00052##

(133) LRMS: m/z=620 [M+H].sup.+

2.5 N-(6-(4-(5-(3-(pyridin-4-yl)ureido)-1,3,4-selenadiazol-2-yl)butyl)pyridazin-3-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide

(134) ##STR00053##

(135) LRMS: m/z=620 [M+H].sup.+

2.6 2-(pyridin-2-yl)-N-(5-(4-((5-(2-(pyridin-2-yl)acetamido)-1,3,4-selenadiazol-2-yl)amino)piperidin-1-yl)-1,3,4-selenadiazol-2-yl)acetamide

(136) ##STR00054##

(137) LRMS: m/z=632 [M+H].sup.+

2.7 2-(3-oxobenzo[d][1,2]selenazol-2(3H)-yl)-N-(5-(4-((5-(2-(3-oxobenzo[d][1,2]selenazol-2(3H)-yl)acetamido)-1,3,4-thiadiazol-2-yl)amino)piperidin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

(138) ##STR00055##

(139) LRMS: m/z=776 [M+H].sup.+

2.8 2-(5-methoxy-1-methyl-1H-indol-3-yl)-N-(5-(4-((5-(2-(5-methoxy-1-methyl-1H-indol-3-yl)acetamido)-1,3,4-selenadiazol-2-yl)amino)piperidin-1-yl)-1,3,4-selenadiazol-2-yl)acetamide

(140) ##STR00056##

(141) LRMS: m/z=796 [M+H].sup.+

2.9 (R)-2-(pyridin-2-yl)-N-(5-(3-(((5-(2-(pyridin-2-yl)acetamido)-1,3,4-selenadiazol-2-yl)oxy)methyl)pyrrolidin-1-yl)-1,3,4-selenadiazol-2-yl)acetamide

(142) ##STR00057##

(143) LRMS: m/z=633 [M+H].sup.+

2.10 2-(pyridin-2-yl)-N-(5-(4-((5-(2-(pyridin-2-yl)acetamido)-1,3,4-selenadiazol-2-yl)oxy)piperidin-1-yl)-1,3,4-selenadiazol-2-yl)acetamide

(144) ##STR00058##

(145) LRMS: m/z=633 [M+H].sup.+

2.11 N,N′-(((1,3-phenylenebis(azanediyl))bis(methylene))bis(1,3,4-selenadiazole-5,2-diyl))bis(2-(pyridin-2-yl)acetamide)

(146) ##STR00059##

(147) LRMS: m/z=668 [M+H].sup.+

(148) Besides, for testing the compounds get in example 1, the compound described as follow formula:

(149) ##STR00060##

(150) The results of such tests above are shown as follows:

(151) TABLE-US-00002 A549 GDH KGA Max- IC.sub.50 IC.sub.50 IC.sub.50 INH R1 R2 R3 X μM μM μM % —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 0.11 2.05 84 —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— S >10 0.14 9.7 55 R.sub.1 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 0.027 0.16 90 R.sub.1 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— S >10 0.28 0.82 80 —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 0.21 >10 40 —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— S >10 0.57 >10  0 R.sub.1 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 0.06 3.1 91 R.sub.1 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— S >10 0.13 6.5 80 —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 1.4 6.3 62 0 —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— S >10 2.5 9 50 R.sub.1 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 0.06 0.3 66 R.sub.1 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— S >10 0.13 0.87 75 —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 4 >10 17 R.sub.1 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 1.9 >10 17 —NH.sub.2 —CH.sub.2CH.sub.2SCH.sub.2CH.sub.2— Se >10 0.3 4 56 >10 0.001 0.017 77 >10 0.002 0.04 70 >10 0.001 0.017 90 >10 0.005 0.01 90

(152) In summary, the above is only a preferred embodiment of the invention, equal changes and modification within the scope of the invention patent, should belong to the scope of the invention patent.