US 2004/0106619 A1 · Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient

Abstract

A pharmaceutical composition for prevention and/or treatment for HIV infection or AIDS induced by the infection which comprises, as an active ingredient, a triazaspiro[5.5]undecane derivative, a quaternary ammonium salt thereof, an N-oxide thereof, or a non-toxic salt thereof, and if necessary, it may be combined with at least one member of other agents for prevention and/or treatment for HIV infection (wherein all symbols are as defined in the specification.). 1 The triazaspiro[5.5]undecane derivatives, the quaternary ammonium salts thereof or the N-oxides thereof, or the non-toxic salts thereof are useful in preventing and/or treating HIV infection and AIDS induced by the infection.

A pharmaceutical composition for prevention and/or treatment for HIV infection, which comprises, as an active ingredient, at least one triazaspiro[5.5]undecane derivative represented by formula (I)

838
wherein R1 is
(1) hydrogen,
(2) C1-18 alkyl,
(3) C2-18 alkenyl,
(4) C2-18 alkynyl,
(5) —COR6,
(6) —CONR7R8,
(7) —COOR9,
(8) —SO2R10,
(9) —COCOOR11,
(10) —CONR12COR13,
(11) Cyc1 or
(12) C1-18 alkyl, C2-18 alkenyl or C2-18 alkynyl substituted by 1-5 substituents optionally selected from (a) halogen, (b) —CONR7R8, (c) —COOR9, (d) —OR14, (e) —SR15, (f) —NR16R17, (g) —NR18COR19, (h) —SO2NR20R21, (i) —OCOR22, (j) —NR23SO2R24, (k) —NR25COOR26, (l) —NR27CONR28R29, (m) Cyc1, (n) keto and (o) —N(SO2R24)2,
R6-R9, R11-R21, R23, R25 and R27-R29 are each independently
(1) hydrogen,
(2) C1-8 alkyl,
(3) C2-8 alkenyl,
(4) C2-8 alkynyl,
(5) Cyc1 or
(6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituents optionally selected from (a) Cyc1, (b) halogen, (c) —OR30, (d) —SR31, (e) —NR32R33, (f) —COOR34, (g) —CONR35R36 (h) —NR37COR38, (i) —NR39SO2R40 and (j) —N(SO2R40)2,
R7 and R8, R20 and R21, or R28 and R29, taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR195-(C2-6 alkylene)-, wherein R195 is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substituted by phenyl,
R10, R22, R24 and R26 are each independently
(1) C1-8 alkyl,
(2) C2-8 alkenyl,
(3) C2-8 alkynyl,
(4) Cyc1 or
(5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituents optionally selected from (a) Cyc1, (b) halogen, (c) —OR30, (d) —SR31, (e) —NR32R33, (f) —COOR34, (g) —CONR35R36, (h) —NR37COR38, (i) —NR39SO2R40 and (j) —N(SO2R40)2,
R30-R37 and R39 are each independently hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1,
R35 and R36, taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR196-(C2-6 alkylene)-wherein R196 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl,
R38 and R40 are each independently C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1,
Cyc1 is C3-15 mono-, bi- or tri-(fused or spiro)carbocyclic ring or 3-15 membered mono-, bi- or tri-(fused or spiro)cyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulfur atoms, wherein Cyc1 may be optionally substituted by 1-5 of R51,
R51 is
(1) C1-8 alkyl,
(2) C2-8 alkenyl,
(3) C2-8 alkynyl,
(4) halogen,
(5) nitro,
(6) trifluoromethyl,
(7) trifluoromethoxy,
(8) nitrile,
(9) keto,
(10) Cyc2,
(11) —OR52,
(12) —SR53
(13) —NR54R55,
(14) —COOR56,
(15) —CONR57R58,
(16) —NR59COR60,
(17) —SO2NR61R62,
(18) —OCOR63,
(19) —NR64SO2R65,
(20) —NR66COOR67,
(21) —NR68CONR69R70,
(22) —B(OR71)2,
(23) —SO2R72,
(24) —N(SO2R72)2,
(25)—S(O)R72 or
(26) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituents optionally selected from (a) halogen, (b) Cyc2, (c) —OR52, (d) —SR53, (e) —NR54R55, (f) —COOR56, (g) —CONR57R58, (h) —NR59COR60, (i) —SO2NR61R62, (j) —OCOR63, (k) —NR64SO2R65, (l) —NR66COOR67, (m) —NR68CONR69R70, (n) —B(OR71)2, (o) —SO2R72, (p) —N(SO2R72)2, (q) —S(O)R72 and (r) keto,
R52-R62, R64, R66 and R68-R71 are each independently
1) hydrogen,
2) C1-8 alkyl,
3) C2-8 alkenyl,
4) C2-8 alkynyl,
5) Cyc2 or
6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc2, —OR73, —COOR74 or —NR75R76,
R57 and R58, R61 and R62 or R69 and R70 taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR197-(C2-6 alkylene)-(wherein R197 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl.),
R63, R65, R67 and R72 are each independently
1) C1-8 alkyl,
2) C2-8 alkenyl,
3) C2-8 alkynyl,
4) Cyc2 or
5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc2, —OR73, —COOR74 or —NR75R76,
R73-R76 are each independently hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2,
Cyc2 has the same meaning as Cyc1, wherein Cyc2 may be optionally substituted by 1-5 of R77,
R77 is
1) C1-8 alkyl,
2) halogen,
3) nitro,
4) trifluoromethyl,
5) trifluoromethoxy,
6) nitrile,
7) —OR78,
8) —NR79R80,
9) —COOR81,
10) —SR82,
11) —CONR83R84,
12) C2-8 alkenyl,
13) C2-8 alkynyl,
14) keto,
15) Cyc6,
16) —NR161COR162,
17) —SO2NR63R164,
18) —OCOR165,
19) —NR166SO2R167,
20) —NR168COOR169,
21) —NR17° CONR171R172,
22) —SO2R173,
23) —N(SO2R167)2,
24) —S(O)R173 or
25) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituents optionally selected from (a) halogen, (b) —OR78, (c) —NR79R80, (d) —COOR81, (e) —SR82, (f) —CONR83R84, (g) keto, (h) Cyc6, (i) —N161COR162, (j) —SO2NR163R164, (k) —OCOR165, (l) —NR166SO2R167, (m) —NR168COOR169, (n) —NR170CONR171R172, (o) —SO2R173, (p) —N(SO2R167)2 and (q) —S(O)R173,
R78-R84, R161-R164, R166, R168 and R170-R172 are each independently, (a) hydrogen, (b) C1-8 alkyl, (c) C2-8 alkenyl, (d) C2-8 alkynyl, (e) Cyc6, (f) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc6, —OR174, —COOR175, —NR176R177 or —CONR178R179,
R83 and R84, R163 and R164, or R171 and R172 taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR198-(C2-6 alkylene)-, wherein R198 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl,
R165, R167, R169 and R173 are each independently (a) C1-8 alkyl, (b) C2-8 alkenyl, (c) C2-8 alkynyl, (d) Cyc6 or (e) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc6, —OR174, —COOR175, —NR176R177 or —CONR178R179,
R174-R177 are each independently
1) hydrogen,
2) C1-8 alkyl,
3) Cyc6 or
4) C1-8 alkyl substituted by Cyc6,
R178 and R179, taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR199-(C2-6 alkylene)-, wherein R199 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl,
Cyc6 is C3-8 mono-carbocyclic ring or 3-8 membered mono-cyclic hetero ring containing 1-4 nitrogen atoms, 1-2 oxygen atoms and/or 1-2 sulfur atoms, wherein Cyc6 may be optionally substituted by 1-5 of R180,
R180 is
(1) C1-8 alkyl,
(2) halogen,
(3) nitro,
(4) trifluoromethyl,
(5) trifluoromethoxy,
(6) nitrile,
(7) —OR181,
(8) —NR182R183,
(9) —COOR184,
(10) —SR185 or
(11) —CONR186R187,
R181-R187 are each independently
1) hydrogen,
2) C1-8 alkyl,
3) phenyl or
4) C1-8 alkyl substituted by phenyl,
R182 and R183 or R186 and R187, taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR200-(C2-6 alkylene)-, wherein R200 is hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted by phenyl,
R2 is
(1) hydrogen,
(2) C1-8 alkyl,
(3) C2-8 alkenyl,
(4) C2-8 alkynyl,
(5) —OR90,
(6) Cyc3 or
(7) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituents optionally selected from (a) halogen, (b) —OR90, (c) —SR91, (d) —NR92R93, (e) —COOR94, (f) —CONR95R96, (g) —NR97COR98, (h) —SO2NR99R100, (i) —OCOR101, (j) —NR102SO2R103, (k) —NR104COOR105, (l) —NR106CONR107R108, (m) Cyc3, (n) keto and (o) —N(SO2R103)2,
R90—R100, R102, R104 and R106-R108 are each independently
1) hydrogen,
2) C1-8 alkyl,
3) C2-8 alkenyl,
4) C2-8 alkynyl,
5) Cyc3 or
6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc3,
R95 and R96, R99 and R100, or R107 and R108, taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR201-(C2-6 alkylene)-,
R201 is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted by phenyl,
R101, R103 and R105 are each independently
1) C1-8 alkyl,
2) C2-8 alkenyl,
3) C2-8 alkynyl or
4) Cyc3, or C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc3,
Cyc3 has the same meaning as Cyc1,
wherein Cyc3 may be optionally substituted by 1-5 of R109, and R109 has the same meaning as R51,
R3 and R4 are each independently
(1) hydrogen,
(2) C1-8 alkyl,
(3) C2-8 alkenyl,
(4) C2-8 alkynyl,
(5) —COOR120,
(6) —CONR121R122,
(7) Cyc4 or
(8) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by 1-5 substituents selected from (a) halogen, (b) nitrile, (c) Cyc4, (d) —COOR20, (e) —CONR121R122, (f) —OR123, (g) —SR124, (h) —NR125R126, (i) —NR127COR128, (j) —SO2NR129R130, (k) —OCOR131, (l) —NR132SO2R133, (m) —NR134COOR135, (n) —NR136CONR137R138, (o) —S—SR139, (p) —NHC(═NH)NHR140, (q) keto, (r) —NR145CONR146COR147 and (s) —N(SO2R133)2,
R120-R130, R132, R134, R136-R138, R145 and R146 are each independently
1) hydrogen,
2) C1-8 alkyl,
3) C2-8 alkenyl,
4) C2-8 alkynyl,
5) Cyc4 or
6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4, halogen, —OR148, —SR149, —COOR150 or —NHCOR141,
R121 and R122 R129 and R130, or R137 and R138, taken together, are
1) C2-6 alkylene,
2) —(C2-6 alkylene)-O—(C2-6 alkylene)-,
3) —(C2-6 alkylene)-S—(C2-6 alkylene)- or
4) —(C2-6 alkylene)-NR202-(C2-6 alkylene)-, wherein R202 is hydrogen, C1-8 alkyl, phenyl, C1-8 alkyl substituted by phenyl,
R131, R133, R135, R139 and R147 are each independently
1) C1-8 alkyl,
2) C2-8 alkenyl,
3) C2-8 alkynyl,
4) Cyc4 or
5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4, halogen, —OR148, —SR149, —COOR150 or —NHCOR141,
R140 is hydrogen, —COOR142 or —SO2R143,
R141-R143 are each independently
1) C1-8 alkyl,
2) C2-8 alkenyl,
3) C2-8 alkynyl,
4) Cyc4 or
5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4,
R148-R150 are each independently
1) hydrogen,
2) C1-8 alkyl,
3) C2-8 alkenyl,
4) C2-8 alkynyl,
5) Cyc4 or
6) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted by Cyc4,
Cyc4 has the same meaning as Cyc1, wherein Cyc4 may be optionally substituted by 1-5 of R144, and R144 has the same meaning as R51,
R3 and R4, taken together, are
839
wherein R190 and R191 are each independently the same meaning as R3 or R4,
R5 is
(1) hydrogen,
(2) C1-8 alkyl,
(3) Cyc5 or
(4) C1-8 alkyl substituted by Cyc5,
wherein Cyc5 has the same meaning as Cyc1, and Cyc5 may be optionally substituted by 1-5 of R160,
R160 has the same meaning as R51,
a quaternary ammonium salt thereof, an N-oxide thereof, or a non-toxic salt thereof.

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Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient

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Drugs containing triazaspiro[5.5]undecane derivatives as the active ingredient

Life of this patent

Abstract

Claims8