RU97110114A - NEW AMINO ACID DERIVATIVES WITH IMPROVED ACTIVITY AGAINST MULTIPLE DOSE STABILITY - Google Patents
NEW AMINO ACID DERIVATIVES WITH IMPROVED ACTIVITY AGAINST MULTIPLE DOSE STABILITYInfo
- Publication number
- RU97110114A RU97110114A RU97110114/04A RU97110114A RU97110114A RU 97110114 A RU97110114 A RU 97110114A RU 97110114/04 A RU97110114/04 A RU 97110114/04A RU 97110114 A RU97110114 A RU 97110114A RU 97110114 A RU97110114 A RU 97110114A
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- RU
- Russia
- Prior art keywords
- straight
- alkyl
- branched chain
- group
- alkenyl
- Prior art date
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- 150000003862 amino acid derivatives Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 19
- -1 pyraxolyl Chemical group 0.000 claims 15
- 125000004169 (C1-C6) alkyl group Chemical class 0.000 claims 14
- 125000003342 alkenyl group Chemical group 0.000 claims 13
- 125000000304 alkynyl group Chemical group 0.000 claims 13
- 125000000217 alkyl group Chemical group 0.000 claims 10
- 229910052739 hydrogen Inorganic materials 0.000 claims 10
- 239000001257 hydrogen Substances 0.000 claims 10
- 229910052760 oxygen Inorganic materials 0.000 claims 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 7
- 229910052757 nitrogen Inorganic materials 0.000 claims 6
- 229910052717 sulfur Inorganic materials 0.000 claims 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 4
- 229910005965 SO 2 Inorganic materials 0.000 claims 4
- 125000005842 heteroatoms Chemical group 0.000 claims 4
- 230000036457 multidrug resistance Effects 0.000 claims 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 239000008194 pharmaceutical composition Substances 0.000 claims 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 125000002883 imidazolyl group Chemical group 0.000 claims 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 3
- 125000006727 (C1-C6) alkenyl group Chemical class 0.000 claims 2
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical class 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 2
- 230000000240 adjuvant Effects 0.000 claims 2
- 150000001408 amides Chemical class 0.000 claims 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 2
- 239000011230 binding agent Substances 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000004432 carbon atoms Chemical group C* 0.000 claims 2
- 150000003857 carboxamides Chemical class 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- XPXMKIXDFWLRAA-UHFFFAOYSA-N hydrazinide Chemical compound [NH-]N XPXMKIXDFWLRAA-UHFFFAOYSA-N 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000001041 indolyl group Chemical group 0.000 claims 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims 2
- 230000001404 mediated Effects 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 150000002829 nitrogen Chemical group 0.000 claims 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 2
- 239000001301 oxygen Substances 0.000 claims 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 2
- 125000001424 substituent group Chemical group 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims 1
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
- 125000005955 1H-indazolyl group Chemical group 0.000 claims 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical class 0.000 claims 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 claims 1
- 102000018075 Subfamily B ATP Binding Cassette Transporter Human genes 0.000 claims 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 125000003828 azulenyl group Chemical group 0.000 claims 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 230000003034 chemosensitisation Effects 0.000 claims 1
- 239000006114 chemosensitizer Substances 0.000 claims 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drugs Drugs 0.000 claims 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N imidazolidine Chemical group C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims 1
- 125000000842 isoxazolyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- 125000002971 oxazolyl group Chemical group 0.000 claims 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 102000004169 proteins and genes Human genes 0.000 claims 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims 1
- 125000003373 pyrazinyl group Chemical group 0.000 claims 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims 1
- 125000005412 pyrazyl group Chemical group 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims 1
- 125000005493 quinolyl group Chemical group 0.000 claims 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 230000002194 synthesizing Effects 0.000 claims 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 0 BC(C(C)C(C)(C)N(*)C(C(C(*C)C(C(*)=O)=O)I)=O)C1CC1 Chemical compound BC(C(C)C(C)(C)N(*)C(C(C(*C)C(C(*)=O)=O)I)=O)C1CC1 0.000 description 1
Claims (17)
где R1, B и D независимо друг от друга обозначают:
Ar, (C1-C6)-алкил с прямой или разветвленной цепью, (C2-C6)-алкенил с прямой или разветвленной цепью, (C5-C7)-циклоалкилзамещенный (C1-C6)-алкил с прямой или разветвленной цепью, (C5-C7)-циклоалкилзамещенный (C3-C6)-алкенил с прямой или разветвленной цепью, (C5-C7)-циклоалкилзамещенный (C1-C6)-алкил с прямой или разветвленной цепью, (C5-C7)-циклоалкилзамещенный (C3-C6)-алкенил с прямой или разветвленной цепью, Ar-замещенный (C1-C6)-алкенил или алкинил с прямой или разветвленной цепью, Ar-замещенный (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью;
где любая из CH2 групп указанных алкильных цепей может быть необязательно замещена гетероатомом, выбираемым из группы, включающей O, S, SO2 и NR, где R выбран из группы, включающей водород, (C1-C4)-алкил с прямой или разветвленной цепью, (C3-C4)-алкенил с прямой или разветвленной цепью и (C1-C4) мостиковый алкил, где мостик образован между азотом и атомом углерода указанной содержащей гетероатом цепи с образованием кольца и где указанное кольцо необязательно конденсировано с Ar группой;
B и D могут также обозначать водород;
при условии, что R1 не является водородом;
J выбран из группы, включающей (C1-C6)-алкил с прямой или разветвленной цепью, (C3-C6)-алкенил с прямой или разветвленной цепью, Ar-замещенный (C1-C6)-алкенил с прямой или разветвленной цепью и Ar-замещенный (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью;
K выбран из группы, включающей (C1-C6)-алкил с прямой или разветвленной цепью, Ar-замещенный (C1-C6)-алкил с прямой или разветвленной цепью, Ar-замещенный (C2-C6)-алкенил или алкинил с прямой или разветвленной цепью и циклогексилметил;
X выбран из группы, включающей Ar, -OR2 и NR3R4;
где R2 имеет те же значения, что и R1; и
R3 и R4 независимо друг от друга имеют те же значения, что B и D; или R3 и R4, вместе взятые, образуют 5-7-членное гетероциклическое алифатическое или ароматическое кольцо;
где Ar является карбоциклической ароматической группой, выбираемой из группы, включающей фенил, 1-нафтил, 2-нафтил, инденил, азуленил, флуоренил и антраценил;
или Ar является гетероциклической ароматической группой, выбираемой из группы, включающей: 2-фурил, 3-фурил, 2-тиенил, 3-тиенил, 2-пиридил, 3-пиридил, 4-пиридил, пирролил, оксазолил, тиазолил, имидазолил, пираксолил, 2-пиразолинил, пиразолидинил, изоксазолил, изотриазолил, 1,2,3-оксадиазолил, 1,2,3-триазолил, 1,3,4-тиадиазолил, пиридазинил, пиримидинил, пиразинил, 1,3,5-триазинил, 1,3,5-тритианил, индолизинил, индолил, изоиндолил, 3H-индолил, индолинил, бензо[b]фуранил, бензо[b]тиофенил, 1H-индазолил, бензимидазолил, бензтиазолил, пуринил, 4H-хинолизинил, хинолинил, 1,2,3,4-тетрагидрохинолинил, изохинолинил, 1,2,3,4-тетрагидроизохинолинил, циннолинил, фталазинил, хиназолинил, хиноксалинил, 1,8-нафтиридинил, птеридинил, карбазолил, акридинил, феназинил, фенотиазинил и феноксазинил;
где Ar может иметь один или несколько заместителей, которые независимо друг от друга выбраны из группы, включающей водород, галоген, гидроксил, нитро, -SO3H, трифторметил, трифторметокси, (C1-C6)-алкил с прямой или разветвленной цепью, O-[(C1-C6)-алкил с прямой или разветвленной цепью], O-[(C3-C4)-алкенил с прямой или разветвленной цепью] , O-бензил, O-фенил, 1,2-метилендиокси, -NR5R6, карбоксил, N-(C1-C5)-алкил с прямой или разветвленной цепью или C3-C5-алкенил с прямой или разветвленной цепью)карбоксамиды, N, N-ди-(C1-C5)-алкил с прямой или разветвленной цепью или C3-C5-алкенил с прямой или разветвленной цепью)карбоксамиды, морфолинил, пиперидинил, O-M, CH2-(CH2)q-M, 0-(CH2)q-M, (CH2)q-O-M и CH=CH-M;
где R5 и R6 независимо друг от друга выбраны из группы, включающей водород, (C1-C6)-алкил с прямой или разветвленной цепью, (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью и бензил; M выбран из группы, включающей 4-метоксифенил, 2-пиридил, 3-пиридил, 4-пиридил, пиразил, хинолил, 3,5-диметилизоксазоил, 2-метилтиазоил, тиазоил, 2-тиенил, 3-тиенил и пиримидил; и q означает 0-2; и
m означает 0 или 1.1. The compound of formula I]
where R 1 , B and D independently denote:
Ar, (C 1 -C 6) straight chained or branched chain, (C 2 -C 6) straight chained or branched alkenyl, (C5-C7) cycloalkyl substituted straight chained or branched chain (C5-C6) alkyl, (C5 -C7) cycloalkyl-substituted (C3-C6) -alkenyl with a straight or branched chain, (C5-C7) -cycloalkyl-substituted (C1-C6) -alkyl with a straight or branched chain, (C5-C7) -cycloalkyl-substituted (C3-C6) straight-chained or branched alkenyl, Ar-substituted (C 1 -C 6) alkenyl or straight or branched alkynyl, Ar-substituted straight or branched C (C 3 -C 6) alkenyl or alkynyl;
where any of the CH 2 groups of said alkyl chains may be optionally substituted with a heteroatom selected from the group including O, S, SO 2 and NR, where R is selected from the group including hydrogen, (C 1 -C 4) -alkyl with a straight or branched chain , Straight chained or branched (C3-C4) -alkenyl and (C1-C4) bridged alkyl, wherein a bridge is formed between nitrogen and a carbon atom of said hetero atom-containing chain to form a ring and where said ring is optionally condensed with an Ar group;
B and D may also be hydrogen;
with the proviso that R 1 is not hydrogen;
J is selected from the group comprising (C 1 -C 6) alkyl with a straight or branched chain, (C 3 -C 6) alkenyl with a straight or branched chain, Ar-substituted (C 1 -C 6) alkenyl with a straight or branched chain and Ar- substituted (C3-C6) alkenyl or straight or branched alkynyl;
K is selected from the group comprising (C 1 -C 6) -alkyl with a straight or branched chain, Ar-substituted (C 1 -C 6) -alkyl with a straight or branched chain, Ar-substituted (C 2 -C 6) -alkenyl or alkynyl with a straight or branched chain and cyclohexylmethyl;
X is selected from the group consisting of Ar, -OR 2 and NR 3 R 4 ;
where R 2 has the same meaning as R 1 ; and
R 3 and R 4 independently of one another have the same meaning as B and D; or R 3 and R 4 together form a 5-7 membered heterocyclic aliphatic or aromatic ring;
where Ar is a carbocyclic aromatic group selected from the group comprising phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl;
or Ar is a heterocyclic aromatic group selected from the group including: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl , 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1 , 3,5-trityanil, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, , 3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
where Ar may have one or more substituents that are independently selected from the group comprising hydrogen, halogen, hydroxyl, nitro, -SO 3 H, trifluoromethyl, trifluoromethoxy, (C 1 -C 6) -alkyl with a straight or branched chain, O - [(C1-C6) -alkyl with a straight or branched chain], O - [(C3-C4) -alkenyl with a straight or branched chain], O-benzyl, O-phenyl, 1,2-methylenedioxy, -NR 5 R 6 , carboxyl, N- (C1-C5) alkyl with a straight or branched chain or C3-C5 alkenyl with a straight or branched chain) carboxamides, N, N-di- (C1-C5) alkyl with a straight or branched chain or C3-C5-alkeny l with a straight or branched chain) carboxamide, morpholinyl, piperidinyl, OM, CH 2 - (CH 2 ) q -M, 0- (CH 2 ) q -M, (CH 2 ) q -OM and CH = CH-M;
wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, straight chained or branched (C 1 -C 6 ) -alkyl, (C 3 -C 6) -alkenyl or straight or branched alkynyl and benzyl; M is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, and pyrimidyl; and q is 0-2; and
m means 0 or 1.
-(CH2)r-(Z)-(CH2)s-Ar,
где r означает 1-4;
s означает 0-1;
Ar имеет значения, указанные в пункте 1; и
каждый Z независимо от других выбран из группы, включающей CH2, O, S, SO, SO2 и NR, где R выбран из группы, включающей водород, (C1-C4)-алкил с прямой или разветвленной цепью, (C3-C4)-алкенил или алкинил с прямой или разветвленной цепью и (C1-C4)-мостиковый алкил, где мостик образован между атомом азота и Ar группой.2. The compound of formula I according to claim 1, wherein at least one of B or D independently of the other is represented by the formula
- (CH 2 ) r - (Z) - (CH 2 ) s -Ar,
where r is 1-4;
s is 0-1;
Ar is as defined in paragraph 1; and
each Z is independently selected from the group including CH 2 , O, S, SO, SO 2 and NR, where R is selected from the group including hydrogen, (C 1 -C 4) -alkyl with a straight or branched chain, (C3-C4 ) alkenyl or alkynyl with a straight or branched chain and (C1-C4) -bridged alkyl, where a bridge is formed between the nitrogen atom and the Ar group.
где J и K независимо друг от друга обозначают (C1-C6)-алкил с прямой или разветвленной цепью или Ar-замещенный (C1-C6)-алкил с прямой или разветвленной цепью;
каждый Ar независимо от других имеет значения, указанные в пункте 3, и каждый w означает 1 или 2.4. The compound of formula II or III:
where J and K are independently of each other (straight chained or branched C 1 -C 6) -alkyl or straight-chained or branched Ar-substituted C 1 -C 6 -alkyl;
each Ar, independently of the others, is as defined in paragraph 3, and each w is 1 or 2.
где Pyr - пиридильный радикал, Ph - фенильная группа и Im - имидазолильная группа.5. The compound of formula I ', selected from the group, where B, D, J, K and R 1 for each compound have the following values:
where Pyr is a pyridyl radical, Ph is a phenyl group and Im is an imidazolyl group.
(S)-N-(4-Фторбензил)-2-(метил-(2-оксо-2-(3,4,5-триметоксифенил)ацетил)амино)-3-фенил-N-(3-(пиридин-4-ил)-1-(2-(пиридин-4-ил)-этил)пропил)пропионамид (соединение 6);
(S)-N-(4-Хлорбензил)-2-(метил-(2-оксо-2-(3,4,5-триметоксифенил) ацетил)амино)-3-фенил-N-(3-(пиридин-4-ил)-1-(2-(пиридин-4-ил)-этил) пропил)пропионамид (соединение 8);
(S)-N-Бензил-3-(4-хлорфенил)-2-(метил-(2-оксо-2-(3,4,5-триметоксифенил)ацетил)амино)-N-(3-(пиридин-4-ил)-1-(2-(пиридин-4-ил)этил)пропил)пропионамид (соединение 9); и
(S)-N-4-Фторбензил-3-(4-хлорфенил)-2-(метил-(2-оксо-2-(3,4,5- триметоксифенил)ацетил)амино)-N-(3-(пиридин-4-ил)-1-(2-(пиридин-4-ил) этил)пропил)пропионамид (соединение 19).6. A compound selected from the group including:
(S) -N- (4-Fluorobenzyl) -2- (methyl- (2-oxo-2- (3,4,5-trimethoxyphenyl) acetyl) amino) -3-phenyl-N- (3- (pyridine- 4-yl) -1- (2- (pyridin-4-yl) ethyl) propyl) propionamide (compound 6);
(S) -N- (4-Chlorobenzyl) -2- (methyl- (2-oxo-2- (3,4,5-trimethoxyphenyl) acetyl) amino) -3-phenyl-N- (3- (pyridine- 4-yl) -1- (2- (pyridin-4-yl) ethyl) propyl) propionamide (compound 8);
(S) -N-Benzyl-3- (4-chlorophenyl) -2- (methyl- (2-oxo-2- (3,4,5-trimethoxyphenyl) acetyl) amino) -N- (3- (pyridine- 4-yl) -1- (2- (pyridin-4-yl) ethyl) propyl) propionamide (compound 9); and
(S) -N-4-Fluorobenzyl-3- (4-chlorophenyl) -2- (methyl- (2-oxo-2- (3,4,5-trimethoxyphenyl) acetyl) amino) -N- (3- ( pyridin-4-yl) -1- (2- (pyridin-4-yl) ethyl) propyl) propionamide (compound 19).
где m, B, D, J и K имеют значения, указанные в пункте 1;
R7 обозначает Ar, (C1-C6)-алкил с прямой или разветвленной цепью, (C2-C6)-алкенил или алкинил с прямой или разветвленной цепью, (C5-C7)-циклоалкилзамещенный (C1-C6)-алкил с прямой или разветвленной цепью, (C5-C7)-циклоалкилзамещенный (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью, (C5-C7)-циклоалкенилзамещенный (C1-C6)-алкил с прямой или разветвленной цепью, (C5-C7)-циклоалкенилзамещенный (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью, Ar-замещенный (C1-C6)-алкил с прямой или разветвленной цепью, Ar-замещенный (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью;
где любая из CH2 групп указанных алкильных цепей может быть необязательно замещена гетероатомом, выбираемым из группы, включающей O, S, SO2 и NR, где R выбран из группы, включающей водород, (C1-C4)-алкил с прямой или разветвленной цепью, (C3-C4)-алкенил или алкинил с прямой или разветвленной цепью и (C1-C4)-мостиковый алкил, где мостик образован между азотом и атомом углерода указанной содержащей гетероатом цепи с образованием кольца и где указанное кольцо необязательно сконденсировано с Ar группой;
W является O или S;
Y является O или N, где,
когда Y означает O, тогда R8 является одиночной парой (термин "одиночная пара") относится к одиночной паре электронов, такой как одиночная пара электронов, присутствующая на двухвалентном кислороде) и R9 выбран из группы, включающей Ar, (C1-C6)-алкил с прямой или разветвленной цепью и (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью;
и
когда Y означает N, тогда R8 и R9 независимо друг от друга выбирают из группы, включающей Ar, (C1-C6)-алкил с прямой или разветвленной цепью и (C3-C6)-алкенил или алкинил с прямой или разветвленной цепью; или R8 и R9, вместе взятые, образуют гетероциклическое 5-6-членное кольцо, выбираемое из группы, включающей пирролидин, имидазолидин, пиразолидин, пиперидин и пиперазин;
где Ar имеет значения, указанные в пункте 1.7. The compound of formula XXXI:
where m, B, D, J and K have the meanings indicated in paragraph 1;
R 7 is Ar, straight chained or branched (C 1 -C 6 ) -alkyl, (C 2 -C 6) alkenyl or straight or branched alkynyl, (C 5 -C 7 ) -cycloalkyl-substituted (C 1 -C 6) -alkyl with a straight or branched chain, (C5-C7) cycloalkyl-substituted (C3-C6) alkenyl or straight-chained or branched alkynyl, (C5-C7) -cycloalkenyl-substituted (C1-C6) alkyl with straight or branched chain, (C5-C7) -cycloalkenyl-substituted (C3-C6) -alkenyl or alkynyl with a straight or branched chain, Ar-substituted (C1-C6) -alkyl with a straight or branched chain, Ar-substituted (C3-C6) -alkenyl or alkynyl with a straight line or once branched chain;
where any of the CH 2 groups of said alkyl chains may be optionally substituted with a heteroatom selected from the group including O, S, SO 2 and NR, where R is selected from the group including hydrogen, (C 1 -C 4) -alkyl with a straight or branched chain , (C3-C4) alkenyl or straight-chained or branched alkynyl and (C1-C4) -bridged alkyl, where a bridge is formed between the nitrogen and the carbon atom of the indicated heteroatom containing chain to form a ring and where the said ring is optionally condensed with an Ar group;
W is O or S;
Y is O or N, where,
when Y is O, then R 8 is a single pair (the term "single pair") refers to a single pair of electrons, such as a single pair of electrons present on divalent oxygen) and R 9 is selected from the group consisting of Ar, (C1-C6) straight or branched alkyl and (C3-C6) alkenyl or straight or branched alkynyl;
and
when Y is N, then R 8 and R 9 are independently selected from the group consisting of Ar, (C 1 -C 6) straight or branched chain and (C 3 -C 6) alkenyl or straight or branched alkynyl; or R 8 and R 9 taken together form a heterocyclic 5-6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine and piperazine;
where Ar is as defined in paragraph 1.
r означает 1-4;
s означает 0-1;
Ar имеет значения, указанные в п. 1; и
каждый Z независимо от других выбран из группы, включающей CH2, O, S, SO, SO2 и NR, где R выбран из группы, включающей водород, (C1-C4)-алкил с прямой или разветвленной цепью, (C3-C4)-алкенил или алкинил с прямой или разветвленной цепью и (C1-C4)-мостиковый алкил, где мостик образован между атомом азота и Ar группой.9. The compound of formula XXXI according to claim 7 or 8, where at least one of B or D independently of the other is expressed by the formula - (CH 2 ) r - (Z) - (CH 2 ) s -Ar, where
r is 1-4;
s is 0-1;
Ar is as defined in paragraph 1; and
each Z is independently selected from the group including CH 2 , O, S, SO, SO 2 and NR, where R is selected from the group including hydrogen, (C 1 -C 4) -alkyl with a straight or branched chain, (C3-C4 ) alkenyl or alkynyl with a straight or branched chain and (C1-C4) -bridged alkyl, where a bridge is formed between the nitrogen atom and the Ar group.
(a) связывание аминокислоты формулы IV с амином формулы V:
с получением амида формулы VI
(b) удаление защитных групп из амида формулы VI с получением аминоамида формулы VII:
(c) ацилирование аминоамида формулы (VII) соединением формулы VIII:
где B, D, J, K, X и R1 имеют значения, указанные в п. 1.17. The method of synthesis of the compounds of formula I according to any one of paragraphs. 1 to 3, comprising the steps of:
(a) linking an amino acid of formula IV to an amine of formula V:
to obtain the amide of formula VI
(b) removing the protecting groups from an amide of formula VI to obtain an aminoamide of formula VII:
(c) acylation of an aminoamide of formula (VII) with a compound of formula VIII:
where B, D, J, K, X and R 1 have the meanings indicated in paragraph 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US34083094A | 1994-11-16 | 1994-11-16 | |
| US08/340,830 | 1994-11-16 | ||
| US08/377,285 | 1995-01-23 |
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|---|---|
| RU97110114A true RU97110114A (en) | 1999-05-20 |
| RU2165410C2 RU2165410C2 (en) | 2001-04-20 |
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| RU97110114/04A RU2165410C2 (en) | 1994-11-16 | 1995-11-13 | Derivatives of amino acid, method of their synthesis, pharmaceutical composition and method of suppression of multidrug resistance |
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|---|---|
| US (1) | US5543423A (en) |
| EP (1) | EP1420009A3 (en) |
| KR (1) | KR100404717B1 (en) |
| CN (1) | CN1099407C (en) |
| AR (1) | AR004655A1 (en) |
| PE (1) | PE52396A1 (en) |
| RU (1) | RU2165410C2 (en) |
| ZA (1) | ZA959304B (en) |
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- 1995-11-03 AR ARP950100046A patent/AR004655A1/en active IP Right Grant
- 1995-11-03 ZA ZA959304A patent/ZA959304B/en unknown
- 1995-11-13 CN CN95196279A patent/CN1099407C/en not_active Expired - Fee Related
- 1995-11-13 KR KR1019970703249A patent/KR100404717B1/en not_active IP Right Cessation
- 1995-11-13 EP EP03029635A patent/EP1420009A3/en not_active Withdrawn
- 1995-11-13 RU RU97110114/04A patent/RU2165410C2/en not_active IP Right Cessation
- 1995-11-16 PE PE1995284732A patent/PE52396A1/en not_active Application Discontinuation
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