FI120974B - Borester- och -syraföreningar samt användning därav - Google Patents
Borester- och -syraföreningar samt användning därav Download PDFInfo
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- FI120974B FI120974B FI20041415A FI20041415A FI120974B FI 120974 B FI120974 B FI 120974B FI 20041415 A FI20041415 A FI 20041415A FI 20041415 A FI20041415 A FI 20041415A FI 120974 B FI120974 B FI 120974B
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- Prior art keywords
- alkyl
- aryl
- cell
- compound according
- hydroxy
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000004633 phorbol derivatives Chemical class 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
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- AMMGCGVWJMRTQI-UHFFFAOYSA-N prop-1-en-2-yl carbonochloridate Chemical compound CC(=C)OC(Cl)=O AMMGCGVWJMRTQI-UHFFFAOYSA-N 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
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- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
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- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
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- VHXJRLYFEJAIAM-UHFFFAOYSA-N quinoline-2-sulfonyl chloride Chemical compound C1=CC=CC2=NC(S(=O)(=O)Cl)=CC=C21 VHXJRLYFEJAIAM-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 235000018770 reduced food intake Nutrition 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000025600 response to UV Effects 0.000 description 1
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- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
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- 125000006413 ring segment Chemical group 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000025185 skeletal muscle atrophy Effects 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 239000002884 skin cream Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- UVFAEQZFLBGVRM-MSMWPWNWSA-N succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 UVFAEQZFLBGVRM-MSMWPWNWSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DTWNKTDZTLVHLG-RDJZCZTQSA-N tert-butyl (2s,3s)-3-hydroxy-2-naphthalen-1-yl-5-oxopyrrolidine-1-carboxylate Chemical compound O[C@H]1CC(=O)N(C(=O)OC(C)(C)C)[C@H]1C1=CC=CC2=CC=CC=C12 DTWNKTDZTLVHLG-RDJZCZTQSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IIHPVYJPDKJYOU-UHFFFAOYSA-N triphenylcarbethoxymethylenephosphorane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OCC)C1=CC=CC=C1 IIHPVYJPDKJYOU-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Claims (14)
1. Förening, kännetecknad av formeln k R- j R* li5 L »A i vilken formel P är väte eller en skyddsgrupp för en aminogrupp, med förutsättningen att P inte är R7-C(O)-, R7-NH-C(0)-, R7-0-C(0)- eller R7-S02-, där R7 är en heteroaryl eller en heteroarylalkyl, eller R7-C(0)-, där R7 ärN-morfolinyl; B1, i var förekomst oberoende är N eller CH; X1, i var förekomst oberoende är -C(0)-NH-, -CH2-NH-, -CH(OH)-CH2-, -CH(OH)-CH(OH)-, -CH(OH)-CH2-NH-, -CH=CH-, -C(0)-CH2-, -S02-NH-, -S02-CH2-eller -CH(OH)-CH2-C(0)-NH-, med förutsättningen att da B1 är N, är den till B1 kopplade X1 en -C(0)-NH-; X2 är -C(0)-NH-, -CH(OH)-CH2-, -CH(OH)-CH(OH)-, -C(0)-CH2-, -S02-NH-, -SO2-CH2- eller -CH(OH)-CH2-C(0)-NH-; R är väte eller alkyl, eller R bildar tillsammans med bredvidliggande R1, eller da A är no 11, bildar tillsammans med bredvidliggande R2 ett mono-, bi- eller tricykliskt, mättat eller delvis mättat ringsystem, som innehäller kväve, med 4-14 ringmedlemmar, och, som altemativt kan vara substituerad med en eller tvä av följande: keto, hydroxi, alkyl, aryl, alkoxi eller aryloxi; R1 i var förekomst, R2 och R3 oberoende är väte, alkyl, cykloalkyl, aryl, en mättad, delvis omättad eller aromatisk heterocykel med 5-10 medlemmar, eller -CH2-R5, där vilken som heist närnnda aryl, aralkyl, alkaryl eller heterocykelns ringdel kan vara altemativt substituerad; R5 i var förekomst är aryl, aralkyl, alkaryl, cykloalkyl, en mättad, delvis omättad eller aromatisk heterocykel med 5-10 medlemmar eller -W-R6, där W är en kalkogen och R6 är alkyl, där vilken som heist nämnda aryl, aralkyl, alkaryl eller heterocykelns ringdel kan vara altemativt substituerad; med den förutsättningen att minst en av följande R1, R2 eller R3 är naftylmetyl, pyridylmetyl eller kinolinylmetyl; Z1 och Z2 är, oberoende av varandra, alkyl, hydroxi, alkoxi eller aryloxi eller Z1 och Z2 bildar tillsammans en struktur, som är härledd frän en dihydroxiförening med minst tvä hydroxigrupper, avskiljda via minst tvä sammanbindande atomer i en kedja eller en ring, varvid nämnda kedja eller ring bestär av kolatomer och altemativt en heteroatom eller heteroatomer, vilka kan vara N, S eller O; och A är 0, 1 eller 2: med den förutsättningen att föreningen är nagon annan än isovaleryl-fenylalanin-norvalin-[(naftylmetyl), (4,4,5,5-tetrametyl-1,3,2-dioxaborolan-2-yl)]metylamid, (3-t-butylsulfonyl)propionyl-norvalin-(l-naftylmetyldihydroxiboryl)metylamid eller (3-t-butylsulfonyljpropionyl-norvalin-[ 1 -naftylmetyl(4,4,5,5-tetrametyl-1,3,2-dioxaborollan-2-yl)]metylamid.
2. Föreningen enligt patentkrav 1, kännetecknad av att P är R7-C(0)- eller R7-S02-, R -NH-C(O) - och R är alkyl, aryl, alkaryl eller aralkyl, av vilka vilken som heist kan vara altemativt substituerad, eller da P är R7-C(0)-, kan R7 även vara en mättad eller delvis mättad heterocykel.
3. Föreningen enligt patentkrav 1, kännetecknad av att P är R7-C(0)- eller R7-SC>2-; och R7 är Cö-io-aryl eller C6-io-ar(Ci^)alkyl, av vilka vilken som heist kan vara altemativt substituerad. Föreningen enligt patentkrav 1, kännetecknad av att B1 är CH och X1 och X2 är var och en -C(0)-NH-.
5. Föreningen enligt patentkrav 1, kännetecknad av att Ri och R2 är oberoende valda ur gruppen, som innefattar alkyl och -CH2-R5, varvid R5är Cö-io-aryl, Ci_io-alk(C6-io)aryl, C3-io-cykloalkyl, eller en heterocykel med 5-, 6-, 9- eller 10 medlemmar.
6. Föreningen enligt patentkrav 1, kännetecknad av att ringsystemet, som innehäller kväve, väljs ur gruppen, som innefattar O. n, H. o, O and ^ A ^
7. Föreningen enligt patentkrav 1, kännetecknad av att R väljs ur gruppen, som innefattar metyl, etyl, isopropyl, isobutyl och n-butyl.
8. Föreningen enligt patentkrav 1, kännetecknad av att Z1 och Z2, oberoende av varandra, är Ci_4-alkyl, hydroxi, Ci_6-alkoxi eller CVm-aryloxi, eller Z1 och Z2 bildar tillsammans en struktur, som är härledd ur en dihydroxiförening, som väljs ur gruppen, som innefattar pinakol, perfluorpinakol, pinandiol, etylenglykol, dietylenglykol, 1,2-cyklohexandiol, 1,3-propandiol, 2,3-butandiol, glycerol eller dietanolamin.
9. Föreningen enligt patentkrav 8, kännetecknad av att Z1 och Z2 bäda är hydroxi.
10. Föreningen enligt patentkrav 1, kännetecknad av att A är noll.
11. Föreningen enligt patentkrav 1, kännetecknad av att R2 är kinolinylmetyl.
12. Farmaceutisk sammansättning, kännetecknad av att den omfattar föreningen enligt nägot föregäende patentkrav, dess farmaceutiskt godkännbara sait eller boronatester samt en farmaceutiskt godkännbar bärare eller diluent.
13. Farmaceutiska sammansättningen enligt patentkrav 12, kännetecknad av att nämnda förening är närvarande i en mängd, som är effektiv för inhibering av proteasomfunktionen i ett däggdjur.
14. Användning av en förening enligt nägot av patentkraven 1 - 11 för framställning av en farmaceutisk sammansättning, som används för (a) inhibering av tillväxten av cancerceller, (b) minskning av nedbrytningshastigheten av muskelprotein i cellen, (c) minskning av NF-KB-aktiviteten i cellen, (d) minskning av hastigheten för nedbrytning av intracellulärt protein i cellen, (e) minskning av nedbrytningshastigheten av p53-protein i cellen, (f) inhibering av nedbrytningen av cyklin i cellen, (g) förhindrande eller värd av ett inflammatoriskt tillständ, (h) inhibering av förekomsten av antigener i cellen, (i) inhibering av NF-KB-beroende celladhesion eller (j) inhibering av replikationen av HIV. 1 Användningen enligt patentkrav 14, kännetecknad av att patienten har ett diagnoserat, eller har en risk för att utveckla ett, tillständ, som väljs ur gruppen, som innefattar vävnadsavstötning, organavstötning, artrit, infektion, dermatos, inflammatorisk tarmsjukdom, astma, osteoporos, osteoartrit och autoimmunsjukdom.
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US08/442,581 US6083903A (en) | 1994-10-28 | 1995-05-16 | Boronic ester and acid compounds, synthesis and uses |
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PCT/US1995/014117 WO1996013266A1 (en) | 1994-10-28 | 1995-10-27 | Boronic ester and acid compounds, synthesis and uses |
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