TW202104230A - 用於治療自體免疫疾病之六氫-1H-吡并[1,2-a]吡化合物 - Google Patents
用於治療自體免疫疾病之六氫-1H-吡并[1,2-a]吡化合物 Download PDFInfo
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- TW202104230A TW202104230A TW109111749A TW109111749A TW202104230A TW 202104230 A TW202104230 A TW 202104230A TW 109111749 A TW109111749 A TW 109111749A TW 109111749 A TW109111749 A TW 109111749A TW 202104230 A TW202104230 A TW 202104230A
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- Prior art keywords
- methyl
- hexahydro
- amino
- carbonitrile
- quinoline
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- 238000011282 treatment Methods 0.000 title claims description 25
- 208000023275 Autoimmune disease Diseases 0.000 title description 3
- XPPVFPABNTZREL-UHFFFAOYSA-N C1C=2N(CCN1)CCNC=2 Chemical class C1C=2N(CCN1)CCNC=2 XPPVFPABNTZREL-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 451
- 238000000034 method Methods 0.000 claims abstract description 58
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- -1 5-oxa-2,8-diazaspiro[3.5]nonyl Chemical group 0.000 claims description 413
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- CIIFKVFOVFJZDM-UHFFFAOYSA-N quinoline-8-carbonitrile Chemical compound C1=CN=C2C(C#N)=CC=CC2=C1 CIIFKVFOVFJZDM-UHFFFAOYSA-N 0.000 claims description 201
- 238000002360 preparation method Methods 0.000 claims description 189
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 102
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 90
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 85
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- 238000006243 chemical reaction Methods 0.000 claims description 53
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- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 48
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 33
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- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
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- JYCGXZGGVUKKNQ-UHFFFAOYSA-N tert-butyl formate piperazine Chemical compound C(C)(C)(C)OC=O.N1CCNCC1 JYCGXZGGVUKKNQ-UHFFFAOYSA-N 0.000 description 1
- CBYPCXLWNJUVLF-UHFFFAOYSA-N tert-butyl n-(2-azaspiro[3.3]heptan-6-yl)carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CC11CNC1 CBYPCXLWNJUVLF-UHFFFAOYSA-N 0.000 description 1
- BZSDDSIFAGBZLT-RNFRBKRXSA-N tert-butyl n-[(3r,4r)-4-fluoropyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CNC[C@H]1F BZSDDSIFAGBZLT-RNFRBKRXSA-N 0.000 description 1
- BZSDDSIFAGBZLT-RQJHMYQMSA-N tert-butyl n-[(3s,4r)-4-fluoropyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CNC[C@H]1F BZSDDSIFAGBZLT-RQJHMYQMSA-N 0.000 description 1
- PIGDOXPNNMFBNA-YUMQZZPRSA-N tert-butyl n-[(3s,4s)-4-methoxypyrrolidin-3-yl]carbamate Chemical compound CO[C@H]1CNC[C@@H]1NC(=O)OC(C)(C)C PIGDOXPNNMFBNA-YUMQZZPRSA-N 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 229940044616 toll-like receptor 7 agonist Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- MBMQEIFVQACCCH-QBODLPLBSA-N zearalenone Chemical compound O=C1O[C@@H](C)CCCC(=O)CCC\C=C\C2=CC(O)=CC(O)=C21 MBMQEIFVQACCCH-QBODLPLBSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Life Sciences & Earth Sciences (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Transplantation (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| WO2021094301A1 (en) * | 2019-11-12 | 2021-05-20 | F. Hoffmann-La Roche Ag | Hydropyrazino[1,2-b]isoquinoline compounds for the treatment of autoimmune disease |
| US12503471B2 (en) | 2019-11-19 | 2025-12-23 | Hoffmann-La Roche Inc. | Triazatricycle compounds for the treatment of autoimmune disease |
| JP2023502087A (ja) | 2019-11-19 | 2023-01-20 | エフ．ホフマン－ラ ロシュ アーゲー | 自己免疫疾患の処置のためのヒドロ－１Ｈ－ピロロ［１，２－ａ］ピラジン化合物 |
| CR20220236A (es) | 2019-11-28 | 2022-10-03 | Bayer Pharma AG | Aminoquinolonas sustituidas como inhibidores de dgk alfa para la activación inmune |
| US12421229B2 (en) | 2019-12-03 | 2025-09-23 | Hoffmann-La Roche Inc. | Hydropyrido[1,2-α]pyrazine compounds for the treatment of autoimmune disease |
| WO2022013136A1 (en) * | 2020-07-14 | 2022-01-20 | F. Hoffmann-La Roche Ag | Hydroisoquinoline or hydronaphthyridine compounds for the treatment of autoimmune disease |
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| HUE037689T2 (hu) | 2012-09-14 | 2018-09-28 | Hoffmann La Roche | Pirazol-karboxamid származékok mint TAAR-modulátorok különféle rendellenességek, mint például depresszió, cukorbetegség és Parkinson-kór kezelésében történõ alkalmazásra |
| EP3080124A1 (en) * | 2013-12-13 | 2016-10-19 | Takeda Pharmaceutical Company Limited | Pyrrolo[3,2-c]pyridine derivatives as tlr inhibitors |
| PT3889145T (pt) * | 2015-12-17 | 2024-04-02 | Merck Patent Gmbh | 8-ciano-5-piperidino-quinolinas como antagonistas de tlr7/8 e suas utilizações para tratamento de distúrbios imunitários |
| EP3807271A1 (en) * | 2018-06-13 | 2021-04-21 | F. Hoffmann-La Roche AG | Pyridinyl heterocyclyl compounds for the treatment of autoimmune disease |
| US20210395239A1 (en) * | 2018-09-27 | 2021-12-23 | Hoffmann-La Roche Inc. | Heterocyclyl compounds for the treatment of autoimmune disease |
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| PE20212178A1 (es) | 2021-11-09 |
| JP7692838B2 (ja) | 2025-06-16 |
| KR20210149163A (ko) | 2021-12-08 |
| CR20210513A (es) | 2021-11-02 |
| CN113710672A (zh) | 2021-11-26 |
| SG11202110401WA (en) | 2021-10-28 |
| BR112021020297A2 (pt) | 2021-12-14 |
| US20220340597A1 (en) | 2022-10-27 |
| PH12021552533A1 (en) | 2022-06-20 |
| IL286870A (en) | 2021-10-31 |
| WO2020207991A1 (en) | 2020-10-15 |
| AU2020272467A1 (en) | 2021-10-14 |
| JP2022527588A (ja) | 2022-06-02 |
| EP3953356C0 (en) | 2023-07-26 |
| EP3953356A1 (en) | 2022-02-16 |
| MA55594A (fr) | 2022-02-16 |
| MX2021012223A (es) | 2021-11-03 |
| CL2021002621A1 (es) | 2022-05-13 |
| CN113710672B (zh) | 2025-01-03 |
| EP3953356B1 (en) | 2023-07-26 |
| CA3135129A1 (en) | 2020-10-15 |
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