HRP20191821T1 - Antiproliferativni spojevi i načini njihove uporabe - Google Patents
Antiproliferativni spojevi i načini njihove uporabe Download PDFInfo
- Publication number
- HRP20191821T1 HRP20191821T1 HRP20191821TT HRP20191821T HRP20191821T1 HR P20191821 T1 HRP20191821 T1 HR P20191821T1 HR P20191821T T HRP20191821T T HR P20191821TT HR P20191821 T HRP20191821 T HR P20191821T HR P20191821 T1 HRP20191821 T1 HR P20191821T1
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- dioxopiperidin
- oxoisoindolin
- difluoro
- acetamide
- Prior art date
Links
Classifications
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Transplantation (AREA)
- Communicable Diseases (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201462023775P | 2014-07-11 | 2014-07-11 | |
| EP15739485.9A EP3166937B1 (en) | 2014-07-11 | 2015-07-10 | Antiproliferative compounds and methods of use thereof |
| PCT/US2015/039926 WO2016007848A1 (en) | 2014-07-11 | 2015-07-10 | Antiproliferative compounds and methods of use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20191821T1 true HRP20191821T1 (hr) | 2019-12-27 |
Family
ID=53682892
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20191821TT HRP20191821T1 (hr) | 2014-07-11 | 2015-07-10 | Antiproliferativni spojevi i načini njihove uporabe |
Country Status (31)
| Country | Link |
|---|---|
| US (6) | US9499514B2 (OSRAM) |
| EP (2) | EP3594211B1 (OSRAM) |
| JP (3) | JP6779870B2 (OSRAM) |
| KR (1) | KR102477960B1 (OSRAM) |
| CN (2) | CN106660991B (OSRAM) |
| AR (1) | AR101189A1 (OSRAM) |
| AU (1) | AU2015287688B2 (OSRAM) |
| BR (1) | BR112017000550B1 (OSRAM) |
| CA (1) | CA2954784C (OSRAM) |
| CL (1) | CL2017000075A1 (OSRAM) |
| CO (1) | CO2017000223A2 (OSRAM) |
| CY (1) | CY1122340T1 (OSRAM) |
| DK (1) | DK3166937T3 (OSRAM) |
| EA (1) | EA033633B1 (OSRAM) |
| EC (1) | ECSP17002135A (OSRAM) |
| ES (2) | ES2968308T3 (OSRAM) |
| HR (1) | HRP20191821T1 (OSRAM) |
| HU (1) | HUE046000T2 (OSRAM) |
| IL (2) | IL276946B (OSRAM) |
| LT (1) | LT3166937T (OSRAM) |
| MX (2) | MX373935B (OSRAM) |
| PL (1) | PL3166937T3 (OSRAM) |
| PT (1) | PT3166937T (OSRAM) |
| RS (1) | RS59619B1 (OSRAM) |
| SA (1) | SA517380693B1 (OSRAM) |
| SG (2) | SG11201700126RA (OSRAM) |
| SI (1) | SI3166937T1 (OSRAM) |
| SM (1) | SMT201900686T1 (OSRAM) |
| TW (1) | TWI660952B (OSRAM) |
| WO (1) | WO2016007848A1 (OSRAM) |
| ZA (1) | ZA201700217B (OSRAM) |
Families Citing this family (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9732154B2 (en) | 2014-02-28 | 2017-08-15 | Janssen Biotech, Inc. | Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia |
| US9603927B2 (en) | 2014-02-28 | 2017-03-28 | Janssen Biotech, Inc. | Combination therapies with anti-CD38 antibodies |
| US9499514B2 (en) * | 2014-07-11 | 2016-11-22 | Celgene Corporation | Antiproliferative compounds and methods of use thereof |
| SG11201701867SA (en) | 2014-09-09 | 2017-04-27 | Janssen Biotech Inc | Combination therapies with anti-cd38 antibodies |
| WO2016089960A1 (en) | 2014-12-04 | 2016-06-09 | Janssen Biotech, Inc. | Anti-cd38 antibodies for treatment of acute myeloid leukemia |
| MA42136A (fr) | 2015-05-20 | 2018-03-28 | Janssen Biotech Inc | Anticorps anti-cd38 pour le traitement de l'amyloïdose à chaînes légères et d'autres tumeurs malignes hématologiques positives à cd38 |
| US10668149B2 (en) | 2015-06-22 | 2020-06-02 | Janssen Biotech, Inc. | Combination therapies for heme malignancies with anti-CD38 antibodies and survivin inhibitors |
| US20170044265A1 (en) | 2015-06-24 | 2017-02-16 | Janssen Biotech, Inc. | Immune Modulation and Treatment of Solid Tumors with Antibodies that Specifically Bind CD38 |
| PH12018500950B1 (en) | 2015-11-03 | 2023-09-20 | Janssen Biotech Inc | Subcutaneous formulations of anti-cd38 antibodies and their uses |
| US10781261B2 (en) | 2015-11-03 | 2020-09-22 | Janssen Biotech, Inc. | Subcutaneous formulations of anti-CD38 antibodies and their uses |
| AR107321A1 (es) * | 2016-01-08 | 2018-04-18 | Celgene Corp | Compuestos antiproliferativos, y sus composiciones farmacéuticas y usos |
| US10189808B2 (en) | 2016-01-08 | 2019-01-29 | Celgene Corporation | Solid forms of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide, and their pharmaceutical compositions and uses |
| MX390772B (es) * | 2016-01-08 | 2025-03-21 | Celgene Corp | Métodos para tratar cáncer y el uso de biomarcadores como predictor de sensibilidad clínica a terapias. |
| CA3010797C (en) | 2016-01-08 | 2024-01-02 | Celgene Corporation | Formulations of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
| KR20190015300A (ko) * | 2016-06-06 | 2019-02-13 | 셀진 코포레이션 | 2-(4-클로로페닐)-n-((2-(2,6-다이옥소피페리딘-3-일)-1-옥소아이소인돌린-5-일)메틸)-2,2-다이플루오로아세트아마이드에 의한 혈액 악성종양의 치료 |
| US11535603B1 (en) | 2016-09-30 | 2022-12-27 | Deuterx, Llc | Deuterium-enriched piperidinonyl-oxoisoindolinyl acetamides and methods of treating medical disorders using same |
| CN106928253A (zh) * | 2017-03-09 | 2017-07-07 | 武汉工程大学 | 一种唑啉草酯的制备方法 |
| MX2019015886A (es) * | 2017-06-30 | 2020-09-10 | Celgene Corp | Composiciones y metodos de uso de 2-(4-clorofenil)-n-((2-(2,6-diox opiperidin-3-il)-1-0xoisoindolin-5-il)metil)-2,2-difluoroacetamid a. |
| US11618787B2 (en) | 2017-10-31 | 2023-04-04 | Janssen Biotech, Inc. | Methods of treating high risk multiple myeloma |
| CN107827721B (zh) * | 2017-11-17 | 2021-03-16 | 上海恩氟佳科技有限公司 | 一种合成4-氟环己酮的方法 |
| US20210069356A1 (en) * | 2018-01-02 | 2021-03-11 | Celgene Corporation | Isotopologues of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide |
| AU2019294835B2 (en) * | 2018-06-29 | 2025-04-17 | Dana-Farber Cancer Institute, Inc. | Ligands to cereblon (CRBN) |
| CA3125189A1 (en) * | 2018-12-31 | 2020-07-09 | Celgene Corporation | Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5yl) methyl)-2,2-difluoroacetamide |
| US12479817B2 (en) | 2019-02-15 | 2025-11-25 | Novartis Ag | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
| AR119057A1 (es) * | 2019-05-31 | 2021-11-17 | Celgene Corp | Compuestos de 1-oxo-isoindolin-5-carboxamida sustituida, composiciones de estos y métodos de tratamiento con dichos compuestos |
| CA3154923A1 (en) | 2019-10-21 | 2021-04-29 | Celgene Corporation | Substituted 4-aminoisoindoline-1,3-dione compounds and second active agents for combined use |
| WO2021091946A1 (en) | 2019-11-05 | 2021-05-14 | Celgene Corporation | Combination therapy with 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide |
| GB201916600D0 (en) * | 2019-11-14 | 2020-01-01 | Syngenta Crop Protection Ag | 81991-gb-reg-org-nat-1 |
| BR112022009514A2 (pt) * | 2019-11-19 | 2022-08-16 | Bristol Myers Squibb Co | Compostos úteis como inibidores de proteína helios |
| CN114761004A (zh) * | 2019-12-06 | 2022-07-15 | 细胞基因公司 | 用于制备2-(4-氯苯基)-n-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-5-基)甲基)-2,2-二氟乙酰胺的方法 |
| JP2023519974A (ja) * | 2020-03-31 | 2023-05-15 | オラム・セラピューティクス・インコーポレイテッド | neoDegraderコンジュゲート |
| EP4171550A1 (en) | 2020-06-25 | 2023-05-03 | Celgene Corporation | Methods for treating cancer with combination therapies |
| IL300308A (en) * | 2020-08-03 | 2023-04-01 | Captor Therapeutics S A | Low molecular weight protein complexes and their applications |
| MX2023003114A (es) | 2020-09-23 | 2023-03-23 | St Jude Childrens Res Hospital Inc | Analogos de n-(2-(2,6-dioxopiperidin-3-il)-1,3-dioxoisoindolin-5-i l)arilsulfonamida sustituidos como moduladores de la proteina cereblon. |
| MX2023008296A (es) | 2021-01-13 | 2023-09-29 | Monte Rosa Therapeutics Inc | Compuestos de isoindolinona. |
| WO2022235900A1 (en) * | 2021-05-06 | 2022-11-10 | Celgene Corporation | Methods of treatment with n-((r)-1-(3-chloropyridin-2-yl)- 2,2,2-trifluoroethyl)-2-((s)-2,6-dioxopiperidin-3-yl)-1- oxoisoindoline-5-carboxamide |
| EP4091449A1 (en) * | 2021-05-19 | 2022-11-23 | Syngenta Crop Protection AG | Weed control method |
| CN117320550A (zh) * | 2021-05-19 | 2023-12-29 | 先正达农作物保护股份公司 | 杂草控制方法 |
| WO2023037268A1 (en) * | 2021-09-08 | 2023-03-16 | Orum Therapeutics, Inc. | Linkers for use in antibody drug conjugates |
| WO2024027694A1 (zh) * | 2022-08-01 | 2024-02-08 | 苏州开拓药业股份有限公司 | 一种蛋白降解剂 |
| TW202423411A (zh) * | 2022-10-06 | 2024-06-16 | 南韓商歐倫醫療公司 | 新降解劑綴合物 |
| WO2024169913A1 (zh) * | 2023-02-15 | 2024-08-22 | 石药集团巨石生物制药有限公司 | 一种度胺类分子胶衍生物及其用途 |
| WO2024178348A2 (en) * | 2023-02-24 | 2024-08-29 | Ppm Biopharma Llc | Pleiotropic pathway modifier compounds and method of treating diseases |
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