Benzoxazepine compounds and methods of use thereof
阅读说明：本技术 苯并氧氮杂*噁唑烷酮化合物及其使用方法 (Benzoxazepine compounds and methods of use thereof ) 是由 M-G·布劳恩 E·哈南 S·T·施塔本 R·埃利奥特 R·A·赫尔德 C·麦克劳德 于 2016-07-01 设计创作，主要内容包括：本申请描述了具有磷酸肌醇-3-激酶(PI3K)调节活性或功能的苯并氧氮杂<Image he="66" wi="58" file="DDA0002567479740000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>噁唑烷酮化合物及其立体异构体、互变异构体或药学上可接受的盐,所述化合物选自下述式I结构,并且具有本申请所述的取代基和结构特征。本申请还描述了包含式I化合物的药物组合物和药物,以及单独使用此类PI3K调节剂和与其它治疗剂组合使用以治疗介导或依赖于PI3K失调的疾病或病症的方法。<Image he="548" wi="614" file="DDA0002567479740000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Benzoxazepines having phosphoinositide-3-kinase (PI3K) modulating activity or function are described Oxazolidinone compounds, and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, selected from the structures of formula I, below, and having the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include compounds of formula I, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, to treat diseases or conditions that are mediated or dependent on PI3K dysregulation.)
1. A compound selected from formula I, and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof:
wherein:
R1is selected from-CH3、-CH2CH3、-CH(CH3)2、-CHF2、-CH2F and-CF3；
X is selected from:
wherein the wavy line represents the attachment site; and is
R2Is selected from H, C1-C6Alkyl, cyclopropyl and cyclobutyl optionally substituted by F, -OCH3or-OH.
2. The compound of claim 1, which is of formula Ia:
3. the compound of claim 1 of formula Ib:
4. a compound according to claim 2 or 3, wherein R1Selected from-CHF2and-CH2F。
5. The compound of any one of claims 1-4, wherein R2is-CH3。
6. The compound of any one of claims 1-5, selected from:
(S) -2- ((2- ((R) -4-isopropyl-2-oxooxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem
(S) -1- (2- ((R) -4-methyl-2-oxooxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem
(S) -1- (2- ((S) -2-oxo-4- (trifluoromethyl) oxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem
(S) -2- ((2- ((R) -4-ethyl-2-oxooxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem -9-yl) oxy) propionamide;
(S) -2- ((2- ((S) -2-oxo-4- (trifluoromethyl) oxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem-9-yl) oxy) propionamide;
(S) -1- (2- ((S) -4- (difluoromethyl) -2-oxooxazoleAlk-3-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem
(S) -2- ((2- ((S) -4- (difluoromethyl) -2-oxooxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem-9-yl) oxy) propionamide;
(S) -1- (2- ((S) -4- (fluoromethyl) -2-oxooxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem
(S) -2- ((2- ((S) -4- (fluoromethyl) -2-oxooxazolidin-3-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem-9-yl) oxy) propionamide.
7. A pharmaceutical composition consisting of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutically acceptable carrier, glidant, or excipient is selected from the group consisting of silicon dioxide, powdered cellulose, microcrystalline cellulose, metal stearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.
9. A process for preparing a pharmaceutical composition comprising combining a compound of any one of claims 1-6 with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
10. Use of a compound according to any one of claims 1-6 in the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from breast cancer and non-small cell lung cancer.
11. The use of claim 10, wherein the medicament further comprises an additional therapeutic agent selected from the group consisting of: 5-FU, docetaxel, eribulin, gemcitabine, cobicistinib, iptasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, palbociclib, bevacizumab, pertuzumab, trastuzumab-maytansine conjugate, trastuzumab, and letrozole.
12. The use of claim 10 or 11, wherein the cancer is breast cancer.
13. The use of claim 12, wherein the breast cancer is estrogen receptor positive (ER +) breast cancer.
14. The use of claim 12, wherein the breast cancer subtype is basal or tubular epithelial.
15. The use of claim 12, wherein the cancer expresses a PIK3CA mutant selected from the group consisting of: E542K, E545K, Q546R, H1047L and H1047R.
16. The use of claim 12 wherein the cancer expresses a PTEN mutant.
17. The use of claim 12, wherein the cancer is HER2 positive.
18. The use of claim 12, wherein the patient is HER2 negative, ER (estrogen receptor) negative, and PR (progesterone receptor) negative.
19. A kit for therapeutic treatment of breast cancer, comprising:
a) the pharmaceutical composition of claim 7; and
b) instructions for use in the therapeutic treatment of breast cancer.
Technical Field
The present invention relates generally to benzoxazepinesA pharmaceutical combination of oxazolidinone compounds which have activity against hyperproliferative disorders such as cancer. The invention also relates to the use of said compounds for in vitro, in situ and in vivo diagnosisMethods of disrupting or treating mammalian cells or associated pathological conditions.
Background
Upregulation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is a common feature of most cancers (Yuan and Cantley (2008) Oncogene 27: 5497-. Genetic alterations of this pathway have been detected in a variety of human cancers (Osaka et al (2004) Apoptosis 9:667-76) and serve primarily to stimulate cell proliferation, migration and survival. Activation of this pathway occurs after point mutation or amplification of the PIK3CA gene encoding the p110 α (alpha) PI3K isoform (Hennessy et al (2005) nat. Rev. drug Discov.4: 988-Asn 1004). Genetic deletion or loss of a functional mutation in the tumor suppressor PTEN, a phosphatase that functions in opposition to PI3K, also increases PI3K pathway signaling (Zhang and Yu (2010) clin. cancer res.16: 4325-30). These aberrations increase downstream signaling through kinases such as Akt and mTOR and increased activity of the PI3K pathway has been proposed as a hallmark of resistance to Cancer treatment (Opel et al (2007) Cancer res.67: 735-45; Razis et al (2011) Breast Cancer res.treat.128: 447-56).
Phosphatidylinositol-3-kinase (PI3K) is the major signaling node for critical survival and growth signals of lymphomas and is antagonized by the activity of the phosphatase PTEN. The phosphoinositide 3-dependent kinase (PI3K) signaling pathway is the most severely deregulated pathway in hormone receptor positive breast cancer (HR + BC). The PI3K pathway is deregulated in aggressive forms of lymphoma (Abubaker (2007) Leukemia 21: 2368-. 8% of DLBCL (diffuse large B-cell lymphoma) cancers have a PI3CA (phosphatidylinositol-3-kinase catalytic subunit alpha) missense mutation and are 37% PTEN negative by immunohistochemical testing.
Phosphatidylinositol is one of a variety of phospholipids found in cell membranes and is involved in intracellular signal transduction. Cell signaling via 3' -phosphorylated phosphoinositides has been implicated in a variety of cellular processes such as malignant transformation, growth factor signaling, inflammation and immunity (Rameh et al (1999) J. biol chem.274: 8347-8350). The enzyme responsible for the production of these phosphorylated signaling products, phosphatidylinositol-3-kinase (also known as PI3 kinase or PI3K), was originally identified as having activity associated with viral oncoproteins and growth factor receptor tyrosine kinases, which phosphorylate Phosphatidylinositol (PI) and its phosphorylated derivatives at the 3' -hydroxyl of the inositol ring (Panayotou et al (1992) Trends Cell Biol 2: 358-60). Phosphoinositide-3-kinase (PI3K) is a lipid kinase that phosphorylates lipids at the 3-hydroxyl group of the inositol ring (Whitman et al (1988) Nature,332: 664). The 3-phosphorylated phospholipids generated by PI3 kinase (PIP3) act as second messengers that recruit kinases such as Akt and PDK1 (phosphoinositide-dependent kinase 1) having a lipid binding domain including the Pleckstrin Homology (PH) region (Vivanco et al (2002) Nature Rev. Cancer 2: 489; Phillips et al (1998) Cancer 83: 41).
The PI3 kinase family includes at least 15 different enzymes subdivided by structural homology and classified into three categories according to sequence homology and the products formed by enzymatic catalysis. Class I PI3 kinase is composed of 2 subunits: the 110kd catalytic subunit and the 85kd regulatory subunit. The regulatory subunit contains the SH2 domain and binds to tyrosine residues that are phosphorylated by growth factor receptors or oncogene products with tyrosine kinase activity, thereby inducing PI3K activity of the p110 catalytic subunit, which phosphorylates its lipid substrate. Class I PI3 kinases are involved in cytokine, integrin, growth factor, and important signaling events downstream of immune receptors, suggesting that control of this pathway may lead to important therapeutic effects such as modulation of cell proliferation and carcinogenesis. Class I PI3K phosphorylates Phosphatidylinositol (PI), phosphatidylinositol-4-phosphate and phosphatidylinositol-4, 5-diphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3, 4-diphosphate and phosphatidylinositol-3, 4, 5-triphosphate, respectively. Class II PI3K phosphorylates PI and phosphatidylinositol-4-phosphate. Class III PI3K can phosphorylate only PI. The key PI3 kinase isoform in cancer is the class I PI3 kinase p110 α, as shown by recurrent mutations in the oncogene in p110 α (Samuels et al (2004) Science 304: 554; US 5824492; US 5846824; US 6274327). Other isoforms may be important in Cancer and are also implicated in cardiovascular and immunoinflammatory diseases (Workman P (2004) Biochem Soc Trans 32: 393-396; Patel et al (2004) Proc. am. Assoc. of Cancer Res. (Abstract LB-247)95th Annulalmimeting, March 27-31, Orlando, Florida, USA; Ahmadi K and Waterfield MD (200) 4) "Phosphonoside 3-Kinase: Function and Mechanisms" Encyclopedia of biological chemistry (Lennarz W J, Lane M D eds) Elsevier/Academic Press). Oncogene mutations in p110 α have been found very frequently in solid tumors of the colon, breast, brain, liver, ovary, stomach, lung and head and neck. About 35-40% hormone receptor positivity (HR)+) Breast cancer tumors have the PIK3CA mutation. PTEN abnormalities have been found in glioblastoma, melanoma, prostate cancer, endometrial cancer, ovarian cancer, breast cancer, lung cancer, head and neck cancer, hepatocellular cancer, and thyroid cancer.
PI3 kinase (PI3K) is a heterodimer composed of p85 and p110 subunits (Otsu et al (1991) Cell 65: 91-104; Hiles et al (1992) Cell 70: 419-29). Four different class I PI3K have been identified, designated PI3K α, β, and ω and each is composed of different 110kDa catalytic and regulatory subunits. Three of the catalytic subunits, p110 α, p110 β and p110, each interact with the same regulatory subunit p 85; whereas p110 γ interacts with a different regulatory subunit p 101. The expression pattern of each of these PI3K in human cells and tissues is different. In each of the PI3K α, β and subtypes, the p85 subunit, through its SH2 domain, interacts with phosphorylated tyrosine residues in the target protein (present in an appropriate sequence context) to localize PI3 kinase to the plasma membrane (Rameh et al (1995) Cell,83: 821-30; Volinia et al (1992) Oncogene,7: 789-93).
The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drug development because such drugs are expected to inhibit cell proliferation, inhibit signaling from mesenchymal cells that maintain cancer cell survival and chemoresistance, reverse the repression of apoptosis, and overcome cancer cells' intrinsic resistance to cytotoxic agents. PI3K is activated by receptor tyrosine kinase signaling and by mutations in the p110 catalytic subunit of activating PI3K, loss of the tumor suppressor PTEN or by rare activating mutations in AKT.
Taselisib (GDC-0032, Roche RG7604, CAS registry number 1282512-48-4, Genentech Inc.) was named 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f]Imidazo [1,2-d ] s][1,4]Oxazazem-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide, having potent PI3K activity (WO 2011/036280; US 8242104; US8343955) and is being studied in patients with locally advanced or metastatic solid tumors. Taselisib (GDC-0032) is a β -isoform retention inhibitor of the PI3K catalytic subunit, with a 31-fold higher selectivity for the α subunit compared to the β subunit. Taselisib exhibits higher selectivity for mutant PI3K alpha isoform compared to wild-type PI3K alpha (oliver AG et al, AACR 2013.Abstract DDT 02-01). Taselisib is currently being developed for the treatment of patients with Estrogen Receptor (ER) positive, HER2 negative metastatic breast cancer (mBC) and non-small cell lung cancer (NSCLC). In a phase Ia study with a single drug taselisib, a Partial Response (PR) was observed in 6/34 enrolled patients. All 6 responses were observed in patients with PIK3CA mutant tumors (Juric d. et al AACR 2013), indicating a need to determine the PIK3CA mutation status in patients treated with taselisib.
Recent clinical data for PI3K inhibitors have suggested PI3K activity as a source of gastrointestinal toxicity (Akinleye et al Pharmatitidylinosol 3-kinase (PI3K) inhibitors as nutrients therapeutics "Journal of Hematology & Oncology 2013,6: 88-104; C.Saura et al" Phase Ib Study of the PI3K Inhibitor Taselisib (GDC-0032) in Combination with Letrole in Patientsw Horminor Horminend Receptor-Positive Advance Cancer "San Antonio Breastcancer Symposium-December 12,2014(PD 5-2; Lopez et al" Taselisib, a selective Inhibitor of PIK3CA, inhibition of platelet 3CA, reaction of
The identity of Idelalisib (GS-1101, CAL-101,gilead Sciences Inc., CASreg.No.870281-82-6, 5-fluoro-3-phenyl-2- [ (1S) -1- (7H-purin-6-ylamino) propyl]-4(3H) -quinazolinone) is a selective PI3K (delta) inhibitor and is approved for the treatment of Chronic Lymphocytic Leukemia (CLL) (US 6800620; US 6949535; US 8138195;US 8492389; US 8637533; US 8865730; US 8980901; RE 44599; RE 44638). Diarrhea and colitis are among the most common adverse events reported after Idelalisib treatment (Brown et al, "Idlalisib, an inhibitor of phosphatilinosol 3-kinase p110d, for delayed/recurrent clinical cytological leukoderma" (2014) Blood 123(22): 3390-3397;
There is a need for additional modulators of PI3K α for use in the treatment of cancer, in particular inhibitors of PI3K α that are selective for tumors expressing mutant PI3K α relative to cells expressing non-mutant PI3K α. There is a particular need for agents that selectively inhibit PI3K α isoforms relative to PI3K β, PI3K, and PI3K γ isoforms, which may be expected to result in enhanced therapeutic windows.
Disclosure of Invention
The present invention relates generally to benzoxazepines having selective activity in modulating mutant forms of the PI3K alpha (alpha) isoform and having the structure of formula I
and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof. Various substituents are defined herein.
Another aspect of the invention is a pharmaceutical composition comprising a benzoxazepine of formula IAn oxazolidinone compound and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
Another aspect of the invention is a method of treating cancer in a patient having cancer comprising administering to the patient a therapeutically effective amount of a benzoxazepine of formula I
Another aspect of the invention is a kit for the therapeutic treatment of breast cancer, comprising:
a) benzoxazepines of the formula I
b) instructions for therapeutic treatment of breast cancer.
Drawings
FIGS. 1A and 1B show the x-ray eutectic structure of PI3K α (alpha) with: A) taselisib (GDC-0032), and B) Compound 106.
Figures 2A and 2B show the inhibition of KPL4 tumor growth after treatment with a) compound 102 and B) compound 103.
Detailed Description
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying drawings and formula. While the invention will be described in conjunction with the listed embodiments, it will be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize a variety of methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. If one or more of the incorporated documents, patents, and similar materials differ or contradict the present application (including but not limited to defined terms, usage of terms, described techniques, etc.), the present application controls. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned in this application are incorporated in their entirety by reference into this application. Unless otherwise indicated, the nomenclature used herein is based on the IUPAC systematic nomenclature
Definition of
When stating the number of substituents, the term "one or more" refers to substitution of one substituent to the maximum possible number, i.e., replacement of one hydrogen by a substituent to replacement of all hydrogens. The term "substituent" means an atom or group of atoms that replaces a hydrogen atom on a parent molecule. The term "substituted" means that the specified group bears one or more substituents. When any group can carry multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the possible substituents. When stating the number of substituents, the term "one or more" refers to substitution of one substituent to the maximum possible number, i.e., replacement of one hydrogen by a substituent to replacement of all hydrogens.
The term "alkyl" as used herein refers to a compound having 1 to 12 carbon atoms (C)1-C12) Wherein the alkyl group may be optionally independently substituted with one or more of the following substituents. In another embodiment, the alkyl group has 1 to 8 carbon atoms (C) 1-C8) Or 1-6 carbon atoms (C)1-C6). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, isopropyl, -CH (CH)3)2) 1-butyl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methyl-1-propyl (i-Bu, isobutyl, -CH)2CH(CH3)2) 2-butyl (s-Bu, sec-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl (t-Bu, tert-butyl, -C (CH)3)3) 1-pentyl (n-pentyl, -CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)31-heptyl, 1-octyl, and the like.
The terms "carbocycle", "carbocyclyl", "carbocycle", and cycloalkyl "refer to a compound having 3 to 12 carbon atoms (C)3-C12) Monovalent non-aromatic saturated or partially unsaturated rings in the form of a single ring or in the form of a ring having 7 to 12 carbon atoms. Has 7-12 original genes Bicyclic carbocyclic rings of members may be arranged, for example, as bicyclo [4,5 ]]System, bicyclo [5,5 ]]System, bicyclo [5,6 ]]Systems or bicyclo [6,6 ]]The bicyclic carbocyclic ring having 9 or 10 ring atoms of the system may be arranged as a bicyclo [5,6 ]]Systems or bicyclo [6,6 ]]Systems or arrangements for bridging systems such as bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane and bicyclo [3.2.2]Nonane. Spiro carbocyclyl moieties are also included within the scope of this definition. Examples of spiro carbocyclyl moieties include [2.2]Pentyl, [2.3 ] or]Hexyl and [2.4 ]]A heptyl group. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Carbocyclyl is optionally independently substituted with one or more substituents described herein.
"aryl" means having 6 to 20 carbon atoms (C)6-C20) A monovalent aromatic hydrocarbon group of (a), which is obtained by: one hydrogen atom is removed from a single carbon atom in the parent aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ar". Aryl includes bicyclic groups containing an aromatic ring fused to a saturated, partially unsaturated, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, groups derived from benzene (phenyl), substituted benzenes, naphthalenes, anthracenes, biphenyls, indenyls, indanyl, 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthalene, and the like. Aryl groups may be optionally substituted independently with one or more substituents described herein.
The terms "heterocycle" (heterocyclic), "heterocyclyl" and "heterocyclic" are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) carbocyclic group of 3 to about 20 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms being C, wherein one or more ring atoms are optionally independently substituted with one or more substituents described below. The heterocyclic ring may be a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S) or a monocyclic ring having 7 to 10 ring members (4 to 9 carbon atoms)And 1-6 heteroatoms selected from N, O, P and S) bicyclic (e.g., bicyclo [4,5 ]]System, bicyclo [5,5 ]]System, bicyclo [5,6 ]]Systems or bicyclo [6,6 ]]A system). Heterocycles are described in Paquette, Leo a.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York,1968) (in
The term "heteroaryl" refers to a monovalent aromatic group in the form of a 5, 6 or 7 membered ring containing one or more heteroatoms independently selected from nitrogen, oxygen and sulfur and includes fused ring systems (wherein at least one ring is aromatic) having 5 to 20 atoms. Examples of heteroaryl groups are pyridyl (including, for example, 2-hydroxypyridyl), imidazolyl, imidazopyridyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups are optionally independently substituted with one or more substituents described herein.
The terms "treatment" and "treatment" refer to a therapeutic treatment in which the aim is to slow down (lessen) the development or spread of an undesired physiological change or disorder, such as arthritis or cancer. For purposes of this application, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "treatment" may also refer to prolonging survival compared to survival expected in the absence of treatment. Those in need of treatment include those suffering from a condition or disorder.
The phrase "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats a particular disease, condition, or disorder; (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder; or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more symptoms associated with cancer to some extent. The drug may prevent the growth of cancer cells and/or kill existing cancer cells to some extent, and may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be determined, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).
The term "cancer" refers to or is used to describe the physiological state in mammals that is typically characterized by dysregulation of cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More specific examples of the above cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung, and squamous carcinoma of the lung; peritoneal cancer; hepatocellular carcinoma; gastric or stomach cancer, including gastrointestinal cancer; pancreatic cancer; a glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; hepatoma; breast cancer; colon cancer; rectal cancer; colorectal cancer; endometrial or uterine cancer; salivary gland cancer; renal cancer or kidney cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer tumor; anal cancer; penile cancer; and head and neck cancer.
A "hematologic malignancy" is a type of cancer that affects the blood, bone marrow, and lymph nodes. Since the three are closely related by the immune system, diseases affecting one of the three will also typically affect the other two: although lymphoma is a lymph node disease, it often spreads to the bone marrow affecting the blood. Hematological malignancies are malignancies ("cancers") and are typically treated by hematological and/or oncology specialists. "hematology/oncology" is a sub-specialty in medical medicine in some centers and considered a separate department in others (among which are surgical and radiation oncologists). Not all hematological diseases are malignant ("cancerous"); these other blood disorders may also be treated by hematologists. Hematological malignancies can originate from two major blood cell lineages: myeloid and lymphoid cell lines. Myeloid cell lines typically produce granulocytes, erythrocytes, platelets, macrophages and mast cells; lymphoid cell lines give rise to B cells, T cells, NK cells and plasma cells. Lymphomas, lymphocytic leukemias and myelomas are from lymphoid cell lines, while acute and chronic myelogenous leukemias, myelodysplastic syndromes, and myeloproliferative diseases are derived from myeloid cells. Leukemias include Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), Chronic Myeloid Leukemia (CML), acute monocytic leukemia (AMOL), and Small Lymphocytic Lymphoma (SLL). Lymphomas include hodgkin lymphoma (all four subtypes) and non-hodgkin lymphoma (NHL, all subtypes).
A "chemotherapeutic agent" is a compound useful in the treatment of cancer, regardless of the mechanism of action. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle toxic plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. Examples of chemotherapeutic agents include: ibrutinib (IMBRUVICA)TMAPCI-32765, Pharmacyclics Inc./Janssen Biotech Inc.; CAS Reg.No.936563-96-1, US7514444), idelalisib (formerly CAL-101, GS 1101, GS-1101, Gilead Sciences Inc.; CASreg.No.1146702-54-6), erlotinib (erlotinib) ((R) Luo Tib)Genentech/OSI Pharm.), docetaxel (docetaxel)
Chemotherapeutic agents include inhibitors of B cell receptor targets, such as BTK, Bcl-2, and JAK inhibitors.
Further examples of chemotherapeutic agents include oxaliplatin (oxaliplatin) ((a))
The following are also included in the definition of "chemotherapeutic agents": (i) anti-hormonal agents such as anti-estrogens (anti-estrogen) and Selective Estrogen Receptor Modulators (SERMs) including, for example, tamoxifen (including
Therapeutic antibodies are also included in the definition of "chemotherapeutic agents", such as alemtuzumab (Campath), bevacizumab (bevacizumab) ((r))
A "metabolite" is a product produced by the in vivo metabolism of a particular compound or salt thereof. Metabolites of compounds can be identified using conventional techniques known in the art and their activity can be determined using the assays described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method comprising contacting a compound of formula I of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.
The term "package insert" refers to instructions typically contained in commercial packages of therapeutic products that contain information regarding indications, usage, dosage, administration, contraindications, and/or precautions related to the use of the therapeutic products described above.
The term "chiral" refers to a molecule that has a mirror image partner (mirror image partner) non-superimposability, while the term "achiral" refers to a molecule that can be superimposed with its mirror image partner.
The term "stereoisomers" refers to compounds having the same chemical composition but differing in the spatial arrangement of atoms or groups.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography.
"enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
The stereochemical definitions and general knowledge used herein generally correspond to those of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The present invention is intended to include all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers), and mixtures thereof, such as racemic mixtures, forming part of the present invention. Many organic compounds exist in optically active form, i.e. they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) designate the symbols by which the compound rotates plane polarized light, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers and mixtures of the above isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when a chemical reaction or process is not stereoselective or stereospecific. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, which are not optically active. Enantiomers can be separated from racemic mixtures by chiral separation methods such as Supercritical Fluid Chromatography (SFC). The assignment of configuration at chiral centers in separated enantiomers may be tentative and depicted in the table 1 structure for illustration purposes, while stereochemistry is established deterministically, such as from X-ray crystallographic data.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert through a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
The term "pharmaceutically acceptable salt" refers to salts that are biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts. The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The term "pharmaceutically acceptable acid addition salts" refers to those pharmaceutically acceptable salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and organic acids selected from aliphatic, alicyclic, aromatic, aryl-aliphatic, heterocyclic, carboxylic and sulfonic organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid (methanesulfonic acid) "methanesulfonic acid (mesylate)", ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
The term "pharmaceutically acceptable base addition salts" refers to pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and polyamine resins.
"solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
The term "EC50"is the half maximal effective concentration and means the plasma concentration of the particular compound required to achieve 50% of the maximal in vivo specific effect.
The term "Ki" is an inhibition constant and denotes the absolute binding affinity of a particular inhibitor to a receptor. If no competing ligand (e.g., radioligand) is present, it is measured using a competitive binding assay and is equal to the concentration at which the particular inhibitor occupies 50% of the receptor. Ki values can be logarithmically converted to pKi values (-log Ki), with higher values indicating exponentially greater potency.
The term "IC50"is the half maximal inhibitory concentration and refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. Can connect IC50Logarithmic conversion of values to pIC50Value (-log IC)50) Where higher values indicate exponentially greater potency. IC (integrated circuit)50The values are not absolute values but depend on experimental conditions, which can be converted into absolute inhibition constants (Ki) using, for example, the Cheng-Prusoff equation (biochem. Pharmacol. (1973)22: 3099). Other percentage rejection parameters may be calculated, such as IC70、IC90And the like.
The terms "compound of the invention" and "compound of formula I" include compounds of formula I and stereoisomers, geometric isomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof.
Any formula or structure given herein, including compounds of formula I, is also intended to represent hydrates, solvates, and polymorphs of the above compounds, and mixtures thereof.
Any formula or structure given herein, including compounds of formula I, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically-labeled compounds have the structure depicted in the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),11C、13C、14C、15N、18F、31P、32P、35S、36Cl and125I. the invention includes various isotopesLabelled compounds of the invention, e.g. radioisotopes such as3H、13C and14those compounds of the present invention into which C is introduced. The isotopically labeled compounds described above are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays or in the treatment of patients with radioactivity. Therapeutic compounds of the invention labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) properties, including absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements). Warp beam 18The F-labeled compounds are useful for PET or SPECT studies. Isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared as follows: the procedures disclosed in the schemes or examples and preparations below were performed and the non-isotopically labeled reagents were replaced with readily available isotopically labeled reagents. In addition, with heavier isotopes, especially deuterium (i.e. deuterium)2H or D) may result in some therapeutic advantages (e.g. increased in vivo half-life or reduced dosage requirements or improved therapeutic index) due to better metabolic stability. It is to be understood that deuterium in the present application is considered as a substituent in the compounds of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. Any atom in the compounds of the present invention that is not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a location is specifically designated as "H" or "hydrogen," it is understood that the location has a concentration of hydrogen that is the natural abundance isotopic composition of hydrogen. Thus, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.
Benzoxazepines
The present invention provides benzoxazepines of formula IOxazolidinone compounds and pharmaceutical formulations thereof, which are potentially useful for the treatment of cancer and have the following structure:
and stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof, wherein:
R1is selected from-CH3、-CH2CH3、-CH(CH3)2、-CHF2、-CH2F and-CF3；
X is selected from:
wherein the wavy line represents the attachment site; and is
R2Selected from H, C1-C6Alkyl, cyclopropyl and cyclobutyl optionally substituted by F, -OCH3or-OH.
Benzoxazepines of the formula I
exemplary embodiments of compounds of formula Ia include those wherein R2is-CH3And R is1Selected from-CHF2and-CH2F。
Benzoxazepines of the formula IOxazolidinone compounds include those of formula Ib:
exemplary embodiments of compounds of formula Ib include those in which R1Selected from-CHF2and-CH2F。
Exemplary embodiments of compounds of formula I include the compounds in table 1.
The compounds of formula I according to the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof, such as racemic mixtures, form part of the present invention. In some cases, stereochemistry has not been determined or has been tentatively assigned.
In addition, the present invention includes all diastereomers, including cis-trans (geometric) and conformational isomers. For example, if the compounds of formula I contain double or fused rings, then the cis and trans forms and mixtures thereof are included within the scope of the present invention.
In the structures shown herein, the compounds of the present invention are intended to include all stereoisomers if the stereochemistry of any particular chiral atom is not specified. If stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomer is so indicated and defined.
The compounds of the invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like and the invention is intended to include both solvated and unsolvated forms.
The compounds of the invention may also exist in different tautomeric forms and all such forms are included within the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert through a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.
Biological evaluation
The relative potency of a compound of formula I as an inhibitor of enzymatic activity (or other biological activity) can be determined as follows: the concentration at which each compound inhibits the activity to a predetermined degree is determined, and the results are compared. Generally, the preferred determination is the concentration that inhibits 50% of activity in a biochemical assay, i.e., the 50% inhibitory concentration or "IC50". IC can be determined using conventional techniques known in the art50The value is obtained. In general, ICs50Can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of inhibitor under investigation. The experimentally obtained enzyme activity values are then plotted against the inhibitor concentration used. Concentration of inhibitor showing 50% enzyme activity (compared to activity in the absence of any inhibitor) as IC50The value is obtained. Similarly, other inhibitory concentrations may be defined by appropriate activity determinations. For example, in some cases, it may be desirable to determine the 90% inhibitory concentration or IC90And the like.
Exemplary compounds of formula I in table 1 were prepared, characterized, and tested for binding to PI3K in various isoforms and mutant forms according to the methods of the present invention, and have the following structure, corresponding names (ChemBioDraw, Version 12.0.2, Cambridge soft corp., Cambridge MA) and biological activity. When more than one name is associated with a compound of formula I or an intermediate, the compound should be defined in terms of chemical structure.
Table 1.
TASELISIB
Designated taselisib, GDC-0032, and Roche RG7604(CAS Reg.No.).1282512-48-4, Genentech Inc.) under the IUPAC name: 2- (4- (2- (1-isopropyl-3-methyl-1H-1, 2, 4-triazol-5-yl) -5, 6-dihydrobenzo [ f)]Imidazo [1,2-d ] s][1,4]Oxazazem-9-yl) -1H-pyrazol-1-yl) -2-methylpropanamide, having the structure:
including stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof.
Taselesib can be prepared and characterized as described in WO 2011/036280, US 8242104 and US 8343955.
pictilisib
The compounds designated pictiliib, GDC-0941, Roche, RG-7321 and pictreliib, (CASReg.No.957054-30-7, Genentech Inc.,) are potent multi-target class I (pan) PI3K isoform inhibitors. GDC-0941 is currently undergoing phase II clinical trials for the treatment of advanced solid tumors. GDC-0941 is named 4- (2- (1H-indazol-4-yl) -6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) thieno [3,2-d ] pyrimidin-4-yl) morpholine (US 7781433; US 7750002; Folkes et al (2008) journal.of Med.chem.51(18): 5522-:
including stereoisomers, geometric isomers, tautomers and pharmaceutically acceptable salts thereof.
Biochemical inhibition of PI3K isoforms
The ability of the compounds of the invention to act as PI3K a inhibitors was determined using the method of example 901, with selectivity relative to PI3K β, PI3K and PI3K γ. Also included in tables 2A and 2B are FP Ki data determined using the method from example 901 of US 8242104.
Table 2A shows the biochemical inhibition of the four PI3K isoforms by the compounds of formula I of table 1. In addition, two clinically tested PI3K compounds taselisib and pictilisib were included as a comparator. Representative compounds of the invention exhibited strong activity against PI3K α and significantly enhanced selectivity relative to the other isoforms PI3K β, PI3K and PI3K γ when compared to taselisib (GDC-0032) and pictiliib (GDC-0941). In particular, the selectivity ratios in the second column from the right of Table 2A show that each of the compounds of formula I101-109 has a PI3K α/selectivity ratio much higher than taselisib or pictilisib. In fact, both taselisib and pictilisib are more active on PI3K than PI3K α, i.e. their selectivity ratio is less than 1. The selectivity ratio of the compound 101-109 of the formula I ranges from 15 times to 52 times.
Table 2B shows biochemical inhibition of selectivity ratio by two PI3K isoforms alpha and PI3K alpha of certain comparative compounds of US8242104 and compounds bearing dimethyl oxazolidin-2-one groups from US 8263633 (compound 356, column 149). The comparative compounds shown in table 2B are examples from the broad genus described in each of US8242104 and US 8263633. Neither US8242104 nor US 8263633 disclose compounds within the scope of the compounds of formula I of the present invention. Although the representative comparative example of US8242104 as described in table 2B shows a PI3K α to PI3K selectivity ratio >1, the maximum selectivity ratio observed was 269-fold. The compounds of the formula I101-109 thus achieve a significantly higher selectivity ratio than the examples of US 8242104.
Other representative examples of PI3K inhibitors, such as taselisib (WO 2011/036280; US 8242104; US8343955) and US8242104 in current clinical trials exhibit significant activity on the PI3K (delta) isoform. This lack of selectivity for PI3K (delta) is consistent with the GI toxicity observed clinically for taselisib. There is a need for PI3K α (alpha) inhibitors, which contain the advantageous features of the representative examples of US8242104, which at the same time lack activity against PI 3K. The present invention provides compounds that satisfy this activity and selectivity profile.
The unexpected property of PI3K a selectivity is beneficial in abrogating the gastrointestinal toxicity observed in clinical PI3K inhibitor candidates. Recent clinical data for PI3K inhibitors have suggested PI3K activity as a source of gastrointestinal toxicity (Akinleye et al, "Phosphositidylinosol 3-kinase (PI3K) inhibitors as cancer therapeutics" Journal of Hematology & Oncology 2013,6: 88-104). See table 2 for PI3K inhibitors in clinical trials.
Due to the significantly higher selectivity of PI3K α (alpha) inhibition over PI3K (delta) inhibition, the toxicity driven by compound 101-109 versus PI3K (delta) of formula I is expected to achieve a greater magnitude of clinical activity (margin) driven by PI3K α (alpha) inhibition compared to taselisib and piculisib tested clinically. Thus, the compounds of formula I of the present invention are useful as therapeutic agents with reduced toxicity profile relative to drugs with greater inhibition of the normal function of PI3K β, PI3K, or PI3K γ.
TABLE 2AThe biochemical inhibitory effect of the compounds of formula I and of the comparative compounds taselisib and pictilisib on the PI3K isoform
TABLE 2BComparison of the Biochemical inhibition of PI3K isoforms of Compounds
Interaction of Compounds with PI3K
A reasonable basis for PI3K α selectivity of compounds of formula I may exist in certain binding interactions.
The ability of the compounds of the invention to specifically interact with PI3K α was determined by resolving the x-ray co-crystal structure of a representative compound having PI3K α using the method of example 902. Has PI3K alpha relative to other isoformsThe optimized structural design of isoform-selective PI3K inhibitors may include precise positioning and arrangement of atoms and functional groups to interact with isoform-specific residues in the binding site. In particular, it was found that]Imidazo [1,2-d ] s][1,4]OxazazemSubstitution at position 2 of the ring system has a significant effect on the specific activity of the compounds on PI3K α. The oxazolidinone ring of the compounds of formula I is capable of multiple improved interactions with proteins relative to the triazole ring.
FIG. 1A shows the x-ray structure of taselisib binding at the PI3K α (alpha) active site. The N4 atom of the triazole ring cannot be directly linked to Tyr 836: ( Distance of) or Ser774(2.74 and Ser 774)Distance between ligand and residue, no complementary polarity). Fig. 1B shows the x-ray structure of compound 106 bound at the PI3K α active site and shows that the oxazolidinone ring is capable of multiple improved interactions with proteins relative to the triazole ring. The carbonyl function being close to the Tyr836 side chain
All compounds of the invention contain an oxazolidone ring and are capable of improved interaction with Tyr836 of PI3K α. Some embodiments of the invention also include fluorinated substituents on the oxazolidone ring and are capable of improving interaction with Ser774 of PI3K a. These two binding interactions may contribute to the increased selectivity to PI3K α observed with embodiments of the present invention relative to embodiments of US 8242104. Residues Ser774 and Tyr836 are not unique to PI3K a isoforms, PI3K contains the same residue at the same position, and enhanced isoform selectivity of oxazolidinone inhibitors is not predicted from these crystal structures. Subtle changes in secondary and tertiary protein structure may lead to subtle differences in the positioning and orientation of identical residue identity between different isoforms. Even in the face of the x-ray crystal structures of the two protein isoforms, these differences are difficult to predict and explain. The surprising and unexpected properties of improved molecular interactions and enhanced isoform selectivity of oxazolidinone inhibitors are retained over the entire range of compounds exemplified in table 1.
Oxazolidinones are structurally distinct from triazoles in that: oxazolidinones have a carbonyl group, are more polar, and are not aromatic. Triazoles have no carbonyl group, are less polar, and have aromaticity.
The oxazolidinone ring provides further benefits over the triazole ring in terms of increased sp3 character and reduced number of aromatic rings. It is generally accepted in the literature that an increased number of aromatic rings is associated with an increased risk of promiscuous binding. In contrast, an increase in the ratio of sp3 carbons (# sp3 carbon/# total carbon) correlates with improved physicochemical properties and reduced promiscuous binding, thereby reducing the risk of off-target toxicology. These concepts are described in references Lovering et al, "Escape From Flatland", (2009) J.Med.Chem.,52: 6752-. Replacing the triazole aromatic ring exemplified in US 8242104 with the saturated heterocyclic oxazolidinone contained in each example of the present invention means to removeFavorable reduction of target toxicology risks. All the exemplified compounds in US 8242104 are mostly occupied by compounds having an aromatic ring at this position, examples in which 4 carboxamide functions replace the aromatic ring, and there are no examples of saturated cyclic or heterocyclic systems. Aromatic and saturated heterocycles are generally not interchangeable due to their significantly different binding interactions and steric requirements. Not in 5, 6-dihydrobenzo [ f ]Imidazo [1,2-d ] s][1,4]Oxazazem
Thus, the compounds of the invention are described in 5, 6-dihydrobenzo [ f ]]Imidazo [1,2-d ] s][1,4]Oxazazem
Selective inhibition of mutant PI3K alpha (alpha)
The ability of the compounds of the invention to act preferentially against cells containing mutant PI3K α was determined by measuring inhibition of the PI3K pathway in the SW48 near isogenic cell line PI3K α wild type (parent), helical domain mutant E545K and kinase domain mutant H1047R as described in example 903.
Statistical analysis: unless otherwise stated, EC50 values represent geometric means of a minimum of 4 independent experiments. All statistics were performed using KaleidaGraph software (version 4.1.3). Student's t-test was performed using unpaired data with the same variance to compare activity against mutant and wild type cells. P <0.05 was considered significant.
Table 3A shows the inhibition of P-PRAS40 in SW48 near isogenic cells by the compounds of formula I of Table 1. Both of these compounds exhibited increased activity on mutant PI3K alpha cells relative to wild-type PI3K alpha cells, with a selectivity ratio > 2-fold and a p-value < 0.05. The compounds of the invention showed similar activity to taselisib, with equal or higher selectivity to taselisib in SW48 mutant PI3K alpha cells relative to activity in wild-type PI3K alpha cells (see table 3B).
Table 3B shows the inhibition of P-PRAS40 in SW48 near isogenic cells by certain comparative compounds of US 8242104, compounds with a dimethyloxazolidin-2-one group from US 8263633 (compound 356, column 149) and piculisib. The comparative compounds shown in table 3B are examples from the broad genus described in each of US 8242104 and US 8263633. Neither US 8242104 nor US 8263633 disclose compounds within the scope of the compounds of formula I of the present invention. Comparative compounds contain examples in which the activity of mutant PI3K alpha cells was not significantly increased relative to wild-type PI3K alpha cells (see comparative compounds pictiliib, 375, 436, 469 and 486, p >0.05 for one or both tested mutations). These compounds are structurally similar to comparative compounds that the mutant PI3K alpha cells do not exhibit significantly increased activity relative to wild-type PI3K alpha cells (see comparative compounds taselisib, 469, 540, 544 and 356, for one or both tested mutations p > 0.05). None of the compounds of the comparison provided a common structural element teaching selective inhibition in mutant PI3K alpha cells. More broadly, no structural element of the compound of formula I is selected in US 8242104 or US 8263633 to achieve increased or comparable activity against mutant PI3K alpha cells relative to wild-type PI3K alpha cells. This unexpected property is retained over the entire range of compounds exemplified in table 1.
Table 3A.Inhibition of SW48 near isogenic cells by P-PRAS40 with compounds of formula I
Table 3B.Comparison chemical combinationInhibition of P-PRAS40 by SW48 near isogenic cells
Antiproliferative activity of PI3K mutant tumor cells
The ability of the compounds of the invention to reduce the viability of PI3K mutant tumor cells was determined by measuring antiproliferative EC50 in HCC1954 and KPL4 cells (PI3K a mutant H1047R) and MCF7 cells (PI3K a mutant E545K) using the method of example 904. Table 4 shows that compounds 102, 103 and 105 of formula I inhibit the proliferation of HCC1954, KPL4 and MCF7 cells with similar levels of potency as the comparative compounds taselisib (compound 196, US8242104), pictilisib and compound 436(US 8242104).
Table 4.Antiproliferative activity in mutant PI 3K-alpha tumor cells
In vivo efficacy in tumor xenograft models
The ability of the compounds of the invention to inhibit tumor growth in an in vivo tumor xenograft model was determined using the method described in example 905 using KPL4 breast cancer cell line (PI3K a mutant H1047R). Figures 2A and 2B show that compounds 102 and 103 of formula I, respectively, are able to strongly inhibit the growth of KPL4 tumors in vivo in a dose-dependent manner using daily PO (oral) administration. All doses of compounds 102 and 103 were well tolerated and no treatment-related weight loss was observed.
Administration of Compounds of formula I
The compounds of the present invention may be administered by any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive therapy, the compound may be administered by intralesional administration (including perfusion or contacting the graft with an inhibitor prior to transplantation). It will be appreciated that the preferred route may vary, for example, with the condition of the recipient. When the compound is administered orally, it may be formulated into pills, capsules, tablets, and the like, together with a pharmaceutically acceptable carrier or excipient. When the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and into unit dose injectable forms, as described below.
The dose for treating a human patient may be from about 1mg to about 1000mg of a compound of formula I. A typical dose may be from about 10mg to about 300mg of the compound. The dose may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the particular compound, including absorption, distribution, metabolism, and excretion. In addition, toxicity factors can affect the dosage and administration regimen. When administered orally, the pills, capsules or tablets may be taken daily or less frequently for the specified period of time. The protocol may be repeated for multiple treatment cycles.
Methods of treatment using compounds of formula I
The compounds of formula I of the present invention are useful in treating human or animal patients suffering from diseases or disorders such as cancer due to abnormal cell growth, function or behaviour associated with PI3K and may therefore be treated by a method comprising administering thereto a compound of the present application as defined above. A human or animal patient suffering from cancer may also be treated by a method comprising administering thereto a compound of the invention as defined above. The condition of the patient may thus be improved or alleviated.
The methods of the invention also include treating a cancer selected from the group consisting of breast, ovarian, cervical, prostate, testicular, genitourinary tract, esophageal, laryngeal, glioblastoma, neuroblastoma, gastric, skin, keratoacanthoma, lung, epidermoid, large cell, non-small cell lung (NSCLC), small cell, lung adenocarcinoma, bone, colon, adenoma, pancreatic, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver and biliary passages, kidney carcinoma, pancreatic, myeloid disorders, lymphoma, hairy cell, oral, nasopharyngeal, pharyngeal, lip, tongue, mouth, small intestine, colon-rectal, large intestine, rectal, brain and central nervous system, hodgkin's, leukemia, colon-rectum, colon, stomach, and central nervous system, colon, kidney, colon, or colon-rectum, Bronchial, thyroid, liver and intrahepatic bile duct cancers, hepatocellular, gastric, glioma/glioblastoma, endometrial, melanoma, renal and renal pelvis cancers, bladder, uterine corpus cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, Chronic Lymphocytic Leukemia (CLL), myelogenous leukemia, oral and pharyngeal cancers, non-hodgkin lymphoma, melanoma and villous colon adenoma.
Colon, breast, cervical, gastric, lung malignancies and multiple myeloma are most likely to respond to PI3K modulators or inhibitors based on expression analysis, immunohistochemical analysis and cell line distribution.
The present invention relates to the use of a compound as described above for the treatment of cancer in a patient, wherein the cancer is selected from breast cancer and non-small cell lung cancer.
The present invention relates to the use of a compound as described above for the manufacture of a medicament for the treatment of cancer in a patient, wherein the cancer is selected from breast cancer and non-small cell lung cancer.
The present invention relates to a compound as described above for use in the treatment of cancer in a patient, wherein the cancer is selected from breast cancer and non-small cell lung cancer.
The invention as described above.
Pharmaceutical preparation
For use of the compounds of the present invention for therapeutic treatment of mammals, including humans, they are generally formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice. This aspect of the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.
Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient.
Suitable carriers, diluents, additives and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient employed will depend upon the means and purpose of administering the compounds of the present invention. The solvent is generally selected based on a solvent (GRAS) deemed safe by one of skill in the art for administration to a mammal. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g.,
The formulations may be prepared using conventional dissolution and mixing operations. For example, the bulk drug substance (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide easily controllable dosages of the drug and to enable patient compliance with prescribed regimens.
The pharmaceutical composition (or formulation) for administration may be packaged in a variety of ways depending on the method of administering the drug. Typically, the article of manufacture for dispensing comprises a container in which the pharmaceutical formulation is stored in a suitable form. Suitable containers are known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, and the like. The container may also include anti-pry means to prevent inadvertent access to the contents of the package. Additionally, the container has a label thereon that describes the contents of the container. The tag may also include suitable warning information.
Pharmaceutical formulations of the compounds of the present application can be prepared for various routes and types of administration. For example, a compound of formula I having a desired purity may be optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers in the form of a lyophilized formulation, a milled powder or an aqueous solution (Remington's Pharmaceutical Sciences (1980) 16 th edition, Osol, a.ed.). The formulation can be carried out as follows: mixed at ambient temperature at a suitable pH and in a suitable purity with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular use and compound concentration, but can be from about 3 to about 8. Formulations in acetate buffer at
The drug may be stored in the form of a solid composition, a lyophilized formulation, or an aqueous solution.
The pharmaceutical compositions of the present invention will be formulated, dosed and administered in a manner consistent with good medical practice (i.e., amount, concentration, schedule, course, vehicle and route of administration). Factors to be considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the drug, the method of administration, the timing of administration and other factors known to medical practitioners. The "therapeutically effective amount" of the compound to be administered will depend on the above factors considered and is the minimum amount required to ameliorate or treat the hyperproliferative disorder.
As a general proposition, the initial pharmaceutically effective amount of inhibitor per dose administered parenterally will be about 0.01-100mg/kg, i.e., about 0.1-20mg/kg, of patient body weight per day, with a typical initial range of compounds employed being 0.3 to 15 mg/kg/day.
Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; defend Preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants, such as TWEENTM、PLURONICSTMOr polyethylene glycol (PEG). The active pharmaceutical ingredient may also be embedded in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin-microcapsules and poly (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. See Remington's Pharmaceutical Sciences 16 th edition, Osol, A. eds (1980).
Sustained release formulations of the compounds of formula I can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g. poly (2-hydroxyethyl methacrylate) or poly (vinyl alcohol)), polylactide (US3773919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOTTM(microspheres for injection composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly D- (-) -3-hydroxybutyric acid.
Formulations include those suitable for the routes of administration described herein. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. Techniques and formulations are generally described in Remington's pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). The above method comprises the step of bringing into association the active ingredient with the carrier as one or more accessory ingredients. In general, the formulations are prepared as follows: the active ingredient is combined with a liquid carrier or a finely divided solid carrier or both uniformly and intimately thereafter the product is shaped as required.
Formulations of a compound of formula I suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of formula I. Compressed tablets may be prepared as follows: the active ingredient in free-flowing form, e.g. powder or granules, optionally mixed with binders, lubricants, inert diluents, preservatives, surfactants or dispersing agents, is compressed in a suitable machine. Molded tablets may be prepared as follows: the mixture of powdered active ingredient moistened with an inert liquid diluent is moulded in a suitable machine. The tablets may optionally be coated or scored and optionally formulated for slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups or elixirs may be prepared for oral administration. Formulations of compounds of formula I intended for oral administration may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic physiologically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
For the treatment of the eye or other external tissues such as mouth and skin, the formulations may preferably be administered in the form of a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream together with an oil-in-water cream base. If desired, the aqueous phase of the cream base may comprise polyhydric alcohols, i.e. alcohols having two or more hydroxyl groups such as propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycols (including PEG 400) and mixtures thereof. Topical formulations may desirably contain compounds that enhance absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs. The oil phase of the emulsions of the present application may be constituted by known ingredients in a known manner. When the phase may comprise emulsifiers alone, it comprises, as required, a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included as a stabilizer together with a lipophilic emulsifier. It is also preferred to include both oil and fat. At the same time, the emulsifier, with or without stabilizer, constitutes the so-called emulsifying wax and said wax, together with the oil and fat, constitutes the so-called emulsifying cream base, which forms the oily dispersed phase of the cream. Emulsifiers and emulsion stabilizers suitable for use in the formulations herein include
Aqueous suspensions of the compounds of formula I contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Pharmaceutical compositions of the compounds of formula I may be in the form of sterile injectable aqueous or oleaginous suspensions, such as sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the methods known in the art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution in 1, 3-butanediol or as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain from about 1 to 1000mg of the active substance compound and a suitable and convenient amount of carrier material which may comprise from about 5 to about 95% (weight: weight) of the total composition. Pharmaceutical compositions can be prepared to provide an administration amount that can be readily measured. For example, aqueous solutions intended for intravenous infusion may contain from about 3 to 500 μ g of active ingredient per mL of solution, thereby enabling an appropriate volume of infusion at a rate of about 30 mL/hr.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in the above formulations at a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base (usually sucrose and acacia or tragacanth); lozenges comprising the active ingredient in an inert base (such as gelatin and glycerin or sucrose and acacia); and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have, for example, a particle size of 0.1 to 500 microns (including between 0.1 and 500 microns and in increments such as particle sizes of 0.5, 1, 30, 35 microns, etc.), which are administered as follows: rapid inhalation is through the nasal passages or inhalation is through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds heretofore used to treat or prevent the conditions described below.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind described above. Preferred unit dosage formulations are those containing the active ingredient in a daily dose or unit daily sub-dose, or suitable fraction thereof, as herein described.
The present invention also provides a veterinary composition, which thus comprises at least one active ingredient as described above and a veterinary carrier. Veterinary carriers are substances which can be used for the purpose of administering the composition and can be solid, liquid or gaseous substances which are inert or acceptable in the veterinary field and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
Combination therapy
The compounds of formula I may be used alone or in combination with other therapeutic agents for the treatment of diseases or disorders described herein, such as inflammatory or hyperproliferative disorders (e.g., cancer). In some embodiments, the compound of formula I is combined in a pharmaceutical combination formulation or administration regimen as a combination therapy with an additional second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or that can be used to treat inflammation, immune response disorders, or hyperproliferative disorders (e.g., cancer). The additional therapeutic agent can be a Bcl-2 inhibitor, a JAK inhibitor, an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, an apoptosis enhancer, a neurotrophic factor, a cardiovascular disease therapeutic agent, a liver disease therapeutic agent, an antiviral agent, a blood disease therapeutic agent, a diabetes therapeutic agent, and an immunodeficiency disorder therapeutic agent. The second therapeutic agent may be an NSAID anti-inflammatory agent. The second therapeutic agent can be a chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or administration regimen preferably has complementary activities to the compound of formula I such that they do not adversely affect each other. The above compounds are suitably present in combination in amounts effective for the intended purpose. In one embodiment, the compositions of the present application comprise a compound of formula I, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent, such as an NSAID.
The combination therapy may be administered on a simultaneous or sequential schedule. When administered first and second, the combination may be administered in two or more administrations. Combined administration includes co-administration and sequential administration in any order using separate formulations or a single pharmaceutical formulation, wherein it is preferred that there is a period of time during which both (or all) active agents exert their biological activities simultaneously.
Suitable dosages for any of the above co-administered drugs are those currently used and may be reduced due to the combined effect (synergy) of the newly identified drug and other therapeutic agent or treatment.
Combination therapy may provide a "synergistic effect" and prove to be "synergistic", i.e. the effect achieved when the active ingredients are used together is greater than the sum of the effects achieved with the compounds separately. When the active ingredients are: (1) co-formulated in a combined unit dose formulation and administered or delivered simultaneously; (2) delivered alternately or in parallel in separate formulations; or (3) when administered by some other regimen, a synergistic effect may be achieved. When delivered in alternation therapy, synergy can be achieved when the compounds are administered or delivered sequentially, e.g., by separate injections in different syringes, separate pills or capsules, or separate infusions. Typically, during alternation therapy, an effective dose of each active ingredient is administered sequentially, i.e., one after the other, while in combination therapy, an effective dose of two or more active ingredients are administered together.
In a specific embodiment of therapy, a compound of formula I, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, may be combined with other therapeutic agents, hormonal agents, or antibody agents, such as those described herein, as well as with surgical therapy and radiation therapy. The combination therapies of the present invention thus comprise administering at least one compound of formula I, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof, and methods of treatment using at least one other cancer. The amounts of the compound of formula I and the other pharmaceutically active therapeutic agent and the associated timing of administration will be selected so as to achieve the desired combined therapeutic effect.
Additional therapeutic agents for use in combination with the compound of formula I include 5-FU, docetaxel, eribulin, gemcitabine, cobicistinib, iptasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, palbociclib, bevacizumab, pertuzumab, trastuzumab-maytansine conjugate, trastuzumab, and letrozole.
Metabolites of compounds of formula I
In vivo metabolites of formula I as described herein also fall within the scope of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of formula I, including compounds produced by a method comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolite thereof.
Metabolites are typically identified as follows: preparation of the Compounds of the invention radiolabeled (e.g.14C or3H) Isotopes, which are administered parenterally to animals such as rats, mice, guinea pigs, monkeys, or to humans in detectable doses (e.g., greater than about 0.5mg/kg), allowed a time sufficient for metabolism to occur (typically about 30 seconds to 30 hours) and their conversion products isolated from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes that survive in the metabolite). The metabolite structure is determined in a conventional manner, for example by MS, LC/MS or NMR analysis. Typically, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. The metabolites may be used in diagnostic assays for therapeutic dosages of the compounds of the present invention, provided they are not otherwise present in the body.
Article of manufacture
Another embodiment of the invention provides an article of manufacture or "kit" containing materials useful for the treatment of the above-mentioned diseases and conditions. In one embodiment, the kit comprises a container containing a compound of formula I or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically contained in commercial packages of therapeutic products containing information regarding the indications, usage, dosage, administration, contraindications and/or precautions involved in using the above-described therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container may be formed from a variety of materials such as glass or plastic. The container may contain a compound of formula I or a formulation thereof effective to treat the condition and may have a sterile interface (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of formula I. The label or package insert indicates that the composition is used to treat the selected condition, e.g., cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a condition such as a hyperproliferative condition, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotrauma disease or event. In one embodiment, the label or package insert indicates that compositions comprising a compound of formula I are useful for treating conditions resulting from abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other conditions. Alternatively or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also contain other substances desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
The kit may also comprise instructions for administering the compound of formula I and the second pharmaceutical formulation (if present). For example, if the kit comprises a first composition comprising a compound of formula I and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially or separately to a patient in need thereof.
In another embodiment, the kit is suitable for delivering a solid oral form of a compound of formula I, such as a tablet or capsule. The kit preferably comprises a plurality of unit doses. The kit may comprise a card having the dosages arranged in the order of their intended use. An example of such a kit is a "blister pack". Blister packs are known in the packaging industry and are widely used for packaging pharmaceutical unit dose forms. Memory aids, for example in the form of numbers, letters or other indicia or with calendar instructions indicating those days on which administration may be performed in the treatment schedule, may be provided as desired.
According to one embodiment, a kit may comprise (a) a first container having a compound of formula I contained therein; and optionally (b) a second container having a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution, and dextrose solution. It may also contain other substances desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
In some other embodiments where the kit comprises a composition of formula I and a second therapeutic agent, the kit may comprise containers for holding separate compositions, such as separate bottles or separate foil packages, although separate compositions may also be contained in a single, undivided container. Typically, the kit comprises instructions for administering the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g. oral and parenteral) or at different dosage intervals or when the attending physician requires titration of the individual components combined.
Preparation of Compounds of formula I
Compounds of formula I can be synthesized by synthetic routes that include methods analogous to those known in the chemical arts, and particularly in view of the specification of the application, and those for other heterocycles, see: comparative Heterocyclic Chemistry II, Katritzky and Rees eds, Elsevier,1997, e.g., Vol.3; liebigs Annalen der Chemie, (9):1910-16, (1985); helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung,40(12):1328-31, (1990), each of which is expressly incorporated by reference. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods known to those skilled in the art (e.g., by the methods outlined in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967. version 2006) or Beilsteins dbuch der organischen Chemie,4, Aufl. ed. Springer-Verlag, Berlin (including supplements) (also available from the Beilstein in-line database)).
Synthetic chemical transformations and protecting group methodologies (protection and deprotection) and necessary reagents and intermediates useful in the synthesis of compounds of formula I are known in the art and are described, for example, in r.larock, Comprehensive organic transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective group in Organic Synthesis, 3 rd edition, John Wiley and Sons (1999); and L.Patquette, edition, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its successors.
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