Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity, The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.

Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity (see Rameh et al., J. Biol Chem, 274:8347-8350 (1999) for a review). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (PI 3-kinase; PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol 2:358-60 (1992)).
The levels of phosphatidylinositol-3,4,5-triphosphate (PIP3), the primary product of PI 3-kinase activation, increase upon treatment of cells with a variety of stimuli. This includes signaling through receptors for the majority of growth factors and many inflammatory stimuli, hormones, neurotransmitters and antigens, and thus the activation of PI3Ks represents one, if not the most prevalent, signal transduction events associated with mammalian cell surface receptor activation (Cantley, Science 296:1655-1657 (2002); Vanhaesebroeck et al. Annu Rev. Biochem, 70: 535-602 (2001)). PI 3-kinase activation, therefore, is involved in a wide range of cellular responses including cell growth, migration, differentiation, and apoptosis (Parker et al., Current Biology, 5:577-99 (1995); Yao et al., Science, 267:2003-05 (1995)). Though the downstream targets of phosphorylated lipids generated following PI 3-kinase activation have not been fully characterized, it is known that pleckstrin-homology (PH) domain- and FYVE-finger domain-containing proteins are activated when binding to various phosphatidylinositol lipids (Sternmark et al., J Cell Sci, 112:4175-83 (1999); Lemmon et al., Trends Cell Biol, 7:237-42 (1997)). Two groups of PH-domain containing PI3K effectors have been studied in the context of immune cell signaling, members of the tyrosine kinase TEC family and the serine/threonine kinases of the AGC family. Members of the Tec family containing PH domains with apparent selectivity for PtdIns (3,4,5)P3 include Tec, Btk, Itk and Etk. Binding of PH to PIP3 is critical for tyrsosine kinase activity of the Tec family members (Schaeffer and Schwartzberg, Curr. Opin. Immunol. 12: 282-288 (2000)) AGC family members that are regulated by PI3K include the phosphoinositide-dependent kinase (PDK1), AKT (also termed PKB) and certain isoforms of protein kinase C(PKC) and S6 kinase. There are three isoforms of AKT and activation of AKT is strongly associated with PI3K-dependent proliferation and survival signals. Activation of AKT depends on phosphorylation by PDK1, which also has a 3-phosphoinositide-selective PH domain to recruit it to the membrane where it interacts with AKT. Other important PDK1 substrates are PKC and S6 kinase (Deane and Fruman, Annu Rev. Immunol. 22—563-598 (2004)). In vitro, some isoforms of protein kinase C (PKC) are directly activated by PIP3. (Burgering et al., Nature, 376:599-602 (1995)).
Presently, the PI 3-kinase enzyme family has been divided into three classes based on their substrate specificities. Class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, whereas Class III PI3Ks can only phosphorylate PI.
The initial purification and molecular cloning of PI 3-kinase revealed that it was a heterodimer consisting of p85 and p110 subunits (Otsu et al., Cell, 65:91-104 (1991); Hiles et al., Cell, 70:419-29 (1992)). Since then, four distinct Class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., p110α, p110β and p110δ, each interact with the same regulatory subunit, p85; whereas p110γ interacts with a distinct regulatory subunit, p101. As described below, the patterns of expression of each of these PI3Ks in human cells and tissues are also distinct. Though a wealth of information has been accumulated in recent past on the cellular functions of PI 3-kinases in general, the roles played by the individual isoforms are not fully understood.
Cloning of bovine p110α has been described. This protein was identified as related to the Saccharomyces cerevisiae protein: Vps34p, a protein involved in vacuolar protein processing. The recombinant p110α product was also shown to associate with p85α, to yield a PI3K activity in transfected COS-1 cells. See Hiles et al., Cell, 70, 419-29 (1992).
The cloning of a second human p110 isoform, designated p110β, is described in Hu et al., Mol Cell Biol, 13:7677-88 (1993). This isoform is said to associate with p85 in cells, and to be ubiquitously expressed, as p110β mRNA has been found in numerous human and mouse tissues as well as in human umbilical vein endothelial cells, Jurkat human leukemic T cells, 293 human embryonic kidney cells, mouse 3T3 fibroblasts, HeLa cells, and NBT2 rat bladder carcinoma cells. Such wide expression suggests that this isoform is broadly important in signaling pathways.
Identification of the p110δ isoform of PI 3-kinase is described in Chantry et al., J Biol Chem, 272:19236-41 (1997). It was observed that the human p110δ isoform is expressed in a tissue-restricted fashion. It is expressed at high levels in lymphocytes and lymphoid tissues and has been shown to play a key role in PI 3-kinase-mediated signaling in the immune system (Al-Alwan etl al. JI 178: 2328-2335 (2007); Okkenhaug et al JI, 177: 5122-5128 (2006); Lee et al. PNAS, 103: 1289-1294 (2006)). P110δ has also been shown to be expressed at lower levels in breast cells, melanocytes and endothelial cells (Vogt et al. Virology, 344: 131-138 (2006) and has since been implicated in conferring selective migratory properties to breast cancer cells (Sawyer et al. Cancer Res. 63:1667-1675 (2003)). Details concerning the P110δ isoform also can be found in U.S. Pat. Nos. 5,858,753; 5,822,910; and 5,985,589. See also, Vanhaesebroeck et al., Proc Nat. Acad Sci USA, 94:4330-5 (1997), and international publication WO 97/46688.
In each of the PI3Kα, β, and γ subtypes, the p85 subunit acts to localize PI 3-kinase to the plasma membrane by the interaction of its SH2 domain with phosphorylated tyrosine residues (present in an appropriate sequence context) in target proteins (Rameh et al., Cell, 83:821-30 (1995)). Five isoforms of p85 have been identified (p85α, p85β, p55γ, p55α and p50α) encoded by three genes. Alternative transcripts of Pik3r1 gene encode the p85 α, p55 α and p50α proteins (Deane and Fruman, Annu Rev. Immunol. 22: 563-598 (2004)). p85α is ubiquitously expressed while p85β, is primarily found in the brain and lymphoid tissues (Volinia et al., Oncogene, 7:789-93 (1992)). Association of the p85 subunit to the PI 3-kinase p110α, β, or δ catalytic subunits appears to be required for the catalytic activity and stability of these enzymes. In addition, the binding of Ras proteins also upregulates PI 3-kinase activity.
The cloning of p110γ revealed still further complexity within the PI3K family of enzymes (Stoyanov et al., Science, 269:690-93 (1995)). The p110γ isoform is closely related to p110α and p110β (45-48% identity in the catalytic domain), but as noted does not make use of p85 as a targeting subunit. Instead, p110γ binds a p101 regulatory subunit that also binds to the βγ subunits of heterotrimeric G proteins. The p101 regulatory subunit for PI3Kgamma was originally cloned in swine, and the human ortholog identified subsequently (Krugmann et al., J Biol Chem, 274:17152-8 (1999)). Interaction between the N-terminal region of p101 with the N-terminal region of p110γ is known to activate PI3Kγ through Gβγ. Recently, a p101-homologue has been identified, p84 or p87PIKAP (PI3Kγ adapter protein of 87 kDa) that binds p110γ (Voigt et al. JBC, 281: 9977-9986 (2006), Suire et al. Curr. Biol. 15: 566-570 (2005)). p87PIKAP is homologous to p101 in areas that bind p110γ and Gβγ and also mediates activation of p110γ downstream of G-protein-coupled receptors. Unlike p101, p87PIKAP is highly expressed in the heart and may be crucial to PI3Kγ cardiac function.
A constitutively active PI3K polypeptide is described in international publication WO 96/25488. This publication discloses preparation of a chimeric fusion protein in which a 102-residue fragment of p85 known as the inter-SH2 (iSH2) region is fused through a linker region to the N-terminus of murine p110. The p85 iSH2 domain apparently is able to activate PI3K activity in a manner comparable to intact p85 (Klippel et al., Mol Cell Biol, 14:2675-85 (1994)).
Thus, PI 3-kinases can be defined by their amino acid identity or by their activity. Additional members of this growing gene family include more distantly related lipid and protein kinases including Vps34 TOR1, and TOR2 of Saccharomyces cerevisiae (and their mammalian homologs such as FRAP and mTOR), the ataxia telangiectasia gene product (ATR) and the catalytic subunit of DNA-dependent protein kinase (DNA-PK). See generally, Hunter, Cell, 83:1-4 (1995).
PI 3-kinase is also involved in a number of aspects of leukocyte activation. A p85-associated PI 3-kinase activity has been shown to physically associate with the cytoplasmic domain of CD28, which is an important costimulatory molecule for the activation of T-cells in response to antigen (Pages et al., Nature, 369:327-29 (1994); Rudd, Immunity, 4:527-34 (1996)). Activation of T cells through CD28 lowers the threshold for activation by antigen and increases the magnitude and duration of the proliferative response. These effects are linked to increases in the transcription of a number of genes including interleukin-2 (IL2), an important T cell growth factor (Fraser et al., Science, 251:313-16 (1991)). Mutation of CD28 such that it can no longer interact with PI 3-kinase leads to a failure to initiate IL2 production, suggesting a critical role for PI 3-kinase in T cell activation.
Specific inhibitors against individual members of a family of enzymes provide invaluable tools for deciphering functions of each enzyme. Two compounds, LY294002 and wortmannin, have been widely used as PI 3-kinase inhibitors. These compounds, however, are nonspecific PI3K inhibitors, as they do not distinguish among the four members of Class I PI 3-kinases. For example, the IC50 values of wortmannin against each of the various Class I PI 3-kinases are in the range of 1-10 nM. Similarly, the IC50 values for LY294002 against each of these PI 3-kinases is about 1 μM (Froman et al., Ann Rev Biochem, 67:481-507 (1998)). Hence, the utility of these compounds in studying the roles of individual Class I PI 3-kinases is limited.
Based on studies using wortmannin, there is evidence that PI 3-kinase function also is required for some aspects of leukocyte signaling through G-protein coupled receptors (Thelen et al., Proc Natl Acad Sci USA, 91:4960-64 (1994)). Moreover, it has been shown that wortmannin and LY294002 block neutrophil migration and superoxide release. However, inasmuch as these compounds do not distinguish among the various isoforms of PI3K, it remains unclear from these studies which particular PI3K isoform or isoforms are involved in these phenomena and what functions the different Class I PI3K enzymes perform in both normal and diseased tissues in general. The co-expression of several PI3K isoforms in most tissues has confounded efforts to segregate the activities of each enzyme until recently.
The separation of the activities of the various PI3K isozymes has been advanced recently with the development of genetically manipulated mice that allowed the study of isoform-specific knock-out and kinase dead knock-in mice and the development of more selective inhibitors for some of the different isoforms. P110α and p110β knockout mice have been generated and are both embryonic lethal and little information can be obtained from these mice regarding the expression and function of p110 alpha and beta (Bi et al. Mamm. Genome, 13:169-172 (2002); Bi et al. J. Biol. Chem. 274:10963-10968 (1999)). More recently, p110α kinase dead knock in mice were generated with a single point mutation in the DFG motif of the ATP binding pocket (p110αD933A) that impairs kinase activity but preserves mutant p110α kinase expression. In contrast to knock out mice, the knockin approach preserves signaling complex stoichiometry, scaffold functions and mimics small molecule approaches more realistically than knock out mice. Similar to the p110α KO mice, p110αD933A homozygous mice are embryonic lethal. However, heterozygous mice are viable and fertile but display severely blunted signaling via insulin-receptor substrate (IRS) proteins, key mediators of insulin, insulin-like growth factor-1 and leptin action. Defective responsiveness to these hormones leads to hyperinsulinaemia, glucose intolerance, hyperphagia, increase adiposity and reduced overall growth in heterozygotes (Foukas, et al. Nature, 441: 366-370 (2006)). These studies revealed a defined, non-redundant role for p110α as an intermediate in IGF-1, insulin and leptin signaling that is not substituted for by other isoforms. We will have to await the description of the p110β kinase-dead knock in mice to further understand the function of this isoform (mice have been made but not yet published; Vanhaesebroeck).
P110γ knock out and kinase-dead knock in mice have both been generated and overall show similar and mild phenotypes with primary defects in migration of cells of the innate immune system and a defect in thymic development of T cells (Li et al. Science, 287: 1046-1049 (2000), Sasaki et al. Science, 287: 1040-1046 (2000), Patrucco et al. Cell, 118: 375-387 (2004)).
Similar to p110γ, PI3K delta knock out and kinase-dead knock-in mice have been made and are viable with mild and like phenotypes. The p110δD910A mutant knock in mice demonstrated an important role for delta in B cell development and function, with marginal zone B cells and CD5+ B1 cells nearly undetectable, and B- and T cell antigen receptor signaling (Clayton et al. J. Exp. Med. 196:753-763 (2002); Okkenhaug et al. Science, 297: 1031-1034 (2002)). The p110δD910A mice have been studied extensively and have elucidated the diverse role that delta plays in the immune system. T cell dependent and T cell independent immune responses are severely attenuated in p110δD910A and secretion of TH1 (INF-γ) and TH2 cytokine (IL-4, IL-5) are impaired (Okkenhaug et al. J. Immunol. 177: 5122-5128 (2006)). A human patient with a mutation in p110δ has also recently been described. A taiwanese boy with a primary B cell immunodeficiency and a gamma-hypoglobulinemia of previously unknown aetiology presented with a single base-pair substitution, m.3256G to A in codon 1021 in exon 24 of p110δ. This mutation resulted in a mis-sense amino acid substitution (E to K) at codon 1021, which is located in the highly conserved catalytic domain of p110δ protein. The patient has no other identified mutations and his phenotype is consistent with p110δ deficiency in mice as far as studied. (Jou et al. Int. J. Immunogenet. 33: 361-369 (2006)).
Isoform-selective small molecule compounds have been developed with varying success to all Class I PI3 kinase isoforms (Ito et al. J. Pharm. Exp. Therapeut., 321:1-8 (2007)). Inhibitors to alpha are desirable because mutations in p110α have been identified in several solid tumors; for example, an amplification mutation of alpha is associated with 50% of ovarian, cervical, lung and breast cancer and an activation mutation has been described in more than 50% of bowel and 25% of breast cancers (Hennessy et al. Nature Reviews, 4: 988-1004 (2005)). Yamanouchi has developed a compound YM-024 that inhibits alpha and delta equipotently and is 8- and 28-fold selective over beta and gamma respectively (Ito et al. J. Pharm. Exp. Therapeut., 321:1-8 (2007)).
P110β is involved in thrombus formation (Jackson et al. Nature Med. 11: 507-514 (2005)) and small molecule inhibitors specific for this isoform are thought after for indication involving clotting disorders (TGX-221: 0.007 uM on beta; 14-fold selective over delta, and more than 500-fold selective over gamma and alpha) (Ito et al. J. Pharm. Exp. Therapeut., 321:1-8 (2007)).
Selective compounds to p110γ are being developed by several groups as immunosuppressive agents for autoimmune disease (Rueckle et al. Nature Reviews, 5: 903-918 (2006)). Of note, AS 605240 has been shown to be efficacious in a mouse model of rheumatoid arthritis (Camps et al. Nature Medicine, 11: 936-943 (2005)) and to delay onset of disease in a model of systemic lupus erythematosis (Barber et al. Nature Medicine, 11: 933-935 (205)).
Delta-selective inhibitors have also been described recently. The most selective compounds include the quinazolinone purine inhibitors (PIK39 and IC87114). IC87114 inhibits p110δ in the high nanomolar range (triple digit) and has greater than 100-fold selectivity against p110α, is 52 fold selective against p110β but lacks selectivity against p110γ (approx. 8-fold). It shows no activity against any protein kinases tested (Knight et al. Cell, 125: 733-747 (2006)). Using delta-selective compounds or genetically manipulated mice (p110δD910A) it was shown that in addition to playing a key role in B and T cell activation, delta is also partially involved in neutrophil migration and primed neutrophil respiratory burst and leads to a partial block of antigen-IgE mediated mast cell degranulation (Condliffe et al. Blood, 106: 1432-1440 (2005); Ali et al. Nature, 431: 1007-1011 (2002)). Hence p110δ is emerging as an important mediator of many key inflammatory responses that are also known to participate in aberrant inflammatory conditions, including but not limited to autoimmune disease and allergy. To support this notion, there is a growing body of p110δ target validation data derived from studies using both genetic tools and pharmacologic agents. Thus, using the delta-selective compound IC 87114 and the p110αD910A mice, Ali et al. (Nature, 431: 1007-1011 (2002)) have demonstrated that delta plays a critical role in a murine model of allergic disease. In the absence of functional delta, passive cutaneous anaphylaxis (PCA) is significantly reduced and can be attributed to a reduction in allergen-IgE induced mast cell activation and degranulation. In addition, inhibition of delta with IC 87114 has been shown to significantly ameliorate inflammation and disease in a murine model of asthma using ovalbumin-induced airway inflammation (Lee et al. FASEB, 20: 455-465 (2006). These data utilizing compound were corroborated in p110δD910A mutant mice using the same model of allergic airway inflammation by a different group (Nashed et al. Eur. J. Immunol. 37:416-424 (2007)).
There exists a need for further characterization of PI3Kδ function in inflammatory and auto-immune settings. Furthermore, our understanding of PI3Kδ requires further elaboration of the structural interactions of p110δ, both with its regulatory subunit and with other proteins in the cell. There also remains a need for more potent and selective or specific inhibitors of PI3K delta, in order to avoid potential toxicology associated with activity on isozymes p110 alpha (insulin signaling) and beta (platelet activation). In particular, selective or specific inhibitors of PI3Kδ are desirable for exploring the role of this isozyme further and for development of superior pharmaceuticals to modulate the activity of the isozyme.

This patent is subject to a terminal disclaimer.


A damping unit for a film packing device a first roller, a damping roller and a second roller connected to the base of the film packing device respectively. The first roller includes a frame connected to the base and a first tube and a second tube are connected to the frame. The damping roller is located between the first and second rollers and has a spring biased on a top thereof so as to control its speed of rotation. The film goes partially around the first tube, the second tube, at least half of an outer periphery of the damping roller and then partially around the second roller before being wrapped around the object.

(1) Field of the Invention
The present invention relates to a damping unit for film packing device, and more particularly, to a tension adjustable damping unit for film packing device.
(2) Description of the Prior Art
A conventional film packing device is used to wrap multiple layers of film to objects so as to protect the objects from scrape or rains. The conventional film packing device is shown in FIG. 6 and generally includes a base 60 which is connected with a mandrel 61 which is movable up and down relative to the base 60. A roll 70 of film is mounted to the mandrel 61 and the film 71 is pulled from the roll 70 to wrap around the objects. The objects are located on a rotatable support board and rotated to drag the film 71 to wrap around them. However, the shapes of the objects to be wrapped may not the same so that each point on the object is located at different distance from the mandrel 61. The tension of the film 71 is larger when the object is located closer to the mandrel 61 and smaller when the object is located far from the mandrel 61. The film 71 bends due to the gravity or even attached to each other if the object is located at a distance from the mandrel 61. Therefore, it is important to keep the film 71 with proper tension when packing the objects at different distances.
The present invention intends to provide a damping unit for film packing device wherein the speed of the rotation of the roll of the film can be adjusted so that when the film is dragged by the rotation of the objects, the tension of the film can be maintained.


Corrosion of metal surfaces, particularly aluminum or aluminum alloy surfaces, is inhibited by contacting the metal surfaces with a solution comprising a mercapto-substituted silane and then preferably baking the metal to cure the silane coating. Multifunctional organo-mercapto-substituted silanes are preferred in the practice of the process. Preferably, the treatment solution is an aqueous mixture of the mercapto-substituted silane and selected solvents.

The present invention relates to a composition and method for its use in preventing or inhibiting corrosion of metals, particularly aluminum and aluminum alloys. Treatment of the metal surfaces with the composition of this invention inhibits corrosion of that surface and also improves adhesion of subsequent organic coatings to the treated surface.
Many metals are susceptible to corrosion. In this regard, atmospheric corrosion is of particular concern. Such corrosion may affect the performance and/or appearance of the metals affected, and the products produced therefrom. In addition, when polymer coatings such as paints, adhesives or sealants are applied to the metal, corrosion of the underlying metal may cause a loss of adhesion between the polymer coating and the base metal. A loss of adhesion between the polymer coating and the base metal may similarly lead to corrosion of the metal. Aluminum and aluminum alloys frequently require corrosion protection and improvements in adhesion between the base aluminum (or aluminum alloys) and subsequent polymer coatings. Aluminum alloys, in particular, can be susceptible to corrosion since the alloying elements used to improve the metal""s mechanical properties may decrease corrosion resistance.
Specifications for testing the effectiveness of the corrosion inhibition and adhesion promotion of various treatments have been established. Examples of the foregoing include ASTM standard D3359-87, Military specification MIL-C-5541D and ASTM standard B117.
Prior art techniques for improving corrosion resistance of metals widely employ the use of chromate conversation coatings to passivate the surface. Such chromate treatments are undesirable, however, because the chromium used is highly toxic, carcinogenic, and environmentally undesirable. Phosphate conversion coatings are also used, but generally provide substantially less corrosion protection unless used in conjunction with a chromate.
Recently, various techniques for eliminating the use of chromates in corrosion inhibition and adhesion promotion treatments have been proposed. U.S. Pat. No. 5,108,793 discusses treating the metal with an inorganic silicate followed by treating the silicate coating with a silane. U.S. Pat. No. 5,292,549 teaches the treatment of metals with a solution of a silane and a crosslinking agent in order to form a siloxane film for temporary corrosion protection.
U.S. Pat. No. 5,200,275 discusses treating a lead or tin coated steel surface with a silicate and a metal salt followed by a further optional treatment with a silane. U.S. Pat. No. 5,759,629 discusses the use of a hydrolyzed vinyl silane in a method for inhibiting corrosion on metal sheet. U.S. Pat. No. 5,322,713 discusses the treatment of metal sheet with an alkaline aluminate coating followed by a rinse with a hydrolyzed organofunctional silane.
U.S. Pat. No. 5,759,629 discusses treatment of a metal sheet with a hydrolyzed vinyl silane for corrosion inhibition. U.S. Pat. No. 5,750,197 discusses treatment of metals with a solution containing a multifunctional silane having at least two trisubstituted silyl groups, wherein the substituents are either alkoxy or acetoxy. An optional second treatment solution containing an organofunctional silane may also be employed, particularly if the metal is to be painted.
Many of the foregoing proposed techniques, however, have been proven to be ineffective, or to require time consuming, energy inefficient, multi-step processes. Thus, there remains a need for a simple, low cost, effective technique for inhibiting corrosion of metals, particularly for aluminum and aluminum alloys.
It is an object of this invention to provide an improved method of inhibiting corrosion of metals, especially aluminum and aluminum alloys, which is simple to apply, cost effective and environmentally friendly. It is another object of this invention to provide a treatment for metals which improves the adhesion of subsequent organic coatings to the metal while at the same time improving the corrosion resistance of the metal.
The foregoing objectives can be accomplished by treating a metal, particularly aluminum or aluminum alloys, with a treatment composition comprising a mercapto-substituted silane. The treatment composition is applied directly to the metal surface, preferably without any intervening treatment other than cleaning, deoxidizing or etching, by spray, flood or other means of direct contact. The treatment composition is preferably applied at room temperature and preferably has a pH between 3 and 5.
Preferably, the metal surface is cleaned, deoxidized and/or etched prior to treatment with the mercapto-substituted silane. A variety of known cleaners, deoxidizers and etchants may be employed for this purpose, with the appropriate choice being made with the specific metal surface to be prepared in mind.
Once the mercapto-substituted silane is applied to the metal surface the treated metal should be baked in order to dry and cure the coating. After curing, the treatment with the mercapto-substituted silane may be repeated and baked again, as desired.
The compositions and methods of this invention are particularly suitable for treating aluminum and aluminum alloys. The inventors have found that treating aluminum or aluminum alloys with the mercapto-substituted silane containing composition of this invention provides both increased corrosion resistance and enhanced adhesion of subsequent organic coatings to the treated surface.
The inventors have found that the corrosion resistance of metal, particularly aluminum and aluminum alloys, can be greatly enhanced by applying a treatment solution comprising a mercapto-substituted silane, preferably followed by a bake dry and cure. The mercapto-substituted silane of this invention is preferably a multifunctional mercapto-substituted organic silane of the following chemical formula:
Wherein R1, R2 and R3 are independently selected from the group consisting of alkoxy groups (e.g., methoxy, ethoxy, or similar alkoxy groups), alkyl groups and hydrogen groups, and wherein n is an integer from 0 to 10, but is preferably an integer from 1 to 4. A particularly preferred mercapto-substituted silane is gamma-mercaptopropyltrimethoxy silane which has the following structure:
The inventors have found gamma-mercaptopropyltrimethoxy silane to be the most preferred mercapto-substituted silane for use in this invention. Gamma-mercaptopropyltrimethoxy silane is available from the Witco Corporation of Greenwich, Conn. under the tradename SILQUEST(copyright) A-189 Silane. Other useful mercapto-substituted silanes include (3-mercaptopropyl) methyl dimethoxy silane available from the Fluka Chemie AG of Buchs, Switzerland. The inventors have unexpectedly discovered that the mercapto group on these mercapto-substituted silanes provides significantly better corrosion protection than is provided by other silanes which do not have the mercapto substituted group. Thus, the inventors believe that the mercapto-substitution on the silane provides significant and unexpected improvements in corrosion protection and adhesion promotion in relation to non-mercapto-substituted silanes.
The mercapto-substituted silane is preferably solubilized, with a suitable solvent, into a treatment solution. The concentration of mercapto-substituted silane in the treatment solution may be from 0.5 to 10% by weight but is preferably from 2 to 4% by weight. Mercapto-substituted silanes, such as gamma-mercaptopropyltrimethoxy silane, may not be soluble in water alone to the extent necessary to practice this invention effectively. The inventors have discovered that a combination of water with an appropriate solvent are required to effectively solubilize these mercapto-substituted silanes in a water matrix. Appropriate solvents for this purpose include N-methyl-2-pyrrolidone, butyrolactone, diethylene glycol butyl ether, hexylene glycol, ethylene glycol monobutyl ether and alcohols. Most preferred as a solubilization matrix for the mercapto-substituted silanes is a combination of water and ethylene glycol monobutyl ether. Preferably, the mercapto-substituted silane is added to the solvent (e.g., ethylene glycol monobutyl ether) and then that mixture is added to the water, with stirring to form the treatment solution. The inventors have found that an aqueous solution of ethylene glycol monobutyl ether does an excellent job of solubilizing the mercapto-substituted silane and leaves behind a spot free finish as it evaporates from the treated surface. The concentration of solvent in the water must be adjusted in order to properly solubilize and/or maintain the mercapto-substituted silane in solution. The inventors have found that ratios of water to ethylene glycol monobutyl ether concentration, based on volume percentages of from 65/35 to 94/6 were suitable for mercapto-substituted silane concentrations of from 5 to 0.5 volume percent. The aqueous solution of the mercapto-substituted silane will hydrolyze the silane and will improve its effectiveness in treating the metal surfaces.
The pH of the treatment solution should be less than 7 and is preferably between about 3 and 5. The inventors have found that using an aqueous solution of the foregoing solvents and the mercapto-substituted silane, the treatment solution will naturally make up at a pH of about 4. Acetic acid can be used to make any needed adjustments to pH. The concentration of mercapto-substituted silane may range from 0.5 to 10 percent by volume, but is preferably from 2 to 5 percent by volume of the treatment solution. The concentration of mercapto-substituted silane in the treatment solution will affect the corrosion protection achieved, with better corrosion protection achieved at higher concentrations.
The process of this invention has been found to increase the corrosion resistance of metals generally, not including zinc and zinc plated surfaces, but is particularly effective on aluminum and aluminum alloys. Thus, the inventors have found this process to be especially useful on aluminum, and aluminum alloys such as 6061-T6 aluminum alloy, 2024-T3 aluminum alloy and 356 aluminum alloys.
The treatment solution is applied to the metal surfaces by immersion, spraying, flooding or other similar means of contact. Preferably, the contact occurs at room temperature and lasts for from 15 seconds to several minutes.
The inventors have found that it is important to dry and bake the treated metal after application of the mercapto-substituted silane in order to properly cure the silane coating on the metal surface. Baking may occur at from 60xc2x0 C. to 300xc2x0 C. for from several minutes to several hours, preferably at from 80xc2x0 C. to 250xc2x0 C. for from 20 minutes to 2 hours. However, the inventors have found that baking at a temperature of about 200xc2x0 C. for about 1 hour provides optimum performance. Baking temperatures greater than or less than about 200xc2x0 C. have been found to decrease the amount of corrosion protection achieved with the process.
The silane treatment solution of this invention can become unstable over time. As the silane becomes hydrolyzed by the water it will have a tendency to precipitate and the solution will begin to take on a white cloudy appearance. It is believed that this instability may also arise from the polymerization of the silane molecules in the solution to form 2 or 3 member chains. This potential instability can be controlled by increasing the concentration of solvent in the treatment solution before, or at the first sign of cloudiness. As a result of this potential instability, it may be useful to prepare a concentrated solution of the mercapto-substituted silane without water that is storage stable and is then added to water to prepare the treatment solution. In this regard, a storage stable concentrate of mercapto-substituted silane can be prepared by dissolving the silane in a solvent, such as ethylene glycol monobutyl ether, without water. For example, a concentrate of 90% by volume ethylene glycol monobutyl ether and 10% by volume gamma-mercaptopropyltrimethoxy silane can be prepared and is storage stable. A 20% by volume solution of this concentrate in water can then used as the treatment solution.
The metal is preferably cleaned, deoxidized and/or etched prior to contacting it with the treatment solution of this invention. Prior preparation of the metal surface generally increases the activity of that surface towards subsequent treatments, in this case, towards the mercapto-substituted silane treatment. As a result, prior preparation of the surface will generally yield better corrosion resistance results after treatment with the process of this invention. However, preferably the surface is not treated with any non-mercapto-substituted silanes, silicates, chromates or other conversion coatings prior to treatment with the mercapto-substituted silane. Preferably, the metal surfaces are cleaned and etched prior to treatment with the process of this invention. A variety of cleaners and etchants are known for preparing a variety of metal surfaces. For cleaning the surfaces of aluminum and aluminum alloys, both acid and alkali based cleaners are available. One preferred alkali based cleaner is ISOPREP 49L available from MacDermid, Incorporated of Waterbury, Conn. ISOPREP 49L is typically used at 10% v/v concentration with water at 150xc2x0 F. for 2-5 minutes. A preferred acid based cleaner is ISOPREP 160 also available from MacDermid, Incorporated. ISOPREP 160 is typically used at 10% v/v concentration with water at 160xc2x0 F. for 2-5 minutes. These aluminum cleaners are typically relatively weakly basic or acidic in comparison to the etchants.
Aluminum and aluminum alloys can be effectively etched using strongly acidic or strongly basic solutions. Two preferred etchants for aluminum and aluminum alloys include ISOPREP 161 and ISOPREP 35, both available from MacDermid, Incorporated. ISOPREP 161 is a strongly acidic etchant typically used at 10% v/v concentration with water at 140xc2x0 F. for 30 seconds to 2 minutes. ISOPREP 35 is a strongly basic etchant typically used at 4 oz/gal concentration in water at 160xc2x0 F. for 30 seconds for 2 minutes.
Although the inventors have found that treatment of the metal with a cleaner and an etchant prior to treatment with the mercapto-substituted silane of this invention generally improves the corrosion resistance provided by the process, the best choice of cleaners and etchants may depend upon the metal being treated. For instance, the inventors have found that strongly acid etchants work better on 6061-T6 aluminum alloy while strongly basic etchants work better on 2024-T3 aluminum alloy.
It is preferred that the metal surface be treated with the mercapto-substituted silane directly after the cleaning, deoxidizing, and/or etching process, without any intervening treatment with another type of silane or conversion coating. The inventors have surprisingly found that other silanes (i.e., non-mercapto-substituted silanes) do not provide nearly the same corrosion protection as the mercapto-substituted silanes of this invention and if the other silanes are applied prior to the mercapto-substituted silane, they may interfere with the mercapto-substituted silane""s ability to effectively react with the surface and provide corrosion protection.
The corrosion resistance of a treated metal part is typically measured by exposing the treated metal part to a 5% by weight sodium chloride solution in a salt spray chamber. Corrosion resistance is measured as the maximum number of hours the part can endure before corrosion becomes apparent in a specified manner on its surface. Military specification MIL-C-5541D provides specific procedures for measuring the corrosion resistance of a treated part. ASTM B117 is another widely used specification for determining the corrosion resistance of a metal treated part with a salt spray procedure. Similar specifications, such as ASTM D-3359-87, have been prepared to test the adhesion of organic coatings to treated metal surfaces. These adhesion procedures usually include a cross-hatch tape test whereby the organic coating is cut in a specified cross-cut pattern and tape is applied and removed to determine the quantity, if any, of the organic coating that is removed.
The inventors have found that salt spray corrosion resistance in excess of 1,000 hours on 6061-T6 aluminum alloy and in excess of 350 hours on 2024-T3 aluminum alloy can be achieved with the process of this invention. In addition, excellent adhesion of organic coatings to the treated metal surfaces can be achieved with the process of this invention.

Composition and method for inhibiting corrosion of aluminum and aluminum alloys using mercapto substituted silanes


A semiconductor memory device includes a semiconductor substrate in which a cell region and a core and peripheral region are defined. The device further comprises isolation layers formed in the semiconductor substrate to define active regions, a first gate electrode structure formed in the cell region and a second gate electrode structure formed in the core and peripheral region. Source and drain regions formed in the active regions on respective sides of each of the gate electrode structures and self-aligned contact pads are formed in the cell region in contact with the source and drain regions. An insulating interlayer is formed on the semiconductor substrate between the self-aligned contact pads, and etch stoppers are formed on the insulating interlayer between the self-aligned contact pads in the cell region.

1. Field of the Invention
The present invention relates generally to a semiconductor memory device and a method of manufacturing the same. More particularly, the invention relates to a semiconductor memory device having an etch stopper formed in a cell region and a method of manufacturing the semiconductor memory device.
A claim of priority is made to Korean Patent Application No. 10-2005-0015371, filed on Feb. 24, 2005, the disclosure of which is hereby incorporated by reference in its entirety.
2. Description of Related Art
As the integration density of semiconductor memory devices increases, contact holes formed in the semiconductor devices become increasingly narrow. As a result, the aspect ratio of the contact holes tends to increase, and therefore contact holes and associated contacts are often required to be formed using multi-step processes.
The integration density of dynamic random access memory (DRAM) devices is typically very high. Because of this, active regions between adjacent gate electrodes in DRAMs are generally so narrow that it is difficult to form contacts connected to the active regions. One approach to forming contacts in narrow regions is to form a hard mask layer and spacers over and around the gate electrodes before forming self aligned contact pads between the gate electrodes. Then, bitline contacts or storage node contacts are formed over the self-aligned contact pads. This approach is often referred to as "self aligned contact technology."
Typically, the self-aligned contacts have a larger diameter than the bitline contacts or the storage node contacts. However, as the integration density of DRAM devices continues to increase, the diameter of the self-aligned contact pads reduces and approaches the diameter of the bitline and storage node contacts. As a result, slight misalignments between the bitline or storage node contacts and node can cause serious problems in the manufacture of DRAM devices. Illustrations of some common problems are described below in relation to FIG. 1.
Referring to FIG. 1, a conventional semiconductor memory device comprises a semiconductor substrate 10 in which a cell region "A" and a core and peripheral region "B" are defined. A plurality of isolation layers 15 defining active regions 10a are formed in semiconductor substrate 10, and junction regions 25a and 25b are formed between isolation layers 15 in respective cell and core and peripheral regions "A" and "B".
A first insulating interlayer 30 is formed over semiconductor substrate 10 and a second insulating interlayer 40 is formed over first insulating interlayer 30.
In cell region "A", a plurality of self-aligned contact pads 35 are formed in first insulating interlayer 30 over junction regions 25a, and a plurality of bitline contact holes 45 are formed in second insulating interlayer 40 to expose self-aligned contact pads 35.
In core and peripheral region "B", a gate electrode structure 20 is formed in first insulating layer 30 on side junction region 25b and an interconnection contact hole 50 is formed in first and second insulating interlayer 30 and 40 to expose side junction region 25b. Each gate electrode structure 20 comprises a gate insulating layer 16 formed on semiconductor substrate 10, a gate electrode material 17 formed on gate insulating layer 16, a hard mask layer 18 formed over gate electrode material 17, and spacers 19 formed on the sidewall of gate insulating layer 16, gate electrode material 17, and hard mask layer 18.
Typically, the respective diameters of self-aligned contact pads 35 and bitline contact holes 45 are slightly different from each other, or they are slightly misaligned with each other. As a result, portions of first insulating interlayer 30 adjacent to self-aligned contact pads 35 may be removed when bitline contact holes 45 are formed. Due to the partial loss of first insulating interlayer 30, active regions 10a may also be partially removed, causing leakage current in the semiconductor memory device.
Storage node contact holes (not shown) are typically formed after bitlines are formed in bitline contact holes 45. The storage node contact holes are generally formed between the bitlines to contact self-aligned contact pads 35. However, the storage node contact holes are almost inevitably misaligned with the self-aligned contact pads. As a result, the first insulating interlayer 30 is almost inevitably etched when the storage node contact holes are formed, causing further damage to active regions 10a.
Interconnection contact hole 50 is typically formed in core and peripheral region "B" at the same time when bit line contact holes 45 are formed in cell region "A". Unfortunately, however, as the integration density of core and peripheral region "B" increases, interconnection contact hole 50 tends to expose more than just junction region 25b. For instance, interconnection contact hole 50 may expose parts of gate electrode structure 20.
Consequently, spacers 19 and hard mask layer 18 may be partially lost during the formation of interconnection contact hole 50. As a result, gate electrode material 17 may be exposed and may be short-circuited by a conductive material formed later in interconnection contact hole 50.
To solve these problems, some conventional memory devices interpose etch stoppers between first insulating layer 30 and second insulating interlayer 40 to prevent first insulating interlayer 30 from being etched when bitline contact holes 45 are formed. A conventional memory device employing this technique is disclosed, for example, in U.S. Pat. No. 6,787,906 (the '906 patent).
In the '906 patent, etch stoppers are formed on first insulating layer 30. Accordingly, bitline contact holes 45 and storage node contact holes can be formed without further etching first insulating layer 30. However, the etch stoppers are also formed in core and peripheral region "B", making it difficult to form interconnection contact hole 50. Since interconnection contact hole 50 penetrates first and second insulating layers 30 and 40, if the etch stoppers are interposed between first and second insulating interlayers 30 and 40, it is difficult to expose junction region 25b.

Semiconductor memory device having local etch stopper and method of manufacturing the same