This invention relates to 1,3-dihydroxy-20,20-dialkyl-vitamin D3 analogs of Formula (I):

1. Field of the Invention
This invention relates to 1,3-dihydroxy-20,20-dialkyl-vitamin D3 analogs, compositions comprising the analogs and methods of treatment of osteoporosis, secondary hyperparathyroidism, cancer and autoimmune diseases using such analogs.
2. Description of Related Art
a. Osteoporosis
Osteoporosis is the most common form of metabolic bone disease and may be considered the symptomatic, fracture stage of bone loss (osteopenia). Although osteoporosis may occur secondary to a number of underlying diseases, 90% of all cases appear to be idiopathic. Postmenopausal women are at risk for idiopathic osteoporosis (postmenopausal or Type I osteoporosis); another particularly high risk group for idiopathic osteoporosis is the elderly of either sex (senile or Type II osteoporosis). Osteoporosis has also been related to corticosteroid use, immobilization or extended bed rest, alcoholism, diabetes, gonadotoxic chemotherapy, hyperprolactinemia, anorexia nervosa, primary and secondary amenorrhea, transplant immunosuppression, and oophorectomy. Postmenopausal osteoporosis is characterized by fractures of the spine, while femoral neck fractures are the dominant features of senile osteoporosis.
The mechanism by which bone is lost in osteoporotics is believed to involve an imbalance in the process by which the skeleton renews itself. This process has been termed bone remodeling. It occurs in a series of discrete pockets of activity. These pockets appear spontaneously within the bone matrix on a given bone surface as a site of bone resorption. Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone of generally constant dimension. This resorption process is followed by the appearance of osteoblasts (bone forming cells) which then refill with new bone the cavity left by the osteoclasts.
In a healthy adult subject, osteoblasts and osteoclasts function so that bone formation and bone resorption are in balance. However, in osteoporotics an imbalance in the bone remodeling process develops which results in bone being replaced at a slower rate than it is being lost. Although this imbalance occurs to some extent in most individuals as they age, it is much more severe and occurs at a younger age in postmenopausal osteoporotics, following oophorectomy, or in iatrogenic situations such as those resulting from corticosteroid therapy or the immunosuppression practiced in organ transplantation.
Various approaches have been suggested for increasing bone mass in humans afflicted with osteoporosis, including administration of androgens, fluoride salts, and parathyroid hormone and modified versions of parathyroid hormone. It has also been suggested that bisphosphonates, calcitonin, calcium, 1,25-dihydroxy vitamin D3 and some of its analogs, and/or estrogens, alone or in combination, may be useful for preserving existing bone mass.
Vitamin D3 is a critical element in the metabolism of calcium, promoting intestinal absorption of calcium and phosphorus, maintaining adequate serum levels of calcium and phosphorus, and stimulating flux of calcium into and out of bone. The D vitamins are hydroxylated in vivo, with the resulting 1xcex1,25-dihydroxy metabolite being the active material. Animal studies with 1,25-(OH)2 vitamin D3 have suggested bone anabolic activity. Aerssens et al., in Calcif Tissue Int, 55:443-450 (1994), reported upon the effect of 1xcex1-hydroxy vitamin D3 on bone strength and composition in growing rats with and without corticosteroid treatment. However, human usage is restricted to antiresorption due to the poor therapeutic ratio (hypercalciuria and hypercalcemia as well as nephrotoxicity).
Dechant and Goa, in xe2x80x9cCalcitriol. A review of its use in the treatment of postmenopausal osteoporosis and its potential in corticosteroid-induced osteoporosisxe2x80x9d, Drugs Aging [NEW ZEALAND 5 (4): 300-17 (1994)], reported that 1,25-dihydroxy vitamin D3 (calcitriol) has shown efficacy in the treatment of postmenopausal osteoporosis (and promise in corticosteroid-induced osteoporosis) based upon a clinical trial in 622 women with postmenopausal osteoporosis. Patients with mild to moderate disease (but not those with more severe disease) who received calcitriol (0.25 microgram twice daily) had a significant 3-fold lower rate of new vertebral fractures after 3 years of treatment compared with patients receiving elemental calcium 1000 mg/day. In patients commencing long term treatment with prednisone or prednisolone, calcitriol 0.5 to 1.0 micrograms/day plus calcium 1000 mg/day, administered with or without intranasal calcitonin 400 IU/day, prevented steroid-induced bone loss. Overall, calcitriol was well tolerated. At recommended dosages hypercalcaemia was infrequent and mild, generally responding to reductions in calcium intake and/or calcitriol dosage. The narrow therapeutic window of calcitriol required that its use be adequately supervised, with periodic monitoring of serum calcium and creatinine levels. This study clearly identifies the key limitation of calcitriol therapy as the close proximity of therapeutic and toxic doses.
This invention provides novel vitamin D3 derivatives which have more favorable therapeutic doses.
b. Cancer
Epidemiologic studies have correlated sun or UV light exposure with a lower incidence of a variety of malignancies, including breast, colon and prostate cancer. Evidence from receptor studies demonstrates that besides the classic target organs, such as intestine, kidney and bone, vitamin D receptors (VDR) are present on a wide variety of human normal and cancer cell lines and fresh tissue. Growth inhibition with vitamin D or 1,25-dihydroxycholecalciferol does not always translate into potential therapeutic efficacy in vivo. Early in vivo studies have focused on the anti-proliferative effects of 1,25-dihydroxycholecalciferol and its analogues in murine leukemia model systems where 1,25-dihydroxycholecalciferol has been shown to induce not only an anti-proliferative effect, but also a differentiating effect. Therapeutic efficacy in vivo has its limitations due to the hypercalcemia observed with high dose treatment of the parent 1,25-dihydroxycholecalciferol. As a result, a number of analogues have been developed that produce significant anti-tumor effects without hypercalcemia.
Steinmeyer et al in U.S. Pat. No. 5,585,368 discloses 1xcex1-25-dihydroxy-20-disubstituted vitamin D3 analogs for the treatment of hyperproliferative disorders of the skin, malignant tumors such as leukemia, colon and breast cancers, autoimmune diseases such as diabetes and for the treatment of sebaceous gland diseases. Danielsson, C. et al in J. Cell Biochem., 63, No. 2, 199-206 (1996) disclose 20-methyl analogues of 1,25-dihydroxy vitamin D3, including 1xcex1-25-dihydroxy-20-methyl-23(E)-ene-cholecalciferol for the treatment of hyperproliferative disorders. This invention provides novel vitamin D3 derivatives for the treatment of hyperproliferative disorders of the skin, malignant tumors such as leukemia, colon and breast cancers, autoimmune diseases such as diabetes and for the treatment of sebaceous gland diseases which have more favorable therapeutic ratios or margins.
c. Hyperparathyroidism
Secondary hyperparathyroidism is routine in patients with chronic renal failure. It is established that the reduction of renal 1,25(OH)2 vitamin D3 (calcitriol) synthesis is one of the principal mechanisms leading to the secondary hyperparathyroidism in these patients and it has been shown that calcitriol possesses direct suppressive action on PTH synthesis. Therefore, administration of calcitriol has been recommended for the treatment of secondary hyperparathyroidism in these patients. However, as described above, calcitriol has potent hypercalcemic effects giving it a narrow therapeutic window which limits its usage, especially at high doses. It would therefore be desirable to have an alternative means of treating hyperparathyroidism and repleting circulating vitamin D3 activity without incurring these undesirable hypercalcemic effects.
This invention provides novel vitamin D3 derivatives which have more favorable therapeutic windows.
One aspect of the invention concerns Vitamin D3 analogs of the Formula (I):
wherein:
X is hydrogen or xe2x95x90CH2;
R1 and R2 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl, or R1 and R2 together form xe2x95x90CH2;
R3 and R4 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R3 and R4 together with C25 form a (C3-C9)cycloalkyl or (C3-C9)cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, provided that:
(i) when R1 and R2 are (C1-C4)alkyl or R1 and R2 together with C20 form a cyclopropyl group or xe2x95x90CH2, R3 and R4 are (C1-C4)alkyl, trifluoromethyl or R3 and R4 together with C25 form (C3-C6)cycloalkyl and A is a single bond, then B is not a trans double bond;
(ii) when B is a single bond, then R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl group; and
(iii) when R1 and R2 are (C1-C4)alkyl, R3 and R4 are (C1-C4)alkyl, Xxe2x95x90CH2 and A is a single bond, then B is not a double bond.
A second aspect of this invention relates to a method for treating osteoporosis or secondary hyperparathyroidism via administration of a compound of Formula (I), wherein:
X is hydrogen or xe2x95x90CH2;
R1 and R2 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl, or R1 and R2 together form xe2x95x90CH2;
R3 and R4 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R3 and R4 together with C25 form a (C3-C9)cycloalkyl or (C3-C9)cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, in an amount therapeutically effective to restore bone density to an asymptomatic level, without inducing hypercalciuria, hypercalcemia, or nephrotoxicity.
A third aspect of this invention relates to a method for treating cancer via administration of a compound of Formula (I), wherein:
X is hydrogen or xe2x95x90CH2;
R1 and R2 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl, or R1 and R2 together form xe2x95x90CH2;
R3 and R4 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R3 and R4 together with C25 form a (C3-C9)cycloalkyl or (C3-C9)cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, in an amount therapeutically effective, without inducing hypercalciuria, hypercalcemia, or nephrotoxicity provided that:
(i) when R1 and R2 are (C1-C4)alkyl or R1 and R2 together with C20 form a cyclopropyl group or xe2x95x90CH2, R3 and R4 are (C1-C4)alkyl, trifluoromethyl or R3 and R4 together with C25 form (C3-C6)cycloalkyl and A is a single bond, then B is not a trans double bond;
(ii) when B is a single bond, then R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl group; and
(iii) when R1 and R2 are (C1-C4)alkyl, R3 and R4 are (C1-C4)alkyl, Xxe2x95x90CH2 and A is a single bond, then B is not a double bond.
A fourth aspect of this invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a vitamin D3 analog of Formula (I).
The vitamin D3 analogs of the present invention have the following general structure:
wherein:
X is hydrogen or xe2x95x90CH2;
R1 and R2 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl, or R1 and R2 together form xe2x95x90CH2;
R3 and R4 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R3 and R4 together with C25 form a (C3-C9)cycloalkyl or (C3-C9)cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, provided that:
(i) when R1 and R2 are (C1-C4)alkyl or R1 and R2 together with C20 form a cyclopropyl group or xe2x95x90CH2, R3 and R4 are (C1-C4)alkyl, trifluoromethyl or R3 and R4 together with C25 form (C3-C6)cycloalkyl and A is a single bond, then B is not a trans double bond;
(ii) when B is a single bond, then R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl group; and
(iii) when R1 and R2 are (C1-C4)alkyl, R3 and R4 are (C1-C4)alkyl, Xxe2x95x90CH2 and A is a single bond, then B is not a double bond.
A method for treating osteoporosis or secondary hyperparathyroidism via administration of a compound of Formula (I), wherein:
X is hydrogen or xe2x95x90CH2;
R1 and R2 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl, or R1 and R2 together form xe2x95x90CH2;
R3 and R4 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R3 and R4 together with C25 form a (C3-C9)cycloalkyl or (C3-C9)cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, in an amount therapeutically effective to restore bone density to an asymptomatic level, without inducing hypercalciuria, hypercalcemia, or nephrotoxicity.
A method for treating cancer via administration of a compound of Formula (I), wherein:
X is hydrogen or xe2x95x90CH2;
R1 and R2 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl, or R1 and R2 together form xe2x95x90CH2;
R3 and R4 are, independently of each other, a (C1-C4)alkyl or (C1-C4)fluoroalkyl, or R3 and R4 together with C25 form a (C3-C9)cycloalkyl or (C3-C9)cyclofluoroalkyl;
A is a single or a double bond; and
B is a single, double or triple bond;
and prodrugs thereof, in an amount therapeutically effective, without inducing hypercalciuria, hypercalcernia, or nephrotoxicity, provided that:
(i) when R1 and R2 are (C1-C4)alkyl or R1 and R2 together with C20 form a cyclopropyl group or xe2x95x90CH2, R3 and R4 are (C1-C4)alkyl, trifluoromethyl or R3 and R4 together with C25 form (C3-C6)cycloalkyl and A is a single bond, then B is not a trans double bond;
(ii) when B is a single bond, then R1 and R2 together with C20 form a (C3-C6)cycloalkyl or (C3-C6)cyclofluoroalkyl group; and
(iii) when R1 and R2 are (C1-C4)alkyl, R3 and R4 are (C1-C4)alkyl, Xxe2x95x90CH2 and A is a single bond, then B is not a double bond.
As used herein, the term (C1-C4) alkyl means a fully-saturated hydrocarbon radical having one to four carbon atoms; a (C1-C4) fluoroalkyl is an alkyl radical, as defined above, in which one or more hydrogen atoms attached to the carbon backbone have been substituted with one or more fluorine atoms. A (C3-C6) cycloalkyl is a cyclic saturated hydrocarbon radical having three to six ring carbon atoms; a (C3-C6) cyclofluoroalkyl is a cycloalkyl radical, as defined above, in which one or more hydrogen atoms attached to the carbon backbone have been substituted with one or more fluorine atoms. A (C3-C9) cycloalkyl is a cyclic saturated hydrocarbon radical having three to nine ring carbon atoms; a (C3-C9) cyclofluoroalkyl is a cyclic saturated hydrocarbon radical having three to nine carbon atoms in which one or more hydrogen atoms attached to the carbon backbone have been substituted with one or more fluorine atoms.
Further as used herein, by double bond it is meant an unsaturated linkage between two adjacent carbon atoms in which two pairs of electrons are shared equally, and wherein each carbon atom bears two single-bonded substituents in either a cis (Z) or a trans (E) configuration about the double bond.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy group in compound (I) is bonded to any group that may be cleaved i vivo to regenerate the free hydroxyl group. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) and ethers of hydroxy functional groups in compounds of Formula (I), and the like. Such compounds are routinely made by one of skill in the art by acylating or etherifying the hydroxy group in the parent molecule.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The compounds of the present invention may be generically described as 1xcex1,25-dihydroxy-20,20-dialkyl and 1xcex1,25-dihydroxy-20,20-dialkyl-19-nor analogs of vitamin D3.
The compounds of the invention are named using the numbering system shown in FIG. (1) below.
For example, a compound of the invention where X is xe2x95x90CH2, R1 and R2 together form a cyclopropyl group, A is a single bond and B is a triple bond is named as 1xcex1-25-dihydroxy-23-yne-20,21,28-cyclopropyl-cholecalciferol.
The following Table I provides some representative examples of compounds of the present invention:
and are named as:
1. 1,25-dihydroxy-23-yne-20,21,28-cyclopropyl-cholecalciferol.
2. 1,25-dihydroxy-23-yne-20,21,28-cyclopropyl-19-nor-cholecalciferol.
3. 1,25-dihydroxy-23-yne-26,27-hexafluoro-20,21,28-cyclopropyl-cholecalciferol.
4. 1,25-dihydroxy-23-yne-26,27-hexafluoro-20,21,28-cyclopropyl-19-norcholecalciferol.
5. 1,25-dihydroxy-23-(Z)-ene-26,27-hexafluoro-20,21,28-cyclopropyl-cholecalciferol.
6. 1,25-dihydroxy-23-(Z)-ene-26,27-hexafluoro-20,21,28-cyclopropyl-19-norcholecalciferol.
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred.
A preferred group of compounds are those wherein:
A is a single or a double bond, preferably a single bond; and
B is a triple bond.
Another preferred group of compounds are those wherein:
A is a double bond; and
B is a double bond.
Yet another preferred group of compounds are those wherein:
A is a single or a double bond, preferably a single bond; and
B is a cis double bond.
Within these preferred groups of compounds, more preferred groups are those wherein:
R1 and R2 together with C20 form a (C3-C6)cycloalkyl, preferably a cyclopropyl; and
R3 and R4 are, independently of each other, a (C1-C4)alkyl or a (C1-C4)fluoroalkyl, preferably methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or 2,2,2-trifluoroethyl, more preferably methyl or trifluoromethyl.
Analogs of this invention may generally be prepared by reaction and combination of fragments of Vitamin D3 molecules (see e.g., Shiuey et al., J. Org. Chem, 55:243 (1990); Wovkulich, P. M. et al., Tetrahedron, 40, 2283 (1984); Baggiolini E. B. et al J. Org. Chem., 51, 3098-3108, (1986) and Steinmeyer et al., U.S. Pat. No. 5,585,368.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), or Sigma (St. Louis, Mo.) or they can be prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Vol. 1-15 (John Wiley and Sons, 1991); March""s Advanced Organic Chemistry, (John Wiley and Sons 4th Edition) and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
The preparation of compounds of Formula (I) and the intermediates used in their preparation is illustrated by the reaction schemes below.
In general, a compound of Formula (I) is prepared by coupling a 4H-inden-4-one derivative of Formula (II) where R1, R2, R3, R4, A and B are as described in the Summary of the Invention and R5 is hydrogen or a hydroxy protecting group (e.g., trialkylsilyl, preferably trimethylsilyl) with a diphenylphosphine oxide derivative of a compound of Formula (III) where X is hydrogen or xe2x95x90CH2, as shown in Scheme I below.
The coupling reaction is carried out in the presence of a strong base such as an alkyllithium like n-butyllithium in a mixture of hexane and tetrahydrofuran at xe2x88x9278xc2x0 C. to give a trisily derivative of compound of Formula (I). Removal of the sily protecting groups with tetrabutylammnonium fluoride in a suitable polar organic solvent such as tetrahydrofuran provides a compound of Formula (I).
It should be noted that although the shown intermediates have hydroxy groups typically protected as silylethers, the scope of the invention includes the use of alternative hydroxyl protecting groups known in the art as described in T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Wiley, New York (1991) and J. F. McOmie, xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d Plenum Press, London (1973), together with alternative methods for deprotection.
Synthesis of compounds of Formula (III) are known and conventional in this art. See, for example, U.S. Pat. No., 5,585,368 to Steinmeyer et al., U.S. Pat. No. 5,384,314 to Doran et al., U.S. Pat. No. 5,428,029 to Doran et al., U.S. Pat. No. 5,451,574 to Baggiolini et al.; pending U.S. patent application Ser. No. 60/018,219; Shiuey et al., J. Org. Chem., 55:243-247 (1990), Kiegel, J. et al. and Tetr. Lett., 32:6057-6060 (1991), Perlman, K. L., et al., Tetr. Lett., 32:7663-7666 (1991).
Synthesis of compounds of Formula (II) is described in Scheme II below.
Detailed descriptions of the synthesis of compounds of Formula (I) where R1 and R2 together form a cyclopropyl ring, X is xe2x95x90CH2 or H2, A is a single bond, B is a triple bond and R3 and R4 are either methyl or trifluoromethyl are described in Examples 2, 3, 5 and 6.
Detailed descriptions of the synthesis of compounds of Formula (I) where R1 and R2 together form a cyclopropyl ring, X is xe2x95x90CH2 or H2, A is a single bond, B is a cis double bond and R3 and R4 are trifluoromethyl are described in Examples 8 and 9.
The 4H-inden-4-one derivatives of Formula (II) are prepared as shown in Scheme II below.
As shown above, preparation of a compound of Formula (II) involves preparation of a common intermediate, 1-[(5-hydroxy)-3-alkynyl]-inden-4-ol derivative (VII), which is then converted to a compound of Formula (II) where B is either a double or a triple bond by following method (a) or method (b) respectively.
Compound (VII) is prepared by condensation of lithium acetylide derived from a 1-(3-alkynyl)-4-tert-butyldimethylsilyloxy-7a-methyl-indene derivative (IV) with a ketone of Formula (V) where R3 and R4 are as defined in the Summary of the Invention to give a 1-[(5-hydroxy)-3-alkynyl]-4-tert-butyldimethysilyloxy-7a-methyl-indene derivative (VI). The condensation reaction is carried out in the presence of a strong base such as n-butyllithium in an aprotic organic solvent such as tetrahydrofuran and at low temperatures ranging between xe2x88x9250 to xe2x88x92100xc2x0 C. Removal of the silyl group with tetrabutylammonium fluoride in an suitable organic solvent such as tetrahydrofuran gives the 1-[(5-hydroxy)-3-alkynyl]-inden-4-ol derivative (VII).
A detailed description of the synthesis of compounds of Formula (IV) where R1 and R2 together form a cyclopropyl ring and A is a single bond is given in Example 1. Synthesis of other compounds of Formula (IV) and alternative methods for preparing compounds of Formula (VII) have been described in copending U.S. application Ser. No. 08/857,569, published as EP 0 808,832 A2, whose disclosure is hereby incorporated by reference.
A compound of Formula (II) where B is a triple bond and R5 is hydrogen is prepared, as shown in method (a), by oxidation of the hydroxy group at the 4-position in compound (VII) to the keto group with a suitable oxidizing agent such as pyridinium dichromate at room temperature. The oxidation reaction is carried out in a chlorinated hydrocarbon solvent such as methylene chloride, chloroform and the like. A compound of Formula (II) where R5 is hydrogen is converted to the corresponding compound of Formula (II) where R5 is trialkylsilyl, preferably trimethylsilyl, by reacting it with a suitable silylating agent such as 1-trimethylsilylimidazole in a non-alcoholic organic solvent such as tetrahydrofuran, methylene chloride, preferably methylene chloride, and the like.
Synthesis of compounds of Formula (II) where A is a single bond, B is a triple bond, R1 and R2 together form a cyclopropyl ring, R1 is trimethylsilyl or hydrogen and R3 and R4 are methyl or trifluoromethyl are described in Examples 1 and 4.
Alternatively, a compound of Formula (II) where B is a double bond is prepared, as shown in method (b), by partial reduction of the triple bond in compound (VII) with a suitable reducing agent to give a 3-alkene-4H-inden-4-ol of Formula (VIII). The choice of the reducing agent depends on the configuration about the double bond. If the E configuration is desired, then the reduction is carried out with lithium aluminum hydride in the presence of an alkali metal alkoxide, such as sodium methoxide, and in an aprotic organic solvent like ether or more preferably tetrahydrofuran. If the Z configuration is desired, then the reduction is carried out with Lindlar""s catalyst. Compound (VIII) is then converted to a compound of Formula (II) where B is a double bond and R5 is hydrogen or a silyl group by carrying out the oxidation and silylation steps as described above. Synthesis of a compound of Formula (II) where A is a single bond, B is a cis double bond, R1 and R2 together form a cyclopropyl ring, R5 is trimethylsilyl and R3 and R4 are trifluoromethyl is described in Example 7.
A reaction scheme showing the preparation of a compound of Formula (I) where A is a single bond, B is a single bond, R1 and R2 form a cyclopropyl ring and X is xe2x95x90CH2 is shown below in Scheme III and is described further in Example 10.
The starting material is reduced, preferably by catalytic hydrogenation, to give the completely saturated side chain derivative which is then oxidized to give the corresponding ketone. Condensation with a diphenylphosphine oxide as previously described in Scheme I followed by removal of the silyl protecting groups gives the desired compound. One of skill in the art will recognize that similar procedures may be used to form other compounds of the invention where R1-R4 and X may vary as described in the Summary of the Invention.
The compounds of this invention are useful for the prevention and treatment of a variety of mammalian conditions manifested by loss of bone mass. In particular, the compounds of this invention are anabolic agents and are indicated for the prophylaxis and therapeutic treatment of osteoporosis and osteopenia in mammals without inducing hypercalciuria, hypercalcemia, or nephrotoxicity. As used herein, xe2x80x9chypercalciuriaxe2x80x9d is excessive calcium in the urine, in humans corresponding to an excretion of greater than about 4 mg/kg/day. This often results in nephrolithiasis (renal calculi). xe2x80x9cHypercalcemiaxe2x80x9d is an excessive concentration of calcium in the serum; in humans (and rats) this corresponds to greater than about 10.5 mg/dl. xe2x80x9cIntolerable hypercalcemiaxe2x80x9d, usually occurring at serum calcium concentrations greater than about 12 mg/dl, is associated with emotional lability, confusion, delirium, psychosis, stupor, and coma.
The compounds of this invention are expected to be useful in the treatment of Type I (postmenopausal), Type II (senile), and Type III (iatrogenic) osteoporosis, including that associated with immunosuppressive drugs used in organ transplantation, as well in the treatment of osteodystrophy due to renal dialysis and secondary hyperparathyroidism.
Compounds of this invention are also useful in treating diseases caused by elevated levels of parathyroid hormone. In one aspect, compounds of the invention are used in treating secondary hyperparathyroidism associated with renal failure and in particular with reversing or reducing the bone loss associated with renal insufficiency. Other aspects include the treatment of renal osteodystrophy associated with late stage secondary hyperparathyroidism. Other aspects include the treatment of primary hyperparathyroidism.
Compounds of Formula (I) are also useful in treating neoplastic diseases such as leukemia, colon cancer, breast cancer and prostate cancer.
Compounds of Formula (I) are also useful in treating immunosuppressive and autoimmune diseases. Such diseases include, but are not limited to, multiple sclerosis, systemic lupus erythematosus, diabetes, thyroiditis and allograft rejection. In particular, compounds of Formula (I) are useful to treat diseases via modulation of the activity of the vitamin D3 receptor (VDR). The utility of these compounds is demonstrated in vivo using murine models for these diseases as is well known in the art. See, e.g., Lemire et al., Autoimmunity, 12:143-148 (1992); Lemireet. al., J. Clin. Invest., 87:1103-1107 (1991), Lemire et al., Endocrinology, 135:2818 (1994), and Lemire et al., J. Cellular Biochem., 49:26-31 (1992).
The bone anabolic activity of the compounds of the invention was demonstrated in vivo in the ovariectomized rat model as described in detail in Example 10. The anti-cell proliferation activity of the compounds of the invention was demonstrated in vitro as described in detail in Examples 11 and 12. The parathyroid hormone suppressive activity of the compounds of the invention was demonstrated in vivo as described in detail in Example 13.
In general, the compound of this invention may be administered in amounts between about 0.0002 and 5 xcexcg per day, preferably from about 0.001 to about 2 xcexcg per day, most preferably from about 0.002 to about 1 xcexcg per day. For a 50 xcexcg human subject, the daily dose of active ingredient may be from about 0.01 to about 250 xcexcg, preferably from about 0.05 to about 100 xcexcg, most preferably from about 0.1 to about 50 xcexcg per day. In other mammals, such as horses, dogs, and cattle, other doses may be required. This dosage may be delivered in a conventional pharmaceutical composition by a single administration, by multiple applications, or via controlled release, as needed to achieve the most effective results, preferably once or twice daily by mouth. In certain situations, alternate day dosing may prove adequate to achieve the desired therapeutic response.
The selection of the exact dose and composition and the most appropriate delivery regimen will be influenced by, inter alia, the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient. In the treatment of corticosteroid induced osteopenia, it is expected that the requisite dose will be greater for higher doses of corticosteroids.
Representative delivery regimens include oral, parenteral (including subcutaneous, intramuscular and intravenous), rectal, buccal (including sublingual), pulmonary, transdermal, and intranasal, most preferably oral.
A further aspect of the present invention relates to pharmaceutical compositions comprising as an active ingredient a compound of the present invention, in admixture with a pharmaceutically acceptable, non-toxic carrier. As mentioned above, such compositions may be prepared for parenteral (subcutaneous, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; for pulmonary or intranasal administration, particularly in the form of powders, nasal drops or aerosols; and for rectal or transdermal administration.
The compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., (1985). Formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered spray. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
Orally administrable compositions may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form, including, for example, tablets, coated tablets, capsules, lozenges, aqueous or oily suspensions, solutions, emulsions, elixirs, and powders suitable for reconstitution with water or another suitable liquid vehicle before use. Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethylcellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form.
Preferred solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. SEG capsules are of particular interest because they provide distinct advantages over the other two forms (see Seager, H., xe2x80x9cSoft gelatin capsules: a solution to many tableting problemsxe2x80x9d; Pharmaceutical Technology, 9, (1985). Some of the advantages of using SEG capsules are: a) dose-content uniformity is optimized in SEG capsules because the drug is dissolved or dispersed in a liquid that can be dosed into the capsules accurately, b) drugs formulated as SEG capsules show good bioavailability because the drug is dissolved, solubilized or dispersed in an aqueous-miscible or oily liquid and therefore when released in the body produce drug dispersions of high surface area and c) degradation of drugs that are sensitive to oxidation during long-term storage is prevented because the dry shell of soft gelatin provides a barrier against the diffusion of oxygen.
The dry shell formulation typically comprises of about 40% to 60% concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30 to 40% concentration of water. Other materials such as preservatives, dyes, opacifiers and flavours also may be present. The liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.

Abstract: compositions comprising the analogs, methods of preparing the analogs and methods of treatment of osteoporosis, secondary hyperparathyroidism, cancer and autoimmune diseases using such analogs.


A system and method for covering or uncovering a trailer comprising supports adapted to be operatively connected to the ends of a trailer to position a roller, with a cover attached thereto, from one side of the trailer to the other side to thereby cover the trailer and any cargo loaded thereon. The system and method may be performed by a single person anywhere along the transportation route, and the apparatus may be located at a terminal and moved from trailer to trailer. The system and method may also be used to selectively position straps over the top of cargo loaded on a trailer for securing cargo onto the trailer.

The present invention relates to a covering system for a trailer and any cargo loaded thereon, and finds its greatest utility in the side to side covering and uncovering of cargo on a flat bed trailer.
Protecting cargo from the weather is a major concern of the trucking industry. A trucker may depart a warehouse with cargo loaded and a clear weather forecast, only to encounter inclement weather along the route. The handling of a heavy tarp is a burden at any location, and is particularly problematic along side the roadway, after dark or in a blinding snowstorm. High winds are a particular problem because of the sail area presented by the tarp and the limited number of available hands when in transit to handle the tarp from various positions alongside or atop the trailer. Serious injury has been known to result from an attempt by a driver to single handedly manipulate a tarp atop a trailer or on the cargo on a trailer in high winds.
There have been many attempts to address this issue by providing a mechanical apparatus for covering a load. Where the trailer is an open topped box truck, the problem is less severe, and mechanical tarp unrolling systems are well known. For example, the U.S. Pat. No. 5,803,528 and U.S. Pat. No. 5,806,911 to Haddad, Jr., the O""Daniel U.S. Pat. No. 5,829,818, and the Russell et al. U.S. Pat. No. 5,388,882 disclose a pivoting arm disposed alongside both sides of the open top box for mechanically unrolling a tarp from a roller carried between the distal ends of the pivoting arms. Such systems are generally not intended to protect the cargo from the weather, but to prevent the truck""s cargo (i.e., gravel, sand, trash, etc.) from spilling onto the highway and damaging other vehicles. Such systems generally depend on the sides of the box for support of the system and for supporting and thus controlling the tarp as it is unrolled, and are unsuited for flat bed trailers.
Mechanical covers for such open top truck boxes have also been proposed for side to side covering of the box. For example, the Tsukamoto U.S. Pat. No. 4,673,208; the Wilkens U.S. Pat. No. 5,765,901; and the Ellingson U.S. Pat. No. 4,691,957 disclose box top covering systems where the tarp is unrolled from a roller carried between the distal ends of arms pivotably mounted at the ends of the boxes. In these systems, the vertical sides of the truck body provide support and thus help control the tarp as it is unrolled across the top of the box, and such systems are unsuited for flat bed trailers.
The problem is particularly acute for flat bed trailers where the cargo is generally loaded by fork lift from the sides of the trailer. For example, the Trickett U.S. Pat. No. 4,842,323 discloses a roller for a tarp which is positioned at the front of a trailer from which a tarp may be pulled rearward to cover a trailer from front to back with any cargo loaded thereon. However, the truck driver must stand atop the trailer and its cargo and manually pull on the tarp over the cargo the length of the trailer. The danger of being blown off of the top of the cargo as the tarp unwraps is significant in windy conditions, and the physical strength required may be beyond that of many drivers.
Accordingly it is an object of the present invention to provide novel systems and methods which obviate many of the deficiencies of known trailer covering systems, and which allows the cargo to be covered in a safe efficient manner anywhere along the route.
It is another object of the present invention to provide novel systems and methods for covering a trailer and any cargo loaded thereon.
It is still another object of the present invention to provide novel cargo covering systems and methods in which the covering and uncovering may be completed by a single truck driver.
It is yet another object of the present invention to provide a novel cargo covering systems and methods for a flat bed trailer in which the covering and uncovering mechanism does not interfere with the loading and unloading of the trailer cargo, from either side or from above.
Still another object of the present invention is to provide a novel cargo covering system and method which may be selectively used with different trailers.
Another problem encountered by truck drivers occurs during the securing of the cargo to the trailer using straps or other tie down means. Straps must be properly positioned over the cargo, attached to the trailer, and then tightened to secure the cargo to the trailer prior to transport. Typically a truck driver will attempt to properly position the straps over the cargo by throwing the straps from one side of the truck to the other. Many times the result is that some straps land on top of the cargo, some straps are twisted, and other straps fall between the cargo requiring the truck driver to climb atop the trailer and cargo and manually pull the straps over the cargo. Unlike the cover, the straps are easy to pull and have a small sail area, but the chance of injury increases whenever a driver must climb and stand atop the trailer and cargo, or retrieve a strap caught on or between the cargo. In addition, many straps have metal ends or buckles and a person positioned on the opposite side of the trailer, may be injured if struck by a strap thrown over the cargo.
Accordingly, it is yet still another object of the present invention is to provide a novel cargo covering system and method in which straps or other tie down means may be selectively positioned over the cargo loaded on a trailer to secure the cargo to the trailer and/or to secure the cargo cover to the trailer or the cargo.
These and many other objects and advantages of the present invention will be readily apparent to one skilled in the art to which the invention pertains from a perusal of the claims, the appended drawings, and the following detailed description of the preferred embodiments.

Covering system for a trailer and method


A radio-frequency (RF) shield pad is “dressed” by automatically removing melted solder from the shield pad by traversing a pattern of the shield pad. After an RF shield has been removed from a shield pad of a printed circuit board (PCB), the PCB is pre-heated to a temperature sufficient to heat solder on the shield pad and to prevent thermally stressing the PCB during the dressing process. The solder is melted, such as by a heated tip of a desoldering tool, and the melted solder is vacuumed while the tip automatically traverses the pattern of the shield pad, until all or a threshold amount of the melted solder has been removed from the shield pad. After the PCB has been reworked, solder paste is automatically disposed on the RF-shield pad, the RF shield is temporarily mounted on the RF-shield pad, and the PCB is processed in a reflow oven, thereby securely attaching the RF shield to the PCB.

A typical electronic device contains many components spaced closely together on a printed circuit board (PCB). In some designs, the PCB contains components sensitive to radio-frequency (RF) signals and enclosed within RF shields that protect them from RF signals. Generally, in these designs the RF shield is soldered to the PCB at an RF-shield contact pad on the PCB, thereby both securing the RF shield to the PCB and grounding it to the PCB ground.
When the RF-sensitive components must be reworked, by repairing and replacing them or by substituting new components, these RF shields are removed from the RF-shield pad. The shield pad is "dressed" to remove excess solder from it. As one example, an operator places the hot tip of a desoldering iron adjacent to the solder to melt the solder and then vacuums the melted solder from the RF-shield pad. After the components have been reworked, fresh solder paste is applied to the RF-shield pad, the RF shield is replaced at the RF-shield pad, and the entire PCB is subject to a reflow process to securely reattach the RF shield to the RF-shield pad.
There are several drawbacks to dressing RF-shield pads in this manner. The operator might not remove all or a sufficient amount of the solder, leaving residue solder on the RF-shield pad. The residue solder forms an uneven surface on the PCB, which can damage a nozzle dispensing solder paste for the reflow process. During the reflow process, the residue solder can flow and electrically couple adjacent components, shorting these components together. When the residue solder and fresh solder paste harden, the resulting seal between the RF shield and RF-shield pad might have gaps, exposing the RF-sensitive components to RF signals when the electronic device is being used. During the reflow process, the residue solder might decrease the strength or integrity of the seal. Finally, components on the PCB can be damaged if inadvertently touched by the hot tip of a soldering iron. All of these drawbacks make this method of dressing less reliable, more time-consuming, and, thus, more expensive.

Method of and system for dressing RF shield pads


Earth-boring tools and components thereof include a particle-matrix composite material having encapsulated diamond particles embedded within a matrix material. Diamonds in the particles comprise less than about 25% by volume of the composite material, the matrix material comprises less than about 50% by volume of the composite material, and encapsulant material surrounding the diamonds at least substantially comprises a remainder of the volume of the composite material. Methods of forming at least a portion of an earth-boring tool include embedding encapsulated diamond particles in a volume of matrix material to form a particle-matrix composite material. The composite material is formed in such a manner as to cause diamonds to comprise less than about 25% of the composite material, the matrix material to comprise less than about 50% of the composite material, and encapsulant material surrounding the diamonds to at least substantially comprise a remainder of the composite material.

Impregnated diamond earth-boring bits may be used for drilling hard or abrasive rock formations such as sandstones. Typically, an impregnated diamond bit has a solid head or crown that is cast in a mold. The crown is attached to a steel shank that has a threaded end that may be used to attach the crown and steel shank to a drill string. The crown may have a variety of configurations and generally includes a cutting face comprising a plurality of cutting structures, which may comprise at least one of cutting segments, posts, and blades. The posts and blades may be integrally formed with the crown in the mold, or they may be separately formed and attached to the crown. Channels separate the posts and blades to allow drilling fluid to flow over the face of the bit.
Impregnated diamond bits may be formed such that the cutting face of the drill bit (including the posts and blades) comprises a particle-matrix composite material that includes diamond particles dispersed throughout a matrix material. The matrix material itself may comprise a particle-matrix composite material, such as particles of tungsten carbide, dispersed throughout a metal matrix material, such as a copper-based alloy.
While drilling with an impregnated diamond bit, the matrix material surrounding the diamond particles wears at a faster rate than do the diamond particles. As the matrix material surrounding the diamonds on the surface of the bit wears away, the exposure of the diamonds at the surface gradually increases until the diamonds eventually fall away. As some diamonds are falling away, others that were previously buried become exposed, such that fresh sharp diamonds are continuously being exposed and used to cut the earth formation being drilled.
Typically, an impregnated diamond bit is formed by mixing and distributing diamond particles and other hard particles, such as, particles of tungsten carbide, in a mold cavity having a shape corresponding to the bit to be formed. The diamond particles and hard particles are then infiltrated with a molten metal matrix material such as, for example, a copper-based metal alloy. After infiltration, the molten metal matrix material is allowed to cool and solidify. The resulting impregnated diamond bit may then be removed from the mold. Alternatively, a mixture of diamond particles, hard particles, and powder matrix material may be pressed into the a desired shape to form a green bit body, and the green bit body may then be sintered one or more times to form an impregnated diamond bit having a desired final density.
During such fabrication processes, the diamond particles may not be uniformly dispersed throughout the matrix material. The diamond particles have a tendency to agglomerate together, leaving a greater density of diamonds in some regions of the bit relative to other regions of the bit. This may result in two or more diamond particles lying in contact with one another rather than being uniformly dispersed, as desired. These diamond-to-diamond contacts may substantially weaken the impregnated diamond bit and may result in uneven drilling and chipping or fracture of the blade or post on the bit.

Encapsulated diamond particles, materials and impregnated diamond earth-boring bits including such particles, and methods of forming such particles, materials, and bits


An apparatus for providing a varying impedance point in a circuit corresponding to a frequency of an input signal applied to the apparatus. Device sizes of the apparatus can be selected to provide varying impedance for desired frequency ranges.

1. Technical Field of the Invention
This invention pertains to integrated circuits. In particular, this invention pertains to a frequency dependant impedance device for providing a high impedance point in a circuit without requiring off chip components.
2. Background Art
Two implementations of frequency dependant impedances are outlined below. First, biasing for a PIN diode. PIN diodes can be thought of as light controlled current sources. For differential sensing one or both sides of the PIN diode must be AC coupled to a differential transimpedance amplifier (FIG. 3B). For typical data rates (ATM, FDDI) the lower cutoff needs to be around 200 KHz. In order to allow the use of an on die AC coupling capacitor in the range of about 10 pF a large input impedance is required. Use of resistors (FIG. 2B) is not feasible since the PIN can have DC current approaching 1 mA which would prohibit the use of large resistors with a 5 V supply. Diode biasing (FIG. 2C) is also unacceptable because it would require off-chip capacitors since the diodes have a low impedance for small signals. Inductors (FIG. 2A) also would require off-chip components.
Another scenario outlined below includes biasing an MR (magneto-resistive) head. Typically, one side of the head is connected to a current source while the other side of the head, or common mode voltage, is held at a voltage by an amplifier. Ideally, the amp has a current source output. A common problem with a current source output is that an inverting device has a large gain from its gate/base to its drain/collector due to the high impedance of the current source biasing the MR. This gain cause problems when trying to stabilize the amplifier. "Millering" the output device is not an option since the output impedance will go down as the output device is AC coupled into a diode. Off chip capacitors are typically frowned upon because of packaging constraints.
The present invention is especially helpful when a large impedance is required while biasing a device which needs a variable or DC current to operate.

International Business Machines Corporation


A petunia cultivar particularly distinguished by light to dark violet flowers, early flowering and a compact plant habit is disclosed.

The present invention comprises a new and distinct cultivar of petunia, botanically known as Petunia hybrida, and hereinafter referred to by the cultivar name 'Glow Lavender Shades'. 'Glow Lavender Shades' originated from a hybridization in May 2002 in Quedlinburg, Germany. The female parent was a petunia with light purple flowers while the male parent was a petunia with light rose-purple flowers.
The new cultivar was first propagated in Summer of 2006 from mother stock and has been asexually reproduced through vegetative cuttings for five generations. present invention has been found to retain its distinctive characteristics through successive asexual propagations.

Petunia plant named ‘Glow Lavender Shades’


Setting times of calcium phosphate cement compositions are enhanced by the addition of phosphate or carbonate lubricant compositions. Methods for preparing the cement compositions are provided.

Hydroxyapatite, as well as modified forms thereof, assume substantial interest and importance by virtue of the fact that hydroxyapatite is a major naturally occurring building block in bone, teeth and some invertebrate skeletons. There are many situations where bone has been broken, destroyed, degraded, become too brittle, or has been subject to other deteriorating effects. Numerous materials have been devised, as well as various forms of calcium phosphate, to act as supports, substitutes, or interfaces for repairing or replacing the naturally occurring structures. Preformed structures frequently do not bond to the remaining structure, so as to provide a weak juncture, which is subject to failure. Replacement structures, such as Co-Cr or Ti prostheses require that there be a strong bond between the bone to which the prosthetic device is joined and the prosthetic device. Efforts to provide a material which is moldable and will set in place have been subject to the problem of the large amount of blood which is normally present.
The blood creates many problems, in being able to wash away or dissolve mineral salts prior to their setting up as an insoluble mineral. Furthermore, the various components in the blood may become incorporated into the mineral, substantially changing its physical properties. On the other hand, one cannot have the mixture set up too rapidly, since one needs time to ensure the substantial homogeneity of the mixture, the ability to transfer the mixture to the site where it sets up, and frequently one may wish to mold the mixture. Therefore, the restrictions as to the rapidity of setting up and the ease of administering the mixture to a site creates severe limits on the properties of the materials which may be used. There is, therefore, an interest in developing materials which provide for optimum conditions in a variety of situations.
Relevant Literature
Patents of interest include U.S. Pat. Nos. 3,787,900; 3,913,229; 3,679,360; 4,097,935; 4,481,175; 4,503,157; 4,612,053; 4,659,617; 4,693,986; 4,843,112; 4,612,053; and 4,518,430. Other patents of interest include Reissue number 033,221. Articles of interest include Sugawara, J. of Endodontics, 16:162-165 (1990); Sugawara, et al., J. of Dental Research, 66:296 (1987); Brown and Chow, Cements Research Progress 1986, 351-379 (1987); Industry Week, Dec. 9, 1985, p. 76; Japanese Patent No. 89/230367; Chemical Abstracts 112, No. 26, Sect. 163, Abstract No. 240,566; Mirtchi et al., Biomaterials 11:83-88 (1990); Japanese Patent No. 89/234346; Chemical Abstracts, No. 20, Sect. 163, Abstract No. 185,872; Japanese Patent No. 88/115567; Chemical Abstracts 110, No. 12, Sect. 163, Abstract No. 101,875; Lemaitre et al., Silic. Ind. 52:141-146 (1987).

Kits for preparing calcium phosphate minerals


A phase-shift keying (PSK) receiver includes a carrier wave generator generating a carrier wave, an extracting unit extracting an in-phase component I and a quadrature component Q from a received signal on the basis of the carrier wave and the received signal, a comparator comparing the in-phase component I and the quadrature component Q extracted from the received signal to a predetermined threshold values respectively and acquiring 1-bit digital signals corresponding to the in-phase component I and the quadrature component Q respectively; and a BPSK demodulator demodulating the received signal using a binary phase-shift keying (BPSK) scheme on the basis of positional relationship on I-Q constellation between the 1-bit digital signals corresponding to the in-phase component I and the quadrature component Q acquired by the comparator.

1. Technical Field
The present invention relates to a phase-shift keying (PSK) receiver, a PSK demodulating circuit, a communication apparatus, and a PSK receiving method, and more particularly, to a phase-shift keying (PSK) receiver, a PSK demodulating circuit, a communication apparatus, and a PSK receiving method, suitable for application to a technology in which a demodulation operation is performed on the basis of an in-phase component I and a quadrature component Q which are converted into a 1-bit digital signal.
2. Related Art
As a semi-synchronous detection method in the PSK demodulation, there are a method in which a carrier wave is synchronized on the basis of the received in-phase component I and the quadrature component Q (JP-A-2001-024726) and a method in which a carrier wave is synchronized on the basis of a phase θ obtained by applying the following formula (1) to the received in-phase component I and the quadrature component Q (JP-A-9-116584).θ=tan−1(I/Q)  (1)
However, according to the method described in JP-A-2001-024726, since the carrier wave is synchronized on the basis of the in-phase component I and the quadrature component Q, it is necessary to multiply complex values in order to compensate the phase of the received signals. The complex multiplication requires four multipliers, which increases the size of the circuit. In addition, according to the method described in JP-A-9-116584, since a phase θ is obtained on the basis of the in-phase component I and the quadrature component Q, it is necessary to perform the calculation in formula (1). The calculation requires a large-capacity ROM, which increases the size of the circuit.
Moreover, in the described methods, the phase compensation operation requires a multi-bit AD converter, which accelerates the increase in the size of the circuit.

PSK receiver, PSK demodulating circuit, communication apparatus, and PSK receiving method


An accessory strip for a vehicle having a bracket secured to a track at select locations. The bracket includes a cam on an inner end that is received by a cam lock bar. The cam is movable within the track to selected positions where it may be locked in place. The bracket may include a dovetail socket to which articles may be secured by means of a dovetail plug and also may include a hook on which articles may be hung by means of flexible handles, or the like. The accessory strip assembly may be attached to an interior wall or may be formed as an integral track on an interior wall or seat back of a vehicle.

1. Field of the Invention
The present invention relates to an article storage apparatus for a vehicle interior.
2. Background Art
Vehicles are used to transport a wide variety of articles. Sedan or coupe style vehicles are generally provided with a trunk for transporting articles. Sport utility vehicles, full size vans, and mini-vans generally are provided with a rear storage area in the rear portion of the passenger compartment of the vehicle. A wide variety of articles are often transported in such vehicles including luggage, grocery bags, golf clubs, sports equipment, and the like. A problem associated with transporting articles in either the trunk area or rear storage area of a vehicle is that unrestrained articles may shift during transportation. If an article moves while being transported, it may be damaged or may impact another object potentially causing damage to that object.
Various restraining devices have been developed to hold objects while being transported in a trunk or rear storage area of a vehicle. One example of a restraining device is a cargo net that may be secured to the back of a vehicle seat, the floor of the trunk, or the floor of the rear storage area. Cargo nets provide a way to secure loose articles within a storage area or trunk but are not popular with consumers because they are not convenient to use and may become tangled with themselves or with articles that are stored within the cargo nets. Another example of a restraining device used in vehicles such as sport utility vehicles or mini-vans is a bag hook that is fastened to an interior surface such as a seat back. Bag hooks are normally permanently fastened to the vehicle interior in set locations and cannot be adjusted to accommodate differently sized objects. Bag hooks are not well suited to support articles such as cases or flashlights that do not have flexible handles that can be hooked over the bag hooks.
There is a need for a simple, unobtrusive accessory for vehicle interiors that facilitates storing a wide variety of articles in the storage area or trunk of the vehicle.
The above problems are addressed and the need is fulfilled by applicants' invention as summarized below.

Accessory strip for securing articles within a vehicle interior

International Automotive Components Group North America, Inc.


A collapsible, ground-supportable, manually transportable carrier includes a container and transport handles attached to a front end of the container. The container is formed of a plurality of detachable container sections, with adjacent sections being interconnected by a transverse hinge extending along floor portions of the container sections. The hinge comprises hinge elements inter-fitted together and rotatable relative to one another to a position enabling the container sections to be detached from one another. Tensioned cables extend along upper edges of the carrier side wall to oppose pivoting of the hinge elements and thereby maintain the container sections interconnected. The carrier can be ground-supported directly on a floor of a rear container section, or ground-support wheels can be mounted on that rear container section. The container sections, when disassembled, can be nested together, one inside of the other.

The present invention relates to a collapsible, ground-supported, manually transported carrier.
It may be desirable when traveling on foot in relatively remote areas, e.g., when hiking, hunting, cross-country skiing, etc., to possess a ground-supportable carrier, e.g., wheel-supported or runner-supported (i.e., a sled type of carrier), capable of supporting heavy loads. For example, such a carrier could serve to transport large game killed by a hunter, or as a stretcher for an injured person. The carrier should be collapsible to a compact state for easier handling when not in use.
Collapsible, ground-supportable, manually transportable carriers are disclosed, for example, in U.S. Pat. Nos. 2,314,293; 2,316,456; 2,667,996; and 3,104,116. It is desirable that such structures be easy to assemble and collapse while yet being strong and rugged when assembled. On the other hand, the structure should be as light-weight as possible in order to facilitate transport when not in use. Among the shortcomings presented by the prior art is an excessive number of components, including screws, bolts, nuts, etc., whose assembly is time consuming and difficult. Also, in order to provide the requisite strength, relatively thick parts may be employed which are too heavy and/or too large for being conveniently transported.
Therefore, it would be desirable to provide a collapsible, ground-supportable, manually transportable carrier which is strong, rugged, light in weight, and easy to assemble and collapse.

Collapsible, ground-supportable transport carrier


A semiconductor process technique to help reduce semiconductor process effects, such as undesired line edge roughness, insufficient lithographical resolution, and limited depth of focus problems associated with the removal of a photoresist layer. More particularly, embodiments of the invention use a photoacid generator (PAG) material in conjunction with a sacrificial light absorbing material (SLAM) to help reduce these and other undesired effects associated with the removal of photoresist in a semiconductor manufacturing process. Furthermore, embodiments of the invention allow a PAG to be applied in a semiconductor manufacturing process in an efficient manner, requiring fewer processing operations than typical prior art techniques.

As feature sizes continue to decline in modern photolithographic semiconductor manufacturing processes, effects, such as undesired line edge roughness, insufficient lithographical resolution, and limited depth of focus problems can increase. More particularly, photoresist image footprints may become increasingly difficult to control as semiconductor device features become smaller and closer together.
Adhesion promoters may be used to bond the photoresist to the semiconductor substrate or other device surface until the photoresist is exposed to light, thereby defining feature edges and boundaries within the device. Photoresist, however, may persist around the substrate surface and photoresist interface. This is because some regions toward the bottom of the photoresist may not become sufficiently soluble after being exposed to an incident radiation to be completely removed, and instead remain bonded to the substrate by the adhesion promoter. These areas of persisting photoresist may correspond to areas where an incident radiation signal is weakest due to radiation absorption by photoresist or reflective interaction effects between the substrate and photoresist.
A prior art technique for addressing the shortcomings of traditional adhesion promoters is the use of a photoactive adhesion promoter. Photoactive adhesion promoters contain photoacid generators (PAGs), which react to incident light by releasing acid in regions in which the photoresist is exposed to the light. The acid helps to remove the photoresist from these regions, thereby improving the accuracy of features defined by the presence of photoresist.
FIG. 1 illustrates a prior art photoadhesion promoter moiety comprising a PAG. The prior art example of FIG. 1 illustrates a system that is capable of attaching a PAG material to a semiconductor wafer as a self-assembled layer. The photoactive adhesion promoter of FIG. 1 comprises an adhesion promoter and a PAG. The PAG comprises a photon harvesting group and a catalyst group. In the embodiment illustrated in FIG. 1, the adhesion promoter is trimethoxysilane, the photon harvesting group is methyldiphenylsulfonium, and the catalyst group is nonafluorobutanesulfonate. In addition, a linker bonds the adhesion promoter to the photon harvesting group.
The adhesion promoter, photon harvesting group, and the catalyst group may comprise different compounds as well. For example, the adhesion promoter may comprise alkoxysilane, silylchloride (a subclass of silylhalide), phosphate, phosphonate, alkene, thiol, or sulfide.
The photon harvesting group may comprise sulfonium salts, such as triarylsulphonium. Triarylsulphonium is a general class, in which aryl represents any structure with an aromatic group bound to the sulfur atom as well as functionalized aryl groups where functionalization may be heteroatoms, such as fluorine, chlorine, bromine, and functional groups such as alcohol (OH), nitro (NO2), amine (R3N), amide (R2NC(O)R), carboxylic acid (RCOOH), ester (RCOOR), ether (ROR), carbonate (ROC(O)OR).
Furthermore, alkyldiarylsulfonium and dialkylarylsulfonium are a general class of sulfonium salts which may be used, in which aryl is defined as above and alkyl is a hydrocarbon group, such as (CH2)nCH3 where n=0 to 11, as well as functionalized hydrocarbon groups, in which functionalization may be heteroatoms, such as fluorine, oxygen, nitrogen, chlorine, bromine and functional groups such as alcohol (OH), nitro (NO2), amine (R3N), amide (R2NC(O)R), carboxylic acid (RCOOH), ester (RCOOR), ether (ROR), or carbonate (ROC(O)OR). Alternatively, the photon harvesting group may comprise iodonium salts, such as diaryl and alkyaryl, in which aryl and alkyl are as defined above.
The catalyst group may comprise alternative compounds, such as perfluoroalkylsufonate, alkylsulfonate, arylsulfonate, perfluoroalkyl, alkyl and aryl phosphate, or fluoroalkylsulfonamide.
Other photoadhesion promoters include sulfides, nitroaryl derivatives, or aryl sulfates (for example, tosylates). PAGs may include sulfide and onium type compounds such as diphenyl iodide hexafluorophosphate, diphenyl iodide hexafluoroarsenate, diphenyl iodide hexafluoroantimonate, diphenyl p-methoxyphenyl triflate, diphenyl p-tert-butylphenyl triflate, diphenyl p-isobutylphenyl triflate, diphenyl p-tert-butylphenyl triflate, triphenylsulfonium hexafluorophosphate, triphenylsulfonium hexafluoroarsenate, triphenylsulfonium hexafluoroantimonate, bis-(t-butylphenyl)iodonium triflate, triphenylsulfonium triflate, triphenylsulfonium nonafluorobutylsulfonate, diphenyliodonium heptadecafluorooctylsulphonate, and dibutylnaphthysulfonium triflate, as well as the combinations and permutations of the above moieties.
Examples of photo-base generators (PBGs) may include nitrocarbamate or quaternary ammonium dithiocarbamate and other generators described in, for example, Prog. Polym. Sci., volume 21, 145 (1996 Elsevier Science, Ltd.) or in J. Polym. Sci. Part A: Polym. Chem., 39, 1329-1341 (2001).
Sacrificial light absorbing material (SLAM) is typically used to fill holes or trenches in the surface of various semiconductor material (e.g. substrate material) before subsequent processing layers are added. Furthermore, SLAM materials are useful in that they absorb incident light, thereby reducing the effect of sporadic photoresist destruction that can result from light reflected from the material exposed to the light. SLAM is typically spun on to a wafer material and later etched, leaving SLAM in the holes or trenches within the surface in order to create a relatively smooth surface.
FIG. 2 illustrates a prior art dual damascene process, in which a photoresist layer (including a PAG) and a SLAM layer are deposited on a semiconductor surface. A mask layer can be applied, exposing the photoresist layer to incident radiation (ultra-violet light, extreme ultra-violet light, electron beam, x-ray, etc.) in areas that are not covered by the mask layer, removing photoresist from the exposed areas.
Prior art processing techniques typically require at least two processing steps to apply a PAG (typically contained within the photoadhesion promoter of the photoresist) and a SLAM to the wafer. This is because the PAG is typically included in the photoresist, which is applied after the SLAM. Using extra process step or steps to apply PAG and SLAM to a wafer can be costly in terms of processing time and wafer yield, as these steps require time and serve as a potential source of defects within the process.
Furthermore, prior art semiconductor processing techniques, such as those used in a damascene process flow, typically require a bake step, in which the wafer can be heated to extreme temperatures. During a bake, the wafer and SLAM may become porous, allowing amines to be released from the silicon material in the wafer, which can get trapped within a superjacent ILD layer and/or migrate 'upward' to the photoresist layer.
FIG. 2 illustrates the migration path of amines released from the wafer that get trapped in the ILD and then migrate up to the photoresist layer. The amines trapped in the ILD can flow through the SLAM and react with an overlying photoresist layer, thereby deteriorating ("poisoning") the photoactive properties of the photoresist. Resist poisoning can result in a photoresist residue that cannot react with incident light, and therefore remains after the photoresist is developed, causing features within the semiconductor device to be deformed.


An eyeglass mechanism includes a primary frame having two side studs for pivotally coupling two legs. An auxiliary frame for disposing in front of the primary frame includes two sides each having an extension for engaging over the stud. The extensions each may include a magnet for engaging with another magnet engaged in the leg or with the magnetic leg and for securing the auxiliary frame to the primary frame. The extensions each includes a hook for securing to the legs without the magnets.

1. Field of the Invention
The present invention relates to a pair of eyeglasses, and more particularly to a pair of eyeglasses having an auxiliary frame for supporting auxiliary lenses.
2. Description of the Prior Art
The closest prior art of which applicant is aware is U.S. Pat. No. 5,568,207 to Chao and has been assigned to the present assignee. The auxiliary frame may not be engaged with the legs.
The present invention has arisen to provide a novel configuration for securing the auxiliary frame to the primary frame.

Auxiliary frames with ears and lateral projections


A substrate processing chamber, particularly a chemical vapor deposition (CVD) chamber used both for thermal deposition of a conductive material and a subsequently performed plasma process. The invention reduces thermal deposition of the conductive material in a pumping channel exhausting the chamber. The pumping channel is lined with various elements, some of which are electrically floating and which are designed so that conductive material deposited on these elements do not deleteriously affect a plasma generated for processing the wafer.

Semiconductor integrated circuits are fabricated with multiple layers, some of them patterned, of semiconductive, insulating, and conductive materials, as well as additional layers providing functions such as bonding, a migration barrier, and an ohmic contacts. Thin films of these various materials are deposited or formed in a number of ways, the most important of which in modem processing are physical vapor deposition (PVD), also known as sputtering, and chemical vapor deposition (CVD).
In CVD, a substrate, for example, a silicon wafer, which may already have patterned layers of silicon or other materials formed thereon, is exposed to a precursor gas which reacts at the surface of the substrate and deposits a product of the reaction on the substrate to thereby grow a film thereon. A simple example includes the use of silane (SiH.sub.4) to deposit silicon with the hydrogen forming a gaseous byproduct which is evacuated from the chamber. However, the present application is directed more to CVD of a conductive material such as TiN.
This surface reaction can be activated in at least two different ways. In a thermal process, the substrate is heated to a sufficiently high temperature to provide the activation energy for molecules of the precursor gas adjacent to the substrate to react there and deposit a layer upon the substrate. In a plasma-enhanced CVD process (PECVD), the precursor gas is subjected to a sufficiently high field that it forms a plasma. As a result the precursor gas is excited into energetic states, such as ions or radicals, which readily react on the substrate surface to form the desired layered material.
Zhao et al. describe an example of a CVD deposition chamber in U.S. patent application Ser. No. 08/348,273 filed on Nov. 30, 1994, now U.S. Pat. No. 5,558,717, expressly incorporated herein by reference, and which is assigned to a common assignee. This type of CVD chamber is available from Applied Materials, Inc. of Santa Clara, Calif. as the CVD DxZ chamber.
As described in this patent and as illustrated in the cross sectional side view of FIG. 1, a CVD reactor chamber 30 includes a pedestal 32 supporting on a supporting surface 34 a wafer 36 to be deposited by CVD with a layer of material. Lift pins 38 are slidable within the pedestal 32 but are kept from falling out by conical heads on their upper ends. The lower ends of the lift pins 38 are engageable with a vertically movable lifting ring 39 and thus can be lifted above the pedestal's surface 34. The pedestal 32 is also vertically movable, and in cooperation with the lift pins 38 and the lifting ring 39, an unillustrated robot blade transfers a wafer into chamber 30, the lift pins 38 raise the wafer 36 off the robot blade, and then the pedestal 32 rises to raise the wafer 36 off the lift pins 38 and onto its supporting surface 34.
The pedestal 32 then further raises the wafer 36 into close opposition to a gas distribution faceplate 40, often referred to as a showerhead, which includes a large number of passageways 42 for jetting the process gas to the opposed wafer 36. That is, the passageways 42 guide the process gas into a processing space 56 towards the wafer 36. The process gas is injected into the reactor chamber 30 through a central gas inlet 44 in a gas-feed cover plate 46 to a first disk-shaped manifold 48 and from thence through passageways 50 in a baffle plate 52 to a second disk-shaped manifold 54 in back of the showerhead 40.
As indicated by the arrows, the process gas jets from the holes 42 in the showerhead 40 into the processing space 56 between the showerhead 40 and pedestal 32 so as to react at the surface of the closely spaced wafer 36. Unreacted process gas and reaction byproducts flow radially outwardly to an annular pumping channel 60 surrounding the upper periphery of the pedestal 32. The pumping channel 60 is generally closed but on the receiving end includes an annular choke aperture 62 between the pumping channel 60 and the processing space 56 over the wafer 36. The choke aperture 62 is formed between an isolator 64, to be described later, set in a lid rim 66 and an insulating annular chamber insert 68 resting on a ledge 70 on the inside of the main chamber body 72. The choke aperture 62 is formed between the main chamber and a removable lid attached to the chamber so that a fully annular choke aperture 62 can be achieved. The choke aperture 62 has a substantially smaller width than the depth of the processing space 56 between the showerhead 40 and the wafer 36 and is substantially smaller than the minimum lateral dimensions of the circumferential pumping channel 60, for example by at least a factor of five. The width of the choke aperture 62 is made small enough and its length long enough so as to create sufficient aerodynamic resistance at the operating pressure and gas flow so that the pressure drop across the choke aperture 62 is substantially larger than any pressure drops across the radius of the wafer 36 or around the circumference of the annular pumping channel 60. In practice, it is not untypical that the choke aperture 62 introduces enough aerodynamic impedance that the pressure drop from the middle of the wafer 36 to within the pumping channel 60 is no more than 10% of the circumferential pressure drop within the pumping channel 60.
The pumping channel 60 is connected through a constricted exhaust aperture 74 to a pumping plenum 76, and a valve 78 gates the exhaust through an exhaust vent 80 to a vacuum pump 82. The constricted exhaust aperture 74 performs a function similar to that of the choke aperture 62 in introducing an aerodynamic impedance such that the pressure within the pump channel 60 is substantially constant.
The restricted choke and exhaust apertures 62, 74 create a nearly uniform pressure around the circumferential pumping channel 60. The resultant gas distribution flow pattern across the wafer 36 is shown in arrowed lines 84 in FIG. 2. The process gas and its reaction byproducts flow from the center of the showerhead 40 across the wafer 36 and the periphery of the pedestal 32 along radial paths 84 and then through the choke aperture 62 to the pumping channel 60. The gas then flows circumferentially along paths 86 in the pumping channel 60 to the exhaust aperture 74 and then through the exhaust plenum 76 and the exhaust vent 80 to the vacuum pump 82. Because of the restrictions 62, 74, the radial flow 84 across the wafer 36 is nearly uniform in the azimuthal direction.
As shown in FIGS. 1 and 3 (FIG. 3 being a closeup view of the upper right corner of FIG. 1), the ledge 70 in the chamber body 72 supports the chamber shield liner 68, which forms the bottom of the pumping channel 60. The chamber lid rim 66 forms the top and part of the outside wall of the pumping channel 60 along with part of the chamber body 72. The inside upper edge of the pumping channel 60 is formed by the isolator ring 64, which is made of a ceramic or other electrically insulating material which insulates the metallic showerhead 40 from the chamber body 72.
The CVD reactor chamber 30 of FIG. 1 can be operated in two modes, thermal and plasma-enhanced. In the thermal mode, an electrical power source 90 supplies power to a resistive heater 92 at the top of the pedestal 32 to thereby heat the pedestal 32 and thus the wafer 36 to an elevated temperature sufficient to thermally activate the CVD deposition reaction. In the plasma-enhanced mode, an RF electrical source 94 is passed by a switch 96 to the metallic showerhead 40, which thus acts as an electrode. The showerhead 40 is electrically insulated from the lid rim 66 and the main chamber body 72 by the annular isolator ring 64, typically formed of an electrically non-conductive ceramic. The pedestal 32 is connected to a biasing element 98 associated with the RF source 94 so that RF power is split between the showerhead 40 and the pedestal 32. Sufficient voltage and power is applied by the RF source 94 to cause the process gas in the processing space 56 between the showerhead 40 and the pedestal 32 to discharge and to form a plasma.
Only recently has it been attempted to use this general type of CVD reactor to deposit a film of a conductive material, such as titanium nitride (TiN), using the thermal TDMAT process described by Sandhu et al. in U.S. patent application, Ser. No. 07/898,059. A related plasma process is described by Sandhu et al. in U.S. Pat. No. 5,246,881. The deposition of a conductive material in this chamber has presented some problems that are addressed by this invention.
Titanium nitride is a moderately good electrical conductor, but in semiconductor processing it is used primarily to function as a barrier layer and to assist titanium as a glue layer. This process is often applied to the contact structure illustrated in the cross-sectional view of FIG. 4 in which an oxide layer 100, typically SiO.sub.2, is deposited to a thickness of about 1 .mu.m over a substrate 102 having a surface of crystalline silicon or polysilicon. The oxide layer 100 acts as an inter-level dielectric, but to provide electrical contact between levels a contact hole 104 is etched through the oxide layer 100 to be filled with a metal such as aluminum. However, in advanced integrated circuits, the contact hole 104 is narrow, often less than 0.35 .mu.m, and has an aspect ratio of 3 or more. Filling such a hole is difficult, but a somewhat standard process has been developed in which the hole 104 is first conformally coated with a titanium layer 106, and the titanium layer 106 is then conformally coated with a titanium nitride layer 108. Thereafter, an aluminum layer 110 is deposited, usually by physical vapor deposition, to fill the contact hole 104 and to provide electrical interconnection lines on the upper level. The Ti layer 106 provides a glue layer to both the underlying silicon and the oxide on the sidewalls. Also, it can be silicided with the underlying silicon to form an ohmic contact. The TiN layer 108 bonds well to the Ti layer 106, and the aluminum layer 110 wets well to the TiN so that the aluminum can better fill the contact hole 104 without forming an included void. Also, the TiN layer 108 acts as a barrier to prevent the aluminum 110 from migrating into the silicon substrate 102 and affecting its conductivity. In a via structure in which the substrate 102 includes an aluminum surface feature, the Ti layer 106 may not be needed. Even though the electrical conductivities of titanium and titanium nitride are not nearly as high as that of aluminum, they are sufficiently conductive in thin layers to provide a good electrical contact.
Titanium and titanium nitride can be deposited by either CVD or PVD, but CVD enjoys the advantage of more easily forming conformal layers in a hole having a high aspect ratio. The thermal TDMAT process is such a CVD process for conformally coating TiN in a narrow hole.
In the TDMAT process, a precursor gas of tetrakis-dimethylamido-titanium, Ti(N(CH.sub.4).sub.2).sub.4, is injected into the chamber through the showerhead 40 at a pressure of about 1 to 9 Torr while the pedestal 32 holds the substrate 36 at an elevated temperature of about 360.degree. C. or higher. Thereby, a conductive and conformal TiN layer is deposited on the substrate 36 in a CVD process. The TDMAT process is a thermal process not usually relying upon plasma excitation of the precursor gas.
However, it has been found that the TiN layer initially formed by the TDMAT process includes an excessive amount of carbon in the form of included polymers which degrade its conductivity. Thus, the TDMAT deposition is usually followed by a second step of plasma treating the deposited TiN layer. The TDMAT gas in the chamber is replaced by a gas mixture of H.sub.2 and N.sub.2 in about a 50:50 ratio at a pressure of 0.5 to 10 Torr, and the RF power source 94 is switched on to create electric fields between the showerhead 40 and the pedestal 32 sufficient to discharge the H.sub.2 :N.sub.2 gas to form a plasma. The hydrogen and nitrogen species in the plasma reduce the carbonaceous polymer to volatile byproducts which are exhausted from the system. The plasma treatment thereby removes the carbon to improve the quality of the TiN film.
The plasma treatment process, when performed in the same chamber as the thermal CVD deposition, has demonstrated some problems with uniformity and reproducibility. We believe that the problems originate from extraneous metal depositions on reactor surfaces affecting the plasma and producing excess particles within the chamber. We also believe that the depositions occur in two different areas, an area at the top of the pedestal 32 outside of the wafer 36 and an area in and around the pumping channel 60.
A first problem, we believe, relates to extraneous metal deposition on the pedestal 32 because exposed portions of the pedestal 32 are at a temperature equal to and often much greater than that of the wafer 36. As shown in the cross-sectional view of FIG. 3, the portion of the pedestal 32 which extends beyond the outside edge of the wafer 36 is subject to a buildup 120 of deposited material from the following mechanism.
During the thermal phase of the TDMAT process during which the conductive TiN is deposited, the heater 92, shown in FIG. 1, installed in the pedestal 32 heats the pedestal 32, and the heat is transferred thence to the wafer 36. There are several reasons why the exposed portion of the pedestal 32 tends to be at a significantly higher temperature than that of the wafer 36. The showerhead 40 operates at a much lower temperature, typically around 100.degree. C. to readily sink heat from opposed elements. On the other hand, the wafer 36 is incompletely heat sunk on the pedestal 32 and transmits heat conducted to it from the pedestal 32 more poorly than does the directly radiating and more highly thermally conductive pedestal 32. Also, since the chamber is also used for the low-temperature plasma treating phase and additional time is consumed transferring wafers into and out of the chamber, the duty cycle for the high-temperature operation is relatively low and it is necessary to heat the wafer 36 to the required high processing temperatures. To quickly raise the temperature of the wafer 36 to its processing temperature, the temperature of the pedestal 32 is raised to a higher temperature than that of the wafer 36. For all these reasons, the processing temperature of the wafer 36 may be set to 360.degree. C. while the exposed portion of the pedestal tends to be at a significantly higher temperature of 425.degree. C.
Since the rate of deposition on a surface is proportional to the temperature of the surface (the higher the temperature the more rapid the deposition), the higher temperature of the exposed outer edge of the pedestal 32 causes, as illustrated in FIG. 3, a rapid buildup 120 of deposited film. As the thickness of the deposited film increases over the processing cycles of many wafers, deleterious effects may occur. The buildup of film thickness at the edge may create an artificial perimeter rim which prevents the wafer 36 from being in full contact with the surface of the pedestal 32, as required for efficient processing. Similarly, once the buildup 120 has developed past some film thickness of the film, successively deposited film layers do not completely adhere to the underlying layers. Portions of the film can then form particles or flakes that separate from the pedestal and float onto the wafer 36 being processed. The particles can create defects on the processed wafer.
A second problem related to extraneous metal deposition arises in that the conductive TiN film is also deposited, to a lesser extent because of lower surface temperatures, on other surfaces exposed to the process gas along its path from the showerhead 40 to and through the pumping channel 60 on its way to the chamber vacuum system 82. FIG. 5 shows an example of the buildup of a metal film 124 over and around the isolator ring 64 that can cause an electrical short between the electrically biased showerhead 40 and the grounded lid rim 66. FIG. 5 shows only an exaggerated film buildup 124 on the upper surface of the chamber. In reality, the film builds up on all surfaces, but the other buildup is not shown for clarity.
Another example of extraneous film deposition illustrated in FIG. 6 is the buildup of a conductive film 128 over the insulating alumina chamber insert 68 to the point that it extends across the pumping channel 60 and contacts the electrically grounded main chamber body 72. This extraneous deposition 128 thus extends the ground potential associated with the chamber body 72 and the lid rim 66 to the inner, upper edge of the insulating annular insert 68 closely adjacent the upper peripheral edge of the pedestal 32. The location and quality of plasma in the processing space 56 depends on the distance between the powered plasma source electrodes and surrounding surfaces and the difference between their respective electrical potentials. When, during a long process run, the chamber insert 68 effectively changes from being disposed as a insulator between the chamber body 72 and the plasma to being a grounded conductor, the location and quality of the plasma will be affected, particularly around the edges of the wafer 36. The distortion of the plasma due to the proximity of a closely adjacent electrical ground causes non-uniformity in the plasma, which affects the thickness of the film deposition and its surface properties.
During plasma processing, variations in uniformity of the plasma will affect the surface uniformity of the film produced. Therefore, variations in the intensity of the plasma will affect the uniformity of film properties. The conductivity, which is the inverse of the insulating quality, of the insulating members surrounding the location of the plasma changes as a conductive film is formed on their surfaces and as the conductive film forms a conductive path to adjacent conductive elements at different potentials. This variation in the conductive quality of the ostensibly insulating elements causes variations in the plasma which reduce the process repeatability.
A third problem related to extraneous metal deposition arises in that some electrically floating elements which are exposed to the plasma will accumulate a charge from the plasma. In the instance where these charged pieces are close to a grounded or electrically powered part, there is always a chance of arcing between the floating part and a ground or the electrode. In the instance when the wafer is supported on the pedestal, the wafer may act as a floating element which can become charged to cause arcing. Arcing creates particles and defects in the substrate. Therefore arcing to the wafer should be avoided and the uniformity of the envelope for the plasma treating the surface of the substrate should be held as uniform as possible.
To avoid these potentially deleterious effects, it is common practice to schedule a cleaning or maintenance cycle involving removal and replacement or cleaning of the pedestal before buildup of film can create undesired effects. However, this remedy is disadvantageous. Not only are pedestals expensive, but their replacement or cleaning involves a shut down of expensive equipment and additional operator time.
The buildup of unwanted film thickness on either the perimeter of the susceptor or across insulating members in the chamber requires they be periodically cleaned to prevent short-circuiting or unacceptable variations in the plasma treatment. The buildup of a thickness of an unwanted film creates a risk of short-circuiting by causing variations in the intensity and location of the electrical fields exciting the gas to a plasma state. Also, when the risk of conduction or arcing becomes high, a cleaning or maintenance cycle is initiated to restore the original distribution of the electrical field. Other consumable or maintainable components also require replacement or cleaning at certain intervals. Presently the risk of conductance and arcing sets the cleaning/maintenance interval. The mean number of wafers between cleans could be increased dramatically if the problem of film thickness adherence and conductivity across insulating members to grounded members, as described above, could be reduced or eliminated.
A CVD chamber, schematically illustrated in FIG. 7, is similar to that of FIG. 1 except that it is radiantly, not resistively, heated. It has been applied to the deposition of conductive materials and where plasma treatment of one sort or another was performed in the chamber. In this chamber, an argon treatment sputtering gas was energized into a plasma 130 between a pedestal electrode 132 and a counter electrode 134. An RF power source 136 provided RF power to energize the plasma. It was found, however, that, if the plasma was to be well confined in the processing space above the wafer, it was necessary to feed the RF power to a matching network 138 that selectably split the power between the pedestal electrode 132 and the counter electrode 134. It is believed that thus splitting the RF power better confines the plasma because the plasma with a grounded electrode tends to spread outside of the area of the wafer and to be more affected by the extraneously deposited metal layers described above. The matching network 138 allowed the RF power split to the pedestal electrode 132 to be the fraction of 30%, 50%, or 70% of the total power.
It is desired that CVD chambers of the type shown in FIG. 1, which were designed for deposition of dielectrics, be adapted to allow them to deposit metallic materials.
Therefore, it is desired that this chamber be improved to alleviate the problems of plasma instability and arcing. It is further desired that the frequency for routine maintenance and cleaning be reduced.

Removable pumping channel liners within a chemical vapor deposition chamber