This invention describes the new 9α-substituted estratrienes of general formula I

The efficiency of estrogens in the treatment of hormone-deficiency-induced symptoms such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapies for prevention of bone mass loss in peri- and postmenopausal women, is well documented and generally accepted (Grady et al. 1992, Ann Intern Med 117:1016-1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with ovarian dysfunction that is caused in some other way reduces the risk of cardiovascular diseases compared to women who are not treated with estrogen (Grady et al., loc. cit.).
In conventional estrogen or hormone replacement therapy (=HRT), natural estrogens, such as estradiol, and conjugated estrogens that consist of equine urine are used either by themselves or in combination with a gestagen. Instead of the natural estrogens, derivatives that are obtained by esterification, such as, e.g., 17β-estradiol-valerate, can also be used.
Because of the stimulating action of the estrogens that are used on the endometrium, which results in an increase of the risk of endometrial carcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166:1986-1992), estrogen/gestagen combination preparations are preferably used in hormone replacement therapy. The gestagenic component in the estrogen/gestagen combination avoids hypertrophy of the endometrium, but the occurrence of undesirable intracyclic menstrual bleeding is also linked to the gestagen-containing combination.
Selective estrogens represent a more recent alternative to the estrogen/gestagen combination preparations. Up until now, selective estrogens have been defined as those compounds that have an estrogen-like effect on the brain, bones and vascular system, owing to their antiuterotropic (i.e., antiestrogenic) partial action, but they do not have a proliferative effect on the endometrium.
A class of substances that partially meet the desired profile of a selective estrogen is the so-called "Selective Estrogen Receptor Modulators" (SERM) (R. F. Kauffman, H. U. Bryant 1995, DNAP 8 (9):531-539). In this case, these are partial agonists of estrogen receptor subtype "ERα." This substance type is ineffective, however, with respect to the therapy of acute postmenopausal symptoms, such as, e.g., hot flashes. As an example of a SERM, the raloxifene that was recently introduced for the indication of osteoporosis can be mentioned.
For the treatment of fertility disorders of women, frequently caused by ovarian dysfunction that is caused by surgery, medication, etc., new possible therapies are also opened up by the use of new selective estrogens. The in-vitro fertility treatment is a process that has been established for more than 20 years. Numerous methods for treating ovarian-induced infertility with exogenic gonadotropins are known. By administration of gonadotropins such as FSH (FSH=follicle-stimulating hormone), a stimulation of the ovaries, which is to make possible a healthy follicular maturation, is to be produced.
The follicle is the functional unit of the ovary and has two purposes: it accommodates the oocytes and provides for the latter the possibility for growth and for maturation. Folliculogenesis comprises the development of an ovarian follicle from a primordial stage to a continuously increasing antral follicle, which represents the last stage before ovulation. Only an optimally developed antral follicle can release a mature ovocyte by ovulation.
Patients with ovarian-induced infertility (PCOS=syndrome of polycystic ovaries) suffer from a disrupted follicular maturation, which is associated both with hormonal and ovulatory disruptions and with inadequately matured ovocytes. The number of primary and secondary follicles is approximately twice as high here as in the normal ovary (Hughesden et al., Obstet. Gynecol. Survey 37, 1982, pp. 59-77).
There are indications that the early development stages of folliculogenesis (which relates to the development of primordial follicles to antral follicles) are gonadotropin-independent. It is not clearly explained how great the influence of known paracrine and autocrine factors is on early folliculogenesis (Elvin et al., Mol. Cell Endocrinol. 13, 1999, pp. 1035-1048; McNatty et al., J. Reprod. Fertil. Suppl. 54, 1999, pp. 3-16).
Gonadotropins such as FSH are mainly involved in the last development stages of folliculogenesis in follicular maturation, i.e., in the development of the early antral follicle to a mature follicle that can undergo ovulation.
The in-vivo and in-vitro infertility is preferably treated with gonadotropins (FSH and antiestrogens) (White et al., J. Clin. Endocrinol. Metab. 81, 1996, pp. 3821-3824). In in-vitro fertilization treatment, oocytes are removed from preovulatory antral follicles to be able to mature in vitro into an ovocyte that can be fertilized. After fertilization and preembryonal development, one to three embryos are implanted in the uterus of the woman.
In many respects, the treatment with exogenic gonadotropins is accompanied by numerous risks and side effects. The greatest risk consists in an overstimulation of the ovaries, which in severe cases can represent a serious danger to life (OHSS=Ovarian Hyperstimulation Syndrome). Other side effects are the high costs of the in-vitro fertility treatment that must be paid by the coupled. Negative side effects such as weight gain, bloatedness, nausea, vomiting and an as yet unknown long-term risk of developing cancer are attributed to the gonadotropin treatment.
One method to avoid the above-mentioned drawbacks and risks is to ensure the maturation and stimulation in vivo of follicular growth in the case of ovarian-induced infertility with a suitable active ingredient before treatment with exogenic gonadotropins begins.
Estrogen Receptor Beta (ERβ)
Several years ago, estrogen receptor β (ERβ) was discovered as a second subtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93:5925-5930; Mosselman, Dijkema (1996) Febs Letters 392:49-53; Tremblay et al. (1997), Molecular Endocrinology 11:353-365). The expression pattern of ERβ differs from that of the ERα (Kuiper et al. (1996), Endocrinology 138:863-870). ERβ thus predominates over ERα in the rat prostate, while ERα predominates over ERβ in the rat uterus. The highest concentrations of ERβ and mRNA were found in the ovaries (Couse et al. Endocrinology 138, 1997, pp. 4612-4613).
Other organ systems with comparatively higher ERβ-expression comprise the bones (Onoe, Y. et al., 1997, Endocrinology 138:4509-4512), the vascular system (Register, T. C., Adams, M. R. 1998, J. Steroid Molec Biol 64:187-191), the urogenital tract (Kuiper, G. J. M. et al. 1997, Endocrinology 138:863-870), the gastrointestinal tract (Campbell-Thopson 1997, BBRC 240:478-483), as well as the testis (Mosselmann, S. et al. 1996 FEBS Lett. 392, 49-53) including the spermatides (Shugrue et al. 1998, Steroids 63:498-504). The tissue distribution suggests that estrogens regulate organ functions via ERβ. The fact that ERβ is functional in this respect also follows by studies in ERα-(ERKO) or ERβ-(βERKO)-knockout mice: ovariectomy produces bone mass loss in ERKO-mice, which can be eliminated by estrogen substitution (Kimbro et al. 1998, Abstract OR7-4, Endocrine Society Meeting, New Orleans). Estradiol in the blood vessels of female ERKO mice also inhibits vascular media and smooth muscle cell proliferation (Iafrati, M. D. et al. 1997, Nature Medicine 3:545-548). These protective actions of estradiol are carried out in the ERKO mouse presumably via ERβ.
The fact that ERα and ERβ have a functionally different action was confirmed after successful production of αERKO and βERKO mice. ERα consequently plays an important role in the adult uterus, in mammary gland tissue, in the negative regulation of the gonadotropin activity, while ERβ is mainly bonded in the processes of ovarian physiology, especially that of folliculogenesis and ovulation (Couse et al., Endocrine Reviews 20, 1999, pp. 358-417).
Observations of βERKO mice provide an indication on a function of ERβ in the prostate and bladder: in the case of older male mice, symptoms of prostate and bladder hyperplasia occur (Krege, J. H. et al. 1998, Proc Natl Acad Sci 95:15677-15682). In addition, female ERKO mice (Lubahn, D. B. et al. 1993, Proc Natl Acad Sci 90:11162-11166) and male ERKO mice (Hess, R. A. et al. 1997, Nature 390:509-512) as well as female βERKO mice (Krege, J. H., 1998, Proc Natl Acad Sci 95:15677-15682) have fertility disorders. Consequently, the important function of estrogens with respect to maintaining testis and ovary functions as well as fertility is confirmed.
It was possible to achieve a selective estrogenic action on specific target organs by subtype-specific ligands based on the different tissue or organ distribution of the two subtypes of the ERs. Substances with a preference for ERβ compared to ERα in the in-vitro receptor binding test were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138:863-870). A selective action of subtype-specific ligands of the estrogen receptor on estrogen-sensitive parameters in vivo was not previously shown.
The object of this invention is therefore to prepare compounds that have in vitro a dissociation with respect to the binding to estrogen receptor preparations from rat prostates and rat uteri. The compounds are to show in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri.
The ERβ-specific compounds are to produce in vivo a profertility action in the ovary. At the same time, the compounds are to exhibit a dissociation with respect to ovary action in comparison to uterus action. The compounds according to the invention are to have a certain protective action against hormone-deficiency-induced bone mass loss in comparison to uterus-stimulating action.
In the broader sense, a structure-action relationship, which allows for access to compounds that have the above-formulated pharmacological profile, is to be made available by this invention. The compounds according to the invention are to produce enhanced fertility in the ovary while at the same time affecting the uterus very little in cases of ovarian-associated infertility.
According to the invention, the object above is achieved by the provision of 9α-substituted estra-1,3,5(10)-triene derivatives of general formula I
in which radicals R3, R7, R7′, R9, R13, R16 as well as R17 and R17′, independently of one another, have the following meaning:                R3 means a hydrogen atom or a group R18, in which                    R18 means a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 6 carbon atoms, a trifluoromethyl group, an optionally substituted aryl, heteroaryl or aralkyl radical, an acyl radical COR19, in which R19 is an optionally substituted, straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and optionally partially or completely halogenated, or            R18 means a group R20SO2, in which                            R20 is an R21R22N group, whereby R21 and R22, independently of one another, mean a hydrogen atom, a C1-C5-alkyl radical, a group C(O)R23, in which R23 means an optionally substituted, straight-chain or branched-chain hydrocarbon radical with up to 10 carbon atoms that is saturated or unsaturated in up to three places and is optionally partially or completely halogenated, an optionally substituted C3-C7-cycloalkyl radical, an optionally substituted C4-C15-cycloalkylalkyl radical or an optionally substituted aryl, heteroaryl or aralkyl radical, or, together with the N atom, a polymethylenimino radical with 4 to 6 C atoms or a morpholino radical,                                                R7 and R7′, in each case independently of one another, are a hydrogen atom or a halogen atom,        R9 is a straight-chain or branched-chain alkenyl or alkinyl radical with 2 to 6 carbon atoms, which optionally can be partially or completely fluorinated,        R13 is a methyl group or an ethyl group,        R16 is a hydroxy group or a group R18O—, R20SO2— or OC(O)R23 with R18, R20 and R23 in each case in the meaning that is indicated under R3,        R17 and R17′, in each case independently of one another, are a hydrogen atom or a halogen atom,        R16 can in each case be in α- or β-position.
According to a variant of the invention, gonatriene derivatives are preferred, in which R7 and R7′ are a hydrogen atom, R9 is a vinyl, ethinyl or prop-1-inyl group, R16 is a hydroxy group, and R17 and R17′ in each case are a hydrogen atom.
In addition, the following combinations of halogen substitution, preferably fluorine, in C-atoms 7 and 17 are preferred: 7-mono or 7-di and R17 as well as R17′, in each case a hydrogen, 17-mono or 17-di and R7 as well as R7′, in each case a hydrogen as well as 7-mono/17-mono, 7-mono/17-di, 7-di/17-mono, 7-di/17-di. The 7α-position or the 17β-position is preferred in the monofluorine compounds.
Another variant of the invention in particular calls for compounds in which R16 stands for a group R18O— or R20SO2—O— with R18 and R20 in each case in the meaning that is indicated under R3.
Preferred according to this invention are the following compounds:                9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol        9α-Allyl-estra-1,3,5(10)-triene-3,16α-diol        18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol        18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol        3-Methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol        9α-Allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol        18a-Homo-3-methoxy-9α-vinyl-estra-1,3,5(10)-trien-16α-ol        18a-Homo-9α-allyl-3-methoxy-estra-1,3,5(10)-trien-16α-ol        9α-(2′,2′-Difluorovinyl)-estra-1,3,5(10)-triene-3,16α-diol        9α-(2′,2′-Difluorovinyl)-3-methoxy-estra-1,3,5(10)-trien-16α-ol        16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate        9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate        18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-sulfamate        18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-sulfamate        9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate        9α-Allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate        18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate        18a-Homo-9α-allyl-estra-1,3,5(10)-triene-3,16α-diyl-disulfamate        16α-Hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate        9α-Allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate        18a-Homo-16α-hydroxy-9α-vinyl-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate        18a-Homo-9α-allyl-16α-hydroxy-estra-1,3,5(10)-trien-3yl-(N-acetyl)-sulfamate        9α-(Prop-(Z)-enyl)-estra-1,3,5(10)-triene-3,16α-diol        9α-(n-Propyl)-estra-1,3,5(10)-triene-3,16α-diol        9α-Ethinyl-estra-1,3,5(10)-triene-3,16α-diol        9α-Vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate        18a-Homo-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol-diacetate        16α-Valeroyloxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol        16α-Acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol        18a-Homo-16α-acetoxy-9α-vinyl-estra-1,3,5(10)-trien-3-ol        7α-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol        7α-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol        17β-Fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol        17β-Fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol        18a-Homo-7α-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol        18a-Homo-7α-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol        18a-Homo-17β-fluoro-9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol        18a-Homo-17β-fluoro-9α-allyl-estra-1,3,5(10)-triene-3,16α-diol
Other possible configurations of this invention will emerge from the subclaims.
Hydrocarbon radical R18 is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, or hexyl radical.
Alkoxy groups OR18 in the compounds of general formula I in each case can contain 1 to 6 carbon atoms, whereby methoxy, ethoxy, propoxy, isopropoxy and 1-butyloxy groups are preferred.
Representatives of the C1-C5-alkyl radicals R21 and R22 are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and neopentyl.
As representatives of straight-chain or branched-chain hydrocarbon radicals R22 with 1 to a maximum of 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl can be mentioned; methyl, ethyl, propyl and isopropyl are preferred.
As a C3-C7-cycloalkyl group, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group can be mentioned.
A C4-C15-cycloalkylalkyl radical has 3 to 7 carbon atoms in the cycloalkyl portion; typical representatives are the cycloalkyl groups that are mentioned directly above. The alkyl portion has up to 8 carbon atoms.
As examples of a C4-C15-cycloalkylalkyl radical, the cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylpropyl groups, etc., can be mentioned.
In terms of this invention, an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.
Aryl always also includes a heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.
As substituents that can be present on an aryl or heteroaryl radical, for example, a methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen- (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C1-8 alkyl) or di(C1-8 alkyl)amino, whereby both alkyl groups are identical or different, di)aralkyl)amino, whereby both aralkyl groups are identical or different, carboxyl, carboxyalkoxy, C1-C20-acyl or C1-C20-acyloxy groups can be mentioned.
An aralkyl radical is a radical that contains in the ring up to 14, preferably 6 to 10, C atoms, and in the alkyl chain 1 to 8, preferably 1 to 4, C atoms. Thus, as aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are suitable.
The alkyl groups or hydrocarbon radicals can be partially or completely substituted by 1-5 halogen atoms, hydroxy groups or C1-C4-alkoxy groups.
A vinyl or allyl radical is primarily defined with a C2-C6-alkenyl radical.
A C2-C6-alkinyl radical is preferably defined as an ethinyl radical or a prop-1-inyl radical.
C1-10-Acyl radicals mean, for example, acetyl, propionyl, butyryl, valeroyl, isovaleroyl, pivaloyl, hexanoyl, octyl, nonyl, or decanoyl.
One or two hydroxyl groups at C atoms 3 and 16 can be esterified with an aliphatic, straight-chain or branched-chain, saturated or unsaturated C1-C14-mono- or polycarboxylic acid or an aromatic carboxylic acid.
Suitable as such carboxylic acids for esterification are, for example:
Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propionic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, and elaidic acid.
Esterification with acetic acid, valeric acid or pivalic acid is preferred.
Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, and mesaconic acid.
Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid, hydratropic acid, atropoic acid, cinnamic acid, nicotinic acid, and isonicotinic acid.
Esterification with benzoic acid is preferred.
As prodrugs, the esters of the 9α-substituted estratrienes according to the invention have advantages compared to the unesterified active ingredients with respect to their method of administration, their type of action, strength and duration of action.
Especially the sulfamates of 9α-substituted estratrienes according to the invention have pharmacokinetic and pharmacodynamic advantages. Related effects were already described in other steroid-sulfamates (J. Steroid Biochem. Molec. Biol, 55, 395-403 (1995); Exp. Opinion Invest. Drugs 7, 575-589 (1998)).
In this patent application, steroids on which the 9α-substituted estra-1,3,5(10)-triene skeleton is based are described for the treatment of estrogen receptor β-mediated disorders and conditions as selective estrogens, which have in-vitro dissociation with respect to their binding to estrogen receptor preparations from rat prostates and rat uteri and which have in vivo preferably a dissociation with respect to ovary action in comparison to uterus action. In addition, the compounds have a certain protective action against hormone-deficiency-induced bone mass loss.
It was found that the 9α-substituted estra-1,3,5(10)-trienes according to general formula I are suitable as selective estrogens for the treatment of various conditions and disorders that are characterized by a higher content of estrogen receptor β than estrogen receptor α in the corresponding target tissue or target organ.
The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids thereof) and the use of the compounds of general formula I for the production of pharmaceutical agents, especially for the indication mentioned below.
The new selective estrogens that are described here can be used as individual components in pharmaceutical preparations or in combination especially with gestagens. Especially preferred is the combination of selective estrogens with ERα-selective antiestrogens that are peripherally-selectively active, i.e., that do not pass through the blood-brain barriers, as well as with selective estrogen receptor modulators (SERM). The ERβ-selective compounds according to the invention can be used in particular for the production of pharmaceutical agents for treating fertility disorders, for prevention and therapy of prostate hyperplasia, for prevention and treatment of hormone-deficiency-induced mood swings in women and men and for use in hormone replacement therapy (HRT) in men and women.
A therapeutic product that contains an estrogen and a pure antiestrogen for simultaneous, sequential or separate use for the selective estrogen therapy of perimenopausal or postmenopausal conditions is already described in EP-A 0 346 014.
Because of their dissociation of action in the ovary in comparison to the action of the uterus, the substances and the pharmaceutical agents that contain them are especially suitable for the treatment in the case of ovarian dysfunction that is caused by surgery, medication, etc., such as female infertility for stimulation of folliculogenesis for treatment by itself in terms of enhanced fertility, for supporting in-vitro fertility treatment (IVF) in connection with an in-vivo treatment and for treatment of ovarian-induced disorders in later age ("late fertility") as well as for treatment of hormone-deficiency-induced symptoms.
The substances are also suitable for therapy of ovarian diseases such as polycystic ovarian syndrome, POF (premature ovarian failure) syndrome, and ovulation disorders.
Finally, the compounds of general formula I can be used in connection with selective estrogen receptor modulators (SERM) or raloxifene, specifically in particular for use in hormone replacement therapy (HRT) and for treatment of gynecological disorders.
The substances are also suitable as individual components for the treatment of perimenospausal and postmenopausal symptoms, in particular hot flashes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy and hormone-deficiency-induced mental disorders. The substances are also suitable for hormone substitution and for the therapy of hormone-deficiency-induced symptoms in ovarian dysfunction that is caused by surgery, medication, etc.
In addition, the substances can also be used to prevent hormone-deficiency-induced bone mass loss and osteoporosis, to prevent cardiovascular system diseases, in particular vascular diseases such as arteriosclerosis, high blood pressure and to prevent hormone-deficiency-induced neurodegenerative diseases, such as Alzheimer's disease, as well as hormone-deficiency-induced impairment of memory and learning capacity.
In addition, the substances can be used as active ingredients in preparations for treating inflammatory diseases and diseases of the immune system, in particular autoimmune diseases, such as, e.g., rheumatoid arthritis, multiple sclerosis, lupus, Crohn's disease and other inflammatory intestinal diseases, inflammatory diseases of the skin, such as psoriasis, as well as for treating endometriosis.
In addition, the substances are effective against inflammatory diseases of the respiratory system, the lungs and bronchial tubes, such as, e.g., asthma.
The medication is suitable for therapy and prophylaxis of estrogen-deficiency-induced diseases both in women and in men.
In men, the compounds are especially suitable for therapy of hormone-deficiency-induced bone mass loss and osteoporosis, for prevention of cardiovascular diseases, in particular vascular diseases such as arteriosclerosis, high blood pressure and for prevention of hormone-deficiency-induced neurodegenerative diseases, such as Alzheimer's disease, as well as hormone-deficiency-induced impairment of memory and learning capacity, and are suitable for prevention and therapy of prostate hyperplasia.
The substances can be used for prophylaxis and therapy of age-related dysfunctions or diseases of men. In particular, they can be used for prevention and treatment of an age-related drop of androgens, such as testosterone and DHEA, as well as of the growth hormone.
In addition, the medication can be used for treating inflammatory diseases and diseases of the immune system, in particular autoimmune diseases in men, such as, e.g., rheumatoid arthritis, MS (multiple sclerosis) and Crohn's disease and other inflammatory intestinal diseases, as well as inflammatory diseases of the respiratory system, the lungs, and the bronchial tubes. The amount of a compound of general formula I that is to be administered fluctuates within a wide range and can cover any effective amount. On the basis of the condition that is to be treated and the type of administration, the amount of the compound that is administered can be 0.01 μg/kg—100 mg/kg of body weight, preferably 0.04 μg/kg—1 mg/kg of body weight, per day.
In humans, this corresponds to a dose of 0.8 μg to 8 g, preferably 3.2 μg to 80 mg, daily.
According to the invention, a dosage unit contains 1.6 μg to 2000 mg of one or more compounds of general formula I.
The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredients one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopädie der technischen Chemie [Ullman's Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., issued by Czetsch-Lindenwald, Hilfsstoffe für Pharmazie and angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, p. 72 and ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor K G, Aulendorf in Württemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue.
For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, very often oils with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifying agent are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated so that a delayed release of active ingredient is made possible.
As inert materials, implants can contain, for example, biodegradable polymers, or synthetic silicones such as, for example, silicone rubber. In addition, for percutaneous administration, the active ingredients can be added to, for example, a patch.
For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena®) that are loaded with active compounds of general formula I for local administration, various polymers are suitable, such as, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.
To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with α-, β-, or γ-cyclodextrin or derivatives of the latter (PCT/EP95/02656).
According to the invention, the compounds of general formula I can also be encapsulated with liposomes.
Methods
Estrogen Receptor Binding Studies
The binding affinity of the new selective estrogens was tested in competitive experiments with use of 3H-estradiol as a ligand to estrogen receptor preparations from rat prostates and rat uteri. The preparation of prostate cytosol and the estrogen receptor test with prostate cytosol was carried out as described by Testas et al. (1981) (Testas, J. et al., 1981, Endocrinology 109:1287-1289).
The preparation of rat uterus cytosol as well as the receptor test with the ER-containing cytosol were basically performed as described by Stack and Gorski (1985) (Stack, Gorski 1985, Endocrinology 117, 2024-2032) with some modifications as described in Fuhrmann et al. (1995) (Fuhrmann, U. et al. 1995, Contraception 51:45-52).
The substances that are described here have higher binding affinity to the estrogen receptor of rat prostates than to estrogen receptors of rat uteri. In this case, it is assumed that ERβ predominates in the rat prostates over ERα, and ERα predominates in rat uteri over ERβ. Table 1 shows that the ratio of the binding to prostate and uterus receptors qualitatively coincides with the quotient of relative binding affinity (RBA) to human ERβ and ERα of rats (according to Kuiper et al. (1996), Endocrinology 138:863-870) (Table 1).
TABLE 1hERαhERβERβ/Rat uterusRat prost.prost. ER/EstrogenRBA*RBA*ERαER(RBA)ER(RBA)uterus EREstradiol10010011001001Estrone60370.6320.817α-Estra-58184.108.40.206.5diolEstriol14211.542055-Andro-61730.1550stene-diolGenisteine53670.110100Coumes-9418521.32418trol*Cited from: Kuiper et al. (1996), Endocrinology 138: 863-870
Table 2 shows the results for 4 of the 9α-vinyl-estra-1,3,5(10)-triene-3,16α-diol derivatives (compounds 1; 2; 4; 5) according to the invention.
TABLE 2RBARBARatRatCompoundUterusProstate9α-Vinyl-estra-1,3,5(10)-3,16α-diol (1)1.21009α-Vinyl-estra-1,3,5(10)-17F-3,16α-diol (2)22009α-Di-F-Vinyl-estra-1,3,5(10)-3,16α-diol (4)0.249α-Di-F-Vinyl-estra-1,3,5(10)-13-Methyl-3,16α-diol0.26(5)
Compounds 1; 2; 4; 5 according to the invention show a higher binding affinity to the estrogen receptor of rat prostates than to the estrogen receptor of rat uteri.
In addition, the predictability of the prostate-ER versus the uterus-ER test system was confirmed with respect to tissue-selective action by in-vivo studies. Substances with a preference for prostate-ER are dissociated in vivo preferably with respect to ovary and uterus action as well as pituitary gland action in favor of action on the ovary.
Studies for Dissociation of Action of the Ovary/Uterus and Pituitary Gland
The studies with respect to the action on uterus growth and ovulation (indirect effect by influencing the secretion of pituitary gland hormones) are performed on adult female rats (body weight of 220-250 g). The substances are subcutaneously administered four times on four consecutive days. The first administration is carried out in the metestrus. One day after the last administration, the autopsy is carried out. The number of ovocytes in the tube (effect on the ovulation) as well as the uterus weight are determined.
While estradiol produces a dose-dependent ovulation inhibition and an increase in uterus weight with an ED50 of 0.004 mg/kg of body weight, substance 1 according to the invention up to a dose of 0.4 mg/kg of body weight does not exert any effect on ovulation and uterus weight.
Ovary Studies
The substances were tested in vivo on hypophysectomized juvenile rats. In a modification of this operative method, a GnRH antagonist is administered to the animals. It is examined whether the substance stimulates follicular proliferation (maturation) in the ovary. The ovary weight is the measurement parameter.
In each case, five animals (body weight 40-50 g) are assigned randomly to the treatment groups. The animals are fed as much as they want with a standard diet (altromin) in Makrolon cages in air-conditioned rooms with a lighting program (10 hours of darkness, 14 hours of light) and are given acidified tap water to drink. For the s.c. administration, the test substance as well as the control substance (estradiol E2) are dissolved in benzylbenzoate/castor oil (1+4 v/v).
Juvenile female rats are either hypophysectomized on day 0 and subcutaneously treated (administration 1×daily) from day 1 to day 4 with estradiol, compound 1 or 2 according to the invention, or subcutaneously treated (administration 1×daily) with a vehicle (castor oil/benzyl benzoate). In the modified version of the method, 0.5 mg/animal/day of Cetrorelix is administered to the animals simultaneously with compound 2 or the vehicle and the control substance estradiol over four days of treatment. In both cases, the animals are sacrificed 24 hours after the last administration, and the ovary weight is determined.
0.5 mg/animal/day of compound 1 that is administered subcutaneously over 4 days produces a comparable increase in ovary weight in hypophysectomized animals like estradiol with a dose of 0.1 mg/animal/day. The vehicle does not produce any effect.
Substance 1 according to the invention thus shows a clear dissociation of action in the ovary in comparison to the uterus action and the pituitary gland action and is excellently suited for the preferred indication, the treatment of female infertility, because of its follicle-stimulating action.
In the GnRH antagonist-treated animals, concentrations of 0.1 and 0.3 mg/animal/day of compound 2 in the ovary already show the same action as the dose of 1 mg/animal/day of estradiol that is used (FIG. 1). Even lower dosages (0.01, 0.03 mg/animal/day) show an ovary action and can eliminate the antagonistic effect of Cetrorelix (FIG. 2).
Key to FIG. 1:    Ovar=Ovary    Feuchtgewicht (%)=Moist weight (%)    0,1 mg=0.1 mg    0,3 mg=0.3 mg    1,0 mg=1.0 mg
Key to FIG. 2:    Ovar=Ovary    Feuchtgewicht (%)=Moist weight (%)    0,003 mg=0.003 mg    0,01 mg=0.01 mg    0.03 mg=0.03 mg    0,1 mg=0.1 mg
Substance 2 according to the invention thus also shows a clearly positive action on the ovary by stimulating the follicular maturation and therefore is also suitable for the treatment of female sub- or infertility.
Production of the Compounds According to the Invention
For the production of the compounds of general formula I according to the invention, primarily two synthesis strategies that can generally be applied are used.
On the one hand, in particular 3,16-protected derivatives of estra-1,3,5(10)-triene-3,16ξ-diols, but also optionally the free diols, can be used for modifications of individual positions of the steroid skeleton.
On the other hand, correspondingly modified estrone analogs, which can be obtained in large numbers in known ways [for a typical synthesis process, see J. Chem. Soc. Perk. 1, 1973, 2095 for C(9); Steroids 54, 1989, 71 for C(7)], include a flexible access to the compounds according to the invention by transposition of oxygen functionality (Z. Chem. 1970, 221) from C(17) to C(16).
For the case of the 3-methyl ether, after the ketone is converted into a sulfonyl hydrazone, the formation of the C(16)-C(17) olefin (Z. Chem. 1970, 10, 221 ff; Liebigs Ann. Chem. 1981, 1973 ff), in which hypobromide is stored in a regio-/stereo-controlled way, is carried out in the simplest case by reaction with phenyl sulfonylhydrazide, in a degradation reaction. Reductive dehalogenation and removal of the protective group of C(3) yield the 16β-alcohol, which can be converted according to known methods into the 16α-epimer.
Another variant for the introduction of the hydroxyl group at C-atom 16 is in the hydroboration of the 16(17)-double bond with sterically exacting boranes. It is known of this reaction that it results in 16-oxidized products (Indian J. Chem. 1971, 9, 287-8). Consequently, the reaction of estra-1,3,5(10), 16-tetraenes with, for example, 9-borabicyclo[3,3,1]nonane after oxidation with alkaline hydrogen peroxide yields 16α-hydroxyestratrienes. To a lesser extent, the epimeric 16β-hydroxy steroids are formed in this reaction. After the cleavage of the 3-methoxy group, estra-1,3,5(10)-triene-3,16α-diols are obtained. By inversion of the configuration at C-atom 16, e.g., by Mitsunobu reaction (synthesis 1980, 1), in turn the 16β-hydroxyestratrienes are obtained.
For further production possibilities of the C(16)-C(17) olefinic intermediate stage, see also DE 199 06 159 A1.
The introduction of fluorine substituents is carried out via nucleophilic substitution reactions of hydroxyl groups with fluoroamine reagents (Org. React. 1974, 21, 158-173). If the hydroxyl groups are converted into the corresponding tosylates in advance, then the fluorinated compounds are obtained by reaction with tetra-n-butylammonium fluoride (J. Chem. Res. (M) 1979, pp. 4728-4755). Fluorine compounds are also accessible by reaction of corresponding alcohols with diethylamino sulfur trifluoride (DAST) (U.S. Pat. No. 3,976,691). Geminal difluorine compounds are produced, for example, by reaction of carbonyl compounds with sulfur tetrafluoride (U.S. Pat. No. 3,413,321) or diethylamino sulfur trifluoride (DAST) (U.S. Pat. No. 3,979,691).
For synthesis of the 9α-substituted 17β-fluoroestra-1,3,5(10)-triene-3,16-diols according to the invention, 17-oxo-estra1,3,5(10)-trienes are converted into the 17,17-difluoroestra-1,3,5(10)-trienes (U.S. Pat. No. 3,976,691). The thus accessible 17,17-difluoroestra-1,3,5(10)-trienes are converted by treatment with aluminum oxide into 17-fluoroestra-1,3,5(10),16-tetraene (U.S. Pat. No. 3,413,321). Another possibility for the production of fluoro-olefins exists in the reaction of the corresponding ketones with diethylamino sulfur trifluoride (DAST) in the presence of polar catalysts, such as fuming sulfuric acid (U.S. Pat. No. 4,212,815). The reaction of 17-fluoroestra-1,3,5(10),16-tetraenes with boranes and subsequent oxidation with alkaline hydrogen peroxide yields the 17β-fluoroestra-1,3,5(10)-trien-16α-ols (Org. React. 1963, 13, 1-54).
Access to the 9α-alkenyl- or 9α-alkinyl-substituted estra-1,3,5(10)-triene-3,16α-diols according to the invention is carried out first from the 3,16-dihydroxy-estra-1,3,5(10)-trienes that are protected in 3- and 16-position. By reaction with trimethyl silyl cyanide in the presence of lithium perchlorate, the regio- and stereoselective introduction of a 9α-cyano grouping (Synlett, 1992, 821-2) is carried out. After the protective groups are cleaved, the 9α-cyano compound is converted by reduction first into a 9α-formyl compound and then by a Wittig reaction (Org. React. Vol. 14, 270) into the 9α-alkenyl- or 9α-alkinyl-substituted compound.
The estratriene sulfamates according to the invention are accessible in a way that is known in the art from the corresponding hydroxy steroids by esterification with sulfamoyl chlorides in the presence of a base [Z. Chem. 15, 270-272 (1975); Steroids 61, 710-717 (1996)].
Subsequent acylation of the sulfamate group results in the (N-acyl)sulfamates according to the invention. For the (N-acryl)sulfamates, pharmacokinetic advantages were already detected (cf. DE 195 40 233 A1).
The regioselective esterification of polyhydroxylated steroids with N-substituted and N-unsubstituted sulfamoyl chlorides is carried out after partial protection of those hydroxyl groups that are to remain unesterified. Silyl ethers have turned out to be protective groups with selective reactivity that is suitable for this purpose since these silyl ethers are stable under the conditions of sulfamate formation, and the sulfamate group remains intact when the silyl ether(s) is (are) again cleaved for regeneration of the (residual) hydroxyl group(s) still contained in the molecule (Steroids 61, 710-717 (1996)).
The production of the sulfamates according to the invention with an additional hydroxyl group in the molecule is also possible in that the starting material is suitable hydroxy-steroid ketones. First, depending on the goal, one or more hydroxyl groups that are present are subjected to sulfamoylation. Then, the sulfamate groups optionally can be converted with a desired acyl chloride in the presence of a base into the (N-acyl)sulfamates in question. The now present oxosulfamates or oxo-(N-acyl)sulfamates are converted by reduction into the corresponding hydroxysulfamates or hydroxy-(N-acyl)sulfamates (Steroids 61, 710-717 (1996)). Sodium borohydride and the borane-dimethyl sulfide complex are considered as suitable reducing agents.
The examples below are used for a more detailed explanation of the invention.
Analogously to the degradation of the 9α-vinyl grouping, other compounds of general formula I can be obtained with use of reagents that are homologous to the reagents that are described in the examples.
Etherification and/or esterification of free hydroxy groups is carried out according to the methods that are common to one skilled in the art.

9-α-substituted estratrienes as selectively active estrogens

Abstract: in which R3, R7, R7′, R13, R16 as well as R17 and R17′ have the meanings that are indicated in the description and R9 means a straight-chain or branched-chain, optionally partially or completely halogenated alkenyl radical with 2 to 6 carbon atoms, an ethinyl or prop-1-inyl radical, as pharmaceutical active ingredients that exhibit in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo preferably a preferential action on the ovary in comparison to the uterus, their production, their therapeutic use and pharmaceutical dispensing forms that contain the new compounds.

Abstract: The invention also describes the use of these compounds for treating estrogen-deficiency-induced diseases and conditions.


A method of printing an image on a substrate by applying to the substrate a film which is chemically activated by heat, and scanning the film by a beam of radiation according to the image to be printed, to chemically activate the film by heat and thereby to produce a pattern in the film according to the image scanned. The film includes a reagent capable of undergoing a redox reaction when heated in the presence of another reagent present with the film when scanned by the beam, to produce the redox reaction between the two reagents.

The present invention relates to a method of printing an image on a substrate. The invention can be used in lithography, information recording, chemical milling and printing, but is particularly useful for producing printed circuit boards, and is therefore described below with respect to this application. It will be appreciated, however, that the invention could advantageously be used in many other applications.
Printed circuit boards (PCBs) are constructed of a substrate of insulating material, such as epoxy glass, having an electrically conductive pattern or net printed on one or both faces. Many techniques have been developed for printing the conductive pattern. The techniques commonly used today start with a substrate having a copper layer on one or both faces. In the production line, the board is coated with a photoresist film, namely a protective film sensitive to light. The photoresist film is exposed to ultraviolet light through a phototool or mask which is photographically constructed according to the desired pattern to be printed, producing a latent image of the pattern in the exposed areas of the photoresist film. The exposed portions of the photoresist film may be rendered less soluble or more soluble. The portions of the photoresist film which are more soluble are removed to bare the copper thereunder. According to some techniques, the so-bared copper is metal-plated; then the remainder (insoluble portion) of the photoresist protective film is removed to bare the copper thereunder, and the so-bared copper portions are completely removed by etching. According to other techniques, the portions of the copper bared by removing the soluble portions of the photoresist are etched, and then the insoluble portions of the photoresist are removed.
The foregoing process for producing printed circuit boards, as well as IC integrated circuit wafers or the like, thus requires the preliminary preparation of the phototools. The preparation of phototools takes considerable lead time, which is not suitable for modern manufacturing demands requiring just-in-time manufacturing techniques. The use of phototools also requires high investment in materials, machines, special environmental storage, and man-power to operate the phototool department. In addition, the large number of steps, and particularly the large number involving human operations, significantly affect the yield.
Because of the foregoing drawbacks in utilizing phototools, efforts are being made for developing new imaging techniques. Particularly promising are direct imaging techniques wherein the pattern is directly imaged on the photoresist by using a beam, such as an X-ray beam, an electron beam, an ion beam, or a laser beam. The beam is operated by using computer-controlled means to provide a sequence of preprogrammed on/off modulating writing signals as the beam is caused to scan the photoresist.
In the basic direct imaging process (as well as in the conventional flood exposure process), ultra- violet or visible radiation is used to expose photographically the photoresist and to activate a photochemical reaction which produces a latent image. The latent image is developed to produce a protective layer pattern. Since the photoresist is sensitive to light (ultraviolet or visible), a safety light must be used from the time the photoresist layer is applied until the protective layer pattern is produced and stabilized.
Another direct-imaging technique is known (e.g. as described in U.S. Pat. No. 4,013,466) in which a visible (blue) flood exposure is used to activate a photochemical reaction in the photoresist, as in the prior art of flood and laser direct-imaging. Here, however, the conventional phototool is replaced by an "eraseable phototool" in the form of a liquid crystal (LC) exposed to an infrared laser to induce a phase transition by the local heating produced by the laser; see for example U.S. Pat. No. 4,013,466. The liquid crystal thus serves as an "eraseable phototool" in place of the regular phototool or photo mask. However, this process also requires the use of a safety light. Moreover, because of the sensitivity of the liquid crystal to ultraviolet light, this process requires the use of a special expensive photoresist, and also only visible light.
Still another direct-imaging technique is described by V. M. Andreev, et al., Autometria, No. 3, 1990, pp. 102-105. In this method, an insulating substrate is coated with a film of a complex salt of copper hypophosphite [Cu(H.sub.2 PO.sub.2).sub.2 ], or its aminoammonia complexes, and is thermally decomposed when subjected to a laser beam. This results in the formation of fine, dispersed copper particles which exhibit catalytic activity in electroless copper plating processes. This method thus concerns depositing copper particles to be used as a catalytic agent for a subsequent electroless copper plating process, and not the formation of a protective layer for use in subsequent etching or plating processes involved in printed circuit techniques.

Method of printing an image on a substrate particularly useful for producing printed circuit boards


An improved cable lock having a lock housing and a flexible shackle has a longitudinally elongated latch housing with a cylindrical side surface in which is formed a latch reception slot, receiving an L-shaped latch body. The latch body fits flush with the housing surface and is released by rocking one of its arms. A resilient ring is carried on the axis of the lock housing and has its circumferential surface exposed along the cylindrical side of the lock housing. A mechanism selectively compresses and decompresses the ring, respectively causing the ring to expand or retract radially for friction locking into a storage tube. A clamp is provided for mounting the storage tube into the seat post of a cycle, and a guide tube assists passage around the bend.

A lock having a flexible shackle such that the lock can be stored in a tubular housing such as the handle bar of a cycle is shown in U.S. Pat. No. 4,970,883 to Johnson. Additional prior art, as shown by U.S. Pat. No. 3,354,675 to Quigg, has provided for a cable lock incorporated into a ski pole and having its ends permanently attached between separable pole portions. A coaxial combination lock selectively permits the handle portion of the pole to be removed so that the midsection of the cable can be wrapped around the poles and skis, after which the handle is reassembled and locked to the pole by the lock mechanism.
Similarly, U.S. Pat. No. 3,297,333 to Schwedt et al. provides for a ski pole having a wrist strap with one releasable end and one permanently attached end. An end mounted combination lock on the pole handle allows release and relocking of the releasable end, permitting the wrist strap to serve as a shackle to be wrapped about the remaining equipment.
Another ski pole mounted lock is disclosed in U.S. Pat. No. 4,267,715 to Aylesworth. A cable is permanently mounted by one end within the pole, while the opposite, free end can be freely extended and wrapped around ski equipment. The free end then is engaged and wrapped around ski equipment. The free end then is engaged between telescoping jaws on the pole, which are controlled by a lock carried coaxially on the pole.
U.S. Pat. No. 3,335,585 to Stratton discloses another ski pole lock in which the cable has an enlarged end that is retained within the pole. The second, free end carries a keeper and can be withdrawn through the pole's handle and engaged about ski equipment. Thereafter the keeper on the second end is inserted into a lock carried in the handle and secured.
U.S. Pat. No. 3,899,904 to Brimhall, II, is similar to Stratton, with the additional feature that one ski pole may carry the captive end of the cable, while the second ski pole may carry a lock that received the keeper on the free end of the cable when the cable is engaged about ski equipment.
U.S. Pat. No. 3,687,472 to Stuble, Jr., discloses the use of a hollow ski pole for storage of a cable and cylindrical lock. A cap on the pole's handle covers the storage passage and can be opened to permit the lock and cable to be withdrawn. Otherwise, the cable lock is capable of forming a locked loop around the ski equipment when the lower end of the cable is inserted into the top of the lock. It is proposed that the lower end of the cable be elastically fastened to the bottom of the pole cavity by a retention bungee. Otherwise, it appears that this lock mechanism is not secured within the pole, but merely is housed inside.
From the state of the prior art, it can be seen that cable locks have been incorporated into equipment that stores some or all of the cable and lock. However, most of the prior art locks require some degree of structural alteration to the equipment, which hinders wide usage of such locks unless a manufacturer chooses to incorporate such a lock as part of the original equipment design. Other locks purport to be added with only minor modification of the equipment, and these are the types of locks to which the present invention is addressed.
Another problem is that if the coaxial lock in many of the above designs were to fail, the cable cannot be removed or used. In other designs, even if the cable can be reached, the ski pole or other host item no longer can function as a lock.
Further, if the handle bar of a cycle must be used for storage of a lock, there could be interference with other items such as wiring or cables that might be routed in the handle bar.
So as to eliminate the possibility of interference and the need for special adaptation, it would be desirable to create a cable lock that, at least in one embodiment, requires absolutely no modification to existing tubular storage areas of the equipment.
Further, it would be desirable to create a concealed storage system that employs notoriously vacant tubular members such that the cable lock can be inserted in a streamlined process.
Finally, it would be desirable to create a cable lock that stores in a tube, wherein the lock is free of all varieties of lateral obstructions or protrusions. Such a lock design minimizes the opportunities for interference with the interior of a tube.
To achieve the foregoing and other objects and in accordance with the purpose of the present invention, as embodied and broadly described herein, the cable lock and concealed storage system of this invention may comprise the following.


The invention is a system for automatically adjusting drive modes based on weight. The system includes a weight determination system, a data input device configured to receive input data, and a processing device. The processing devices includes a processor and non-volatile memory. The processor is configured to receive weight data from the weight determination system, receive the input data from the data input device, and receive a user input. The processor is also configured to determine at least one drive mode setting based on the weight data, the input data and the user input, send the drive mode setting data to a vehicle control system, and communicate the drive mode setting to a user.

Many factors affect the safety and stability of a vehicle under various driving conditions. Because of these differences, many vehicle manufacturers offer different "drive modes" or "driving modes" that may be selected by a driver at the beginning of a trip. Drive modes allow a vehicle to have multiple characteristics in the way that it drives, rides and handles as opposed to a single set of characteristics. Normally, a vehicle with multiple drive modes allows the driver to manually select the drive mode based on the driver's preferences.
For example, an "economy" drive mode may adjust the fuel delivery system, air-fuel ratios and acceleration rate of a vehicle to reduce the amount of fuel required and thereby conserving energy. This economy setting may not be desirable if the driver needs maximum performance while driving more aggressively which requires more power. A "performance" drive mode may allow for this type of driving. Typically, there is a method of selecting the desired drive mode by the driver.
In cases where the vehicle is a tow vehicle towing a trailer, there may be a "tow/haul" button that changes a vehicle's transmission shift patterns. Pulling a heavy load requires more power. The tow/haul mode may reduce shift cycles and may also boost torque and engage an engine braking mode to help drivers maintain control while driving up and down hills.
Current limitations exist to how effective drive mode settings may be for a specific vehicle in various scenarios. For example, the tow/haul setting may make adjustments based on a factory preset load. However, the load may be higher or much lower than the factory preset. Even if a driver has the ability to determine the weight of the vehicle and the trailer along with the weight of all loads in the bed and in the trailer, there may be no way to communicate this information to the vehicle control system in order to modify or adjust the drive mode settings.
Without a method of determining the weights of the loads along with how these weights impact the drive modes, it is difficult for the user or driver to confirm that a given drive mode is safe for a specific set-up. Therefore, a method is needed to determine the vehicle and trailer weights, communicate the weight information to the vehicle control system, and adjust the drive mode based on the weight.

System for automatically adjusting drive modes


The invention relates to a device and a method for switching currents in a stator winding (1) of a generator/electric motor combination, said stator winding (1) comprising at least one winding which can be short-circuited or switched in a highly-resistive manner by means of at least one device (T1, D1; T2, D2). Said at least one winding is connected to a capacitor (C), by which means the voltage peaks thereof can be reduced as a result of switching processes, and energy stored in the stator winding can be temporarily stored. At least one switchable decoupling element (2) is arranged between the winding and the capacitor (C). The energy to be temporarily stored can be branched off as a charging current to the capacitor by means of the decoupling element (2), as a result of the disconnection of the device in a non-working cycle, and the temporarily stored energy can be fed back into the stator winding (1) as a working current in the working cycle. The decoupling element (2) is temporally controlled during the feedback in such a way that the capacitor voltage UC does not fall below a set voltage value.

Such a generator-electric motor combination is known from DE 44 08 719 C1. It is proposed here that the generator-electric motor combination have a housing, in which a rotor and a stator, both of the generator and of the electric motor are arranged, having a hollow cylindrical generator-rotor fastened to an input shaft and a hollow cylindrical motor-rotor fastened to an output shaft, the rotors lying axially next to each other, and having permanent magnets of alternating polarity distributed on their interior in the peripheral direction, and having a hollow cylindrical stator arranged within the hollow cylindrical rotors with at least one winding, in which the two rotors are switched relative to each other, depending on the position of the permanent magnets. The stator winding, depending on the desired force direction of the electric motor, is shorted or switched to high resistance by mutual switching of power semiconductors of a half-bridge of the known device, functioning as switching elements, according to the pole position of the electric motor.
A shortcoming in the known device is that during switching off of the current in the stator winding, the energy stored in the inductance is necessarily lost. In addition, another drawback is that the switching elements are threatened by the extremely high voltage peaks that occur during switching off.
To solve this problem, it is known from DE 198 53 516 A1 to divide the winding into two winding parts with an inductance by at least one tap, in which a capacitor is connected into the tap, which separates the two winding parts of the winding electrically at least partially when exposed to a high frequency disengagement current. Because of this, the energy in the inductance is temporarily stored in the capacitor and in the operating cycle, when the winding is shorted again, it is fed back into the winding. In addition to temporary power storage, the capacitor limits the peak voltage occurring on the semiconductor switching element according to the formula I2*L/2=U2*C/2, since the voltage on the capacitor cannot jump. A switch, additionally incorporated in the capacitor branch, prevents undesired charging of the capacitor in the nonworking cycle (winding is switched to high resistance), as well as oscillation of the current as a result of the oscillation properties of the LC circuit.
A shortcoming in this circuit is that the time constant of the energy accumulator for charging and discharge at a given inductance is dependent on the size of the capacitor. On the one hand, there is then a need for a large capacitance, in order to reduce the peak voltage, and, on the other hand, the capacitance should be low, in order to switch steep pulses through a limited time constant.

Device method for switching of currents in a stator winding of a generator-electric motor combination


Cooperative touch fasteners have a sheet-form base with an upper face and a lower face. Extending outwardly from, and integral with the upper face of the base is a plurality of fastener elements. Additionally, the lower face of the sheet-form base has a pressure adhesive property and is coated with a cross-linkable adhesive. The cooperative touch fasteners can be used to alter garments, hang window coverings and attach finishing covers. Additionally, the fasteners can be used in place of snaps and buttons, in medical devices, with diapers and in conjunction with a variety of manufacturing techniques.

The majority of consumers purchase clothing and other garments in standard sizes, such as small, medium and large. Often times, these garments are not a perfect fit for the consumer. For example, if a person buys a shirt or coat that is large enough around the torso, the sleeves of the shirt might require shortening. The consumer can pay to have the garment altered, which for many is cost prohibitive, or if the consumer has the sewing skills and equipment, he can alter the garment himself. Frequently, the consumer has neither the money nor the skills to alter his clothing but instead wears clothes that don't have an ideal fit. Thus, it is desirable to provide to consumers a product that allows the user to alter clothing without sewing. It is also desirable that manufacturers be able to adjust the positioning of fasteners on products.
Improved means for adjusting and securing fasteners, particularly touch fasteners such as hook-and-loop or inter-engaging projection array fasteners, to underlying substrates are sought. Also sought are improved means of temporarily holding a fastener in place until permanent binding is achieved.
Some products employed to alter garments include a fabric tape which may be ironed on to a garment by melting a fusible resin, e.g., a thermoplastic polymer, carried on one surface of the tape (see, e.g., U.S. Pat. No. 5,006,393). Some tapes include cooperating touch fastener elements extending from the opposite surface of the tape. When the garment is subjected to heat greater than the melting point of the resin, as may occur during drying in a clothes dryer, the resin can melt and cause the tape to disengage from the garment.


A device protects at least a portion of an A/C condenser of an automotive vehicle against damage from stones and other road debris. The device includes a guard having a plurality of spaced apart louvers for intercepting and deflecting the stones and other road debris but permitting air to pass through the guard between the louvers.

An A/C condenser of an automotive vehicle can be damaged by stones and other road debris if not properly protected. Some protection devices in present use have not performed adequately. Others have been mounted on the fascia of the vehicle. Because different vehicles often have different fascias, a protection device mounted on a facia has to be custom made to fit each different fascia design.


Visible light cured polymerizable thiol-ene compositions comprising at least one monomer or oligomer having a plurality of free-radically polymerizable ethylenically unsaturated groups, at least one compound having a plurality of thiol groups, at least one acyl phosphine oxide photoinitiator and optional adjuvants, such as stabilizers, pigments, fillers, and polymerization inhibitors are disclosed. The polymerized compositions are useful, as protective coatings, or anti-chip coatings or as repair putties on exterior coated substrates such as plastics, wood and metal, especially for the automotive and marine industries.

In labor intensive, cost sensitive businesses such as the automobile aftermarket time savings such as rapid cure or cure on demand coatings are premium benefits. In addition, there is an intense effort by researchers and the industry to provide high and 100% solids formulations to reduce the use of solvents for user health and environmental reasons.
Current body putties (sometimes included in the term "body fillers") are based on unsaturated polyester resins which are cured by a free radical curing mechanism initiated by organic peroxides. Drying times to allow sanding take 20-30 minutes. This delays the repair process and is especially inefficient if needed repairs are noticed in the paint booth where delays seriously impact shop productivity.
Radiation curable compositions containing carbon--carbon (C--C) unsaturated monomers and polythiols were developed in the early 1970s. U.S. Pat. No. 4,234,676 describes a composition comprising a C--C unsaturated polymer, a cross linkable monomer, a polythiol, and curing agent directed primarily at printing plate production.
U.S. Pat. No. 4,808,638 (Steinkraus, et al) describes a composition comprising a norbornene resin, polythiol, and free radical initiator which can be photocured in visible light when a iron arene complex is present.
U.S. Pat. No. 4,139,385 (Crivello) describes a composition comprising a polyolefin, polythiol, and onium salt photoinitiator. The films, 75 micrometers, (3 mil) thick were curable by a cationic mechanism with UV light as an initiator.

Visible light polymerizable thiol-ene composition


An exemplary method for generating a test vector to activate a Trojan triggering condition includes the operations of obtaining a design graph representation of an electronic circuit; constructing a satisfiability graph from the design graph representation, wherein the satisfiability graph includes a set of vertices representing rare signals of the electronic circuit and satisfiability connections between the vertices; finding a plurality of maximal satisfiable cliques in the satisfiability graph, wherein a maximal satisfiable clique corresponds to a triggering condition for a payload of the electronic circuit; generating a test vector for each of the maximal satisfiable cliques; and performing a test for the presence of a hardware Trojan circuit in the electronic circuit using the generated test vectors as input signals.

Hardware Trojans are serious threat to security and reliability of computing systems. It is hard to detect these malicious implants using traditional validation methods, since an adversary is likely to hide them under rare trigger conditions. While existing statistical test generation methods are promising for Trojan detection, they are not suitable for activating extremely rare trigger conditions in stealthy Trojans.

Trigger activation by repeated maximal clique sampling

University of Florida Research Foundation, Inc.


A method of preparing a sealing surface of a container for application of a seal. A lip of the container may be heated, rinsed, and dried to establish the sealing surface. Then the seal may be applied to the sealing surface.

Various sealing processes have been developed for sealing containers. For example, U.S. Pat. No. 4,396,655 discloses a method involving first heating a container lip or rim surface by flame treatment to oxidize the material existent thereon, coating the lip with a thin coating of a silane compound, and then applying a second thin coating of an ethylene acrylic acid (EAA) copolymer. The container is filled and then fusion sealed using a thin foil membrane having a thin Surlyn ionomer layer over its sealing surface—the EAA coating of the container fusion bonds to the Surlyn layer of the membrane.
A general object of the present disclosure, in accordance with one aspect of the disclosure, is to provide a sealed, glass container for carrying product.
The present disclosure embodies a number of aspects that can be implemented separately from or in combination with each other.
A method of preparing a sealing surface of a glass container for application of a seal in accordance with one aspect of the present disclosure includes heating the sealing surface, rinsing the sealing surface with a rinsing fluid, and then drying the sealing surface.
In accordance with another aspect of the disclosure, there is provided a method of manufacturing sealed containers carrying product that includes preparing a sealing surface of a container for receiving a seal, placing product into the container, and applying the seal to the sealing surface. The preparation of the sealing surfaces further may include heating at least a lip of the container, then cooling at least the lip, then rinsing at least the lip, and drying at least the lip.

Preparing a sealing surface of a container


Disclosed is a height adjusting apparatus for a suction brush of an upright vacuum cleaner, by which a user can facilely adjust a gap between the suction brush and a cleaning surface. The apparatus comprises a suction brush body; a height adjusting knob rotatably disposed at a seating portion formed in the suction brush body, and having a cam curve portion formed at a part of an end of the height adjusting knob inserted into the suction brush body, the cam curve portion having a height difference between a starting point and an end point thereof and a plurality of recessed grooves formed between the starting point and the end point; a height adjusting shaft integrally formed with a rod member which is contacted with the cam curve portion and lifted up and down according to a rotational direction of the height adjusting knob; and a brush front wheel rotatably coupled to the height adjusting shaft.

1. Field of the Invention
The present invention relates to an upright vacuum cleaner, and more particularly, to a height adjusting apparatus for a suction brush of an upright vacuum cleaner, by which a user can facilely adjust a gap between the suction brush and a surface (hereinafter, called 'cleaning surface) of an object to be cleaned.
2. Description of the Related Art
Generally, an upright vacuum cleaner includes a main body having a driving motor for generating a suction force, and a suction brush disposed at a lower side of the main body to be rotated at a desired angle.
In the main body, there are provided a filtering means and a dust collecting container, etc. Foreign substance sucked through the suction brush by the suction force of the driving motor is filtered by the filtering means and then collected in the dust collecting container.
Furthermore, on an upper portion of the main body, there is provided a handle with an on/off switch. Therefore, a user grasps the handle and moves the vacuum cleaner along a cleaning surface. Then, the dust or foreign substance on the surface of the object to be cleaned is sucked through the suction brush.
In this upright vacuum cleaner, there is provided a height adjusting apparatus for adjusting a height between the suction brush and the cleaning surface. Such height adjusting apparatus is classified into various types such as a lever type, a knob type, etc.
The lever type is operated by a user's foot, as described in Korean Patent Laid-Open Publication No. 2001-0012060. Since the lever type is operated by the user's foot, it is easy to adjust the height. However, its components may be complicated, and the apparatus may be also damaged by excessive force due to the using of foot.
The knob type is described in Korean Patent No 1986-001635 as an example. In this knob type, the user rotates a knob with his/her hand to lift up and down a shaft supporting a front wheel of the vacuum cleaner and thus adjust the height of the suction brush. It is easy to use, but there is a problem that, since the height of the suction brush is easily changed by an external impact, it is difficult to expect the apparatus to be stably operated. In other words, there is provided a stepped portion at a bottom surface of the knob so as to lift up and down the shaft. Since an elastic member for supporting the shaft tends to easily lose its supporting force by the external impact, when the suction brush is bumped against a wall or an obstacle during a cleaning operation, the knob is optionally rotated, so that the height adjusted by the user is changed. Therefore, there is an inconvenience that the user has to adjust the height of the suction brush again.

Height adjusting apparatus for suction brush of upright vacuum cleaner


An electronic device includes a processor and a memory coupled to the processor. The memory stores instructions that, when executed by the processor, cause the processor to perform operations including determining whether a text prompt received from a wireless device corresponds to first synthesized speech data stored at the memory. The operations include, in response to a determination that the text prompt does not correspond to the first synthesized speech data, determining whether a network is accessible. The operations include, in response to a determination that the network is accessible, sending a text-to-speech (TTS) conversion request to a server via the network. The operation further include, in response to receiving second synthesized speech data from the server, storing the second synthesized speech data at the memory.

A wireless device, such as a speaker or wireless headset, can interact with an electronic device to play music stored at the electronic device (e.g., a mobile phone). The wireless device can also output a voice prompt to identify a triggering event detected by the wireless device. For example, the wireless device outputs a voice prompt indicating that the wireless device has connected with the electronic device. To enable output of the voice prompt, pre-recorded (e.g., pre-packaged or "native") speech data is stored at a memory of the electronic device. Because the pre-recorded speech data is generated without knowledge of user specific information (e.g., contact names, user-configurations, etc.), providing natural-sounding and detailed voice prompts based on the pre-recorded speech data is difficult. To provide more detailed voice prompts, text-to-speech (TTS) conversion can be performed at the electronic device using a text prompt generated based on the triggering event. However, TTS conversion uses significant processing and power resources. To reduce resource consumption, TTS conversion can be offloaded to an external server. However, accessing the external server to convert each text prompt consumes power at the electronic device and uses an Internet connection each time. Additionally, quality of the Internet connection or a processing load at the server can disrupt or prevent completion of TTS conversion.

Voice prompt generation combining native and remotely-generated speech data


A low temperature CVD method is provided for depositing high quality stoichiometric, poly-crystalline silicon carbide films and for depositing emitter quality, heavily doped silicon carbide films, suitable for application in silicon hetero-junction bipolar transistors. The process is compatible with bipolar-CMOS device processing and comprises pyrolysis of di-tert-butyl silane in an oxygen free ambient, with n-type doping provided by phosphorus source comprising tert-butyl phosphine. Advantageously oxygen is excluded from the reactant gas mixture and the method includes pre-cleaning the susbtrate with nitrogen trifluoride and passivating the silicon carbide film with fluorine species from nitrogen trifluoride.

Silicon carbide has recently attracted attention as a wide band gap emitter material for silicon heterojunction bipolar transistors. Si-HBTs. SiC emitters have been shown to block hole back injection in npn transistors allowing heavily doped base regions to be used, while maintaining reasonable current gain. This in turn permits a narrowing of the base region, improving high frequency performance.
Conventional known methods for formation of device quality single crystalline .beta.-SiC require epitaxial growth by reaction of silanes and a hydrocarbon, typically acetylene or propane, at temperatures higher than 900.degree. C., and typically 1400.degree. C., for example as described in U.S. Pat. No. 4,923,716 to Brown et al. issued 8 May 1990, entitled "Chemical Vapour deposition of silicon carbide". Such high temperatures are undesirable in a bipolar CMOS (BiCMOS) process for forming wide band gap emitters in Si-HBTs, and in particular for high speed bipolar transistors which have a very thin (about 50 nm) highly doped base. To suppress dopant redistribution in the base and preserve ultra shallow base profiles during emitter formation, alternative low temperature processes for deposition of amorphous and polycrystalline SiC.sub.x deposition are required.
Polycrystalline silicon carbide emitters for HBTs have been formed at a deposition temperature as low as 900.degree. C. as described by T. Sugii, T. Aoyama, Y. Furumura, and T. Ito, Proceedings of the First Topical Symposium on Silicon Based Heterostructures, edited by S. S. Iyer et al., Toronto, Canada, October 1990, pp. 124. Also, as described in the latter article and references therein, amorphous SiC emitters were fabricated by deposition at 700.degree. C., but the material was heavily doped with fluorine to passivate dangling bonds. In the latter process, in which SiC.sub.x was deposited from a gaseous reactant mixture of disilane Si.sub.2 H.sub.6 and acetylene C.sub.2 H.sub.2 with phosphine PH.sub.3, and difluorosilane SiH.sub.2 F.sub.2 as a source of fluorine, acceptably low film resistivity could only be obtained if the atomic carbon fraction were 20% or less.
As described in U.S. Pat. No. 5,053,255 to Boeglin entitled "CVD process for the thermally depositing silicon carbide films onto a substrate " issued 1 Oct. 1991, silicon carbide may be deposited at low temperature by pyrolysis of di-tert-butylsilane (DTBS). DTBS is a less toxic, air stable, non corrosive liquid, and is thus preferred over silane and other gaseous sources of silicon for CVD (chemical vapour deposition) being less hazardous in use. However, the latter process was found to produce silicon carbide films with an appreciable oxygen content .about.6%. An alternative method using Plasma CVD as described in U.S. Pat. No 5,061,514 to Boeglin entitled "CVD process for the plasma depositing silicon carbide films onto a substrate", issued 29 Oct. 1991 allows reaction to be carried out at a lower temperature, in the range from 100.degree. C. to 400.degree. C., but the resulting film was carbon rich and contained a substantial amount (12%) of oxygen. In forming Si-HBTs the presence of oxygen may create generation-recombination centres which may increase junction leakage.
Thus for application in Si-HBTs, a process with a reduced thermal budget (i.e. process temperature and time product) is required to form emitter quality SiC.sub.x with low resistivity, i.e., by incorporation of controlled amounts of impurities comprising, for example, phosphorus or boron, and fluorine, and reduction of other impurities which may be detrimental to electrical characteristics, e.g., oxygen.


A system and method for diagnosing faults in a communication network using a distributed alarm correlation system. The alarm correlation system may include node-level alarm correlation tools (ACTs) located at nodes in the network to provide node-level alarm correlation producing node-level correlation results. The node-level ACTs may share diagnostic knowledge with other node-level alarm correlation tools at other nodes. Each of the node-level ACTs may also share the diagnostic knowledge and the node-level correlation results with a higher-level ACT. The higher-level ACT may provide higher-level alarm correlation to produce higher-level correlation results.

The capacity of long-haul communication systems, such as "undersea" or "submarine" systems, has been increasing at a substantial rate. For example, some long-haul optically amplified undersea communication systems are capable of transferring information at speeds of 10 gigabits per second (Gbps) or greater on a single optical channel. In order to maximize the transmission capacity of an optical communication system, a single optical fiber may carry multiple optical channels (e.g., 64 or more) in a process known as wavelength division multiplexing (WDM). Because such a high capacity communication system is particularly subject to risk at various points on the network, network management and remote diagnosis have been used by system owners and operators to meet Service Level Agreements (SLAs).
A simplified communication network 10 is shown in FIG. 1. The communication network 10 is comprised of interconnected equipment referred to as network elements (NE) 12. In an optical communication network, for example, network elements can include transceivers, amplifiers, combiners, splitters, and telemetry equipment. As the number of transmission channels in a fiber and the number of fibers in a cable increases to accommodate the increased capacity of the optical network, the amount of equipment or network elements 12 also increases. Multiple network elements 12 can be housed together at a processing location or node 14, which sometimes is referred to as a cable station in a communication network. Field personnel can be located at the node or cable station to maintain the equipment.
Network management or traffic control activities are coordinated at a Network Management Center (NMC) or centers, 16 connected to the network nodes 14. A Network Management System (NMS) 18 can be located at the NMC 16 to provide data used for proactive maintenance and network capacity planning. One type of NMS 18 provides a comprehensive, graphically integrated view of the network topology for use in monitoring and trouble-shooting activities.
The NMS 18 may responsible for providing fault management by manipulating and storing fault indicators such as network element Quality of Service (QoS) alarms that indicate the violation of SLAs. In addition, the NMS 18 may be used to provide other network management functions such as configuration management, performance management, security management, and accounting management. At the high-level NMC 16, operators using the NMS 18 may access and/or manage network components (e.g., the individual nodes and/or network elements). At some nodes 14, field personnel can be given access to the NMS screens pertaining to equipment under their control or remotely managed nodes.
Using the NMS 18, network operators may diagnose and maintain communication networks using a centralized approach. The NMS 18 maintains a centralized decision process using a centralized server and an operator at the NMC 16 essentially coordinates management across the whole network. Correlation rules and topological configuration information are centrally located for the entire network and a centralized alarm correlation and root cause analysis is performed. This centralized approach to fault diagnosis often excludes expert knowledge distributed throughout the NMC area of control and does not adequately adapt to changes in network topology. In a global network where nodes may be widely distributed geographically, command and control issues may also arise.
Accordingly, there is a need for a system and method for fault diagnosis that shares any new diagnostic knowledge between the nodes and distributes the alarm correlation to local points or nodes in the network. There is also a need for a system and method for fault diagnosis that provides hierarchical processing at both the node level and at a higher level.

System and method for fault diagnosis using distributed alarm correlation


A piston ring includes a lateral surface which covers a circumferential surface of a piston and support segments with retaining surfaces which engage with the top and bottom of the piston. A piston ring joint allows the piston ring to be elastically deformed in the radial direction and is provided with a tongue at one end of the lateral surface, which tongue engages in an opening in the other end of the lateral surface. The tongue is designed with retaining segments which extend in the circumferential direction and continue as extensions of the support segments. The retaining segments engage supportively with the top and bottom of the piston. The opening is provided with carrier segments at least in certain areas of the circumference of the piston ring extensions of the support segments and holding the ends of the piston ring in place axially with respect to the piston, the carrier segments being supported in the axial direction of the piston on the retaining segments. The piston ring joint of the piston ring has at least one sealing surface between the ends of the piston ring.

1. Field of the Invention
The invention relates to a piston ring which covers a circumferential surface of a piston and in which retaining surfaces of the piston ring engage the top and bottom of the piston.
2. Description of the Related Art
U.S. Patent Application Publication No. US 2002/0043768 discloses a piston ring for covering a circumferential surface of a piston, i.e., a flat piston of a vibration damper. To improve the sealing function, the piston ring disclosed by this reference includes support segments with retaining surfaces in the area of the piston ring joint. However, if there is an unfavorable combination between the tolerance field for the diameter of the piston with the piston ring and the tolerance field of the cylinder of the vibration damper, a leakage gap may form in the area of the joint, which reveals itself as a wide range of variation in the damping forces at very high damping force values. It would, of course, be possible to specify even narrower tolerance fields. However, the piston ring is preferably an injection-molded plastic part and the manufacturing tolerances of the production process determine the limits of the tolerance fields. If the tolerance fields were to be narrowed too much, the production of the piston rings would be associated with a disproportionate increase in the amount of waste.


A scroll compressor has a moving scroll and a stationary scroll in contact with each other. A seal ring for defining a back pressure space at a rear side of the moving scroll is provided and its position is adjusted between a sealing position and a leakage position with respect to an end plate of the moving scroll.

In general, a scroll compressor includes in a casing a compressor mechanism including a first scroll having an end plate and a spiral wrap formed thereon and a second scroll having an end plate and a spiral wrap formed thereon and engaging with the first scroll. Usually, the first scroll is a stationary scroll which is prohibited from revolving in the casing and the second scroll is a moving scroll which is driven by a drive shaft to revolve about the drive shaft with a certain turning radius. In the scroll compressor, the moving scroll revolves about the drive shaft to vary the capacity of a compressor chamber defined between the stationary scroll and the moving scroll, thereby compressing gas such as refrigerant.
As an example of the above-described scroll compressor, Japanese Unexamined Patent Publication No. H8-334094 describes a scroll compressor including a position adjustment means for adjusting the position of one of the stationary and moving scrolls along the axial direction of the compressor mechanism. In the scroll compressor, the position adjustment means is configured to change the relative position of the scrolls between a compression position at which the wraps of the scrolls are in sealed contact with each other to define a compressor chamber therebetween and a non-compression position at which the wraps are not in the sealed contact. The scroll compressor is driven with the scrolls always at the compression position to work at 100% capacity. The scroll compressor is also able to work at a capacity less than 100% by intermittently shifting the scrolls to the non-compression position.
In the scroll compressor described in Japanese Unexamined Patent Publication No. H8-334094, an electromagnetic valve is used as the position adjustment means for making either one of a high pressure path and a low pressure path, both of which are connected to a chamber formed at the front side of the stationary or moving scroll, communicate with the chamber, thereby applying high or low pressure to the stationary or moving scroll. The scrolls are pressed against each other when the high pressure is applied, while they are separated when the low pressure is applied. For example, the chamber may be space inside a seal ring which is pressed against the bottom surface of the moving scroll (back pressure space).

Scroll compressor having a position adjustment device urging the movable scroll towards the stationary scroll by moving a seal formed between a support and the movable scroll


An electrostatic capacitance sensor 1 includes a semiconductor substrate 4. A first fixing plate 2 is joined to a one-side surface 4a of the semiconductor substrate 4, and a second fixing plate 3 is joined to other-side surface 4b of the semiconductor substrate 4, whereby a space portion S is formed. Then, static electricity suppressing means 70 for suppressing static electricity from being generated in the space portion S is provided in the electrostatic capacitance sensor 1.

The present invention relates to an electrostatic capacitance sensor.
Heretofore, as shown in Japanese Patent Laid-Open Publication No. 2010-127648 (hereinafter, referred to as Patent Literature 1), an electrostatic capacitance sensor has been known, in which an upper fixing plate and a lower fixing plate are joined respectively to front and back surfaces of a semiconductor substrate including a frame portion and movable bodies having movable electrodes.
In this Patent Literature 1, fixed electrodes arranged apart from the movable electrodes of the movable bodies so as to be opposite thereto are formed on the upper fixing plate. Moreover, central portions of the movable bodies are supported by beams, and gravitational center positions of both end sides of each of the movable bodies are made asymmetric to each other while taking, as a boundary, each of the central portions supported by the beams concerned, whereby the movable bodies swing in the event where an acceleration is inputted thereto.
Then, a difference of electrostatic capacitance to be changed between both end sides of each of the movable electrodes and the fixed electrodes in the event where the movable bodies swing is arithmetically operated, whereby a magnitude of the acceleration to be inputted is detected.

PANASONIC INTELLECTUAL PROPERTY MANAGEMENT CO., LTD.


Embossed fibrous structures having one or more line element embossments and one or more linear elements and to methods for making same are provided.

Fibrous structures with line element embossments are known. However, the clarity of the line element embossments have been problematic and have resulted in consumer negatives.
Accordingly, there is a need for a fibrous structure that comprises one or more line element embossments wherein the clarity of the line element embossment is superior to known fibrous structures comprising line element embossments and for methods for making same.

Embossed fibrous structures and methods for making same


A shoulder motion exercise device, kit, and method of use having a retainer, a plurality of connectors, an extender, and a slider. The device aids in the stretching and exercise of at least a shoulder and a portion of the torso.

The present invention relates to a shoulder exercise device and method of use. The human shoulder is one of the most anatomically complex joints of the human body, and is capable of some of the most complex patterns of human motion. In many sports, such as baseball, tennis and golf, just to name a few, the shoulder is subject to severe stresses and is susceptible to many types of injury. It is well-established that a regular program of shoulder stretching and strengthening exercises may decrease the incidence of injury. Unfortunately, even though golf, for example, is considered a low-intensity activity, it is not an injury-free activity. More unfortunately, the golf swing is a unique type of motion that is not easily replicated in a training modality. Most golf-related injuries are associated with overuse or poor swing mechanics, and it has been reported that between 8% to 21% of total reported golf injuries occur at the shoulder. To develop effective training and rehabilitative techniques for any athlete, there must be a clear understanding of the mechanics involved in accomplishing the sport.
With more individuals golfing, particularly in the senior sector, injuries are bound to occur. The shoulder joint ranks among the top 5 most injured sites. Problems at the shoulder due to aging include loss of flexibility, rotator cuff degeneration, and acromioclavicular joint degenerative arthritis; all of which can be aggravated by the repetitive nature of the golf swing.
The literature abounds with the importance of sport-specific warm-up, training, and rehabilitation programs. More unfortunately, the golf swing is a unique type of motion that is not easily replicated in a training modality. A review of the literature reveals that shoulder range of motion (ROM) and flexibility is strongly correlated to the age of the subject. Studies discussing shoulder injuries in golf also frequently mention the effects of aging, including the relationship between degenerative changes and rotator cuff tears. Data has revealed that Senior PGA Tour professionals had less upper body rotation at peak backswing than younger PGA Tour professionals. This leads us to ask not only what the normal motions at the shoulder throughout the golf swing are, but also if those motions change with aging and its associated reductions in flexibility and ROM.
Thus, it can be inferred that increasing shoulder ROM and strength, while maintaining the mechanics of a sound golf swing, would be highly helpful to golfers of many skill levels. Perhaps because of the complexity of shoulder motions, various descriptors have been used to describe shoulder motions. For the purposes of this specification, the following terms are defined and used:
Vertical Elevation (VE) As seen in FIG. 1, an absolute angle between the humerus and a vector connecting a point midway on a line between the shoulder joint centers (S) to a point midway on a line between the femoral joint centers (F) (trunk vector=T). Clinically, this is a combination of shoulder forward flexion and shoulder abduction. An angle of 0° is defined when the upper arm is parallel to the trunk vector and next to the body. In the golf context, the usual motion of gripping a golf club with both hands in preparation for a swing involves placing the hands in close proximity to one another with a slight degree of vertical elevation of the shoulders. Vertical elevation is pictorially seen in FIG. 1, with 0 degrees of vertical elevation representing the arm in a substantially fully dependent position, 90 degree of vertical elevation representing the arm substantially parallel to the shoulder, and 180 degree of vertical elevation representing the arm substantially fully raised above the head.
Horizontal Adduction (HA) As seen in FIG. 2, motion of the humerus as represented by the motion of an axial line along the length of the humerus (H) in the plane perpendicular to the trunk vector (T) described above (transverse plane of the body). An angle of 0° is defined when the upper arm lies in the plane defined by the trunk vector and the vector connecting the shoulder joint centers (S). For convenience in labeling anterior and posterior motion, an angle of 90 degrees would represent the arm at substantially a right angle to the vector connecting the shoulder joint centers, denominated either +90 degrees for horizontal adduction to the front and −90 degrees for horizontal adduction to the rear. As a function of variable human flexibility, most individuals can horizontally adduct the arm in a forward direction to greater that +90 degrees and even cross the midline, while most individuals cannot horizontally adduct the arm rearward to the full −90 degree range. For the purpose of this specification, the term horizontal adduction is used to denote movement away from the midline, and the term horizontal abduction is used to denote movement towards or crossing the midline of the torso.

This patent is subject to a terminal disclaimer.

Shoulder motion exercise device and method of use