Certain compounds, structurally related to natural compounds which can be extracted i.a. from bull testes and from human follicular fluid, can be used for regulating the meiosis in oocytes and in male germ cells. Some of these compounds are useful in the treatment of infertility, whereas other compounds are useful as contraceptives. These compounds have the structural formula

The present invention relates to pharmacologically active compounds and to their use as medicaments. More particularly it has been found that the sterol derivatives described herein can be used for regulating meiosis.
In L. F. Fieser and M. Fieser: Steroids; Reinhold Publishing Corporation, 1967, 5xcex1-bromocholest-ane-3xcex2,6xcex2-diol; 7xcex1-bromocholestane-3xcex2,6xcex1-diol; 7xcex1-bromocholestane-3xcex2,6xcex2diol; 7xcex1-bromo-cholestane-3xcex2,5xcex1-diol-6-one; 7xcex2-bromocholestane-3xcex2,5xcex1-diol-6-one; 3xcex2-bromocholestane-2xcex1-ol; 5xcex1-chlorocholestane-3xcex2,6xcex1-diol; 5xcex1-chlorocholestane-3xcex2,6xcex2-diol; 6xcex2-chlorocholestane-3xcex2,-5xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2,6xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2,6xcex2diol; cholestane-2xcex1,3xcex1-diol; cholestane-2xcex1,3xcex2-diol; cholestane-2xcex2,3xcex1-diol; cholestane-2xcex2,3xcex2-diol; cholestane-3xcex1,4xcex1-diol; cholestane-3xcex1,4xcex2-diol; cholestane-3xcex2,4xcex2-diol; cholestane-3xcex1,5xcex1-diol; cholestane-3xcex2,5xcex1-diol; cholestane-3xcex2,6xcex1-diol; cholestane-3xcex2,6xcex2-diol; cholestane-3xcex2,22xcex1-diol, cholestane-3xcex2,22xcex2-diol; cholestane-3xcex2,7xcex1,8xcex1-triol; xcex945-cholestene-3xcex2,4xcex1-diol; xcex945-cholestene-3xcex2,4xcex2-diol; xcex945-cholestene-3xcex2,20xcex1-diol; xcex945-cholestene-3xcex2,22xcex1-diol; xcex945-cholestene-3xcex2,22xcex2-diol; xcex945-cholestene-3xcex2,24xcex1-diol; xcex945-cholestene-3xcex2,24xcex2-diol; xcex946-cholestene-3xcex2,5xcex1-diol; xcex948(14)-cholestene-3xcex2,9xcex1-diol; xcex9411-cholestene-3xcex1,24-diol; xcex945-cholestene-3xcex2,6-diol-7-one; xcex945-cholestene-4xcex1-ol-3-one; xcex945-cholestene-3xcex2,4xcex2,7xcex1-triol; coprostane-3xcex1,5xcex2-diol; coprostane-3xcex2,5xcex2-diol; coprostane-3xcex2,6xcex2-diol; coprostane-4xcex2,5xcex2-diol-3-one and 20xcex2-hydroxy-20-isocholesterol are mentioned in the subject index.
In German patent application having publication no. 1,183,079, a process for preparing 4xcex1-hydroxy-5a-cholestan-3-one is mentioned in Example 5. This compound is not stated to have any utility other than as an intermediate.
In German patent application having publication no. 1,224,738, cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-acetate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-formiate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-sulphate and cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-phosphate are mentioned in Examples 1-5, respectively. It is mentioned that the compounds described therein can be used for the treatment of arteriosclerosis.
In German patent application having publication no. 2,201,991 C2, a process for the preparation of insecticides such as 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxycholest-7-en-6-one is described.
German patent application having publication no. 2,236,778 B2 relates to a novel insecticide, i.e., cholest-7-en-2xcex2,3xcex2,5xcex2, 11xcex1,14xcex1,20(R)-heptahydroxy-6-one.
In German patent application having publication no. 2,409,971 B2, 5,24-cholestadien-3xcex2-ol; 5-cholesten-3xcex2,24,25-triol-3xcex2-acetate; 5-cholesten-3xcex2,24,25-triol-3xcex2,24-diacetate; 5,25-cholestadien-3xcex2-ol acetate; 5-cholesten-3xcex2,25,26-triol-3xcex2-acetate and 5-cholesten-3xcex2,25,26-triol are mentioned in Examples 1, 1, 2, 3, 3 and 6, respectively. It is mentioned that the compounds described therein are valuable intermediates for the technical preparation of 24,25(or 25,26)-dihydroxycholecalciferol.
In German patent application having publication no. 2,453,648B2, cholest-5xcex1-an-3xcex2,6xcex1-diol; cholest-5xcex2-an-3xcex2,6xcex2-diol; cholest-5xcex1-an-3,6-dione; cholest-5xcex1-an-6xcex2-ol-3-one and cholest-5xcex1-an-2xcex1-bromo-6xcex2-ol-3-one are mentioned as intermediates in column 6.
In German patent application having publication no. 2,415,676, cholestan-3p,25-diol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol; cholestan-5xcex1,25-diol-3-one; cholest-4-en-25-ol-3-one and cholesta-4,6-dien-25-ol-3-one are mentioned as compounds III, IV, X, Xl XII and XIII, respectively. It is suggested that the compounds described therein may be substantially stronger that vitamin D3.
In German patent application having publication no. 2,546,715 A1, a process for preparing 1xcex1,3xcex2dihydroxycholest-5-en and 1xcex1,3xcex2-dihydroxycholest-6-en is mentioned in Example 1 (compounds V and II). It is suggested that the compounds described therein are useful additives to foodstuff and can be used in vitamin compositions.
In German patent application having publication no. 2,822,486A1, 3xcex1,6xcex1-dihydroxy-5xcex2-cholestan-24-one; 3xcex1,6xcex1,24-trihydroxy-5xcex2-cholestan; 3-chlorocholest-5,24-dien; 3xcex2-hydroxycholest-5-en-24-on acetate and 3-chlorocholest-5-en-24-on are mentioned in Example 3,4,5a and 6c and as formula VlI, respectively. It is mentioned that the compounds described therein can be used as intermediates for the preparation of desmosterin, derivatives thereof and other active vitamin D.
In German patent application having publication no. 3,241,172 A1, cholestan-25-fluoro-3xcex2,22(S)-diol; cholestan-25-chloro-3xcex2,22(S)-diol; cholestan-25-methyl-3xcex2,22-diol; cholestan-25-methyl-3xcex2,22-diol-3-hydrogenbutandioate and cholestan-25-methyl-3xcex2,22-diol-bis-hydrogenbutandioate are mentioned in claims 2, 3, 5, 6 and 7, respectively. It is mentioned that the compounds described therein inhibit the activity of HMGCOA reductase and the formation of blood cholesterol.
In German patent application having publication no. 3,390,016C2, a process for preparing 1xcex1,25-dihydroxy-26,26,26,27,27,27-hexafluorocholes-5-en is described. It is mentioned that this compound can easily be converted into a compound having vitamin D3 like activity.
In Danish patent application having publication no. 123,767, a process for preparing 2xcex2,3xcex2,14xcex1,22,25-pentahydroxy-xcex947-5xcex2-cholesten-6-one is mentioned. It is mentioned that the compounds described therein have an action on the central nervous system.
In European patent application having publication no. 15,122 B1, 25-hydroxy-3xcex2-[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 3xcex2[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 25-hydroxy-24-oxocholesterol-3xcex2-acetate; 24-oxocholesterol-3xcex2-acetate; 25-hydroxy-24-oxocholesterol; 24,25-dihydroxycholesterol; 3xcex1,6xcex1,25-trihydroxy-24-oxo-5xcex2-cholestane; 1xcex1,25-dihydroxy-24-oxocholesterol; 1xcex1,24,25-trihydroxycholesterol; 3xcex2-hydroxy-24-oxo-cholesta-5,7-dien; 3xcex2,25-dihydroxy-24-oxocholesta-5,7-dien; 3xcex2-hydroxy-24-oxocholesta-5,7-dien; 1xcex1,3xcex2-dihydroxy-24-oxocholesta-5,7-dien and 1xcex1,3xcex2,25-trihydroxy-24-oxocholesta-5,7-dien are mentioned in Examples 1, 1, 4, 4, 5ii, 5(1), 6i, 7, 7(2), 8iii, 8iv, 8iv, 9iii and 9iv, respectively. It is mentioned that the compounds described therein are useful intermediates convertible into active vitamin D3.
In European patent application having publication :no. 63,678B1, (24R)-3xcex2,24,25-trihydroxycholest-5-en; (24RS)-3xcex2,24,25-trihydroxycholest-5-en and (24R)-1xcex2,3xcex2,24,25-tetrahydroxycholest-5-en are mentioned in Examples 1e, 3e and 4f, respectively. It is mentioned that the compounds described therein can be used as intermediates in the preparation of vitamin D3 derivatives.
In European patent application having publication no. 322,036A1, 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8-en-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxycholesta-8,14-dien-2xcex1,11xcex2,12xcex1-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2xcex1,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2-ol-11-one and mono(4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol)-3xcex2-succinate are described in Tables I (1+2), II (5-9) and III (11-14). It is mentioned that the compounds described therein are anti-inflammatory.
In European patent application having publication no. 349,869A2, 1xcex1,3xcex2-dihydroxycholest-5-ene and 1xcex1,3xcex2,24-trihydroxycholest-5-ene are mentioned in Examples 1 and 2, respectively. It is mentioned that the latter compound is useful for the production of 1xcex1,24-dihydroxy-vitamin D3.
In British patent application having publication no. 2,089,810 A, cholesta-5,7-diene-3xcex2,23(R),25-triol and cholesta-5,7-diene-3xcex2,23(S),25-triol are mentioned in Example 1. It is mentioned that the compounds described therein should find application as a substitute for 25-hydroxy vitamin D3 in various therapeutic applications.
In Norwegian patent application having publication no. 144,264, 1xcex1,3xcex2-dihydroxycholest-5-en and 1xcex1,3xcex2,25-trihydroxycholest-5-en are mentioned in Example 1 and 3, respectively. It is mentioned that the compounds described therein can be used within the veterinary field.
In Swedish patent application having publication no. 314,978, a process wherein xcex947-cholesten-2xcex2,3xcex2-diol-6-one is used as starting material (for the preparation of xcex947-koprosten-2xcex2,3xcex2,14xcex1-triol-6-one) is described in Example 3. The latter compound is active against insecticide metamorfose hormones.
In Swedish patent application having publication no. 330,883, 2xcex2,3xcex2, 14xcex1,22(R),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one and 2xcex2,3xcex2,14xcex1,22(S),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one are mentioned in Examples 4 and 5, respectively. It is mentioned that the compounds described therein have valuable pharmacological properties; however, none is specified.
In Swedish patent application having publication no. 430,508, cholest-5-en-3xcex2,22(R,S),25-triol; cholest-5-en-25-fluoro-3xcex2,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3xcex2-semisuccinate; cholest-5-en-25-chloro-3xcex2,22-diol and cholest-5-en-25-chloro-22-ol-3xcex2-hemisuccinate are mentioned in Examples 5, 8, 9, 11 and 12, respectively. It is mentioned that the compounds described therein have pharmaceutical activities, e.g., inhibiting (HMG-CoA) reductase.
In U.S. Pat. No. 3,931,403, 3xcex1,7xcex1,12xcex1,24,25-pentahydroxy coprostane; 3xcex1,7xcex1, 12xcex1,25-tetrahydroxy coprostane; 3xcex1,7xcex1,25-trihydroxy coprostane; 3xcex1,7xcex1,24,25-tetrahydroxy coprostane; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,24xcex1,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,-12xcex1,24xcex2,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25,26-pentol and 5,3cholestane-3xcex1,7xcex1,12xcex1,25-tetrol are mentioned in Examples I and II. It is mentioned that the compounds described therein can be used to prepare a composition possessing antimicrobial, antibiotic and bacteriostatic properties.
In U.S. Pat. No. 4,011,250, 1xcex1,2xcex1,3xcex2-trihydroxycholesta-5,7-diene and 1xcex1,2xcex1-dihydroxy-3xcex2-acetoxycholesta-5-ene are described as intermediates in Example 1 and 3, respectively.
In U.S. Pat. No. 4,254,045, cholest-5-en-2,fluoro-1 a,3,diol is mentioned as compound 3. It is mentioned that the compounds described therein have vitamin D-like activity.
In U.S. Pat. No. 4,329,295, the preparation of 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol 3 hydrogen butanedioate and 24-cyclopropyl-5a-cholane-3xcex2,22(S)-diol is described in Examples 3-6, respectively. It is mentioned that the compounds described therein inhibit the activity of HMG Co A reductase.
In U.S. Pat. No. 4,670,190, cholesta-1,4,6-trien-3-one; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2-dihydroxy-5xcex1-cholestane; 1xcex1,3xcex2-dihydroxycholesta-5,7-diene 1xcex1,3xcex2-25-trihydroxycholest-5-ene; 1xcex1,25-dihydroxycholesterol; and 1xcex1,25-dihydroxycholesterol-3-benzoate are described in Examples 1a, 1c, 2bxe2x80x2, 3c, 4c, 9b and 9c, respectively. It is mentioned that the compounds described therein have therapeutic applications.
Other known compounds are cholest-5-en-35,20(S)-diol (Sigma, St. Louis, Mo, USA, Cat. No. H 6378), cholest-5-en-3p,22(S)-diol, (Sigma, St. Louis, Mo, USA, Cat. No. H 5884), cholest-5-en-3xcex2,4xcex2-diol (Steraloid Inc., Wilton, N.H., USA, Cat. No. C 6410, Batch L 1066), cholest-5-en-3xcex2,22(R)-diol (Sigma, St. Louis, Mo., USA, Cat. No. H 9384) and 2xcex2,3xcex2,14xcex122(R),25-pentahydroxycholest-7-en-6-one.
In none of the above publications is there any mentioning of the compounds being able to regulate meiosis. The content of the above publications is incorporated by reference.
Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1 n) of chromosomes and 2c DNA. The second rneiotic division proceeds without a DNA synthesis. This division therefore results in the formation of the haploid germ cells with only 1 c DNA.
The meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly. All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty. Thus, from early life the female has a stock of oocytes which is drawn upon until the stock is exhausted. Meiosis in females is not completed until after fertilization, and results in, only one ovum and two abortive polar bodies per germ cell. In contrast, only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces 4 spermatozoa.
Only little is known about the mechanisms which control the initiation of meiosis in the male and in the female. In the oocyte, new studies indicate that follicular purines, hypoxanthine or adenosine, could be responsible for meiotic arrest (Downs, S. M. et al. Dev Biol 82 (1985) 454-458; Eppig, J.J. et al. Dev Biol 119 (1986) 313-321; and Downs, S. M. Mol Reprod Dev 35 (1993) 82-94). The presence of a diffusible meiosis regulating substance was first described by Byskov et aL in a culture system of fetal mouse gonads (Byskov, A. G. et al. Dev Biol 52 (1976) 193-200). A meiosis activating substance (MAS) was secreted by the fetal mouse ovary in which meiosis was ongoing, and a meiosis preventing substance (MPS) was released from the morphologically differentiated testis with resting, non-meiotic germ cells. It was suggested that the relative concentrations of MAS and MPS regulated the beginning, arrest and resumption of meiosis in the male and in the female germ cells (Byskov, A. G. et al. in The Physiology of Reproduction (eds. Knobil, E. and Neill, J. D., Raven Press, New York (1994)). Clearly, if meiosis can be regulated, reproduction can be controlled. A recent article (Byskov, A. G. et aL Nature 374 (1995), 559-562) describes the isolation from bull testes and from human follicular fluid of certain sterols that activate oocyte meiosis. Unfortunately, these sterols are rather labile and utilization of the interesting finding would thus be greatly facilitated if more stable meiosis activating compounds were available.
Compounds being known to stimulate the meiosis and being different from the compounds claimed in the present patent application are described in WO 96/27658.
The compounds described herein have advantages compared with the known compounds.
It is a purpose of the present invention to provide compounds and methods useful for relieving infertility in females and males, particularly in mammals, more particularly in humans.
It is a further purpose of the present invention to provide compounds and methods useful as contraceptives in females and males, particularly in mammals, more particularly in humans.
According to the present invention there are provided novel compounds with interesting pharmacological properties. In particular, the compounds of formula 1a, 1b and 1c are useful for regulating the meiosisin oocytes and in male germ cells.
In one aspect, the present invention relates to compounds of formula 1a:
wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected fromn the group comprising hydrogen, halogen, hydroxy and branched or unbranched C1-C6alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R3 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and =NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R14, an additional bond between the carbon atoms at which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R13, an additional bond between the carbon atoms at which R4 and R3 or R6or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and =NOR23 wherein, R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and =NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R16 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R8 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl, R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8 R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl and with the further general proviso that R9, R10 and R11 are not all hydroxy and with the further general proviso that it is not 5xcex1-bromocholestane-3xcex2,6xcex2-diol; 7xcex1-bromo-cholestane-3xcex2,6xcex1-diol; 7xcex1-bromocholestane-3xcex2,6xcex2-diol; 7xcex1-bromocholestane-3xcex2,5xcex1-diol-6-one; 7xcex2-bromocholestane-3xcex2,5xcex1-diol-6-one; 3xcex2-bromocholestane-2xcex1-ol; 5xcex1-chlorocholestane-3xcex2,6xcex1-diol; 5xcex1-chlorocholestane-3xcex2,6xcex2-diol; 6xcex2-chlorocholestane-3xcex2,5xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2-6xcex1-diol; xcex947,9(11)-cholestadiene-3xcex2,6xcex2-diol; cholestane-2xcex1,3xcex1-diol; cholestane-2xcex1,3xcex2-diol; cholestane-2xcex2,3xcex1-diol; cholestane-2xcex2,3xcex2-diol; cholestane-3xcex1,4xcex1-diol; cholestane-3xcex1,4xcex2-diol; cholestane-3xcex2,4xcex2-diol; cholestane-3xcex1,5xcex1-diol; cholestane-3xcex2,5xcex1-diol; cholestane-3xcex2,6xcex1-diol; cholestane-3xcex2,6xcex2-diol; cholestane-3xcex2,22xcex1-diol; cholestane-3xcex2,22xcex2-diol; cholestane-3xcex2,7xcex1,8xcex1-triol; triol; xcex945-cholestene-3xcex2,4xcex1-diol; xcex945-cholestene-3xcex2,4xcex2-diol; xcex945-cholestene-3xcex2,20xcex1-diol; xcex945-cholestane-3xcex2,22xcex1-diol; xcex945-cholestene-3xcex2,22xcex2-diol; xcex945-cholestene-3xcex2,24xcex1-diol; xcex945-cholestene-3xcex2,24xcex2-diol; xcex946-cholestene-3xcex2,5xcex1-diol; xcex948(14)-cholestene-3xcex2,9xcex1-diol; xcex9411-cholestene-3xcex1,24-diol; xcex945-cholestene-3xcex2,6-diol-7-one; xcex945-cholestene-4xcex1-ol-3-one; xcex945-cholestene-3xcex2,4xcex2,7xcex1-triol; coprostane-3xcex1,5xcex2-diol; coprostane-3xcex2,5xcex2-diol; coprostane-3xcex2,6xcex2-diol; coprostane-4xcex25xcex2-diol-3-one; 20xcex2hydroxy-20-isocholesterol; 4xcex1-hydroxy-5xcex1-cholestan-3-one; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6pacetate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-formiate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-sulphate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-phosphate; 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxycholest-7-en-6-one; cholest-7-en-2xcex2,3xcex2,5xcex2,11xcex1,14xcex1,20(R),22(R)-heptahydroxy-6-one; 5,24-cholestadien-3xcex2-ol; 5-cholesten-3xcex2,24,25-triol-3xcex2-acetate; 5-cholesten-3xcex2,24,25-triol-3xcex2,24-diacetate; 5,25-cholestadien-3xcex2-ol acetate; 5-cholesten-3xcex2,25,26-triol-3xcex2-acetate; 5-cholesten-3xcex2,25,26-triol; 24,25(or 25,26)-dihydroxy-cholecalciferol; cholest-5xcex1-an-3xcex2,6xcex1-diol; cholest-5xcex2-an-3xcex2,6xcex2-diol; cholest-5xcex1-an-3,6-dione; cholest-5xcex1-an-6xcex2-ol-3-one; cholest-5xcex1-an-2xcex1-bromo-6xcex2-ol-3-one; cholestan-3xcex2,25-diol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol; cholestan-5xcex1,25-diol-3-one; cholest4-en-25-ol-3-one; cholesta-4,6-dien-25-ol-3-one; 1xcex1,3xcex2-dihydroxycholest-5-en; 1xcex1,3xcex2-dihydroxycholest-6-en; 3xcex1,6xcex1-dihydroxy-5xcex2-cholestan-24-one; 3xcex1,6xcex1,24-trihydroxy-5xcex2cholestan; 3-chlorocholest-5,24-dien; 3xcex2-hydroxycholest-5-en-24-on acetate; 3-chlorocholest-5-en-24-on; cholestan-25-fluoro-3xcex2,22(S)-diol; cholestan-25-chloro-3xcex2,22(S)-diol; cholestan-25-methyl-3xcex2,22-diol; cholestan-25-methyl-3xcex2,22-diol-3-hydrogenbutandioate; cholestan-25-methyl-3xcex2,22-diol-bis-hydrogenbutandioate; 1xcex1,25-dihydroxy-26,26,26,27,27,27-hexafluorocholes-5-en; 2xcex2,3xcex2,14xcex1,22,25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; 25-hydroxy-3xcex2-[(tetrahydro-2H-pyran-2-yl)oxy]cholest-5-en-24-on; 3p-[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-en-24-on; 25-hydroxy-24-oxocholesterol-3p-acetate; 24-oxocholesterol-3xcex2-acetate; 25-hydroxy-24-oxocholesterol; 24,25-dihydroxycholesterol; 3x,6a,25-trihydroxy-24-oxo-5xcex2-cholestane; 1xcex1,25-dihydroxy-24-oxocholesterol; 1xcex1,24,25-trihydroxycholesterol; 3xcex2-hydroxy-24-oxocholesta-5,7-dien; 3xcex2,25-dihydroxy-24-oxocholesta-5,7-dien; 3xcex2-hydroxy-24-oxo-cholesta-5,7-dien; 1xcex1,3xcex2-dihydroxy-24-oxocholesta-5,7-dien; 1xcex1,3xcex2,25-trihydroxy-24-oxo-cholesta-5,7-dien; (24R)-3xcex2,24,25-trihydroxycholest-5-en; (24RS)-3xcex2,24,25-trihydroxycholest-5-en; (24R)-1xcex2,3 xcex2, 24,25-tetrahydroxycholest-5-en; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-3xcex211xcex2-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxycholesta-8,14-dien-2xcex1,11xcex2,12xcex1-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2xcex1,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2-ol-11-one; mono(4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol)-3xcex2-succinate; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2,24-trihydroxycholest-5-ene; cholesta-5,7-diene-3xcex2,23(R),25-triol; cholesta-5,7-diene-3xcex2,23(S),25-triol; 1xcex1,3xcex2-dihydroxycholest-5-en; 1xcex1,3xcex2,25-trihydroxycholest-5-en; xcex947-cholesten-2xcex2,3xcex2-diol-6-one; 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; 2xcex2,3xcex2,14xcex1,22(S),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; cholest-5-en-3xcex2,22(R,S),25-triol; cholest-5-en-25-fluoro-3xcex2,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3xcex2-semisuccinate; cholest-5-en-25-chloro-3xcex2,22-diol; cholest-5-en-25-chloro-22-ol-3xcex2-hemisuccinate; 3xcex1,7xcex1,12xcex1,24,25-pentahydroxy coprostane; 3xcex1,7xcex1,12xcex1,25-tetrahydroxy coprostane; 3xcex1,7xcex1,25-trihydroxy coprostane; 3xcex1,7xcex1,24,25-tetrahydroxy coprostane; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,24xcex1,25-pentol; 5xcex2cholestane-3xcex1,7xcex1,12xcex1,24xcex2,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25,26-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25-tetrol; 1xcex1,2xcex1,3xcex2-trihydroxycholesta-5,7-diene; 1xcex1,2xcex1-dihydroxy-3xcex2-acetoxycholesta-5-ene; cholest-5-en-2xcex2-fluoro-1xcex1,3xcex2diol; 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol 3 hydrogen butanedioate; 24-cyclopropyl-5xcex1-cholane-3xcex2,22(S)-diol; cholesta-1,4,6-trien-3-one; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2-dihydroxy-5xcex1-cholestane; 1xcex1,3xcex2-dihydroxycholesta-5,7-diene; 1xcex1,3xcex2-25-trihydroxycholest-5-ene; 1xcex1,25-dihydroxycholesterol; 1xcex1,25-dihydroxycholesterol-3-benzoate; cholest-5-en-3xcex2,20(S)-diol; 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxycholest-7-en-6-one and cholest-5-en-3xcex2,22(S)-diol; cholest-5-en-3xcex2,20(S)-diol; cholest-5-en-3xcex2,22(S)-diol; cholest-5-en-3xcex2,4xcex2-diol; cholest-5-en-3xcex2,22(R)-diol and 2xcex2,3xcex2,14xcex1,22(R),25-pentahydroxy-cholest-7-en-6-one.
In another embodiment, the invention relates to esters of compound of formula Ia. Such esters are formally derived by esterification of one or more hydroxylic groups of a compound of formula Ia with an acid which, for example, can be selected from the group of acids comprising succinic acid and other aliphatic dicarboxylic acids, nicotinic acid, isonicotinic acid, ethylcarbonic acid, phosphoric acid, sulphonic acid, sulphamic acid, benzoic acid, acetic acid, propionic acid and other aliphatic monocarboxylic acids.
In still another preferred embodiment, the present invention relates to compounds of formula Ib and esters thereof as a medicament.
Compounds of formula Ib have the following structural formula:
wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected from the group comprising hydogen, halogen, hydroxy and branched or unbranched C1-C6alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R3is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and =NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R4, an additional bond between the carbon atoms at which R13 and R4 or R14 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R3, an additional bond between the carbon atoms at which R14 and R3 or R6 or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and xe2x95x90NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R16 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R3 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6 R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl, with the further general proviso that R9, R10 and R11 are not all hydroxy, and with the further general proviso that it is not cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemisuccinate-6xcex2-acetate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-hemi-succinate-6xcex2-formiate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-sulphate; cholestan-3xcex2,5xcex1,6xcex2-triol-3xcex2-phosphate; cholestan-3xcex2,25-diol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol-3xcex2-acetate; cholestan-3xcex2,5xcex1,25-triol; cholestan-5xcex1,25-diol-3-one; cholest-4-en-25-ol-3-one; cholesta-4,6-dien-25-ol-3-one; 1xcex1,3xcex2-dihydroxycholest-5-en; 1xcex1,3xcex2-dihydroxycholest-6-en; 3xcex1,6xcex1-dihydroxy-5xcex2-cholest-an-24-one; 3xcex1,6xcex1,24-trihydroxy-5xcex2-cholestan; 3-chlorocholest-5,24-dien; 3xcex2-hydroxycholest-5-en-24-on acetate; 3-chlorocholest-5-en-24-on; cholestan-25-fluoro-3xcex2,22(S)-diol; cholestan-25-chloro-3xcex2,22(S)-diol; cholestan-25-methyl-3xcex2,22-diol; cholestan-25-methyl-3xcex2,22-diol-3-hydrogenbutandioate; cholestan-25-methyl-3xcex2,22-diol-bis-hydrogenbutandioate; 2xcex2,3xcex2,14xcex1,-22,25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; (24R)-3xcex2,24,25-trihydroxycholest-5-en; (24RS)-3xcex2,24,25-trihydroxycholest-5-en; (24R)-1xcex2,3xcex2,24,25-tetrahydroxycholest-5-en; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2xcex1,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,3xcex2,11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxy-cholesta-8,14-dien-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-2xcex1,3xcex2-11xcex2-triol; 4,4-dimethyl-24-methylene-12xcex1-acetoxycholest-8-en-3xcex2,11xcex2-diol; 4,4-dimethyl-24-methylenecholest-8-en-2,3xcex2,11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-cholesta-8,14-dien-2xcex1,11xcex2,12xcex1-triol; 4,4-dimethyl-24-methylenecholesta-8,14-dien-2xcex1,3xcex2,-11xcex2,12xcex1-tetraol; 4,4-dimethyl-24-methylene-3xcex2-sulphooxy-12xcex1-acetoxycholest-8-en-2-ol-11-one; mono(4,4-dimethyl-24-methylene-12xcex1-acetoxycholesta-8,14-dien-2xcex1,11xcex2-diol)-3xcex2-succinate; cholesta-5,7-diene-3xcex2,23(R),25-triol; cholesta-5,7-diene-3xcex2,23(S),25-triol; 2xcex2,3xcex2,-14xcex1,22(R),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; 2xcex2,3xcex2,14xcex1,22(S),25-pentahydroxy-xcex947-5xcex2-cholesten-6-one; cholest-5-en-3xcex2,22(R,S),25-triol; cholest-5-en-25-fluoro-3xcex2,22(R,S)-diol; cholest-5-en-25-fluoro-22(R,S)-ol-3xcex2-semisuccinate; cholest-5-en-25-chloro-3xcex2,22-diol; cholest-5-en-25-chloro-22-ol-3xcex2-hemisuccinate; 3xcex1,7xcex1,12xcex1,24,25-pentahydroxy coprostane; 3xcex1,7xcex1,-12xcex1,25-tetrahydroxy coprostane; 3xcex1,7xcex1,25-trihydroxy coprostane; 3xcex1,7xcex1,24,25-tetrahydroxy coprostane; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,24xcex1,25-pentol; 5xcex2-cholestane-3xcex1, 7xcex1,12xcex1,24xcex2,25-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25,26-pentol; 5xcex2-cholestane-3xcex1,7xcex1,12xcex1,25-tetrol; cholest-5-en-2xcex2-fluoro-1xcex1,3xcex2-diol; 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol-3-acatate, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol, 24-cyclopropylchol-5-ene-3xcex2,22(S)-diol 3 hydrogen butanedioate; 24-cyclo-propyl-5xcex1-cholane-3xcex2,22(S)-diol; cholesta-1,4,6-trien-3-one; 1xcex1,3xcex2-dihydroxycholest-5-ene; 1xcex1,3xcex2-dihydroxy-5xcex1-cholestane; 1xcex1,3xcex2-dihydroxycholesta-5,7-diene; 1xcex1,3xcex2-25-trihydroxy-cholest-5-ene; 1xcex1,25-dihydroxycholesterol; and 1xcex1,25-dihydroxycholesterol-3-benzoate, as a medicament.
In a further preferred embodiment, this invention relates to compounds of formula Ic or esters thereof in the manufacture of a medicament for use in the regulation of meiosis.
Compounds of formula Ic have the following structural formula:
wherein R1 and R2, which are different or identical with the proviso that they are not both hydroxy, are selected from the group comprising hydrogen, halogen, hydroxy and branched or unbranched C1-C6 alkyI which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or oxo or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R3 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR26 wherein R26 is hydrogen or C1-C3 alkyl, or R3 designates, together with R9 or R14, an additional bond between the carbon atoms at which R3 and R9 or R14 are placed; R4 is selected from the group comprising hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR27 wherein R27 is hydrogen or C1-C3 alkyl, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms at which R4 and R13 or R15 are placed; R5 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6 an additional bond between the carbon atoms at which R5 and R6 are placed; R6 is hydrogen or hydroxy or R6 designates, together with R5, an additional bond between the carbon atoms at which R5 and R6 are placed; R9 is hydrogen, hydroxy, halogen or oxo or R9 designates, together with R3 or R10, an additional bond between the carbon atoms at which R9 and R3 or R10 are placed; R10 is hydrogen, halogen or hydroxy, or R10 designates, together with R9, an additional bond between the carbon atoms at which R10 and R9 are placed; R11 is selected from the group comprising hydroxy, optionally substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, halogen, C1-C4 alkandiyl (bound to the same carbon atom of the sterol skeleton) and xe2x95x90NOR28 wherein R28 is hydrogen or C1-C3 alkyl, or R11 designates, together with R12, an additional bond between the carbon atoms at which R11 and R12 are placed; R12 is selected from the group comprising hydrogen, hydroxy, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms at which R12 and R11 are placed; R13 is hydrogen, hydroxy or halogen or R13 designates, together with R4 or R14, an additional bond between the carbon atoms at which R13 and R4 or R4 are placed; R14 is hydrogen, hydroxy or halogen, or R14 designates, together with R3, R6 or R13, an additional bond between the carbon atoms at which R14 and R3 or R6or R13 are placed; R15 is selected from the group comprising hydrogen, halogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo and xe2x95x90NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms at which R15 and R4 are placed; R16 is selected from the group comprising hydrogen, halogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms at which R16 and R17 are placed; R17 is hydrogen or hydroxy, or R17 designates, together with R16, an additional bond between the carbon atoms at which R17 and R18 are placed; R18 and R19 are both hydrogen, or one of R18 and R19 is hydrogen while the other is halogen, hydroxy or methoxy, or R18 and R19 together designate oxo; R25 is selected from the group comprising C1-C4 alkyl and hydroxymethyl, or R25 and R31 together designate methylene or oxo; R29 is hydrogen, halogen, methyl, hydroxy or oxo; R30 is hydrogen, halogen, methyl or hydroxy; R31 is hydrogen, halogen, methyl or hydroxy, or R31, together with R25, designates methylene or oxo; and A is a carbon atom or a nitrogen atom; and when A is a carbon atom, R7 is selected from the group comprising hydrogen, hydroxy and halogen; and R8 is selected from the group comprising hydrogen, halogen, hydroxy, C1-C4 alkyl, methylene and oxo, or R7 designates, together with R8, an additional bond between the carbon atoms at which R7 and R8 are placed; R20 is selected from the group comprising C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl; R21 is selected from the group comprising C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom at which they are placed, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons; and R8 is selected from the group comprising hydrogen, hydroxy, C1-C4 alkyl, cyano and oxo; and R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; with the general proviso that at least one of R1, R2, R6, R8, R9, R10, R12, R13, R14, R18, R19, R29, R30 and R31 is hydroxy or R25 is hydroxymethyl, and with the further general proviso that R9, R10 and R11 are not all hydroxy and with the further general proviso that it is not, for use in the regulation of meiosis.
In a further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof as a medicament, in particular as a medicament for use in the regulation of meiosis. The compound may be used neat or in the form of a liquid or solid composition containing auxiliary ingredients conventionally used in the art.
In the present context, the expression xe2x80x9cregulating the meiosisxe2x80x9d is used to indicate that certain of the compounds of the invention can be used for stimulating the meiosis in vitro, in vivo, or ex vivo. Thus, the compounds which may be agonists of a naturally occurring meiosis activating substance, can be used in the treatment of infertility which is due to insufficient stimulation of meiosis in females and in males. Other compounds of the invention, which may be antagonists of a naturally occurring meiosis activating substance, can be used for regulating the meiosis, preferably in vivo, in a way which makes them suited as contraceptives. In this case the xe2x80x9cregulationxe2x80x9d means partial or total inhibition.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the regulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the stimulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the inhibition of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the regulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the stimulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a still further preferred aspect, the present invention relates to the use of a compound of formula Ic above or an ester thereof in the inhibition of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In a yet still further preferred aspect, the present invention relates to a meth od of regulating the meiosis in a mammalian germ cell which method comprises administering an effective amount of a compound of formula Ic above or an ester thereof to a germ cell in need of such a treatment.
In a still further aspect, the present invention relates to a me thod of regulating the meiosis in a mammalian germ cell wherein a compound of formula Ic above or an ester thereof is administered to the germ cell by administering the compound to a mammal hosting said cell.
In a still further aspect, the present invention relates to a method wherein the germ cell the meiosis of which is to be regulated by means of a compound of formula Ic above or an ester thereof is an oocyte.
In a still further aspect, the present invention relates to a method of regulating the meiosis in an oocyte wherein a compound of formula Ic above or an ester thereof is administered to the oocyte ex vivo.
In a still further aspect, the present invention relates to a method of regulating the meiosis of a male germ cell by administering a compound of formula Ic above or an ester thereof to the cell.
In a still further aspect, the present invention relates to a method whereby mature male germ cells are produced by administering in vivo or in vitro a compound of formula Ic above or an ester thereof to testicular tissue containing immature cells.

Abstract: wherein the substituents are as defined in the specification.


A method and a terminal for acquiring a transmission resource in vehicle to everything are provided. In the implementations of the present disclosure, available resources in a current resource pool are sensed, and if the terminal needs to send data before a sensing result is acquired, whether the current resource pool permits random selection of a transmission resource is determined, if the current resource pool permits the random selection of a transmission resources, a transmission resource is randomly selected from the current resource pool.

A Vehicle to Everything (V2X) system adopts a direct communication mode of terminal-to-terminal, which has higher spectral efficiency and lower transmission delay. In the V2X system, two types of terminals are usually involved, one is Vehicle User Equipment (VUE) and the other is Pedestrian User Equipment (PUE).
Generally, due to factors such as a power supply mode of the equipment, processing capability of the VUE is higher than that of the PUE. The VUE has full sensing capability, while the PUE has partial sensing capability or no sensing capability. In a process of data transmission, the VUE and the PUE with partial sensing capability can sense available resources in a current resource pool, and randomly select a transmission resource from the available resources for data transmission.
However, the sensing requires certain processing time, for example, 1 s, etc. When the sensing is not finished, the terminal cannot acquire a sensing result. At this time, if the terminal needs to send data, the terminal may randomly select a transmission resource from a pre-configured exceptional resource pool to send the data. In this mode, the exceptional resource pool needs to be additionally configured, which increases spectrum fragments, and reduces the overall amount of available resources.

Method and terminal for acquiring transmission resource in vehicle to everything

GUANGDONG OPPO MOBILE TELECOMMUNICATIONS CORP., LTD.


A pipe coupling, comprising a sleeve having at least one end adapted for the insertion of a pipe and being provided with a substantially conically shaped supporting surface for a sealing ring. A compression ring is provided by which the sealing ring may be compressed around the pipe. The sealing ring is composed of a circumferentially compressible, but in cross section rather undeformable annular core, which is more particularly bent of a helical body having substantially circular windings, and a sheath of elastomeric material which forms the actual seal. The sheath completely encloses the annular core both cross sectionally and circumferentially. The supporting surface has a progressively decreasing diameter in the pressing direction.

Such a pipe coupling is known from FR-A-2.072.296 (corresponding to U.S. Pat. No. 3,712,647), showing a sealing ring having a sealing sheath which encloses the helical core annulus both in circumferential and cross section direction. More particularly, it shows a construction with which the sealing sheath does not completely enclose the core annulus, so that a circular slit is formed on one axial end of the ring.
It has now been found that the construction in which the core annulus is completely enclosed by the sealing sheath also in the cross section plane, is particularly suitable for use in conjunction with a sleeve, which is designed to accomodate and interconnect pipes of various diameters. This construction is more particularly suitable for bridging the differences in outer diameter occurring with pipes of the same nominal diameter (i.e: inner diameter) but formed of different material. It is considered that with a sealing ring having such a sealing sheath, in contrast to an embodiment having a slit on on axial end of the ring, it is easier to tangentially compress the ring in a uniform manner.
Based on this insight, it is the aim of the present invention to provide an improved sleeve portion so as to take maximum advantage of the wide limits of use of the selected sealing ring, while keeping the cross sectional diameter of the sealing ring relatively small (which means a relatively thin sealing ring).


A detector detects information about a firmware system. The detector includes an interface that receives a generic instruction. The generic instruction may be a function call made through an EFI shell. The detector has a controller communicatively connected to the interface. The controller receives the generic instruction and gathers information about the firmware system. Gathering information about the firmware system permits platform-specific firmware system functions to be written to the firmware system. The controller gathers information about the firmware system by accessing a data-gathering function based on the generic instruction. The controller retrieves the information through the data-gathering function and transfers the information to the interface.

Microprocessors can operate to control a myriad of hardware devices; an example of one such hardware device is an input/output (I/O) controller. For a microprocessor to properly control a hardware device, the microprocessor is directed by a series of instructions known as software. Software instructions exist on a variety of levels relative to the microprocessor. Software instructions that exist to directly control the microprocessor at a very basic level are typically known as firmware. When operational, the firmware and the microprocessor behave as a firmware system.
A basic input/output system (BIOS) developed by Phoenix Technologies Ltd. is an example of firmware. Typically, the BIOS operatively controls microprocessors having an "x86" architecture. Microprocessors having an "x86" architecture are similar to many microprocessors from Intel Corporation and Advanced Micro Devices, Incorporated (AMD). The BIOS is typically stored in a read only memory (ROM) and directs a microprocessor to test hardware devices when started. The BIOS also loads and starts an operating system, such as DOS or Windows, both produced by Microsoft Corporation. The BIOS also supports data transfers among hardware devices. The BIOS is fairly transparent to a user of the operating system.
Until recently, a BIOS would serve to load and start an operating system of a computer. However, advancements in software engineering have led to the development of a firmware interface known as an Extensible Firmware Interface (EFI), developed by Intel Corporation. The EFI includes a layer of software that resides between a firmware system and the operating system. The EFI offers a higher-level set of software controllers, known as drivers, as components to the firmware system. The controllers direct functions of the firmware system and in turn direct various hardware devices through a higher-level programming language, such as the "C" programming language. A benefit to the EFI includes decoupling the operating system from the firmware system, which makes the operating system substantially independent of the firmware system. Moreover, an interface between the firmware system and the operating system is easier to maintain since the EFI is typically written in the higher level programming language than the firmware, which may be written in an assembly programming language.
An EFI includes an application programming interface (API) having a command line interface known as a shell. The EFI may include a collection of boot services, runtime services, loaded drivers, and loaded protocols. The EFI shell is similar to other command line interfaces. An example of another command line interface is a DOS shell developed by Microsoft Corporation. While the DOS shell allows a user to access functions of the operating system, the EFI shell allows a user to access functions of a single firmware system. Accessing functions of the firmware system is performed through information gathering functions that obtain information relative to the firmware system. Since the EFI shell interacts with a single firmware system, the information gathering functions of the EFI shell serve to gain access to that particular firmware system. An illustration of the EFI can be seen in FIG. 1.
FIG. 1 shows a prior art software architecture including an EFI 102 for computing system 100. EFI 102 is communicatively connected to operating system 104. EFI 102 is also communicatively connected to firmware system 112. Firmware system 112 includes firmware instruction set 114 that is typically stored in a read only memory device. Firmware system 112 also includes hardware 116, which typically includes a microprocessor that accesses the read only memory device to process firmware instruction set 114.
EFI 102 includes EFI operating system loader 106, which serves to load and start operating system 104. EFI 102 also includes a variety of service functions in EFI boot service 108; the service functions include runtime services 105, boot devices 107, EFI drivers 109, and protocol handlers 111. These service functions, 105, 107, 109, and 111, start, commonly referred to as "booting" and "handshaking", associated hardware devices when computer system 100 is initialized. EFI 102 also includes EFI shell 110, which allows a user to interact with firmware system 112 through the variety of functions stored in EFI boot service 108.
Firmware developers often develop and implement software tools through EFI shell 110. These software tools are occasionally necessary to direct the microprocessor to perform a new desired function. However, present information gathering functions of the EFI shell are developed for a single firmware system, such as firmware system 112. The information gathering functions are incapable of interacting with other firmware systems.
Many manufacturers of computer systems purchase microprocessors and develop firmware to suit their particular needs. Some manufactures even develop multiple firmware systems for different products. EFI 102 and EFI shell 110 are not portable to multiple firmware platforms. Accordingly, the prior art requires matching between the particular firmware system 112 and EFI 102, which complicates the design of information gathering functions.
The invention provides certain features to advance the state of the art by providing, among other features, a detector for detecting information about a firmware system. Other features will be apparent in the description that follows.

Detector and operational method for a firmware interface

Hewlett-Packard Development Company, L.P.


A method and apparatus for injection molding an article including a radially extending child resistant feature. Finish block halves are provided that include a pocket and that are closable together to form a neck-finish mold cavity. Mold body halves are provided that include a core portion and that are closable together to form a body mold cavity. The core portion is advanceable toward the pocket to cooperate therewith to define a cavity for forming the child resistant feature. The core portion may be integrally formed into one or more of the mold body halves, or may be separately mounted and relatively movable with respect thereto.

Child resistant features are widely sought for medicine containers, poison containers, and yet undiscovered applications. One type of child resistant feature is particularly popular for rigid bottles that are injection molded, as typified by U.S. Pat. No. 6,039,195 to Konefal et al. Konefal et al. disclose a container having an open upper end and external threads formed on a neck finish proximate the open upper end. Just below the threads, a deflectable release element is integrally formed on the container. The release element extends radially outwardly from the neck finish and defines an open space between the release element and the neck finish. The release element ordinarily engages lugs formed in a closure member of the container to resist removal of the closure member by a child, unless the release element is pressed radially inwardly and/or axially downwardly. The release element is easily manufactured using a regular injection molding process.
However, many types of useful articles are produced by single stage or multi-stage injection blow molding (IBM) process. Such articles could benefit from incorporation of the above-described child resistant features. IBM processes typically involve thermoplastic materials, such as high density polyethylene, polypropylene, polyethylene terephthalate, and the like. IBM apparatuses for molding such articles typically include a mold assembly having a core pin that inserts within a pair of mold halves that are split longitudinally, and that open and close together in a direction that is transverse with respect to a longitudinal axis of the core pin. Accordingly, the core pin and closed mold halves cooperate to define a mold cavity that corresponds in size and shape to the desired size and shape of the article being molded. A suitable thermoplastic resin is injected into the mold assembly through a gate at one end of the closed assembly to fill the mold cavity and thereby form the article.
Unfortunately, however, the release element of the above-described child resistant container is difficult to manufacture using current injection blow molding processes and apparatuses, because the release element can be damaged when the mold halves retract away from each other. In other words, the non-symmetrical and relatively complex geometry between the release element and the container renders it impossible to quickly extract the container from the molds without some type of damage to the release element.

Method of injection molding a preform including a radially extending element

Owens-Illinois Prescription Products Inc.


A vehicular fuel system with onboard fuel characterization including an onboard combustion modifier source capable of supplying a combustion modifier agent, such as hydrogen, and a fuel tank capable of storing a fuel. An injector-igniter is operative to direct inject the fuel and a proportionate amount of the modifier agent into a cylinder of an internal combustion engine. An engine control unit is operatively connectable to the combustion modifier source and the injector. The system may further comprise a mixing valve operative to proportionately mix the fuel and modifier agent. The combustion modifier source may be a tank containing hydrogen or a thermo-chemical reactor, for example.

Long standing and difficult problems with alternative fuels such as natural gas and various landfill fuels and mixtures that may be derived from anaerobic processes such as thermal dissociation, endothermic reformation, and/or digestion of sewage, garbage, farm wastes, and forest slash include: chemical and physical property variability, fuel heating value variability, condensates such as water including acid, and other contaminates.
Modern engines and fuel systems are designed to operate with specific fuel characteristics. The variability in the above described, less than optimum sources of fuel have compromised or defeated various past attempts to provide satisfactory power, operational control, drivability, fuel economy, and emissions in instances that alternative fuels have been substituted for gasoline or diesel fuel in internal combustion engines. Even in instances in which elaborate compensations are made to overcome these problems for a specific fuel, when the properties of that fuel vary or if it is desired to switch to another fuel, the fuel system is generally unable to compensate for such large changes in fuel properties.
Accordingly, there is a need for fuel systems and methods for operating internal combustion engines on various, less than optimal fuels while maintaining satisfactory power, operational control, drivability, fuel economy, and emissions standards.

Injector-igniter with fuel characterization


A display device including a first substrate. The first substrate including an active region and a dummy region formed in an outer edge of the active region, the active region including a plurality of pixel regions and being configured to implement an actual image, the dummy region including a gate in panel (GIP) circuit, control signal lines, a ground, and common lines. The GIP circuit is overlapped by at least a part of the control signal lines, the ground, and the common lines with an insulating layer interposed therebetween. The display device further includes a thin film transistor (TFT) for a shift register is provided in each of a plurality of stages of the GIP circuit; and a source contact hole and a gate contact hole of each TFT for the shift registers, the source contact hole and the gate contact hole being formed along a corresponding control signal line.

1. Field of the Invention
The present invention relates to a display device, and particularly, to a display device in which a bezel is minimized by overlapping circuit lines in an outer edge region with an insulating layer interposed therebetween and directly connecting thin film transistors (TFTs) with the circuit lines.
2. Discussion of Background Art
Liquid crystal displays (LCDs) in related art can display an image by adjusting light transmittance of a liquid crystal having dielectric anisotropy using an electric field. An LCD device can include a liquid crystal panel in which pixel regions are arranged in a matrix form and a driving circuit for driving the liquid crystal panel.
The liquid crystal panel includes first and second substrates attached to each other and a liquid crystal layer formed therebetween. A plurality of gate lines and a plurality of data lines can be arranged to cross each other perpendicularly to define pixel regions. A pixel electrode is formed in each pixel region, and a thin film transistor (TFT) is formed at each crossing of a gate line and a data line. A TFT is turned on according to a scan signal of a gate line to apply a data signal of a data line to each pixel electrode to drive the liquid crystal layer.
A black matrix blocking light transmission in a region other than the pixel region and a color filter layer formed in each pixel region to implement an actual color are disposed on the second substrate.
The driving circuit can include a gate driver that drivers the plurality of gate lines, a data driver that drives the plurality of data lines, a timing controller that supplies a control signal for controlling the gate driver and the data driver, a data signal, and the like. The gate driver includes a shift register to sequentially output scan pulses respectively to gate lines.
The shift register includes a plurality of stages dependently connected to each other. The plurality of stages sequentially output the scan pulses to sequentially scan the gate lines of the liquid crystal panel. Among the plurality of stages, a first stage receives a start signal, as a trigger signal, from the timing controller, and the other stages, excluding the first stage, receive an output signal, as a trigger signal, from the first stage (a stage in front of them). Each of the plurality of stages receives at least one clock pulse among a plurality of clock pulses each having a sequential phase difference. Accordingly, scan pulses are sequentially output from the first stage to the final stage.
The gate driver can include a gate driver integrated circuit (IC) in which the shift register is installed. The gate driver IC can be provided and connected to a gate line pad of the liquid crystal panel using a TCP process, for example. The data driver can use a data driver IC and a gate driver can form, via a gate-in-panel (GIP) technique, a shift register on an LCD device to reduce material cost, the number of processes, and a process time.
FIG. 1 is a plan view of a related art LCD device having a GIP structure. The LCD device can have a GIP structure, a first substrate 1, and a second substrate 2. The first substrate 1 and the second substrate 2 are attached together using a sealant 10 with a predetermined space maintained therebetween. Here, the first substrate 1 is formed to be larger than the second substrate 2 to form a non-display region in which a data driver, for example, can be mounted. A display region is formed at an inner side based on the sealant 10, with which the first substrate 1 and the second substrate 2 are attached.
The display region of the attached first and second substrates 1 and 2 is divided into an active region A/A and a dummy region D. A gate line, a data line, a pixel electrode, and a TFT are formed in the active region A/A of the first substrate 1. A black matrix layer and a color filter layer are formed in the active region A/A of the second substrate 2.
The dummy region D of the first substrate 1 can include a GIP gate driver 3, a GIP dummy gate driver 4, a ground 11, control signal lines 12, a GIP circuit 13 configured as a shift register, and a common line 14. The gate driver 3, the GIP dummy gate driver 4, a ground 11, and the control signal lines 12 are for applying various signals such as a clock signal, an enable signal, a start signal, or a common voltage, for example, which are output from a timing controller to the GIP gate driver 3 and the GIP dummy gate driver 4. A black matrix formed to block light transmission to the dummy region D can be formed in the dummy region D of the second substrate 2.
A size of a bezel in related art including a dummy region can be minimized to reduce a size of a display device and obtain a fine appearance, while maintaining a screen with the same size.
FIG. 2 is an enlarged plan view of a region 'A' in FIG. 1. The LCD device having a GIP structure includes the ground 11, the control signal lines 12, the shift GIP circuit 13, and the common line 15 disposed in the dummy region D. The dummy region D needs to have a predetermined width d1 or greater. Thus, a limitation in reducing the area of the dummy region D results in a limitation in reducing the bezel area, making it impossible to manufacture an LCD device having a very small (narrow) bezel area.
A TFT 23 is formed in the shift GIP circuit 13 and a control signal from the control signal lines 12 is input to the TFT 23. The TFT 23 is connected to the signal lines 12 through a metal line 24. Here, to connect the plurality of control signal lines 12 by the metal line 24, the TFT 23 is electrically insulated from the crossing control signal lines 12 by an insulating layer formed on the control signal lines 12. The metal line 24 is formed on the insulating layer, and a contact hole is subsequently formed on a source electrode of the TFT 23 to electrically connect the control signal lines 12 and the TFT 23.
Thus, the related art LCD device having a GIP structure has a complicated structure and processes, increasing manufacturing costs and a probability of generating a defect due to the complicated structure.

Disply device for minimizing thickness of bezel area


In a papermaking machine for forming tissue paper, a turning bar is disposed having a curved surface about which a web of tissue paper is turned. The bar has an internal air plenum which supplies air to two sets of holes or slots. The first set is arranged to direct air normal to the curved surface of the bar or in the machine direction, the second set is arranged to direct air toward the edges of the tissue which is turned around the bar. The second holes or slots produce air jets which apply a cross machine direction tension to the web which prevents wrinkling of the web. The first set of holes or slots forms jets of air that prevent the tissue web from contacting the turning bar.

1. Field of the Invention
The present invention relates to devices for handling paper webs which support a web on a cushion of air in general, and to devices for supporting tissue paper webs in particular.
2. Description of the Prior Art
Lightweight webs of paper with high absorbency are created by pressing or thru-air drying the wet web and placing it onto a large diameter dryer roll and scraping the dried web off the roll with a doctor blade. The scraping of the dryer roll results in creping of the web. Creping shortens the machine direction length of the web while at the same time making the web thicker and also breaks some of the fiber bonds within the paper. These changes in the web make it better able to absorb water. Creped paper webs are fabricated into products such as facial tissues, paper napkins, paper towel, and toilet paper.
The creping action of the doctor blade results in a web which is easily stretched in the machine direction and to a lesser extent in the cross machine direction. However, stretching of the tissue web is undesirable because it reduces the absorbency of the web. For this reason it is important to avoid excessive pulling or tensioning of the web such as can result when the web is turned or directed around one or more rollers, foils or turning bars. One solution is to utilize turning bars or foils with air jets which support the web on a cushion of air. This type of air support is often used with coated paper when handling the paper before the coating has dried completely.
Tissue paper, because of its ability to stretch, can easily become wrinkled as the unconstrained paper moves over these supports, leading to wrinkles in the finished product. Wrinkles lower the product's functionality by reducing absorbency and detracting from the appearance of the products formed from tissue paper.
U.S. Pat. No. 4,342,313 to Reba discloses a turning bar where more air is supplied to the center of the web by varying the width of a slit along the length of the turning bar to establish a desired air flow profile. Reba suggests that by making the slit wider in the center than at the edges, more air cushioning in the middle of the web is obtained which creates cross machine direction spreading and improved guiding of the web.
Long et al. U.S. Pat. No. 5,209,387 describes an apparatus for conveying photographic film where the web of film is controlled with reasonable precision by adjusting the gas pressure or changing the size or angle of the gas apertures.
What is needed is a simple turning bar about which a web of tissue paper can be turned without wrinkling or significant stretching.


A method of reducing reflected Radio Frequency (RF) power in substrate processing chambers may include accessing input parameters for a processing chamber that are derived from a recipe to perform a process on a substrate. The input parameters may be provided to a model that has been trained using previous input parameters and corresponding sensor measurements for the chamber. A predicted amount of reflected RF power may be received from the model and it may be determined whether the predicted reflected RF power is optimized. The input parameters may be repeatedly adjusted and processed by the model until input parameter values are found that optimize the reflected RF power. Optimized input parameters may then be provided to the chamber to process the substrate.

In the manufacture of integrated circuits and other electronic devices, plasma processes are often used for deposition or etching of various material layers. Plasma-enhanced chemical vapor deposition (PECVD) process is a chemical process wherein electro-magnetic energy is applied to at least one precursor gas or precursor vapor to transform the precursor into a reactive plasma. Plasma may be generated inside the processing chamber, i.e., in-situ, or in a remote plasma generator that is remotely positioned from the processing chamber. This process is widely used to deposit materials on substrates to produce high-quality and high-performance semiconductor devices.
Plasmas used in the processing chamber may be ignited by providing radio frequency (RF) energy to the chamber from an RF source. The voltages/currents provided by the RF source may be tightly controlled such that energy can be provided uniformly to the plasma. However, variations in the conditions of the processing chamber and/or equipment between substrate processes may cause variations in how quickly a plasma can be ignited. Input parameters for the control system and the RF source may quickly ignite a plasma in one session, then cause a delay in plasma ignition during a subsequent session using identical parameters. When the plasma fails to ignite quickly, RF energy may be reflected back into the RF source. This can damage the RF source, cause defects in the substrate, and increase the difficulty of igniting the plasma.
Therefore, there is a need for improved systems and methods that can be used to optimize the input parameters that are part of a recipe for processing chambers to minimize the amount of RF power reflected back into the RF source. These and other technical problems are solved by the embodiments disclosed herein.

Plasma ignition optimization in semiconductor processing chambers


A user interface and methods for providing a user interface comprising graphical representations of data, metrics, and other information specific to a particular user. The data, metrics, and other information may be derived from publically available information, private information, or both.

Healthcare providers are constantly looking for ways to improve their clinical, operational, and financial performance. A critical tool in doing so is the ability to efficiently analyze volumes of comprehensive data for each of the foregoing aspects of the healthcare provider's business.
The methods and systems of the present disclosure provide an online, customizable application and interface that allows users to analyze various metrics, optionally including: clinical; operational; financial; and satisfaction metrics. The interface of the present disclosure includes multiple interactive graphical representations, with each representation corresponding to a particular set of data or information.
Corresponding reference characters indicate corresponding parts throughout the several drawings.


A communication apparatus that is connected to an information processing apparatus is provided. The communication apparatus includes: an information processing apparatus discovery unit configured to discover the information processing apparatus; a secure communication packet conversion unit configured to convert a non-secure communication packet transmitted by the discovered information processing apparatus into a secure communication packet; and a non-secure communication packet conversion unit configured to convert the secure communication packet destined for the information processing apparatus into the non-secure communication packet.

1. Field of the Invention
The present invention relates to a communication apparatus for providing IPSec communication and the like to an information processing apparatus such as an image forming apparatus.
2. Description of the Related Art
Currently, a technology called IPSec (Security Architecture for Internet Protocol) exists. This protocol is used for securing IP (Internet Protocol) that is used in the Internet and the like. This protocol has functions for encrypting communications of IP and for authenticating communications and the like.
For performing the IPSec communication, since computational processing for encryption is performed, large amount of CPU resources are consumed. Therefore, when using the IPSec, high speed communication is not expected unless the CPU is upgraded.
Therefore, for realizing the IPSec in an apparatus using a small CPU, it has been considered to use a hardware accelerator from the past.
The hardware accelerator is largely classified into two types. One is a coprocessor type. The accelerator of the coprocessor type is implemented in the apparatus that performs the IPSec communication. The coprocessor is embedded, separately from the CPU, as a circuit for performing IPSec processing. When performing the IPSec communication, processing for encryption is not performed in the CPU, but is performed by the coprocessor that is an IPSec processing specific circuit. Since the processing is not performed in the general CPU, but performed in the specific hardware, high speed processing can be performed.
Another type of hardware accelerator is one that is inserted between an apparatus that performs IPSec communication and a communication route.
In this type, the apparatus that needs IPSec communication performs IP communication as usual, and packets that are output from the apparatus pass through the hardware accelerator so that the packets are transmitted to the external network. In addition, packets flow into the apparatus from the network after passing through the hardware accelerator.
The hardware accelerator converts the IPSec packet into a normal IP packet, and converts the IP packet to be transmitted to the external network into the IPSec packet.
Since the bridge type IPSec accelerator basically realizes the IPSec communication by itself, high speed processing is possible and the IPSec accelerator does not affect the apparatus. By the way, following documents relate to the prior art.
[Patent document 1] Japanese Laid-Open Patent Application NO. 2002-317148.
[Patent document 2] Japanese Laid-Open Patent Application NO. 2003-78813.
[Patent document 3] Japanese Laid-Open Patent Application NO. 2004-86590.
[Patent document 4] Japanese Laid-Open Patent Application NO. 2002-251071.
However, for using the bridge type accelerator, settings for the apparatus to be connected should be made manually, and there is a case where settings may be necessary for the apparatus to be connected. Thus, there is a problem in that time and effort are necessary in using the accelerator.

Communication apparatus, communication method, communication program and recording medium


A lancing unit (U1) includes a lancing member (2), an auxiliary part (3) which is separate from the lancing member (2), and a supporter (1) detachably supporting these. Preferably, the lancing unit (U1) further includes a cap (29) which covers a needle (21) of the lancing member (2) and which is detachable from the lancing member (2), and the lancing member (2) is supported by the supporter (1) via the cap (29).

For diabetes treatment, management of the blood glucose level by a patient himself or herself is important for maintaining the blood glucose level in a normal range. Particularly, for a patient of insulin-dependent diabetes, regular measurement of the blood glucose level is essential to maintain the blood glucose level in a normal range. However, it is troublesome to often go to a medical institution for measuring the blood glucose level. Conventionally, therefore, apparatuses which enable the extraction and analysis of blood without going to a medical institution have been proposed. For example, JP-A 2001-74731 discloses a lancing unit and a lancing apparatus as shown in FIGS. 26A and 26B.
The lancing unit 9 shown in FIG. 26A includes a lancet 90 as a lancing member, and a first housing 91A accommodating part of the lancet. The first housing 91A is fixedly fitted to a second housing 91B. As shown in FIG. 26B, the second housing 91B is provided with a test strip 92 and a blood introduction portion 95. The first housing 91A has an opening 91a which is closed by a cover 93 so that a sterilized needle 90a of the lancet 90 can be kept hygienically clean. The first and the second housings 91A and 91B are wrapped by a wrapping member 94 in the form of a bag or case.
The lancing unit 9 having the above-described structure is assembled by setting the needle 90a of the lancet 90 into the first housing 91A after the needle 90a is sterilized and then fixing the first housing 91A to the second housing 91B. With such an assembling method, the sterilization of the lancet 90 can be performed independently without adversely affecting the test piece 92. For example, unlike the above, when the sterilization of the lancet 90 is performed after the lancing unit 9 is completely assembled, a constituent of the test piece 92 may be unduly changed due to the sterilization process. With the above assembling method, however, such a problem can be avoided.
As shown in FIG. 26B, the lancing apparatus 8 includes a housing case 80. The first and the second housings 91A and 91B can be mounted to the apparatus when they are pushed to a front end 80a of the housing case 80. Therefore, the lancet 90 and the test piece 92 can be mounted simultaneously. When the lancet 90 pushes a lancet holder 81 to the right in the figure, a spring 82 is compressed to bring the lancing apparatus 8 into a locked state. Thereafter, when an operation switch 83 is operated with the lancing apparatus 8 pressed against the skin of a human body, the lancet holder 81 and the lancet 90 advance to the left in the figure due to the resilient force of the spring 82, whereby the needle 90a of the lancet 90 lances the skin of the human body. The blood bleeding from the skin as a result of the lancing is introduced to the test sheet 92 through the blood introducing portion 95. The blood can be analyzed by optically detecting the color reaction of the test piece 92.
However, the above-described prior art arrangement has the following problems.
First, in the prior art arrangement, to mount the lancet 90 and the test piece 92 to the lancing apparatus 8, both of the first and the second housings 91A and 91B of the lancing unit 9 need be mounted to the lancing apparatus 8. Therefore, the front end of the lancing apparatus 8 needs to be made relatively large. As a result, the size of the lancing apparatus 8 increases, which is inconvenient for carrying.
Secondly, from a hygienic point of view, the needle 90a of the lancet 90 need be hermetically sealed in the first housing 91A of the lancing unit 9. For this purpose, the portion where the first housing 91A and the lancet 90 are fitted together need be hermetically sealed. On the other hand, after the first housing 91A along with the lancet 90 is mounted to the lancing apparatus 8 and the lancet holder 81 is advanced, the lancet 90 needs to move smoothly relative to the first housing 91A in accordance with the movement of the lancet holder. However, to hold the lancet 90 in the first housing 91A in such a manner as to satisfy the above two requirements is not easy. Thus, the needle 90a of the lancet 90 sometimes is not hermetically sealed, or the lancet 90 after it is mounted to the lancing apparatus 8 sometimes does not move smoothly.
Thirdly, in the lancing apparatus 8, it is desirable that the blood introduction portion 95 is located as close to the lancing position as possible. This is because, as the blood introduction portion 95 is farther from the lancing position, the blood is less likely to come into contact with the blood introduction portion 95 properly. Even when the blood comes into contact with the blood introduction portion 95, the amount of blood reaching the test piece 92 is small, whereby accurate analysis result may not be obtained. Since the first case 91A is fixed to the housing 80 while the lancet 90 moves reciprocally along a predetermined path, the distance s between the path and the blood introduction portion 95 is always constant. In the prior art arrangement, therefore, to locate the blood introduction portion 95 close to the lancing position, the blood introduction portion 95 need be provided close to the needle 90a of the lancet 90 in the state of the lancing unit 9 shown in FIG. 26A (though this figure does not show the blood introduction portion). However, in actually designing and manufacturing the lancing unit 9, various points need be taken into consideration such as reduction in size of the entire unit and the airtightness of the first case 91A, so that it is sometimes difficult to locate the blood introduction portion 95 sufficiently close to the needle 90a of the lancet 90. Therefore, in the prior art arrangement, it is difficult to locate the blood introduction portion 95 sufficiently close to the lancing position, so that the amount of blood introduced to the test piece 92 is sometimes insufficient.
Fourthly, since the lancing unit 9 requires the cover 93 in addition to the first and the second housings 91A and 91B, the number of parts of the lancing unit 9 is large, whereby the manufacturing cost is relatively high.