The present invention provides a compound consisting of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having low activity following oral administration or its parent scaffold and said group has the following general formula (1):

The present invention relates to hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds having anti-estrogenic activity.
In treating diseases caused by abnormal tissue growth that is dependent upon a certain sexual steroidal hormone such as estrogen, it is highly important to significantly inhibit, more preferably completely eliminate, the effect induced by the hormone. For this purpose, it is desirable to reduce the level of hormone capable of acting on the steroidal hormone receptor site. For instance, anti-estrogenic agents are commonly administered for alternative or combination therapy to limit the production of estrogen to the amount less than required to activate the receptor site. However, such conventional technique for blocking estrogen production could not sufficiently inhibit the effect induced through the estrogen receptor. Practically, even when estrogen is completely absent, some of the receptors may be activated. It was therefore considered that estrogen antagonists could provide better therapeutic effect in comparison to the technique for blocking only the production of sexual steroidal hormone. Thus, numerous estrogen antagonists have been developed. For example, many patent publications including U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 and WO 96/22092 disclose various anti-estrogenic compounds. Sometimes, however, prior art antagonists may themselves act as agonists, and therefore activate rather than block the receptor. For example, Tamoxifen has been most widely used as an anti-estrogenic agent. However, this agent has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertile., 1967, 13, 101).
As another non-steroidal anti-estrogenic compound, WO 93/10741 discloses a benzopyran derivative having an aminoethoxyphenyl substituent(s) (Endorecherche), the typical compound of which is EM-343 having the following structure:
Said compound also has the agonistic effect. It is therefore required to develop an anti-estrogenic compound which is substantially or completely free of agonistic effect and which can effectively block the estrogen receptor.
In addition, it has been known that 7xcex1-substituted derivatives of estradiol, for example, 7xcex1-(CH2)10CONMeBu derivatives, are steroidal anti-estrogenic agents without agonistic effect (see, EP-A 0138504, U.S. Pat. No. 4,659,516). Further, an estradiol derivative having a 7xcex1-(CH2)9SOC5H6F5 substituent has also been disclosed as a 7xcex1-substituted derivative of estradiol (see, Wakeling et al., Cancer Res., 1991, 51, 3867).
Non-steroidal anti-estrogenic agents without agonistic effect have been first reported by Wakeling et al. in 1987 (see, A. Wakeling and Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661 discloses phenol derivatives having anti-estrogenic activity. These phenol derivatives generally have a naphthalene scaffold and include, typically, the following compounds:
Some chroman and thiochroman derivatives have been reported as anti-estrogenic compounds having no agonistic effect (WO 98/25916). Although the existing anti-estrogenic compounds having no agonistic effect show a substantial therapeutic effect when administered via intravenous or subcutaneous injection, they show a highly reduced therapeutic effect when administered orally, due to their low bioavailability by oral route. Therefore, for convenience""s sake in the case of administration, it is desired to develop anti-estrogenic compounds which show a sufficient effect when administered orally and at the same time have no agonistic effect. Also, it is generally desired to develop agents which show a sufficient effect when administered orally.
The object of the present invention is to provide hydroxycarbonyl-halogenoalkyl derivatives designed to significantly increase oral activity of compounds having low activity following oral administration, compounds having anti-tumor activity, compounds having estrogenic activity or compounds having anti-estrogenic activity by enhancing their absorption from the intestinal tract and/or improving their stability against metabolism.
Our research efforts were directed to achieving the above object, and we have found that a side chain of general formula (1) allowed estrogenic compounds to show a significantly increased activity by oral route when attached to the parent scaffolds of the compounds. The present invention has been accomplished on the basis of this finding.
Namely, the present invention provides a compound consisting-of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having low activity following oral administration or its parent scaffold and said group has the following general formula (1):
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof.
The present invention also provides a compound consisting of a moiety and a group chemically bonded to said moiety, wherein said moiety contains a compound having anti-tumor activity or its parent scaffold and said group has the following general formula (1):
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the first-mentioned compound or enantiomers thereof.
The present invention further provides a compound consisting of a moiety and a group chemically bonded to a moiety, wherein said moiety contains a compound having estrogenic activity or its parent scaffold or a compound having anti-estrogenic activity or its parent scaffold and said group has the following general formula (1):
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14, and
n represents an integer of 2 to 7,
or enantiomers of the first-mentioned compound, or hydrates or pharmaceutically acceptable salts of the first-mentioned compound or enantiomers.
The present invention even further provides a compound having the following general formula (2):
in which
R1 represents a hydrogen atom or a salt-forming metal,
R2 represents a linear or branched C1-C7 halogenoalkyl group,
m represents an integer of 2 to 14,
n represents an integer of 2 to 7, and
A represents a group selected from the following formulae (3) to (8) and (10) to (26):
in which
in formulae (6), (7), (14) and (24), each of R3 and R6 represents a linear or branched C1-C5 alkyl group,
in formulae (10), (11) and (12), Z10 represents a hydrogen atom or an acyl group,
in formulae (13), (21) and (22), each of Z1, Z2, Z3, Z4, Z5 and Z6 independently represents a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkyl group,
in formula (15), R7 represents a hydrogen atom or a linear or branched C1-C5 alkyl group,
in formula (16), each of Z7, Z8, and Z9 independently represents a hydrogen atom or a hydroxyl group,
in formulae (18) and (20), R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group,
in formula (23), each of R21, R22, R23 and R24 independently represents a hydrogen atom, a linear or branched C1-C5 alkyl group, a linear or branched C1-C7 halogenoalkyl group, a halogen atom or an acyl group, and
in formulae (25) and (26), X represents a halogen atom,
or enantiomers of the compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof.
Furthermore, the present invention provides a pharmaceutical composition comprising a compound of general formula (2) as an active ingredient. The present invention also provides an anti-estrogenic pharmaceutical composition comprising the above compound as an active ingredient. The present invention further provides a therapeutic agent for breast cancer comprising a compound of general formula (2) as an active ingredient.
As used herein, the term xe2x80x9cparent scaffold(s)xe2x80x9d refers to a partial structure shared by a class of compounds having the same or similar pharmacological effects or physicochemical properties. The parent scaffolds include, but are not limited to, the following structures: steroid, indole, naphthalene, benzofuran, benzothiophene, benzopyran, benzoxazine, 3,4-diphenyl-[4.3.0]-nonane, 4-(1,2-diphenyl-1-butenyl)phenol, flavone, erythromycin, alkaloid, cephalosporin, xcex2-lactam, and derivatives thereof.
Compounds having low activity following oral administration refer to those compound which are incapable of showing adequate activity for a desired pharmacological effect when administered orally because they are poorly absorbed from the intestinal tract or rapidly metabolized in the body. Examples include certain types of anti-tumor compounds, certain types of estrogenic compounds (e.g., estradiol) and anti-estrogenic compounds.
Compounds having anti-tumor activity include all types of compounds capable of inhibiting tumor growth. The present invention is particularly advantageous to those compounds showing low activity by oral route.
Compounds having estrogenic activity refer to those compounds which have affinity for the estrogen receptor and enhance the signaling mediated by the estrogen receptor. Examples include estradiol.
Compounds having anti-estrogenic activity refer to those compounds which have an antagonistic activity against estrogen""s pharmacological effects. Examples include the compounds described in the prior art reports mentioned above.
The present invention provides compounds wherein a moiety is chemically bonded to a group, wherein said moiety containing a compound having low activity following oral administration, a compound having anti-tumor activity, a compound having estrogenic activity or a compound having anti-estrogenic activity or the parent scaffolds of these compounds and said group having the general formula (1). As used herein, the term xe2x80x9cchemically bondedxe2x80x9d means that the group is bonded through a covalent bond and the like, including a Cxe2x80x94C bond, a Cxe2x80x94O bond, a Cxe2x80x94N bond, etc. The moiety containing the above-mentioned compounds or their parent scaffolds may take any structure as long as these bonds are possible. A Cxe2x80x94C bond is preferably used to improve stability against metabolism and hence activity by oral route.
Salt-forming metals as R1 include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, rare earth metals such as cerium and samarium, as well as zinc and tin. Among these, alkali metals and alkaline earth metals are preferred.
R1 may preferably be a hydrogen atom, an alkali metal and an alkaline earth metal.
Halogens in the linear or branched C1-C7 halogenoalkyl groups as R2 include fluorine, chlorine, bromine and iodine, with fluorine being preferred. R2 may contain one or more halogen atoms. When R2 contains two or more halogen atoms, they may be the same or different, preferably the same halogen atoms. In particular, R2 is preferably a perhalogenoalkyl group. Alkyls in the linear or branched C1-C7 halogenoalkyl groups under consideration include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl and n-heptyl. Preferred are linear or branched C1-C4 alkyls, i.e., methyl, ethyl, n-propyl, i-propyl and n-butyl.
Examples of the linear or branched C1-C7 perhalogenoalkyl group as R2 include the above-listed linear or branched C1-C7 alkyl groups, provided that they are perhalogenated, preferably perfluorinated. Also preferred are perhalogenated linear or branched C1-C5 alkyl groups and a group of the following general formula (9):
in which each of R4 and R5 which may be the same or different represents a linear or branched C1-C3 perhalogenoalkyl group. Among them, perfluorinated groups are preferred. More specifically, a perfluoromethyl group, a perfluoroethyl group, a perfluoro-n-propyl group and a perfluoro-n-butyl group are particularly preferred.
In the case where R2 in general formula (2) is a group of general formula (9), examples of the linear or branched C1-C3 perhalogenoalkyl group as R4 and R5 include the above-listed linear or branched C1-C3 alkyl groups, provided that they are perhalogenated, preferably perfluorinated. Further, perhalogenated C1 alkyl groups are preferred and a perfluorinated group is particularly preferred. More specifically, a perfluoromethyl group is preferred.
In the case where R2 in general formula (2) is a group of general formula (9), R2 is preferably a 1,1,1,3,3,3-hexafluoroisopropyl group.
Having the definition given above, R2 is preferably a perfluoroethyl group, a perfluoro-n-propyl group, a perfluoro-n-butyl group, and a 1,1,1,3,3,3-hexafluoro-isopropyl group.
Examples of the linear or branched C1-C5 alkyl group as used herein include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1-ethylpropyl.
Examples of the linear or branched C2-C5 alkenyl group as used herein include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl and 3-butenyl.
Examples of the linear or branched C2-C5 alkynyl group as used herein include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl and 3-butynyl.
Examples of the acyl group as used herein include, but are not limited to, alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl and phenylacetyl; alkenylcarbonyl groups such as acryloyl, propyoloyl, methacryloyl, crotonoyl and isocrotonoyl; and arylcarbonyl groups such as benzoyl.
Examples of the linear or branched C1-C7 halogenoalkyl group as R21, R22, R23 and R24 may be the same groups as previously listed for R2.
Group A may preferably be any one of the groups having formulae (3) to (8) and (10) to (23), particularly groups having formulae (3) to (6), (17) to (20) and (23), and more particularly groups having formulae (3), (4) and (17) to (20).
m may preferably be an integer of 4 to 10.
n may preferably be an integer of 2 to 7.
The group of general formula (1), which is one component of the compound according to the present invention, has an asymmetric center, while the other component may have an asymmetric center. Further, the compound of general formula (2) according to the present invention may have an asymmetric center in group A in addition to the asymmetric center in the group of general formula (1). For this reason, the compounds of the present invention have enantiomers. All individual enantiomers and mixtures thereof are intended to be within the scope of the present invention. When group A having an asymmetric center is a steroid scaffold represented by any one of formulae (3), (4) and (17) to (20), the group of general formula (1) is preferably attached to the steroid parent scaffold at 7xcex1- or 11xcex2-position.
Also, in the general formulae(1) and (2), both compounds with R- and S-configulation of the asymmetric carbon to which carboxylic acid or its metal salt is attached are preferable.
Among compounds of general formula (2), preferred are those compounds in which R1 is a hydrogen atom, an alkali metal or an alkaline earth metal; R2 is a perfluoroethyl group, a perfluoro-n-propyl group, a perfluoro-n-butyl group or a 1,1,1,3,3,3-hexafluoroisopropyl group; m is an integer of 4 to 10; and n is an integer of 2 to 6.
The compounds of the present invention may be obtained as hydrates.
Pharmaceutically acceptable salts include, but are not limited to, the above-mentioned metal salts, for example, sodium, potassium and calcium salts.
The compound according to the present invention may be administered as a pharmaceutical composition in any dosage form suitable for the intended route of administration, in combination with one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersants, auxiliary agents, preservatives, buffers, binders, stabilizers and the like. The compound and composition may be administered parenterally or orally.
The dose of the compound can be suitably determined according to the physique, age and physical condition of a patient, severity of the disease to be treated, elapsed time after onset of the disease, etc. Because the compound of the present invention is expected to show a significantly high activity by oral route, it is generally used in an amount of 0.1 to 500 mg/day when orally administered and in an amount of 0.1-1000 mg/day to 0.1-1000 mg/month when parenterally administered (by intravenous, intramuscular, or subcutaneous route) for adult patient.
The compound of general formula (1), particularly the compound of general formula (2), can be prepared according to any one of the following Reaction Schemes A to K and 1 to 19. In these Reaction Schemes A to K and 1 to 19 (i.e., Processes A to K and 1 to 19), R2, R3, R6, R7, Z1, Z2, Z3, Z4, Z5. Z6, Z7, Z8, Z9, Z10, m and n are as defined above in general formulae (1) and (2); each of R11, R12, R13 and R16 represents a protecting group; R33 represents a linear or branched alkyl group; each of Y1, Y2, Y3, Y4, Y5 and Y6 independently represents a hydrogen atom, an alkyl group (e.g., a linear or branched C1-C5 alkyl group) or OR11; each of L1 and L2 represents a leaving group; X represents a halogen atom; m1 is mxe2x88x922; R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group.
The compound of the present invention may include various stereoisomers because it contains one or more asymmetric carbon atoms. To obtain a single stereoisomer, there are two techniques, one of which uses a chiral column to resolve a mixture of stereoisomers and the other involves asymmetric synthesis. The chiral column technique may be carried out using a column commercially available from DAICEL under the trade name of CHIRALPAK-OT(+), OP(+) or AD, or CHIRALCEL-OA, OB, OJ, OK, OC, OD, OF or OG, for example. Regarding asymmetric synthesis, Processes 14 to 16 illustrate the asymmetric synthesis of the inventive compound with respect to an asymmetric carbon atom, to which a side chain carboxyl group is attached.
Note: Compound (I) can be synthesized by the method described in J. Org. Chem., 60(1995) 5316-5318.
Note: Compound (XXI) can be synthesized by the method described in DE4218743A1.
in which
R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group, and
M represents a metal.
in which
R8 represents a linear or branched C1-C5 alkyl group, a linear or branched C2-C5 alkenyl group or a linear or branched C2-C5 alkynyl group, and
M represents a metal.
in which
each of Y1, Y2 and Y3 independently represents a hydrogen atom, an alkyl group (e.g., a linear or branched C1-C5 alkyl group) or OR11, and
each of Z1, Z2 and Z3 independently represents a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkyl group.
in which
each of Y1, Y2, Y3, Y4, Y5 and Y6 independently represents a hydrogen atom, an alkyl group (e.g., a linear or branched C1-C5 alkyl group) or OR11, and
each of Z1, Z2, Z3, Z4, Z5 and Z6 independently represents a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkyl group.
In the above Reaction Schemes 14 and 15 (Processes 14 and 15), R2, R11, R12, X, m, n, X, L1 and L2 are as defined above, R* represents a chiral auxiliary, and m and M3 are integers that satisfy the relation m=m3+3.
[Process A]
Process A illustrates the synthesis of compound (VI) starting with compound (I). Compound (I) can be synthesized by the method described in J. Org. Chem., 60(1995) 5316-5318.
Step 1: Preparation of Compound (III)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (I) is reacted with compound (II) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (III).
Step 2: Preparation of Compound (IV)
Using a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (III) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or benzene) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (IV).
Step 3: Preparation of Compound (V)
When R11 is, for example, a methyl group, compound (IV) is treated with an acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or boron tribromide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (V).
Step 4: Preparation of Compound (VI)
Compound (V) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or a water/methanol mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (VI).
[Process B]
As shown below, compound (VI) given by Process A can also be prepared starting with compound (I) in the following manner.
Step 1: Preparation of Compound (VIII)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (I) is reacted with compound (VII) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (VIII).
Step 2: Preparation of Compound (IX)
Using a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound (VIII) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or benzene) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (IX).
Step 3: Preparation of Compound (X)
Compound (IX) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or a water/methanol mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (X).
Step 4: Preparation of Compound (XI)
In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of an acid (e.g., hydrogen chloride, sulfuric acid or p-toluenesulfonic acid), compound (X) is heated to a temperature ranging from 50xc2x0 C. to the boiling point of the reaction mixture to give compound (XI).
Step 5: Preparation of Compound (VI)
When R11 is, for example, a methyl group, compound (XI) is treated with an acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or boron tribromide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (VI).
[Process C]
As shown below, compound (VI) given by Processes A and B can also be prepared starting with compound (XII) in the following manner.
Step 1: Preparation of Compound (XIV)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XII) is reacted with compound (XIII) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XIV).
Step 2: Preparation of Compound (IV)
Compound (XIV) is dehydrated using an acid (e.g., hydrochloric acid, hydrobromic acid, hydrobromic acid/acetic acid) in an inert solvent (e.g., methanol, ethanol) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at 50xc2x0 C., and further processed by hydrogenation analogous to Process A to give compound (IV).
Step 3: Preparation of Compound (VI)
Compound (IV) is subjected to hydrolysis and deprotection analogous to Process A or B to give compound (VI).
[Process D]
As shown below, compound (VI) given by Processes A, B and C can also be prepared starting with compound (XII) in the following manner.
Step 1: Preparation of Compound (XVI)
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound (XII) is reacted with compound (XV) in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XVI).
Step 2: Preparation of Compound (XVII)
Compound (XVI) is dehydrated using an acid (e.g., hydrochloric acid, hydrobromic acid, hydrobromic acid/acetic acid) in an inert solvent (e.g., methanol, ethanol) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at 50xc2x0 C., and further processed by hydrogenation analogous to Process A to give compound (XVII).
Step 3: Preparation of Compound (VI)
Compound (XVII) is subjected to hydrolysis, decarboxylation and deprotection by a procedure analogous to Process A or B to give compound (VI).
Compound (XII) used as a starting material in Processes C and D can be prepared according to the method described in Tetrahedron., 30(1977) pp. 609-616.
[Process E]
Process E illustrates the synthesis of compound (XXIX) starting with compound (XXI).
Step 1: Preparation of Compound (XXII)
In the presence of an organic base (e.g., triethylamine or pyridine), compound (XXI) is treated with an acid chloride (e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride) in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably dichloromethane) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to convert (CH2)mOH in compound (XXI) into (CH2)m-L1, in which L1 is xe2x80x94Oxe2x80x94SO2CH3 or xe2x80x94Oxe2x80x94SO2xe2x80x94C6H4-p-CH3, for example. The compound thus obtained is then treated with a metal halide (e.g., sodium iodide or potassium iodide) in an inert solvent (e.g., acetone, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably acetone) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XXII).
Step 2: Preparation of Compound (XXIV)
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (XXII) is reacted with a malonic ester (XXIII) (e.g., diethyl malonate or dimethyl malonate) in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from room temperature to the boiling point of the reaction mixture to give compound (XXIV).
Step 3: Preparation of Compound (XXVI)
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (XXIV) is reacted with an alkyl halide (XXV), in which L2 represents a halogen atom, in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from room temperature to the boiling point of the reaction mixture to give compound (XXVI).
Step 4: Preparation of Compound (XXVII)
Compound (XXVI) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g., water, ethanol, methanol, a water/ethanol mixture or a water/methanol mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (XXVII).
Step 5: Preparation of Compound (XXVIII)
In a solvent (e.g., dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of an acid (e.g., hydrogen chloride, sulfuric acid or p-toluenesulfonic acid), compound (XXVII) is heated to a temperature ranging from 50xc2x0 C. to the boiling point of the reaction mixture to give compound (XXVIII).
Step 6: Preparation of Compound (XXIX)
When R11 is, for example, a methyl group, compound (XXVIII) is treated with an acid (e.g., hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or boron tribromide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (XXIX).
Compound (XXI) used as a starting material in Process E can be prepared according to the method described in DE4218743A1.
[Process F]
Compound (XXIX) given by Process E can also be prepared starting with compound (XXII) according to the following steps.
Step 1: Preparation of Compound (XXXI)
In the presence of a base (e.g., sodium hydride, sodium hydroxide or potassium t-butoxide), compound (XXII) is reacted with compound (XXX) in an inert solvent (e.g., tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture to give compound (XXXI).
Step 2: Preparation of Compound (XXIX)
Compound (XXXI) is converted into compound (XXIX) by a procedure analogous to Process E.
[Process G]
Process G illustrates the synthesis of compound (ILVIII) starting with compound (ILI).
Step 1: Preparation of Compound (ILIII)
In the presence of a base (e.g., sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium hydride, preferably potassium carbonate), compound (ILI) is reacted with compound (ILII) in an inert solvent (e.g., acetone, methyl ethyl ketone, tetrahydrofuran, preferably acetone) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give compound (ILIII).
Step 2: Preparation of Compound (ILIV) via Claisen Rearrangement
Compound (ILIII) is dissolved in an inert solvent (e.g., N,N-dimethyl aniline, N,N-diethyl aniline, nitrobenzene, dichlorobenzene, dibromobenzene, preferably N,N-dimethyl aniline) and then heated to a temperature ranging from 180xc2x0 C. to the boiling point of the reaction mixture, preferably from 180xc2x0 C. to 200xc2x0 C., to give compound (ILIV).
Step 3: Preparation of Compound (ILV)
In the presence of a base (e.g., triethylamine, diethylisopropylamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, preferably pyridine), compound (ILIV) is reacted with Tf2O (trifluoromethanesulfonic anhydride) in an inert solvent (e.g., dichloromethane, chloroform, benzene, toluene, preferably dichloromethane) at a temperature ranging from 0xc2x0 C. to room temperature to give compound (ILV).
Step 4: Preparation of Compound (ILVII)
In the presence of a palladium or nickel catalyst, compound (ILV) is reacted with compound (ILVI) in an inert solvent (e.g., ether, tetrahydrofuran, dioxane, dimethyl-formamide, water, preferably dioxane) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound (ILVII).
Step 5: Preparation of Compound (ILVIII)
Compound (ILVII) is converted into compound (ILVIII) by a procedure analogous to Process A, B, C or D.
[Process H]
Process H illustrates the synthesis of compound (LIV) starting with compound (LI) synthesized by the method described in U.S. Pat. No. 4,904,661.
Step 1: Preparation of Compound (LII)
Compound (LI) is reacted with a reducing agent (e.g., lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride) in an inert solvent (e.g., tetrahydrofuran, dioxane, diethyl ether) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LII).
Step 2: Preparation of Compound (LIII)
In the presence of a suitable acid (e.g., zinc iodide, boron trifluoride), compound (LII) is reacted with allyl-trimethylsilane in an inert solvent (e.g., dichloroethane, dichloromethane, chloroform) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LIII).
Step 3: Preparation of Compound (LIV)
Compound (LIII) is subjected to analogous procedure to Process A, B, C or D, that is, metathesis, reduction, hydrolysis, decarboxylation, deprotection, etc. to give compound (LIV).
[Process I]
Compound (LIV) can also be synthesized starting with compound (LI) in the following manner.
Step 1: Preparation of Compound (LVI)
In the presence of a base (e.g., sodium hydride, n-butyllithium, t-butyllithium, lithium diisopropylamide, potassium tert-butoxide), compound (LI) is reacted with compound (LV) in an inert solvent (e.g., tetrahydrofuran, dioxane, diethyl ether) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., to give compound (LVI).
Step 2: Preparation of Compound (LVII)
In the presence of a suitable acid (e.g., zinc iodide, boron trifluoride), compound (LVI) is reacted with sodium cyanoborohydride in an inert solvent (e.g., dichloroethane, dichloromethane, chloroform) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LVII).
Step 3: Preparation of Compound (LVIII)
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide), compound (LVII) is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound (LVIII). Compound (LVIII) can be directly prepared form compound (LVI) through hydrogenation using a catalyst (e.g., palladium on activated carbon, palladium hydroxide or platinum oxide) in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature.
Step 4: Preparation of Compound (LIV)
Compound (LVIII) is reacted by a procedure analogous to Process E or F to give compound (LIV).
[Process J]
Process J illustrates the synthesis of compound (LXII) starting with compound (LIX).
Step 1: Preparation of Compound (LXI)
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide), compound (LIX) is reacted with compound (LX) in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LXI).
Step 2: Preparation of Compound (LXII)
Compound (LXI) is subjected to metathesis, reduction, hydrolysis and deprotection by a procedure analogous to Process A, B, C or D to give compound (LXII).
[Process K]
Compound (LXII) can also be synthesized starting with compound (LIX) in the following manner.
Step 1: Preparation of Compound (LXIV)
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide), compound (LIX) is reacted with compound (LXIII) in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound (LXIV).
Step 2: Preparation of Compound (LXII)
Compound (LXIV) is reacted by a procedure analogous to Process E or F to give compound (LXII).
Compounds of general formula (2) in which group A is represented by formula (8) can be prepared, for example, as shown in Examples 6 to 10 by the same or equivalent procedure.
[Process 1]
Compound 2 is prepared starting with compound 1 by a procedure analogous to Process E. Compound 1 used as a starting material can be prepared according to the method described in WO99/64393.
[Process 2]
Compound 4 is prepared starting with compound 3 by a procedure analogous to Process E. Compound 5 can be obtained by oxidizing compound 4 according to the method described in WO99/64393. Compound 3 used as a starting material can be prepared according to the method described in WO99/64393.
[Process 3]
Process 3 illustrates the synthesis of compound 9 starting with compound 6. Compound 6 used as a starting material can be synthesized by, for example, the methods described in J. Org. Chem., 50(1985) 2121-2123 and J. Org. Chem., 61(1996) 3890-3893.
Step 1: Preparation of Compound 8
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide), compound 6 is reacted with compound 7 in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to 50xc2x0 C., to give compound 8.
Step 2: Preparation of Compound 9
Compound 8 is reacted by a procedure analogous to Process E to give compound 9.
[Process 4]
Process 4 illustrates the synthesis of compound 20 starting with compound 10.
Step 1: Preparation of Compound 11
In the presence of an acid catalyst such as sulfuric acid, compound 10 is heated in an alcohol (e.g., methanol, ethanol) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound 11.
Step 2: Preparation of Compound 12
Amino and hydroxyl groups of compound 11 prepared in Step 1 are protected to give compound 12.
Step 3: Preparation of Compound 13
Compound 12 is treated with a reducing agent (e.g., lithium borohydride, etc.) in a solvent (e.g., methanol, ethanol or ethanol/tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give compound 13.
Step 4: Preparation of Compound 15
Compound 13 is subjected to Mitsunobu reaction with compound 14 to give compound 15.
Step S: Preparation of Compound 16
Compound 15 is subjected to deprotection of the amino group to give compound 16.
Step 6: Preparation of Compound 17
In the presence of a base (e.g., potassium carbonate, potassium t-butoxide, sodium t-butoxide), compound 16 is reacted by addition of a metal catalyst such as palladium along with a ligand such as diphenylphosphino ferrocene or 2,2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, preferably by addition of a tris(dibenzylideneacetone)dipalladium catalyst along with 2,2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, in an inert solvent (e.g., benzene, toluene, xylene, dioxane or tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at 100xc2x0 C., to give compound 17.
Step 7: Preparation of Compound 19
In the presence of a base (e.g., sodium hydride, n-butyllithium, potassium tert-butoxide, potassium carbonate) and, if necessary, by addition of a reagent such as sodium iodide, compound 17 is reacted with compound 18 in an inert solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide, acetone) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound 19.
Step 8: Preparation of Compound 20
Compound 19 is reacted by a procedure analogous to Process A or B to give compound 20.
[Process 5]
Process 5 illustrates the synthesis of compound 27 starting with compound 21.
Step 1: Preparation of Compound 23
Compound 21 is subjected to protection with TBS, then reacted with aldehyde 22, and then protected at its amino group, to give compound 23.
Step 2: Preparation of Compound 25
Compound 23 prepared in Step 1 is alkylated with compound 24 to give compound 25.
Step 3: Preparation of Compound 26
Compound 25 is subjected to deprotection of the amino group and then treated with a reducing agent (e.g., lithium aluminum hydride, etc.) in a solvent (e.g., tetrahydrofuran, ether) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give compound 26.
Step 4: Preparation of Compound 27
Compound 26 is reacted by a procedure analogous to Process 4 to give compound 27.
[Process 6]
Process 6 illustrates the synthesis of compound 35 starting with compound 28.
Compound 35 can be synthesized starting with compound 28 in the following manner.
Step 1: Preparation of Compound 29
Compound 29 is prepared from compound 28 by the method described in Synthesis, 12(1995) 1493-1495 or by an equivalent method.
Step 2: Preparation of Compound 32
In the presence of a base (e.g., lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, potassium hexamethyl-disilazide, sodium hydride, n-butyllithium, t-butyllithium, lithium diisopropylamide, potassium tert-butoxide, aqueous potassium hydroxide, aqueous sodium hydroxide), compound 29 is reacted with compound 30 or 31 in an inert solvent (e.g., 1,2-dimethoxyethane, tetrahydrofuran, dioxane, t-butyl methyl ether, diethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, toluene) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9278xc2x0 C. to 0xc2x0 C., to give compound 32.
Step 3: Preparation of Compound 33
Compound 32 is isomerized under a basic condition (e.g., tetrabutylammonium fluoride/tetrahydrofuran, sodium methoxide/methanol, sodium ethoxide/ethanol, potassium methoxide/methanol, sodium methoxide/propanol, aqueous potassium hydroxide, aqueous sodium hydroxide), followed by deprotection of R12 and purification via recrystallization, to give a single isomer of formula 33. In the case where R12 is a t-butyldimethylsilyl group, compound 32 is isomerized simultaneously with the removal of TBS by treatment with tetrabutylammonium fluoride and further purified via recrystallization to give the single isomer of formula 33.
Step 4: Preparation of Compound 34
In the presence of a suitable acid (e.g., trifluoroacetic acid, boron trifluoride etherate, titanium tetrachloride, aluminum chloride, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid), compound 33 is reacted with triethylsilane in an inert solvent (e.g., dichloroethane, dichloromethane, chloroform, t-butyl methyl ether, toluene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound 34.
Step 5: Preparation of Compound 35
Compound 34 is reacted by a procedure analogous to Process A or B to give compound 35.
[Process 7]
Process 7 illustrates the synthesis of compound 38 starting with compound 36.
Compound 38 can be synthesized starting with compound 37 by a procedure analogous to Process 3. Compounds 36 and 37 used as starting materials can be synthesized by the methods described in J. Med. Chem., 40(1997) 2117-2122 and J. Med. Chem., 33(1990) 3222-3229 or by equivalent methods.
[Process 8]
Process 8 illustrates the synthesis of compound 40 starting with compound 39.
Compound 40 can be synthesized starting with compound 39 by a procedure analogous to Process 3. Compound 39 used as a starting material can be synthesized by, for example, the methods described in EP0826670A1 and J. Org. Chem., 60(1995) 739-741.
[Process 9]
Compound 42 or 43 can be synthesized in the following manner. Compound 42 can be synthesized from compound 41 by Jones oxidation, PCC oxidation, Swern oxidation, or ruthenium oxidation (e.g., TPAP) of the 17-hydroxyl group. Compound 42 is further reacted with R8-M, in which R8 represents a lower alkyl group or a lower alkenyl group or a lower alkynyl group and M represents a metal such as lithium, sodium, potassium, magnesium, calcium or aluminum, in an inert solvent (e.g., dimethyl sulfoxide, tetrahydrofuran, ether, dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound 43.
Compound 41 used as a starting material can be synthesized by Process E, F or 6.
[Process 10]
Compound 45 or 46 can be synthesized in the following manner. Compound 45 can be synthesized from compound 44 by Jones oxidation, PCC oxidation, Swern oxidation, or ruthenium oxidation (e.g., TPAP) of the 17-hydroxyl group. Compound 45 is further reacted with R8-M, in which R8 represents a lower alkyl group or a lower alkenyl group or a lower alkynyl group and M represents a metal such as lithium, sodium, potassium, magnesium, calcium or aluminum, in an inert solvent (e.g., dimethyl sulfoxide, tetrahydrofuran, ether, dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from 0xc2x0 C. to room temperature, to give compound 46.
Compound 44 used as a starting material can be synthesized by Process A, B, C or D.
[Process 11]
Compound 53 can be synthesized in the following manner.
Compound 47 is subjected to protection of its hydroxyl groups, and then oxidized between 9- and 11-position using DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) and the like to give compound 48.
Compound 48 is converted into compound 49 by the method described in J. Org. Chem., 1995, 60, 5316-5318.
Compound 49 is subjected to Swern oxidation, Jones oxidation, PCC oxidation, or ruthenium oxidation (e.g., TPAP) to give compound 50.
Compound 50 is reacted with an organometallic reagent (e.g., allylmagnesium halide) in an inert solvent (e.g., tetrahydrofuran, ether) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9248xc2x0 C. to room temperature, to give compound 51.
Compound 51 is dehydrated to remove its hydroxyl group using thionyl chloride/pyridine and the like to give compound 52.
Compound 52 can be converted into compound 53 by Process A, B, C or D.
[Process 12]
Compound 55 can be synthesized by subjecting compound 54 to reactions analogous to Process 3. Compound 54 can be synthesized according to documented methods (Drugs Future, 1978, 3, 211-215; J. Med. Chem., 1967, 10, 78-84; J. Med. Chem., 1998, 41, 2928-2931).
[Process 13]
Compound 56 can be converted into compound 57 by the following steps: 1) 1,2-addition with Xxe2x80x94Mgxe2x80x94(CH2)mOR12, 2) dehydration, 3) reduction and 4) deprotection (R12), and then subjected to reactions analogous to Scheme E to give compound 58.
[Process 14]
In the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium, compound 59 is reacted with chiral olefin 60 in a solvent (e.g., methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to give compound 61. Compound 61 is then subjected to the following reactions in the order stated, (a) reduction, deprotection and hydrolysis or (b) reduction, hydrolysis and deprotection, to give compound 62.
(a) Reduction, Deprotection and Hydrolysis
1) Reduction
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound 61 is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give a reduction product.
2) Deprotection
Next, deprotection of the phenolic hydroxyl group is carried out to give a deprotected product.
3) Hydrolysis
By way of example, if R* is a group of formula 63, the deprotected product is further treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/water mixture, a dioxane/water mixture, a dimethoxyethane/water mixture, a methanol/water mixture, an ethanol/water mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give compound 62.
(b) Reduction, Hydrolysis and Deprotection
1) Reduction
In the presence of a catalyst (e.g., palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst), compound 61 is hydrogenated in an inert solvent (e.g., methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature ranging from 0xc2x0 C. to the boiling point of the reaction mixture, preferably at room temperature, to give a reduction product.
2) Hydrolysis
By way of example, if R* is a group of formula 63, the reduced product is further treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide, or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (e.g., a tetrahydrofuran/water mixture, a diethyl ether/water mixture, a dioxane/water mixture, a dimethoxyethane/water mixture, a methanol/water mixture, an ethanol/water mixture) at a temperature ranging from room temperature to the boiling point of the reaction mixture, preferably at room temperature, to give a carboxylic acid.
3) Deprotection
Next, deprotection of the phenolic hydroxyl group is carried out to give compound 62.
The chiral olefin of formula 60 used in the above process can be synthesized as shown in Reaction Scheme 15.
[Process 15]
[Synthesis of Chiral Olefin]
In the presence of a base (e.g., lithium diisopropylamide, lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) and HMPA, compound 67 is reacted with R2(CH2)n-L1 in an inert solvent (e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9230xc2x0 C. to room temperature, to give compound 60.
Chiral olefin 60 can also be synthesized in the following manner.
In the presence of a base (e.g., lithium diisopropylamide, lithium hexamethyl-disilazide, sodium hexamethyl-disilazide, butyllithium) and HMPA, compound 68 is reacted with compound 69 in an inert solvent (e.g., tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature ranging from xe2x88x9278xc2x0 C. to the boiling point of the reaction mixture, preferably from xe2x88x9230xc2x0 C. to room temperature, to give compound 60.
[Process 16]
Compound 70 can be converted into compound 73 by a procedure analogous to Process 14.
[Process 17]
Compound 75 having substituents R21., R22, R23 and R24 on its benzene ring can be converted into compound 77 by a procedure analogous to Process G. Each of R21, R22, R23 and R24 independently represents a hydrogen atom, a linear or branched C1-C5 alkyl group, a linear or branched C1-C7 halogenoalkyl group, a halogen atom or an acyl group.
[Process 18]
Compound 78 is reacted with compound 79 in the presence of a base to give compound 80. Compound 81 can be synthesized from compound 80 according to Processes 3 and K.
[Process 19]
Compound 82 synthesized according to the method described in J. Med. Chem., 1057(1984) is subjected to Friedel-Craft reaction with compound 83 and then treated according to Process 3.

Compounds with hydroxycarbonyl-halogenoalkyl side chain

Abstract: in which

Abstract: R1 represents a hydrogen atom, etc.,

Abstract: R2 represents a C1-C7 halogenoalkyl group, etc.,

Abstract: m represents an integer of 2 to 14, and

Abstract: n represents an integer of 2 to 7,

Abstract: or enantiomers of the compound, or hydrates or pharmaceutically acceptable salts of the compound or enantiomers thereof. The above compound is advantageous in pharmaceutical use because the group of general formula (1) allows compounds such as anti-estrogenic ones to show a significantly increased activity following oral administration when attached to the parent scaffolds of the compounds.


Disclosed herein is a semiconductor device comprising an array having a hierarchical bit line structure, global bit lines adjacent to each other, local bit lines corresponding to the global bit lines, hierarchical switches, precharge circuits precharging the global bit lines, precharge circuits precharging the local bit lines, and a control circuit. When performing a test of the array, precharge voltages for the global bit lines are set to potentials different from each other, and the control circuit controls the potentials to be applied to the local bit lines through the global bit lines and the hierarchical switches.

1. Field of the Invention
The present invention relates to a semiconductor device having a bit line structure hierarchized into global bit lines and local bit lines, and relates to a control method thereof.
2. Description of Related Art
In recent years, miniaturization of memory cells has been achieved in semiconductor devices such as DRAM, and thus an increase in the number of memory cells connected to a bit line has caused a performance problem such as an increase in bit line capacitance. In order to overcome such a problem, a configuration in which the bit lines are hierarchized into global bit lines and local bit lines has been proposed. In a hierarchical memory cell array of this kind, data stored in a memory cell is read out to a local bit line and thereafter transmitted to a global bit line through a hierarchical switch. In a general DRAM, the bit lines need to be precharged to a predetermined voltage before a read operation, and therefore a configuration provided with a precharge circuit and wiring lines for a precharge voltage (precharge lines) is employed (for example, see Patent Reference 1). On the other hand, in the hierarchical memory cell array, the local bit lines and the global bit lines need to be separately precharged, and therefore a configuration in which precharge circuits and wiring lines are provided for both the local bit lines and the global bit lines should be employed. For example, a hierarchical bit line structure is known, in which a plurality of local bit lines are electrically connected to one global bit line through corresponding hierarchical switches. Normally, since there is provided a predetermined number of local bit lines corresponding to each one of the global bit lines, an area for arranging a plurality of precharge circuits and a plurality of precharge lines is required in relation to the predetermined number of local bit lines.    [Patent Reference 1] Japanese Patent Application Laid-open No. 2004-288299 (U.S. Pub. No. 2004/0204891 A1)
In general, one of the test operations for the DRAM is a voltage stress test of memory cells. The voltage stress test is performed by writing different voltages into the memory cells through adjacent bit lines to which the memory cells are connected for the purpose of determining whether or not the memory cells operate normally. Particularly, a large voltage stress can be applied to a plurality of bit lines by supplying a high voltage to odd numbered bit lines and supplying a low voltage to even numbered bit lines. However, when the voltage stress test is performed for the hierarchical memory cell array, two kinds of precharge circuits and two kinds of precharge lines need to be provided to supply at least two kinds of voltages different from each other to a plurality of local bit lines adjacent to one another that extend in the same direction. Particularly, the precharge lines extend in a direction intersecting the local bit lines, inevitably resulting in an increase in area. For example, when there are M local bit lines corresponding to each one of the global bit lines, it is only necessary to provide M precharge lines in a normal operation, and however 2M precharge lines need to be provided for the purpose of performing the voltage stress test of the memory cells. This causes a problem that the area of the memory cell array remarkably increases.

Semiconductor device and control method thereof


An improved fastener assembly (10) for securing a rocker arm cover (11) to an engine block (13) is described. In the preferred embodiment, the fastener assembly is comprised of a bolt (15) with an unthreaded shaft (15b) between a head (15a) and a threaded end (15c) along a longitudinal axis of the bolt. The bolt is in a slideable relationship within a cylindrical opening (19a) through a grommet (19) and a secured washer (17). Projections or interference portions (15e) on the unthreaded shaft adjacent to the threaded section and opposite the head, restrict the axial movement of the bolt within the grommet and the washer. While the rocker arm cover is being alilgned on the engine block, the bolt is in an up position with the projecting surfaces adjacent to the washer. Once the rocker arm cover is aligned, the bolt is threadingly mated with a threaded aperture (13a) in the engine block. The amount of torque that can be applied to the bolt is controlled by a shoulder (15g) of the unthreaded shaft section contacting the engine block.

(1) Field of the Invention
The present invention relates to an improved fastener assembly which is particularly useful for assembling a rocker arm cover to an engine block. In particular, the present invention relates to a three piece fastener assembly comprised of a bolt having a head and a partially threaded shaft that is mounted for axial movement inside of a rubber-like or elastic grommet with an intermediate washer secured to the grommet adjacent to the bolt head. The washer engages a stop means on a lower portion of the bolt between the head and the threaded end, to prevent removal of the bolt from the grommet and washer. During assembly, the fastener assembly is positioned in an opening in the rocker arm cover or the like with the bolt in a raised position so that it does not interfere with the alignment of the rocker arm cover on the engine block. The stop means keep the bolt from slideably releasing from the grommet and the washer while the bolt is in the raised position. Arrow tabs project from the grommet and lock under the rocker arm cover to retain the fastener assembly in the rocker arm cover opening or the like. After the rocker arm cover is aligned on the engine block, the bolt is threadingly mated with a threaded aperture in the block, the extent of which is controlled by an annular shoulder portion of an unthreaded section of the shaft of the bolt. When the bolt is threaded into the engine block, the grommet is compressed somewhat by the washer and serves to both muffle noise that is generated in the engine block and to prevent moisture and fluid from leaking into or out of the engine block.
(2) Prior Art
The prior art has described various types of screw fastener assemblies comprised of a bolt and a washer member for securing a first workpiece to a second workpiece. Most of the prior art devices are designed to seal a washer member mounted on an expandable and flexible gasket against a workpiece so that when a fastener member is tightened against the washer, the gasket is not deformed to the extent that the gasket no longer provides an effective means for sealing out moisture and liquid from the opening in the workpiece through which the fastener has been secured. Other devices provide for axial play between a fastening bolt and a washer, but have more parts and are more complicated than the present invention. These fastener assemblies are more expensive to manufacture and since fastener assemblies are manufactured by the millions, a reduction in manufacturing costs of a few cents translates into a substantial yearly savings. Illustrative of the prior art fastener devices are U.S. Pat. Nos. 3,126,935 to Tuozzo; 3,202,022 to Weidner, Jr.; 3,286,577 to Weidner, Jr.; 3,422,721 to Yonkers; 3,670,618 to Jellison; 4,292,876 to De Graan; 4,521,147 to King, Jr. et al; 4,732,519 to Wagner and British Patent No. 2,601,560 to McKee, Jr.
Tuozzo describes a retractable screw fastener having a stand-off bushing, a threaded fastener and a resilient gasket. The stand-off is assembled to one of two workpieces being joined by the use of a flaring tool. The threaded fastener is formed essentially in the shape of a bolt with a head at one end of a shaft and a threaded section at the other end. The threaded section is larger than the shaft so that when the threaded section is inserted into the resilient gasket, the fastener slides through an opening in the gasket, but is not able to slide back out. The shaft is free to slide inside the washer so that when the washer is inserted into the stand-off opposite the flared end, the shaft of the fastener is slid down the gasket and the threaded end is threadably mated to an aperture in the other of the two parts to be joined. This is a complex fastener assembly and requires more handling of the workpieces to be joined than in the present invention.
Weidner, Jr. describes two types of fastener assemblies. U.S. Pat. No. 3,202,033 describes a bonded washer having a backing member secured to a sealing member. The washer has a shoulder that is provided to control the driving and sealing action of the washer. U.S. Pat. No. 3,286,577 provides a stiff backing sealing member and a resilient sealing member which overcomes the problem of the sealing member flowing away from the opening in the first workpiece being joined to the second workpiece. Neither of the Weidner, Jr. fastener devices allow for axial play between a fastening bolt and the washer which are mounted together.
Yonkers describes a washer like member which provides for self-aligning and sealing of a bolt and nut or a similar fastening device. The member comprises an arcuate washer having a ring-shaped plastic filler joined to the concave side thereof which defines a generally convex arcuate outer surface for sealing on a workpiece and having a longitudinal axis without the bolt or nut being perpendicular to a plane defining the face of the workpiece. The washer is not secured to the bolt prior to mounting.
Jellison describes a composite washer having a dome-shaped metal member and a resilient member such as neoprene bonded to the metal member. The resilient member comprises two components, the first of which is bonded to the metal member along its bottom surface at the high portion of the dome and substantially adjacent a central opening. The second component is positioned in a partially overlapping relationship with the first component and is also bonded to the metal member along the bottom surface, radially removed from the washers central opening. The metal member is shaped to restrict the resilient member from moving radially outward and to urge a radially inward movement. The bolt is not secured to the washer prior to fastening.
De Graan describes an improved steel and neoprene bonded washer having a crowned steel washer with an inner elastomeric washer. The elastomeric washer is adjacent to the concave surface of the crowned washer. The steel washer has a generally flat outer ring and a conical portion extending from the outer ring toward the central opening. The angle of the sides of the conical portion is between 30.degree. and 50.degree. with respect to the flat portion. The bolt is not secured to the washer prior to fastening.
King, Jr. et al describes a blind fastener including an outer sleeve member, a stem, an inner sleeve member and a deformable washer which fits between the inner and outer sleeve members. The inner sleeve member is driven into the outer sleeve member from the accessible side of two workpieces while being supported on the stem so as to radially expand the outer sleeve member into interference fit with the hole. The deformable washer is placed between the head flanges on the inner and outer sleeve members and is sized so that the washer is deformed to expand the countersunk head flange on the outer sleeve member into interference fit with the countersink in the workpieces during the final driving movement of the inner sleeve member. After the inner sleeve member is driven into the outer sleeve member, the stem is pulled from the accessible side of the workpieces to form the blind head on the outer sleeve member on the blind side of the workpieces. The blind head former on the stem provides for grip adjustment by wire drawing or similar grip adjustment techniques normally used for blind fasteners so that the breakneck groove in the stem can be lined up with the head on sleeve member to allow the stem to be separated flush with the head. Because of the interference fit, locking grooves on the stem engage the inner sleeve member to mechanically lock the stem in position in the sleeve members. The bolt is not secured to the washer prior to fastening.
British Patent No. 892,870 to McKee, Jr. describes a fastener for securing corrugated and other forms of sheeting to the surface of building structures. Sealing washers are mounted on the washers and prevent moisture from entering through openings in the sheeting and the adjacent building structure member through which the shank of the fastener passes. The bolt is not secured by a metal washer to the fastener and the bolt is not axially moveable.
Wagner describes a fastener assembly that is adapted for use in connection with a first and a second apertured workpiece. The bolt is axially moveable in a washer but is designed to hold the bolt and washer together. The Wagner fastener assembly comprises a fastener, a washer and a rubber grommet. The washer has a depending sleeve portion on which the grommet is radially mounted. The fastener has a head and a shank with the shank having an intermediate unthreaded portion, a distal threaded portion and a pair of discrete protuberances or wings spaced apart on the unthreaded shank portion adjacent to the distal threaded shank portion for limiting the axial movement of the fastener along an opening through the sleeve portion of the washer. The sleeve also serves to limit the amount of torque that can be applied to the threaded shank portion when the fastener is used to join the two workpieces. The use of a sleeved washer as the torque limiting element and the use of annular wings on the unthreaded shank portion as the axial limiting element for the fastener in the sleeved washer, increases the cost of manufacturing the Wagner fastener assembly as compared to the present invention.


Approaches presented herein enable maneuvering collaborative robots to rescue persons in a hydrological disaster. A plurality of robots are dispersed in a body of water to spread out and seek victims using cooperative foraging techniques within resource constraints. A location of victims located by a robot using sensing techniques is communicated to other robots. A situational assessment is performed using victim location information to determine a number of robots to deploy to the location. The deployed robots are directed to perform coordinated maneuvers to create a connected floatation unit to support floatation of victims for rescue.

Hydrological disasters such as flooding are no longer limited to people living on the flood plains, as can be seen in more recent cases affecting urban areas. Search and rescue missions in flooded areas, especially in urban centers, can be highly risky and should be carried out swiftly and accurately to ensure the safety of rescue crews and casualties. In many cases, robots have been employed to assist in these operations. A robot is a programmable mechanical device that can perform tasks and interact with its environment, without the aid of human interaction.
Robotics is the science and technology behind the design, manufacturing, and application of robots. Soft robotics is the specific subfield of robotics dealing with constructing robots from highly compliant materials, similar to those found in living organisms. Soft robotics draws heavily from the way in which living organisms move and adapt to their surroundings. In contrast to robots built from rigid materials, soft robots allow for increased flexibility and adaptability for accomplishing tasks, as well as improved safety when working around humans. The advent of soft robotics has provided an opportunity to introduce autonomous agents that can provide search and rescue services in a cost-effective and safe manner.

Maneuvering collaborative devices for a rescue mission

International Business Machines Corporation


A portable cleat including a primary connector element having a principal axis and opposed ends and a secondary connector element attached to the primary connector element at at least one of the ends, said secondary connector element having angularly disposed arms.

Cleats are well known expedients for securing and tying down objects. Prior art cleats come in a variety of sizes and configurations and range from simple to complex. A search conducted by applicant located four patents which are representative of the prior art. The four patents are U.S. Pat. No. 2,962,998, issued to Long, U.S. Pat. No. 3,715,782, issued to Newell, U.S. Pat. No. 3,939,793, issued to Brockelsby, and U.S. Design Pat. No. 257,421 issued to Cox.
The arrangements disclosed in the above-identified patents carry out the same function; in particular, they are devices fixed in position and providing means for retaining a line at said fixed position.


The present application provides an air inflation device and a tire repair machine comprising the air inflating device. The air inflating device comprises a housing (1), a compressor device (2) including a compressor main body (21), and an outlet nozzle (22) that is connected to the compressor main body (2) as a compressed air discharge opening; the compressor device (2) is stored in the housing (1), and the housing (1) is divided into a second chamber (11) and a third chamber (12) by the compressor device (2); a fan (212) and the outlet nozzle (22) are located in the second chamber (11). The air inflating device and the tire repair machine of the present application have a simple structure and a strong practicality.

In an existing tire repair machine, an air inflating device usually takes up a large space. Moreover, an air compressed process of the air inflating device is exothermic, and heat generated during the air compressed process cannot be dissipated quickly, which will prolong tire inflation time.
In a conventional compressor mechanism, for example, in U.S. Pat. Nos. 8,016,002 B2, 7,547,201 B2, 8,684,046 B2, 8,997,801 B, US20130199666 A1, U.S. Pat. No. 6,789,581 B2 and EP2497627 A1, a hot spot such as an outlet nozzle connected to a compression chamber is located far away from a fan on a motor. On top of that, air paths for heat dissipation and an air intake for compression are not optimized, so that interference between the air paths exists.
Moreover, in U.S. Pat. Nos. 8,752,595 B2 and 7,789,110 B2, components in some available products are closely packed. There is no description about air flow within the compressor. Besides, there is barely enough room for air flowing from/to ventilation holes. Thus, heat dissipation of the compressor is not optimized.
In additions, some compressors have a heat dissipation structure, particularly, a housing with ventilation holes and directed air flow. However, the distance between the fan on the motor and the hot spot is not minimized. The air intake for heat dissipation and air intake for air compression is from the same ventilation holes, as shown in US 2013 0228316 A1.

Air inflating device and tire repair machine comprising same


The invention relates to a pillar finisher which is arranged to visually conceal regions of a vehicle body and with its outer exposed surfaces to be involved in forming the external appearance of a vehicle, wherein the pillar finisher in the intended final installed state forms a mount for a functional seal, in particular a window drop seal. To prevent a malposition of the functional seal relative to the pillar finisher from having negative effects with regard to the function of the seal or the quality impression of the mounted assembly, provision is made that a covering lip, functionally separate from the position of the functional seal, is fixedly associated with the pillar finisher on the edge side.

The invention relates to a pillar finisher which is arranged in order to visually cover regions of a vehicle body and with its outer exposed surfaces to be involved in forming the external appearance of a vehicle, wherein the pillar finisher in the intended final installed state forms a mount for a functional seal, in particular a window drop seal.

Pillar cover with fixedly allotted cover lip

DURA Automotive Body & Glass Systems GmbH


An information reception device comprising an imaging portion; a light reception portion for light reception of optional information subjected to optical modulation; a specification portion for specifying an optical modulation region contained in a capture angle of the imaging portion; a decoding portion for controlling the light reception portion in order to carry out light reception of the optical modulation region specified by the specification portion and decoding the optional information from the optical modulation content contained in the region; and a reproduction portion for reproducing the optional information decoded by the decoding portion. By acquiring a region essential for detection of optical modulation, acceleration of the information decoding process is achieved. Furthermore, position adjustment of the optical modulation region is easily accomplished.

In the past, a landmark display for a building, etc.; an advertisement display; recreational facility information or congestion situation of an amusement park, etc.; description of an item in a store window; explanation of an exhibit in a museum or public show, etc. has been performed using "visual information," such as characters, graphic symbols, etc., written on "information presentation signs," such as paper, banners, billboards, plates, etc.
However, when someone wants to look for a specific information notice in an environment with a lot of information presentation signs, a problem occurs in that the information notice is not conspicuous with the surrounding information presentation signs. For example, when product A and product B are adjacently exhibited at a store, the item description of product A may be mistaken for the item description of product B.
Consequently, with the use of information transmission by optical space transmission as in the conventional prior art 1 (reference to Japanese Laid-Open Patent Application No. 2001-245253 titled "IMAGING DEVICE"/Page 2, Page 5, FIG. 1 and FIG. 10), the information presentation for a product and the corresponding relationship of its presentation information can be clarified as well as erroneous assumption of information comprehension can be eliminated. Furthermore, an information reception device which also considers information integrity has been devised.
Specifically, this conventional prior art 1 discloses time-oriented image capturing with an electronic still camera and memorization of an optical tag unit mounted near a product arranged in a showcase. The data is recognized as information subjected to optical modulation from the time-oriented optical variation of the optical tag unit which resides in that stored image. Afterwards, the data about that particular product is extracted from this information subjected to optical modulation. The same extracted information is displayed superimposed on the captured image. However, in this conventional prior art 1, there exists a technological problem in that extraction of the optical tag unit information cannot be performed accurately, for example, when there is a light source (for example, disturbance light, such as flicker of a fluorescent light) in the vicinity which is prone to optical variations by the same pattern as the optical variation pattern of a blinking optical tag unit.
In view of such a problem, as in the conventional prior art 2 (reference to Japanese Laid-Open Patent Application No. 2003-179556 titled "INFORMATION TRANSMISSION METHOD, INFORMATION TRANSMISSION SYSTEM, IMAGING APPARATUS AND INFORMATION TRANSMISSION METHOD"/Pages 7˜8 and FIGS. 7˜10), an information reception device, information transmission system and information transmission method has been devised which always extracts information properly and avoids adverse effect produced by disturbance light.
Specifically, this conventional prior art 2 uses a light reception unit having an image sensor, such as a CCD (Charge-Coupled Device), etc. An optical variation from a light-emitting unit (equivalent to the optical tag unit in the conventional prior art 1) is detected which exists in the capture angle (also referred to as the field of view) of the image sensor. While binarization of a bit pattern sequence is being carried out by converting the variation level of that optical variation into modulation information, the operation determines whether or not any bit pattern sequence coincides with previously prepared binarized bit pattern sequences which did not correlate reciprocally. Subsequently, by generating a two-value logic signal (1/0) based on that determination result, the transmitted information from the light emitting unit is reproduced. In this manner, the light generation pattern of this light emitting unit is made unique and the effect of disturbance light is decreased.
However, in the conventional prior art 2, although the adverse influence by disturbance light can be avoided, there is a problem with wastefulness in processing an image.
Basically, in the conventional prior art 2, even if carrying out the above-mentioned binarization processing, logic processing of a bit pattern sequence after binarization processing, etc., a "partial read-out" is performed from an image within the capture angle of the image sensor and the read-out area is shifted for every cycle. These processes are unchanging by being targeted at all of the pixels of an image frame outputted from an image sensor. In other words, this method is none other than performing detection and capture of the point light source pertaining to all regions of an image within the capture angle of the image sensor. Therefore, as explained below, wasteful processing cannot be refused.
Assuming that the total number of pixels within the capture angle of the image sensor (full dots) is 1280×960 dots and supposing that a partial read-out of 320×240 dots is possible for this image sensor, the above-mentioned conventional prior art 2 binarization processing, logic processing of a bit pattern sequence after binarization processing, etc. will be performed for each area in which an image of 1280×960 dots is divided into 4×4 blocks. In this case, since one processing is performed applying to the pixels of 320×240 dots for one area, if observing only one processing, the processing load is definitely less. However, the visual recognition size of the point light source located at a distance, namely, the point light source of the light emitting unit, is considerably small. In a lot of cases, this level is completely obtained in one divided area. Thus, processing is inefficient for the other divided areas which do not include a point light source.

Information reception device, information transmission system, and information reception method


Embodiments are related to substrates having one or more well structures each exhibiting substantially vertical sidewalls and substantially planar bottoms.

LED displays, LED display components, and arrayed LED devices include a large number of diodes placed at defined locations across the surface of the display or device. Fluidic assembly may be used for assembling diodes in relation to a substrate. Such assembly is often a stochastic process whereby LED devices are deposited into wells on a substrate. Forming such wells into the surface of a substrate using traditional approaches typically relies on forming the wells in a polymer film deposited on a glass substrate. Such polymer films exhibit poor transparency and thermal stability. The poor transparency can lead to a yellow or grey hue emanating from a display. The limited thermal stability limits process compatibility with subsequent electrical contact formation and passivation.
Hence, for at least the aforementioned reasons, there exists a need in the art for advanced systems and methods for manufacturing physical structures on a substrate.

Fluidic assembly substrates and methods for making such


A metrology tool may include an illumination sub-system to illuminate sample within two or more acquisition fields with two or more illumination beams, where the two or more acquisition fields are distributed along a scan direction in a non-overlapping configuration, and where a translation stage translates a metrology target on the sample along the scan direction sequentially through the two or more acquisition fields. The metrology tool may further include an imaging sub-system to image the two or more acquisition fields while the sample is scanned along the scan direction. The imaging sub-system may include a field-repositioning optical relay to relay images of the two or more acquisition fields to a scanning detector including one or more pixel columns distributed along a column direction, where the field-repositioning optical relay positions the images of the two or more acquisition fields on the scanning detector along the column direction.

Scanning metrology systems interrogate a sample as the sample is in motion and provide a promising approach to achieving high-throughput measurements to meet increasing demands on the number and/or sensitivity of metrology measurements. However, scanning metrology presents additional challenges when multiple measurements of a particular location on a sample (e.g., a location of a metrology target) with different measurement parameters are desired. For example, performing multiple scans of the sample with different illumination or collection configurations may provide a desired dataset, but the time required for multiple scans may offset the throughput capabilities of scanning metrology. By way of another example, splitting collected light into multiple paths based on certain optical parameters of the collected light such as wavelength or polarization may provide some ability to generate measurements using different collection conditions, but this approach lacks the ability to modify illumination parameters during a scan and inefficiently uses illumination light resulting in increased measurement noise. It is therefore desirable to provide systems and methods to cure the above deficiencies.


A low profile computer case having two centrifugal blowers mounted in a partition therein. An intake port of a first blower faces a bottom panel of the case and an intake port of the second blower faces a top panel of the case. Standoff dimensions are defined between the respective intake ports and panels to permit operation of the blowers.

1. Field of the Invention
The invention relates to computer cases and computers and more specifically, the invention relates to a low profile computer case and computer.
2. Description of the Related Art
As computers become more ubiquitous in society, it becomes more desirable to reduce the size of computer systems. Currently, there is a clear trend toward more powerful and more compact computer systems. Accordingly, the consumed power per unit density, i.e. the power density, of the average computer has increased tremendously over the past several years. However, such an increase in power density runs into a limitation of heat dissipation. More specifically, the higher the power density, the more heat generated and the more difficult it is to dissipate the heat. Of course, heat adversely affects the operation of most microprocessor based components and other computer components. Accordingly, the desire to reduce the size and increase the power of computers is at odds with the need to maintain components at temperatures within desired operating ranges.
Essentially, there are two processes by which heat in a computer case is dissipated. The first process is "air exchange cooling" which consists of replacing heated air in the case with cooler air, e.g. ambient air. The second process is "forced cooling" in which air is moved across the surface of a specific component to raise the convective heat transfer coefficient for the surface of the component thereby cooling the component faster than if the component was in static air. Most computer cases incorporate both heat dissipation processes to some degree. Both processes require the movement of air.
It is well known to use fans to move air through computer cases to cool various components therein. Conventionally, such fans are placed in a front panel or a back panel of the computer case. However, the desire to reduce the size of computers requires that front and back panel space be utilized efficiently for accessible components such as communication ports and power connections on the back panel, and removable media and fixed media drives on the front panel. Accordingly, the use of a fan in the front or back panel wastes precious panel space. Fans have been placed in side panels to avoid this problem. However, popular rack mount systems, such as systems complying with Engineering Industries Association Standard 310-C (EIA-310-C), require that the computer case be mountable in a rack having sides that closely oppose side panels of the computer case. Accordingly, side panels of the racks may interfere with operation of fans mounted in side panels of computer cases and thus the practice of mounting fans in side panels of computer cases has limited application. Further, it is often desirable to mount sliding rails on the computer case to permit it to be slid out of the rack for maintenance and the like. Such rails interfere with fans mounted in side panels. The use of shelves to avoid the need for rails restricts vertical room.
It is also known to provide one or more fans in an interior of a computer case. U.S. Pat. No. 5,793,610 is exemplary of references disclosing such an arrangement. U.S. Pat. No. 5,793,610 discloses a computer case having a support member in an interior of the case. Plural cooling fans are mounted in the support member. If one of the fans fails, air tends to re-circulate back through the opening in which the failed fan is mounted and thus a complex louver arrangement is provided.
U.S. Pat. No. 5,168,424 discloses a data storage unit having a housing and internal plate 105. Two open loop dc centrifugal fans are mounted in plate 105 to draw air from an area housing memory devices to an area housing a power supply. U.S. Pat. No. 5,168,424 uses dual entry open loop centrifugal fans to adjust for a variable impedance to air flow caused by varying numbers of memory devices on the upstream side of the fans. The downstream side of the fans contains only a power supply over which air flows to vents in a front panel and thus does not present significant impedance to the system. The intake ports of the fans are positioned opposite data storage devices. The use of two centrifugal fans having intake ports opposite devices requires a large amount of space in the chassis and thus the arrangement disclosed in U.S. Pat. No. 5,168,424 is not suitable for a low profile computer chassis which includes a motherboard and other components that require additional space in the chassis.
EIA-310-C, the disclosure of which is incorporated herein by reference, specifies three different rack sizes and the sizes and tolerances of cases that can be disposed in the racks in an attempt to insure that computers and components from various venders will fit in the same racks. There are three standard panel widths, i.e. rack sizes, 19″, 24″, and 30″, with 19″ being the most common. The vertical or height dimension of the racks is divided into a plurality of individual units known as a "U". In particular, one U equals 44.45 mm+0.4 mm. The horizontal or width dimension of a case for a 19″ rack is 482.6 mm+0.4 mm. Many computer servers or the like are housed in a 6U case, i.e. a case that fits in the width dimension of the 19″ rack noted above and is 265.9 mm high (44.45 mm×6=266.7 mm−0.8 mm tolerance to permit sliding the case into and out of the rack as prescribed by EIA-310-C).
In accordance with the recent trend in miniaturization, servers have been reduced to 2U cases, i.e. cases 88.1 mm in height. However, conventional 2U servers have at most four media drives in the front panel because of the need for fans and to allow for adequate air flow for forced cooling. While components, such as media drives have gotten smaller, at any given time they are designed to fit into standard form factors, such as "half height" drives (approximately 1⅝″ in height) and "low profile" drives (approximately 1″ in height). Accordingly, case size and cooling considerations have limited the number of components, such as various media drives, that can be housed in a 2U case. Accordingly, the functionality and flexibility of conventional computers and computer components in 2U cases is limited.
It is important to utilize the limited width of EIA-320-C to its fullest extent also. Accordingly, conventional cases made to fit into standard EIA-310-C racks have side walls with a lip that extends across the top of the case to a small degree to allow a top panel to be screwed onto the lip from the top of the case thereby maximizing the width of the case. As noted above, many cases designed for rack mounting have slide out rails, i.e. drawer slides with rollers, that permit the case to be easily slid out of the rack and maintained in position for repair, maintenance and troubleshooting. The case including the slide out rails must fit within the standard rack width. Therefore, the use of rails, further limits the effective width of a case. Finally, an increased number of components results in an increased number of communication and power cables. If the cables are too bulky and not managed properly, they further restrict air flow and thus cooling. Cabling is one more consideration that puts increased component density at odds with cooling requirements.