An universal gas permeable, vapor releasing cover for adapting cooking vessels for use in a microwave oven includes a patterned array of openings to permit venting of vapors and gases in a relatively flat microwave permeable cover designed to accommodate varying sized vessels of the general shape described by the lid. A set of such covers can serve all popular shapes of such vessels. The holes may be tapered to reduce clogging.

I. Field of the Invention
The present invention is directed generally to covers or lids for microwave cooking vessels and, more particularly, an universal microwave permeable cover designed to accommodate varying sized open-top vessels and which is provided with an array of openings designed to uniformly vent gases and vapors built up when food is heated in the vessel.
II. Description of the Related Art
The number of microwave ovens in use by the general public has grown at a very high rate. The speed, ease and convenience of preparing foods in microwave ovens has created an increased demand for foods designed specifically to be cooked in microwave ovens and, in addition, for specialty cooking vessels designed to be used to prepare foods in microwave ovens. In general, cooking vessels specifically designed and configured for use in microwave ovens tend to be rather expensive and specialized or limited with respect to use. Such devices include, for example, microwave popcorn poppers illustrated and described in U.S. Pat. No. 4 873 406 to Connor, pressure cookers for microwave ovens, illustrated in U.S. Pat. No. 4 796 777 to Dalquist, et al. and other such containers as are illustrated in Sugisawa, et al., 4 703 149. Many microwave heating packages have been designed with a variety of vent holes and Daniels, 4 745 249, Levendusky, et al., 4 560 850, and Pawlowski, 4 896 009, are illustrative of vessels and packages of a given size which may have one or more vapor permeable vent openings designed for the escape of vapors, the permeation of microwaves, or the like.
While all of these uniquely designed cooking vessels have advanced the art of microwave cooking and provide a convenience to the user, each individual device is typically comparatively expensive; and in order to have a relatively complete set of microwave cooking vessels to meet a variety of cooking needs, the consumer has to invest a significant amount of money to obtain an array of vessel types, each being of relatively limited versatility. Accordingly, most consumers simply utilize open-topped vessels such as casserole dishes, various types of bowls and the like which are compatible with use in microwave ovens and already in their possession to accomplish most microwave cooking and heating. Often transparent polymer film coverings are placed or wrapped over the vessels to provide an inexpensive top seal to retain moisture. However, upon removal of the polymer film, a great deal of steam is often expelled in the user's face and this may lead to steam burns or may even result in the user dropping the dish he has just removed from the microwave oven. Moreover, such coverings can be used but once. The alternative is to leave the dish uncovered, but this leads to undesirable dehydration of the contents and possibly the loss of food into the oven from the container due to steam expansion upon heating by microwaves. If one attempts to provide vent holes in the film, the film often tears and thereby frustrates these efforts.


A compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof:

The present invention relates to phosphonic acid derivatives having inhibitory activity against carboxypeptidase B, and to pharmaceutical compositions which comprise at least one of said derivative as an active ingredient and are useful for therapeutic and preventive treatment of various thrombosis, diseases caused by a vascular disorder, and organ disorders resulting from reduction of fibrinolysis.
Numbers of patients suffering from circulatory diseases have been increasing due to growth of aged population and changes in social circumstances. Among the aforementioned diseases, those caused by thrombus such as cerebral infarction and myocardial infarction show an increasing tendency. For these diseases, various antithrombotic treatments have been clinically applied.
The antithrombotic treatments are classified basically into anticoagulant, antiplatelet, and thrombolytic treatments. Among them, the thrombolytic treatments involve the lysis of formed thrombus, per se. In that sense, they are considered as more reasonable remedies for therapeutic treatment of thrombosis than the anticoagulant treatments, which prevent generation and development of secondary thrombus. At present, enzymatic agents such as urokinase and plasminogen activator have been clinically used as thrombolytic agents, and their clinical effectiveness has been recognized as one of therapeutic treatments for patients suffering from thrombosis.
Detailed mechanisms as to fibrinolysis have been being revealed with the progress of biochemical researches. A factor, which was reported as a fibrinogenolysis-inhibitory factor TAFI (thrombin activatable fibrinolysis inhibitor factor) activated by stimulation of coagulation, was revealed to be identical to plasma carboxypeptidase B (J. Biol. Chem. 14477(1995)). It was elucidated that plasma carboxypeptidase B inhibits fibrinolysis by interrupting plasminogen, which is a fibrinolytic enzyme mainly acting in the lysis of thrombus (fibrin), from binding to thrombi (J. Clin. Invest., 2534(1995)., J. Biol. Chem., 16603(1996), Thromb. Haemost., 829(1998), Circulation, 1328(1996)). Accordingly, plasma carboxypeptidase B inhibitors are expected to be used as agents for therapeutic and preventive treatments of various thromboses, which are antithrombotic agents based on enhancement of the lysis of thrombi.
As substances inhibiting pancreatic carboxypeptidase B, GEMSA (Biochemistry, 401(1978)., Arch. Biochem. Biophys., 487(1979)), SQ24798 (Biochemistry, 1427(1979)) and the like have been known so far.
Plasminogen activators and the like, which have been clinically used as thrombolytic agents at present, are not fully satisfactory from a clinical therapeutic viewpoint as their low safety such as hemorrhagic adverse effects and poor pharmacokinetics such as a short half-life, although their thrombolytic activities in an acute stage after thrombus formation are reliable.
In order to provide a thrombolytic agent having higher safety, the inventors of the present invention conducted researches to find a compound having inhibitory activity against plasma carboxypeptidase B. As a result, they found that phosphonic acid derivatives have potent inhibitory activity against carboxypeptidase B.
The present invention thus provide a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
wherein R1 represents hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, amino group, a substituted amino group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group;
R2 and R3 may be the same or different and independently represent hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, amino group, a substituted amino group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group, or R2 and R3 may form a 5 to 7 membered carbon-ring together with the carbon atom to which they bind;
X represents xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94;
A represents a group of the following formula (II):
[in which R7 and R8 may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R9 and R10 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group, an acyl group, carboxyl group, an alkoxycarbonyl group, carbamoyl group, a substituted carbamoyl group, amino group, a substituted amino group, nitro group, xe2x80x94SR11 group (R11 represents an alkyl group, phenyl group, or a substituted phenyl group), xe2x80x94SOR12 group (R12 represents an alkyl group, phenyl group, a substituted phenyl group, an alkoxyl group, an aryloxy group, amino group, or a substituted amino group), or xe2x80x94SO2R13 group (R13 represents an alkyl group, phenyl group, a substituted phenyl group, an alkoxyl group, an aryloxy group, amino group, or a substituted amino group);
m represents an integer of from 1 to 8; and
xe2x80x94(C)mxe2x80x94 represents a saturated or unsaturated carbon chain], or
A represents a group of the following formula (III):
[in which R7 and R8 may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R24, R25, R26 and R27 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, or a substituted amino group;
p and q independently represent an integer of from 0 to 2;
xe2x80x94(C)pxe2x80x94 and xe2x80x94(C)qxe2x80x94 independently represent single bond, or a saturated or unsaturated carbon chain; and
B represents a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, or a substituted heterocyclic group], or
A represents a group of the following formula (TV):
[in which R20 represents hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group, or amidino group;
R28 and R29 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, or an alkylamino group;
n and o independently represent an integer of from 0 to 5;
r represents an integer of from 0 to 4;
xe2x80x94(C)rxe2x80x94 independently represents single bond, or a saturated or unsaturated carbon chain; and
Y represents CH or nitrogen atom], or
A represents a group of the following formula (XIV):
[in which R7 and R8 may be the same or different and independently represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, or amidino group;
R30, R31, R32 and R33 may be the same or different and independently represent hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, oxo group, amino group, or an alkylamino group;
s represents an integer of from 0 to 3;
t represents an integer of from 1 to 3;
xe2x80x94(C)sxe2x80x94 and xe2x80x94(C)txe2x80x94 independently represent single bond, or a saturated or unsaturated carbon chain; and
V represents xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94]; and,
E represents hydrogen atom, or xe2x80x94CH2CH2xe2x80x94 to form together with A a piperidine ring group or a N-substituted piperidine ring group.
The present invention also provides a medicament which comprises as an active ingredient a substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof. According to a preferred embodiment, there is provided the aforementioned medicament in the form of a pharmaceutical composition which comprises the aforementioned substance as an active ingredient together with a pharmacologically acceptable carrier. These medicaments are useful for therapeutic and/or preventive treatment of thrombotic diseases.
The present invention also provides an inhibitor against carboxypeptidase B which comprises as an active ingredient the substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof.
The present invention further provides a use of the substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof for the manufacture of the aforementioned medicament; and a method for therapeutic and/or preventive treatment of thrombotic diseases which comprises the step of administering to a mammal including a human a therapeutically and/or preventively effective amount of the substance selected from the group consisting of the compound represented by the aforementioned general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof.
In the specification, the alkyl group or an alkyl which constitutes a part of a substituent (e.g., alkoxyl groups) means a C1-10 alkyl group unless otherwise specifically mentioned, which encompasses straight chain alkyl groups including methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group and the like as typical examples; branched chain alkyl groups such as isopropyl group, s-butyl group, t-butyl group, 2-pentyl group, 3-pentyl group, and 1,1-dimethylpropyl group; cyclic alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group; and alkyl groups as combinations of a straight or branched chain alkyl group and a cyclic alkyl group, such as cyclopropylmethyl group, cyclopropylethyl group, and cyclobutylmethyl group. In the groups containing an alkenyl moiety, the number of double bonds contained in the alkenyl moiety is not particularly limited. The alkenyl moiety may be any of a straight chain, a branched chain, cyclic moiety, or a combination thereof unless otherwise specifically mentioned, and is preferably straight chain or branched chain A double bond contained in the alkenyl moiety may be in either Z- or E-configuration.
In the specification, the acyl group or an acyl group which constitutes a part of a substituent means a functional group selected from the group consisting of formyl group, straight chain or branched chain C2-10 alkylcarbonyl groups, C7-15 aralkylcarbonyl groups, and C4-7 cycloalkycarbonyl groups. Examples include, for example, formyl group, acetyl group, propionyl group, butenyl group, benzoyl group, pivaloyl group and the like, and is preferably acetyl group.
The halogen atom means fluorine atom, chlorine atom, bromine atom, or iodine atom, and preferably fluorine atom or chlorine atom.
In the specification, the aryl group or an aryl group which constitutes a part of a substituent means, unless otherwise specifically mentioned, a 6 to 14-membered (monocyclic to tricyclic, preferably monocyclic or bicyclic) aromatic ring group such as phenyl, 1-naphthyl, 2-naphthyl, biphenyl, and 2-anthrylnaphthyl.
A heteroring means a 5 to 14-membered, preferably 5 to 10-membered, (monocyclic to tricyclic, preferably monocyclic or bicyclic) heteroring which contains 1 to 4, preferably 1 to 3, heteroatoms of 1 or 2 kinds selected from oxygen atom, nitrogen atom, and sulfur atom other than carbon atom. Examples include, for example, furan ring, pyrrole ring, pyrrolidine ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, triazole ring, pyrane ring, pyridine ring, piperidine ring, dioxane ring, morpholine ring, pyridazine ring, pyrimidine ring, pyrazine ring, piperazine ring, triazine ring and the like, and preferably imidazole ring, triazole ring, pyridine ring, piperidine ring, pyrimidine ring, pyrazine ring, piperazine ring and the like. The heterocyclic group or a heterocyclic group which constitutes a part of the substituent means a residue of the aforementioned heteroring.
A carbon ring preferably means a saturated or unsaturated 5 to 7-membered ring. Examples include, for example, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclopentyl ring, cyclohexane ring, cycloheptane ring, benzene ring and the like.
When m represents an integer of 2 or more, the description:
shows an alkylene group which consists of xe2x80x9cmxe2x80x9d groups of the methylene defined in the parenthesis bound to each other in a chain, and respective xe2x80x9cmxe2x80x9d groups of R9 and R10, each existing one to every xe2x80x9cmxe2x80x9d groups of the methylene, are independent and may be the same or different. The aforementioned description should not be interpreted as mere repetition of xe2x80x9cmxe2x80x9d groups of the same methylene. The other alkylene groups defined by p, q, r, s, or t are described in the same manner.
In formula (I), the alkyl group represented by R1, R2, or R3, or an alkyl group existing on the substituent represented by R1, R2, or R3 is preferably a C1-8 alkyl group, more preferably a C1-6 alkyl group, and further preferably a C1-4 alkyl group. When the alkyl group represented by R1, R2, or R3 is a cyclic alkyl group, the group may preferably be a C3-7 cycloalkyl group. Examples include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and the like.
One or more hydrogen atoms on the alkyl group represented by R1, R2, or R3 may be substituted. Examples of the substituent include hydroxyl group, phenyl group, a substituted phenyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, an acyl group, carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, amino group, a substituted amino group, nitro group, oxo group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, xe2x80x94SR4 group (R4 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl groups and the like)), xe2x80x94SOR5 groups (R5 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group), xe2x80x94SO2R6 group (R6 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group) and the like. Preferred substituents include hydroxyl group, phenyl group, a substituted phenyl group (substituted with hydroxyl group, a halogen atom, an alkoxyl group, an amino group), a halogen atom, an alkoxyl group, an acyl group (e.g., acetyl group), carboxyl group, amino group, oxo group, and a heterocyclic group. The position of the substituent on the alkyl group is not particularly limited. When 2 or more substituents exist on the alkyl group, they may be the same or different.
In formula (I), the alkoxyl group represented by R1, R2, or R3, or an alkoxyl group existing on the substituent represented by R1, R2, or R3 is preferably a C1-8 alkoxyl group, more preferably a C1-6 alkoxyl group, and further preferably a C1-5 alkoxyl group.
One or more hydrogen atoms on the alkoxyl group represented by R1, R2, or R3 may be substituted. Examples of the substituent include hydroxyl group, phenyl group, a substituted phenyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, an acyl group, carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, carbamoyl group, a substituted carbamoyl group, amino group, a substituted amino group, xe2x80x94SR21 group (R21 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like)), xe2x80x94SOR22 group (R22 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group), xe2x80x94SO2R23 group (R23 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group) and the like. A preferred substituent includes phenyl group. The position of the substituent on the alkoxyl group is not particularly limited. When 2 or more substituents exist on the alkoxyl group, they may be the same or different.
In formula (I), one or two hydrogen atoms of the amino group represented by R1, R2, or R3 may be substituted. When two hydrogen atoms are substituted, the substituents may be the same or different. Examples of the substituent include an alkyl group, an alkenyl group, an acyl group, an acylalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, an alkylsulfonylalkyl group, an arylsulfonyl groups, an arylsulfonylalkyl group and the like. Examples of the substituted amino group include methylamino group, ethylamino group, n-propylamino group, isopropylamino group, allylamino group, phenylamino group, benzylamino group, cyclohexylamino group, dimethylamino group, allylmethylamino group, allylcyclohexylamino group, formylamino group, acetylamino group, benzoylamino group, pivaloylamino group, acetylmethylamino group, phthaloylamino group, methoxycarbonylamino group, isopropoxycarboonylamino group, methoxycarbonylmethylamino group, benzyloxycarbonylamino group, methylsulfonylamino group, phenylsulfonylamino group, benzenesulfonylamino group, and methyl(methylsulfonyl)amino group. Methylamino group, allylamino group, acetylamino group, methylsulfonylamino group, dimethylamino group, allylmethylamino group, or benzoylamino group is preferred.
In formula (I), the carbon ring represented by R1, R2, or R3, or the carbon ring represented by R2 and R3 together with the carbon atom to which they bind may be substituted with a halogen atom, an alkyl group, an alkoxyl group, oxo group, an acyl group, carbamoyl group, amino group, or a substituted amino group. A specific example includes 1-(3,5-dioxo)cyclohexyl group.
In formula (I), the heteroring represented by R1, R2, or R3 may be substituted with an alkyl group, an alkoxyl groups, oxo group, an acyl group, carbamoyl group, amino group, or a substituted amino group.
In formula (I), the group or atom represented by X is preferably oxygen atom.
In group (II), group (III), and group (XIV) represented by A in formula (I), examples of the group represented by R7 or R8 include hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group and the like), an aryloxycarbonyl group (e.g., phenoxycarbonyl group and the like), carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, ethylcarbamoyl group, N,N-dimethylcarbamoyl group, N,Nxe2x80x2-diethylcarbamoyl group and the like), an arylalkylcarbamoyl group (e.g., benzylcarbamoyl group and the like), and amidino group. Hydrogen atom, methyl group, ethyl group, formyl group, or amidino group is preferred, and hydrogen atom or methyl group is more preferred.
In group (II) represented by A in formula (I), examples of the group represented by R9 or R10 include hydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group (e.g., phenoxy group and the like), an acyl group, carboxyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl group, isopropoxycarbonyl group and the like), carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, N,N-dimethylcarbamoyl group, and the like), an alkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), amino group, an alkylamino groups (e.g., methylamino group, ethylamino group, dimethylamino group and the like), an alkenylamino group (e.g., allylmethylamino group and the like), an acylamino group (e.g., acetylamino group, formylamino group, benzoylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group and the like), nitro group, xe2x80x94SR11 group {R11 represents an alkyl group, phenyl group or a substituted phenyl group (examples of the substituent include C1-4 alkyl groups, C1-4 alkoxyl groups and the like)}, xe2x80x94SOR12 group {R12 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include C1-4 alkyl groups, C1-4 alkoxyl groups and the like), an alkoxyl group (e.g., methoxy group, n-propoxy group and the like), an aryloxy group (e.g., phenoxy group and the like), amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}, and xe2x80x94SO2R13 group {R13 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group (e.g., methoxy group, n-propoxy group and the like), an aryloxy group (e.g., phenoxy group and the like), amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}. Hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, or acetyl group is preferred, and hydrogen atom is more preferred.
In group (II) represented by A in formula (I), the integer represented by m is preferably from 2 to 6, and more preferably 4 or 5.
In group (III) represented by A in formula (I), examples of the group represented by R24, R25, R26, or R27 include hydrogen atom, a halogen atom, hydroxyl group, an alkyl group, amino group, and a substituted amino group (examples of the substituent include C1-4 alkyl groups and the like).
In group (III) represented by A in formula (I), the carbon ring represented by B is preferably cyclohexane ring or benzene ring. One or more hydrogen atoms on the carbon ring represented by B may be substituted. Examples of the substituent include hydroxyl group, a halogen atom, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group (e.g., phenoxy group and the like), an acyl group (e.g., formyl group, acetyl group, benzoyl group and the like), carboxyl group, an alkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, N,N-dimethylcarbamoyl group and the like), an alkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), amino group, an alkylamino group (e.g., methylamino group, ethylamino group; dimethylamino group and the like), an alkenylamino group (e.g., allylmethylamino group and the like), an acylamino group (e.g., acetylamino group, formylamino group, benzoylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group and the like), nitro group, xe2x80x94SR14 group {R14 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like)}, xe2x80x94SOR15 group {R15 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)} and xe2x80x94SO2R16 group {R16 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}. Hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, acetyl group, carbamoyl group, carboxyl group, or nitro group is preferred.
In group (III) represented by A in formula (I), the heteroring represented by B is preferably imidazole ring, triazole ring, pyridine ring, piperidine ring, pyrimidine ring, pyrazine ring, or piperazine ring. One or more hydrogen atoms on the heteroring represented by B may be substituted. Examples of the substituent include hydroxyl group, a halogen atom, phenyl group, an alkyl group, an alkoxyl group, an aryloxy group (e.g., phenoxy group and the like), an acyl group (e.g., formyl group, acetyl group, benzoyl group and the like), carboxyl group, an alkoxycarbonyl group, carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, N,N-dimethylcarbamoyl group and the like), an alkenylcarbamoyl group (e.g., allylcarbamoyl group and the like), amino group, an alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group and the like), an acylamino group (e.g., acetylamino group, formylamino group, benzoylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e g., methoxycarbonylamino group and the like), nitro group, xe2x80x94SR17 group {R17 represents an alkyl group, phenyl group, or a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like)}, xe2x80x94SOR18 group {R18 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like.), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}, and xe2x80x94SO2R19 group {R19 represents an alkyl group, phenyl group, a substituted phenyl group (examples of the substituent include a C1-4 alkyl group, a C1-4 alkoxyl group and the like), an alkoxyl group, amino group, or an alkylamino group (e.g., methylamino group, dimethylamino group and the like)}. Hydrogen atom, fluorine atom, chlorine atom, methyl group, ethyl group, acetyl group, carbamoyl group, carboxyl group, or nitro group is preferred.
In group (IV) represented by A in formula (I), examples of the group represented by R20 include hydrogen atom, alkyl groups, acyl groups, alkoxycarbonyl groups, carbamoyl group, alkylcarbamoyl groups (e.g., methylcarbamoyl group and the like), and amidino group. Hydrogen atom or amidino group is preferred.
In group (IV) represented by A in formula (I), examples of the group represented by R28 or R29 include hydrogen atom, halogen atoms, hydroxyl group, alkyl groups, amino group, and alkylamino groups. Hydrogen atom is preferred.
In group (IV) represented by A in formula (I), the group or atom represented by Y is preferably CH.
In group (IV) represented by A in formula (I), the integer represented by n or o is preferably 2.
In group (IV) represented by A in formula (I), the integer represented by r is preferably 2.
In group (XIV) represented by A in formula (I), examples of the group represented by R30, R31, R32, or R33 include hydrogen atom, halogen atoms, hydroxyl group, alkyl groups, amino group, oxo group, alkylamino groups and the like. Hydrogen atom, an alkyl group, or oxo group is preferred.
In group (XIV) represented by A in formula (I), the group or atom represented by V is preferably xe2x80x94Oxe2x80x94.
In group (XIV) represented by A in formula (I), the integer represented by s or t is preferably 1 or 2.
In formula (I), examples of the N-substituent of the piperidine ring represented by E together with A include hydrogen atom, an alkyl group, a substituted alkyl group (examples of the substituent include hydroxyl group, a halogen atom, amino group, an alkylamino group, an acylamino group, an alkoxycarbonylamino group, carbamoylamino group, guanidino group, oxo group, amidino group and the like), an acyl group, and amidino group. Hydrogen atom, an aminoalkyl group, an aminoalkyl group having oxo group, or amidino group is preferred.
In formula (I), examples of the substituent of the substituted phenyl group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2 or R3, include hydroxyl group, a halogen atom, phenyl group, an alkyl group (e.g., a C1-4 alkyl group and the like), an alkoxyl group (e.g., a C1-4 alkoxyl group and the like), an acyl group (e.g., formyl group, acetyl group, propionyl group, butenyl group, benzoyl group, pivaloyl group and the like), carboxyl group, an alkoxycarbonyl group (e.g., a C1-4 alkoxycarbonyl group and the like), an arylalkyloxycarbonyl group (e.g., benzyloxycarbonyl group and the like), an aryloxycarbonyl group (phenoxycarbonyl group and the like), amino group, an alkylamino group (e.g., a C1-4 alkylamino group, dimethylamino group, cyclohexylamino group and the like), an alkenylamino group (e.g., allylamino group, allylmethylamino group, allylcyclohexylamino group and the like), an arylamino group (e.g., phenylamino group and the like), an arylalkylamino group (e.g., benzylamino group and the like), an acylamino group (e.g., formylamino group, acetylamino group, benzoylamino group, pivaloylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group, phthaloylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group, isopropoxycarbonylamino group and the like), an aryloxycarbonylamino group (e.g., benzyloxycarbonylamino group and the like), an alkoxycarbonylalkylamino group (e.g., methoxycarbonylmethylamino group and the like), an alkylsulfonylamino group (e.g., methylsulfonylamino group, methyl(methylsulfonyl)amino group and the like), an alkylsulfonylalkylamino group, an arylsulfonylamino group (e.g., benzenesulfonylamino group and the like), an arylsulfonylalkylamino group, carbamoyl group, an alkylcarbamoyl group (e.g., methylcarbamoyl group, ethylcarbamoyl group, N,N-dimethylcarbamoyl group, N,Nxe2x80x2-dimethylcarbamoyl group and the like), an arylalkylcarbamoyl group (e.g., benzylcarbamoyl group and the like), and nitro group. Hydroxyl group, a halogen atom, an alkoxyl group, or amino group is preferred.
In formula (I), an example of the substituent of the substituted alkoxyl group, which may substitute on the alkyl group or alkoxyl group represented by R1, R2, or R3, includes a C1-4 alkoxyl group. Methoxy group or isopropoxy group is preferred.
In formula (I), examples of the alkoxycarbonyl group or aryloxycarbonyl group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2, or R3, include a C2-5alkoxycarbonyl group, benzyloxycarbonyl group, and phenoxycarbonyl group. Methoxycarbonyl group or isopropoxycarbonyl group is preferred.
In formula (I), examples of the substituted carbamoyl group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2, or R3, include a N-(C1-4 alkyl)carbamoyl group, a N,N-di(C1-4 alkyl)carbamoyl group, and a N,Nxe2x80x2-di(C1-4 alkyl)carbamoyl group. Methylcarbamoyl group or N,N-dimethylcarbamoyl group is preferred.
In formula (I), examples of the substituted amino group, which may substitute on the alkyl group or the alkoxyl group represented by R1, R2, or R3, include an alkylamino group (e.g., methylamino group, ethylamino group, n-propylamino group, isopropylamino group, cyclohexylamino group, dimethylamino group and the like), an alkenylamino group (e.g., allylamino group, allylmethylamino group, allylcyclohexylamino group and the like), an arylamino group (e.g., phenylamino group and the like), an arylalkylamino group (e.g., benzylamino group and the like), an acylamino group (e.g., formylamino group, acetylamino group, benzoylamino group, pivaloylamino group, phthaloylamino group and the like), an acylalkylamino group (e.g., acetylmethylamino group and the like), an alkoxycarbonylamino group (e.g., methoxycarbonylamino group, isopropoxycarbonylamino group and the like), an alkoxycarbonylalkylamino group (e.g., methoxycarbonylmethylamino group and the like), an arylalkyloxycarbonyl group (e.g., benzyloxycarbonylamino group and the like), an alkylsulfonylamino group (e.g., methylsulfonylamino group, methyl(methylsulfonyl)amino group and the like), an alkylsulfonylalkylamino group, an arylsulfonylamino group (e.g., phenylsulfonylamino group and the like), and an arylsulfonylalkylamino group. Methylamino group, allylamino group, acetylamino group, or methylsulfonylamino group is preferred.
Among the compounds represented by general formula (I), preferred compounds include those wherein X is xe2x80x94Oxe2x80x94.
Other preferred compounds include those wherein A is group (II).
Other preferred compounds also include those wherein E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
More preferred compounds are those wherein R1 is an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, phenyl group, a substituted phenyl group, or a heterocyclic group, R2 and R3 may be the same or different and independently are hydrogen atom, an alkyl group, a substituted alkyl group, phenyl group, or a heterocyclic group, or R2 and R3 form a 5 to 7-membered carbon ring together with the carbon atom to which they bind, X is xe2x80x94Oxe2x80x94, A is group (II), and E is hydrogen atom, or E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
Other class of more preferred compounds are those wherein R1 is an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, phenyl group, a substituted phenyl group, or a heterocyclic group; R2 and R3 may be the same or different and are independently hydrogen atom, an alkyl group, a substituted alkyl group, phenyl group, or a heterocyclic group, or R2 and R3 form a 5 to 7-membered carbon ring together with the carbon atom to which they bind; X is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94; A is
(a) group (II) in which R7 and R8 may be the same or different and are independently hydrogen atom, carbamoyl group, or amidino group; R9 and R10 may be the same or different and are independently hydrogen atom or an alkyl group; m is an integer of from 1 to 8; and xe2x80x94(C)mxe2x80x94 is a saturated carbon chain;
(b) group (III) in which both R7 and R8 are hydrogen atom; R24, R25, R26, and R27 may be the same or different and are independently hydrogen atom or an alkyl group; p and q are independently an integer of from 0 to 2; xe2x80x94(C)pxe2x80x94 and xe2x80x94(C)qxe2x80x94 are independently single bond or a saturated carbon chain; and B is a carbocyclic group;
(c) group (IV) in which R20 is hydrogen atom; R28 and R29 may be the same or different and are independently hydrogen atom or an alkyl group; n and o are independently an integer of from 0 to 5; r is independently an integer of from 0 to 4; xe2x80x94(C)rxe2x80x94 is independently single bond or a saturated carbon chain; and Y is CH; or
(d) group (XIV) in which both R7 and R8 are hydrogen atom; R30, R31, R32, and R33 may be the same or different and are independently hydrogen atom, an alkyl group, or oxo group; s is an integer of from 0 to 3; t is an integer of 1 to 3; xe2x80x94(C)sxe2x80x94 and xe2x80x94(C)txe2x80x94 are independently single bond or a saturated carbon chain; and V is xe2x80x94Oxe2x80x94; and E is hydrogen atom, or E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
Further preferred compounds include those wherein R1 is an alkyl group, a substituted alkyl group, an alkoxyl group, a substituted alkoxyl group, phenyl group, a substituted phenyl group, or a heterocyclic group; R2 and R3 may be the same or different and are independently hydrogen atom, an alkyl group, a substituted alkyl group, phenyl group, or a heterocyclic group, or R2 and R3 form a 5 to 7-membered carbon ring together with the carbon atom to which they bind; X is xe2x80x94Oxe2x80x94; A is:
(a) group (II) in which R7 and R8 may be the same or different and are independently hydrogen atom, carbamoyl group, or amidino group; R9 and R10 may be the same or different and are independently hydrogen atom or an alkyl group; m is an integer of from 1 to 8; and xe2x80x94(C)mxe2x80x94 is a saturated carbon chain; or
(b) group (XIV) in which both R7 and R8 are hydrogen atom; R30, R31, R32, and R33 may be the same or different and are independently hydrogen atom, an alkyl group, or oxo group; s is an integer of from 0 to 3; t is an integer of from 1 to 3; xe2x80x94(C)sxe2x80x94 and xe2x80x94(C)txe2x80x94 are independently single bond or a saturated carbon chain; and V is xe2x80x94Oxe2x80x94; and E is hydrogen atom, or E is xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A.
Still further preferred compounds include those wherein R1 is an alkyl group or a phenylalkyl group; R2 and R3 may be the same or different and are independently an alkyl group; X is xe2x80x94Oxe2x80x94; A is group (II) in which R7 and R8 may be the same or different and are independently hydrogen atom, carbamoyl group, or amidino group; R9 and R10 may be the same or different and are independently hydrogen atom or an alkyl group;
m is an integer of from 1 to 8; and xe2x80x94(C)mxe2x80x94 is a saturated carbon chain; and E is hydrogen atom.
Preferred specific examples of the compound represented by general formula (I) include, but not limited thereto:
(S)-6-amino-2-(((R)-1-(benzyloxycarbonylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-ethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(((3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((cyclopropyl(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-5-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-cyclohexyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-cyclobutyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-4-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoic acid,
(S)-6-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-4-ureido-butanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclohexyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)-5-ureido-pentanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-4-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)butanoic acid,
(S)-5-guanidino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)pentanoic acid,
(S)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-(1S)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
6-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylhexanoic acid,
(S)-6-amino-2-((3,3-dimethyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(2-methyl-1-(4-phenylbutanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((4,4,4-trifluoro-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoic acid,
(R)-7-amino-2-((1-(3-phenylpropanoylamino)cyclopentyl)(hydroxyphosphinoyl)oxy)heptanoic acid,
(S)-7-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)heptanoic acid,
2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)-4-(piperidin-4-yl)butanoic acid,
1-(trans-(4-aminomethylcyclohexyl))-1-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)acetic acid,
3-aminoacetoxy-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)propanoic acid,
8-amino-2-(2-methyl-(1R)-(3-phenylpropanoylamino)propyl(hydroxyphosphinoyl)oxy)octanoic acid,
(S)-6-amino-2-((1-phenyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-phenylpropanoylamino)-1-(tetrahydropyran-4-yl)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-5-amino-2-((3-methyl-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)pentanoic acid,
(S)-6-amino-2-((2-hydroxy-1-(3-phenylpropanoylamino)ethyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-cycloheptyl-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(piperidin-4-yl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((4-amino-1-(3-phenylpropanoylamino)butyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(4-methylcyclohexyl)-1-(3-phenylpropanoylamino)methyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(((1R)-((2S)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-(1R)-phenylacetylaminopropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-((2R)-amino-3-phenylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-cyclopentylpropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(2,4-difluorobenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-benzoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-(2-methoxyphenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(4-methoxyphenyl)acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-heptanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(2-amino-2-phenylacetylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-((pyridin-2-yl)acetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-(((1R)-(4-methoxybenzoylamino)-2-methylpropyl)(hydroxyphosphinoyl) oxy)hexanoic acid,
(S)-6-amino-2-((1-dodecanoylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-2-((1-acetylamino-2-methylpropyl)(hydroxyphosphinoyl)oxy)-6-aminohexanoic acid,
(S)-6-amino-2-((1-(3-(4-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-(3-aminophenyl)propanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(trifluoroacetylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(3-phenyl-(2S)-(3-phenylpropanoylamino)propanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-((3R)-hydroxybutanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-methoxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(3,4,5-trimethoxybenzoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((1-(3-carboxypropanoylamino)-2-methylpropyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(pyridin-2-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
(S)-6-amino-2-((2-methyl-1-(morpholine-4-carbonylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid,
4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid,
1-amidino-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid,
1-(2-aminoethyl)-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid,
(R)-6-amino-2-((2-methyl-(1R)-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)hexanoic acid, and
7-amino-2-((2-methyl-1-(3-phenylpropanoylamino)propyl)hydroxyphosphinoyl)methylheptanoic acid.
The compound represented by the aforementioned formula (I) may optionally have one or more asymmetric carbon atoms and exist as a stereoisomer (an optical isomer or a diastereoisomer) based on the asymmetric carbon atom(s). Any mixtures of the stereoisomers and racemates as well as the stereoisomers in a pure form fall within the scope of the present invention, and any of the aforementioned substances may be used as an active ingredient of the medicament of the present invention. When the compound represented by the aforementioned formula (I) has an olefinic double bond, the compound may exist as a geometrical isomer in either Z- or E-form or a mixture thereof, any of which falls within the scope of the present invention. The geometrical isomer in a pure form or a mixture thereof may be used as an active ingredient of the medicament of the present invention.
Among the compounds of formula (I) according to the present invention, those wherein X is oxygen atom or xe2x80x94NHxe2x80x94 in formula (I) can be prepared by synthetic method (I), (II), or (III) shown below. The compounds wherein X is xe2x80x94CH2xe2x80x94 and E is hydrogen atom can be prepared by the following synthetic method (IV), (V), (VI), or (VII). The compounds wherein X is xe2x80x94CH2xe2x80x94 and E is xe2x80x94CH2CH2xe2x80x94 that forms a piperidine ring group or a N-substituted piperidine ring group together with A can be prepared by synthetic method (VI) or (VII). However, preparations of the compounds of the present invention are not limited to these methods.
In order to synthesize the compound of formula (I) of the present invention, the amino group (the amino group herein defined includes an amino group on the piperidine ring formed by E together with A.), imino group, and carboxyl group used in the following synthetic methods (I) to (VII) may be protected, if desired. As a protecting group, ordinary protecting groups can be used. Preferably, examples for an amino group or an imino group includes methoxycarbonyl group, tert-butyloxycarbonyl group, benzyloxycarbonyl group, methoxybenzyloxycarbonyl group, nitrobenzyloxycarbonyl group, allylbenzyloxycarbonyl group, acetyl group, trifluoroacetyl group, trichloroacetyl group, benzoyl group, phthaloyl group, trityl group, benzyl group, methoxybenzyl group, allyl group, formyl group and the like, and examples for carboxyl group include methyl group, tert-butyl group, benzyl group, paramethoxybenzyl group, nitrobenzyl group, allyl group, benzhydryl group, trityl group and the like.
Synthetic Method (I)
[In the scheme, R1, R2, R3, A, and E have the same meanings as those defined in formula (I), W represents oxygen atom or xe2x80x94NHxe2x80x94, and Z represents hydrogen atom, hydroxyl group, or alkoxyl group.]
A compound of the formula (VII) can be prepared according to the method described in Tetrahedron Lett., 7333 (1991), U.S. Pat. No. 4,616,005 or the like. Specifically, the method comprises condensing a compound of formula (V) and a compound of formula (VI) by applying, for example, the dehydration method using N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), benzotriazoleoxytrisdimethylaminophosphonium tetrafluorophosphate (BOP) or the like, the acid halide method using thionyl chloride, oxalyl chloride, phosphorus oxychloride or the like, the mixed acid anhydride method using pivaloyl chloride, a chloroformic acid ester or the like in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 30xc2x0 C.
As the amine of formula (VI), a commercially available compound may be used, or the amine can be synthesized according to the method described in Synthesis, 370(1998), Liebigs. Ann. Chem., 861(1988), J. Chem. Soc. Perkin trans. 1, 2845(1984) or the like. Where Z is hydrogen atom in the compound of formula (VII), the hydrogen atom can be converted into hydroxyl group by an ordinary oxidation in this step, and the hydroxyl group may be converted into an alkoxyl group, if desired.
The condensation between the compound of formula (VII) and a carboxylic acid compound of formula (VIII) can be carried out according to the method described in J. Am. Chem. Soc., 297(1991), J. Org. Chem., 658(1994), J. Med. Chem., 3303(1998), Synthesis, 556(1986), J. Med. Chem., 1459(1990), Tetrahedron Lett., 1751(1986) or the like. Specifically, the method comprises condensing the compound of formula (VII) and the compound of formula (VIII) by applying, for example, the dehydration method using N-(dimethylaminopropyl)-Nxe2x80x2-ethylcarbodiimide hydrochloride, N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), benzotriazoleoxytrisdimethylaminophosphonium tetrafluorophosphate (BOP) or the like, the acid halide method using thionyl chloride, oxalyl chloride, phosphorus oxychloride or the like, the mixed acid anhydride method using pivaloyl chloride, a chloroformic acid ester or the like in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 30xc2x0 C. The compound wherein X is oxygen atom or xe2x80x94NHxe2x80x94 in formula (I) can be synthesized through deprotection at need after the condensation, or when Z is hydrogen atom, by performing oxidation according to a conventional method after the condensation, and then deprotection at need.
Synthetic Method (II)
[In the scheme, R1, R2, R3, A, E, W, and Z have the same meanings as those defined above.]
The compound of formula (I) can be synthesized according to the method shown in the aforementioned synthetic method (I).
Where Z is hydrogen atom in a compound of formula (IX), the hydrogen atom can be converted into hydroxyl group by an ordinary oxidation in this step, and the resulting hydroxyl group may be converted into an alkoxyl group, if desired.
The condensation between the compound of formula (V) and the compound of formula (IX) can be performed in the same manner as those described in the aforementioned synthetic method (I). The compound wherein X is oxygen atom or xe2x80x94NHxe2x80x94 in formula (I) can be synthesized through deprotection at need after the condensation, or where Z is hydrogen atom, by an oxidation in a conventional manner after the condensation, and then deprotection at need.
Synthetic Method (III)
[In the scheme, R1, R2, R3, A, E, W, and Z have the same meanings as those defined above.]
A compound of formula (X) can be prepared according to the method described in Tetrahedron Lett., 5457(1996), Ibid., 6073(1996) or the like. Specifically, the compound of formula (X) wherein Z is hydroxyl group or an alkoxyl group can be obtained by reacting a compound of formula (VIII) with a phosphorylating agent such as 2-chloro-4H-1,3,2-benzodioxaphophorin-4-one, 2-chloro-1,3,2-dioxaphophorane, 2-cyanoethyl N,Nxe2x80x2-diisopropylchlorophosphoramidate, and phosphorus trichloride in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours, at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9230xc2x0 C. to 30xc2x0 C., and then performing hydrolysis or alcoholysis, if desired. When Z is hydroxyl group in formula (X), a compound wherein Z is an alkoxyl group in formula (X) can also be obtained by performing esterification by a conventional method.
A compound of formula (IX) can be synthesized according to the method described in Tetrahedron Lett., 5457(1996) or the like. Specifically, the compound of formula (IX) wherein Z is hydroxyl group or an alkoxyl group can be obtained by reacting the compound of formula (X) with the compound of formula (XI), per se, or under irradiation by ultrasound or in the presence of a Lewis acid such as boron trifluoride, titanium chloride, tin chloride and yttrium triflate, in a solvent which does not participate in the reaction for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9230xc2x0 C. to 60xc2x0 C., and then performing deprotection at need. The compound of formula (I) can be synthesized according to the method of synthetic method (I).
Synthetic Method (IV)
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, and Z represents hydrogen atom.]
A compound of formula (VII) can be synthesized by the method shown in the aforementioned synthesis method (I).
The reaction of the compound of formula (VII) and a compound of formula (XII) can be carried out according to the method described in Bioorg. Med. Chem. Lett., 1257(1996), J. Med. Chem., 1652(1989), J. Am. Chem. Soc., 297(1991), Tetrahedron, 3375(1998), Tetrahedron Lett., 2933(1990), U.S. Pat. No. 357,941 or the like. Specifically, the method comprises activating or esterifying the compound of formula (VII), if desired, by using a silyl group or the like to elevate the reactivity of the compound of formula (VII), and subjecting the compound of formula (XII) to Michael addition in a solvent which does not participate in the reaction or without solvent, for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from 0xc2x0 C. to 50xc2x0 C. The compound wherein X is xe2x80x94CH2xe2x80x94 and E is hydrogen atom in formula (I) can be synthesized through deprotection at need after the Michael addition.
A compound of formula (XII) can be synthesized according to the method described in J. Med. Chem., 2461(1994) or the like.
Synthetic Method (V)
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, and Z represents hydrogen atom.]
A compound of formula (XIII) can be synthesized according to the method shown in the aforementioned synthetic method (IV).
The condensation between the compound of formula (V) and the compound of formula (XIII) can be performed according to the method shown in the aforementioned synthetic method (I), and the compound wherein X is xe2x80x94CH2xe2x80x94 and E is hydrogen atom in formula (I) can be synthesized through deprotection at need after the condensation.
Synthetic Method (VI)
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, E represents hydrogen atom or xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A, and Z represents hydrogen atom.]
The compound of formula (VII) can be synthesized by the method shown in the aforementioned synthetic method (I).
A compound of formula (XVI) can be synthesized according to the method described in J. Med. Chem., 2461(1994) or the like.
The condensation between the compound of formula (VII) and the compound of formula (XVI) can be performed according to the method described in Bioorg. Med. Chem. Lett., 1629(1996). Specifically, the compound wherein X is carbon atom in formula (I) can be synthesized by activating the hydroxyl group in formula (XVI) with trifluoromethanesulfonic anhydride, methanesulfonyl chloride, toluenesulfonyl chloride or the like, or substituting the hydroxyl group in formula (XVI) with a halogen atom by a conventional method, and by activating or esterifying the compound of formula (VII) with silyl group or the like at need to elevate the reactivity of the compound of formula (VII), and then, carrying out the reaction in a solvent which does not participate in the reaction or without solvent, in the presence of base at need such as triethylamine, diisopropylethylamine, pyridine, lutidine, potassium carbonate, sodium hydrogencarbonate, sodium hydride and lithium diisopropylamide, for a reaction time of from 0.5 to 72 hours, preferably from 2 to 24 hours at a reaction temperature of from xe2x88x9278xc2x0 C. to 100xc2x0 C., preferably from xe2x88x9278xc2x0 C. to 60xc2x0 C., and performing deprotection at need.
Synthetic Method (VII)
[In the scheme, R1, R2, R3, and A have the same meanings as those defined above, E represents hydrogen atom or xe2x80x94CH2CH2xe2x80x94 that forms piperidine ring group or a N-substituted piperidine ring group together with A, and Z represents hydrogen atom.]
A compound of formula (XVII) can be synthesized according to the method shown in the aforementioned synthetic method (VI). The condensation between the compound of formula (V) and the compound of formula (XVII) can be performed according to the method shown in the aforementioned synthetic method (I), and the compound wherein X is xe2x80x94CH2xe2x80x94 in formula (I) can be synthesized through deprotection after the condensation.
Specific preparations of the compound of the present invention encompassed within formula (I) are shown in Examples of the specification. Those of ordinary skill in the art can easily prepare the compound of the present invention falling within formula (I) by referring to the aforementioned general explanation and specific explanation in examples, and by appropriately selecting a starting material, a reagent, reaction conditions and the like, and if necessary, applying appropriate modifications and alterations to these methods.
The compound of formula (I) according to the present invention may exist as a salt, and may preferably exist as a pharmacologically acceptable salt. Such salts include medicinally acceptable nontoxic salts, for example, alkali metal salts and alkaline-earth metal salts such as sodium salt, potassium salt, and calcium salt, hydrogen halide salts such as hydrochloride, inorganic salts such as nitrate, sulfate and phosphate, salts of sulfonic acids such as methanesulfonic acid and benzenesulfonic acid, salts of organic acids such as fumaric acid, succinic acid, citric acid, oxalic acid and maleic acid, salts of amino acids such as glutamic acid and aspartic acid, and the like.
The compound of formula (I) according to the present invention may exist as a hydrate or a solvate. Preferred solvates include a solvate with ethanol and the like. Any salts, hydrates, and solvates of the compound of formula (I) fall within the scope of the present invention.
The compound of formula (I) according to the present invention have thrombolytic activity based on inhibition of carboxypeptidase B in human plasma. Accordingly, a substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof is useful as an active ingredient of medicaments for therapeutic and/or preventive treatment of various thrombotic diseases such as myocardial infarction, cerebral infarction, angina, pulmonary embolus, chronic arterial obliteration, acute arterial thrombus and embolus, angitis syndrome, diabetic gangrene, thrombophlebitis and deep vein thrombosis, thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, disseminated intravascular coagulation, and anti-phospholipid antibody syndrome, and pathologic conditions such as diabetes, hyperlipemia, and inflammation in which thrombotic tendency due to the decrease of in vivo fibrinoliablity have been recognized.
The substance selected from the group consisting of the compound of formula (I) according to the present invent ion and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof is also effective as a carboxypeptidase B inhibitor. As the carboxypeptidase B inhibitor according to the present invention, the aforementioned substance, per se, can be used. For example, the inhibitor can also be used as a reagent for enzymes.
The substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof, per se, may be used as a medicament. However, the medicament of the present invention is preferably provided as a pharmaceutical composition which comprises the aforementioned substance together with a pharmacologically acceptable carrier, and can be administered to a human as well as an animal other than human by either an oral or parenteral (e go, intravenous, intramuscular, subcutaneous, rectal, transdermal and the like) administration. Two or more of the aforementioned substances may be formulated in combination in the pharmaceutical composition.
The pharmaceutical composition which comprises as an active ingredient a substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof can be prepared as a formulation suitable for a route of administration. Specifically, the pharmaceutical composition can be prepared typically in any one of formulations including preparations for parenteral administration such as injections for intravenous or intramuscular administration, drip infusions, inhalants, transdermal preparations, transmucosal preparations, rectal preparations, oleaginous suppositories, and aqueous suppositories, and preparations for oral administration such as capsules, tablets, granules, powders, pills, fine granules, and troches.
As the pharmacologically acceptable carrier used for the manufacture of these various preparations, one or more solid or liquid carriers suitable for administration to humans as well as animals other than humans can be used. Examples of the solid carriers include, for example, starch, lactose, crystalline cellulose, calcium carbonate and the like. Examples of the liquid carriers include, for example, physiological saline, ethanol and the like.
One or more kinds of commonly used excipients, bulking agents, binders, moisturizing agents, disintegrators, surface active agents, lubricants, dispersants, buffering agents, preservatives, solubilizing aids, antiseptics, corrigents, soothing agents, stabilizers and the like may be used as the pharmacologically acceptable carrier. Examples of usable nontoxic carriers include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose and its salts arabic, polyethylene glycol, syrup, Vaseline, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like.
The content of the substance selected from the group consisting of the compound of formula (I) according to the present invention and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof contained in the pharmaceutical composition may vary depending on dosage forms. Generally, the amount may be from about 1% to about 70% by weight, preferably from about 5% to about 50% by weight based on the total weight of the composition.
A dose can be appropriately chosen in view of the use of the medicament, the age, sexuality and conditions of a patient and the like. The dose may generally be from about 0.1 mg to 1,000 mg, and preferably from 1 mg to 300 mg per day for an adult for therapeutic treatment of thrombotic diseases. The aforementioned dose can be administered once a day or several times a day as divided portions.

Phosphonic acid derivative having inhibitory activity against carboxypeptidase B

Abstract: wherein R1 represents hydrogen atom, an alkyl group, a substituted alkyl group and the like; R2 and R3 represent hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxyl group and the like; X represents xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94; A represents the following group (II):

Abstract: [in which R7 and R8 represent hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group and the like; R9 and R10 represents hydrogen atom, a halogen atom, hydroxyl group, phenyl group, an alkyl group and the like] and the like; and E represents hydrogen atom and the like, which has inhibitory activity against carboxypeptidase B and is useful for therapeutic and/or preventive treatment of a thrombotic disease.


Concave serrations are provided in an inner surface of a conductor crimping portion of a crimp terminal. A number of circular concave portions are provided in the inner surface of the conductor crimping portion as the concave serrations so as to be scattered in a state of being spaced aside from one another. A diameter of an inner bottom surface of each circular concave portion is set within a range of 0.15 (an error range is ±0.04) mm to 0.8 (the error range is ±0.04) mm. A serration angle between an extension surface of the inner bottom surface and an inner side surface of each circular concave portion is set within a range of 60 to 90 degrees. A shortest distance of a flat surface portion between peripheries of mutually adjacent circular concave portions is set to be 0.17 (the error range is ±0.09) mm.

1. Field of the Invention
The present invention relates to an open-barrel type crimp terminal having concave serrations in an inner surface of a conductor crimping portion having a U-letter shaped cross section.
2. Description of the Related Art
Conventionally, a general crimp terminal is, for example, provided with an electrical connection portion, a conductor crimping portion, and a sheath crimping portion as shown in Patent Literature 1 (Japanese Patent Application Laid-Open Publication No. 2010-198776). The electrical connection portion is provided at a front in a longitudinal direction of the terminal (in a same direction as a longitudinal direction of a conductor of an electrical wire connected to the terminal), and is connected to a terminal of a mating connector. The conductor crimping portion is provided closer to a rear than the electrical connection portion in the longitudinal direction of the terminal, and is crimped to the conductor exposed at a terminal of the electrical wire. The sheath crimping portion is provided closer to the rear than the conductor crimping portion in the longitudinal direction of the terminal, and is crimped to an insulation-coated portion of the electrical wire.
The conductor crimping portion is formed to have a substantially U-letter shaped cross section. The conductor crimping portion has a bottom plate, and a pair of conductor crimping pieces that are extended upward from both left and right side edges of the bottom plate and that crimp the conductor of the electrical wire arranged on an inner surface of the bottom plate so as to wrap it. The sheath crimping portion is formed to have a substantially U-letter shaped cross section. The sheath crimping portion has a bottom plate, and a pair of sheath crimping pieces that are extended upward from the both left and right side edges of the bottom plate and that crimp the electrical wire (insulation-coated portion) arranged on the inner surface of the bottom plate so as to wrap it. In an inner surface of the conductor crimping portion, provided is a plurality of concave groove-shaped serrations that extend in a direction perpendicular to a direction where the conductor of the electrical wire extends (terminal longitudinal direction).
FIG. 1(a) shows an expanded shape of a conductor crimping portion of a crimp terminal of a conventional example. A conductor crimping portion 213 of a crimp terminal 200 is formed of a bottom plate 215, and a pair of conductor crimping pieces 213a and 213a that are extended upward from both left and right side edges of the bottom plate 215 and that crimp a conductor of an electrical wire arranged on an inner surface of the bottom plate 215 so as to wrap it. Although FIG. 1(a) shows the expanded shape of the conductor crimping portion, actually, the conductor crimping portion 213 is bent to have a substantially U-letter shaped cross section in an uncrimped state. In an inner surface of the conductor crimping portion 213, provided is a plurality of concave groove-shaped serrations 220 that extend in a direction perpendicular to a direction where the conductor of the electrical wire extends.
FIG. 1(b) is an arrow cross-sectional view taken along a line B-B of FIG. 1(a). A cross-sectional shape of the concave groove-shaped serration 220 is usually a rectangle or an inverted trapezoid. In the present description, an angle θ between an extension surface of an inner bottom surface and an inner side surface of the serration 220 is called a serration angle. This serration angle θ is generally set in a range of 45 to 90 degrees.
In order to pressure-bond the conductor crimping portion 213 of the crimp terminal 200 to the conductor (illustration is omitted) of a terminal of the electrical wire, the crimp terminal 200 is placed on a placement surface (top surface) of a lower mold (an anvil, illustration is omitted), and the conductor of the electrical wire is inserted between the pair of conductor crimping pieces 213a and 213a of the conductor crimping portion 213 to be placed on the top surface of the bottom plate 215. Then, an upper mold (clamper) is then lowered relatively to the lower mold, and thereby tip sides of the conductor crimping pieces 213a are gradually tilted inside the crimp terminal 200 in a guide inclined surface of the upper mold. When the upper mold (clamper) is further lowered relatively to the lower mold, the tips of the conductor crimping pieces 213a and 213a are rounded so as to be folded to a conductor side in a curved surface continuous to a central chevron portion from the guide inclined surface of the upper mold, and bite into the conductor of the electrical wire while rubbing against each other. Thereby, the conductor crimping pieces 213a and 213a are crimped so as to wrap the conductor therein. By the above operation, the conductor crimping portion 213 of the crimp terminal 200 can be connected to the conductor of the electrical wire by crimping. In this crimping, the conductor of the electrical wire gets into the serrations 220 of the inner surface of the conductor crimping portion 213 while causing a plastic deformation by a pressure force. Thereby, electrical and mechanical joining of the terminal 200 and the electrical wire is enhanced.
By the way, when a shape of the concave serration 220, particularly the serration angle θ significantly decreases (herein, change of this serration angle is also referred to as "angle deformation") by a pressure force at the time of crimping, a stress that is transmitted to an element wire of the conductor is reduced, thereby a serration function is not sufficiently exerted, and/or a relative sliding distance between the terminal and the conductor decreases, thereby an adhesion amount (a coupling amount of metal at a molecular or an atomic level) enough to sufficiently secure crimping performance can not be obtained. As a result of it, there is a problem of leading to deterioration of the crimping performance.
For example, as shown in FIG. 2(a), in a case of the conventional concave groove-shaped serrations 220, it has been confirmed that the serration angle significantly decreases as a compression rate becomes larger. In addition, although as shown in FIG. 2(b), a stress applied to the conductor increases as the compression rate becomes larger, it has been confirmed that an increase rate of the stress is considerably reduced in a case where angle deformation occurs as compared with a case where it does not occur.
Accordingly, in order to improve the crimping performance, it is important to make higher the stress working on the conductor and to increase an adhesion amount between the terminal and the conductor by crimping. In order to make the stress of the conductor higher and to increase the adhesion amount, it is necessary to sufficiently fulfill a serration function by suppressing the angle deformation of the serrations, and to increase a relative sliding distance between the terminal and the conductor.


A new and distinct Actinidia deliciosa cultivar named ‘Renact’ is disclosed, characterized by unique self-fertility resulting in fruit of a useful size. The new variety is an Actinidia deliciosa, typically useful for home gardening applications.

The new cultivar is a product of a planned breeding program under the direction of the inventor, Jean Renault, a citizen of France. 'Renact' was discovered as a seedling, resulting from an open pollination of the seed parent variety Actinidia deliciosa 'Hayward' unpatented. The pollen parent is unknown. 'Renact' was discovered at a commercial nursery in 1995, located in Gorron, France.
The new variety was observed for several years, and first propagated by semi-hardwood cuttings in 2005, at a commercial nursery in Gorron, France. Subsequent evaluations of the variety have shown the characteristics to be true to type.


A symbol information reader may include an imager; an image memory configured to save image data of a recording medium; and a position detecting processor configured to retrieve the image data and detect the positions of symbols on the recording medium. The position detecting processor may be configured to calculate the amount of change in luminance value of scanning lines in a predetermined area of the image data and discriminate a provisional area possibly corresponding to the symbol, acquire correlations of the provisional area with neighboring areas and create a map showing an area with high correlation values, search the correlation map for the presence of the symbols and label on areas judged having the symbols, set an area for each of the multiple symbols and makes divisions, and detect positions of the symbols printed on the recording medium.

A barcode is an example of a symbol information representing various information, in which multiple bars and spaces are alternately arranged. The barcode is used for ID cards in which personal numbers, etc. are recorded in the form of barcodes.
A barcode reader is used to scan the entire surface of such an ID card, take the image in and read a barcode in the image (referring to Patent reference 1). A symbol information reader disclosed in Patent reference 1 acquires the center of gravity position of a symbol labeling map (a barcode map), acquires the left, right, top and bottom edge positions of the barcode symbol on the symbol labeling map, having the center of gravity position as the original point, and detects the position of the barcode symbol.

Symbol information reader and symbol information reading method


A picture display device including a generator circuit for generating a periodical waveform for addressing picture elements on a picture display screen, this generator circuit including a time-determining network with a capacitor. To reduce the influence of tolerances, the picture display device is provided with a compensation circuit including a second generator for generating a second periodical waveform and a source for applying a compensation current to the first-mentioned capacitor in dependence upon the second waveform, the second waveform generator including a time-determining network with a second capacitor and both capacitors being integrated in one semiconductor body.

1. Field of the Invention
The invention relates to a picture display device including a generator circuit for generating a periodical waveform for addressing picture elements on a picture display screen, said circuit comprising a time-determining network including a capacitor.
Recently, advanced techniques have made it possible to integrate time-determining RC networks in a semiconductor body. This integration requires very strict tolerances of the order of 1 to 2% in order to preclude adjustments. However, when integrating these networks, the tolerance is of the order of 5 to 10% for the capacitors and 10 to 15% for the resistors, and moreover, the resistors have a noticeable temperature coefficient.
2. Description of the Related Art
A circuit in a picture display device for generating periodical waveforms for addressing picture elements on a picture display screen, for example, the deflection in a picture display tube, comprises inter alia generators, for example, sawtooth generators or controllable oscillators which are synchronized with line and field frequency signals, respectively, present in an incoming video signal. The integrated circuit of the Philips type TDA 8370 is an example of such a circuit. If the time-determining elements of the generators are also to be integrated in the same semiconductor body comprising the greater part of the circuit, the tolerances may lead to inadmissible variations in the nominal frequency and in the nominal amplitude of the waveforms generated by the generators.

Picture display device including a waveform generator/and a compensation circuit, and integrated circuit incorporating the same


Disclosed herein is a segmental ultrasonic cleaning apparatus configured to remove scales and/or sludge deposited on a tube sheet. The segmental ultrasonic cleaning apparatus includes a plurality of segment groups arranged in a ring shape on a top surface of a tube sheet along an inner wall of the steam generator, in which each of the segment groups includes an ultrasonic element segment and a guide rail support segment loosely connected to each other by metal wires through hand holes located at a lower portion of the steam generator, such that ultrasound waves radiated from an ultrasonic transducer in each of the ultrasonic element segments travels along the surface of the tube sheet, with the segment groups tightly connected in the ring shape by tightening the metal wires via wire pulleys of flange units.

1. Field of the Invention
The present invention relates to a segmental ultrasonic cleaning apparatus capable of removing scales and sludge in a heat exchanger using ultrasound waves and, more particularly, to a segmental ultrasonic cleaning apparatus configured to remove scales and/or sludge deposited on a top surface of a tube sheet, which supports tubes of a steam generator in a nuclear power plant, through concentration of ultrasound energy on the top surface of the tube sheet.
2. Description of the Related Art
Typically, scales and/or sludge are deposited on a tube surface and a tube sheet supporting tubes of a commercial heat exchanger during heat exchange, as is known in the art. Particularly, despite continuous management of quality of reactor water flowing into a steam generator in a nuclear power plant, metallic scales and/or sludge are deposited in the steam generator, thereby causing deterioration in heat exchange efficiency affecting output of the nuclear power plant as well as corrosion of the steam generator which results in a reduction of the life cycle of the steam generator.
Therefore, for the nuclear power plant, it is necessary to perform periodic cleaning of the steam generator. Currently, the cleaning method for the steam generator is generally classified into chemical cleaning and high-pressure water jet cleaning. Chemical cleaning permits cleaning of the entirety of the steam generator. However, since chemical cleaning entails considerable cleaning costs and causes chemical damage to the steam generator in addition to consuming large amounts of water, the chemical cleaning is performed only when necessary. On the other hand, high-pressure water jet cleaning is performed once per scheduled overhaul to remove scales and/or sludge deposited on top of a tube sheet in the steam generator. However, the high-pressure water jet cleaning typically permits cleaning of only a region that high-pressure jet water can reach. For example, a steam generator of a Korean standard nuclear power plant includes more tubes than other types of steam generators, such that a distance between the tubes is very narrow, thereby forming a shadow zone which some of the high-pressure water cannot reach during high-pressure water jet cleaning, thereby deteriorating cleaning efficiency.
In the nuclear power plant, ultrasonic elements are often used to clean the steam generator. In this case, with the steam generator filled with water or a liquid cleaning agent, the ultrasonic elements are immersed therein to remove scales and/or sludge from the top surface of the tube sheet via ultrasonication. Typically, due to the characteristics of ultrasound waves, the ultrasound waves are propagated to a portion contacting the liquid. Thus, when using the ultrasonic elements to clean the steam generator, there is a problem in that the range of the ultrasound waves is increased but the energy density of the ultrasound waves is significantly lowered as the distance from a source of the ultrasound waves increases.

Segmental ultrasonic cleaning apparatus for removing scales and sludge on top of tube sheet in heat exchanger


In a boiling water reactor nuclear plant, hydrogen is injected into the feed water to neutralize radiolysis which causes stress corrosion in stainless steel components. It has been discovered that by inhibiting volatile ammonia, and other gaseous nitrogen compounds from leaving the liquid phase portions of the plant to the steam phase portions of the plant, radiation is reduced to acceptable levels. Formation of ammonia is inhibited chemically, by altering the reaction paths for volatile nitrogen species with trace additives in the parts per billion range, suitable additives include nitrous oxide, copper, zinc, carbon dioxide, and other components. It has also been found that by manipulating the pH, the formation of the voltage nitrogen compounds, especially ammonia, is decreased. Similarly, by physically altering plant operating conditions to reduce sparging or scrubbing of the gases from areas of high radiation, confinement of the N-16 within the liquid phase of the plant within the reactor vessel occurs. It is further found that by decreasing the total hydrogen concentration in the core region, the N-16 volatility can be limited. This includes alternate hydrogen injection points and enhancement of the hydrogen-oxygen recombination reaction by e.g., catalysis by radiation or by surfaces. The possibility of increasing the N-16 holdup time in the steam phase is also considered. Finally, the concept of operating at a higher electrochemical potential which requires a lower hydrogen concentration and hence less N-16 converted to the volatile form is also described.

Boiling water reactors (BWRs) operating over long periods of time have stainless steel components which are subject to IGSCC. The injection of hydrogen into the feedwater of BWRs has been demonstrated as an effective means of suppressing the stress corrosion cracking of these stainless steel components. Under normal water chemistry conditions, the oxygen concentration is approximately 200 parts per billion (ppb) and the hydrogen concentration is approximately 10 ppb. Under hydrogen water chemistry conditions, the concentrations necessary to prevent ISGCC are in the range of 2-15 ppb oxygen and 100 ppb hydrogen. These concentrations are approximate and vary among reactors.
To inspect for the presence of stress corrosion, non-destructive testing is used. Such non-destructive testing of piping joints requires plant shutdown while the inspection occurs. Thus, even the threat of IGSCC costs the plant expensive down time.
Unfortunately, and coincident with this hydrogen treatment, higher levels of radiation in the main steam lines and turbines have been observed. These higher levels of radiation in the more heavily shielded plants have not caused a significant problem. Heavily shielded turbines, condensers and steam piping have prevented the radiation from finding its way through to operating personnel and occupied areas. Unfortunately, many plants include heavy shielding in the turbine, condenser and steam piping side of the plant which is only adequate to limit dose rates under normal water chemistry. This being the case, the increased levels of radiation have tended to limit the use of hydrogen water chemistry to prevent stress corrosion.
BWR operation under normal water chemistry produces a small fraction of N-16 formed by the n,p reaction of 0-16 and exists in a chemical form which tends to be volatile. As this fraction is transported in the aqueous phase in the reactor and the water coolant is converted to steam, a portion of the volatile fraction is swept into the steam phase and transported to the turbine.
N-16 is a radioactive nuclide whose half-life is approximately 7 seconds. In its decay, high energy gamma radiation of 6 and 7 MeV is emitted. Thus, during normal plant operation a significant radiation field emanates from the steam lines and turbine. Because of the intensity and relatively high energy of the gamma radiation, significant shielding is required to limit the radiation field intensity. In spite of the shielding, the influence of the N-16 source can be measured even at significant distances from the source.
We have discovered as a part of the present invention that the observed radiation levels are caused at least in part by the N-16 being converted into volatile nitrogen compounds, including ammonia, which are transported in the steam phase.
Under hydrogen water chemistry conditions, a larger fraction of the N-16 is converted to a volatile form. Thus, the radiation levels in the steam phase increase significantly when compared to the levels without hydrogen addition. Dependent on the reactor, the levels have been measured by us to increase from 1.2 to 5 times at the hydrogen concentration necessary to prevent IGSCC in the recirculation system. For some plants the increase is sufficient to exceed safety dose rate limits not only close to the source, but also in surrounding buildings and grounds and at site boundaries. This is perceived as one of the most detrimental aspects of hydrogen water chemistry. Thus, it would be highly desirable if a method could be found to limit the N-16 volatility, i.e., the quantity transported to the steam.

Method to control N-16 radiation levels in steam phase BWRs


A power-on reset (POR) circuit comprises a transistor connected ad diodes for setting temperature time delay coupled to a power supply voltage, a transistor switch, and buffering circuits. The trip point voltage of the POR circuit depends only on one type of transistor, such as the switching transistor so that the p-to-n skew variations do not affect the trip point. The switching transistor has a resistor connected from base to ground and another resistor connected to the power supply voltage to limit current flow during transitions.

The invention broadly relates to a power-on reset circuitry, especially those circuits that are adapted for low power consumption and high-density integrated circuits.
In semiconductor integrated circuits (IC) with latches and memory components, initial conditions are important. Incorrect initial conditions cause severe timing problems, as well as wrong states to the IC circuits. Power-on reset circuits are designed to correct initial value problems to the IC circuits. When the power supply voltage is first applied to an IC circuit, the power-on reset circuit detects the rising power supply voltage and provides a reset signal for initializing flip-flops, latches, counters, registers and other such internal components of a semiconductor IC circuit. When the power supply voltage is on, the reset signal is at first maintained low for a sufficient time to allow stabilization of the respective components of the circuit. After a predetermined time, the reset signal is switched to a logic high to reset the components of the circuit for as long as the power supply is needed to be on. We hold the part in reset until a voltage is reached that it can operate.
To achieve effective power-on reset (POR) circuits, consideration must be given to steady-state power dissipation, chip layout, production costs and the stability of the reset signal. It is customary to design a POR circuit on the same IC area as the main circuit. Some of the IC area is devoted to the POR circuit. In addition, to save the layout area, the use of passive elements such as resistors and capacitors that occupy a relatively large area, and depletion mode transistors which require additional manufacturing steps, must be avoided. Therefore, it is desirable to have the POR occupy as little area as possible.
It is also desirable for a POR circuit to have as little current flow as possible during operation because current flow represents power consumption. The values of parasitic components vary with manufacturing process, temperature, and voltage variations. The co-existence of a plurality of p-channel and n-channel MOS transistors in many POR circuits create parasitic paths and unwanted current flows. During transition, e.g., the reset signal switched from low to high, current tends to find a way to flow from high voltage areas to lower voltage areas such as electrical ground. Therefore, parasitic components probably created by the p-type to n-type skew variations during fabrication process also needed to be minimized.
It is also desirable to have a reset signal that is stable with temperature and voltage variations. When the reset signal is not stable, the initial conditions may confuse the IC circuit at the change of condition. Usually, the reset signal varies due to temperature change and variations between p-channel and n-channel transistors during manufacturing process. The reset signal needs to change at an exact voltage level called trip voltage. If there is a skew in p-channel to n-channel in the design of the MOS triggering device such as inverters in a POR circuit, the trip voltage is shifted to an undesired value, thus delaying the reset signal and causing serious timing problems.
A large variety of power-on reset circuits have been proposed to solve the above problems, such as the one described in FIG. 1.
With reference to FIG. 1, a 3.8 volt power-on reset circuit 100 generates a reset pulse when a power supply voltage 102 ramps up from 0 volt to 5 volts. When the power supply voltage reaches 3.8 volts, the POR circuit 100 detects this voltage and generates a reset pulse.
The POR circuit 100 employs the principle of a time delay circuit coupled to a pulse detector and a series of inverter buffers to generate a reset pulse. The delay circuit has a series of diode-connected transistors to set a trip point voltage. When the trip point voltage is reached, the POR circuit 100 begins to operate. The pulse detector detects the threshold voltage and generates a pulse. The buffers either pass or invert the pulse to the output.
The operation of the POR circuit 100 can be observed at key nodes A, B and C. Referring again to FIG. 1, the gate of a first p-type zero-threshold transistor 118 of the POR circuit 100 forms node A and coupled to two inverters 136 and 138. These two inverters are coupled together in series. The output terminal of the first inverter 136 forms node B and coupled to the input of the input terminal of the second inverter 138. The output terminal of the second inverter 138 forms node C and an output PORS.
The trip point of the POR circuit 100 is set by a transistor 128. The transistor 128 has its drain coupled to the power supply voltage 102, its gate coupled to the drain and to the first terminal of a CMOS capacitor 130. The second terminal of the CMOS capacitor is coupled to the electrical ground 130. The source of the transistor 128 is coupled to the input terminal of a third inverter 132. The output terminal of the third inverter 132 is coupled to the input terminal of the fourth inverter 134.
Usually, it takes milliseconds for the power supply voltage 102 to rise from 0 volt to full value. When the power supply voltage 102 reaches the threshold voltage of 3.8 volts, the three diode-connected transistors 108, 110, and 112 start to conduct. The voltage at node A follows the rising power supply voltage 102. Before the trip point voltage set by the transistor 128 is reached, the p-type transistors 118, 120, and 122 pull down the voltage of node A to ground. The transistor 128 pulls up the output PORS because the drain is at a voltage higher than the gate and the source, which are tied together. Therefore, before the threshold voltage is reached, the voltage of node A is zero. After the trip point voltage has been reached, the voltage at node A tracks the rising voltage of the power supply voltage VCC. The transistor 128 is in the cut-off state and the voltage at the PORS terminal goes low. Thus, the voltage at the terminal C goes high. The capacitor 130 is charged up during the period the voltage at A is zero. Therefore, there are no current flows from VCC To ground when the POR circuit transitions from high to low.
An object of the invention is to provide a power-on reset circuit that has a trip point independent of the fabrication process variation and zero power consumption during operation.
Another object of the present invention is to provide a power-on reset circuit that is immune to narrow width effects within sub-micron CMOS transistor logic channel.
The above objects have been achieved by a power-on reset circuit which is implemented entirely by devices coupled together in series including a temperature-independent time delay circuit, a switching transistor having a resistor to ground for reducing leakage current and a trip point dependent on only one type of transistor, and buffers. The trip point voltage depends on only one type of transistor so that p-to-n skew due to process variations or temperature changes is not a factor. Finally, the resistor reduces threshold leakage current during voltage transitions. This permits wide transistors to be used, instead of narrow long transistors in the stack. These transistors switch more abruptly once threshold is reached, so process variations are no longer a significant factor in power consumption.