A method of effecting serotonin-2-receptor antagonism in a mammal in need thereof, which entails administering to the mammal an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof:

This invention relates to novel pyrroloazepine derivatives. More specifically, this invention is concerned with pyrrolo[3,2-c]azepine derivatives, pyrrolo-[3,4-c]azepine derivatives and salts thereof, said derivatives and salts having strong serotonin-2 receptor antagonistic action of excellent selectivity and being useful, for example, for the prevention or treatment of ischemic heart diseases such as angina pectoris, arrhythmia, myocardial infarction, congestive heart failure and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, peripheral circulatory disturbances such as arteriosclerosis obliterans, thromboangiitis obliterans, Raynaud disease and Buerger disease, hypertension; their preparation process; and therapeutics containing them as effective ingredients.
Serotonin is a compound contained abundantly in platelets, which are a blood component, and in a central nervous system, it acts as a neurotransmitter. In platelets, it is released upon stimulation by thromboxane A2, ADP, collagen or the like, and synergistically acts on release of various platelet aggregation factors through activation of serotonin-2 receptors in the platelets and vascular smooth muscle cells and also on vasoconstriction by norepinephrine through xcex11 receptors, thereby inducing strong platelet aggregation and vasoconstriction [P. M. Vanhoutte, xe2x80x9cJournal of Cardiovascular Pharmacologyxe2x80x9d, Vol. 17 (Supple. 5), S6-S12 (1991)].
Serotonin is also known to potentiate proliferation of vascular smooth muscle cells [S. Araki et al., xe2x80x9cAtherosclerosisxe2x80x9d, Vol. 83, pp. 29-34(1990)]. It has been considered that, particularly when endothelial cells are injured as in arteriosclerosis or myocardial infarction, the vasoconstricting action and thrombus forming action of serotonin are exasperated, thereby reducing or even stopping blood supply to myocardial, cerebral and peripheral organs [P. Golino et al., xe2x80x9cThe New England Journal of Medicinexe2x80x9d, Vol. 324, No. 10, pp. 641-648(1991), Y. Takiguchi et al., xe2x80x9cThrombosis and Haemostasisxe2x80x9d, Vol. 68(4), pp. 460-463(1992), A. S. Weyrich et al., xe2x80x9cAmerican Journal of Physiologyxe2x80x9d, Vol. 263, H349-H358(1992)].
Being attracted by such actions of serotonin or serotonin-2 receptors, various attempts are now under way to use a serotonin-2 receptor antagonist as a pharmaceutical for ischemic diseases of the heart, the brain and peripheral tissues.
Several compounds, led by sarpogrelate, are known to have serotonin-2 receptor antagonistic action. They however do not include anything having the pyrrolo[3,2-c]azepine skeleton or the pyrrolo[3,4-c]azepine skeleton. Those known to have serotonin-2 receptor antagonistic action are accompanied with many problems to be improved in potency, toxicity, side effects or the like. On the other hand, medicines which have anti-serotonin action and xcex11-blocking action in combination are considered to become extremely effective medicines for the treatment and prevention of hypertension and ischemic heart diseases, because they have possibility to reduce side effects, such as orthostatic hypotension and reflex tachycardia, induced by antihypertensive action on the basis of the xcex11-blocking action and hypertension is a serious risk factor for ischemic heart diseases.
In view of the foregoing circumstances, the present inventors have proceeded with extensive research, resulting in the finding of pyrroloazepine derivatives which have strong serotonin-2 receptor antagonistic action and low toxicity and less side effects and are useful for the treatment and prevention of ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances. It has also been found that the compounds according to the present invention include those also having xcex11-blocking action in combination and that such compounds are useful as antihypertensives or the like having less side effects and are widely usable for the treatment and prevention of circulatory diseases.
The present invention has been completed based on the above described findings. A first object of the present invention is to provide a pyrroloazepine derivative or a salt thereof, said pyrroloazepine derivative being represented by the following formula (I):
wherein
the ring P represented by
means a pyrrole ring represented by the following structure:
in which R1 represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, and R2 represents a hydrogen atom or an alkyl group;
the dashed line indicates the presence or absence of a bond; and, when the bond indicated by the dashed line is present, Z2 is not present and Z1 represents a hydrogen atom but, when the bond indicated by the dashed line is absent, Z1 and Z2 are both hydrogen atoms; Z1 represents a hydrogen atom and Z2 represents a group OR3 in which R3 represents a hydrogen atom, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group; Z1 and Z2 both represent groups SR4 in which R4 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group; or Z1 and Z2 are combined together to represent an oxygen atom, a group NOR5 in which R5 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, or a group
in which L represents a substituted or unsubstituted ethylene group or a substituted or unsubstituted trimethylene group;
A represents an alkylene group, an alkenylene group or an alkynylene group; and
Y represents a group
in which W represents CH, Cxe2x95x90 or a nitrogen atom; and, when W represents CH, m stands for 0 or 1, n stands for 1 or 2, G represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group
in which R6 represents a substituted or unsubstituted aryl group, a group
in which R7 represents a hydroxyl group, an alkoxy group or an aralkyloxy group, or a substituted or unsubstituted cyclic or acyclic acetal group; when W represents Cxe2x95x90, m stands for 1, n stands for 1 or 2, G represents a group
in which the double bond is coupled with W and R8 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; when W represents a nitrogen atom, m stands for 0 or 1, n stands for 2 or 3, and G represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group xe2x80x94CHR9xe2x80x94 in which R9 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; E1 and E2 each independently represents a hydrogen atom or a lower alkyl group; and D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group.
Another object of the present invention is to provide a preparation process of the pyrroloazepine derivative (I) or its salt.
A further object of the present invention is to provide a pharmaceutical which comprises the pyrroloazepine derivative (I) or its pharmaceutically-acceptable salt as an effective ingredient and is usable for the treatment or the like of circulatory diseases.
In the pyrroloazepine derivatives (I) of the present invention, the ring P represents any one of the following pyrrole rings:
wherein R1 and R2 have the same meanings as defined above.
Preferred examples of the group R1 bonded to the nitrogen atom of the pyrrole ring can include linear or branched alkyl groups having 1-8 carbon atoms preferably, such as methyl, ethyl, n-propyl, isopropyl and n-pentyl; cycloalkyl groups having 3-8 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl; cycloalkyl-alkyl groups having 4-8 carbon atoms, such as cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl; aralkyl groups having 7-22 carbon atoms, such as diphenylmethyl, benzyl and phenethyl; and aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl. One or more hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and ethoxy. Particularly preferred examples of the group R1 can be methyl, ethyl, benzyl and phenyl.
Preferred examples of the group R2 bonded to a carbon atom of the pyrrole ring can include a hydrogen atom; and linear or branched alkyl groups having 1-8 carbon atoms preferably, such as methyl, ethyl, n-propyl, isopropyl and n-pentyl.
On the other hand, preferred examples of the group A in the compound (I) according to the present invention can include linear or branched alkylene groups having 2-10 carbon atoms, such as ethylene, trimethylene, tetramethylene, pentamethylene and octamethylene; linear or branched alkenylene groups having 4-10 carbon atoms, such as 2-butenylene and 3-pentenylene; and linear or branched alkynylene groups having 4-10 carbon atoms, such as 2-butynylene and 3-pentynylene. One or more of the hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms. Among the above groups, trimethylene and tetramethylene are particularly preferred.
Further, preferred examples of the group Z1 and the group Z2 in the compound (I) according to the present invention can include the following combinations: when the bond indicated by the dashed line is present, Z1 represents a hydrogen atom; when the bond indicated by the dashed line is absent, Z1 and Z2 are both hydrogen atoms, Z1 represents a hydrogen atom and Z2 represents the group OR3, Z1 and Z2 both represent the groups SR4, and Z1 and Z2 are combined together to represent an oxygen atom, the group NOR5 or the group
Preferred examples of R3 in the group OR3 can include a hydrogen atom; linear or branched alkyl groups having 1-4 carbon atoms preferably, such as methyl and ethyl; and aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl. One or more of the hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy. Of these, hydrogen atom and methyl group are particularly preferred.
Preferred examples of R4 in the group SR4 can include linear or branched alkyl groups having 1-4 carbon atoms preferably, such as methyl and ethyl; aryl groups having 6-14 carbon atoms such as phenyl and naphthyl; and aralkyl groups having 7-22 carbon atoms such as benzyl and phenethyl. One or more of the hydrogen atoms of each of these groups may be substituted, for example, by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4 carbon atoms, such as methoxy and/or ethoxy.
In addition, preferred examples of R5 in the group NOR5 can include a hydrogen atom; linear or branched alkyl groups having 1-4 carbon atoms preferably, such as methyl and ethyl; aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl; and aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl. One or more of the hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy. Of these, hydrogen atom and methyl group are particularly preferred.
Further, preferred examples of L in the group
can include ethylene and trimethylene. One or more of the hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl, aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl, and/or alkylidene groups having 1-4 carbon atoms preferably, such as methylidene and/or ethylidene.
In the compound (I) according to the present invention, Y is a group
wherein D, E1, E2, G, W, m and n have the same meanings as defined above. The group (hereinafter called the xe2x80x9ccentral heterocyclic groupxe2x80x9d) represented by the following formula:
wherein E1, E2, W and n have the same meanings as defined above is a heterocyclic group derived from pyrrolidine, piperidine, piperazine or homopiperazine, and two or less of the hydrogen atoms on the ring may be substituted by a like number of alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl.
When the central heterocyclic group is a heterocyclic group derived from pyrrolidine or piperidine, preferably a piperidine group, m stands for 0 or 1 (with the proviso that m stands for 1 when W represents Cxe2x95x90), and G represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group, a sulfonyl group, an alkylene group (an alkylene group having 1-4 carbon atoms preferably, with a methylene group being particularly preferred), an alkenylene group (an alkenylene group having 2-5 carbon atoms preferably, with a 2-propenylene group being particularly preferred), a group
in which R6 represents a substituted or unsubstituted aryl group, a group
in which R7 represents a hydroxyl group, an alkoxy group or an aralkyloxy group, a group
in which the double bond is coupled with W, R8 represents an alkyl. group having 1-4 carbon atoms preferably, such as methyl or ethyl, an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl, or an aralkyl group having 7-22 carbon atoms, such as benzyl or phenethyl, and these groups may be in substituted forms, or a cyclic or acyclic acetal group in which one or more of the hydrogen atoms may be substituted.
Here, R6 represents, for example, an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl. Illustrative of one or more substituents on its ring can be halogen atoms such as fluorine, chlorine and/or bromine; alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl; alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy; and/or hydroxyl groups. of these, preferred is a phenyl group which may be either unsubstituted or substituted by one or more fluorine atoms.
Further, R7 represents a hydroxyl group; an alkoxy group having 1-4 carbon atoms, such as methoxy or ethoxy; or a substituted or unsubstituted aralkyloxy group having 7-22 carbon atoms, such as benzyloxy, 4-fluorobenzyloxy or 2-phenylethoxy.
Exemplary substituents for R8 can include one or more of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, alkoxyl groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy groups, and hydroxyl groups. Illustrative of the substituent for the cyclic or acyclic acetal can be halogen atoms such as fluorine, chlorine and bromine, alkyl groups having 1-4 carbon atoms preferably, such as methyl and ethyl, aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl, aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl, and alkylidene groups having 1-4 carbon atoms preferably, such as methylidene and ethylidene.
Exemplary cyclic or acyclic acetal groups include groups represented by the following formulas:
As a particularly preferred example of G when the central heterocyclic group is one derived from pyrrolidine or piperidine, a carbonyl group can be mentioned.
When the central heterocyclic group is a group derived form piperazine or homopiperazine, preferably a piperazine group, m stands for 0 or 1 (preferably 0), and G represents a carbonyl group, a sulfonyl group, an alkylene group (preferably, an alkylene group having 1-4 carbon atoms, with a methylene group being particularly preferred), an alkenylene group (preferably, an alkenylene group having 3-6 carbon atoms, with a 2-propenylene group being particularly preferred), a group xe2x80x94CHR9xe2x80x94 in which R9 represents an alkyl group having 1-4 carbon atoms preferably, such as methyl or ethyl, an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl, or an aralkyl group having 7-22 carbon atoms, such as benzyl or phenethyl).
The above-described R9 may be substituted further by one or more of halogen atoms such as fluorine, chlorine and/or bromine, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy.
As a preferred example of G when the central heterocyclic group is one derived from piperazine or homopiperazine, a substituted or unsubstituted phenylmethylene group can be mentioned.
Preferred examples of group D can include aromatic hydrocarbon groups having 6-28 carbon atoms preferably, such as a phenyl group in which one or more of the hydrogen atoms may be substituted and a naphthyl group in which one or more of the hydrogen atoms may be substituted.
Other preferred examples of D can include aromatic heterocyclic groups, preferably those each of which is monocyclic or dicyclic and contains the same or different three or less oxygen, sulfur and/or nitrogen atomsxe2x80x94such as pyridyl, pyrimidyl, benzisothiazolyl, benzisoxazolyl, indazolyl and indolyl groups in which one or more of hydrogen atoms may be substituted.
Examples of the substituents for the above aromatic hydrocarbon group or aromatic heterocyclic group can include halogen atoms such as fluorine, chlorine and bromine; alkyl groups having 1-4 carbon atoms preferably, such as methyl and ethyl; alkoxyl groups having 1-4 carbon atoms preferably, such as methoxy and ethoxy; aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl; aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl; aralkyloxy groups having 7-22 carbon atoms preferably, such as benzyloxy; cyano groups; nitro groups; carboxyl groups; alkoxycarbonyl groups (with an alcohol moiety thereof having 1-6 carbon atoms preferably); lower alkylsulfonylamino groups (with an alkyl moiety thereof having 1-4 carbon atoms preferably); carbamoyl groups; and hydroxyl groups.
Among these examples of group D, preferred ones can include phenyl groups which may be substituted by one or more of halogen atoms, alkoxy groups and/or hydroxyl groups; benzisothiazolyl groups which may be substituted by one or more halogen atoms; benzisoxazolyl groups which may be substituted by one or more halogen atoms; and indazolyl groups which may be substituted by one or more halogen atoms. Particularly preferred are an unsubstituted phenyl group; and phenyl groups substituted by one or more of fluorine atoms, chlorine atoms, methoxy groups and/or hydroxyl groups.
Many of the compounds (I) according to the present invention have isomers. It is to be noted that these isomers and mixtures thereof are all embraced by the present invention.
Various processes can be employed for the preparation of the pyrroloazepine derivatives (I) according to the present invention. It is however preferred to prepare them, for example, by any one or a combination of the following processes.
Process 1:
Pyrroloazepine derivatives (IIa) and (IIb) useful as starting materials can be synthesized, for example, by the following process:
Process (a)
Each compound of the formula (IIa) can be obtained in accordance with the following reaction scheme, namely, by reacting a 1-substituted pyrrole-3-carboxylic acid or a derivative thereof represented by the formula (XXIa) with a xcex2-alanine or a derivative thereof represented by the formula (XXII) or an organic or inorganic salt thereof and, if necessary, conducting deprotection to obtain a compound represented by the formula (XXIIIa) and then subjecting the thus-obtained compound to a ring-closing reaction. When the group R2 of the compound (XXIa) is a hydrogen atom, the compound represented by the formula (IIb) can also be prepared together with the compound (IIa) [they will hereinafter be collectively called xe2x80x9cthe pyrroloazepine derivative (II)xe2x80x9d].
wherein R14 represents a hydrogen atom or a carboxyl-protecting group, Q represents a hydroxyl group, an alkoxy group or an eliminative group easily replaceable by an amino group, and R1 and R2 have the same meanings as defined above.
The compound represented by the formula (XXIa), which is the starting material in the above-described reaction, can be synthesized by various processes. Describing one example of such processes, a compound (XXIb)xe2x80x94which is different from the compound (XXIa) in that R2 is a hydrogen atomxe2x80x94can be obtained in accordance with the following reaction scheme, namely, by causing a propiolic acid ester represented by the formula (XXVII) to act on an N-substituted-N-formylglycine represented by the formula (XXVI) in the presence of an acid anhydride such as acetic anhydride or propionic anhydride to obtain a compound (XXVIII) and then converting the thus-obtained compound by a method known per se in the art.
wherein R15 represents an alkyl group, an aralkyl group or an aryl group, and R1 and Q have the same meanings as defined above.
The compound (XXVI) and compound (XXVII), which are employed as starting materials in the above reaction scheme, are either known compounds or compounds available following a known process. Illustrative of the group R15 in the compound (XXVII) can be linear or branched alkyl groups such as methyl, ethyl and isopropyl; aralkyl groups such as benzyl; and aryl groups such as phenyl. Of these, methyl and ethyl are particularly preferred. Further, examples of the acid anhydride can include acetic anhydride and propionic anhydride. Of these, acetic anhydride is particularly preferred. The reaction between the compound (XXVI) and the compound (XXVII) can be conducted by adding 1 mol or more of an acid anhydride and approximately 1 to 5 mol of the compound (XXVII) to 1 mol of the compound (XXVI), heating the resultant mixture to 80xc2x0 C. to the reflux temperature and then stirring the same for 4 to 24 hours or so. This reaction can be conducted in the acid anhydride (preferably, acetic anhydride) or by adding a solvent which does not take part in the reaction, such as toluene.
Further, as another process for obtaining the 1-substituted pyrrole-3-carboxylic acid or the derivative thereof, a process can be mentioned in which in accordance with the following reaction scheme, a group R1xe2x80x3 is introduced by a method known per se in the art into a compound (XXIX) obtained by the process disclosed in a publication [A. M. van Leusen et al, Tetrahedron Letters, 5337-5340 (1972)] to convert the compound into another compound (XXX) and then converting it further into a compound represented by the formula (XXIc) by a method known per se in the art.
wherein R1xe2x80x3 represents an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group or a substituted or unsubstituted aralkyl group, and R2 and Q have the same meanings as defined above.
Examples of the eliminative group, which is easily replaceable with an amino group and is represented by the group Q in the compounds (XXIa), (XXIb) and (XXIc), can include halogen atoms, carboxylic acid residues and the like.
On the other hand, as the carboxyl-protecting group represented by the group R14 in the compound (XXII), it is possible to use, in addition to lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl and aralkyl groups having 7-20 carbon atoms, such as benzyl and 9-anthrylmethyl, conventional protecting groups such as those described in T. W. Greene: xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (John Wiley and Sons, Inc.) and the like.
For the synthesis of the compound (XXIIIa), it is possible to use any one of various processes disclosed in xe2x80x9cCompendium of Organic Synthetic Methodsxe2x80x9d (WILEY-INTERSCIENCE; A Division of John Wiley and Sons, Inc.) and the like. Illustrative processes can include a process in which a 1-substituted-pyrrole-3-carboxylic acid [the compound (XXIa) in which Qxe2x95x90OH] and a xcex2-alanine or a derivative thereof represented by the compound (XXII) or an organic or inorganic salt thereof are treated with an organic compound such as diethyl phosphorocyanidate (DEPC), diphenylphosphoryl azide (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride or 2-iodo-1-methylpyridinium iodide or an inorganic compound such as silicon tetrachloride or tin tetrachloride, if necessary, in the presence of an organic or inorganic base; and a process in which a 1-substituted-pyrrole-3-carboxylic acid is converted into its acid halide, symmetric acid anhydride, mixed acid anhydride, its active ester such as p-nitrophenyl ester, or the like by a method known per se in the art, and is then reacted with the compound (XXII), if necessary, in the presence of an organic or inorganic base.
Each compound (XXIIIa) thus obtained is subjected to a ring-closing reaction, optionally after removing the protecting group by virtue of a suitable method such as the action of an acid or a base, or catalytic reduction. This ring-closing reaction is conducted by treating the compound (XXIIIa) together with an organic acid such as methanesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid, an inorganic acid such as sulfuric acid or polyphosphoric acid or a mixture of such an organic or inorganic acid and phosphorus pentoxide at room temperature to 170xc2x0 C., preferably at 80-120xc2x0 C.
In this case, a solvent which does not take part in the reaction may be added as needed.
As an alternative, the ring-closing reaction can also be practiced by, optionally after addition of a catalyst, treating the compound (XXIIIa) with oxalyl chloride, thionyl chloride, thionyl bromide, oxalyl bromide, phosgene, phosphorus trichloride, phosphorus tribromide, phosphoryl chloride, phosphoryl bromide or the like to convert it into its corresponding acid halide and then treating the acid halide at xe2x88x9220xc2x0 C. to reflux temperature in the presence of a Lewis acid such as aluminum chloride, aluminum bromide, boron trifluoride-ether complex or tin tetrachloride in a solvent such as dichloromethane, 1,2-dichloroethane or nitromethane. In the above-described reactions, the compound (IIa) and the compound (IIb) can be formed at varied ratios by changing the reaction conditions.
Process (b)
Among the pyrroloazepine derivatives (IIa) and (IIb), compounds (IIaxe2x80x3) and (IIbxe2x80x3) in each of which the group R1 is other than an aryl group can be obtained in accordance with the following reaction scheme.
Namely, the compound (IIaxe2x80x3) and the compound (IIbxe2x80x3) can be obtained by providing a compound (XXId) as a raw material, treating it in a similar manner as in the process (a) to obtain a compound (IIaxe2x80x2) and a compound (IIbxe2x80x2), and then introducing a group R1xe2x80x3 to the pyrrole-N positions of these compounds (IIaxe2x80x2) and (IIbxe2x80x2).
wherein R1xe2x80x3, R2, R14 and Q have the same meanings as defined above, and X4 represents an eliminative group. The conversion from the compound (IIaxe2x80x2) into the compound (IIaxe2x80x3) can be effected by treating the compound (IIaxe2x80x2) with an organic or inorganic base and then reacting the compound represented by the formula (XXXIa) or (XXXIb), or by causing the compound (XXXIa) or the compound (XXXIb) to act on the compound (IIaxe2x80x2) in the presence of such a base.
Examples of the eliminative group represented by the group. X4 in the compound (XXXIa) can include halogen atoms such as chlorine and bromine, alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxy groups such as p-toluenesulfonyloxy. Exemplary organic or inorganic bases can include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, triethylamine, sodium methoxide, and potassium t-butoxide. Further, illustrative solvents usable in the above reaction include acetone, 2-butanone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, and dimethylsulfoxide. The reaction is conducted at xe2x88x9220xc2x0 C. to reflux temperature.
On the other hand, the conversion from the compound (IIbxe2x80x2) into the compound (IIbxe2x80x3) can also be effected under similar conditions as in the above-described conversion from the compound (IIaxe2x80x2) into the compound (IIaxe2x80x3).
Incidentally, the compounds obtained following the above-described process (a) and process (b)xe2x80x94said compounds being represented by the following formulas (XIXa) and (XIXb):
wherein R1xe2x80x2 represents a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkyl-alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group, and R2 has the same meaning as defined abovexe2x80x94are useful as intermediates for the production of pharmaceutical products.
Process 2:
Among the pyrroloazepine derivatives (I), compounds (Ia) in each of which Z1 and Z2 are combined together to represent an oxygen atom can be synthesized, for example, by any one of the following processes.
Process (a)
Each compound (Ia) can be obtained in accordance with the following reaction scheme, namely, by reacting a compound represented by the formula (II) with a compound represented by the formula (III) to convert the compound (II) into a compound represented by the formula (IV) and then reacting a nitrogen-containing compound represented by the formula (V) or a salt thereof with the compound (IV).
wherein X and X1 represent the same or different eliminative groups, and A, the ring P and Y have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (II) into the compound (IV) can be effected by treating the compound (II) with an organic or inorganic base and then reacting the compound (III), or by causing the compound (III) to act on the compound (II) in the presence of such a base.
The groups X and X1 in the compound (III) are eliminative groups. Illustrative can be halogen atoms such as chlorine and bromine, alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxy groups such as p-toluenesulfonyloxy.
Exemplary organic or inorganic bases can include sodium hydride, potassium hydroxide, sodium bis(trimethylsilyl)amide, n-butyl lithium, lithium diisopropylamide, and potassium t-butoxide.
Further, illustrative solvents usable in the above reaction can include diethyl ether, tetrahydrofuran, dioxane and toluene. The reaction can be conducted preferably at xe2x88x9278xc2x0 C. to room temperature.
The above-described process is to synthesize each compound (IV) from its corresponding compound (II) as a raw material. Among the compounds (IV), those containing a chlorine atom or bromine atom as X can each be synthesized directly from pyrrole-3-carboxylic acid or its derivative by the following process (axe2x80x2) or process (axe2x80x3) without going through the corresponding compound (II).
Process (axe2x80x2)
Each compound represented by the formula (IVaxe2x80x2) is obtained in accordance with the following reaction scheme, namely, by reacting a 1-substituted-pyrrole-3-carboxylic acid or a derivative thereof represented by the formula (XXIa) with an N-substituted-xcex2-alanine or a derivative thereof represented by the formula (XXIV) or an organic or inorganic salt thereof and, if necessary, conducting deprotection to obtain a compound represented by the formula (XXV) and then subjecting the thus-obtained compound or an inorganic or organic salt thereof to a ring-closing reaction. When R2 represents a hydrogen atom, the compound (IVbxe2x80x2) can also be prepared together with the compound (IVaxe2x80x2) [the compound (IVaxe2x80x2) and the compound (IVbxe2x80x2) may hereinafter be collectively called xe2x80x9c(IVxe2x80x2)xe2x80x9d].
wherein X3 represents a chlorine atom or a bromine atom, and A, R1, R2, R14 and Q have the same meanings as defined above.
In the above-described reaction scheme, the compound represented by the formula (XXIV) can be synthesized with reference to the process disclosed in a publication [A. Fkyerat et al., xe2x80x9cTetrahydronxe2x80x9d, Vol. 49, pp. 11237-11252 (1993)] or a conventionally-known process. Further, the conversion from the compound (XXIa) to the compound (IVaxe2x80x2) and the compound (IVbxe2x80x2) can be effected under similar conditions as in the conversion from the compound (XXIa) to the compound (IIa) and the compound (IIb) described above under Process (a) of Process 1.
Process (axe2x80x3)
Among the compounds (IV), a compound (IVaxe2x80x2xe2x80x3) and a compound (IVbxe2x80x2xe2x80x3) in each of which the group R1 is other than an aryl group can be obtained in accordance with the following reaction scheme, namely, by introducing a group R1xe2x80x3 into the pyrrole-N positions of the corresponding compounds (IVaxe2x80x3) and (IVbxe2x80x3) which are available in a similar manner as in the above-described process (axe2x80x2) [the compound (IVaxe2x80x2xe2x80x3) and the compound (IVbxe2x80x2xe2x80x3) may hereinafter be collectively called xe2x80x9c(IVxe2x80x2xe2x80x3)xe2x80x9d].
wherein A, R1xe2x80x3, R2, R14, Q, X3 and X4 have the same meanings as defined above.
The conversion from the compound (XXId) into the compounds (IVaxe2x80x3) and the compound (IVbxe2x80x3) can be effected under the same conditions as in the conversion from the compound (XXIa) into the compound (IVaxe2x80x2) and the compound (IVbxe2x80x2) described above under Process (axe2x80x2) of Process 2. On the other hand, the conversion from the compound (IVaxe2x80x3) into the compound (IVaxe2x80x2xe2x80x3) and that from the compound (IVbxe2x80x3) into the compound (IVbxe2x80x3) can be effected under similar conditions as in the conversion from the compound (IIaxe2x80x2) into the compound (IIaxe2x80x3) and that from the compound (IIbxe2x80x2) into the compound (IIbxe2x80x3) described above under Process (b) of Process 1.
To prepare the compound (Ia) from the thus-obtained compound (IV), compound (IVxe2x80x2) or compound (IVxe2x80x2xe2x80x3) and the nitrogen-containing compound (V), it is only necessary to react the nitrogen-containing compound (V) or an organic acid salt or inorganic acid salt thereof with the compound (IV), compound (IVxe2x80x2) or compound (IVxe2x80x2xe2x80x3), for example, in a solvent such as methanol, ethanol, dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, 2-butanone, tetrahydrofuran, dioxane or toluene at 0xc2x0 C. to 150xc2x0 C. In this reaction, an organic base such as triethylamine, pyridine, collidine or potassium t-butoxide or an inorganic base such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydroxide or sodium hydride can be used as needed. Further, an alkali iodide such as potassium iodide or sodium iodide can also be added as needed.
Each of the nitrogen-containing compounds (V) is either a known compound or a compound readily available by a known process or a process similar to such a known process. Examples of the nitrogen-containing compound (V) can include 1-phenylpiperazine, 1-(2-fluorophenyl)piperazine, 1-(3-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine, 1-(4-hydroxyphenyl)piperazine, 1-(4-nitrophenyl)piperazine, 1-(2-chlorophenyl)piperazine, 1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine, 1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine, 1-(4-methoxyphenyl)piperazine, 1-(4-methanesulfonamidophenyl)piperazine, 1-(4-cyanophenyl)piperazine, 1-(4-carbamoylphenyl)piperazine, 1-(4-methoxycarbonylphenyl)piperazine, 1-(2-pyridyl)piperazine, 1-(2-pyrimidinyl)piperazine, 1-benzylpiperazine, 1-diphenylmethylpiperazine, 1-cinnamylpiperazine, 1-benzoylpiperazine, 1-(4-benzyloxybenzoyl)piperazine, 1-(4-hydroxybenzoyl)piperazine, 1-(2-furoyl)piperazine, 1-(1,2-benzisoxazol-3-yl)piperazine, 4-phenylpiperidine, 4-benzylpiperidine, xcex1,xcex1-bis(4-fluorophenyl)-4-piperidinemethanol, 4-(4-fluorobenzoyl)piperidine, 4-benzoylpiperidine, 4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine, 3-(4-fluorobenzoyl)piperidine, 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine, 4-(6-fluoro-1H-indazol-3-yl)piperidine, 3-benzoylpyrrolidine, 3-(4-fluorobenzoyl)pyrrolidine, 4-(4-fluorophenoxy)piperidine, 4-[(4-fluorophenyl)thio]piperidine, 4-[(4-fluorophenyl)sulfinyl]piperidine, 4-[(4-fluorophenyl)sulfonyl]-piperidine, 4-[bis(4-fluorophenyl)methylene]piperidine, and 4-(4-fluorobenzoyl)piperidine ethylene acetal.
Process (b)
Further, the compound (Ia) can also be obtained by causing a nitrogen-containing compound represented by the formula (VI) to act on the compound represented by the formula (II) in accordance with the following reaction formula:
wherein A, the ring P, X and Y have the same meanings as defined above.
The conversion from the compound (II) into the compound (Ia) is conducted by causing the compound (VI) to act either after treatment of the compound (II) with an inorganic base or an organic base or in the presence of an inorganic base or an organic base. Reaction conditions are similar to those employed upon conversion from the compound (II) into the compound (IV) and described above under Process (a) of Process 2. Further, the compound (VI) can be synthesized by reacting the compound (III) with the compound (V) in a manner known per se in the art.
Process 3:
Among the pyrroloazepine derivatives (I), the compounds (Ib) and (Id) in each of which Z1 and Z2 both represent groups SR4 or Z1 and Z2 are combined together to represent the group
wherein L has the same meaning as defined above can be synthesized by any one of the following processes.
Process (a)
The compound (Ib) is obtained in accordance with the following reaction scheme, namely, by reacting a thiol compound, which is represented by the formula (VIIa) or (VIIb) [the compound (VIIa) and the compound (VIIb) may hereinafter be collectively called xe2x80x9cthe thiol compound (VII)xe2x80x9d], with a compound (II) and then causing a nitrogen-containing compound (VI) to act.
wherein Z1xe2x80x2 and Z2xe2x80x2 both represent groups SR4 in which R4 has the same meaning as defined above or are combined together to represent a group xe2x80x94Sxe2x80x94Lxe2x80x94Sxe2x80x94 in which L has the same meaning as defined above, and A, L, the ring P, R4, X and Y have the same meanings as defined above.
For the conversion from the compound (II) into the compound (VIII), a suitable method can be selected from those disclosed, for example, in T. W. Greene: xe2x80x9cProtective Groups in organic Synthesisxe2x80x9d (John Wiley and Sons, Inc.) and the like. Describing one example, there is a process in which the thiol compound (VII) and boron trifluoride-ether complex are caused to act on the compound (II) in chloroform. Further, the conversion from the compound (VIII) into the compound (Ib) can be effected under the same conditions as in the conversion from the compound (II) into the compound (Ia) described above under Process (b) of Process 2.
Process (b)
Each compound represented by the formula (Id) can be obtained by causing the thiol compound (VII) to act on a compound (Ic) in accordance with the following reaction scheme.
in which, when W represents CH, Gxe2x80x2 represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group
in which R6 has the same meaning as defined above, a group
in which R7 has the same meaning as defined above, or a substituted or unsubstituted cyclic or acyclic acetal group; when W represents Cxe2x95x90, Gxe2x80x2 represents a group
in which the double bond is coupled with W and R8 represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; when W represents a nitrogen atom, Gxe2x80x2 represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group xe2x80x94CHR9xe2x80x94 in which R9 has the same meaning as defined above; D, E1, E2, m and n have the same meanings as defined above; and
A, L, the ring P, R4, Z1xe2x80x2 and Z2xe2x80x2 have the same meanings as defined above.
The compound (Ic) as the starting material is a compound which can be synthesized by Process 2. The conversion from the compound (Ic) into the compound (Id) can be effected under similar conditions as in the conversion of from the compound (II) into the compound (VIII) described above under Process (a) of Process 3.
Process 4:
Among the pyrroloazepine derivatives (I), the compounds (Ie) and (If) in each of which Z1 and Z2 are combined together to represent a group NOR5 can each be synthesized by any one of the following processes.
Process (a)
Each compound (Ie) is obtained in accordance with the following reaction scheme, namely, by causing hydroxylamine or a derivative thereof (IX) or a salt thereof to act on a compound represented by the formula (IV) and then causing a nitrogen-containing compound (V) to act.
wherein A, the ring P, R5, X and Y have the same meanings as defined above.
The reaction between the compound (IV) and the hydroxylamine or its derivative (IX) is effected, if necessary, in the presence of an organic base such as pyridine, triethylamine, collidine or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide. The hydroxylamine or its derivative (IX) may also be used in the form of an organic acid salt or an inorganic acid salt.
The reaction is conducted at 0xc2x0 C. to reflux temperature, preferably 0xc2x0 C.-100xc2x0 C. by using a suitable solvent, for example, methanol, ethanol, propanol, tetrahydrofuran, dimethylformamide or dimethylsulfoxide as needed.
Further, the conversion from the thus-obtained compound (X) into the compound (Ie) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (Ia) shown above under Process (a) of Process 2.
Process (b)
Each compound (If) is obtained by causing hydroxylamine or its derivative (IX) or a salt thereof to act on a compound (Ic) in accordance with the following reaction formula.
wherein A, the ring P, R5 and Yxe2x80x2 have the same meanings as defined above.
The conversion from the compound (Ic) into the compound (If) can be effected under similar conditions as the conversion from the compound (IV) into the compound (X) shown above under Process (a) of Process 4.
Process 5:
Among the pyrroloazepine derivatives (I), the compounds (Ig) and (Ih) in each of which Z1 represents a hydrogen atom and Z2 represents a hydroxyl group can each be synthesized by any one of the following processes.
Process (a)
Each compound (Ig) is obtained in accordance with the following reaction scheme, namely, by reducing a compound represented by the formula (IV) and then causing a nitrogen-containing compound (V) to act.
wherein A, the ring P, X and Y have the same meanings as defined above.
The conversion from the compound (IV) into the compound (XI) is conducted by treating the compound (IV) with a reducing agent such as sodium borohydride, sodium cyanoborohydride or borane at xe2x88x9278xc2x0 C. to reflux temperature, preferably xe2x88x9220xc2x0 C. to room temperature or by treating the compound (IV) with hydrogen gas in the presence of a catalyst.
The conversion from the compound (XI) into the compound (Ig) can be effected under similar conditions as the conversion from the compound (IV) into the compound (Ia) shown above under Process (a) of Process 2.
Process (axe2x80x2)
The compounds (Ig/xcex1-OH) and (Ig/xcex2-OH)
wherein A, the ring P and Y have the same meanings as defined above, which are optically active substances of the compound (Ig), can each be selectively synthesized by effecting asymmetric reduction in the reduction step from the compound (IV) into the compound (XI) shown above under Process (a) of Process 5.
For the asymmetric reduction, a variety of methods can be applied. As a typical example, a method making use of an oxazaborolidine-borane reducing reagent can be mentioned.
The compounds (Ig/xcex1-OH) and (Ig/xcex2-OH), optically active substances, can be obtained by reducing a compound, which is represented by the following formula (IV):
wherein A, the ring P and X have the same meanings as defined above, with a borane reducing reagent in the presence of a chiral oxazaborolidine represented by the following formulas (XIIa) or (XIIb) [the compound (XIIa) and the compound (XIIb) will hereinafter be collectively called xe2x80x9cthe compound (XII)xe2x80x9d]:
wherein R10 represents a hydrogen atom, an alkyl group or an aryl group, and then causing a compound, which is represented by the following formula (V):
Hxe2x80x94Yxe2x80x83xe2x80x83(V)
wherein Y has the same meaning as defined above, to act.
The chiral oxazaborolidine (XII) employed in the above reaction is a known catalyst, and its preparation processes are disclosed in publications [E. J. Corey et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 109, pp. 7925-7926 (1987); E. J. Corey et al., xe2x80x9cTetrahedron Lett.xe2x80x9d, Vol. 31, pp. 611-614 (1990); M. P. DeNinno et al., xe2x80x9cTetrahedron Lett.xe2x80x9d, Vol. 31, pp. 7415-7418 (1990); S. Wallbaum et al., xe2x80x9cTetrahedron: Asymmetryxe2x80x9d, Vol. 3, pp. 1475-1504 (1992)], Japanese Patent Application Laid-Open (Kokai) No. HEI 4-224556 and the like.
Preferred examples of R10 in the chiral oxazaborolidine (XII) can include a hydrogen atom, a methyl group, an n-butyl group and a phenyl group. Particularly preferred is a methyl group. Specific examples of the chiral oxazaborolidine (XII) can include (R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol and (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol.
The chiral oxazaborolidine (XII) is used in an amount sufficient to convert the reactant into a stoichiometric or less amount of the target product, preferably in 0.05 to 0.2 equivalent relative to the compound (IV).
Illustrative of the borane reducing agent which is employed as a reducing agent can include borane-dimethyl sulfide complex and borane-tetrahydrofuran complex, with borane-dimethyl sulfide complex being particularly preferred. The reducing agent is used preferably in an amount of from 1.5 to 3.0 equivalents relative to the compound (IV).
The reaction is conducted preferably in an inert gas atmosphere such as nitrogen gas or argon gas, in a solvent, for example, toluene, xylene, tetrahydrofuran, 1,2-dimethoxyethane, n-hexane or cyclohexane or a mixed solvent system thereof, preferably in toluene or tetrahydrofuran, at xe2x88x9220xc2x0 C. to room temperature, preferably xe2x88x925 to +5xc2x0 C.
Incidentally, it is desired to keep the water content of the reaction system as low as possible during the reaction so that inactivation of the borane reducing agent is suppressed, deactivation of the catalyst is prevented and lowering in the optical purity is reduced. As an illustrative method for this purpose, it can be mentioned to conduct the reaction in the presence of a dehydrating agent. Preferred examples of the dehydrating agent can include molcular sieves 3A, molcular sieves 4A and molcular sieves 5A.
As another example of the asymmetric reduction method, an asymmetric reduction method of the asymmetric hydrogen transfer, said method making use of a ruthenium catalyst, can be mentioned.
Namely, the compounds (Ig/xcex1-OH) and (Ig/xcex2-OH) are obtained by reducing a compound, which is represented by the following formula (IV):
wherein A, the ring P and X have the same meanings as defined above, in a solvent as a hydrogen source in the presence of a chiral ruthenium complex, and then reacting a nitrogen-containing compound represented by the following formula (V):
Hxe2x80x94Yxe2x80x83xe2x80x83(V)
wherein Y has the same meaning as defined above. The chiral ruthenium complex is available from a arenedichloro-ruthenium complex, which is represented by the following formula (XIII):
[RuCl2(xcex76-arene)]2xe2x80x83xe2x80x83(XIII)
wherein arene represents benzene, toluene, mesitylene, p-cymene or hexamethylbenzene, and a chiral aminosulfonamide compound represented by the following formula (XIVa) or (XIVb):
wherein R11 represents a phenyl group which may be substituted by one or more methyl groups or a naphthyl group which may be substituted by one or more methyl groups, and R12 represents a hydrogen atom or a methyl group.
The chiral ruthenium complex, which is used in the above-described reaction and is prepared from the arenedichloro-ruthenium complex (XIII) and the chiral aminosulfonamide compound (XIVa) or (XIVb), is a known catalyst and is disclosed in publications [R. Noyori et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 117, pp. 7562-7563 (1995); R. Noyori et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 118, pp. 2521-2522 (1996)] and the like.
As a specific example of the arenedichloro-ruthenium complex (XIII), di-xcexc-chlorobis[xcex7-mesitylene]chlororuthenium(II) can be mentioned.
On the other hand, preferred examples of the group R11 in the chiral aminosulfonamide compound (XIVa) or (XIVb) can include phenyl, p-tolyl, 2,4,6-trimethylphenyl and 1-naphthyl, with p-tolyl being particularly preferred. Further, as a preferred example of R12, a hydrogen atom can be mentioned. Specific examples of the chiral aminosulfonamide compound (XIVa) or (XIVb) can include (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine, (1S,2S)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine.
The chiral ruthenium complex is used in an amount sufficient to convert the reactant into a stoichiometric or less amount of the target product, preferably in 0.005 to 0.02 equivalent relative to the compound (IV).
The asymmetric reducing reaction can be conducted either in a mixed system of an azeotropic mixture of formic acid and triethylamine and, if necessary, an appropriate solvent, for example, tetrahydrofuran, acetonitrile, dichloromethane, toluene or N,N-dimethylformamide or in 2-propanol in the presence of a catalytic amount of sodium hydroxide. Preferably, it is conducted in a mixed system of a formic acid-triethylamine azeotropic mixture and tetrahydrofuran or in a mixed system of a formic acid-triethylamine azeotropic mixture and dichloromethane.
The reaction is conducted at room temperature to 60xc2x0 C., preferably at room temperature.
Other illustrative methods can include an asymmetric reducing reaction of the hydrogen transfer type, which makes use of a chiral iridium complex catalyst [disclosed in A. Pfaltz et al., xe2x80x9cHelv. Chim. Acta., Vol. 74, p. 232 (1991)xe2x80x9d or the like]; an asymmetric hydriding reaction making use of a chiral ruthenium complex catalyst [disclosed in R. Noyori et al., xe2x80x9cTetrahydron Lett.xe2x80x9d, Vol. 32, pp. 4163-4166 (1991), R. Noyori et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 117, pp. 2675-2676 (1995), R. Noyori et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 117, pp. 10417-10418 (1995), or the like]; a chiral rhodium complex catalyst [disclosed in J. Bakos et al., xe2x80x9cJ. Organomet. Chem.xe2x80x9d, Vol. 197, 85 (1980) or the like]; a chiral iridium complex catalyst [H. Takaya et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 115, p. 3318 (1993) or the like], or the like; asymmetric reduction making use of chiral diisopinocamphenylchloroborane [H. C. Brown et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 110, pp. 1539-1546 (1988) or the like]; and asymmetric reduction making use of chiral BINAL-H [disclosed in R. Noyori et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 101, pp. 3129-3131 (1979), R. Noyori et al., xe2x80x9cJ. Am. Chem. Soc.xe2x80x9d, Vol. 106, pp. 6709-6716 (1984), or the like].
Process (b)
Each compound (Ih) is obtained by reducing a compound represented by the compound (Ic) in accordance with the following reaction formula.
wherein A, the ring P and Yxe2x80x2 have the same meanings as defined above.
The conversion from the compound (Ic) into the compound (Ih) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (XI) shown above under Process (a) of Process 5.
Process (bxe2x80x2)
The compounds (Ih/xcex1-OH) and (Ih/xcex2-OH)
wherein A, the ring P and Yxe2x80x2 have the same meanings as defined above, which are optically active substances of the compound (Ih), can each be selectively synthesized by effecting asymmetric reduction in the reduction step from the compound (Ic) into the compound (Ih) shown above under Process (b) of Process 5.
For the asymmetric reduction, a variety of methods can be applied. As a typical example, a method making use of an oxazaborolidine-borane reducing reagent can be mentioned. The reaction can be effected under similar conditions as in Process (axe2x80x2) of Process 5 except that the amount of the borane reducing reagent is increased to 4.0 to 7.0 equivalents relative to the compound (Ic).
As another example of the asymmetric reduction method, an asymmetric reduction method of the hydrogen transfer type, said method making use of a ruthenium catalyst, can be mentioned. The reaction can be effected under similar conditions to those shown above under Process (axe2x80x2) of Process 5.
Also applicable are the methods shown above under Process (axe2x80x2) of Process 5, namely, the asymmetric reducing reaction of the hydrogen transfer type, which makes use of the chiral iridium complex catalyst; the asymmetric hydriding reaction making use of the chiral ruthenium complex catalyst, the chiral rhodium complex catalyst, the chiral iridium complex catalyst or the like; and the asymmetric reduction making use of the chiral diisopinocamphenylchloroborane; and the asymmetric reduction making use of chiral BINAL-H.
Process 6:
Among the pyrroloazepine derivatives (I), compounds (Ii) in each of which Z1 represents a hydrogen atom and Z2 represents the group OR13 can be synthesized, for example, by any one of the following processes.
Process (a)
Each compound (Ii) can be obtained in accordance with the following reaction scheme, namely, by reacting a compound represented by the formula (XV) with a compound represented by the formula (XI) to obtain a compound represented by the formula (XVI) and then reacting a nitrogen-containing compound represented by the formula (V) with the compound (XVI).
wherein R13 represents a substituted or unsubstituted alkyl group or a substituted or unsubstituted aralkyl group, X2 represents an eliminative group, and A, the ring P, X and Y have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (XI) into the compound (XVI) can be conducted by causing the compound (XV) to act on the compound (XI) either after treatment of the compound (XI) with an inorganic base or an organic base or in the presence of such a base.
The group X2 in the compound (XV) is an eliminative group. Illustrative can be halogen atoms such as chlorine and bromine, alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxy groups such as p-toluenesulfonyloxy.
Exemplary organic or inorganic bases, which are usable in the above reaction, can include sodium hydride, sodium bis(trimethylsilyl)amide, lithium diisopropylamide, and potassium t-butoxide. Further, illustrative solvents usable in the above reaction can include tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and toluene. The reaction may be conducted at xe2x88x9278xc2x0 C. to reflux temperature.
The conversion from the compound (XVI) into the compound (Ii) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (Ia) described above under Process (a) of Process 2.
Process (axe2x80x2)
The compounds (Ii/xcex1-OR13) and (Ii/xcex2-OR13)
wherein A, the ring P, R13 and Y have the same meanings as defined above, which are optically active substances of the compound (Ii), can each be prepared by the process shown above under Process (a) of Process 6 except that compounds (XI/xcex1-OH) and (XI/xcex2-OH):
wherein A, the ring P and X have the same meanings as defined above are used as starting materials instead of the compound (XI). The compounds (XI/xcex1-OH) and (XI/xcex2-OH) are compounds which are obtained by subjecting the compound (IV) to asymmetric reduction in accordance with the method shown above under Process (axe2x80x2) of Process 5.
Process (b)
Each compound (Ii) is obtained by causing a compound (XV) to act on a compound represented by the formula (Ig) in accordance with the following reaction formula:
wherein A, the ring P, R13, X2 and Y have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (Ig) into the compound (Ii) can be effected under similar conditions as in the conversion from the compound (XI) into the compound (XVI) described above under Process (a) of Process 6.
Process (bxe2x80x2)
The compounds (Ii/xcex1-OR13) and (Ii/xcex2-OR13), which are optically active substances of the compound (Ii), can each be prepared by the process shown above under Process (b) of Process 6 except that compounds (Ig/xcex1-OH) and (Ig/xcex2-OH):
wherein A, the ring P and Y have the same meanings as defined above are used as starting materials instead of the compound (Ig).
Process 7:
Among the pyrroloazepine derivatives (I), the compounds (Ij) in each of which the bond indicated by the dashed line is present and Z1 represents a hydrogen atom can be synthesized by any one of the following processes.
Process (a)
Each compound (Ij) is obtained in accordance with the following reaction scheme, namely, by subjecting a compound represented by the formula (XI) to dehydration treatment to obtain a compound represented by the formula (XVII) and then causing a nitrogen-containing compound (V) to act on the compound (XVII).
wherein A, the ring P, X and Y have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (XI) into the compound (XVII) can be achieved by adding a solvent such as water, methanol, ethanol, ethyl acetate, chloroform or toluene to the compound (XI) as needed and then treating the compound (XI) with an acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or the like at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at xe2x88x9220xc2x0 C. to room temperature.
As an alternative, the conversion from the compound (XI) into the compound (XVII) can also be effected by causing methanesulfonyl chloride, p-toluenesulfonyl chloride, phosphorus trichloride, phosphorus oxychloride, thionyl chloride or the like and a base such as triethylamine, pyridine or collidine to act on the compound (XI), if necessary, in a solvent such as dichloromethane, chloroform or toluene.
The conversion from the compound (XVII) into the compound (Ij) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (Ia) described above under Process (a) of Process 2.
Process (b)
Each compound (Ij) is obtained by subjecting a compound represented by the formula (Ig) to dehydration treatment in accordance with the following reaction formula:
wherein A, the ring P and Y have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (Ig) into the compound (Ij) can be effected under similar conditions as in the conversion from the compound (XI) into the compound (XVII) described above under Process (a) of Process 7.
Process 8:
Among the pyrroloazepine derivatives (I), compounds (Ik) in each of which Z1 and Z2 both represent hydrogen atoms can be synthesized by any one of the following processes.
Process (a)
Each compound (1k) is obtained in accordance with the following reaction scheme, namely, by reducing a compound represented by the formula (XVII) to obtain a compound represented by the formula (XVIII) and then reacting a nitrogen-containing compound (V) with the compound (XVIII).
wherein A, the ring P, X and Y have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (XVII) into the compound (XVIII) can be conducted by treating, in the presence of a catalyst such as palladium-carbon or platinum, the compound (XVII) with hydrogen gas in an ordinarily-employed solvent at xe2x88x9278xc2x0 C. to reflux temperature, preferably at room temperature.
The conversion from the compound (XVIII) into the compound (Ik) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (Ia) described above under Process (a) of Process 2.
Process (b)
Each compound (Ik) is obtained by reducing a compound represented by the formula (Ij) in accordance with the following reaction formula:
wherein A, the ring P and Y have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (Ij) into the compound (Ik) can be effected under similar conditions as in the conversion from the compound (XVII) into the compound (XVIII) described above under Process (a) of Process 8.
Incidentally, among the compounds obtained in the course of the above-described processes 1 to 8, the compounds which are represented by the following formula (XX):
wherein the dashed line, A, the ring P, X, Z1 and Z2 have the same meanings as defined above are useful as intermediates for the preparation of pharmaceutical products.
If necessary, the compounds (I) of the present invention obtained according to the above-described processes can each be reacted with one of various acids to convert the compound into its salt. Then, the resulting salt can be purified by a method such as recrystallization or column chromatography.
Exemplary acids usable for the conversion of the pyrroloazepine derivatives (I) into their salts can include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid; and organic acids such as maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannic acid.
Further, the compounds (I) according to the present invention include those containing asymmetric centers. Each racemic mixture can be isolated by one or more of various methods, whereby a single optically-active substance can be obtained. Usable methods include, for example:
(1) Isolation by an optically active column.
(2) Isolation by recrystallization subsequent to conversion into a salt with an optically active acid.
(3) Isolation by an enzyme reaction.
(4) Isolation by a combination of the above methods (1) to (3).
The pyrroloazepine derivatives (I) and their salts, which are obtained as described above, have strong serotonin-2 blocking action as will be demonstrated in tests to be described subsequently herein.
Moreover, the compounds (I) according to the present invention have also been found to include those also having xcex11 blocking action. From the results of pharmacological tests and toxicity tests, the compounds (I) according to the present invention have also been found to possess such merits as (1) extremely high safety, (2) long action lasting time and (3) high bioavailability. The compounds (I) according to the present invention can therefore be used as therapeutics for the treatment of circulatory diseases such as ischemic heart diseases, cerebrovascular disturbances, peripheral circulatory disturbances and hypertension.
When the pyrroloazepine derivatives (I) according to this invention are used as medicines, they can be administered in an effective dose as they are. As an alternative, they can also be formulated into various preparation forms by known methods and then administered.
Exemplary preparation forms as medicines include orally administrable preparation forms such as tablets, powders, granules, capsules and syrups as well as parenterally administrable preparation forms such as injections and suppositories. Whichever preparation form is used, a known liquid or solid extender or carrier usable for the formulation of the preparation form can be employed.
Examples of such extender or carrier include polyvinylpyrrolidone, arabic gum, gelatin, sorbit, cyclodextrin, tragacanth gum, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol, silica, lactose, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin, mannitol, syrup, and the like.
When the compounds (I) according to the present invention are used as medicines, their dose varies depending on the administration purpose, the age, body weight, conditions, etc. of the patient to be administered. In oral administration, the daily dose may generally be about 0.01-1,000 mg.

Abstract: wherein ring P, the dashed line, Z1, Z2, A and Y are as defined herein.


A developer carrying member of a developer apparatus includes a developer carrying surface having a plurality of grooves, wherein a depth D (mm) of the grooves, a width W (mm) of the grooves, and a volume average particle diameter of the magnetic carrier D50 (mm) satisfy, D (mm)>D50 (mm)×½, and W (mm)>D50 (mm), a magnet, provided inside the developer carrying member, attracts the developer on the developing carrying surface, and a regulating member, provided spaced from the developer carrying member, regulates an amount of the developer carried on the developer carrying surface. An amount M/S (mg/mm2) of the developer carried on a unit area of the developer carrying surface after passing by the regulating member, a gap SB (mm) between a free end of the regulating member and the developer carrying member, a density G (mg/mm3) of the developer, and a groove ratio α which is a ratio of the grooves in the developer carrying surface satisfy, 0.1≤M/S (mg/mm2)≤0.45, 0.2≤SB (mm), and M/S (mg/mm2)×¼≤α×{SB (mm)+D (mm)}×G (mg/mm3)<23/30×M/S (mg/mm2), and 0.06<α.

An image forming apparatus, such as a copying machine, that uses an electrophotographic image formation method, adheres developer to an electrostatic latent image it forms on its image bearing member, such as a photosensitive drum, in order to develop the electrostatic latent image into a visible image. Some developing devices in accordance with the prior art have been known to use two-component developer made up of toner and magnetic carrier. These developing devices have been also known to use a method which develops an electrostatic latent image on their image bearing member (photosensitive drum), into a visible image, with the toner in the two-component developer, by conveying the developer to the immediate adjacencies of the image bearing member, with the use of their rotatable developer bearing member (which hereafter may be referred to simply as development sleeve) while keeping the two-component developer magnetically adhered to the developer bearing member.
Generally, these developing devices are provided with a development sleeve, a stationary magnet, and a developer regulating blade (which hereafter may be referred to simply as regulation blade). The stationary magnet is placed in the development sleeve to magnetically hold developer to the peripheral surface of the development sleeve. The regulation blade is positioned in the adjacencies of the development sleeve, with the presence of a preset amount of gap between itself and the peripheral surface of the development sleeve. Thus, the two-component developer is borne on the development sleeve, and is conveyed to the immediate adjacencies of the photosensitive member while being regulated in the amount to a preset value.
Conventionally, it has been a common practice to employ a development sleeve, the peripheral surface of which has microscopic peaks and valleys formed by blasting (sandblasting) with the use of microscopic particles, or multiple microscopic grooves which extend in parallel to the rotational axis of the development sleeve, in order to ensure that developer is reliably conveyed to the adjacencies of the peripheral surface of the photosensitive member.
However, a development sleeve, the peripheral surface of which has microscopic peaks and valleys formed by sandblasting is problematic in that if the microscopic peaks and valleys are smaller in dimension than a certain value, it is insufficient in performance in terms of developer conveyance. On the other hand, if a development sleeve needs to be increased in the dimension of the peaks and valleys of its peripheral surface, for the sake of increasing the development sleeve in developer conveyance performance, the process of sandblasting the peripheral surface of the development sleeve has to be increased in the intensity with which blasting particles are blasted upon the peripheral surface of the development sleeve, which is problematic in that the blasting process may deform the development sleeve. Generally, therefore, the sandblasted development sleeves which are currently in use are relatively small in the dimension of the peaks and valleys of their peripheral surface. However, in the case of a development sleeve which is small in the dimension of the peaks and valleys of its peripheral surface, its peaks and valleys are relatively quickly worn away by friction, compared to a development roller having relatively large peaks and valleys on its peripheral surface, while it is used for development for a substantial length of time, being therefore problematic in that it is not stable in the developer conveyance performance. This problem may become one of the reasons why a developing device is prematurely reduced in service life.
In recent years, an extremely high level of image quality, reliability, and stability have come to be required of a copying machine and a printer. From the standpoint of satisfying these requirements, it is very important to keep a development sleeve stable in the amount by which it conveys developer.
Thus, development sleeves having multiple grooves which extend in parallel to their axis have been proposed. One of such development sleeves is disclosed in Japanese Laid-open Patent Application H02-50182 (patent document 1). Unlike the method which uses sandblasting to provide the peripheral surface of a development sleeve with microscopic peaks and valleys, forming the abovementioned grooves in the peripheral surface of a development sleeve by putting a development sleeve through a die can provide the peripheral surface of the development sleeve with relatively large grooves (peaks and valleys), without causing the development sleeve to deform. Therefore, a development sleeve, the peripheral surface of which is provided with microscopic grooves with the use of a die is less likely to be affected by friction, being therefore more stable in developer conveyance performance, than a development sleeve, the peripheral surface of which has been sandblasted.
A development sleeve, the peripheral surface of which is provided with grooves is stable in terms of developer conveyance performance, but is problematic in that it requires the gap between itself and the aforementioned developer regulation blade to be relatively small, for the following reason. That is, providing the peripheral surface of a development roller with grooves can make the development sleeve stable in developer conveyance performance, but, it may make the development sleeve excessive in developer conveyance performance. Thus, it may require the gap between the development sleeve and regulation blade to be made relatively small to compensate for the excessive amount by which developer is conveyed by the development sleeve, because unless the gap is reduced, the development roller becomes excessive in the amount of the developer thereon.
Further, in recent years, an extremely high level of image quality has come to be required of an image forming apparatus. Therefore, in order to prevent, as much as possible, an image forming apparatus from becoming worse in the graininess attributable to the friction between the developer on a development sleeve and the toner image formed on the peripheral surface of a photosensitive member, there is a trend to reduce a developing device in the amount by which developer is borne by the peripheral surface of its development sleeve. Concretely, from the standpoint of keeping an image forming apparatus excellent in terms of the level of graininess in which it forms an image, the amount of developer per unit area of the peripheral surface of a development sleeve, on the downstream side of a developer regulation blade in terms of the rotational direction of the development sleeve, is desired to be set to a value in a range of (0.3±0.2) mg/mm2 (=(30±20) mg/cm2). More accurately, it is preferred that the amount by which developer is left coated on the peripheral surface of a development sleeve on the downstream side of the regulation blade is set in terms of the standardized specific gravity G (apparent thickness of developer coat). That is, the apparent thickness M/S of the developer coat on the peripheral surface of a development sleeve, in terms of specific gravity G, is desired to be in a range of 0.029-0.14 mm ((30±20) mg/cm2/3.48 mg/mm3)(M/S [mg/mm2]/specific gravity (density) G [mg/mm3])=0.029-0.14 mm ((30±20) mg/cm2/3.48 mg/mm3).
While a developing apparatus (device) is required to be less in the thickness of the developer on its development sleeve, there is a tendency that a developing device is further reduced in the gap between its development sleeve and regulation blade.
If the gap between a development sleeve and a regulation blade is rendered smaller than a certain value, such a problem is likely to occur that foreign substances, and the like, hang up in the adjacencies of the regulation blade and interfere with the developer coat on the development sleeve. Therefore, the gap between a development sleeve and a regulation blade is desired to be no less than 0.2 mm, preferably, no less than 0.3 mm.
On the other hand, reducing a developing sleeve in developer conveyance performance by imprudently reducing its grooves in depth, in order to allow the gap between the development sleeve and regulation blade to be widened, possibly makes the developer coat unstable, or causes the development sleeve to fail to be coated with the developer. Therefore, it is not desirable.


An additional knurled ring for an optical lens is composed of an annular portion and teeth distributed in a radial direction around the outside of the annular portion. The inner diameter and shape of the additional knurled ring match the outer diameter and shape of an adjusting ring of the optical lens. The additional knurled ring is movably connected with the outside of the adjusting ring of the optical lens. Since the additional knurled ring for the optical lens can be extended towards the front of the lens and beyond the front end of the optical lens, the interference of stray light with the imaging of the optical lens is blocked. Digital scale designations are engraved or printed on the outside of the additional knurled ring for optical lens, the position of the scale and the values of the designations are corresponding to the focal length, aperture, and focal range information of the optical lens. The front end with the enlarged outside diameter of the additional knurled ring for optical lens is movably connected with a cap, and the shape and size of the cap matches the shape and size of the front end of the additional knurled ring.

1. Field of Invention
The present invention relates to an additional knurled ring, and more particular to an additional knurled ring for optical lens adapted for incorporated with different kinds of optical adjusting rings.
2. Description of Related Arts
Nowadays, a conventional optical camera doesn't not include a knurled ring, so that it cannot be incorporated with optical adjusting assistance equipment which are a follow focus of the file lens and a converter. Therefore, the conventional optical camera has the capability and equipment for utilizing manual focus and autofocus to efficiently and precisely to adjust the optical lens of the conventional optical camera. In particular, while the digital conventional optical camera is utilized for shooting, the image shake, focus retardation, and noise generation from autofocus are common problems for the digital conventional optical camera so as to dramatically affect the quality of the images.

Additional knurled ring for optical lens


Filling a gas vessel by initially flowing gas into the vessel at a rate low enough to avoid sudden heating of the gas, then increasing the fill rate until the maximum fill rate is attained, then reducing the flow rate as the vessel approaches the filled condition.

Gas storage vessels, such as gas cylinders or bottles, are commonly filled with gases by charging the gas into the vessel until the desired pressure is reached. It is desirable to fill the vessels as quickly as possible, but it is also important to accurately fill the vessels with the target quantity of gas. One problem that makes it difficult to accurately measure the amount of gas in a gas vessel is the temperature-pressure relationship of contained gases. By virtue of the gas laws, the pressure exerted by a given quantity of gas at constant volume is directly proportional to its temperature. Accordingly, as the temperature of a gas increases, so will the pressure of the gas. Thus, in filling gas storage vessels by pressure measurements it is important that the gas in the vessel when it approaches its "filled" condition be at a preselected temperature to ensure that the correct amount of gas is charged into each vessel being filled.
Since it is desirable to fill the gas vessel in the shortest time period, it is customary to immediately open the fill valve to the wide-open position. This causes an immediate blast of gas to enter the empty vessel, which causes the temperature of the gas being charged into the vessel to rise rapidly as it impinges the walls of the vessel. Rapid filling of the vessel does not continue to cause a rapid temperature increase throughout the filling process, and the initially heated gas cools as additional gas is charged into the vessel. But often the gas temperature does not return to the preselected temperature during the filling process, so that it is difficult or impossible to charge the correct amount of gas into the vessel without the time-consuming step of cooling the gas to the preselected temperature.
The problem is exacerbated when filling the gas vessel with mixtures of gases. In this case, a first gas is charged into the vessel until the vessel contains the desired amount of this gas, and then a second gas is charged into the vessel until the desired amount of that gas is charged into the vessel. This procedure is repeated until all of the gases are charged into the vessel. Since it is generally necessary that the composition of the gas mixture meet narrow specifications. It is important that the temperature of the gas mixture be within narrow limits as the fill endpoint for each component is approached. Thus, if excessive heating occurs during the early stages of the filling process, the gas must be cooled before making the final measurement of the first component, and perhaps cooling may have to be done before final measurement of each component of the gas mixture.
Another phenomenon which makes it difficult to accurately fill gas vessels with specific quantities of gases is that the pressure drop in a gas pipeline through which a gas is flowing is directly proportional to the velocity of the gas flowing through the pipeline: the pressure drop over a given length of pipeline increases as the rate of flow of gas through the pipeline increases. Thus, if a gas vessel is being filled with gas from a gas line which has a pressure gauge upstream of the gas vessel, the pressure at the pressure gauge will be higher than the actual pressure in the vessel, so that if gas is flowing through the fill line at a rapid rate and the pressure gauge is used to determine the cutoff point of the fill process, the gas vessel will not be filled with the correct quantity of gas.
Since time is valuable and accuracy of filling is important, it would be desirable to fill empty gas vessels with single gases or gas mixtures by a method which does not cause a rapid rise of the temperature of the gas when gas is introduced into an empty vessel, and to eliminate or minimize the error caused by differences in pressure at a pressure gauge in the fill line and the actual pressure in the vessel. The present invention provides a method which meets these objectives.


During a reactive ion etching process (FIG. 5) for making lens elements (15, FIG. 4) in a silica substrate (12), the gas constituency in the reactive ion etch chamber is changed to adjust the curvature of lens elements formed in the silica substrate and to reduce the aberrations of such lens elements. For example, two gases, CHF.sub.3 and oxygen may be supplied to the reactive ion etch chamber and, during the reactive ion etch process, the proportion of oxygen is significantly reduced, which reduces the aberrations of the lens elements formed by the process.

Miniature lenses or microlenses are increasingly in demand for such purposes as coupling light from a laser to an optical fiber and coupling light from an optical fiber to a photodetector. The U.S. patent of Basavanhally, U.S. Pat. No. 5,135,590, granted Aug. 4, 1992, describes a method for arranging optical fibers in a matrix configuration as is required, for example, for free-space switching. Such uses would normally require a matrix array of microlenses for containing light projected from the optical fiber ends. Thus, considerable effort has been made in developing methods for making arrays of microlenses which can be used as a unit, or from which individual lenses can be selected for use.
One promising method for making microlens arrays comprises the steps of forming an array of photoresist elements on a silica substrate, melting the elements to cause them to have curved or dome-shaped upper surfaces and thereafter solidifying the elements. The photoresist elements and the substrate are then subjected to reactive ion etching, that is, etching by a reactive gas in which the reaction is enhanced by applied radio frequency power. The photoresist elements cause differential etching in the substrate such that, after all of the photoresist has been etched, the dome shapes of the original photoresist elements are replicated in the silica substrate.
We have found that the reactive ion etching (RIE) method of making microlens arrays often results in lenses having undesirable aberrations. Such aberrations can result in significant losses of optical energy and can limit the functions of optical apparatus. Accordingly, there is a continuing need in the industry for dependable methods for making high quality microlens arrays.


A multistage database search method includes a first stage that only considers textual polygraphic frequencies and a second stage that considers the location of the polygraphs and coarsely approximates the proper alignment between the query and the database strings and a third stage that provides a better approximation of the alignment. The final output is a listing of suggested database records ranked by their similarity to the query.

Over the past decade "database" has transitioned from an application used by a relatively small number of users in highly structured corporate data processing environments, to one at the center of mainstream computing. This occurred in large part because of the decade's striking advances in connectivity. The mid 80's emphasis on local area networks has been replaced with the world Internet. At the same time the set of computer users accessing databases has grown from a somewhat homogeneous and geographically localized collection to a highly diverse group spanning the globe and speaking many languages.
The present invention is a software method, performed by software instructing a computer, which addresses a central problem that is emerging as a result of these changes. That is, the problem of "robust semistructured text retrieval" for small and medium size databases. The crux of the invention resides in a function that compares two text strings returning a numerical indication of their similarity. Typically one of these strings is the user's query and the other is a string from the database. Because this function is very fast it is possible to compare the query with thousands or even hundreds of thousands of database fields while still delivering acceptable response time. Also included is a high-speed heap data structure used to track the "best matches" encountered during a search.
Semistructured text lies between fully structured databases and unconstrained text streams. A fully structured database might, for example, represent a person's name as many fields corresponding to its parts. The semistructured approach represents the name in a less formal way using a single text field. Other examples of semistructured text fields are: addresses, item names or descriptions (as in an online catalog), book or paper titles, company or institution names. Several such fields might be combined into one. For example, the query might be "problmoptimldictionry" and the record is Anderson, Optimal Bounds on the Dictionary Problem LNCS, 401, 1989.
All three of the words in the query above are misspelled, occur in the wrong order and there are no spaces separating the words. Nevertheless, the desired record is identified, using a preferred embodiment of the invention, from a listing of 50,360 paper descriptions in the field of theoretical computer science found in J. Seiferas' "A large Bibliography on Theory/Foundations of Computer Science at ftp://ftp.cs.rochester.edu, 1996-7. Author(s) name, paper title, and related information are combined into a single database text field.
Considerable variation is possible in the description of an item using a semistructured field. A person's last name might be listed first or last. The middle name might be excluded or abbreviated. The ordering of a complex name's parts is not always well determined. In principle, a policy might be established to regularize representation but, in practice, such policies rapidly become complex and confusing. Instead, the problem of directly dealing with these variations is handled by increasing the sophistication of the software that is used to compare queries with semistructured fields. Similar variations occur in user queries where the problem is perhaps greater.
An important benefit of the invention is that the queries are simple free-form expressions of what the user is looking for. There is no query language, and the comparison function is rather robust with respect to typical errors, missing or extra information, and overall ordering. Also, a preferred embodiment of the invention includes no natural-language specific considerations. It operates on byte strings and as such may be used across languages and perhaps for applications that have nothing to do with language (such as DNA comparison).
Using a 200 Mhz Pentium-Pro processor and the preferred embodiment of the invention, processing one byte of database information typically requires roughly 0.5 .mu.s. So 100,000 fields of 30 characters can be processed in 0.15 seconds. It is in some sense a fourth generation implementation of this general approach.
Algorithms of the general type used in the present invention were introduced in the master's thesis of P. N. Yianilos entitled "The definition, computation and application of symbol string similarity functions," Emory University, Department of Mathematics, 1978, and were later used in the commercial spelling correctors of Proximity Technology Inc., and Franklin Electronic Publishers. The linguistic software components of these companies were ultimately used under license in word processing programs from hundreds of publishers, in typewriters, and in tens of millions of hand-held spelling devices.
The PF474 VLSI chip was a special purpose pipelined processor that implemented such an algorithm. The chip is described in an article entitled "A dedicated comparator matches symbol strings fast and intelligently," in Electronics Magazine, McGraw-Hill, December 1983 and in an article by S. Rosenthan entitled "The PF474--a coprocessor for string comparison," in Byte Magazine, 1984, and in U.S. Pat. No. 4,490,811 by Yianilos and Buss entitled "String Comparator Device Systems Circuit and Method." Today's software matches and even exceeds the performance of this devices--although the comparison is not entirely fair since the PF474 was clocked at only 4 Mhz. The same design implemented today would still result in a 1-2 order of magnitude hardware advantage.
The Friendly Finder software utility described by M. J. Miller in an article entitled "First look--friendly program doesn't need exact match to find database search objects," in Info World, 1987 and first introduced in 1987 by Proximity Technology, Inc. implemented the algorithm together with software accelerations and special treatment for bigrams. The result was that small database could be searched on early personal computers without using the PF474 chip. The computational heart of Friendly Finder was also made available under license and called "P2. "
A transition to the bipartite matching viewpoint took place with two articles by Buss and Yianilos, one entitled "Linear and o(n log n) time minimum-cost matching algorithms for quasi-convex tours," in the Proceedings of the 5th Annual ACM-SIAM Symposium on Discrete Algorithms, 1994, pp. 65-76, and another entitled "A bipartite matching approach to approximate string comparison and search," technical report no. 95-193, from NEC Research Institute, Inc., Princeton, N.J., and the algorithms were both improved and in some cases simplified. The result is entirely new algorithms that are still of the same family.
The present invention is the first implementation based on these new developments. The algorithms of Yianilos and Buss lead to linear time algorithms for a large class of graph cost functions including the simple linear costs used by LIKEIT. LIKEIT is a software system implementing the multistage method forming the present invention. Linear time matching algorithms for this particularly simple special case were first present in an article by R. M. Karp and S.-Y. R. Li entitled "Two special cases of the Assignment Problem" in Discrete Mathematics, 13 (1975), pp. 129-142.
A portion of the disclosure of this patent document (LIKEIT SOFTWARE) contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever. v,1-83/2
An alternative approach to string comparison computes "edit distance", described in an article by Hall and Dowling entitled "Approximate String Matching," in Computing Surveys, 12, 1980, pp. 381-402 and in an article by Sankoff and Kruskal entitled "Macromolecules: The Theory and Practice of Sequence Comparison," Addison-Wesley, 1983, that is the minimum-cost transformation of one into the other via some elementary set of operations. The most common form of the approach uses weighted insertion, deletion, and substitution operations and the distance computation is a straightforward dynamic program. There are two problems that led to the present invention. First, the algorithm runs in O(m.multidot.n) time where m, n are the string lengths. The present method runs in O(m+n). Second, the edit distance approach is highly sensitive to global permutation, e.g. changing word order. Humans frequently are not so sensitive and the invention deals well with this issue.
A similar approach, also used in effect by Friendly Finder, is to build an optimal weighted matching of the letters and multigraphs in the query, and those in the each database record. Words receive no special treatment. In this sense it is related to the document retrieval approach of M. Damashek, in an article entitled "Gauging similarity with n-grams: Language-independent categorization of text," in Science, 267, 1995, pp. 843-848 and S. Huffman and M. Damashek entitled "Aquaintance: a novel vector-space n-gram Technique for Document Categorization," in Proc. Text Retrieval Conference (TREC-3), Washington, D.C., 1995, NIST, pp. 305-310.
The automaton based approach to fast string matching introduced in an article by Knuth, Morris and Pratt entitled "Fast pattern matching in strings," in SIAM Journal on Computing, 6, 1977, pp. 323-350, deals with exact matches only. A natural generalization relaxes the requirement of exact equality and allows a bounded (and in practice small) number of errors. Each such error is typically restricted to be either an insertion, deletion, substitution, or sometimes a transposition of adjacent symbols. Given a query string, it is then possible to build an automaton to detect it, or any match within the error bounds, within a second string. The recent work of Manber and Wu, in an article entitled "GLIMPSE: A tool to search through entire file systems," in Proceedings of the Winter 1994 USENIX Conference, 1994, pp. 23-32 and in an article entitled "Fast test searching allowing errors," in Communications of the ACM, 35, 1993, pp. 83-91, demonstrate that text can be scanned at very high speeds within this framework for comparison. The present invention's framework can satisfy queries that do not fall within the practical capabilities of the automaton approach because they are too different from the desired database record. The invention and related approaches are important and effective tools for medium-size textual databases, yet still small enough to scan in their entirety for each query.

Multistage intelligent string comparison method


A control system for controlling delivery of either heated or cooled water over a common water line to a plurality of heat exchangers. The control system includes a hydronic system controller which polls the heating or cooling demands of zone controllers controlling the respective delivery of water to the individual heat exchangers. The hydronic system controller is operative to implement a changeover between delivery of heated water to delivery cooled water or vice versa. The implemented changeover preferably includes checking the temperature of the water being returned to the source or sources for heating or cooling the water as well as defining a changeover time period which must occur in the event that the temperature of the water in the return line is not within a predefined range.

This invention relates to systems for adding or removing heat from a confined space in order to control the temperature in that space. In particular, this invention relates to hydronic systems which employ water as the heat exchange medium for adding or removing heat from a confined space.
Hydronic systems may employ different approaches as to how to deliver water to spaces that are to be heated or cooled. For instance, hydronic systems may use a first conduit to deliver heated water and a second conduit to deliver cooled water to one or more heat exchangers servicing the spaces to be heated or cooled. These systems will also use separate return conduits to circulate the water back to the heating and cooling sources which heat or cool the water before it is again delivered to the one or more heat exchangers. The above described hydronic systems are often referred to as "four pipe" hydronic systems because there are two delivery conduits or pipes which deliver the water to the one or more heat exchangers and two return conduits or pipes which circulate water back to the heating and cooling sources.
Another type of hydronic system uses a single conduit to deliver either heated or cooled water from the heating or cooling sources to the one or more heat exchangers in the spaces to be heated or cooled. This type of hydronic system will also use a single return conduit to circulate the water from the one or more heat exchangers back to the heating and cooling sources. This latter type of hydronic system is typically referred to as a "two-pipe" system because the one or more heat exchangers have one common supply conduit or pipe and one common return conduit or pipe.
The above-described two-pipe hydronic system provides a flow of water to the various heat exchangers at an appreciably lower cost in terms of piping versus the "four-pipe" hydronic system. However the two pipe system cannot easily change from circulating heated water to circulating cooled water to the heat exchangers. In this regard, the cooling source which could be a chiller does not perform well when it is receiving substantially warm water in the return line as a result of the two pipe system having previously been in a heating mode. The same is true for a boiler that is receiving substantially cooler water than it normally is deigned to operate with.
The inability to changeover or switch the two-pipe hydronic system between heating and cooling or vice versa has previously led to switching the system to either heating or cooling, depending on the season of the year. For instance, changeovers would be implemented on particular calendar dates indicating normal change of seasonal weather conditions. On the other hand, a changeover might be implemented depending on a separately sensed outdoor air temperature indicating whether the two-pipe hydronic system should be in either heating or cooling for the day. The above described changeover controls do not allow a hydronic system to respond to heating or cooling demands that may change throughout the day. The above described systems moreover do not respond to different demands for cooling or heating throughout a building on a given day.

This patent is subject to a terminal disclaimer.

Hydronic system control for heating and cooling