A phenothiazine, acridan, acridone oxime, acridone hydrazone and dibenzodiazepine derivative represented by formula (I)

1. Technical Field
The present invention relates to a nitrogen-containing tricyclic compound useful as a medicine, a medicine containing the same and processes for producing the same. More particularly, it relates to a novel nitrogen-containing tricyclic compound useful as a medicine for diseases against which the effect of inhibiting the binding of IgE receptor xcex3 to a tyrosine kinase of 72 kDa is efficacious.
2. Prior Art
The bronchial asthma and the atopic diseases in human beings appear in consequence of highly intriacate vital reactions. It is suspected that most of these conditions are caused because various chemical mediators liberated from mast cells and basophils, as triggered by antigen-antibody reactions, induce vital disturbances as by contracting such smooth muscles as bronchial muscles and vessels of the pulmonary circulation or enhancing permeability of blood vessels.
As the chemical mediators liberated from mast cells and basophils, histamine, leukotrienes, prostaglandins, TNF, etc. have been known. It is well known that histamine, among other substances mentioned above, is the most significant chemical mediator for the allergic rhinitis and the urticaria in human beings. The leucotrienes comprise leucotrienes B4, C4, and D4 and the relation thereof with the asthmatic convulsion has been attracting attention.
Heretofore, the development of medicines for the prevention, alleviation, or elimination of the crisis of symptoms of allergic diseases has been aimed at repressing the creation and liberation of such chemical mediators or antagonizing the effects thereof.
Sodium cromoglycate (Intal(trademark)) having been marketed since 1969 is a typical example of these drugs.
However, the conventional antiallergic agents typified by Intal(trademark) show difference in the chemical mediator liberation inhibitory concentration between in vitro and in vivo. Moreover, sensitivities to these drugs widely vary from patient to patient and their action mechanisms still remain unknown in many points.
Mast cells and basophils closely relating to allergic diseases have a highly affinitive receptor, Fcxcex5 RI, for the IgE antibody on the cell membrane thereof. IgE antibody""s binding to this receptor forms a cross-linkage with the corresponding polyvalent antigen, the intracellular signal transmission mechanism is activated. Then histamine is liberated or leukotrienes and prostaglandins are formed and liberated, thus inducing the onset of the so-called allergic symptoms. It is furthermore considered that the cytokines such as TNF and interleukins thus produced interact with other cells and thus make the diseases chronic.
Under these circumstances, the present inventors have paid their attention to the activation of a non-receptor type tyrosine kinase located at the early stage in the activation of the intracellular signal transmission mechanism upon liberation of chemical mediators from mast cells or basophils. It is known that this tyrosine kinase is activated when it binds to the phosphorylated tyrosine activation motif (TAM) region in the IgE receptor xcex3 chain. By inhibiting this binding to thereby inhibit the activation of the tyrosine kinase of 72 kDa, the activation of the intracellular signal transmission mechanism depending on the IgE antibody in mast cells or basophils can be inhibited. As a result, also the liberation of the above chemical mediators can be inhibited. The present inventors have found out that desired objects can be achieved by using nitrogen-containing tricyclic compounds represented by the following formula (I), thus completing the present invention.
An object of the present invention is to provide a novel acridone derivative and a pharmacologically acceptable salt thereof which is efficacious in preventing or treating asthma, allergic rhinitis, atopic dermatitis, urticaria, hay fever, gastrointestinal allergy, food allergy, etc. Another object of the present invention is to provide a medicine containing as the active ingredient the compound, a hydrate thereof or a pharmacologically acceptable salt thereof.
Accordingly, the present invention relates to a nitrogen-containing tricyclic compound represented by the following formula (I), a hydrate thereof or a pharmacologically acceptable salt thereof:
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are the same or different from each other and each represents hydrogen, hydroxy, cyano, nitro, optionally substituted carbamoyl, halogeno, optionally halogenated lower alkyl, optionally substituted cycloalkyl, optionally halogenated lower alkoxy, acyl, optionally protected carboxy, optionally substituted aryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylated alkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionally halogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protected carboxyalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionally substituted carbamoylalkenyl, optionally halogenated alkynyl, hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substituted carbamoylalkynyl, hydroxyalkoxy, alkoxyalkoxy, optionally protected carboxyalkoxy, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, xe2x80x94Axe2x80x94NR9R10 [wherein A represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or a single bond; and R9 and R10 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl, optionally substituted aryl or acyl, or R9 and R10 may form together with the nitrogen atom to which they are bonded a ring optionally having additional nitrogen, oxygen or sulfur], or
[wherein B represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or a single bond; R11 represents optionally halogenated lower alkyl or amino optionally substituted by lower alkyl; and x represents an integer of from 0 to 2];
provided that two of R1, R2, R3, R4, R5, R6, R7 and R8 adjacent to each other may form together with the carbon atom to which they are bonded a ring optionally containing oxygen, sulfur or nitrogen and optionally substituted;
z represents
[wherein y represents an integer of from 0 to 2],
[wherein y represents an integer of from 0 to 2],
[wherein R12, R13, R14, R15, R16 and R17 are the same or different from each other and each represents hydrogen, optionally substituted carbamoyl, optionally halogenated lower alkyl, optionally substituted cycloalkyl, acyl, optionally halogenated lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally protected carboxy, optionally substituted aryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylated alkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionally halogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protected carboxyalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionally substituted carbamoylalkenyl, optionally halogenated alkynyl, hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substituted carbamoylalkynyl, xe2x80x94Wxe2x80x94NR18R19 (wherein W represents optionally branched alkylene, optionally branched alkenylene, optionally branched alkynylene or a single bond; R18 and R19 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl or acyl, or R18 and R19 may form together with the nitrogen atom to which they are bonded a ring optionally containing additional nitrogen, oxygen or sulfur)];
D represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or
(wherein m and l are each an integer of from 0 to 6; the ring A means an optionally substituted hydrocarbon ring or an optionally substituted heterocycle); and
Q represents optionally substituted carbamoyl, acyl, acylalkyl, optionally protected carboxy, optionally substituted heteroaryl, or xe2x80x94NR20R21 (wherein R20 and R21 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl, optionally halogenated lower alkoxy, hydroxylated alkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally protected carboxyalkyl, acyl, optionally substituted acylalkyl, optionally substituted acylamino, optionally substituted acylaminoalkyl, cyanoalkyl, optionally substituted carbamoylalkyl, optionally substituted aminoalkyl, cyanoalkyl, acylalkyl, cycloalkyl, cycloalkylalkyl or amidino optionally substituted by lower alkyl, or R20 and R21 may form together with the nitrogen atom to which they are bonded an optionally substituted 3- to 8-membered ring which may have, as its ring-member other than carbon, at least one member selected from the group consisting of nitrogen, sulfur, oxygen and xe2x80x94NR22 (wherein R22 represents hydrogen, optionally halogenated lower alkyl, acyl, optionally substituted acylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or xe2x80x94S(O)sxe2x80x94(Y)uxe2x80x94R23 (wherein R23 represents hydrogen, optionally halogenated lower alkyl or optionally substituted aryl; Y represents methylene; s is an integer of from 0 to 2; and u is 0 or 1))];
provided that the following cases are excluded:
(1) the one where R5 and R6 are both hydrogen atoms;
(2) the one where Z is
[wherein y is an integer of from 0 to 2]; R5 is fluoro; and R6 is fluoro or trifluoromethyl; and
(3) the one where Z is
[wherein y is an integer of from 0 to 2]; R5 is carboxy; and R6 is chloro}.
The term xe2x80x9chalogen atomxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8in the formula (I) means fluorine, chlorine, bromine, iodine, etc.
The term xe2x80x9clower alkylxe2x80x9d in xe2x80x9coptionally halogenated lower alkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 means linear or branched C1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-ethylpropyl, n-hexyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl and 1-methyl-2-ethylpropyl groups.
In such a case, the term xe2x80x9coptionally halogenatedxe2x80x9d means that the above alkyl may be substituted by 1 to 3 halogen atoms such as fluorine, chlorine, bromine or iodine. Namely, the xe2x80x9coptionally halogenated lower alkylxe2x80x9d as used in the formula (I) includes trifluoromethyl, dibromoethyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d in xe2x80x9coptionally halogenated lower alkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R20 and R21 means linear or branched C1-6 alkenyl, for example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl groups. The lower alkenyl as used herein further includes the above-mentioned alkenyl substituted by 1 to 3 halogen atoms.
The term xe2x80x9clower alkynylxe2x80x9d in xe2x80x9coptionally halogenated lower alkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means linear or branched C1-6 alkynyl, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propynyl and 2-methyl-3-propynyl groups. The lower alkynyl as used herein further includes the above-mentioned alkynyl substituted by 1 to 3 halogen atoms.
The term xe2x80x9ccycloalkylxe2x80x9d in xe2x80x9coptionally substituted cycloalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means C3-8 ones such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein the above lower alkyl is attached to any carbon atom of the above cycloalkyl.
The term xe2x80x9clower alkoxyxe2x80x9d in xe2x80x9coptionally halogenated lower alkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R20 and R21 means linear or branched C16 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, 2,2-dimethylpropyloxy, 2-ethylpropyloxy, n-hexyloxy, 1,2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, 1,3-dimethylbutyloxy, 1-ethyl-2-methylpropyloxy and 1-methyl-2-ethylpropyloxy groups.
In such a case, the term xe2x80x9coptionally halogenatedxe2x80x9d means that the above alkoxy may be substituted by 1 to 3 halogen atoms such as fluorine, chlorine, bromine or iodine. Namely, the xe2x80x9coptionally halogenated lower alkoxyxe2x80x9d as used herein includes trifluoromethoxy, dibromoethoxy and the like.
The term xe2x80x9cacylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and Q means those derived from saturated aliphatic monocarboxylic acids such as acetyl, propionyl, butyryl, valeryl, isovaleryl and pivaloyl groups, those derived from unsaturated aliphatic carboxylic acids such as acryloyl, propioloyl, methacryloyl, crotonoyl and isocrotonoyl groups, those derived from carbocyclic carboxylic acids such as benzoyl, naphthoyl, toluoyl, hydroatropoyl, atropoyl and cinnamoyl groups, those derived from heterocyclic carboxylic acids such as furoyl, thenoyl, nicotinoyl and isonicotinoyl groups, those derived from hydroxy carboxylic acids or alkoxy carboxylic acids such as glycoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl, salicyloyl, anisoyl, vaniloyl, piperonyloyl and galloyl groups and those derived from various amino acids.
The term xe2x80x9cacylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R12, R13, R14, R15, R16, R17, R20, R21, R22 and Q means those wherein the above acyl is attached to any carbon atom of the above lower alkyl. Examples thereof include acetylmethyl, propionylmethyl, benzoylethyl, naphthoylpropyl, cinnamoylpropyl, salicyloylbutyl, nicotinoylpentyl and glyceroylhexyl groups, though, needless to say, the present invention is not restricted thereto.
The term xe2x80x9cacylalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the acyl is attached to any carbon atom of the above alkenyl. Examples thereof include benzoyl-1-ethylenyl and 3-nicotinoyl-2-propylenyl, though, needless to say, the present invention is not restricted thereto.
The term xe2x80x9cacylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the acyl is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9chydroxylated alkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein 1 to 3 hydroxyl groups are attached to any carbon atom of the above lower alkyl, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl and 3,4-dihydroxybutyl groups.
The term xe2x80x9chydroxyalkenylxe2x80x9d as used in the definition of
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein hydroxy is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9chydroxyalkynylxe2x80x9d as used in the definition of
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, 13, R14, R15, R16 and R17 means those wherein hydroxy is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9calkoxyalkylxe2x80x9d as used in the definition of R1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkyl, for example, methoxymethyl, ethoxymethyl, ethoxyethyl and 2-ethoxypropyl groups, though the present invention is not restricted thereto.
The term xe2x80x9calkoxyalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkenyl, for example, methoxyethylenyl and ethoxypropylenyl groups, though the present invention is not restricted thereto.
The term xe2x80x9calkoxyalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9ccyanoalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21, R22 and R23 means those wherein cyano is attached to any carbon atom of the above lower alkyl, for example, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl and 2-cyanopropyl groups.
The term xe2x80x9ccyanoalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein cyano is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9ccyanoalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein cyano is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9chydroxyalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein hydroxy is attached to any carbon atom of the above lower alkoxy, for example, hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy, 2-hydoxypropoxy and 3-hydroxypropoxy groups.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkoxy, for example, methoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy, ethoxymethoxy, 1-ethoxyethoxy, 2-ethoxyethoxy, 1-methoxypropoxy and 2-methoxypropoxy groups.
The term xe2x80x9carylxe2x80x9d in xe2x80x9coptionally substituted arylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20, R21, R22 and R23 means, for example, phenyl, 1-naphthyl, 2-naphthyl and anthracenyl groups.
The term xe2x80x9carylxe2x80x9d in xe2x80x9coptionally substituted arylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and R22 has the same meaning as the one defined above. In such a case, the term xe2x80x9calkylxe2x80x9d has the same meaning as that of xe2x80x9clower alkylxe2x80x9d defined above.
The term xe2x80x9coptionally substituted heteroarylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21, R22 and Q means those derived from single or fused rings containing 1 to 4 heteroatoms of at least one type selected from the group consisting of sulfur, oxygen and nitrogen atoms. Examples thereof include pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinoxalyl, naphthyridyl, quinazolyl and imidazopyridyl groups.
The term xe2x80x9coptionally substituted heteroarylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and R22 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkyl.
The term xe2x80x9coptionally substituted heteroarylalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9coptionally substituted heteroarylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9coptionally substituted carbamoylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17 and Q means carbamoyl optionally having 1 or 2 substituents on the nitrogen atom.
The terms xe2x80x9coptionally substituted carbamoylalkyl, carbamoylalkenyl and carbamoylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 mean those wherein optionally substituted carbamoyl is attached to any carbon atom of the above lower alkyl, alkenyl and alkynyl.
Examples of the substituents in the optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, optionally substituted carbamoyl, optionally substituted carbamoylalkyl, optionally substituted carbamoylalkenyl and optionally substituted carbamoylalkynyl include hydroxy; lower alkyl such as methyl, ethyl, n-propyl and isopropyl; lower alkoxy such as methoxy, ethoxy, n-propoxy and isopropoxy; halogen atom such as fluorine, chlorine, bromine and iodine; cyano; acyl such as acetyl, propionyl and benzoyl; amino; nitro: optionally protected carboxyl; carbamoyl; acylamino; sulfamoyl; alkylsulfonylamino; arylsulfonylamino; heteroaryl; carboxyalkyl; carboxyalkoxy; heteroarylalkyl; heteroarylalkoxy; methylenedioxy; and ethylenedioxy. The substituents are selected therefrom.
Examples of the protective groups in the xe2x80x9coptionally protected carboxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and Q include lower alkyl such as methyl, ethyl and tert-butyl; lower alkyl substituted by optionally substituted phenyl such as p-methoxybenzyl, p-nitrobenyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl such as 2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy-substituted lower alkyl such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, varelyloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy-substituted lower alkyl such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; lower alkoxycarbonyloxy-substituted lower alkyl such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and 1-(isopropoxycarbonyloxy)ethyl; carboxy-substituted lower alkyl such as carboxymethyl and 2-carboxyethyl; benzoyloxy-substituted lower alkyl optionally substituted by heteroaryl such as 3-phthalidyl, 4-glycyloxybenzoyloxymethyl, etc.;
(substituted dioxolene)-substituted lower alkyl such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; cycloalkyl-substituted lower alkanoyloxy-substituted lower alkyl such as 1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy-substituted lower alkyl such as 1-cyclohexyloxycarbonyloxyethyl. Moreover, various acid amides are also usable therefor. In summary, the carboxy-protective group may be an arbitrary one, so long as it is decomposed by some means to give a carboxylic acid in vivo.
The term xe2x80x9coptionally protected carboxylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein carboxy optionally having the above protective group(s) is attached to any carbon atom of the above lower alkyl.
The term xe2x80x9coptionally protected carboxylalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkoxy. In such a case, the protective group has the same meaning as the one defined above.
The term xe2x80x9coptionally protected carboxyalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkenyl. In such a case, the protective group has the same meaning as the one defined above.
The term xe2x80x9coptionally protected carboxyalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkynyl. In such a case, the protective group has the same meaning as the one defined above.
Examples of the ring in xe2x80x9cR20 and R21 may form together with the nitrogen atom to which they are bonded a ringxe2x80x9d of the formula xe2x80x94NR20R21 as used in the definition of Q include aziridine, azetidine, pyrrolidine, piperidine, perhydroazepine, perhydroazocine, piperazine, homopiperazine, morpholine, thiomorpholine, thiomorpholine dioxide, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihdyrobenzoxazine, 2,3-dihydrobenzothiazine, pyrrole, imidazole, pyrazole, triazole, tetrazole, indole, isoindole, indazole and benzotriazole.
(a) The term xe2x80x9calkylenexe2x80x9d as used in the definition of A, B and W means methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene.
(b) The term xe2x80x9calkenylenexe2x80x9d as used in the definition of A , B and W means ethenylene, propenylene, butenylene, pentenylene, hexenylene, butanedienylene, pentanedienylene, hexanedienylene or hexanetrienylene.
(c) The term xe2x80x9calkynylenexe2x80x9d as used in the definition of A, B and W means ethynylene, propynylene, butynylene, pentynylene, hexynylene, butanediynylene, pentanediynylene, hexanediynylene or hexanetriynylene.
(d) The term xe2x80x9chydrocarbon ringxe2x80x9d as used in the definition of the ring A means cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene, naphthalene, etc.
(e) The term xe2x80x9cheterocyclexe2x80x9d as used in the definition of the ring A means pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, thiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, imidazopyridine, quinoline, naphthyridine, phthalazine, etc.
In the case of the compounds of the present invention having asymmetric carbon atoms, it is needless to say that the optical isomers thereof are also included in the scope of the present invention. Furthermore, hydrates thereof are included in the scope of the present invention.
Examples of the pharmacologically acceptable salts as used in the present invention include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates; organic acid salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates and toluenesulfonates; and salts of amino acids such as aspartic and glutamic acids.
To facilitate the understanding of the present invention, and not by way of limitation, typical examples of the compounds of the present invention will be given. Each compound is expressed in a free state:
1) 1,2-dimethyl-10-[3-[(2-hydroxy-3-methylphenyl)methylamino]propyl]phenothiazine-5-dioxide
2) 1,2-dimethyl-10-[3-[(3-chloro-2-hydroxyphenyl)methylamino]propyl]phenothiazine-5-dioxide
3) 1,2-dimethyl-10-[3-[(5-methoxy-2-furanyl)methylamino]propyl]phenothiazine-5-dioxide
4) 1,2-dimethyl-10-[3-[(3-methoxy-2-thienyl)methylamino]propyl]phenothiazine-5-dioxide
5) 1,2-dimethyl-10-[3-(4-hydroxy-4-phenylpiperidinyl)propyl]phenothiazine-5-dioxide
6) 1,2-dimethyl-10-[3-(4-benzylpiperazinyl)propyl]phenothiazine-5-dioxide
7) 1,2-dimethyl-10-[3-[N-[(2-hydroxyphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide
8) 1,2-dimethyl-10-[3-[N-[(2-hydroxy-3-methylphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide
9) (E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(2-carboxyethyl) ether
10) (E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(1-carboxyethyl) ether.
The compounds of the present invention can be produced by combining generally known methods. Now, main processes generally usable for producing the compounds of the present invention will be illustrated.
Compounds of the formula (I) wherein Z is xe2x80x94S(O)yxe2x80x94 and Q is xe2x80x94NR20R21 can be produced by the following process.
i) A phenothiazine derivative represented by the formula (II) synthesized by a publicly known method [for example, those described in J. Org. Chem., 20, 1577 (1955).; ibid., 35, 4254 (1970).; J. Chem. Soc., (C) 2437 (1970).; and Chem. Ind., 238 (1966).] is reacted in the presence of a base with a compound represented by the formula (III) having leaving groups at both ends to thereby give a phenothiazine derivative represented by the formula (IV). Preferable examples of the base usable herein include sodium hydride, n-butyllithium and t-butoxypotassium. Preferable examples of the leaving groups include halogeno and sulfonate. Any reaction solvent may be used therefor, so long as it remains inert during the reaction. Next, the leaving group Lxe2x80x2 in the compound (IV) is substituted by phthalimide. The resulting phthalimide compound represented by the formula (V) is then treated with hydrazine hydrate to give an amine compound represented by the general formula (VI). Next, this amine compound (VI) is condensed under dehydration with an aldehyde compound (VII: wherein R represents alkyl, alkenyl, alkynyl, aryl or heteroaryl). The Schiff base thus obtained is then treated with a reducing agent such as sodium borohydride to give analkylamine compound represented by the formula (VIII). Any reaction solvent may be used therefor, so long as it remains inert during the reaction.
Alternatively, the phthalimide compound (V) serving as an intermediate may be synthesized in the following manner. Namely, the compound (II) is reacted with a compound having a leaving group L at one end and a protected hydroxyl group at another end to give a compound represented by the formula (IVxe2x80x2). Subsequently, the compound (IVxe2x80x2) is deblocked in a conventional manner to give an alcohol (IVxe2x80x3), which is then reacted with phthalimide under the conditions of the Mitsunobu reaction to give a phthalimide compound.
ii) The compound (IV) is treated with a primary or secondary amine, or the compound (VI) is treated with a compound having a leaving group L (IX and/or Xxe2x80x2) to give a compound represented by the formula (X).
iii) A sulfoxide compound (XI) and a sulfonyl compound (XII) can be produced by oxidizing the sulfur atoms in the compounds (VIII) and (IX) or oxidizing the sulfur atom in the stage of the intermediate (IV) or (VI) in the process of the above i) or ii) followed by appropriate reactions.
Compounds of the formula (I) wherein Z is xe2x80x94C(=NOR12)xe2x80x94 or xe2x80x94C(=NNR13R14) and Q is xe2x80x94NR20R21 can be produced by the following process.
An acridone compound (XIII) synthesized by a publicly known method (for example, the one described in JP-A 7-3161359) is reacted with a compound (III) to give a compound (XIV). Next, this compound (XIV) is reacted with potassium phthalimide to give a compound (XV). Then the compound (XV) is reacted with oxalyl chloride. The acridinium salt thus obtained is reacted with a hydroxylamine derivative (R12ONH2: wherein R12 is as defined above) or a hydrazine derivative (R13R14NNH2: wherein R13 and R14 are each as defined above) to give a compound represented by the formula (XVI) or (XVIxe2x80x2). Then the obtained compound is reacted with hydrazine hydrate to give a primary amine compound represented by the formula (XVII) or (XVIIxe2x80x2). Further, secondary or tertiary amines can be produced in accordance with the methods of i) of ii) in the above production process 1.
Compounds represented by the formula (I) wherein Z is xe2x80x94C(=CR16R17)xe2x80x94 and Q is xe2x80x94NR20R21 can be produced by the following process.
The compound represented by the formula (XIV) given in the production process 2 is reacted with a metal compound Mxe2x80x94CHR16R17 (wherein M means a metal and R16 and R17 are each as defined above such as alkyl lithium, etc.) to give an acridan compound represented by the formula (XVIII). Next, this product is treated in the same manner as the one described in the production process 1 ii) to give an amine compound represented by the formula (IX).
Compounds represented by the formula (I) wherein Z is xe2x80x94C(xe2x95x90O)N(R15)xe2x80x94 or xe2x80x94N(R15C(xe2x95x90O)xe2x80x94and Q is xe2x80x94NR20R21 can be produced by the following process.
The procedure of the step i) or ii) in the production process 1 was repeated while replacing the phenothiazine derivative represented by the formula (II) employed in the production process 1 by a dibenzodiazepine derivative (XX or XXxe2x80x2) produced by a publicly known method [Indian J. Chem., 23B, 85 (1984).] or Production Example 13 or 14. Thus a compound represented by the formula (XXI or XXIxe2x80x2) can be obtained.
Compounds of the formula (I) wherein Q is heteroaryl can be produced by the following process.
The compound represented by the formula (XXII) obtained by the production processes 1, 2, 3 and 4 and having a leaving group Lxe2x80x2 is treated with magnesium to give a Grignard reagent. Next, this Grignard reagent is reacted with an optionally substituted heteroaryl halide derived from, e.g., pyridine or pyrimidine in the presence of 1,3-bis(diphenylphosphino)propane nickel dichloride [Ni(dppp)Cl2] to give a compound represented by the formula (XXIV).
Compounds of the formula (I) wherein Q is optionally substituted carbamoyl, acyl or optionally protected carboxy can be produced by the following process.
The compound represented by the formula (XXII) obtained by the production processes 1, 2, 3 and 4 and having a leaving group Lxe2x80x2 is treated with a reagent for cyanation such as sodium cyanide in the presence of a base to give a nitrile compound (XXV), which is then hydrolyzed to give an unsubstituted carbamoyl compound (XXVI) or an ester or carboxylic acid represented by the formula (XXVII). A substituted carbamoyl compound (XXVIII) can be obtained by alkylating or aralkylating the unsubstituted carbamoyl compound (XXVI) or reacting the ester or a reactive derivative (acid halide, reactive ester, etc.) derived from the carboxylic acid in a conventional manner with a primary or a secondary amine. A protected carboxyl compound can be obtained by reacting the reactive derivative derived from the carboxylic acid with an alcohol derivative.
To illustrate the usefulness of the present invention, pharmacological experimental examples will be given.
(1) Inhibitory Effects on Various Mediators Release from Rat Basophilic Leukemia Cell Line (RBL-2H3)
i) Experimental Method
IgE-sensitized RBL-2H3 cells (i.e., a cell line originating in rat cells) release and produce not only histamine and serotonin but also cytokines such as TNF xcex1 and prostaglandins which are inflammatory mediators after stimulation with IgE sepecific antibody. In this experimental system, inhibitory effects on various mediators release were examined by using serotonin as an indication.
The cells were beforehand labeled with [3H]-labeled serotonin and, at the same time, sensitized with the IgE antibody. After incubating with the compounds of the present invention, the cells were stimulated with the specific antigen. Then the inhibitory activity of each compound was calculated from the amount of the [3H]-labeled serotonin thus liberated into the medium and the amount of [3H]-labeled serotonin liberated when no compound of the present invention was added.
ii) Results of the Experiment
The results are shown in Tables 1 to 3.
The compound numbers correspond to Example Nos. as will be given hereinafter (the same will apply hereinafter).
(2) Inhibitory Effects on Various Mediators Release from Human Basophils
i) Experimental Method
6 ml of 6% dextran (for separating leukocytes, having a high molecular weight) was added to 20 ml of heparinized blood. After stirring well, the resulting mixture was allowed to stand at 37xc2x0 C. for 30 min and thus erythrocytes were precipitated. The upper layer was taken up and phosphate buffered saline (D-PBS) was added thereto followed by centrifugation at 185 g for 8 minutes to give a crude leukocyte fraction. These cells were subjected to hypotonic hematolysis and then suspended in D-PBS(+) containing 0.1%-BSA. The resulting suspension was used in the subsequent experiment as the leukocyte fraction containing basophils. 0.4 ml of this cell suspension was preliminarily heated to 37xc2x0 C. for 5 min and then 0.05 ml of a specimen solution was added thereto followed by a pretreatment at 37xc2x0 C. for 15 min. Next, 0.05 ml of a mite antigen solution was added thereto to induce an antigen-antibody reaction. After 10 min, the reaction was ceased by ice-cooling. Then the reaction mixture was centrifuged at 185 g for 10 min and histamine and peptide leukotrienes in the resulting supernatant were determined by using enzyme immunoassay kits. From the results of the assay, the activities of the acridone derivatives of inhibiting the liberation of histamine and peptide leukotriene were determined.
ii) Results of the Experiment
The results are given in Tables 4 to 7 wherein the term xe2x80x9cleukotrienexe2x80x9d means peptide leukotriene.
(3) Inhibitory Effects on the Interaction between IgE Receptor xcex3 Chain and 72 kDa Tyrosine Kinase
i) Experimental Method
RBL-2H3 cells which are a cell line generally used in studying IgE-mediated intracellular signal transduction in mast cells and basophils were used in this study. Tyrosine-phosphorylated peptide in the tyrosine activation motif (TAM) region in the IgE receptor xcex3 chain was synthesized by Peptide Institute.
In the experiment, cell lysates or cytosolic fraction of RBL-2H3 cells were used. Cell lysates were prepared by solubilizing 1xc3x97107 to 5xc3x97107 cells with a solution containing various protease inhibitors and 1%-NP-40 as a solubilizer. Separately, the cells were homogenized in a Downs homogenizer and centrifuged at 50,000 rpm for 1 hr, and the resulting supernatant was used as the cytosol fraction of the cells. The concentration of the lysate or cytosol was adjusted to 1 mg protein/ml with an isotonic buffer. The phosphorylation experiment of the 72 kDa tyrosine kinase contained in the lysate or cytosol was carried out in the following manner.
An assay buffer [150 mM NaCl, 10 mM KCl, 20 mM Tris (pH 7.5), 0.6 mM MnCl2, 0.5 mM EGTA, 5 mM NaF, 1 mM sodium pyrophosphate and 1 mM sodium orthovanadate] containing the lysate or cytosol in an amount corresponding to 10 mg of protein was incubated together with the compound 101 at 30xc2x0 C. for 3 min. After adding 50 mM of the peptide in the TAM region containing the phosphorylated tyrosine and 50 mM of ATP, the incubation was further effected at 30xc2x0 C. for 15 min. After the completion of the reaction, the sample was electrophoresed on a 10% agarose gel and a tyrosine kinase of 72 kDa was separated. The activation of this kinase was confirmed by examining the phosphorylation of the tyrosine moiety in the kinase per se by western blotting with the use of anti-tyrosine phosphorylation antibody. Then the extent of the phosphorylation was numerically expressed by using an image analyzer and thus the tyrosine kinase phosphorylation inhibitory ratio of the compound 101 was determined.
ii) Results of the Experiment
The results are given in Table 8.
(4) Effect of Inhibiting Activation (Phosphorylation) of Tyrosine Kinase of 72 kDa Due to Antigenic Stimulation in RBL-2H3 Cells
i) Experimental Method
RBL-2H3 cells were incubated for 10 min together with a test compound in a PBS buffer containing 0.1% of BSA and 1 mM of calcium. Next, the cells were reacted with an antigen specific for the IgE receptor for 10 min. After the completion of the antigenic stimulation, the cells were allowed to stand in ice for 1 hr in a 10 mM phosphate buffer (pH 7.5) containing a lysis buffer (1% Triton X-100, 0.1% SDS, 0.5% sodium deoxycholate, 50 mM NaCl, 50 mM NaF, 1 mM phenylmethyl sulfonyl fluoride, 50 xcexcg/ml eupeptin, 10 unit/ml aprotonin) and 0.1% of NaN3 followed by centrifugation to give a cell lysate. This lysate was diluted with a buffer for electrophoresis, heated (95xc2x0 C., 5 min) and then electrophoresed on a 10% SDS-polyacrylamide gel. After the electrophoresis, the sample was electrically transcribed onto a 0.2 xcexcm nitrocellulose membrane and treated with an anti-phosphotyrosine antibody for 1 hr. Then the inhibitory activity was evaluated by the coloring analysis through chemiluminescence.
ii) Results of the Experiment
The results are given in Table 9.
These results indicate that the compounds of the present invention would inhibit the binding of the IgE receptor xcex3 chain to the tyrosine kinase of 72 kDa and thus suppress the liberation of chemical mediators such as serotonin, histamine and leukotrienes.
Therefore, the compounds of the present invention are usable as preventives or remedies for diseases against which the effect of inhibiting binding of the IgE receptor xcex3 chain to a tyrosine kinase of 72 kDa is efficacious. More particularly speaking, the compounds of the present invention are usable as preventives or remedies for diseases caused by the liberation of chemical mediators such as serotonin, histamine and leukotrienes. Still particularly, these compounds are useful in preventing or treating allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, urticaria, hay fever, gastrointestinal allergy or food allergy.
Moreover, the compounds of the present invention are useful from the viewpoint the low toxicity and high safety thereof.
When the compounds of the present invention are used for the above-mentioned diseases, they may be administered both orally and parenterally in the dosage form of tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, ophthalmic ointments, eye drops, nasal drops, ear drops, cataplasmas, lotions, etc.
The administration dose widely varies depending on the type of the disease, the severity of the symptoms, the age, sex and drug sensitivity of the patient. In general, such a compound is administered in a daily dose of from about 0.03 to 1,000 mg, preferably from 0.1 to 500 mg and still preferably from 0.1 to 100 mg once to several times a day. In the case of injections, the dose usually ranges from about 1 xcexcg/kg to 3,000 xcexcg/kg, preferably from about 3 xcexcg/kg to 1,000 xcexcg/kg.
The compounds of the present invention may be processed into preparations by conventional methods with the use of conventional pharmaceutical carriers.
Namely, solid preparations for oral administration are prepared by mixing the principal agent with fillers, binders, disintegrating agents, lubricants, coloring agents, corrigents, antioxidants, etc. and then processed into tablets, coated tablets, granules, powders, capsules, etc. by conventional methods.
Examples of the above-mentioned fillers are lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc.
Examples of the binders are polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. Examples of the lubricants are magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oils, etc.
The coloring agents are those admitted to be added to medicines. Examples of the corrigents include cocoa powder, menthol, aromatic powder, peppermint oil, borneol and powdered cinnamon bark. As the antioxidants, use can be made of any pharmaceutically authorized ones such as ascorbic acid and xcex1-tocopherol. Needless to say, tablets and granules may be appropriately coated with sugar, gelatin, etc., if necessary.
Meanwhile, injections, eye drops, etc. can be prepared by blending the principal agent with, if needed, pH regulating agents, buffer agents, suspending agents, dissolution aids, stabilizers, tonicity agents, antioxidants, preservatives, etc. and then processed in a conventional manner. In such a case, it is also possible, if needed, to give freeze-dried preparations. Injections may be intravenously, hypodermically or intramuscularly administered.
Examples of the above-mentioned suspending agents include methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, tragacanth, sodium carboxymethylcellulose and polyoxyethyelne sorbitan monolaurate.
Examples of the dissolution aids are polyoxyethylene-hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, etc.
Examples of the stabilizers usable herein include sodium sulfite, sodium metasulfite and ether. Examples of the preservatives usable herein include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
Ointments can be produced by blending the principal agent with, if needed, stabilizers, antioxidants, preservatives, etc. and processed in a conventional manner.

Nitrogen-containing tricyclic compounds and drugs containing the same

Abstract: effective against diseases in which histamine, leukotrienes, etc. participate and effective in preventing or treating diseases in which chemical mediators such as histamine and leukotrienes participate, for example, asthma, allergic rhinitis, atopic dermatitis, urticaria, hay fever, gastrointestinal allergy and food allergy.


A method controls the load currents of current mirror loads of logic circuits, for lowering power dissipation at high frequency clock rates while providing stable output signal logic levels insensitive to operating conditions such as varying external radiation well suited for CMOS circuit operation. The method enables segmented control of logic circuits for powering up operational circuits while powering down dormant circuits for efficient power utilization.

Complex digital systems can be built with the use of only a few simple logic circuits or gates, such as inverters, NAND gates and NOR gates. These logic gates are typically implemented as semiconductor integrated circuits (ICs). Each logic circuit or gate is similar in outline and geometry and consists of one or more output drivers driving one or more connected loads. The logic gate can be made using one of several conventional semiconductor processes and/or corresponding devices, such as a bipolar junction transistor, a junction field-effect transistor (JFET), or a metal oxide semiconductor field effect transistor (MOSFET). The driver of a logic gate is usually defined by variety of circuit specification and system parameters. Logic ICs may be grouped into families based on driver specifications. Consequently, bipolar ICs, JFET ICs, and MOS ICs logic families are well known by the driver specifications. The MOSFET is a widely used device for implementing logic gates. MOSFET ICs consist almost entirely of active MOSFET devices which are small, high input impedance, low power consumption and inherently isolated devices. The MOSFET manufacturing process has been refined to produce high yield ICs even at the very large-scale integration (VLSI) levels.
The MOSFETs have a drain to source current ID versus voltage VDS plot for enhancement-mode MOS transistors. Below saturation or pinch-off, the device operates as a non linear voltage controlled resistor in an operating region often called the ohmic region of the MOSFET. Beyond saturation the MOSFET behaves as a voltage controlled current source. An enhancement-mode MOSFET transistor remains in saturation when its gate is shorted to its drain so long the gate-source voltage exceeds the threshold voltage VT of the MOSFET. The ID vs. VDS characteristics make the enhancement-mode MOSFET well suited for implementation as a current mirror load.
The conventional configuration the MOSFET current mirror load consists of a first current enhancement mode MOSFET and a second enhancement-mode MOSFETs having the two gate inputs connected together so that the current in second mirror MOSFET mirrors the current in the first current MOSFET. The first current MOSFET is series connected to a current source CS having a reference current I. Consequently, this same current I is conducted through second mirror MOSFET providing a current mirror load having a load current. The current source is typically implemented by a resistor.
The first current MOSFET which is series connected with the current source and operates in saturation when the VDS exceeds the threshold voltage VT as a result of the gate connected to the drain. When the first current MOSFET and the second mirror MOSFET are identical devices with identical geometries, then the second mirror MOSFET will also be in saturation as long as VDS is greater than or equal to VT. Under these circumstances, the drain current of the second mirror MOSFET is identical to the drain current of the first current MOSFET which is equal to the current I of the current source. The drain current of the second mirror MOSFET is considered a load current IL and is constant as long as the second mirror MOSFET remains in saturation. The current mirror is frequently used in ICs to reproduce current at one location to one or more other locations within a large interconnected integrated circuit. The current of first current MOSFET may be mirrored into several other second mirror MOSFETs. One current source and a respective current MOSFET may be connected to a plurality of mirror MOSFETs providing a respective plurality current mirror loads each having the current IL.
U.S. Pat. No. 4,670,671 entitled High Speed Comparator Having Controlled Hysteresis, discloses a CMOS analog circuit having resistive network comprising a resistive current source and a resistive current transistor for providing a bias voltage connected to two current transistors designated as current sources for an input differential stage and a feedback differential stage. The resistive network has an external control input VON for controlling the current on and off through the mirror transistors. Hence, the current mirror has a controlled current source connected to current transistor connected to a mirror transistors. The current of the mirror transistors that can be externally turned off and on. CMOS analog circuits have used CMOS current mirrors comprising a current source conducting the current I through a current transistor coupled to a mirror transistor conducting the same current as the current transistor and providing a high impedance current mirror load which when integrated into analog amplifiers, provide the amplifier with high gain.
The current mirror continuously conducts currents and as such continuously dissipates power during operation use. Current mirror loads have not been used in conventional CMOS logic circuits which do not dissipate power when in a stable logic state. Constant current loads are not used in logic circuit because high continuous power dissipation results when using constant current loads. Logic CMOS circuits use switching transistors which conduct current and dissipate power during transitions between one logic state to another. Conventional CMOS logic circuit are dynamic, in that, the CMOS logic circuits dissipate power only while charging or discharging the internal transistors and load capacitances as the output signal changes from one state to another state. During logic transitions when power dissipation is dynamic, the power dissipation disadvantageously increases as the frequency of operation increase. With increasing speeds of VLSI operation, dynamic CMOS logic circuits suffer from increased power dissipation. The use of a constant current load at very low level of current may seem to be an advantageous alternative of providing a current load for high impedance driver loads providing rapid switching. However, at very low current, variations of the threshold voltage of the transistors dramatically affects the constant current which may result in the failure of the logic circuit to maintain the proper output logic state.
Logic circuits provide output signal levels which correspond to digital bits one or zero. The ability to distinguish voltage levels determines when a signal is a binary zero or a binary one, and is essential for proper logic circuit operation. It is desirable to provide output signals which have output signal levels that do not vary over operating conditions. It is further desirable to provide low power operating conditions.
In CMOS logic circuits, the output voltage levels are a function of the threshold voltage VT of the FET transistors. An, undesirable feature of MOSFETs is that when they are exposed to radiation, the threshold voltage VT of the devices shifts. This shift in VT affects the operation of MOS ICs, resulting in degraded circuit performance. It is well known that when NMOS devices undergo radiation, the VT tends to become less positive, while the VT of irradiated PMOS devices tends to become more negative. At some point of accumulated exposure to radiation, MOSFET devices would fail. Radiation protection options are disadvantageously limited when producing radiation hardened systems. Often, systems use radiation hardened processing methods and error-correction software to recover from failing devices affected by radiation.
The threshold voltage VT varies during operation when radiated by an external source, such as the sun. Device current levels may change due to the change in the threshold voltage. As the accumulated radiation increases, the threshold voltage of PMOS transistors increases as the threshold voltage of NMOS transistors decreases, affecting current and slowing the operation of the CMOS logic circuit through reduced capacitive charge currents. The affects of changing threshold voltages and resulting changes in operating current have rendered low current low power dissipating current mirror loads ineffective or undesirable in logic circuits. CMOS logic circuits disadvantageously suffer from varying output voltage signal levels and current levels when radiated, and have rendered ineffective the use very low current mirror loads for fast low power operation. These and other disadvantages are solved or reduced using the present invention.


A power tool brake mechanism, in particular a portable power tool brake mechanism, includes at least one mechanical brake unit that has at least one brake element mounted rotatably about a rotation axis and at least one actuating unit that has at least one movably mounted actuating element. The actuating unit is configured to activate and/or deactivate the brake unit. The power tool brake mechanism further includes at least one movement converting unit that has at least one movement converting element configured to convert a movement of the actuating element into a movement of a counter-brake element of the brake unit. The movement of the counter-brake element is at least in a direction that is different from a direction extending along the rotation axis of the brake element.

This application is a 35 U.S.C. §371 National Stage Application of PCT/EP2012/055590, filed on Mar. 29, 2012, which claims the benefit of priority to Serial No. DE 10 2011 076 370.8, filed on May 24, 2011 in Germany, the disclosures of which are incorporated herein by reference in their entirety.


A disc-shaped information recording medium includes a laminate of recording layers on and from which an information signal can be optically recorded and reproduced from one side of the medium. Data areas are provided in the recording layers, respectively. The information signal can be recorded on and reproduced from the data areas while a laser beam emitted from an optical pickup is applied to the data areas. Optical recording test areas are provided in the recording layers, respectively. A test signal can be recorded on and reproduced from the optical recording test areas to decide optimum power values of the laser beam for signal recording. The test areas are out of overlap as viewed in a direction of propagation of the laser beam.

1. Field of the Invention
This invention relates to an information recording medium having a plurality of recording layers which can be accessed from one side of the medium. An example of such an information recording medium is a two-layer single-sided DVD (digital versatile disc). In addition, this invention relates to a method and an apparatus for recording a signal on an information recording medium. Furthermore, this invention relates to a method and an apparatus for recording and reproducing a signal on and from an information recording medium.
2. Description of the Related Art
A two-layer single-sided DVD has a disc substrate whose one side is formed with a laminate of two recording layers. The two recording layers can be optically accessed from one side of the DVD. A two-layer single-sided DVD of a write-once type uses organic dye films as recording layers. A two-layer single-sided DVD of a rewritable type uses phase change films as recording layers.
To record a signal on a DVD, a recording laser beam modulated in accordance with the signal is applied to the DVD. The quality of the recorded signal on the DVD depends on the power of the recording laser beam applied thereto. In general, a recording layer of a DVD has a power calibration area (PCA). Test recording and reproduction are performed on the DVD before a desired information signal is recorded thereon. During a first stage of the test recording and reproduction, test signals are sequentially recorded on the PCA in the DVD while the power of the recording laser beam is changed among different values. The test signals are assigned to the different powers of the recording laser beam, respectively. During a second stage of the test recording and reproduction, the recorded test signals are reproduced, and the reproduced test signals are evaluated. An optimum power of the recording laser beam is decided on the basis of the results of the evaluation of the reproduced test signals. During the recording of a desired information signal on the DVD which follows the test recording and reproduction, the recording laser beam is controlled at the decided optimum power.
In a two-layer single-sided DVD, the near recording layer is semitransparent while the far recording layer is reflective. During the recording of a signal on the near recording layer, a laser beam is focused thereon. During the recording of a signal on the far recording layer, the recording laser beam is applied thereto through the near recording layer. The application of the recording laser beam to the near recording layer to record a signal thereon changes the physical characteristics of the near recording layer from the original. Therefore, during the recording of a signal on the far recording layer, the intensity of the recording laser beam reaching the far recording layer depends on whether or not a portion of the near recording layer through which the recording laser beam passes has undergone signal recording. This fact makes it difficult to accurately decide an optimum power of the recording laser beam for the far recording layer.
In a two-layer single-sided DVD, the two recording layers are different in eccentricity with respect to the disc center. The eccentricity difference is disadvantageous to test recording and reproduction.

Method of recording a signal on an information recording medium, and method of recording and reproducing a signal on and from an information recording medium


Nucleic acid analogues such as peptide-nucleic acids (PNAs) which hybridize strongly to nucleic acids are used to inhibit nucleic acid amplification procedures such as PCR. False positives in subsequent PCR assays are prevented by hybridizing a PNA to PCR amplification products. Assays capable of discriminating between single base mutants are conducted by using a PNA hybridizing to one of the two allelic forms to inhibit a PCR amplification of that form selectively. Asymmetric PCR amplifications are carried out by starting a PCR symmetrically using like quantities of forward and reverse primers, and, once the amplification is established, disabling one primer by hybridizing a PNA thereto.

The present invention relates to the use of nucleic acid analogues in blocking nucleic acid amplification procedures and to diagnostic/analytical techniques based thereon.
Nucleic acid amplification techniques are now in widespread use. These include the "PCR" (polymerase chain reaction) procedures described in EP-A-0200362 and EP-A-0201184 which is the technique in most widespread use, but also the "LCR" (ligase chain reaction) described in EP-A-0320308 and the so-called "NASBA" or "3SR" technique which is described in "Proc. Natl. Acad. Sci. USA" Vol 87. pp 1874-1878 March 1990 and "Nature" Vol 350, No 6313. pp 91-92 7th March 1991.
A major problem in the use of these procedures in diagnostics is the production of false positives by the carry over of amplified nucleic acid sequences from previous reactions. As these procedures are capable of producing a positive result if even a single molecule containing the target sequence is present, it is of course very easy for such a false positive to occur. At present it is necessary for the reaction product of such procedures to be worked up before the success or failure of the amplification procedure can be determined. The involves contact between the reaction product and several pieces of laboratory equipment such as pipettes, as well as with personnel which can lead to traces of the amplification product being available to contaminate future runs.
Much effort is currently going into developing so called "intrinsic" procedures in which the success of the amplification reaction can be monitored without any handling of the amplification product and in an unopened reaction vessel.
New forms of nucleic acid analogue are described in Patent Co-operation Treaty application. No. PCT/EP92/01220 filed on 22nd May 1992 which selectively bind conventional nucleic acids of complementary sequence to form hybrids which are more stable against dehybridisation by heat than are similar hybrids between conventional nucleic acids. We have now found that it is possible to exploit this greater hybrid stability to block selectively nucleic acid amplification procedures. This technique may be used to prevent false positives in such amplification procedures. It may also be exploited as an essential part of certain diagnostics/analytical approaches.
In a first aspect the invention provides a method of inhibiting a nucleic acid amplification procedure comprising providing in said procedure an effective amount of a nucleic acid analogue sufficiently complementary to a sequence of nucleic acid participating in an essential manner in said amplification procedure to hybridises to said sequence sufficiently strongly to prevent the effective participation of said sequence in the amplification procedure. Thus this aspect of the invention includes a method of inhibiting a nucleic acid amplification procedure in which procedure each strand of a double stranded target nucleic acid has a region used as a template for one or more primers which is or are extended or linked to form a second template complementary to said template, wherein a nucleic acid analogue sufficiently complementary to a sequence of a said template or a said primer to hybridise therewith is provided and wherein said nucleic acid analogue hybridises sufficiently strongly to the respective template or primer to block primer template hybridisation or to block primer extension or primer linking under the conditions of the procedure.
Preferably, said procedure is a PCR or LCR or a 3SR procedure. "Anchored" and "inverted" PCR procedures are included.
The "double stranded target nucleic acid" which has in each strand a region acting as a template is not necessarily a starting material, nor need it necessarily be the direct object of desired amplification in the procedure.
In PCR the "double stranded target nucleic acid" will usually be incorporated in the starting material and it will generally be the amplification of at least one strand thereof which is desired. However, one can start a PCR reaction with only one DNA strand, the complementary strand being produced in the first cycle of primer extension. In later cycles, the "double stranded target nucleic acid" will be composed of products from previous cycles predominantly.
In LCR, the "double stranded target nucleic acid" will similarly initially normally be incorporated in the starting material and in later cycles will predominantly be the amplification product.
It is not necessarily the case that primers are hybridised to each strand in the same part of the amplification cycle or, indeed only after the double stranded target nucleic acid has been formed. Thus in the 3SR technique, a starting RNA strand is hybridised to a first primer which is extended as a complementary DNA strand by reverse transcriptase to form the "double stranded target nucleic acid" referred to. After destruction of the hybridised RNA strand by RNase H, a second primer is hybridised to the DNA strand and extended by reverse transcriptase to form a double stranded DNA molecule. Thus by this stage, both strands present in the DNA/RNA will have in their time been hybridised to a primer which has then been extended.
The first primer is so constructed that the DNA/DNA product includes a promoter for an RNA polymerase such as T7 RNA polymerase which using the DNA/DNA product as a template produces multiple RNA copies corresponding to the RNA starting material, which each in turn become starting materials for the first primer and reverse transcriptase to act upon.
Said amplification procedure may be conducted in the absence of said nucleic acid analogue to build-up a desired level of amplification product and said nucleic acid analogue may then be added.
Preferably the said nucleic acid analogue hybridises to said amplification product. This will shut down the amplification and can leave the products in the form of stable nucleic acid--nucleic acid analogue hybrids which are unable to act as templates if they contaminate a subsequent reaction. "Open" rather than "intrinsic" procedures are thereby rendered safe against carry over contamination.
Alternatively or additionally, apparatus to be used in an amplification procedure of said type can be treated with a solution containing said nucleic acid analogue to hybridise said analogue to any amplification product which may be present as a contamination, and the apparatus may be thereafter washed and used in a said amplification procedure, amplification in said procedure of any amplification product present initially as a contamination in said apparatus being prevented by said hybridisation to said analogue.
The invention includes therefore a method of preventing a nucleic acid amplification product from serving as a template in a subsequent amplification procedure, which method comprises hybridising thereto a nucleic acid analogue which forms therewith a hybrid which is stable under the conditions of the subsequent amplification procedure.
The invention also includes a method of preventing any nucleic acid amplification product which may be present in an environment from serving as a contaminating template in a subsequent amplification procedure for the nucleic acid, which method comprises treating the environment with a nucleic acid analogue which forms with said amplification product a hybrid which is stable under the conditions of said subsequent amplification procedure.
In practice, one may wash all or some equipment to be utilised in the procedure with a solution containing the nucleic acid analogue, e.g. in a hybridisation buffer, so as to form a stable hybrid, between the analogue and any nucleic acid present which contains the target sequence for the amplification. The hybrid formed with the nucleic acid analogue is sufficiently stable to withstand the conditions of the subsequent amplification procedure and the contaminant target sequence is thereby prevented from participating in such a procedure to produce a false positive.
The nucleic acid analogue for use in this and other aspects of the invention preferably contains from five to 20 nucleobase binding ligands e.g. from ten to fifteen ligands.
One may provide a nucleic acid analogue which is tailored to halt amplification of a specific nucleic acid sequence or one may provide a reagent containing a mixture of nucleic acid analogue sequences which will stop a number of different amplifications. Preferably, a reagent for this latter purpose contains a multiplicity or multitude of sequences. In the extreme, one may synthesise nucleic acid analogues using a mixture of monomer synthons (including ligands, complementary to each of the four DNA bases) in each step so as to construct molecules each containing a random sequence of ligands. A sufficient quantity of such a reagent should contain a sufficient number of molecules complementary to any amplification product to be able to inhibit any amplification procedure.
Generally, it will be preferred for each molecule of nucleic acid analogue in such a reagent to be at least a 10-mer, more preferably at least a 12-mer, e.g. a 15- to 20-mer.
The selective blocking of amplification procedures may be put to work more actively as part of a diagnostic process.
At present, when using methods such as PCR to amplify a sequence with a view to determining whether a particular sequence is present, such as a single base change from an alternative sequence (e.g. a single base mutation from the "normal" sequence in a gene), the procedures for detecting the sequence in the amplification product are laborious. These include sequencing the entire product to verify the presence of the altered base. They include also detecting an altered pattern of digestion products produced by one or more restriction enzymes if the change or changes in the gene sequence affect a restriction site. They also include hybridising to the product a labelled nucleic acid probe for the mutated sequence under conditions which are sufficiently stringent to differentiate between the possible sequences.

Use of nucleic acid analogues in the inhibition of nucleic acid amplification


A titanium/titanium nitride film stack can be formed with reduced amounts of impurity by depositing onto a substrate a film of titanium using plasma-enhanced chemical vapor deposition of titanium tetrachloride and hydrogen. This film is then subjected to a hydrogen/argon plasma which significantly reduces the chlorine content of the titanium film. The titanium film can then be subjected to an ammonia plasma which will form a thin layer of titanium nitride which is then coated with a thick layer of titanium nitride using plasma-enhanced chemical vapor deposition of titanium tetrachloride and ammonia. The hydrogen/argon anneal significantly reduces the chlorine content of the titanium film and thus the chlorine content at the titanium substrate interface, particularly when the substrate contains aluminum. This enhances the overall reliability of the formed product.

Chemical vapor deposition is currently used to form titanium/titanium nitride film stacks that can be used at the via level. There are several ways to initially deposit the titanium film, including sputtering and chemical vapor deposition. In chemical vapor deposition, the titanium precursor, typically titanium tetrachloride or other titanium tetrahalide, is energized to form elemental titanium which is then deposited on a substrate. A plasma can also be used to excite the titanium. In this method, the plasma, along With for example titanium tetrachioride and hydrogen, are formed into a plasma using RF energy. The plasma is then directed at a substrate and the titanium forms on the substrate.
One problem associated with the deposition of titanium using chemical vapor deposition or plasma enhanced chemical vapor deposition of a titanium halide is the residual halide atoms on the surface of the titanium. Particularly when the titanium is deposited over aluminum, this halide can react with the aluminum forming aluminum halide which has a high resistance. This is a significant problem in via-level applications. This affects the operability, reliability and durability of the formed product.

Method of low temperature plasma enhanced chemical vapor deposition of tin film over titanium for use in via level applications


A micro-optic cell design with a regularly spaced micro-lens array, having a series of randomly positioned lenslets that have been digitally overwritten, wherein the overwritten area is greater than 0 up to 100 percent fill, and wherein a light shaping diffuser pattern is placed on top of the lenslets of the micro-optic cell.

The formation of a regular, repeated micro-lens array (MLA) creates high frequency diffracted orders related to the repeated lens pitch across the transverse and longitudinal axes of the structured surface plane when using coherent light. In addition to these orders, a low frequency diffraction pattern forms, which is related to the shape of the aperture. A method of forming a homogenized image expected from a single lenslet is needed for creating outputs such as flat tops/top hat, which the present disclosure addresses.


Airway monitoring apparatus 30 includes a driver 6 for applying sound in the audible frequency range to the airway of a subject and a detector 7 for monitoring the response of the airway, e.g. by detecting transmitted sound signal components and/or reflected sound signal components. Variations in the detected sound signal, e.g. energy, due to attenuation of the signal, give an indication of the state of the airway, e.g. airway patency, and can be used to monitor sleep-disordered breathing events, such as apnea and hypopnea, and to provide a breathing event index, e.g. AHI. The apparatus may provide servo-control for a respiratory assist device, such as a positive airway pressure device, so as to provide an appropriate pressure level setting. It may allow for home use of such devices and for home titration. It may also assist in discriminating central and obstructive breathing events, and in providing a measure of airway resistance.

Non-invasive determination of the condition of biological tissues is useful in particular where the patient is unable to co-operate or the tissue is inaccessible for easy monitoring.
Techniques presently used in determining the characteristics of biological tissues include x-rays, magnetic resonance imaging (MRI) and radio-isotopic imaging. These are generally expensive and involve some degree of risk which is usually associated with the use of X-rays, radioactive materials or gamma-ray emission. Furthermore, these techniques are generally complicated and require equipment which is bulky and expensive to install and, in most cases, cannot be taken to the bedside to assess biological tissues in patients whose illness prevents them being moved. The present invention provides methods and apparatus which alleviate these difficulties, providing non-invasive, cost-effective and ambulatory means for assessing and monitoring the condition of biological tissues in humans and animals alike.
Sound waves, particularly in the ultra-sound range have been used to monitor and observe the condition of patients or of selected tissues, such as the placenta or fetus. However, the process requires sophisticated and sometimes expensive technology and cannot be used in tissues in which there is a substantial quantity of gas, such as the lung.
Every year in Australia about 5000 newborn infants require a period of intensive care (ANZNN Annual Report, 1996-1997). Respiratory failure is the most common problem requiring support and is usually treated with a period of mechanical ventilation. Over the last decade the mortality of infants suffering respiratory failure has shown an impressive decline, attributable at least in part to improved techniques used in mechanical ventilation, and the introduction of surfactant replacement therapy (Jobe, 1993). The vast majority of infants now survive initial acute respiratory illness, but lung injury associated with mechanical ventilation causes many infants to develop 'chronic lung disease'. Chronic lung disease is characterised by persisting inflammatory and fibrotic changes, and causes over 90% of surviving infants born at less than 28 weeks gestation, and 30% of those of 28-31 weeks gestation, to be dependent on supplementary oxygen at 28 days of age. Of these, over half still require supplementary oxygen when they have reached a post-menstrual age of 36 weeks gestation (ANZNN Annual report, 1996-1997). Assistance with continuous positive airway pressure (CPAP) or artificial ventilation is also commonly required.
Historically, barotrauma and oxygen toxicity have been considered to be the primary culprits in the aetiology of chronic lung disease (Northway et al, 1967; Taghizadeh & Reynolds, 1976). However, trials of new strategies in mechanical ventilation which were expected to reduce barotrauma and/or exposure to oxygen have often had disappointingly little impact on the incidence of chronic lung disease (HIFI Study Group, 1989; Bernstein et al, 1996; Baumer, 2000). Comparison of strategies of conventional mechanical ventilation in animals (Dreyfuss et al, 1985) have indicated that high lung volumes may be more damaging than high intrapulmonary pressures, and has led to the concept of 'volutrauma' due to over-inflation of the lung. At the same time, experience with high frequency oscillatory ventilation (HFOV) has indicated that avoidance of under-inflation may be equally important. HFOV offers the potential to reduce lung injury by employing exceptionally small tidal volumes which are delivered at a very high frequency. However, this technique fails to confer benefit if the average lung volume is low (HIFI Study Group, 1989), yet it appears to be successful if a normal volume is maintained (McCulloch et al, 1988; Gerstmann et al, 1996). This highlights the importance of keeping the atelectasis-prone lung 'open' (Froese, 1989). Evidence of this kind has led to the concept that a 'safe window' of lung volume exists within which the likelihood of lung injury can be minimised. The key to preventing lung injury may lie in maintaining lung volume within that safe window thereby avoiding either repetitive over-inflation or sustained atelectasis. (See FIG. 1).
Attempts to maintain an optimal lung volume in the clinical setting are frustrated by a lack of suitable methods by which the degree of lung inflation can be monitored. In current practice, evaluation of oxygen requirements and radiological examination of the lungs are the principal techniques employed. However, oxygen requirements may be influenced by factors other than lung volume (for example intra- or extracardiac right to left shunting), and the hazards of radiation exposure prevent radiological examination being performed with the frequency required.
Monitoring of infants during mechanical ventilation has been significantly improved over the last decade by the incorporation of a pneumotachograph or hot-wire anemometer into the design of many neonatal ventilators. Although this provides a valuable tool for monitoring tidal volume and compliance, it gives only the most indirect indication (from the shape of the pressure-volume curve) of whether that tidal volume is being delivered in a setting of under-inflation, optimal inflation, or over-inflation. Furthermore, while absolute lung gas volume can be measured using 'gold-standard' techniques of Nitrogen (N2) washout or Helium (He) dilution, these are impractical for routine clinical use.
Even when lung volume is maintained in the "safe window", changes in the lung condition may manifest due to the generally damaged or underdeveloped condition of the lung. Fluid and blood may accumulate in the lung, posing additional threats to the patient. Evaluation with a stethoscope of audible sounds which originate from within the lung (breath sounds) or are introduced into the lung (by percussion, or as vocal sounds) forms an essential part of any routine medical examination. However, in the sick newborn, the infant's small size, inability to co-operate and the presence of background noise greatly limits the value of such techniques.
Whilst determining and monitoring lung condition in newborn babies is difficult, determining lung condition in adults can be equally challenging, particularly if a patient is unconscious or unable to cooperate. This places a further limitation on the presently available techniques for monitoring lung condition. Therefore, a clear need exists for a simple, non-invasive and convenient method by which the condition of the lung can be closely monitored in the clinical setting.
Similarly, there is a need for simple, non-invasive and convenient methods and apparatus for determining the condition of other biological tissues which may be prone to changes in their characteristics, through pathology or otherwise.
For example, it would be very useful to be able to monitor the state of the airways. This can be especially useful for example in the determination of airway patency and in the determination of sleep-disordered breathing.
Sleep-disordered breathing is an increasingly recognised clinical problem, with severe obstructive sleep apnea affecting an estimated 5% of adults and 2% of infants.
In sleep-disordered breathing a reduction in airflow to the lungs may result in reduced blood oxygen levels (hypoxemia) and arousal from sleep. This airflow reduction and arousal can occur many times a night, and can have a number of adverse effects, including excessive daytime sleepiness and an increased incidence of cardiovascular disease and stroke.
In obstructive sleep apnea, a patient's upper airway may be prone to collapse during sleep, thereby causing an obstruction and hypoxemia. This in turn causes the patient to enter a waking state for a short time period. The airway is then re-opened, airflow is re-established, and the patient immediately returns to sleep. This sequence of events may repeat many times throughout the night.
Apnea is generally characterised by a cessation of airflow for 10 or more seconds, and may be classified as obstructive apnea (caused by a blockage of the airway), central apnea (e.g. lack of breathing effort caused by an unstable respiratory control system or as a result of a neurological condition), or mixed apnea (a combination of both).
Sleep-disordered breathing may also relate to hypopnea, which is generally characterised as a reduction of airflow, and for example may be due to an airway that is partially obstructed or may be of central origin, resulting from a reduced output from the respiratory centre in the brain stem. It may also relate to other conditions, such as Upper Airway Resistance Syndrome (UARS), in which there is a reduction in airflow involving arousal, but there may be no significant lowering of blood oxygen levels.
At present, the diagnosis of sleep-disordered breathing is difficult and is generally carried out by a polysomnography test, in which a number of physiological variables of a patient are monitored overnight in a sleep laboratory. This must be followed by a detailed analysis of the resulting data by an experienced sleep scientist, and requires a rigorous comparison of multiple traces. It is expensive, time-consuming and subject to inaccuracies.
Other methods of determining airway obstruction also exist. For example, an oesophageal balloon catheter may be used to measure oesophageal pressure, and, in association with inspiratory airflow, this may be used to calculate upper airway resistance. Such methods are however too invasive for routine clinical use.
The present invention, in its various aspects, aims to provide new and useful apparatus, systems and methods for monitoring the state of an airway and for monitoring patency.

Method and apparatus for determining conditions of biological tissues


An integrated data storage control system provides, in a single integrated circuit, RDC, servo logic, ATA interface, microprocessor, and other formerly discrete components in one highly integrated system design. The integrated circuit is rendered using a single integrated circuit technology type (e.g., digital CMOS) for all components. Analog and digital circuits are combined in such a way as to eliminate or reduce noise or interference in digital circuits from analog circuit components. Individual elements may have their outputs and inputs MUXed together such that individual elements can be selectively switched (during testing modes) such that the integrated circuit emulates or behaves in the same or similar manner as one of the prior art components. The present invention may be applied to magnetic hard disk drives (HDDs) or other types of storage devices such as floppy disk controllers, optical disk drives (e.g., CD-ROMs and the like), tape drives, and other data storage devices.

Prior art computer hard disk drives (HDDs) include a number of circuits for reading data and controlling the HDD. These circuits may include a PRML read channel (RDC), an ATA hard disk controller (HDC), a microcontroller (μc), and a motion control servo block. In such prior art devices, each of these devices may be provided as one or more separate and discrete integrated circuits or chips. Thus, the entire HDD electronics package may comprise a circuit board provided with such a set of chips, along with interconnection circuitry.
Such a design suffers from a number of faults. Most apparent of these is cost. The use of separate discrete components for drive control and read circuitry drives up costs by requiring an increased number of discrete devices, assembly, and interconnection circuitry. In addition, the use of multiple devices decreases overall production yield, as the probability of a faulty device or interconnection occurring increases with the number of such devices in a circuit. HDDs are cost-sensitive devices. In addition, the use of separate, discrete components increases overall power consumption in a hard disk drive or the like.
Ever more complex software drives the demand for more powerful computers with greater storage capacities—at prices equivalent to, or less than, previous generation models. Consumers generally will not replace existing computers unless newer models are faster, more powerful, have a greater storage capacity, and are cheaper (or as costly) as well.
In addition to cost, speed and reliability are also factors. Market pressure creates a need for faster hard drive access times, as computer programs become more complex and hard drives ever increase in capacity. Throughput speeds of over 200 Mb/s may be required, and speeds of over 250 Mb/s are desirable.
In the prior art, such read and controller circuitry was typically provided in separate circuits for a number of valid reasons. Chief among these was the desire to separate digital control signals for the hard drive from the analog read signals from the hard drive. Expertise in managing noisy analog data signals and digital control signals on the same integrated circuit device was simply not available. Although a HDD may be thought of as a digital device by most computer users, the data read from the read head (or written to the write head) of an HDD is in fact a rather noisy analog signal which must be converted to digital form in order to provide the proper data output. In addition, circuitry must generally be provided to supply error correction to such a data stream (due in part to the high noise level in HDD analog signals).
In addition, the use of discrete components for separate HDD functions allowed drive manufacturers to tailor a solution for a particular hard drive design based upon combinations of individual discrete components. An integrated circuit solution for one type of HDD may not be satisfactory for other manufacturers or models. Thus, different integrated circuits may have to be designed for different hard drive manufacturers.
In addition, prior art discrete HDD circuits may be manufactured using different integrated circuit technologies. For example, high performance partial response maximum likelihood (PRML) read channel circuits have been generally realized-using BI-CMOS or N-MOS integrated circuit technology. See, for example, Welland, D. R., et. al., A Digital Read/Write Channel with EPR4 Detection, (ISSCC Digest of Technical Papers, pp. 27G277, February, 1994), Mita, S. et. al., A 150 Mb/s PRML Chip for Magnetic Disk Drives, (ISSCC Digest of Technical Papers, pp. 62-63, February, 1996), Fields, J., et. al., A 200 Mb/s EPRML Channel with Integrated Servo Demodulator for Magnetic Disks, (ISSCC Digest of Technical Papers, pp. 314-315, February, 1997), all of which are incorporated herein by reference. Such circuitry lends itself well to the large analog circuit portions typical of Prior Art read channel circuitry.
In contrast, other HDD system circuits, particularly digital control circuits, may be rendered in digital CMOS. Recent development of critical RDC blocks—such as an extended partial response, class 4 detector (EPR4), servo, finite impulse response (FIR) and interpolated timing recovery (ITR) in digital CMOS circuitry has enhanced volume manufacturability. See, for example, Tyson Tuttle, G., et. al., A 130 Mb/s Read/Write Channel with Digital Servo Detection, (SSCC Digest of Technical Papers, pp. 64-65, February, 1996), and Vishakhadadtta, G., et. al., A 245 Mb/s EPR4 Read/Write Channel with Digital Timing Recovery, (ISSCC Digest of Technical Papers, pp. 388-389, February, 1998), both of which are incorporated herein by reference.
In order to combine analog circuits such as the RDC with digital control circuits, a common integrated circuit technology may be needed in order to combine both analog and digital devices on one integrated circuit chip. As most Prior Art hard drive controller circuits utilize NMOS or Bi-CMOS circuitry, such designs may resist large scale integration. Simply stated, the resultant die size for an NMOS or Bi-CMOS integrated hard drive control may be too large.
Cirrus Logic, Inc., Mass Storage Division, Broomfield Colo., has been one of the few, if only, hard drive controller device manufacturers to utilize CMOS control circuits for both analog and digital circuitry in read channel controllers. The use of CMOS circuitry for both analog an digital devices is non-intuitive, as CMOS does not lend itself well (at least initially) to analog circuit design. However with the reduction from 0.8 micron technology to 0.35, 0.25 micron and smaller technologies, CMOS technology provides surprising advantages.
For example, in a read channel circuit, more analog components can be rendered as digital circuits. While such a design may initially appear to increase die size, as semiconductor technology shrinks to smaller resolutions (e.g., 0.25 micron), the resultant digital circuitry correspondingly shrinks. Analog circuitry, on the other hand, remains relatively static in size as integrated circuit technology shrinks. Thus, overall die size for a CMOS read channel circuit will shrink dramatically with decreases in semiconductor transistor size. Other types of technology (e.g., NMOS or Bi-CMOS) using largely analog circuits, do not show such a distinct shrinkage with decreases in transistor size.
Thus, CMOS read channels may be leveraged in system-level integration and, typically, benefit first from rapid process and lithography improvements. Moreover, the use of CMOS circuitry for an integrated hard drive controller remains a non-intuitive solution to the problem of further integrating hard drive circuitry.
In addition to the above-mentioned obstacles, such an integrated system-on-a-chip solution may be difficult to properly test, due to the inherent complexity of the device. Testing equipment and procedures for individual circuit components (RDC, ATA interface, processor, and the like), both for development and for production, are known in the prior art. However, an integrated HDD controller product may require an entirely new testing regime and equipment in order to properly test individual circuit functions. Moreover, given the level of integration, it might not be possible to properly and thoroughly test all circuits within such an integrated device due to the high level of integration.
In addition to testing difficulties, a large scale integrated device may be difficult to program and test. For example, a hard drive controller system may be programmed by an end user (e.g., hard drive manufacturer) with software or firmware which controls operation of the hard drive. Typically, such software development requires an iterative routine of programming and testing. Testing the hard drive controller may be achieved by running the software and monitoring selected pins of various devices in the hard drive controller.
For a Prior Art hard drive controller comprising a number of discrete circuit components, such development and testing provide little difficulty. However, when developing software for an integrated hard drive controller, a number of intermediate signal lines between components may not be "visible" at input or output pins of the device. Providing additional signal pins for such testing is expensive and difficult. Specialized chips may be made having such extra pins just for testing purposes. However, such chips are not representative of production devices and moreover incur additional cost in manufacturing such specialized devices.
Thus, what is needed is an inexpensive, integrated solution for a HDD read and control circuit which adequately protects digital signals from analog signal noise, using a common integrated circuit technology for all components, while still providing flexibility to be readily modified in design to work with a number of different HDD designs. In addition, a technique for testing individual elements within such a highly integrated circuit preferably using prior art equipment and methods would also be desirable, along with a technique for developing software for such a device.

This patent is subject to a terminal disclaimer.

Systems and methods for data storage devices and controllers


A method of forming a torsional vibration damping disk, including the steps of: stamping a concave surface at a periphery of a disk; heat treating the stamped disk; placing at least one forming element at least partially in contact with at least a portion of the concave surface; and curling the periphery to partially surround the at least one forming element so that the at least one forming element is removable from the disk. In a second embodiment, the method includes the step of removing the at least one forming element after curling the periphery and includes the step of replacing the at least one forming element with at least one spring element.

It is known to provide torsional vibration damping disks (or spring retainer plates) with spring elements located within the periphery of the retainer. Prior art spring retainer plates used one or more support segments radially inward of the spring elements to retain the spring elements within the retainer plate and prevent the spring elements from falling out.
U.S. Pat. No. 6,675,457 discloses a one-piece torsional vibration damper retainer plate in which the annular periphery of the retainer plate is curled. The retainer plate is then heat treated and spring elements are located within the heat treated annular periphery. The final step is to completely curl the annular periphery about the spring elements to form a generally C-shaped channel to substantially surround the spring elements to prevent the spring elements from being removed from the C-shaped channel of the retainer plate. Unfortunately, the spring elements cannot be removed after the final curling. Therefore, if there is a defect in any of the springs, the entire retainer plate must be scrapped, since the spring elements are not replaceable. Further, undesirable deformation in the curled portion can occur since a relatively large portion of the curled portion is manipulated in each step to reduce production costs and the curled portion of the retainer is not fully supported during the curling process.
Thus, there is a long-felt need for a method to form a torsional vibration damping disk from one piece which is capable of holding spring elements without additional components while still allowing removal of the spring elements and reducing deformation of the disk during production.

Method of forming a torsional vibration damping disk