Gamma-secretase inhibitors, useful in the treatment or prevention of Alzheimer""s disease, are disclosed. The preferred compounds have, as the central portion of the molecule, the structure (a) and are di-astereoisomers of known protease inhibitors.

The present invention relates to compounds, their salts, pharmaceutical compositions comprising them, processes for making them and their use in treating Alzheimer""s Disease.
Alzheimer""s Disease (AD) is characterised by the abnormal deposition of amyloid in the brain in the form of extra-cellular plaques and intra-cellular neurofibrillary tangles. The rate of amyloid accumulation is a combination of the rates of formation, aggregation and egress from the brain. It is generally accepted that the main constituent of amyloid plaques is the 4 kD amyloid protein (xcex2A4, also referred to as Axcex2, xcex2-protein and xcex2AP) which is a proteolytic product of a precursor protein of much larger size. The ragged NH2- and COOH-termini of the native Axcex2 amyloid indicates that a complex mechanism of proteolysis is involved in its biogenesis.
The amyloid precursor protein (APP or Axcex2PP) has a receptor-like structure with a large ectodomain, a membrane spanning region and a short cytoplasmic tail. Different isoforms of APP result from the alternative splicing of three exons in a single gene and have 695, 751 and 770 amino acids respectively.
The Axcex2 domain encompasses parts of both extra-cellular and transmembrane domains of APP, thus its release implies the existence of two distinct proteolytic events to generate its NH2- and COOH-termini. At least two secretory mechanisms exist which release APP from the membrane and generate the soluble, COOH-truncated forms of APP (APPs). Proteases which release APP and its fragments from the membrane are termed xe2x80x9csecretasesxe2x80x9d. Most APPs is released by a putative xcex1-secretase which cleaves within the Axcex2 domain (between residues Lys16 and Leu17) to release xcex1-APPs and precludes the release of intact Axcex2. A minor portion of APPs is released by a xcex2-secretase, which cleaves near the NH2-terminus of Axcex2 and produces COOH-terminal fragments (CTFs) which contain the whole Axcex2 domain. Finding these fragments in the extracellular compartment suggests that another proteolytic activity(xcex3-secretase) exists under normal conditions which can generate the COOH-terminus of Axcex2.
It is believed that xcex3-secretase itself depends for its activity on the presence of presenilin-1. In a manner that is not fully understood presenilin-1 appears to undergo autocleavage.
The compounds of the present invention are useful for treating AD by inhibiting the activity of the putative xcex3-secretase thus preventing the formation of insoluble Axcex2 and arresting the production of Axcex2. Further, some of the present compounds also stabilise full-length presenilin-1.
In a further aspect some of the compounds of the present application are useful as inhibitors of presenilin-1 cleavage.
The compounds of the present invention are related to HIV protease inhibitors described in EP-A-337 714 and EP-A-356 223, both in the name of Merck and Co., Inc.. These compounds are aspartyl protease inhibitors. Specifically, a subset of the compounds of the present invention differ from those previously described by the stereochemistry of a hydroxyl group which is a particularly preferred feature of the present invention and has not previously been disclosed for these particular compounds. This is a surprising feature giving rise to the present invention.
The present invention, in one aspect, provides a compound comprising the group:
wherein R2 and R3 are as defined below, which compound is a diastereoisomer of a known protease inhibitor comprising the group
wherein R2 and R3 are as defined below.
The present invention accordingly provides a compound of formula I or a pharmaceutically acceptable salt thereof:
wherein:
R1 is (1) C1-10alkyl, C2-10alkenyl or C2-10alkynyl optionally substituted with one to three substituents independently chosen from:
(i) hydroxy;
(ii) carboxy;
(iii) halogen;
(iv) C1-4alkoxy;
(v) C1-4alkoxycarbonyl;
(vi) xe2x80x94NR6R7 wherein R6 and R7 are independently chosen from hydrogen, C1-5alkyl and C1-5alkoxyC1-5alkyl;
(vii) xe2x80x94CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above;
(viii) xe2x80x94N(R8)QR9 wherein:
Q is C(O), C(S), SO2 or C(NH2);
R8 is hydrogen or C1-4alkyl; and
R9 is hydrogen, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino di(C1-4alkyl)amino wherein each alkyl group is independently chosen;
(ix) C3-7cycloalkyl;
(x) phenyl or naphthyl; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms; each of which is optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy,
(e) NR6R7 wherein R6 and R7 are independently as defined above,
(f) CO2R8 wherein R8 is independently as defined above,
(g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
(h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
(i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
(j) N(R8)COR8xe2x80x2 wherein R8 is independently as defined above and R8xe2x80x2 is independently as defined for R8, and
(k) NR8SO2R8xe2x80x2 wherein R8 and R8xe2x80x2 are independently as defined above; or
(2) phenyl or naphthyl; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms; each of which is optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy,
(e) NR6R7 wherein R6 and R7 are independently as defined above,
(f) CO2R8 wherein R8 is independently as defined above,
(g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
(h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
(i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
(j) N(R8)COR8xe2x80x2 wherein R8 and R8xe2x80x2 are independently as defined above, and
(k) NR8SO2R8xe2x80x2 wherein R8 and R8xe2x80x2 are independently as defined above;
R2 and R3 are independently chosen from C1-10alkyl, C1-10alkoxy, C2-10alkenyl, C2-10alkenyloxy, C2-10alkynyl or C2-10alkynyloxy; phenyl; naphthyl; a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; and a group (CH2)pQ1 wherein Q1 is phenyl, naphthyl, a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S, and a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; and wherein each of R2 and R3 is independently optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-3alkyl, C2-3alkenyl and C2-3alkynyl,
(d) C1-3alkoxy,
(e) NR6R7 wherein R6 and R7 are independently as defined above,
(f) CO2R8 wherein R8 is independently as defined above,
(g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
(h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
(i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
(j) N(R8)COR8xe2x80x2 wherein R8 and R8xe2x80x2 are independently as defined above,
(k) NR8SO2R8xe2x80x2 where R8 and R8xe2x80x2 are independently as defined above;
alternatively R3 may be hydrogen;
R4 and R5 are independently chosen from hydrogen, C1-6alkyl optionally substituted by halogen, hydroxy, thiol, amino, C1-4alkoxy, C1-4 alkylthio, carboxy, C1-4 alkoxycarbonyl and (CH2)qQ2 wherein Q2 is a five-membered unsaturated heterocycle containing 1, 2, 3 or 4 heteratom optionally chosen from O, N, and S providing that not more than one heteroatom is O or S, a six-membered unsaturated heterocycle containing 1, 2 or 3 N atoms and phenyl and naphthyl, or a fused ring which is indolyl, each of the foregoing rings being optionally substituted with one to three groups independently chosen from hydroxy, C1-4alkyl, C1-4alkoxy, thiol, C1-4alkylthio, halogen, amino, carboxy, amido, CO2H and xe2x80x94NHC(NH2)2 and wherein each of the foregoing rings is optionally fused to a benzene ring; and
A is:
(1) hydrogen;
(2) C1-10alkyl, C2-10alkenyl or C2-10alkynyl optionally substituted with one to three substituents independently chosen from:
(i) hydroxy;
(ii) carboxy;
(iii) halogen;
(iv) C1-4alkoxy;
(v) C1-4alkoxycarbonyl;
(vi) xe2x80x94NR6R7 wherein R6 and R7 are independently chosen from hydrogen, C1-5alkyl and C1-5alkoxyC1-5alkyl;
(vii) xe2x80x94CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above;
(viii) xe2x80x94N(R8)QR9 wherein:
Q is C(O), C(S), SO2 or C(NH2);
R8 is hydrogen or C1-4alkyl; and
R9 is hydrogen, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino di(C1-4alkyl)amino wherein each alkyl group is independently chosen;
(ix) C3-7cycloalkyl;
(x) phenyl or naphthyl; a five-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms; each of which is optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy,
(e) NR6R7 wherein R6 and R7 are independently as defined above,
(f) CO2R8 wherein R8 is independently as defined above,
(g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
(h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
(i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
(j) N(R8)COR8xe2x80x2 wherein R8 is independently as defined above and R8xe2x80x2 is independently as defined for R8, and
(k) NR8SO2R8xe2x80x2 wherein R8 and R8xe2x80x2 are independently as defined above; or
(3) a seven-membered heterocycle
having an otherwise unsubstituted carbon atom at the point of attachment to the rest of the compound of formula I,
having at a first atom alpha to the point of attachment a carbon atom which is unsubstituted or substituted by an oxygen or sulphur atom,
having at a first atom beta to the point of attachment, which atom is alpha to the foregoing first atom alpha, a carbon atom or a nitrogen atom,
having at a second atom alpha to the point of attachment a carbon atom, which is optionally substituted by oxygen, or a nitrogen atom,
having at a second atom beta to the point of attachment, which atom is alpha to the foregoing second atom alpha, a carbon atom or a nitrogen atom,
and having at the two remaining atoms carbon atoms;
a double bond may be present between the second atom alpha and the second atom beta;
the seven-membered heterocycle may be fused to one or two aromatic rings via any adjacent pair of atoms other than the point of attachment and the first atom alpha alone or in combination;
the aromatic ring may be benzene or a five-membered heterocycle containing 1, 2, 3 or 4 heteroatoms chosen from O, N and S providing that not more than one heteroatom is O or S or a six-membered heterocycle containing 1, 2 or 3 nitrogen atoms;
alternatively a pair of adjacent carbon atoms in the seven-membered heterocycle, other than the point of attachment and the first atom alpha alone or in combination, may form part of a fused cyclopropyl or cyclopentyl ring;
one to three substitutable atoms of the seven-membered heterocycle are optionally substituted by:
an aromatic ring as defined above optionally substituted by hydroxy, halogen, methoxy or alkyl having one to four carbon atoms;
an alkyl group having one to four carbon atoms optionally substituted by a halogen atom, hydroxy, an aromatic ring as defined above optionally substituted by hydroxy, halogen, methoxy or alkyl having one to four carbon atoms, cycloalkyl having three to seven carbon atoms, methoxy, bicycloalkyl having seven to twelve carbon atoms, heterocycle having five to seven atoms one of which is oxygen, nitrogen or sulphur which is optionally oxidized;
a heterocycle having five to seven atoms one of which is oxygen, nitrogen or sulphur which is optionally oxidized;
cycloalkyl having three to seven carbon atoms;
or bicycloalkyl having seven to twelve carbon atoms;
or the two groups A attached to the same nitrogen atom, together with that atom, form: a five-membered heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms chosen from O, N and S, not more than one of the heteroatoms being O or S; or a six-membered heterocyclic ring optionally containing 1 or 2 further nitrogen atoms; each of which is optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy,
(e) NR6R7 wherein R6 and R7 are independently as defined above,
(f) CO2R8 wherein R8 is independently as defined above,
(g) CONR6R7 or OCONR6R7 wherein R6 and R7 are independently as defined above,
(h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
(i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
(j) N(R8)COR8xe2x80x2 wherein R8 is independently as defined above and R8xe2x80x2 is independently as defined for R8, and
(k) NR8SO2R8xe2x80x2 wherein R8 and R8xe2x80x2 are independently as defined above;
B is Cxe2x95x90O or CHOH in the R configuration;
X is oxygen or a bond;
n is zero or one, and
p is zero, one, two or three; and
q is zero, one, two or three;
with the proviso that no carbon atom is substituted by more than one hydroxy group.
In an embodiment the compounds of the present invention are of formula Ixe2x80x2:
where R1, R2, R3, R4, R5, A and n are as defined above.
In one embodiment the compounds of the present invention are of formula Ixe2x80x3:
where R1, R2, R3, R4, R5, A and n are as defined above.
In another embodiment there are provided compounds of formula Ixe2x80x2xe2x80x3:
where R1, R2, R3, R4 and R5 are as defined above.
The following preferred definitions of substituents apply to each of the formulae I, Ixe2x80x2, Ixe2x80x3 and Ixe2x80x2xe2x80x3 which refer to those substituents.
Preferably R1 is
(1) C1-10alkyl, C2-10alkenyl or C2-10alkynyl optionally substituted with one to three substituents independently chosen from:
(i) hydroxy;
(ii) halogen;
(iii) amino;
(iv) C1-4alkoxy; and
(v) phenyl which is optionally substituted by one or two groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkenyl,
(d) C1-4alkoxy and
(e) amino; or
(2) phenyl which is optionally substituted by one or two groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy and
(e) amino.
When R1 is a heterocyclic ring it may be saturated, partially saturated or unsaturated. Preferably the heterocyclic ring is a heteroaromatic ring.
More preferably R1 is C1-10alkyl optionally substituted with up to three substituents as defined above. Even more preferably R1 is C1-6alkyl optionally substituted by one to three substituents as defined above. Most preferably R1 is C1-6alkyl optionally substituted by halogen, phenyl, hydroxy or C1-4alkoxy. In particular R1 may be tertiary butyl or benzyl.
R2 and R3 may be independently chosen from phenyl; naphthyl; a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; and a group (CH2)pQ1 wherein Q1 is phenyl; naphthyl; a five-membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently chosen from O, N and S, at most one of the heteroatoms being O or S; and a six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; and wherein each of R2 and R3 is independently optionally substituted by one to three groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-3alkyl, C2-3alkenyl and C2-3alkynyl,
(d) C1-3alkoxy,
(e) NR6R7 wherein R6 and R7 are independently as defined above,
(f) CO2R8 wherein R8 is independently as defined above,
(g) CONR6R7 wherein R6 and R7 are independently as defined above,
(h) SO2NR6R7 wherein R6 and R7 are independently as defined above,
(i) CH2NR6R7 wherein R6 and R7 are independently as defined above,
(j) N(R8)COR8xe2x80x2 wherein R8 and R8xe2x80x2 are independently as defined above,
(k) NR8SO2R8xe2x80x2 where R8 and R8xe2x80x2 are independently as defined above;
More preferably R2 and R3 are (CH2)pQ1.
Preferably p is one.
Preferably Q1 is phenyl optionally substituted by one or two groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy and
(e) amino.
In one embodiment R2 and R3 are both benzyl.
More preferably Q1 is phenyl.
Preferably R4 and R5xe2x80x2 are independently chosen from optionally substituted C1-6alkyl and (CH2)qQ2. More preferably R4 and R5 are independently chosen from C1-6alkyl and (CH2)qQ2.
Preferably Q2 is optionally substituted phenyl. More preferably Q2 is phenyl.
In particular R4 and R5 are independently chosen from methyl, benzyl, phenyl, 2-methylpropyl, 1-hydroxyethyl, isopropyl and isobutyl.
A is preferably hydrogen or a group
wherein R7 is phenyl, C1-6alkyl or C3-7cycloalkyl and Y is hydrogen or C1-6 alkyl. More preferably A is hydrogen or a group as defined above wherein R7 is a cyclohexyl group.
X is preferably oxygen.
n may be zero. n may be one.
p is preferably one.
q is preferably zero or one.
Thus a subclass of compounds of formula I and Ixe2x80x2 is provided wherein:
R1 is
(1) C1-10alkyl, C2-10alkenyl or C2-10alkynyl optionally substituted with one or more substituents independently chosen from:
(i) hydroxy;
(ii) halogen;
(iii) amino;
(iv) C1-4alkoxy; and
(v) phenyl which is optionally substituted by one or two groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy and
(e) amino; or
(2) phenyl which is optionally substituted by one or two groups independently chosen from:
(a) halogen, cyano and nitro,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4 alkoxy and
(e) amino;
R2 and R3 are both (CH2)pQ1 wherein Q1 is phenyl optionally substituted by one or two groups independently chosen from:
(a) halogen,
(b) hydroxy,
(c) C1-4alkyl, C2-4alkenyl and C2-4alkynyl,
(d) C1-4alkoxy and
(e) amino;
R4 and R5 are independently chosen from C1-6alkyl optionally substituted by halogen, hydroxy, amino or C1-4alkoxy and (CH2)qQ2 wherein Q2 is phenyl optionally substituted by hydroxy, C1-4alkyl, C1-4alkoxy, thiol, C1-4alkylthio, halogen, amino, carboxy, amido, CO2H and xe2x80x94NHC(NH2)2;
A is hydrogen or
wherein R7 is phenyl, C1-6alkyl or C3-7cycloalkyl;
Y is hydrogen or C1-6 alkyl;
n is zero or one;
p is one; and
q is zero or one.
For the avoidance of doubt each time the moieties A, R6, R7, R8, R8xe2x80x2 and R9 occur more than once in the definition of the compounds of formula (I) they are chosen independently.
As used herein, the expression xe2x80x9cC1-10alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained and branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as xe2x80x9cC1-6alkylxe2x80x9d, xe2x80x9cC1-4alkylxe2x80x9d, xe2x80x9cC2-10alkenylxe2x80x9d, xe2x80x9cC2-4alkenylxe2x80x9d, xe2x80x9cC2-10 alkynylxe2x80x9d and xe2x80x9cC2-4alkynylxe2x80x9d are to be construed in an analogous manner.
The expression xe2x80x9cC3-7cycloalkylxe2x80x9d as used herein includes cyclic propyl, butyl, pentyl, hexyl and heptyl groups such as cyclopropyl and cyclohexyl.
The term xe2x80x9cheterocyclicxe2x80x9d includes rings which are saturated, partially saturated or unsaturated. Unsaturated heterocyclic rings are also known as heteroaromatic rings.
Suitable 5- and 6-membered heteroaromatic rings include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. A suitable 5-membered heteroaromatic ring containing four nitrogen atoms is tetrazolyl. Suitable 6-membered heteroaromatic rings containing three nitrogen atoms include 1,2,4-triazine and 1,3,5-triazine. Suitable saturated heterocyclic rings include piperazine, morpholine, piperidine, tetrahydrofuran and tetrahydrothiophene. Tetrahydrofuran is preferred.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
As used herein the term xe2x80x9cC1-4alkoxyxe2x80x9d includes methoxy and ethoxy groups, and straight-chained, branched and cyclic propoxy and butoxy groups, including cyclopropylmethoxy.
Specific Examples according to the present invention include:
{1S-benzyl-4R-[1-(1S-carbamoyl-2-(R)-hydroxypropylcarbamoyl)-(S)-ethylcarbamoyl]-2R-hydroxy-5-phenylpentyl}-carbamic acid, tert-butyl ester;
{1S-benzyl-4R-[1-(1S-carbamoyl-2-(S)-methylbutylcarbamoyl)-1S-2-methylpropylcarbamoyl]-2R-hydroxy-5-penylpentyl}carbamic acid tert-butyl ester;
{1S-benzyl-4-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-yclarbamoyl)-(S)-ethylcarbamoyl]-2R-hydroxybutyl}-carbamic acid, tert-butyl ester;
{1S-benzyl-4R-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-yclarbamoyl)-(S)-ethylcarbamoyl]-2R-hydroxy-5-phenylpentyl}-carbamic acid, tert-butyl ester;
{1S-benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}-carbamic acid, benzyl ester;
{1S-benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-1S-3-methylbutylcarbamoyl]-2-oxo-5-phenylpentyl}-carbamic acid tert-butyl ester;
{1S-benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester;
{1S-benzyl-4R-[1-(1S-carbamoyl-2-phenylethylcarbamoyl)-S-ethylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester;
(1S-benzyl-4R-{1S-[(carbamoylphenylmethyl)carbamoyl]-S-ethylcarbamoyl}-2R-hydroxy-5-phenylpentyl)carbamic acid tert-butyl ester; and the pharmaceutically acceptable salts thereof.
Examples of pharmaceutically acceptable salts are hydrochlorides, sulfates, citrates, tartrates, acetates, methanesulfonates, phosphates, oxalates and benzoates.
The compounds of the present invention have an activity as inhibitors of xcex3 secretase. In a preferred embodiment the compounds of the invention inhibit proteolysis of PS-1.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycel, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The present invention also provides a compound of the invention or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human body. Preferably the treatment is for a condition associated with the deposition of xcex2-amyloid. Preferably the condition is a neurological disease having associated xcex2-amyloid deposition such as Alzheimer""s disease.
The present invention further provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Alzheimer""s disease.
Also disclosed is a method of treatment of a subject suffering from or prone to Alzheimer""s disease which comprises administering to that subject an effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
For treating or preventing Alzheimer""s Disease, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.01 to 100 mg/kg per day, and especially about 0.01 to 5 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.
There is also provided a process for producing a compound of formula I or a pharmaceutically acceptable salt thereof which comprises reacting a compound of formula II with a compound of formula III:
wherein R1, R2, R3, R4, R5, A, X and n are as defined above and P is hydrogen or a protecting group such as a trialkylsilane group, for example t-butyl dimethylsilyl, followed, if necessary, by deprotection of the resulting compound to produce a compound of formula I. The reaction is generally carried out in the presence of coupling agents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in a solvent such as DMF, generally at about room temperature for six to twelve hours. Any necessary deprotection is achieved by conventional means.
The compound of formula II is produced by reacting a compound of formula IV:
wherein R1, R2, R3 and X are as defined above in a solvent such as dioxane, with a base such as lithium hydroxide in a polar solvent such as water generally at room temperature for above five hours. If desired the resulting compound of formula II in which P is hydrogen is protected by conventional means.
The compound of formula IV is produced by reacting a compound of formula V with a compound of formula VI or a compound of formula VII:
wherein R1, R2 and X are as defined above, R3xe2x80x2 is the acyl derivative of a group R3 as defined above and R3xe2x80x3 is a group R3 bound to an oxo group at the portion of R3 which connects to the compound of formula V. The reaction is generally carried out in the presence of a base such as lithium diisopropylamide in a solvent such as THF generally cooled to xe2x88x9278xc2x0 C. for about thirty minutes. The reaction mixture is subsequently dehydrated without purification and then hydrogenated with, for example, hydrogen over 5% Pd/C catalyst at about 50 psi for about 2 h.
The compound of formula V in which R1 is tertiary butyl and R2 is benzyl can be prepared as described by J. Litera et al., Collect. Czech. Chem. Commun. 1998, 63, 231ff. Compounds of formula V in which R1 is other than tertiary butyl and R2 is other than benzyl can be made by analogous methods.
Compounds of formulae III and VI are commercially available or known in the prior art or can be made from commercially available or known compounds by standard methods.
Alternatively the compounds of the present invention can be made by the following typical experimental procedure or by methods analogous thereto:
in which R1, R2, R3, R4, R5 and n are as defined above and A is hydrogen.
A. 50 mg (0.030 mmol) of FMOC-Sieber amide resin is placed in a Quest 210 solid phase reactor and treated with Piperidine/DMF (0.5 mL; 1:1 mixture) with mixing for 30 minutes. The reactor is drained and washed with DMA (10xc3x971 mL). 1 mL of a 0.1 M solution of FMOC-amino acid 1 in DMA is added followed by 0.2 mL of a DMA mixed solution of HOBT and Hunig""s base (0.5 M in both) and 0.5 mL of a 0.2 M solution of PyBOP in DMA. The reactor is mixed for 60 minutes, drained, and washed with DMA (10xc3x971 mL). The reactor is treated with Piperidine/DMF (0.5 mL; 1:1 mixture) and mixed for 30 minutes. The reactor is drained and washed with DMA (10xc3x971 ML). 1 mL. of a 0.1 M solution of FMOC-amino acid 2 in DMA is added followed by 0.2 mL of a DMA mixed solution of HOBT and Hunig""s base (0.5 M in both) and 0.5 mL of a 0.2 M solution of PyBOP in DMA. The reactor is mixed for 60 minutes, drained, and washed with DMA (10xc3x971 mL). The reactor is treated with Piperidine/DMF (0.5 mL; 1:1 mixture) and mixed for 30 minutes. The reactor is drained and washed with DMA (10xc3x971 mL).
B. 21 mg (0.04 mmol) of the TBS-protected isostere and 5 mg HOBT in 0.5 mL NMP is added to the reactor, followed by Hunig""s base (50 xcexcL) and 0.5 M PyBOP in NMP (0.5 mL). The reactor is mixed for 16 h, filtered, and washed with DMA (5xc3x971 mL), MeOH (2xc3x971 mL) and DCE (10xc3x971 mL).
C. The reactor is treated with 0.5 mL of a 1% solution of TFA in DCM and stood for 10 minutes. The reactor is drained into a test tube containing 2 M NH3 in MeOH (1 mL) and the cleavage repeated a further 5 times (identical conditions). The product is concentrated (SpeedVac), dissolved in 1 mL DCM and washed with water (1 mL) using a phase separation CombiTube. The DCM layer is concentrated (SpeedVac) to give essentially pure TBS-protected product.
D. The product is dissolved in 1 M TBAF in THF (0.5 mL), stood for 7 h, water (2 mL) is added and the product is extracted out with DCM (3xc3x971 mL). The product is purified by flash chromatography (5%MeOH/DCM).
All products are analyzed by analytical LC-MS utilizing diode array detection (210-250 nm) and APcI detection (150-850 amu) using a full 5%xe2x86x9295% MeCN gradient with 0.1% aqueous TFA. A strong M+Na+ peak is oberved in the mass spectrum.
It will be understood that any compound of formula I initially obtained from the above process may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art.
It will also be appreciated that where more than one isomer can be obtained from a reaction then the resulting mixture of isomers can be separated by conventional means.
Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
A typical assay which can be used to determine the level of activity of compounds of the present invention is as follows:
(1) Mouse neuroblastoma neuro 2a cells expressing human app695 are cultured at 50-70% confluency in the presence of sterile 10 mM sodium butyrate.
(2) Cells are placed in 96-well plates at 30,000/well/100 xcexcL in minimal essential medium (MEM) (phenol red-free) +10% foetal bovine serum (FBS), 50 mM HEPES buffer (pH7.3), 1% glutamine, 0.2 mg/mL G418 antibiotic, 10 mM sodium butyrate.
(3) Make dilutions of the compound plate. Dilute stock solution to 5.5% DMSO/110 xcexcM compound. Mfix compounds vigorously and store at 4xc2x0 C. until use.
(4) Add 10 xcexcL compound/well. Mix plate briefly, and leave for 18 h in 37xc2x0 C. incubator.
(5) Remove 90 xcexcL of culture supernatant and dilute 1:1 with ice-cold 25 mM HEPES (pH.3), 0.1% BSA, 1.0 mM EDTA (+broad spectrum protease inhibitor cocktail; pre-aliquotted into a 96-well plate). Mix and keep on ice or freeze at xe2x88x9280xc2x0 C.
(6) Add back 100 xcexcL of warm MEM +10% FBS, 50 mM HEPES (pH7.3), 1% glutamine, 0.2 mg/mL G418, 10 mM sodium butyrate to each well, and return plate to 37xc2x0 C. incubator.
(7) Prepare reagents necessary to determine amyloid peptide levels, for example by ELISA assay
(8) To determine if compounds are cytotoxic cell viability following compound administration is assessed by the use of redox dye reduction. A typical example is a combination of redox dye MTS (Promega) and the electron coupling reagent PES. This mixture is made up according to the manufacturer""s instructions and left at room temperature.
(9) Quantitate amyloid beta 40 and 42 peptides using an appropriate volume of diluted culture medium by standard ELISA techniques.
(10) Add 15 xcexcL/well MTS/PES solution to the cells; mix and leave at 37xc2x0 C.
(11) Read plate when the absorbance values are approximately 1.0 (mix briefly before reading to disperse the reduced formazan product).
The Examples of the present invention all had an ED50 of less than 500 nM, preferably less than 200 nM and most preferably less than 100 nM in the above assay.


A process cartridge detachably mountable to the electrophotographic apparatus main body, integrally including an electrophotographic photosensitive member to carry a toner image; an intermediate transfer belt having a contact part with the photosensitive member; primary transfer member to primarily transfer the toner image from the photosensitive member to the intermediate transfer belt; and electric charge member to give electric charges in polarity opposite to the polarity of the toner at the time of the primary transfer to the toner on the intermediate transfer belt to return the toner on the intermediate transfer belt to the photosensitive member at the contact part to clean the intermediate transfer belt, wherein the intermediate transfer belt has an average glossiness of 30 to 90; glossiness deviation within 10; average film thickness of 40 to 200 xcexcm; and film thickness unevenness within xc2x120% relative to the average film thickness. Also, an electrophotographic apparatus having the process cartridge and an image forming method using the electrophotographic apparatus are disclosed.

1. Field of the Invention
The present invention relates to a process cartridge, an electrophotographic apparatus, an image forming method and an intermediate transfer belt.
2. Related Background Art
Image forming apparatus of electrophotographic system (electrophotographic apparatus) using an intermediate transfer belt is effective as a full color electrophotographic apparatus and a multi-color image forming apparatus that perform sequential laminated transfer of a plurality of component color images of full color image information or multi-color image information to output image forming product that is synthesized and reproduced from the full color image or the multi-color image.
Compared with a conventional transferring apparatus of a full color electrophotographic apparatus (for example, described in Japanese Patent Application Laid-Open No. 63-301960) having an electrophotographic apparatus wherein images are transferred from an electrophotographic photosensitive member to a second image bearing member fastened or attracted onto a transferring drum, a full color electrophotographic apparatus using an intermediate transfer belt does not require any processing or control on the transfer material but can transfer images from the intermediate transfer belt to a transfer material, and therefore has an advantage that various kinds of second image bearing member can be selected regardless of wideness/narrowness of width or longness/shortness of length to cover thin paper (40 g/m2 paper) to thick paper (200 g/m2 paper).
In addition, compared with such a case where rigid cylinder such as an intermediate transfer drum is used, adopting an intermediate belt shape, freedom for disposing inside an electrophotographic apparatus increases, giving rise to an advantage that miniaturization or cost reduction of the main body of the apparatus can be implemented by efficiently utilizing spaces.
However, the life of the intermediate transfer belt is shorter than the main body, and replacement is indispensable under the current state.
In addition, a waste toner container that collects residual developer (hereunder referred to as toner) in the intermediate transfer belt needs to be disposed and treated.
In addition to these, a lot of components such as electrophotographic photosensitive member, developing means and toner, etc. for a printer and a photocopier will need replacement.
As a method to unitize these replacement components and attach to/remove from the main body easily, Japanese Patent Application Laid-Open No. 8-137181 proposes to dispose an intermediate transfer belt and an electrophotographic photosensitive member as respectively independent units detachably mountable to the main body without difficulty.
However, these means involve a number of replacement units to make user""s operation complicated. Moreover, each unit is designed and disposed independently, thereby giving rise to such a problem that the main body gets larger or costs increase.
As means to solve this problem, replacing means to simultaneously remove from/attach to the main body the intermediate transfer belt and the electrophotographic photosensitive member (replacement components) as one-body unit are suitable, and are proposed in Japanese Patent Application Laid-Open No. 6-110261, Japanese Patent Application Laid-Open No. 10-177329 and Japanese Patent Application Laid-Open No. 11-30944 etc.
However, in the method to construct the intermediate transfer belt and the electrophotographic photosensitive member as one-body unit, that is, an intermediate transfer belt-electrophotographic photosensitive member integrated process cartridge (hereinafter to be referred to simply as xe2x80x9cintegrated process cartridgexe2x80x9d as well), the integrated process cartridge as a whole must be replaced even when a problem takes place in the intermediate transfer belt, which on the contrary might increase costs.
In general, in a full color electrophotographic apparatus, image density could be varied due to change in environments for use, or original correct color tone could become unavailable.
Therefore, in case of a full color electrophotographic apparatus using an intermediate transfer belt, it comprises density detecting means as means to obtain accurate density information, bringing density detecting toner image (patch) for respective colors produced on the intermediate transfer belt into radiation with a predetermined light so as to detect density from reflection rates of that reflection light and the intermediate transfer belt and to control image density by feeding the detection results back to the exposure amount and the developing bias, etc. Thus, it is important that glossiness of the surface of the intermediate transfer belt is stable all over the circumference of the belt.
However, at the time of shipment of the integrated process cartridge, or in the case where a user removes and conveys the integrated process cartridge, due to contact between the intermediate transfer belt and the electrophotographic photosensitive member, the intermediate transfer belt and the electrophotographic photosensitive member suffer from vibration, mutual friction, or rubbing frequently and repeatedly. Therefore, cuts and scrapes are given rise to onto the surface of the intermediate transfer belt, and glossiness of the intermediate transfer belt in the contact part decreases.
In addition, while the integrated process cartridge is kept for a long time at the time of shipment, components constructing the intermediate transfer belt and the electrophotographic photosensitive member are oozed so that the contact part fogs and the glossiness decreases.
In addition, increase in number of print causes accumulation of dirt on the surface of the intermediate transfer belt due to toner and paper dust, or occurrence of micro cuts or scratches so that the glossiness of the intermediate transfer belt decreases.
Moreover, in the intermediate transfer belt-electrophotographic photosensitive member integrated process cartridge, the intermediate transfer belt is always brought into contact with the electrophotographic photosensitive member, friction between the intermediate transfer belt and the electrophotographic photosensitive member not only reduces glossiness on the surface of the intermediate transfer belt as a whole but also gives rise to unevenness in glossiness. As a result, density detection is not executed accurately, giving rise to density unevenness for each image. In addition, a belt with glossiness unevenness from the initial period of use intensifies unevenness as it is used, and density unevenness on each image gets worse.
On the other hand, in the electrophotographic apparatus with the intermediate transfer belt and the electrophotographic photosensitive member being respectively independent units, even if the belt used has a glossiness unevenness, that unevenness changes little.
A purpose of the present invention is to provide an intermediate transfer belt-electrophotographic photosensitive member integrated process cartridge that makes maintenance easy, can attain miniaturization as well as cost reduction of the apparatus, can perform density detecting measuring for controlling image forming conditions in more stable and more accurate fashion, and can provide excellent images corresponding with use conditions, a electrophotographic apparatus having the above-described process cartridge, and an image forming method using the above-described electrophotographic apparatus.
In order to solve the above-described problem, the present inventors have intensified their consideration and found out that it works well with the average glossiness of the intermediate transfer belt being 30 to 90 and its deviation being within 10.
Moreover, the intermediate transfer belt-electrophotographic photosensitive member integrated process cartridge mostly is at a standstill with tension being applied for a long period until it is actually used, bending habit will be given in the portion of a spanning roller, execution of density detection in this portion does not provide accurate reflection light, giving rise to density unevenness in each image as a result thereof.
Also, in order to solve the above-described problem, the present inventors have intensified their consideration and found out that it works well with the average film thickness of the intermediate transfer belt being 40 xcexcm to 200 xcexcm and further with its unevenness being within xc2x120% relative to the average value.
That is, the present invention provides a process cartridge detachably mountable to an electrophotographic apparatus main body, the process cartridge integrally comprising:
an electrophotographic photosensitive member to carry a toner image;
an intermediate transfer belt having a contact part with the electrophotographic photosensitive member;
primary transfer means to primarily transfer the toner image at the contact part from the electrophotographic photosensitive member to the intermediate transfer belt; and
electric charge providing means to give electric charges in polarity opposite to the polarity of the toner at the time of the primary transfer to the toner on the intermediate transfer belt to return the toner on the intermediate transfer belt to the electrophotographic photosensitive member at the contact part to clean the intermediate transfer belt,
wherein the intermediate transfer belt has an average glossiness, obtained in the circumference direction, of 30 to 90;
a glossiness deviation of within 10;
an average film thickness of 40 to 200 xcexcm; and
a film thickness unevenness of within xc2x120% relative to the average film thickness.
In addition, the present invention provides an electrophotographic apparatus comprising:
an electrophotographic photosensitive member to carry a toner image;
charging means to charge the electrophotographic photosensitive member;
exposing means to form an electrostatic latent image on the electrophotographic photosensitive member charged with the charging means;
developing means to develop with toner the electrostatic latent image on the electrophotographic photosensitive member formed with the exposing means to form a toner image on the electrophotographic photosensitive member;
an intermediate transfer belt having a contact part with the electrophotographic photosensitive member to perform, after the primary transfer of the toner image from the electrophotographic photosensitive member to the intermediate transfer belt, secondary transfer of the primarily transferred toner image to a transfer material;
primary transfer means to primarily transfer the toner image from the electrophotographic photosensitive member to the intermediate transfer belt at the contact part;
electric charge providing means to give electric charges in polarity opposite to the polarity of the toner at the time of the primary transfer to the toner on the intermediate transfer belt to return the toner on the intermediate transfer belt to the electrophotographic photosensitive member at the contact part to clean the intermediate transfer belt, and
a process cartridge integrally comprising at least the electrophotographic photosensitive member, the intermediate transfer belt, the primary transfer means and the electric charge providing means and being detachably mountable to the electrophotographic apparatus main body,
wherein the intermediate transfer belt has an average glossiness, obtained in the circumference direction, of 30 to 90;
a glossiness deviation of within 10;
an average film thickness of 40 to 200 xcexcm; and
a film thickness unevenness of within xc2x120% relative to the average film thickness.
In addition, the present invention provides an image forming method comprising:
a charging step to charge an electrophotographic photosensitive member;
an exposing step to form an electrostatic latent image on the electrophotographic photosensitive member charged in the charging step;
a developing step to develop with a toner the electrostatic latent image on the electrophotographic photosensitive member formed in the exposing step to form a toner image on the electrophotographic photosensitive member;
a primary transfer step to primarily transfer the toner image formed in the developing step, with primary transfer means, from the electrophotographic photosensitive member to the intermediate transfer belt having a contact part with the electrophotographic photosensitive member;
a secondary transfer step to secondarily transfer the toner image primarily transferred in the primary transfer step to a transfer material;
an electric charge providing step to give electric charges in polarity opposite to the polarity of the toner at the time of the primary transfer step to the toner on the intermediate transfer belt with electric charge providing means; and
an intermediate transfer belt cleaning step to return the toner on the intermediate transfer belt to the electrophotographic photosensitive member at the contact part to clean the intermediate transfer belt,
the image forming method using the electrophotographic apparatus having a process cartridge, the process cartridge integrally comprising at least the electrophotographic photosensitive member, the intermediate transfer belt, the primary transfer means and the electric charge providing means and being detachably mountable to the electrophotographic apparatus main body,
wherein the intermediate transfer belt has an average glossiness, obtained in the circumference direction, of 30 to 90;
a glossiness deviation of within 10;
an average film thickness of 40 to 200 xcexcm; and
a film thickness unevenness of within xc2x120% relative to the average film thickness.
In addition, the present invention is an intermediate transfer belt for the above-described process cartridge.
Incidentally, in Japanese Patent Application Laid-Open No. 10-63111, a method to decrease changes in glossiness of the intermediate transfer member is disclosed and only the average glossiness of the intermediate transfer belt is described. There are no statements on film thickness of the intermediate transfer belt and its unevenness.
In addition, in Japanese Patent Application Laid-Open No. 5-31818, a method of producing a belt having uniform surface is disclosed. There are no statements on film thickness of the intermediate transfer belt and its unevenness.

Process cartridge, electrophotographic apparatus and image forming method


A driving circuit for a display panel comprising a driving voltage generator for outputting a plurality of gamma reference voltages, and a gray scale voltage generating unit for selecting one out of the plurality of gamma reference voltages and generating a gray scale voltage based on the selected gamma reference voltage, a liquid crystal display having the driving circuit, and a method for driving the liquid crystal display. A gamma reference voltage is dynamically changed depending on a user's selection, so that a gray scale voltage is changed, thereby varying the gamma characteristic and the viewing angle of an output image. Accordingly, a user can actively control the gamma characteristic and the viewing angle of an output image to be suitable for a user's preference and environment.

1. Field of the Invention
The present invention relates to liquid crystal displays, and more particularly, to a driving circuit for a display panel capable of actively controlling a gamma characteristic and the viewing angle of an output image according to a user's preference and/or environment, a liquid crystal display having the driving circuit and a method for driving the liquid crystal display.
2. Description of the Related Art
A typical liquid crystal display (LCD) includes an LCD panel, having an upper substrate with color filters and a common electrode formed thereon, and a lower substrate with thin film transistors and pixel electrodes formed thereon, and a liquid crystal layer interposed between both the substrates, and a backlight as a light source positioned behind the LCD panel. Further, a polarizer may be attached to a surface of the LCD panel to control the transmissivity of light from the backlight exiting the liquid crystal layer.
An image displayed on such a conventional LCD has predetermined fixed gamma and viewing angle characteristics, which depends upon a gray scale voltage (or gamma voltage) that is referenced to a data signal applied to a pixel electrode.
However, since a reference voltage when generating a gray scale voltage, i.e., a gamma reference voltage GVDD, is fixed at one state (standard state) in a conventional LCD, it is difficult to change the gamma characteristic and the viewing angle of an output image depending on a user's preference and environment. For example, since a characteristic of a favorite image is different depending on a user, the gamma characteristic of an output image is required to be controlled considering a user's preference. Further, in a conventional LCD, a wide viewing angle is typically required to display better an image in terms of enhanced visibility. However, for the protection of a user's privacy in public places, a narrow viewing angle is also required so as not to display an image to others. Therefore, the viewing angle of an output image needs to be adjusted considering a user's preference and environment.

Driving circuit for display panel having user selectable viewing angle, display having the same, and method for driving the display


A long duration ash probe includes a pressure shell connected to a port in a combustor with a sample coupon mounted on a retractable carriage so as to retract the sample coupon within the pressure shell during sootblowing operation of the combustor. A valve mounted at the forward end of the pressure shell is selectively closeable to seal the sample coupon within the shell, and a heating element in the shell is operable to maintain the desired temperature of the sample coupon while retracted within the shell. The carriage is operably mounted on a pair of rails within the shell for longitudinal movement within the shell. A hollow carrier tube connects the hollow cylindrical sample coupon to the carriage, and extends through the carriage and out the rearward end thereof. Air lines are connected to the rearward end of the carrier tube and are operable to permit coolant to pass through the air lines and thence through the carrier tube to the sample coupon so as to cool the sample coupon.

In order to assess the effects of ash formation on boiler tubes, it was common to insert a small tube through a hole in the combustor wall of the boiler. The main problem with such prior art devices was in the accurate assessment of ash formation on a boiler tube under conditions similar to the actual boiler tubes in a combustion unit. Prior art devices were not capable of long duration since the sootblowing operation of conventional combustion units would disturb the ash deposit on the sample probe.
In addition, the coupon and ash temperature could not be maintained outside the combustor in prior art devices.
It is therefore a general object of the present invention to provide an improved long duration ash probe.
Another object of the present invention is to provide an ash probe which is automatically retractable from the combustion unit during sootblowing operations of the combustion unit.
Still another object is to provide a long duration ash probe capable of monitoring and controlling the temperature of the coupon thereof.
These and other objects will be apparent to those skilled in the art.

Energy & Environmental Research Center Foundation


The disclosed photosensitive matrix comprises, in a standard way, a P type semiconductor substrate, an N type channel layer separated by narrow insulating zones into a plurality of columns and, on a thin layer of insulating oxide placed on the channel layer, a network of transfer grids extending perpendicularly to the insulating zones, dividing the columns into a large number of "pixels". According to the invention, the matrix has, between the substrate and the channel layer, a weakly doped P type base layer, in which are buried anti-blooming diodes consisting of a narrow, strong doped N type drain extending in a direction parallel to the insulation zones. Beneath the drain, there is a strongly doped, P type protective screen. The arrangement gives an optical aperture of the matrix close to unity and a spectral response that is improved towards the red side of the spectrum owing to the thickness of the base layer.

1. Field of the Invention
The invention pertains to a frame transfer CCD matrix provided with vertical type anti-blooming means having, on a first type of semiconductor substrate, a second type of channel layer separated by narrow insulating zones into a plurality of columns and surmounted, with an interposed layer of insulating oxide, by a network of transfer gates, extended perpendicularly to the insulating zones and dividing the columns into a large number of "pixels" or elementary picture (or image) elements.
The invention also pertains to a method for the fabrication of a photosensitive matrix such as this.
2. Description of the Prior Art
As is well known, these photosensitive matrices are designed to convert an optical image, projected on the input face of the matrix, into electrical signals formed by a dual sequence of rows and frames. Each frame has a period of accumulation during which the absorbed photons give rise to electron/hole pairs, with one type of charge collecting in elementary cells or pixels while the other type of charge flows through the semiconductor. After the accumulation period, there is a transfer period where the collected charges are sent sequentially, by columns, to conversion capacitors to give rise to a signal voltage. Of course, the transfer period is shorter than the accumulation period.
The cooperation between the insulating zones and the suitably biased transfer grids determines the formation, for each pixel, during the accumulation period, of discrete potential wells separated by walls. The charges collect in these wells which they gradually fill. The filling current or flow is substantially proportionate to the local illumination. During the transfer period, an appropriate modulation of the grid potentials causes the walls of the potential wells to shift towards the columns, towards the conversion capacitors.
It is seen that the charge accumulation capacity of the wells, in conjunction with the frame transfer frequency, determines a range of exploitable illumination levels between a dark level and a blooming level (the latter corresponding to the total filling of the wells) beyond which the charges flow over the walls and fill the adjacent wells.
A standard way to prevent the blooming of zones of the matrix by the overflow of charges from wells into adjacent wells is to have anti-blooming means to drain the extra charges on a barrier level which is close to the blooming level but is lower than it in terms of absolute value. These anti-blooming means are diodes or drains connected to a suitably biased connection so as to be off for a well potential which is higher than the barrier level, and on for a lower potential, in the case where the substrate is of the P type. In the case of a N type substrate, the on and off potentials are respectively lower than and higher than the barrier level.
In the prior art, these anti-blooming means are classified under two types, horizontal or vertical, depending on whether the direction in which the charges flow towards the drains is parallel or perpendicular to the surface of the matrix (which is conventionally considered to stretch along a horizontal plane).
In the horizontal type, as described notably in the documents FR-A-No. 2 529 388 and FR-A-No. 2 529 390, the diodes are placed on the surface of the matrix, adjacent to the pixels. The result thereof is that these diodes, which are optically inactive, occupy a considerable surface of the matrix. The optical aperture of the matrix, or the ratio of the photosensitive surface to the geometrical surface is reduced.
Anti-blooming structures of the vertical type have also been proposed, where the excess charges are discharged through the substrate by means of a buried PN junction formed by a P type recess in an N type substrate. These structures have an optical aperture close to unity. By contrast, they cause a poor spectral response with a loss in sensitivity for the long wavelengths of spectrum, namely red and infra-red. For, the mean distance of absorption of the photons with the formation of electron-hole pairs is relatively great for the low energy photons in silicon, and exceeds the depth of the recesses, this depth being limited, in particular so that the PN junction is close enough to the associated well.
An object of the invention is the making of a photosensitive charge transfer matrix provided with anti-blooming means, and having a wide optical aperture and a good spectral response.

Fabrication method for a CCD frame transfer photosensitive matrix with vertical anti-blooming system


The invention relates to a process for preparing an instant enzyme formulation; instant enzyme formulations obtainable by this process and feedstuff compositions prepared using instant enzyme formulations of the invention.

Enzymes are widely used in animal nutrition, with the purpose of increasing the bioavailability of certain nutrients or improving the feed conversion efficiency. Thus, for example, the enzyme phytase is used to release the phosphorus bound in phytate and thus ensure its bioavailability. It is further known to add NSP (nonstarch polysaccaride) enzymes to the feed in order, inter alia, to reduce the viscosity of the feed in the alimentary tract and thus improve the conversion efficiency of the feed.
However, feedstuffs containing an added enzyme preparation are frequently pelleted, expanded or extruded, as a result of which, owing to the resultant relatively high temperatures, the enzyme activity is reduced or completely destroyed. To avoid this disadvantage, enzymes in the form of liquid formulations are sprayed onto the already-pelleted feedstuff.
However, the use of liquid enzyme preparations also has disadvantages. Owing to the high water content or the high water activity, enzyme formulations of this type can be stabilized only with great difficulty. Frequently, a sharp drop in activity, an increase in microbial count and an impairment of the appearance of the preparation is observed during storage. In particular, owing to temperature fluctuations, precipitation of the enzymes or other proteins present therein may frequently be observed. In addition to the inadequate keeping quality, moreover, the low activity per unit volume is a serious disadvantage with liquid formulations.
WO 97/12958 discloses enzyme-containing microgranules which are obtained by agglomeration. They comprise an enzyme preparation applied to a support and at least one binder or decomposition accelerator. The granules are, in addition, polymer-coated and have a particle size of less than 0.4 mm. The enzyme content for a typical composition is less than 40% by weight. The preparation of an instant enzyme formulation which is suitable, in particular, as an easily handled feed additive is not described therein.
It is an object of the present invention therefore to provide an improved enzyme formulation which avoids the above-described disadvantages of liquid formulations.

This patent is subject to a terminal disclaimer.

Instant enzyme formulations for animal nutrition


An electric contact of a socket for an electrical part is disposed between a first electrical part and a second electrical part so as to electrically connect the first and second electrical parts, and includes: a first electrical part side contact member contacting the first electrical part; a second electrical part side contact member contacting the second electrical part, the coil spring including a first spring portion abutting against the first electrical part side contact member and a second spring portion abutting against the second electrical part side contact member. When the first electrical part contacts the first electrical part side contact member, an axis of the first spring portion inclines with respect to an axis of the second spring portion, and then, a portion of the first electrical part side contact member on a side contacting the first electrical part is transversely moved.

1. Field of the Invention
The present invention relates to an electric contact disposed between a first electrical part and a second electrical part for electrically connecting them, and also relates to a socket for an electrical part provided with such electric contact.
2. Related Art
A prior art provides a socket for an electrical part provided with an electric contact disposed between a first electrical part and a second electrical part so as to electrically connect them. For example, there has been provided a socket for an electrical part, which is provided with a socket body disposed on a printed circuit board and accommodated with an electrical part, in which the printed circuit board and the electrical parts are electrically connected through a plurality of electric contacts or contact pins disposed to the socket body. In a structure in which the electric contact has a terminal side contact member contacting a terminal of the electrical part and a substrate side contact member contacting the printed circuit board, a coil spring is disposed so as to form a close winging portion between the terminal side contact member and the substrate side contact member for shortening the electrical connection therebetween.
One example of the socket for an electrical part provided with such electrical contact having a coil spring is disclosed in Patent Publication 1 (Japanese Patent Publication No. 3326095). In this Patent Publication 1, there is shown "a socket for an electrical part including a contact provided with a terminal side contact member contacting a terminal of an electrical part, a substrate side contact member contacting a printed circuit board, and a coil spring urging the terminal side contact member and the substrate side contact member in a direction separated from each other, the coil spring being provided with a first spring portion abutting against the terminal side contact member, a second spring portion abutting against the substrate side contact member, and a close winding portion disposed between the first and second spring portions and wound up at the minimum pitch."
There is also disclosed in this Patent Publication 1 that "according to this structure, an electric signal is transmitted through the close winding portion, so that the electric signal may flow along an axial direction of the coil spring at the close winding portion, and accordingly, an increasing in inductance and resistance due to the flow of the high frequency electric signal in a coil-shape at a rough winding portion can be prevented from causing, thus achieving reduction of inductance and resistance".
However, in the invention disclosed in the Patent Publication 1, since the close winding portion is provided between the first and second spring portions, it is difficult to realize a structure in which an axis of the first spring portion inclines with respect to an axis of the second spring portion so that the terminal side contact member is inclined.
Therefore, in a case where the axis of the terminal of the electrical part is shifted from the axis of the terminal side contact member, the terminal side contact member does not follow the shifting of the terminal of the electrical part, which may result in fault in electric connection between the electrical part and the printed circuit board.

Electric contact and socket for electrical part


A radio frequency module includes: a first low-noise amplifier including a first amplification element as an input stage and a second amplification element as an output stage; a second low-noise amplifier including a third amplification element as an input stage and the second amplification element as an output stage, the third amplification element being different from the first amplification element; a first matching circuit connected to an input terminal of the first low-noise amplifier; and a module substrate including a first principal surface and a second principal surface opposite to each other, wherein the first amplification element is disposed on one of the first principal surface and the second principal surface, and the first matching circuit is disposed on the other of the first principal surface and the second principal surface.

In a mobile communication device such as a mobile phone, the disposition and configuration of circuit components of a radio frequency front-end module are increasingly more complex with the progress particularly in multiband communications.
Japanese Unexamined Patent Application Publication No. 2018-137522 discloses a radio frequency module in which power amplifiers, low-noise amplifiers, switches, filters, and so forth are packaged.

Radio frequency module and communication device


A vehicle trunk cover assembly includes two coupled guide rod units which are connectable to the cover and the vehicle body such that the cover is movable between a closed position covering the trunk, a roof transport position in which the front cover end is lifted relative to the trunk, and a loading position in which the rear cover end is lifted relative to the trunk. A locking lever connectable to the vehicle body includes a lock which is movable from an engaged position to a disengaged position upon being actuated. One guide rod unit cooperates with the lock such that the guide rod unit engages the lock when the lock is in its engaged position so that the cover may move into its loading position and disengages from the lock when the lock is in its disengaged position so that the cover may move into its roof transport position.

1. Field of the Invention
The present invention relates to a cover for a receiving space such as a trunk or a storage compartment in a vehicle body.
2. Background Art
EP 0 949 104 A1 (corresponds to U.S. Pat. No. 6,092,335) describes a vehicle having a collapsible roof movable between a closed position in which the roof extends over the vehicle passenger compartment and an opened position in which the roof is stored in the trunk of the vehicle. The front end of a cover covering the trunk is lifted to swivel the cover about an axis in the rear of the vehicle to allow the roof to move in and out of the trunk. The rear end of the cover is lifted to swivel the cover about an axis next to the rear of the roof when the roof is closed to allow items to be loaded into and unloaded out of the trunk.
DE 699 00 921 T2 (corresponds to U.S. Pat. No. 6,092,335) describes a vehicle having a folding roof movable between the closed position and an opened position in which the roof is stored in a storage compartment of the vehicle. A cover covering the compartment is movable into positions which either allow the roof to be stored in the compartment or allow access to the compartment from the rear vehicle side.
DE 44 45 944 C1 (corresponds to U.S. Pat. No. 5,823,606) describes a vehicle having a hardtop. Roof elements of the hardtop are movable into a collapsed position in which they rest in a stowage space of the trunk of the vehicle. A trunk lid articulately connected to the vehicle body may be lifted at its front to allow the roof elements to move into and out of the stowage space and may be lifted at its rear to allow items to be loaded into and unloaded out of the trunk.

Cover for closing a receiving space in the bodywork of a vehicle


A shielding system for high-current applications, having a connecting cable that has an insulated conductor (22) and a cable shielding surrounding the insulated conductor, as well as a shielding housing having a feed-through. In addition, the shielding system has a hollow cylindrical and electrically conductive shielding sleeve. The insulated conductor is fed through the shielding sleeve. The shielding sleeve is situated in the area of the feed-through of the shielding housing, so that the shielding housing abuts a jacket surface of the shielding sleeve. The cable shielding lies against a jacket surface of the shielding sleeve. The cable shielding is electrically connected to the shielding housing via the shielding sleeve.

Electrical connection systems can be used to produce an electrical connection between two or more components. This can be done by plug connections or lines.
In particular, in the case of high-current applications, electromagnetic fields can arise around an electrical conductor. In order to avoid impairment of the environment around the conductor due to these electromagnetic fields, for example a surrounding shielding may be required. In the case of high-current lines, for example a shielding braid can be integrated in the line insulation for this purpose.
Electromagnetic shieldings can also be required for connection systems. Due to the mechanical and electrical demands on these connection systems, and the occurrence of, in part, very high currents in the range of for example 50 to 300 A, high demands are also placed on the quality of the electrical contacting and on the robustness of the mechanical construction. At the same time, an electromagnetic shielding can be required that is as good as possible. In many cases, taking all these demands into account can require compromises with regard to particular features.

Shielding arrangement for high-current applications


A concrete plant with robust recycling capabilities and high energy efficiency is disclosed. In one aspect, a concrete recycling machine used at the concrete plant includes at least a slurry vessel that receives slurry provided from concrete being returned, a motor that drives an agitation device that agitates the slurry in the slurry vessel, and a control system that controls at least one of duration and frequency with which the motor drives the agitation device.

1. Field of the Invention
The present invention relates to concrete plants and, more particularly, to concrete recycling systems for concrete plants. 2. Description of the Related Art
One conventional concrete recycling effort is to reclaim cement slurry. See, e.g., U.S. Pat. No. 4,226,542, which is incorporated herein by reference. More particularly, cement slurry reclamation techniques for concrete plants separate aggregate and coarse sand constituents from returned concrete mix and the remaining ingredients are stored in slurry form for possible consumption during a subsequent production day. Typically, returned concrete mix is dumped into an inlet hopper having a screw classifier for removing aggregate and coarse sand, and a weired channel enabling gravity flow of the water, cement fines and sand fines constituents into a slurry vessel. A motor agitates the slurry within the slurry vessel to prevent setting. Typically, the motor runs constantly while there is slurry in the slurry vessel. Unfortunately, conventional concrete recycling has various limitations or constraints that lead to inefficient recycling. The inefficiencies pertain, for example, to high energy consumption and unusable slurry or slurry water.
Thus, there is a need for improved approaches to perform concrete recycling.
Broadly speaking, the invention relates to an improved concrete plant design with robust recycling capabilities and high energy efficiency. The invention can be implemented in numerous ways and configurations. Several embodiments of the invention are discussed below.
According to one embodiment of the invention, a concrete recycling system includes at least: a slurry vessel that receives slurry provided from concrete being returned, the slurry vessel having an agitation device; a motor that drives the agitation device; and a control system that controls at least one of duration and frequency with which the motor drives the agitation device.
According to another embodiment of the invention, a method for recycling concrete includes at least the operations of: removing at least a portion of aggregates from the concrete, thereby leaving at least slurry; storing the slurry in a slurry vessel, the slurry vessel having an agitation element driven by a motor; and agitating the slurry within the slurry vessel by driving the agitation element with the motor such that the energy used in performing the agitation is varied based on the load on the motor.
According to still another embodiment of the invention, a method for controlling a motor for agitating a cement slurry includes the operations of: activating the motor to agitate the cement slurry; monitoring a load on the motor during the activating; determining a suitable agitation duration based on the load; and deactivating the motor so as cease agitating the cement slurry after the suitable agitation duration has passed since the activating was initiated.
According to yet still another embodiment of the invention, a method for controlling a motor for agitating a cement slurry includes the operations of: monitoring density of the slurry density; determining a suitable agitation duration based on the density; and periodically activating the motor for the suitable agitation duration.
Other aspects and advantages of the invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.


Disclosed is a catheterization package including catheterization-package components and a catheterization tray configured to facilitate a catheterization procedure. The catheterization-package components include a urinary catheter fluidly connected to a urine-drainage bag and a sampling-port access device configured to fluidly connect to a urine-sampling port of the urinary catheter or the urine-drainage bag for aseptic collection of one or more urine samples. The catheterization tray includes at least a first compartment, a second compartment, and a third compartment configured to hold the catheterization-package components. The first compartment is configured to hold the urinary catheter. The second compartment is connected to the first compartment by an intercompartment connection. The second compartment is configured to hold the urine-drainage bag. The third compartment is configured to hold the sampling-port access device. Step-by-step instructions are incorporated into the catheterization tray to facilitate the catheterization procedure. Also disclosed are methods for the catheterization package.

Catheters suitable for draining a patient's bladder include indwelling catheters. Indwelling catheters include Foley catheters, which are typically indicated for surgical and medical patients that require, at least temporarily, assisted bladder voiding. Common indications include acute or chronic urinary retention, medical procedures that may at least temporarily limit a patient's movement, a need for accurate monitoring of fluid input and urine output such as in an intensive care unit ("ICU"), benign prostatic hyperplasia, incontinence, or the effects of various surgical interventions involving the bladder or the prostate.
A standard Foley catheter design includes a balloon disposed at the distal end of the catheter to anchor the catheter in the bladder. The catheter includes at least one lumen to drain urine from the bladder and at least one lumen to inflate the balloon (e.g., with sterile water). The proximal end of the Foley catheter includes at least two ports in communication with the two lumens, a first port that is connected to the drainage lumen and has an interface with fittings for drainage and sampling, and a second port that is connected to the inflation lumen with a valve to ensure the inflation fluid remains within the lumen and balloon once filled. A tip of the standard Foley catheter extends beyond the sides of the balloon into the bladder and includes one or more apertures or "eyes" to drain fluids and debris from the bladder. This standard design has not changed in approximately 100 years, although catheters with various additions (e.g., mechanical anchors, etc.) and improvements have been proposed and investigated.
Catheters suitable for draining a patient's bladder also include intermittent catheters. A typical intermittent catheter differs from an indwelling catheter primarily in that the intermittent catheter does not have a retention balloon or an associated inflation lumen. Rather, the intermittent catheter is typically a single-lumen device, with a plurality of drainage eyes at the distal end and a funnel at the proximal end. Intermittent catheterization is often performed in individuals with malfunctioning urinary systems (e.g., suffering from strictures and traumas), as well as disabled individuals (e.g., para- or quadriplegics) unable to voluntarily urinate. Such individuals will often self-catheterize with an intermittent catheter several times daily.
Intermittent catheters are generally catheters or tubes having a rounded, atraumatic distal tip that is inserted into the bladder of a patient. A molded funnel is typically connected to the proximal end that remains outside the body of the patient or user. The distal tip may include slots or openings on the shaft to facilitate drainage of urine therefrom once the tip is positioned inside the bladder.
Suitable non-limiting examples of urinary catheters, trays, insertion devices, and the like can be found in, for example, U.S. Pat. Nos. 8,328,792, 8,998,882, 10,758,705, and 10,905,848, the disclosures of which are incorporated herein by reference in their entirety.
Research suggests there is variation in all aspects of urine sampling including where the urine sample is taken from a collection system, how the urine-sampling area is cleaned, what device is used to take the urine sample, and how the urine sample is transferred to the lab. Nursing decision makers believe such variation and improper urine-sampling technique leads to an increased risk of contamination and, therefore, false-positive catheter-associated urinary tract infections ("CAUTIs"). Up to 70% of urine cultures reflect false-positive results leading to inaccurate CAUTI diagnoses and inappropriate antibiotic treatments, as well as artificially undermining the time and resources hospitals have dedicated toward reducing the risk of CAUTI by other means. This problem presents an ongoing challenge to those seeking to reduce CAUTI rates.
Disclosed herein are catheterization packages and methods thereof to facilitate catheterization and urine sampling in an effort to reduce CAUTIs and false-positive results leading to inaccurate CAUTI diagnoses.

Catheterization packages and methods thereof


An assembly for controlling an exhaust gas recirculation valve for an internal combustion engine, including a vacuum regulator with an inlet adapted to be connected to a vacuum source, and a solenoid valve with an inlet connected to the outlet of the vacuum regulator and with an outlet arranged to be connected to the control inlet of the recirculation valve to furnish a vacuum to the control inlet as a function of an electrical control signal of the solenoid valve. The body of the vacuum regulator is formed of a single part with the closure cap of the body of the solenoid valve, and a conduit formed in the part communicates the interior of the body of the vacuum regulator with the interior of the body of the solenoid valve.

The present invention relates to a control assembly for an exhaust gas recirculation valve for an internal combustion engine, and more particularly such an assembly including a vacuum regulator whose inlet is arranged to be connected to a vacuum source, and a solenoid valve whose inlet is connected to the outlet of the vacuum regulator and whose outlet is arranged to be connected to the control inlet of the recirculation valve in such a way as to furnish this control inlet with a vacuum as a function of an electrical control signal of the solenoid valve.
Assemblies of this kind are already known and are used to control a valve capable of putting the exhaust loop into communication with the inlet loop of an internal combustion engine in order to recycle a more or less major portion of the exhaust gas.
Exhaust gases are in effect inert. Hence the consequence of recycling them to the inlet is, on the one hand, to lower the combustion temperature by absorption of some of the quantity of heat originating from this combustion process and, on the other hand, to lower the rate of burn and hence to increase the duration of combustion.
The result of this is a reduction in the production of toxic gases and a gain in fuel consumption.
Until now, such assemblies have comprised separate elements installed individually and connected to one another.
This meant great bulk and high installation costs.

Assembly for controlling an exhaust gas recirculation valve for an internal combustion engine


Determination of hydraulic properties such as porosity and permeability of soil is of paramount importance in hydrology and civil engineering. In order to achieve greater accuracy in determination of permeability of soil using falling head permeameter, the two important known constraints of human monitoring error in noting the falling water level between two selected levels and elapse time between these two levels had overcome through electronically sensing the levels between two selected points and activating the timer clock automatically by the pulses coming from senor. The precision in measurement of time lapse in 1/100th of a second enables greater accuracy in estimation of permeability. Provision of perforated Teflon disc above and below the soil core facilitates in application of water uniformly over the entire surface area of soil core at top and similar way permeated water leaving the soil core uniformly without any obstruction. The use of carbon steel seamless tube while collecting soil core facilitated in undisturbed soil core recovery from desired depth section. The permeability test was conducted for various sorted sands of different size ranges and each sample was subjected to repetitive tests and elapsed time for each test was recorded from timer unit. Coefficient of Permeability was calculated for each test. The lab experiment conducted for sorted and unsorted sediments has yielded a consistent performance of Electronic level sensor and timer based falling head soil permeameter.

Soil permeameter is a device in the field of hydraulics, used to measure the permeability property of soil/rock. Permeability is an index of interconnectivity of pores. The coefficient of permeability is a constant of proportionality relating to the ease with which fluid passes through a porous medium. This parameter is very critical in understanding the fluid flow process in porous media and has a wide application in hydraulic engineering and fluid transport modeling studies.
Soil hydraulic conductivity has been historically measured in the laboratory, utilizing a falling or constant head of water applied to soil core samples retrieved from the field or on remolded soil samples. Laboratory measurements are often significantly at variance with in-situ field measurements because of the differing methodologies and the inherent difficulty of obtaining undisturbed soil samples. The hydraulic conductivity of soils at different depths is highly variable due to heterogeneous textural arrangement of soil particles.
It is desirable to have the capability to conduct hydraulic conductivity tests in laboratory by having the undisturbed soil in the form of a core of any desired depth above the permanent water table. Such depths may range from zero to many meters below the ground surface. In addition, it is desirable to have adequate flow capacity for maintaining flow equilibrium in a wide range of soils. Clay soils often have low permeability, whereas sandy or gravelly soils often have high permeability and, therefore, a greater accuracy is necessary in the measurement of time in case of falling head permeameter where the time reflects the permeability characteristics of soil under testing.
Prior art instruments developed for measuring hydraulic conductivity of soils generally fall into two major categories, namely- the lab measurements and in-situ field measurements. In the first type, the soil is collected from the field and subjected to permeability measurement in the lab. The second type is of measuring the permeability of soil at in-situ condition. For the first category of lab measurements, two types of permeameters are available, out of which one applies a constant head and the other a falling head. Both these types apply in principle Darcy's Law for calculation of coefficient of permeability. The second category applied for in-situ measurement of permeability utilizes various methodologies, which include electrical resistivity procedures and gas or liquid injection into the soil through penetrating probes and measuring permeability of unsaturated & saturated regime and complex analysis procedures.
The laboratory measurement of permeability is simpler, but requires collection of soil from the site, safe transportation to the lab, careful setting of lab experiment, and accuracy of measurements and reproducibility of experimental results. Among these two methods of measuring the permeability, namely the constant head has been reported, to be suitable for measuring the permeability of higher ranges, i.e, for coarser soil of more than 200 microns, while the falling head permeameter is for soils less than 200 microns having lower permeability.
The continuing physico-chemical processes ultimately disintegrate the rock into a fine soil texture and deposit in a suitable environment. In most of the semi arid environmental conditions, witnessing regular monsoon cycle, quick removal of the disintegrated rock materials and transport them to places of farther away from place of origin making them further finer particles and gets deposited as low permeable soil layers.
Reference may be made to U.S. Pat. No. 4,072,044 (Farwell et al 1976), U.S. Pat. No. 4,099,406 (Fulkerson, et al 1977) and U.S. Pat. No. 4,969,111 (Merva et al 1990) and scientific literature cited, indicating that the falling head permeameter is preferable for low permeability ranges and several errors/constraints that could affect the test results as reported are:
air trapped in sample; accuracy on measuring the elapsed time of test; uniform supply of water at the head soil core sample; disturbed soil conditions while loading the sample in apparatus; measurement error in head at beginning and at the end of test and area of specimen.

Council of Scientific & Industrial Research


An image forming apparatus includes a conversion unit, an image bearing member, an image forming unit that forms an image on the image bearing member based on image data converted by the conversion unit, a measuring unit that measures a measurement image on the image bearing member, and a controller that controls the image forming unit to form a first measurement image, controls the measuring unit to measure the first measurement image, and generates a conversion condition based on a result of measurement of the first measurement image and a first feedback condition. In forming a chromatic color image after a predetermined number of monochrome images, the controller controls the image forming unit to form a second measurement image, controls the measuring unit to measure the second measurement image, and generates the conversion condition based on a result of measurement of the second measurement image and a second feedback condition.

Field of the Invention
The present disclosure relates to adjusting control of the density of an image formed by an image forming apparatus.
Description of the Related Art
Electrophotographic image forming apparatuses include a charging unit that electrically charges a photosensitive member, an exposing unit that exposes the photosensitive member with a laser beam to form an electrostatic latent image on the photosensitive member, and a developing unit that develops the electrostatic latent image. The developing unit develops the electrostatic latent image with a developer to visualize the image. The image forming apparatus further includes a transfer unit and a fixing unit. The transfer unit transfers the image on the photosensitive member onto a sheet. The fixing unit fixes the image on the sheet to the sheet. Thus, an image is formed on the sheet.
To adjust the density of the image to desired density, an image forming apparatus disclosed in U.S. Pat. No. 5,566,372 forms a measurement image on an image bearing member and corrects a conversion condition for converting image data on the basis of the result of measurement of the measurement image using a measuring means. The image forming apparatus disclosed in U.S. Pat. No. 5,566,372 forms the measurement image on the image bearing member when a power switch is turned on and corrects the conversion condition on the basis of the result of measurement with the measuring means.
However, a plurality of images formed by the image forming apparatus can change in density while being continuously formed. For this reason, to reduce changes in image density while continuously forming a plurality of images, image forming apparatuses need to form a measurement image on the image bearing member at predetermined timing and to correct the conversion condition on the basis of the result of measurement of the measurement image with the measuring means.
Some image forming apparatuses form a color image after forming a monochrome image. In such a case, when the density of an image of a color different from black changes while the image forming apparatuses are continuously forming a plurality of monochrome images, the density of a color image formed after the monochrome images cannot have desired density.

Image forming apparatus that generates conversion condition based on measurement result and first coefficient, and where chromatic color image is formed after predetermined number of monochrome images, generates conversion condition based on new measurement result and second coefficient