Inhibitors of the cytosolic phospholypase A2 enzymes are provided which are of use in controlling a wide variety of inflammatory diseases. The inhibitors of the present invention have the general formula

I. Field of the Invention
The present invention relates to certain alpha-substituted thio and oxo trifluoromethylketone compounds, their salts, hydrates and derivatives thereof, a process for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them and such ketone compounds as inhibitors of phospholipase A2 enzymes that are involved in the human inflammatory diseases and are thus useful agents in the treatment of inflammatory diseases such as asthma, arthritis, inflammatory bowel disease and neurodegenerative diseases.
II. Background of the Invention and Description of the Prior Art
Inflammatory diseases of the skin, such as psoriasis and atopic dermatitis, afflict greater than 5% of the population. And the inflammatory disease such as asthma affects more than 10 million people in U.S. alone. Currently, the treatment of these disorders typically involves topical use or inhalation of corticosteroids and bronchodilators. However, these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy. In addition, topical application of a drug is difficult for many patients where the affected area may be very large.
Phospholipase A2 (PLA2) is the common name for phosphatide 2-acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids. When the fatty acid is arachidonic acid, further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation, and leukotrienes which are linked to asthma. Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor also play a role in inflammation.
PLA2 enzymes exist as secreted forms (MWxcx9c12,000-15,000) and cytosolic forms (MWxcx9c85,000). The cytosolic or cPLA2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.
Inappropriate activation of the cytosolic PLA2 enzymes, therefore, can result in a variety of chronic and acute conditions including asthma, cerebral ischemia [Clemens et al., Stroke, 1996, 27: 527-535], Alzheimer""s Disease [Stephenson et al., Neurobiology of Stroke, 1996, 3: 51-63 and see also U.S. Pat. No. 5,478,857], rheumatoid arthritis, neutrophil and platelet activation [Huang et al., Mediators of Inflammation, 1994, 3: 307-308], chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light [Gresham et al., American Journal of Physiology, 1996, 270; Cell Physiology, 39: C1037-C1050] and macrophage activation [Balsinde et al., Journal of Biological Chemistry, 1996, 271: 6758-6765].
Inhibitors of the cPLA2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases. The literature describes a significant number of compounds said to be phospholipase A2 inhibitors.
Biochemistry, 1993, 32: 5935-5940, discloses a trifluoromethyl ketone analog of arachidonic acid having the formula
as a selective inhibitor of cPLA2.
Bioorganic Med. Chem. Lett., 1995, 5: 519-522, discloses selective cPLA2 inhibitors of the formula
where R is either H or OH.
Japanese published Patent Application JP09268153A (Derwent No. 97-554679/51) discloses cPLA2 inhibitors of the formula RCOCF3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid. The compounds are said to be useful as antiinflammatory or antiallergic drugs.
Certain trifluoromethylketone have been disclosed as inhibitors of fatty acidamide hydrolase in Bioorg. and Med. Chem. Lett., 1999, 9: 265-270.
Published PCT Application WO 98/25893 discloses arylsulfonamide compounds of the general formula
wherein:
A represents a C4-C10 alkyl group, an aryl group, an arylalkyl group, radicals selected from the group consisting of xe2x80x94CHxe2x95x90CHxe2x80x94B, xe2x80x94Oxe2x80x94B, xe2x80x94Sxe2x80x94B, and xe2x80x94NHxe2x80x94B, or radicals of formula xe2x80x94CH2xe2x80x94X,
wherein:
B represents a non-aromatic C3-C8 carbocycle, a C3-C8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and
X is a member selected from the group consisting of a halogen atom, xe2x80x94S-aryl, xe2x80x94S-heterocycle, and xe2x80x94PO3R2 wherein each R is independently selected from the group consisting of a hydrogen atom and C1-C3 alkyl;
R1 and R2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: xe2x80x94(CH2)qxe2x80x94Axe2x80x2 wherein q is an integer of 2 to 4, and Axe2x80x2 is a member selected from the group consisting of a hydroxyl group, a group represented by the formula:
wherein R5 and R6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula:
wherein R7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula:
wherein s is an integer of 2 to 5; or
R1 and R2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula:
wherein g and h are each an integer of 1 to 4, and Bxe2x80x2 stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or
R1 and R2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R1 and R2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;
R3 represents a hydrogen atom, a lower alkyl group, or a C3-C8 cycloalkyl group;
R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom;
n is an integer of 1 to 4, provided that when n is 2, the two R4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A2 activity, particularly cPLA2.
The published PCT Application WO 98/08818 discloses Inhibitors of phospholipase enzymes of formulae I, II and III.
or a pharmaceutically acceptable salt thereof, wherein:
A is independent of any other group and is selected from the group consisting of xe2x80x94CH2xe2x80x94 and xe2x80x94CH2xe2x80x94CH2xe2x80x94;
B is independent of any other group and is selected from the group consisting of xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2O)nxe2x80x94, xe2x80x94(CH2S)nxe2x80x94, xe2x80x94(OCH2)nxe2x80x94, xe2x80x94(SCH2)nxe2x80x94, xe2x80x94(CHxe2x95x90CH)nxe2x80x94, xe2x80x94(Cxe2x89xa1C)nxe2x80x94, xe2x80x94CON(R6)xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94and xe2x80x94N(R6)xe2x80x94;
R1 is independent of any other R group and is selected from the group consisting of xe2x80x94Xxe2x80x94R6, xe2x80x94H, xe2x80x94OHxe2x80x94, halogen, xe2x80x94CN, xe2x80x94NO2, C1-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R2 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94COOH, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94(CH2)mxe2x80x94Zxe2x80x94R5, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94R5, xe2x80x94Zxe2x80x94R5, C1-C10 alkyl, alkenyl and substituted aryl;
R3 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94COOH, xe2x80x94COR5, xe2x80x94CONR5R6, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94(CH2)mxe2x80x94Zxe2x80x94R5, xe2x80x94(CH2)nxe2x80x94Wxe2x80x94R5, xe2x80x94Zxe2x80x94R5, C1-C10 alkyl, alkenyl and substituted aryl;
R4 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94OH, OR6, SR6, xe2x80x94CN, xe2x80x94COR6, xe2x80x94NHR6, xe2x80x94COOH, xe2x80x94CONR6R7, xe2x80x94NO2, xe2x80x94CONHSO2R8, C1-C5 alkyl, alkenyl and substituted aryl;
R5 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94OH, xe2x80x94O(CH2)nR6, xe2x80x94SR6, xe2x80x94CN, xe2x80x94COR6, xe2x80x94NHR6, xe2x80x94COOH, xe2x80x94NO2, xe2x80x94COOH, xe2x80x94CONR6R7, xe2x80x94CONHSO2R8, C1-C5 alkyl, alkenyl, alkinyl, aryl, substituted aryl, xe2x80x94CF3, xe2x80x94CF2CF3 and
R6 is independent of any other R group and is selected from the group consisting of xe2x80x94H, C1-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R7 is independent of any other R group and is selected from the group consisting of xe2x80x94H, C1-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R8 is independent of any other R group and is selected from the group consisting of C1-C3 alkyl, aryl and substituted aryl;
R9 is independent of any other R group and is selected from the group consisting ofxe2x80x94H, xe2x80x94OH, a halogen, xe2x80x94CN, xe2x80x94OR6, xe2x80x94COOH, xe2x80x94CONR6R7, tetrazole, xe2x80x94CONHSO2R8, xe2x80x94COR6, xe2x80x94(CH2)nCH(OH)R6 and xe2x80x94(CH2)nCHR6R5;
R10 is independent of any other R group and is selected from the group consisting of xe2x80x94H, xe2x80x94OH, a halogen, xe2x80x94CN, xe2x80x94OR6, xe2x80x94COOH, xe2x80x94CONR6R7, tetrazole, xe2x80x94CONHSO2R8, xe2x80x94COR6, xe2x80x94(CH2)nCH(OH)R6 and xe2x80x94(CH2)nCHR6R5;
W is, independent each time used including within the same compound, selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94and xe2x80x94N(R6)xe2x80x94;
X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94N(R6)xe2x80x94;
Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CON(R6)xe2x80x94 and xe2x80x94N(R6)COxe2x80x94;
m is, independently each time used including within the same compound, an integer from 0 to 4; and
n is independently of m and is, independently each time used including within the same compound, an integer from 0 to 4.
Drugs, 1998, 1(1): 49-50 discloses a limited series of cPLA2 inhibitors as shown below
U.S. Pat. No. 5,866,318 relates to methods for inhibiting cell death in mammalian cells, particularly in neuronal cells, by administering a suitable inhibitor of phospholipase A2 activity, typically an inhibitor of cPLA2.
WO 97/21676 Patent discloses certain azetidinone compounds as phospholipase inhibitors in the treatment of atherosclerosis.
U.S. Pat. No. 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA2 enzymes. These compounds have the generic formula
wherein:
R1 is selected from
(a) hydrogen,
(b) xe2x80x94C1-6alkyl, and
(c) xe2x80x94C1-6alkyl-phenyl;
or wherein R1 and R5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R2 and R3 are each independently selected from
(a) hydrogen,
(b) xe2x80x94C1-6alkyl, and
(c) xe2x80x94C1-6alkyl-phenyl;
or wherein two R2 or two R3 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R5 is as defined above or is selected from
(a) hydrogen,
(b) xe2x80x94C1-6alkyl,
(c) xe2x80x94C1-6alkyl-phenyl C1-6alkyl,
(d) xe2x80x94OH,
(e) xe2x80x94Oxe2x80x94C1-6alkyl, or
(f) xe2x80x94Oxe2x80x94C1-6alkyl-phenyl C1-6alkyl;
R6 is selected from
(a) hydrogen,
(b) xe2x80x94C1-6alkyl,
(c) xe2x80x94C1-6alkyl-phenyl, wherein the phenyl is optionally substituted with C1-2alkyl;
(d) xe2x80x94OH,
(e) xe2x80x94Oxe2x80x94C1-6alkyl, or
(f) xe2x80x94C1-6alkyl-phenyl, wherein the phenyl is optionally substituted with C1-2alkyl;
or wherein two R6 are joined to form Oxe2x95x90 or are joined together such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;
R8, R9 and R14 are each independently selected from
(a) H,
(b) xe2x80x94C1-6alkyl,
(c) halo,
(d) xe2x80x94CN,
(e) xe2x80x94OH,
(f) xe2x80x94OC1-6alkyl,
(g) xe2x80x94OC1-6alkyl-phenyl,
(h) xe2x80x94SR11,
(i) S(O)R11, or
(j) S(O)2R11;
R10, R15, R16 and R17 are each independently selected from
(a) hydrogen,
(b) xe2x80x94C1-6 alkyl, and
(c) xe2x80x94C1-6 alkyl-phenyl;
R11 is selected from
(a) xe2x80x94C1-6 alkyl,
(b) xe2x80x94C2-6 alkenyl,
(c) xe2x80x94CF3,
(d) -phenyl(R12)2, or
(e) xe2x80x94C2-6 alkenyl-phenyl(R12)2;
R12 is
(a) hydrogen,
(b) xe2x80x94C1-6 alkyl,
(c) Cl, F, I or Br;
R13 is perfluoro C1-6alkyl;
A and B are each independently
(a) covalent bond,
(b) O,
(c) S,
(d) S(O), or
(e) S(O)2;
Q is selected from
(a) xe2x80x94CH(OH)R13,
(b) xe2x80x94COR13,
(c) xe2x80x94COR16,or
(d) xe2x80x94C1-4alkylCOCOOR17;
X1 is selected from
(a) xe2x80x94Oxe2x80x94,
(b) xe2x80x94Sxe2x80x94,
(c) xe2x80x94S(O)xe2x80x94,
(d) xe2x80x94S(O)2xe2x80x94;
Z is
(a) H, or
(b) -phenyl-(R14)3;
m is 0, 1, 2, 3 or 4;
n is 2, 3, 4, 5, 6 or 7; and
r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.
Published application WO 99/15129 discloses selective cPLA2 inhibitors having the formula
wherein W is CHxe2x95x90CH, CHxe2x95x90N, O or S;
R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy,
(C1-C6)alkylthio, halo, hydroxy, cyano,
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl, CF3, (C1-C6)alkylphenyl, phenyl or phenyl substituted by one or more,
preferably 1-3, of (C1-C6)alkyl, xe2x80x94COOxe2x80x94(C1-C6)alkyl,
xe2x80x83in which R2 and R3 are as defined above, halo, hydroxy, xe2x80x94Oxe2x80x94(C1-C6)alkyl, xe2x80x94Sxe2x80x94(C1-C6)alkyl or (C2-C6)alkenyl;
p is 0, 1 or 2;
A is Vxe2x80x94(Rc)nxe2x80x94;
Rc is a straight or branched chain alkyl group;
n is 0 or an integer of from 1 to 6;
Ra and Rb when taken together form an oxo (xe2x95x90O) group, or Ra and Rb are each independently hydrogen or OH;
V is O, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2, xe2x80x94CONH or NHCO when n is an integer of from 1 to 6 or V is (C2-C6) alkenyl or a bond when n is 0 or an integer of from 1 to 6;
D is xe2x80x94(CH2)m or a bond linking the
xe2x80x83ring to Y;
m is an integer of from 1 to 6;
Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2;
xe2x80x83or a bond;
R4 is as defined below for R7;
Z is
in which B is:
X is S or O;
q is an integer from 1 to 6;
R9 is hydrogen or (C1-C6)alkyl;
R10 is hydrogen, CN, NO2, OH, xe2x80x94Oxe2x80x94(C1-C6)alkyl, (C1-C6) alkyl, phenyl or (C1-C6)alkylphenyl;
R5 and R6 are each independently hydrogen or (C1-C18) alkyl;
R7 and R8 are each independently
(a) hydrogen;
(b) (C1-C18)alkyl;
(c) (C1-C18)alkyl substituted by one or more of
(1) phenyl;
(2) phenyl substituted by 1-5 fluoro, 1-3 (for each of the following phenyl substituents) halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6)alkylamino, xe2x80x94CO2H, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or
xe2x80x83in which R2 and R3 are as defined above;
(3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;
(4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 (for each of the following) halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or
xe2x80x83in which R2 and R3 are as defined above, (C1-C6)alkyl or (C1-C6)alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 (for each of the following) halo, 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C1-C6)alkylamino, di(C1-C6)alkylamino, COOH, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, xe2x80x94SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or
xe2x80x83in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;
(5) carboxy or xe2x80x94COOxe2x80x94(C1-C6)alkyl;
(6) hydroxy, halo, xe2x80x94Oxe2x80x94(C1-C6) alkyl or xe2x80x94Sxe2x80x94(C1-C6)alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;
(7) cyano;
(8) halo, trifluoromethyl or trifluoroacetyl;
(9) CH2 Lxe2x80x94R16 in which L is
or xe2x80x94Oxe2x80x94SiR16R18R19 or a bond in which R16 and R17 are each independently (C1-C18)alkyl or (C2-Cl8)alkenyl or (C1-C18)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, amino, 1-3(C1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, CO2H, 1-3 xe2x80x94COO(C1-C6)alkyl,
xe2x80x83or xe2x80x94SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above;
in which B1 is
xe2x80x83or a bond; providing that when B1 is xe2x80x94PO(OR9)2, then R7 becomes R9, and when B1 is
xe2x80x83or xe2x80x94SO2xe2x80x94, then R7 cannot be hydrogen;
X, q, R5, R6, R7, R8, R9 and R10 are as defined in (a);
in which q, R5 and R6 are as defined above;
R18, R19 and R11 are as defined above for R7 and R8 except that they may not be hydrogen, or R18 and R19 taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R7 and R11 are as defined above, or R18, R19 and R11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by (C1-C12)alkyl, (C1-C12)alkoxy, amino, (C1-C12)alkylamino, di(C1-C12)alkylamino,
xe2x80x83xe2x80x94Sxe2x80x94(C1-C12)alkyl,
xe2x80x83in which R2 and R3 are as defined above, phenyl or phenyl (C1-C10)alkyl;
in which R13 is (C1-C18)alkyl or (C1-C18)alkyl substituted by carboxy,
xe2x80x83in which R2 and R3 are as defined above, hydroxy, xe2x80x94Oxe2x80x94(C1-C6) alkyl, xe2x80x94Oxe2x80x94(C1-C6) alkyl or xe2x80x94Sxe2x80x94(C1-C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 (for each of the following phenyl substituents) halo (other than fluoro), (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, (C1-C6) alkylamino, di(C1-C6)-alkylamino, CO2H, COOxe2x80x94(C1-C6) alkyl, SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl or
xe2x80x83in which R2 and R3 are as defined above;
r is 0 or an integer of from 1 to 3;
R7 is as defined above;
M is xe2x80x94(CH2xe2x80x94)mT where
xe2x80x83in which R2 is as defined above, xe2x80x94SO2xe2x80x94 or a bond when MR7 is on nitrogen and providing that when
xe2x80x83then R7 cannot be hydrogen, and
xe2x80x83or a bond when MR7 is on a carbon atom of the heterocyclic ring;
R14 is hydrogen or (C1-C6)alkyl;
m is 0 or an integer of 1-6;
wherein Q is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, and q, R5, R6 and R7 are as defined above, providing that when Q is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, R7 cannot be hydrogen;
(f) R7 wherein R7 is defined above, providing that when Y is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94, R7 cannot be hydrogen; and
R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or
xe2x80x83in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6)alkylamino, CO2H, xe2x80x94COOxe2x80x94(C1-C6)alkyl, xe2x80x94SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or
xe2x80x83in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.
There is nothing in any of the foregoing references, or in the general prior art, to suggest the novel alpha substituted thio, oxo-trifluoromethyl-ketones of the present invention as cytosolic phospholipase A2 inhibitors.
An object of the present invention is to provide novel alpha substituted oxo- or thio-trifluoromethylketone compounds which inhibit cytosolic phopholipase A2 enzymes that are pro-inflammatory mediators. Some of the derivatives covered by the present invention exhibit increased stability and aqueous solubility.
This invention relates to a novel compound of the formula
wherein:
X1 is O or S(O)n;
n is 0, 1 or 2;
Ra and Rb when taken together form an oxo (xe2x95x90O) group, or Ra and Rb are each independently hydrogen or OH;
X is H, CF3, halogen, NR3R4, NH(CO)NHR3R4, C(O)NR3R4, OH, OR8, SH, S(O)nR8, C(O)OR6, NH(CO)OR8, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl or C3-C7 cycloalkyl, said alkyl, alkenyl, alkynyl or cycloalkyl group being optionally substituted by COOR6, CN, C(O)NR3R4, PO3R6, SO3R6, heterocyclic, OH, OR8, SH, S(O)nR8, NR3R4, NH(CO)NR3R4, NH(CO)OR8, OC(O)OR8, aryl or heteroaryl, said aryl or heteroaryl being optionally substituted by one or two groups independently selected from COOR6, SO3R6, OCOR6, PO3R6 or heterocyclic;
R1 and R2 are each independently H, substituted C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl or C3-C7 cycloalkyl, said alkyl group being substituted by, and said alkenyl, alkynyl or cycloalkyl group being optionally substituted by, COOR6, CN, C(O)NR3R4, PO3R6, SO3R6, heterocyclic, OH, OR8, SH, S(O)nR8, NR3R4, NH(CO)NR3R4, NH(CO)OR8, OC(O)OR8, aryl or heteroaryl, said aryl or heteroaryl group being optionally substituted by one or two groups independently selected from COOR6, SO3R6, PO3R6 or heterocyclic;
R3 and R4 are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, heterocyclic or aryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic or aryl group being optionally substituted with COOR6, CN, OR6, NR6R7, SO3R6, PO3R6, halogen, aryl or heteroaryl, said aryl or heteroaryl substituent being optionally substituted with one or two groups independently selected from COOR6, SO3R6, PO3R6 or heterocyclic;
R5 is H, C1-C7 alkyl or C3-C7 cycloalkyl, said alkyl or cycloalkyl group being optionally substituted by COOR6, CN, C(O)NR3R4, PO3R6, SO3R6, heterocyclic, OR3, S(O)nR8, NR3R4, NH(CO)NR3R4, NH(CO)OR8, C(O)2OR8, aryl or heteroaryl, said aryl or heteroaryl group being optionally substituted by one or two groups independently selected from COOR6, SO3R6, PO3R6 or heterocyclic;
R6 and R7 are independently H, C1-C7 alkyl or C3-C7 cycloalkyl;
R8 is the same as R3 but cannot be H;
Z is OR9, S(O)nR9, NR9R10 or CHR9R10;
R9 and R10 are each independently hydrogen, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl or C3-C7 cycloalkyl, said alkyl, alkenyl, alkynyl or cycloalkyl group being optionally substituted with NR11R12, SR11, S(O)R16, SO2R16 or OR11, with the proviso that both R9 and R10 may not both be hydrogen;
R11 and R12 are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl or aryl, said alkyl, alkenyl, alkynyl, cycloalkyl or aryl group being optionally substituted by 1-3 COOR6, OR6, SiR13R14R15, OR13, aryl, biaryl or heteroaryl, said aryl, biaryl or heteroaryl group being optionally substituted with 1-3 halogen, CF3, OR6, COOR6, NO2 or CN, or R11 and R12 taken together with the nitrogen to which they are attached form a 5-7 membered heterocyclic ring with one or more O, N or S heteroatoms, said heterocyclic ring being optionally substituted with COOR6 or C1-C5 alkyl optionally substituted with OR6, COOR6 or C(O)NR3R4; and
R13, R14 and R15 are each independently aryl, benzyl, benzhydryl, biaryl, heteroaryl, aryl(C1-C6)alkyl or heteroaryl(C1-C6)alkyl, said aryl group being optionally substituted with halogen, CF3, OR6, COOR6, NO2, CN or C1-C7 alkyl;
R16 is the same as R11 and R12 but is not hydrogen; or a pharmaceutically acceptable salt thereof, with the proviso that R1 and R2 may not both be hydrogen.
Another aspect of this invention involves methods for inhibiting cytosolic PLA2 in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound of formula I and methods for using the compounds of formula I to treat various diseases characterized by inappropriate activation of the cytosolic PLA2 enzymes such as asthma, allergic rhinitis, cerebral ischemia, Alzheimer""s Disease, rheumatoid arthritis, acute pancreatitis, inflammatory bowel disease, psoriasis, gout, neutrophil and platelet activation, chronic skin inflammation, shock, trauma-induced inflammation such as spinal cord injury, damage to the skin resulting from UV light or burns and macrophage activation. In further aspects, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier and processes for preparing the compounds of formula I.
The object of this invention was to discover a selective cPLA2 inhibitor which is active, both topically and orally, in treating inflammary disease of the skin and other tissues as well as other chronic and acute conditions which have been linked to inappropriate activation of the cPLA2 enzymes. Preferably such compound would also be devoid of undesirable lipid-perturbing activities associated with skin irritation.
The above-mentioned objectives have been met by the compounds of formula I described above.
In the present application the numbers in the subscript after the symbol xe2x80x9cCxe2x80x9d define the number of carbon atoms a particular group can contain. For example, xe2x80x9cC1-C7 alkylxe2x80x9d refers to straight and branched chain alkyl groups with 1 to 7 carbon atoms. Similarly, xe2x80x9cC2-C7 alkenylxe2x80x9d refers to an unsaturated hydrocarbon group containing from 2 to 7 carbon atoms and at least one carbon-carbon double bond. The term xe2x80x9cC2-C7 alkynylxe2x80x9d refers to an unsaturated hydrocarbon group containing from 2 to 7 carbon atoms and at least one carbon-carbon triple bond.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein refers to fluorine, chlorine, bromine or iodine.
xe2x80x9cArylxe2x80x9d as used herein refers to a C6 monocyclic aromatic ring system or a C9 or C10 bicyclic carbocyclic ring system having one or two aromatic rings such as phenyl or naphthyl. It may also refer to a C14 tricyclic carbocyclic ring system having two or three aromatic rings such as anthracenyl or phenanthrenyl. Unless otherwise indicated, xe2x80x9csubstituted arylxe2x80x9d refers to aryl groups substituted with one or more (preferably from 1 to 3) substituents independently selected from (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy-carbonyl, (C1-C6)alkanoyl, hydroxy, halo, mercapto, nitro, amino, cyano, (C1-C6)alkylamino, di(C1-C6)alkylamino, carboxy, aryl, aryl (C1-C6)alkyl, aryl (C1-C6)alkoxy, heterocyclic, heterocyclic (C1-C6)alkyl and the like. The term xe2x80x9cbiarylxe2x80x9d refers to two C6 monocyclic aromatic ring systems or two C9 or C10 bicyclic carbocyclic ring systems linked together such as o-, m- and p-biphenyl or o-, m- and p-binaphthyl. The term xe2x80x9cheteroarylxe2x80x9d refers to a 5- or 6-membered aromatic ring system or a 9- or 10-membered bicyclic aromatic ring system containing one, two or three heteroatoms selected from N, O and S. The term xe2x80x9cbenzhydrylxe2x80x9d refers to a carbon atom bearing two aryl, bis-aryl or heteroaryl groups.
The term xe2x80x9cheterocyclicxe2x80x9d as used herein refers to a 4xe2x80x94, 5- or 6-membered ring containing one, two or three heteroatoms selected from N, O and S. The 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds. The nitrogen heteroatoms can be optionally quaternized or N-oxidized. The sulfur heteroatoms can be optionally S-oxidized. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring. Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzofuranyl, furyl, dihydrofuranyl, tetrahydrofuranyl, pyranyl, dihydropyranyl, dioxolanyl, thienyl, benzothienyl and diaxanyl.
In a preferred embodiment the compounds of general formula I have R1 being hydrogen.
In another preferred embodiment the compounds of general formula I have X being hydrogen.
Another preferred embodiment embraces the compounds of formula I wherein X is hydrogen, R1 is hydrogen and R2 is C1-C7 alkyl substituted by COOH or C1-C7 alkyl substituted by carboxy-substituted phenyl.
Still another preferred embodiment includes the compounds of formula I wherein Z is Yxe2x80x94Z1;
Rc is H, xe2x80x94COCF3, xe2x80x94COC6H5, xe2x80x94COO(C1-C6)alkyl,
xe2x80x83in which R18 and R17 are each independently H or (C1-C6)alkyl, (C1-C18)alkyl or (C1-C18)alkyl substituted by one or more of phenyl or phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, 1-3 nitro, 1-3 cyano, 1-3 hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, 1-3 amino, 1-3 (C1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, 1-3 carboxyl, 1-3 xe2x80x94COO(C1-C6)alkyl, 1-3 xe2x80x94SO3H, 1-3 xe2x80x94SO2NHR19 in which R19 is H or (C1-C6)alkyl, or
xe2x80x83in which R18 and R17 are as defined above;
Z1 is
(a)
xe2x80x83in which n1 is 0, 1 or 2 and R21 and R20 are phenyl or phenyl substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, 1-3 nitro, 1-3 cyano, 1-3 hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, 1-3 amino, 1-3 (C1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, 1-3 carboxy, 1-3 xe2x80x94COO(C1-C6)alkyl, 1-3 xe2x80x94SO3H, 1-3 xe2x80x94SO2NHR19 in which R19 is as defined above, or
xe2x80x83in which R18 and R17 are as defined above;
(b)
xe2x80x83in which n1 is 0, 1 or 2 and R21 and R20 are as defined above;
(c)
xe2x80x83in which R21 and R20 are as defined above;
(d)
xe2x80x83in which R21 and R20 are as defined above;
(e)
xe2x80x83in which R21 and R20 are as defined above; or
(f)
xe2x80x83in which R21 and R20 are as defined above.
A most preferred embodiment is a compound of the formula
wherein X, is O or S(O)n;
n is 0, 1 or 2;
Ra and Rb when taken together form an oxo (xe2x95x90O) group, or Ra and Rb are each independently hydrogen or OH;
R1 is hydrogen;
R2 is C1-C7 alkyl substituted by COOH or C1-C7 alkyl substituted by carboxy-substituted phenyl;
Z is Yxe2x80x94Z1;
Y is xe2x80x94CH2; and
xe2x80x83in which R20 and R21 are phenyl substituted by 1-3 halo; or a pharmaceutically acceptable salt thereof.
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms, and pharmaceutically acceptable salts thereof.
As mentioned above the invention also includes pharmaceutically acceptable salts of the compounds of formula I. A compound of the invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups. Accordingly, a compound may react with any of a number of inorganic bases, and organic and inorganic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an inorganic base. Such salts are known as acid addition and base addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex3-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. Suitable organic bases include trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl-xcex2-phenethylamine, 1-ephenamine, N,Nxe2x80x2-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine, or the like pharmaceutically acceptable amines. The potassium and sodium salt forms are particularly preferred.
It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
The present invention also includes solvated forms of the compounds of formula I, particularly hydrates, in which the trifluoromethyl ketone group exists as a mixture of ketonic I and hydrated forms II and are each independently interconvertible and pharmacologically active.
Biological Activity
The assay determining the activity as cPLA2 inhibitors is the following:
3H-arachidonate-labeled U937 membranes were prepared from U937 cells grown in RPMI 1640 medium containing L-glutamine supplemented with 10% fetal calf serum and 50 xcexcg/ml gentamycin in a 5% CO2 incubator at 37xc2x0 C. Sixteen hours prior to harvesting the cells, 3H-arachidonate (100 Ci/mmol) was added to the cell culture (1xc3x97106 cells/ml, 0.5 xcexcCi/ml). After washing the cells with HBSS (Hank""s Balanced Salts) containing 1 mg/ml HSA (Human Serum Albumin), the cells were lysed by nitrogen cavitation and the homogenate was centrifuged at 2,000xc3x97g for 10 minutes. The supernatant was further centrifuged at 50,000xc3x97g for 30 minutes after which the pellet was resuspended in water and autoclaved at 120xc2x0 C. for 15 minutes to inactivate any residual phospholipase A2 activity. This suspension was then recentrifuged at 50,000xc3x97g for 30 minutes and the pellet resuspended in distilled water.
Assays of cPLA2 activity using these 3H-arachidonate-labeled U937 membranes as substrate typically employ human recombinant cPLA2 [see Burke et al., Biochemistry, 1995, 34: 15165-15174] and membrane substrate (22 xcexcM phospholipid) in 20 mM HEPES [N-(2-hydroxyethyl)piperazine-N1-(2-ethanesulfonic acid)] buffer, pH 8, containing 6 mM CaCl2, 0.9 mg/ml albumin and 4 M glycerol. Enzyme assays are allowed to proceed for 3 hours at 37xc2x0 C. before removing the non-hydrolyzed membranes. The hydrolyzed, radiolabeled fatty acid is then measured by liquid scintillation counting of the aqueous phase.
The effects of inhibitor are calculated as percent inhibition of 3H-arachidonate formation, after correcting for nonenzymatic hydrolysis, as compared to a control lacking inhibitor according to the following formula:
percent inhibition=((Control DPMxe2x88x92Inhibitor DPM)/Control DPM)xc3x97100%
Various concentrations of an inhibitor were tested, and the percent inhibition at each concentration was plotted as log concentration (abscissa) versus percent inhibition (ordinate) to determine the IC50 values.
In this assay the compounds of Examples 1 shown below exhibited cPLA2 IC50 values in the range of from about 1 to 50 xcexcM.
Since the compounds of the present invention are selective inhibitors of cytosolic phospholipase A2, they are of value in the treatment of a wide variety of clinical conditions.
Inflammatory disorders which may be treated by inhibition of cytosolic cPLA2 include such conditions as arthritis, psoriasis, asthma, inflammatory bowel disease, gout, trauma-induced inflammation such as spinal cord injury, Alzheimer""s Disease, cerebral ischemia, chronic skin inflammation, shock, damage to skin resulting from exposure to ultraviolet light or burns, allergic rhinitis, acute pancreatitis, and the like.
The compounds of the present invention have also been found to be very stable towards keto-reduction. It has been shown that a reliable method to assess keto-stability of compounds is to measure the percent of such compounds remaining after incubation with erythrocyte lysates [Rady-Pentek P., et al., Eur. J. Clin. Pharmacol., 1997, 52(2): 147-153]. The assay is the following.
Male Wistar rates were anesthetized with CO2 and then blood was removed by direct cardio-puncture or through a pre-inserted jugular vein canula into syringes that were pre-rinsed with heparin. The blood was then inserted into heparanized tubes and placed on ice. The blood was centrifuges as 3000 rpm for 5 minutes to separate the plasma. The plasma was removed and an equivalent volume of sterile water was mixed with the erythrocyte fraction. This was mixed by inversion and left on ice for several minutes to lyse the erythrocytes. The erythrocyte-water mixture was then centrifuged at 3000 rpm for 5 minutes to pellet the cellular debris.
Each compound was dissolved in methanol (1 ml) to produce a 2 mM solution. From this solution, 50 xcexcl aliquot was made up to 1 ml in 50% methanol to produce a 100 xcexcM stock solution. From this solution, a dose solution was prepared by diluting 100 xcexcl to 2 ml of a 0.1 M potassium phosphate buffer (pH=7.4) to produce a 2 xcexcM final incubation dilution.
The lysate (250 xcexcl) was then aliquoted into eppendorf tubes, 6 for each compound, i.e. 0 time, 15 minutes, 60 minutes in duplicate. To these aliquots was added 200 xcexcl of the dose solution and this was preheated to 37xc2x0 C. for 2-3 minutes prior to the addition of NADPH (1 mM final concentration) to start the reactions. The reactions were terminated with the addition of either 0.5 ml or 1 ml of acetonitrile. Following centrifugation at 8000xc3x97g for 5 minutes, the supernatant was removed and stored at xe2x88x9220xc2x0 C. until analysis could proceed by quantitative LC/MS. Samples were analyzed by electrospray ionization (ESI) on a Micromass ZMD 2000(copyright) single quadrupole mass spectrometer coupled to a Shimadzu HPLC system. The percent of compound remaining following 15 minutes and 60 minutes incubation is calculated relative to the 0 time point.
Administration Modes
The compounds of formula I are usually administered in the form of pharmaceutical compositions. They can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. The compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound defined by formula I and a pharmaceutically acceptable carrier.
In making the compositions employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
The active compound is effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient""s symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
Method of Preparation
The compounds of the present invention can be prepared by various methods which are known in the art. Illustrative methods of preparation are provided in the reaction scheme which follows and in the Examples.
Preparation of compounds of formula I may be accomplished via the synthetic scheme which is described below. The specific examples which follow illustrate the synthesis of representative compounds of the present invention and are not to be construed as limiting the invention in sphere or scope. The methods may be adapted to variations in order to produce compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different fashion will also be evident to one skilled in the art.
Scheme A describes a method to prepare the various xcex1-substituted thio- and oxo-trifluoromethylketones of generic structure I. Thus, the various phenols or thiophenols of type II may be reacted under Mitsunobu conditions with the various lactic acids or esters III to give the compounds of generic formula IV. Subsequent conversion to the trifluoromethylketone analogs I may be performed by hydrolysis of the esters to the corresponding acids followed by conversion to the acid chloride and treatment with trifluoroacetic anhydride or by direct conversion of the esters using trifluorotrimethylsilane.

Alpha-substituted thio, -oxo trifluoromethylketones as phospholipase inhibitors

Abstract: where X, Z, X1, R1, R2, Ra and Rb are as defined in the specification.


A voltage regulator includes a transformer, a plurality of output stages and at least one switch. The transformer has a primary side and a secondary side, and the switch(es) are coupled to the primary side of the transformer to open and close to transfer energy to the transformer. The output stages are coupled to the secondary side of the transformer to receive energy from the transformer and provide output voltages. The output stages prevent current from flowing through the switch(es) during time intervals in which the switch(es) transition from being open to being closed.

The invention generally relates to a voltage regulator, such as switching voltage regulator, for example.
A DC-to-DC voltage regulator typically is used to convert a DC input voltage to either a higher or a lower DC output voltage. One type of voltage regulator is a switching regulator that is often chosen due to its small size and efficiency. The switching regulator typically includes one or more switches that are rapidly opened and closed to transfer energy between an inductor (a stand-alone inductor or a transformer, as examples) and an input voltage source in a manner that regulates an output voltage.
As an example, referring to FIG. 1, one type of switching regulator is a synchronous Buck switching regulator 10 that receives an input DC voltage (called VIN) and converts the VIN voltage to a lower regulated output voltage (called VOUT) that appears at an output terminal 11. To accomplish this, the regulator 10 may include a switch 20 (a metal-oxide-semiconductor field-effect-transistor (MOSFET), for example) that is operated (via a voltage called VSW) in a manner to regulate the VOUT voltage, as described below.
Referring also FIGS. 2 and 3, in particular, the switch 20 opens and closes to control energization/de-energization cycles 19 (each having a constant duration called TS) of an inductor 14. In each cycle 19, the regulator 10 asserts, or drives high, the VSW voltage during an on interval (called TON) to close the switch 20 and transfer energy from an input voltage source 9 to the inductor 14. During the TON interval, a current (called IL) of the inductor 14 has a positive slope. During an off interval (called TOFF) of the cycle 19, the regulator 10 deasserts, or drives low, the VSW voltage to open the switch 20 and isolate the input voltage source 9 from the inductor 14. At this point, the level of the IL current is not abruptly halted, but rather, a diode 18 begins conducting to transfer energy from the inductor 14 to a bulk capacitor 16 and a load (not shown) that are coupled to the output terminal 11. During the TOFF interval, the IL current has a negative slope, and the regulator 10 may close a switch 21 to shunt the diode 18 to reduce the amount of power that is otherwise dissipated by the diode 18. The bulk capacitor 16 serves as a stored energy source that is depleted by the load, and additional energy is transferred from the inductor 14 to the bulk capacitor 16 during each TONinterval.
For the Buck switching regulator, the ratio of the TON interval to the TS interval, called a duty cycle, generally governs the ratio of the VOUT to the VIN voltages. Thus, to increase the VOUT voltage, the duty cycle may be increased, and to decrease the VOUT voltage, the duty cycle may be decreased.
As an example, the regulator 10 may include a controller 15 (see FIG. 1) that regulates the VOUT voltage by using a pulse width modulation (PWM) technique to control the duty cycle. In this manner, the controller 15 may include an error amplifier 23 that amplifies the difference between a reference voltage (called VREF) and a voltage (called VP (see FIG. 1)) that is proportional to the VOUT voltage. Referring also to FIG. 5, the controller 15 may include a comparator 26 that compares the resultant amplified voltage (called VC) with a sawtooth voltage (called VSAW) and provides the VSW signal that indicates the result of the comparison. The VSAW voltage is provided by a sawtooth oscillator 25 and has a constant frequency (i.e., 1/TS).
Due to the above-described arrangement, when the VOUT voltage increases, the VCvoltage decreases and causes the duty cycle to decrease to counteract the increase in VOUT. Conversely, when the VOUT voltage decreases, the VC voltage increases and causes the duty cycle to increase to counteract the decrease in VOUT.
Significant power losses of the regulator 10 may be attributable to the power that is dissipated by the switch 20. Ideally, the product of a voltage (called VC) across the switch 20 arid a current (called IIN) through the switch 20 should be zero because V1 is ideally zero when the switch 20 is closed, and IIN is ideally zero when the switch is open. However, referring to FIGS. 4 and 6, significant switching losses typically occur in a time interval 30 when the switch 20 transitions from the closed state to the open state and a time interval 31 in which the switch 20 transitions from the open state to the closed state due to the overlapping nonzero V1 voltage and IIN current during the time intervals 30 and 31. A snubber circuit may be used for purposes of reducing the level of the V1 voltage (to reduce power losses) during the time intervals 30 and 31. However, the snubber circuit typically reduces the efficiency of the regulator 10.
Also contributing to power losses across a switch (especially a switch that is coupled to a transformer) of a given regulator may be a voltage spike that occurs across the switch when the switch turns off. Besides introducing switching power losses, the voltage spike may also reduce the lifetime of the switch. Typically, the voltage spike is attributable to leakage inductances in the regulator. In this manner, when the switch opens, the currents through the effective leakage inductor is abruptly halted, giving rise to the voltage spike. A snubber circuit may be used for purposes of dampening the magnitude of the voltage spike. However, the snubber circuit may reduce the efficiency of the regulator.
For purposes of converting an AC wall voltage into regulated DC voltages for components 2 (see FIG. 1) of a computer system 1, the regulator 10 may form the second of three stages of a power supply 3 for the computer system 1. A boost switching converter, or voltage regulator 7, may be used for the first stage. The boost voltage regulator 7 converts a rectified AC input voltage (received via input lines 5) into a high DC voltage and shapes the input line current making its harmonic content compliant with various standards. The regulator 10 may be used to convert the high DC voltage that is generated by the boost voltage regulator 7 into comparatively low, isolated and regulated DC voltages (12V, 3.3V and 5V DC voltages, as examples) for power distribution in the computer system 1. The third stage may be a DC-to-DC isolated voltage regulator, typically called a voltage regulator module (VRM), that converts the DC voltages that are furnished by the regulator 10 into lower voltages (1.2V to 2V voltages, as examples) that the VRM 17 tightly regulates and provides via power distribution lines 19 to the components 2 of the computer system 1. Unfortunately, the above-described three stage design may introduce inefficiency; introduce reliability and size problems; and add significant costs that are associated with the power supply 3.
Thus, there is a continuing need for an arrangement that addresses one or more of these problems.


An organic light-emitting diode (OLED) display capable of controlling light transmittance is disclosed. In one aspect, the OLED display includes a plurality of pixels, each including a first region configured to emit light and a second region configured to transmit light therethrough and a plurality of first electrodes respectively formed in the first regions of the pixels. The OLED display also includes a plurality of organic layers respectively formed over the first electrodes, a second electrode formed over all of the organic layers, and a plurality of third electrodes each formed in the second regions of the pixels. The OLED display further includes a plurality of solvents respectively placed over the third electrodes, wherein each of the solvents is configured to selectively block light and a fourth electrode formed over the solvents for all of the pixels.

Field
The described technology generally relates to an organic light-emitting diode (OLED) display.
Description of the Related Technology
Due to their favorable characteristics such as excellent viewing angles, high contrast, fast response speeds, low power consumption, and other characteristics, OLED displays are widely used in consumer electronic devices including MP3 players, mobile phones, TVs, etc. OLED displays are self-emissive and do not require a separate light source, unlike liquid crystal displays (LCDs). Therefore, the thickness and weight of OLED displays can be reduced when compared with LCDs. In addition, OLED displays can include a transmission region (or a transmission window) that is formed separately from the regions in which a transparent thin film transistor (TFT) or a transparent OLED are formed. OLED displays including such transmission regions can appear transparent, allowing light from an external source to pass therethough.

Organic light-emitting diode (OLED) display capable of controlling light transmittance


A solid-state imaging device provided with a light receiving surface, in which plural unit pixels, each having a photoelectric transducer to convert light signals into electric signals, are two-dimensionally arranged; a microlens to focus a light beam, the microlens being arranged in each unit pixel corresponding to the photoelectric transducer; an aperture section, to allow the light beam to enter the photoelectric transducer, the aperture section being arranged in each unit pixel corresponding to the photoelectric transducer; a wiring layer, which comprises plural layers, and is formed between the photoelectric transducer and the microlens, wherein the plural unit pixels are arranged such that each of the photoelectric transducer is located axisymmetrically with a symmetrical axis of a first centerline passing through an approximate center of the light receiving surface.

1. Technical Field
This invention relates to a solid-state imaging device, and specifically to a solid-state imaging device capable of correcting shading, which is caused by angled incident light.
2. Description of Related Art
Nowadays, in such as video cameras and electronic cameras, solid state imaging devices such as CCD image sensors, CMOS image sensors, and amplification type image sensors are widely utilized. Generally, a light receiving section is provided in each pixel of the solid state imaging device with prescribed pitch in length and width, and provided on the periphery of the light receiving section of each pixel is a charge transfer area, in the case of a CCD image sensor, or provided is a wiring area including such as a charge detection amplifier and a gate for signal transfer, in the case of a CMOS image sensor.
FIGS. 10(a) and 10(b) schematically illustrate a structure of a unit pixel in a solid-state imaging device. FIG. 10(a) is a plan view schematically showing unit pixel 3 in the solid-state imaging device, and illustrates a position of photodiode 4 (light receiving section) as a photoelectric transducer in unit pixel 3. Photodiode 4 usually occupies 20-30% of the area of each unit pixel, and the larger the area becomes the higher the sensitivity of the photodiode. In FIG. 10(a), only photodiode 4 and microlens 7 are illustrated, however in actual, such parts as a transistor to read-in signals and a metal wiring are formed in the vicinity of photodiode 4.
FIG. 10(b) is a sectional view of unit pixel 3. As shown in FIG. 10(b), photodiode 4, serving as a photo electric transducer, is embedded in silicone substrate 8, further, above the photodiode, provided are metal wiring layers 5, color filter 6, and microlens 7. In this way, photodiode 4 as the photoelectric transducer, is formed, when viewed from above, under microlens 7, color filter 6, and metal wiring layer 5.
As shown in FIGS. 10(a), 10(b), since it is necessary to arrange a transistor and a wiring, etc., in each unit pixel 3, photodiode 4 is not usually formed at the center of unit pixel 3 (center of photodiode 4 does not coincide with center O′ of unit pixel 3). For example, as shown in FIG. 10(a), photodiode 4 is formed at the area shifted from center O′ of unit pixel 3 in the Y-direction (toward the left side in the figure), and further slightly shifted in the X-direction (downward in the figure), and the transistor and the wiring, etc. are arranged in the other areas.
The solid-state imaging device is structured two-dimensionally by arranging plural unit pixels 3 having this type of structure. In conventional solid-state imaging devices, unit pixels, each having the same structure, are arranged. For example, as shown in FIG. 11, conventional solid state imaging apparatus 10 is structured by arranging unit pixel 3 shown in FIG. 10(a). Therefore, in every unit pixel 3, photodiode 4 is formed at a position shifted in the same direction from center O′ of unit pixel 3. In this conventional case, in every unit pixel 3, photodiode 4 is formed by shifting to left side and further, slightly downward.
In the solid state imaging apparatus having this type of structure, incident light from Z-direction (vertical to the surface of the drawing) enters approximately vertically in the vicinity of center O of the light receiving surface, while in the unit pixel arranged nearer to the periphery of light receiving surface apart from center O, the incident light enters with larger angle. Here, light receiving surface 2 means the surface where incident light enters in the solid-state imaging device, and a whole surface of all unit pixels 3 parallel to the surfaces of the photoelectric transducers is assumed to be light receiving surface 2.
The difference of this incident angle will be described by referring to the sectional view of the unit pixel shown in FIG. 12, which shows the sectional view taken along line B-B′ of FIG. 11. In unit pixel 3, arranged near the center O, the incident light enters approximately vertically to unit pixel 3 as shown by solid lines in FIG. 12. On the other hand, in unit pixel 3 arranged left of line A-A′ of FIG. 11, on the periphery area of light receiving surface 2, the incident light enters at an angle slanted from right to left (from center O of light receiving surface 2 to the periphery) as shown by broken lines in FIG. 12. While, in unit pixel 3 arranged right of line A-A′ of FIG. 11 at the periphery of light receiving surface 2, the incident light enters at an angle slanted from left to right (from center O of light receiving surface 2 to the periphery) as shown by dashed-dotted lines in FIG. 12.
As shown in FIGS. 10(b) and 12, in each unit pixel 3, photodiode 4, which actually perform photoelectric conversion, is not formed at a top surface but is formed below microlens 7, color filter 6, and metal wiring layer 5. Due to this, though there is no problem in cases where the incident light enters vertically to light receiving surface 2, in cases where the incident light enters with an angle, the incident light may be reflected or blocked, by metal wiring layer 5 for example, and the light amount arriving to photodiode 4 may be decreased.
In the pixel structure shown in FIGS. 10(b) and 12, decreased is the receiving light amount by unit pixel 3 arranged at the right of line A-A′ near the periphery of light receiving surface 2. This is because the focusing position of the incident light entering aslant from the left (the light beams indicated by dashed-dotted lines) is deflected out of photodiode 4, and the incident light is reflected or blocked by metal wiring layer 5. While, in unit pixel 3 arranged left of line A-A′ on the periphery area of light receiving surface 2, as shown in FIG. 12, the light beam enters aslant from the right side (the light beams indicated by broken lines), however, since photodiode 4 is formed left in unit pixel 3, the incident light is able to arrives photodiode 4.
Further, in top/bottom direction in FIG. 11, similarly to in the right/left direction, exposure light amount to photodiode 4, in unit pixel 3 arranged at the periphery area of light receiving surface 2 decreases, due to the incident light with an angle.
In this way, since the amount of received light at the periphery area of light receiving surface 2 is decreased compared to that near center O, images at the periphery area become darker and uneven sensitivity (so-called brightness shading) is generated.
FIG. 13(a) shows a graph of the amount of received light in a case where shading is generated. The horizontal axis shows the lateral position of light receiving surface 2, and the vertical axis shows the output value (the amount of received light). In these graphs, the broken line curve indicates the ideal output, and the solid line curve shows the output in the case where the solid-state imaging device relating to the conventional art receives incident light. As shown in this graph, the amount of received light near center O of light receiving surface 2 is large and nearly same as the ideal output. However, nearer the periphery, the amount of received light gradually decreases and goes away from the ideal output value. Thus, in the peripheral area, the amount of received light decreases to darkness. Here, in FIG. 13(a), the amount of received light in the lateral direction is shown, while the amounts of received light at the peripheral area in the top/bottom direction and in the aslant direction similarly decrease to darkness.
Further, the shape of the aperture for photodiode 4 is not necessarily symmetrical, as shown in FIG. 12, for example, there are differences in the amount of received light of photodiode 4 between cases of right slanted incident light and left slanted incident light, therefore, the amount of received light differs in right/left direction or in top/bottom direction on light receiving surface 2. For example in the pixel structure of FIG. 11, the amount of received light in Y-direction (namely the right/left direction) varies as shown by the graph in FIG. 13(b), such that the amount of received light of unit pixel 3 arranged right of center O becomes less than that of unit pixel 3 arranged left of center O. Further, since there are also cases where this difference varies according to the color of the received light, as shown by the graph in FIG. 13(c), slight uneven color (so-called color shading) may be generated in the right/left direction or top/bottom direction.
As a method for correcting such uneven sensitivity (brightness shading), the method in which the pitch of microlens 7 arranged in each unit pixel 3 is made smaller than the pitch of unit pixel 3, and along with going nearer to the periphery of light receiving surface 2, microlens 7 is shifted in the direction to the center of each unit pixel 3 (e.g. Patent Document 1).
Further, a correcting method is known in which a light reflecting section is provided on an inner wall of aperture 9 in unit pixel 3 to correct the uneven sensitivity (brightness shading) (e.g. Patent Document 2).
Patent Document 1: Unexamined Japanese Patent Application Publication No. H01-213079
Patent Document 2: Unexamined Japanese Patent Application Publication No. 2000-198505
According to the method of Patent Document 1, the uneven sensitivity (brightness shading) can be corrected to some extent, however, complete correction of uneven sensitivity (brightness shading) is not possible, and uneven color (color shading) cannot be corrected. Further, according to the method of Patent Document 2, complete correction of uneven sensitivity (brightness shading) is not possible, and similarly to the method of Patent document 1, uneven color (color shading) cannot be corrected.
An object of the present invention is to solve the above-mentioned problems, and to decrease the uneven sensitivity and uneven color by correcting the brightness shading and color shading of the solid-state imaging device.

Solid state imaging device in which each photoelectric transducer of plural unit pixels being located axisymmetrically with a symmetrical axis of a centerline passing through an approximate center of the device


The invention provides a human protein of embryogenesis (PREM) and polynucleotides which identify and encode PREM. The invention also provides expression vectors, host cells, agonists, antibodies and antagonists. The invention also provides methods for treating disorders associated with expression of PREM.

Mammalian embryogenesis is a process which occurs during the first few weeks of development following conception. During this period, embryogenesis proceeds from a single fertilized egg to the formation of the three embryonic tissues, and finally, to an embryo which has most of its internal organs and all of its external features.
The normal course of mammalian embryogenesis depends on the correct temporal and spatial regulation of a large number of genes and tissues. These regulation processes have been intensely studied using transgenic mice. Integration of retroviral or other nucleic acids into the mouse germ line often disrupts a mouse gene at the point of insertion and produces mutations which correlate with developmental abnormalities. One such mutation has been identified as recessive H.beta.58 (Radice, G. et al. (1991) Development 111:801-811). Homozygous H.beta.58 embryos display abnormalities such as reduced embryonic ectoderm, abnormal folding of amnion and chorion tissues due to over-proliferation, and failure of allantois and chorion to form a proper placenta. These phenotypic characteristics suggest that the mouse gene inactivated by the H.beta.58 insertion is involved in the development of the embryonic ectoderm (Radice et al., supra).
The H.beta.58 gene encodes a 38 kDa H.beta.58 protein. In situ hybridization shows that expression of the wild-type H.beta.58 gene begins in the oocyte and continues throughout pre- and post-implantation embryogenesis. In early post-implantation embryos, H.beta.58 expression is low in embryonic ectoderm and high in visceral endoderm. Even though phenotypic effects of the mutation are displayed in the embryonic ectoderm, these results suggest that the effects of the mutation may be exerted indirectly via the visceral endoderm (Lee, J. J. et al. (1992) Development 115:277-288).
The discovery of a new human protein of embryogenesis and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of inflammation and disorders associated with cell proliferation and apoptosis.

Polynucleotides encoding a protein of embryogenesis


A disposable prophy angle is mounted to an electric tooth polisher that has a controller, a handle having a motor and a driving shaft. The prophy angle is mounted to the handle and has a casing, a driven shaft, a surface-polishing member and a crevice-cleaning member. The casing is mounted to the handle and has a cavity and a distal open end. The driven shaft is mounted rotatably in the casing, rotates in response to the motor and has a mount. The surface-polishing and crevice-cleaning members are detachably mounted on the mount simultaneously. The tooth polisher with both the surface-polishing and crevice-cleaning members can be used to clean teeth without the need to replace the members and is timesaving.

1. Field of the Invention
The present invention relates to a tooth cleaner, and more particularly to a disposable prophy angle for an electric tooth polisher. The disposable prophy angle has a mount, a disposable surface-polishing member and a disposable crevice-cleaning member. The members are detachably mounted to the mount simultaneously.
2. Description of the Related Art
Electric tooth polishers are generally tools used by dentists to clean teeth.
With reference to FIG. 6, a conventional electric tooth polisher has a controller (70), a handle (80) and a disposable prophy angle.
The controller (70) is connected to a power source and has a display and a switch.
The handle (80) is connected to the controller (70) through a cable and has a motor.
With further reference to FIGS. 7 to 9, the disposable prophy angle is connected to the handle (80) and has a hollow casing (90), a driven shaft (91), a mount (92), a disposable surface-polishing member (93) and a disposable crevice-cleaning member (94). The driven shaft (91) is mounted rotatably in the casing (90), rotates in response to the motor and has a distal end extending out of the casing (90). The mount (92) is mounted to the distal end of the driven shaft (91). The surface-polishing member (93) is mounted detachably on the mount (92) and rotates to polish the surface of teeth when the tooth polisher is used. The crevice-cleaning member (94) is conical, may replace the surface-polishing member (93) on the mount (92) and rotates to clean the crevices between adjacent teeth.
However, only one of the attachments, the surface-polishing member (93) or the crevice-cleaning member (94), is used on the prophy angle at any one time. To complete the cleaning process, the polishing and then the crevice cleaning, a dentist must replace one of the members (93, 94) with the other during the treatment. The need to change the members (93, 94) is time wasting.
To overcome the shortcomings, the present invention provides a disposable prophy angle for an electric tooth polisher to mitigate or obviate the aforementioned problems.

Disposable prophy angle for an electric tooth polisher


A device for detecting and suppressing noise includes a noise detection device that receives and processes an input signal to determine if the input signal contains noise and provides a detected noise signal indicative of whether or not noise is detected in the input signal. A noise filter receives the input signal and when the detected noise signal does not indicate the presence of noise the noise filter provides an output signal equal to input signal. When the detected noise signal indicates the presence of noise the noise filter processes the input signal through a first filter to provide a filtered signal such that the output signal is equal to the filtered signal. The noise filter comprises a control circuit that receives the input signal and the filtered signal and in response dynamically adjusts a cut-off frequency control signal that controls a cut-off frequency of the first filter.

The invention relates to a device and method for detecting noise in an electronic device, especially noise in impulse form, in a signal with a bandwidth-limited useful component, and a device and method for suppressing such noise.
Probably the most important example of this type of bandwidth-limited signal is an audio signal. The useful component of such an audio signal lies within the audible frequency range of human hearing, or approximately 40 Hz to 16,000 Hz. However, noise impulses that propagate through a line along with the useful component may have frequency components that extend beyond the audible frequency range.
Noise impulses in such an audio signal may occur for a number of reasons. For example, electrical equipment in the vicinity of a radio receiver may become noticeable as noise, such as ignition pulses from a vehicle engine. In addition, processing of the audio signal itself (e.g., from clipping of a digital signal or overflow in a digital demodulator) may result in impulse noise.
To efficiently implement noise suppression, it is first necessary to reliably detect the noise. A variety of techniques have been proposed for detecting and eliminating noise components in a signal.
U.S. Pat. No. 5,479,440 discloses a technique that is based on conversion of time data from the signal to be cleared of noise to the frequency domain, the determination of a threshold below which all frequency components are canceled, and the back-conversion of the spectrum obtained to the time domain. This technique requires a double fast Fourier transform (FFT) and is thus complex and expensive, and accordingly relatively poorly suited for use in devices intended for a broad range of consumers.
U.S. Pat. No. 4,622,520 discloses a method for eliminating noise from an audio signal modulated from a high-frequency carrier. In this method, the strength of the signal component is compared with that of the carrier, and signal components that are stronger than the carrier are detected as noise and suppressed. However, this technique cannot be applied to signals in the baseband since no carrier is available there as a reference for comparison. In addition, the application of this technique to digital signals is problematic due to the required high sampling rates.
U.S. Pat. No. 4,143,333 proposes detecting noise impulses in an audio signal using a differentiating filter. For the duration of the noise the signal is blanked out. This type of noise detection directly from the audio signal is error-prone because it must first be ensured that a loud, high tone in the audio signal is not erroneously detected as impulse noise. In addition, there is the danger that noise will go undetected and thus unattenuated if the noise detection threshold is too high.
Therefore, there is a need for a technique of detecting and suppressing noise in a bandwidth-limited signal that is relatively simple and inexpensive to implement, yet provides reliable detection and suppression.

Device and method for detecting and suppressing noise


A computer system with a memory device having plural memory banks and a method of accessing a selected one of the memory banks, the memory device including local control signal generators that control timing of operations in each respective block of a memory array. Overall timing of the device is controlled by first and second global control signals generated in a command sequencer and decoder. The second global control signal is derived from a delayed version of the first signal, and both signals are applied to local control signal generators along with address bits indicating a selected block. The timing of the global signal generators is determined by row charge and discharge models. Local timing is determined by the global control signals and by local circuitry within the local control signal generators. The second global control signal drives a first portion of a sense amplifier and a delayed version of the second global signal drives a second portion of the sense amplifier. Local control signal generators include latch circuits to produce a latch output signal that activates a selected row.

Conventional computer systems include a processor coupled to a variety of memory devices, including read-only memories ("ROMs") which traditionally store instructions for the processor, and a system memory to which the processor may write data and from which the processor may read data. The processor may also communicate with an external cache memory, which is generally a static random access memory ("SRAM"). The processor also communicates with input devices, output devices, and data storage devices.
processors generally operate at a relatively high speed. Processors such as the Pentium.RTM. and Pentium Pro.RTM. microprocessors from Intel Corporation, are currently available that operate at clock speeds of at least 200 mega hertz (MHz). However, the remaining components of the computer system, with the exception of SRAM cache, are not capable of operating at the speed of the processor. For this reason, the system memory devices, as well as the input devices, output devices, and data storage devices, are not coupled directly to the processor bus. Instead, the system memory devices are generally coupled to the processor bus through a memory controller, and the input devices, output devices, and data storage devices are coupled to the processor bus through a bus bridge. The memory controller allows the system memory devices to operate at a clock frequency that is substantially lower than the clock frequency of the processor. Similarly, the bus bridge allows the input devices, output devices, and data storage devices to operate at a frequency that is substantially lower than the clock frequency of the processor. Currently, for example, a processor having a 200 MHz clock frequency may be mounted on a motherboard having a 66 MHz clock frequency for controlling the system memory devices and other components.
Access to system memory is a frequent operation for the processor. The time required for the processor, operating, for example, at 200 MHz, to read data from or write data to a system memory device operating at, for example, 66 MHz, greatly slows the rate at which the processor is able to accomplish its operations. Thus, much effort has been devoted to increasing the operating speed of system memory devices.
System memory devices are generally dynamic random access memories ("DRAMs"). Initially, DRAMs were asynchronous and thus did not operate at even the clock speed of the motherboard. In fact, access to asynchronous DRAMs often required that wait states be generated to halt the processor until the DRAM had completed a memory transfer. However, the operating speed of asynchronous DRAMs was successfully increased through such innovations as burst and page mode DRAMs, which did not require that an address be provided to the DRAM for each memory access. More recently, synchronous dynamic random access memories ("SDRAMs") have been developed to allow the pipelined transfer of data at the clock speed of the motherboard. However, even SDRAMs are incapable of operating at the clock speed of currently available processors. Thus, typical SDRAMs cannot be connected directly to the processor bus, but instead must interface with the processor bus through a memory controller, bus bridge, or similar device. The disparity between the operating speed of the processor and the operating speed of SDRAMs continues to limit the speed at which processors may complete operations requiring access to system memory.
A solution to this operating speed disparity has been proposed in the form of a computer architecture known as "SyncLink." In the SyncLink architecture, the system memory may be coupled to the processor directly through the processor bus. Rather than requiring that separate address and control signals be provided to the system memory, SyncLink memory devices receive command packets that include both control and address information. The SyncLink memory device then outputs or receives data on a data bus that is coupled directly to the data bus portion of the processor bus.
An example of a computer system 10 using the SyncLink architecture is shown in FIG. 1. The computer system 10 includes a processor 12 having a processor bus 14 coupled to three packetized dynamic random access memory or SyncLink DRAMs ("SLDRAM") devices 16a-16c. The computer system 10 also includes one or more input devices 20, such as a keypad or a mouse, coupled to the processor 12 through a bus bridge 22 and an expansion bus 24, such as an industry standard architecture ("ISA") bus or a peripheral component interconnect ("PCI") bus. The input devices 20 allow an operator or an electronic device to input data to the computer system 10. One or more output devices 30 are coupled to the processor 12 to display or otherwise output data generated by the processor 12. The output devices 30 are coupled to the processor 12 through the expansion bus 24, bus bridge 22 and processor bus 14. Examples of output devices 24 include printers and a video display units. One or more data storage devices 38 are coupled to the processor 12 through the processor bus 14, bus bridge 22, and expansion bus 24 to store data in or retrieve data from storage media (not shown). Examples of storage devices 38 and storage media include fixed disk drives, floppy disk drives, tape cassettes, and compact-disc read-only memory CD Rom drives.
In operation, the processor 12 communicates with the memory devices 16a-16c via the processor bus 14 by sending the memory devices 16a-16c command packets that contain both control and address information. Data is coupled between the processor 12 and the memory devices 16a-16c, through a data bus portion of the processor bus 14. Although all the memory devices 16a-16c are coupled to the same conductors of the processor bus 14, only one memory device 16a-16c at a time reads or writes data, thus avoiding bus contention on the processor bus 14. Bus contention is avoided by each of the memory devices 16a-16c and the bus bridge 22 having a unique identifier, and the command packet contains an identifying code that selects only one of these components.
The computer system 10 also includes a number of other components and signal lines which have been omitted from FIG. 1 in the interests of brevity. For example, as explained below, the memory devices 16a-16c also receive a master clock signal to provide internal timing signals, a data clock signal clocking data into and out of the memory device 16, and a FLAG signal signifying the start of a command packet.
The memory devices 16 are shown in block diagram form in FIG. 2. Each of the memory devices 16 includes a clock divider and delay circuit 40 that receives a master clock signal 42 and generates a large number of other clock and timing signals to control the timing of various operations in the memory device 16. The memory device 16 also includes a command buffer 46 and an address capture circuit 48 which receive an internal clock CLK signal, a command packet CD on a command bus 50, and a FLAG signal on line 52. As explained above, the command packet contains control and address information for each memory transfer, and the FLAG signal identifies the start of a command packet which may include more than one 10-bit packet word. In fact, a command packet is generally in the form of a sequence of 10-bit packet words on the 10-bit command bus 50. The command buffer 46 receives the command packet from the bus 50, and compares at least a portion of the command packet to identifying data from an identification ID register 56 to determine if the command packet is directed to the memory device 16a or some other memory device 16b, c. If the command buffer determines that the command is directed to the memory device 16a, it then provides a command word to a command decoder and sequencer 60. The command decoder and sequencer 60 generates a large number of internal control signals to control the operation of the memory device 16a during a memory transfer.
The address capture circuit 48 also receives the command words from the command bus 50 and outputs a 20-bit address corresponding to the address information in the command. The address information is provided to an address sequencer 64, which generates a corresponding 3-bit bank address on bus 66, a 10-bit row address on bus 68, and a 7-bit column address on bus 70.
One of the problems of conventional DRAMs is their relatively low speed resulting from the time required to precharge and equilibrate circuitry in the DRAM array. The packetized DRAM 16a shown in FIG. 2 largely avoids this problem by using a plurality of memory banks 80, in this case eight memory banks 80a-80h. After a memory read from one bank 80a, the bank 80a can be precharged while the remaining banks 80b-80h are being accessed. Each of the memory banks 80a-80h receives a row address from a respective row latch/decoder/driver 82a-82h. All of the row latch/decoder/drivers 82a-82h receive the same row address from a predecoder 84 which, in turn, receives a row address from either a row address register 86 or a refresh counter 88 as determined by a multiplexer 90. Bank control logic 94 activates only one of the row latch/decoder/drivers 82a-82h as a function of a bank address from a bank address register 96.
The column address on bus 70 is applied to a column latch/decoder 100 which, in turn, supplies I/O gating signals to an I/O gating circuit 102. The I/O gating circuit 102 interfaces with columns of the memory banks 80a-80h through sense amplifiers 104. Data is coupled to or from the memory banks 80a-80h through the sense amplifiers 104 and I/O gating circuit 102 to a data path subsystem 108 which includes a read data path 110 and a write data path 112. The read data path 110 includes a read latch 120 receiving and storing data from the I/0 gating circuit 102. In the memory device 16a shown in FIG. 2, 64 bits of data are applied to and stored in the read latch 120. The read latch then provides four 16-bit data words to a multiplexer 122. The multiplexer 122 sequentially applies each of the 16-bit data words to a read FIFO buffer 124. Successive 16-bit data words are clocked through the FIFO buffer 124 by a read clock signal LATCHR generated from an internal clock by a programmable delay circuit 126. The FIFO buffer 124 sequentially applies the 16-bit words to a driver circuit 128 which, in turn, applies the 16-bit data words to a data bus 130 forming part of the processor bus 14.
The write data path 112 includes a receiver buffer 140 coupled to the data bus 130. The receiver buffer 140 sequentially applies 16-bit words from the data bus 130 to four input registers 142, each of which is selectively enabled by a write clock signal LATCHW from a clock generator circuit 144. Thus, the input registers 142 sequentially store four 16-bit data words and combine them into one 64-bit data word applied to a write FIFO buffer 148. The write FIFO buffer 148 is clocked by the write clock signal LATCHW from the clock generator 144 and an internal write clock WCLK to sequentially apply 64-bit write data to a write latch and driver 150. The write latch and driver 150 applies the 64-bit write data to one of the memory banks 80a-80h through the I/O gating circuit 102 and the sense amplifier 104.
As mentioned above, an important goal of the SyncLink architecture is to allow data transfer between a processor and a memory device to occur at a significantly faster rate. However, the operating rate of a packetized DRAM, including the packetized DRAM shown in FIG. 2, is limited by the time required to process command packets applied to the memory device 16a, the time required to generate control signals and the time required to read and write data to the banks 80a-h. More specifically, not only must the command packets be received and stored, but they must also be decoded and used to generate a wide variety of control signals. The control signals must then be communicated to the various circuitry for accessing the banks 80a-h. However, in order for the memory device 16a to operate at a very high speed, the command packets must be applied to the memory device 16a at a correspondingly high speed.
As the memory device receives and processes command packets at high speeds, the I/O gating circuit 102, sense amplifiers 104, and other circuitry for reading and writing to the memory banks 80a-80h produce internal command signals at very high speeds. These high speed command signals must be delivered to the circuitry associated with each of the eight banks 80a-80h. For example, command signals such as precharge and equilibrate are transmitted to the row latch/decoder/drivers 82a-82h from the decoder and sequencer 60. Delivery of all of the command signals to the eight banks 80a-80h can require several sets of signal lines, each extending from the command decoder and sequencer 60 to each of the latch/decoder/drivers 82a-82h associated with each of the eight memory banks 80a-80h. Each of the lines consume valuable area on a substrate and complicate routing of signal lines.
Additionally, the internal control signals require time to propagate from the command sequencer and decoder 60 to the various circuitry for accessing the banks 80a-h. Routing differences between the bank control logic 94 and the latch/decoder/drivers 82a-82h can therefore cause differences in the times at which the command signals reach the latch/decoder/drivers 82a-82h. These differences in arrival times can become significant at high speeds of operation and eventually limit the operating speed of the packetized DRAM.

Method and apparatus for local control signal generation in a memory device