Disclosed are compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits xcex2-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer""s disease both prophylactically and therapeutically with such pharmaceutical compositions.

1. Field of the Invention
This invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease. This invention also relates to pharmaceutical compositions comprising such compounds as well as methods for inhibiting release of xcex2-amyloid peptide.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Glenner, et al., xe2x80x9cAlzheimer""s Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Proteinxe2x80x9d, Biochem. Biophys. Res. Commun., 120:885-890 (1984).
2 Glenner, et al., xe2x80x9cPolypeptide Marker for Alzheimer""s Disease and its Use for Diagnosisxe2x80x9d, U.S. Pat. No. 4,666,829 issued May 19, 1987.
3 Selkoe, xe2x80x9cThe Molecular Pathology of Alzheimer""s Diseasexe2x80x9d, Neuron, 6:487-498 (1991).
4 Goate, et al., xe2x80x9cSegregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer""s Diseasexe2x80x9d, Nature, 349:704-706 (1990).
5 Chartier-Harlan, et al. xe2x80x9cEarly-Onset Alzheimer""s Disease Caused by Mutations at Codon 717 of the xcex2-Amyloid Precursor Protein Genexe2x80x9d, Nature, 353:844-846 (1989).
6 Murrell, et al., xe2x80x9cA Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer""s Diseasexe2x80x9d, Science, 254:97-99 (1991).
7 Mullan, et al., xe2x80x9cA Pathogenic Mutation for Probable Alzheimer""s Disease in the APP Gene at the N-Terminus of xcex2-Amyloid, Nature Genet., 1:345-347 (1992).
8 Schenk, et al., xe2x80x9cMethods and Compositions for the Detection of Soluble xcex2-Amyloid Peptidexe2x80x9d, International Patent Application Publication No. WO 94/10569, published May 11, 1994.
9 Selkoe, xe2x80x9cAmyloid Protein and Alzheimer""s Diseasexe2x80x9d, Scientfic American, pp. 2-8, November, 1991.
10 Yates, et al., xe2x80x9cN,N-Disubstituted Amino Acid Herbicidesxe2x80x9d, U.S. Pat. No. 3,598,859, issued Aug. 10, 1971.
11 Citron, et al., xe2x80x9cMutation of the xcex2-Amyloid Precursor Protein in Familial Alzheimer""s Disease Increases xcex2-Protein Production, Nature, 360:672-674 (1992).
12 Hansen, et al., xe2x80x9cReexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Killxe2x80x9d, J. Immun. Meth., 119:203-210 (1989).
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
Alzheimer""s Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common irredical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down""s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the xcex2-amyloid peptide (xcex2AP) or sometimes Axcex2, Axcex2P or xcex2/A4. xcex2-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,8292.
Molecular biological and protein chemical analyses have shown that the xcex2-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that xcex2-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyrne(s). The precise biochemical mechanism by which the xcex2-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of xcex2-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the xcex2-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its xcex2-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other xcex2-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting xcex2-amyloid peptide release and/or its synthesis.
This invention is directed to the discovery of a class of compounds which inhibit xcex2-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The class of compounds having the described properties are defined by formula I below:
wherein:
R1 is selected from the group consisting of
(a) phenyl,
(b) a substituted phenyl group of formula II:
xe2x80x83wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring,
Rb and Rbxe2x80x2 are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalornethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rbxe2x80x2 are either both hydrogen or both substituents other than hydrogen,
(c) 2-naphthyl,
(d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl,
(e) heteroaryl, and
(f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy provided that said substituents are not ortho (adjacent) to the heteroaryl attachment to the xe2x80x94NH group;
R2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl provided that the substituents are not ortho (adjacent) to the attachment of the aryl or heteroaryl atom to the carbon atom;
R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and heterocyclic;
X is xe2x80x94C(O)Y where Y is selected from the group consisting of
(a) alkyl,
(b) substituted alkyl with the proviso that the substitution on said substituted alkyl does not include xcex1-haloalkyl, xcex1-diazoalkyl or xcex1-OC(O)alkyl groups,
(c) alkoxy or thioalkoxy,
(d) substituted alkoxy or substituted thioalkoxy,
(e) hydroxy,
(f) aryl,
(g) heteroaryl,
(h) heterocyclic,
(i) xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where Rxe2x80x2 and Rxe2x80x3 are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and
when R3 contains at least 3 carbon atoms, X can also be xe2x80x94CR4R4Yxe2x80x2 where each R4 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Yxe2x80x2 is selected from the group consisting of hydroxyl, amino, thiol, xe2x80x94OC(O)R5, xe2x80x94SSR5, xe2x80x94SSC(O)R5 where R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
and with the proviso that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derived from D-phenylalanine, then X is not xe2x80x94C(O)OCH3.
Accordingly, in one of its method aspects, this invention is directed to a method for inhibiting xcex2-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds of formula I above effective in inhibiting the cellular release and/or synthesis of xcex2-anmyloid peptide.
Because the in vivo generation of xcex2-amyloid peptide is associated with the pathogenesis of AD8,9, the compounds of formula I can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. Accordingly, in another of its method aspects, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk for developing AD which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
In yet another of its method aspects, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in the condition of that patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above.
In formula I above, R1 substituted phenyls are preferably 4-substituted, 3,5-disubstituted or 3,4-disubstituted phenyl substituents wherein the substituents at the 3 and/or 5 positions are defined by Rb, Rbxe2x80x2 as above and the substituents at the 4 position is defined by Rc as above. Particularly preferred 3,5-disubstituted phenyls include, by way of example, 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl, and the like. Particularly, preferred 3,4-disubstituted phenyls include, by way of example, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3-(trifluoromethyl)-4-chlorophenyl, 3-chloro-4-cyanophenyl, 3-chloro-4-iodophenyl, 3,4-methylenedioxyphenyl, and the like. Particularly preferred 4-substituted phenyls include, by way of example, 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)phenyl, 4-(1-ethoxy)ethylphenyl, and the like.
Other preferred R1 substituents include, by way of example, 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, benzothiazol-2-yl, 5-indolyl, phenyl, 2-naphthyl, and the like.
Preferably R2 is selected from the group consisting of alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl provided that the substituents are not ortho to the attachment of the aryl or heteroaryl atom to the carbon atom. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, xe2x80x94CH2CH2SCH3, phenyl and the like.
Preferred R3 substituents include alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-bulyl, sec-butyl, and the like; substituted alkyl groups such as xcex1-hydroxyethyl, xe2x80x94CH2-cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-diiodo-4-hydroxybenzyl, xe2x80x94CH2-indol-3-yl, phenyl, xe2x80x94(CH2)4xe2x80x94NH-BOC, xe2x80x94(CH2)4xe2x80x94NH2, xe2x80x94CH2xe2x80x94(1-N-benzyl-imidazol-4-yl), xe2x80x94CH2xe2x80x94imidazol-4-yl, xe2x80x94CH2CH2SCH3, xe2x80x94(CH2)4NHC(O)(CH2)4CH3, xe2x80x94(CH2)yC(O)OR5 where y is 1 or 2 and R5 is hydrogen, methyl, tert-butyl, phenyl, and the like.
Preferred X substituents include xe2x80x94C(O)Y groups where Y is methoxy, ethyoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, amino (xe2x80x94NH2), N-(iso-butyl)amino, N-methylamino, N,N-dimethylamino, N-benzylamino, and the like as well as where X is xe2x80x94CH2OH and the like.
This invention also provides for novel pharmaceutical compositions comprising a pharmaceutically inert carrier and a compound of the formula I above.
Particularly preferred compounds for use in the methods and compositions of this invention include, by way of example, the following wherein the stereochemistry of the R2 and R3 groups is preferably derived from the L-amino acid:
N-[N-(3,4-dichlorophenyl)alanyl]valine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]valine N-iso-butyl amide
N-[N-(3,4-dichlorophenyl)alanyl]threonine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]valine ethyl ester
N-[N-(3,4-dichlorophenyl)alanyl]valine tert-butyl ester
N-[N-(3,4-dichlorophenyl)alanyl]valine amide
N-(3,4-dichlorophenyl)alanine N-(1-hydroxy-3-methyl-2-butyl) amide
N-[N-(3,4-dichlorophenyl)alanyl]valine N,N-dimethyl amide
N-[N-(3,4-dichlorophenyl)alanyl]valine N-methyl amide
N-[N-(3,4-dichlorophenyl)alanyl]alanine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]leucine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]isoleucine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanoic acid methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]tryptophan methyl ester
N-[N-(3,4-dichlorophenyl)alinyl]aspartic acid xcex1-methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid xcex2-(tert-butyl ester) xcex1-methyl ester
N-[N-(3,4-dichlorophenyl)alinyl]-N-BOC-lysine methyl ester
N-[N-benzothiazol-6-yl)aianyl]-2-aminohexanoic acid methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]lysine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]tyrosine methyl ester
N-[N-(3,5-dichlorophenyl)alanyl]alanine methyl ester
N-[N-(3,5-dichlorophenyl)alanyl]-2-aminopentanoic acid methyl ester
N-[N-(3,5-dichlorophenyl)alanyl]phenylalanine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]aspartic acid xcex2-(methyl ester) xcex1-methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-1-benzylhistidine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid xcex3-(tert-butyl ester) xcex1-methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]leucine amide
N-[N-(3,4-dichlorophenyl)alanyl]glutamic acid xcex1-methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-(3,5-diiodo)tyrosine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-(3-iodo)tyrosine methyl ester
N-[N-(3,5-dichlorophenyl)glycyl]-2-aminopentanoic acid methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-Nxcex5-(hexanoyl)lysine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]phenylalanine amide
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide
N-[N-(3,4-dichlorophenyl)alanyl]-xcex2cyclohexylalanine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanamide
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide
N-[N-(3,4-dichlorophenyl)alanyl]methionine methyl ester
N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N,N-dimethyl)-amide
N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexanamide
N-[N-(3,5-dichlorophenyl)alanyl]-2-aminohexan-(N-methyl)-amide
N-[N-(3,4-dichlorophenyl)alanyl]histidine methyl ester
N-[N-(quinolin-3-yl)alanyl]-2-aminohexanoic acid methyl ester
N-[N-(benzothiazol-2-yl)alanyl]2-aminohexanoic acid methyl ester
N-[N-(3,5-difluorophenyl)alanyl]alanine methyl ester
N-[N-(3,5-difluorophenyl)alanyl]-2-aminohexanoic acid methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanamide
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexan-(N-benzyl)-amide
N-[N-(3,4-dichlorophenyl)alanyl]-2-amino-2-phenylethanol
N-[N-(3,5-dichlorophenyl)phenylglycinyl]alanine methyl ester
N-[N-(3,4-dichlorophenyl)alanyl]-2-aminohexanol
N-[N-(3,5-dichlorophenyl)alanyl]-2-amino-2-phenylethanol
N-[N-(3,5-dichlorophenyl)alanyl]-phenylglycine tert-butyl ester
N-[N-(3,5-di-(trifluoromethyl)phenyl)alanyl]-phenylglycine tert-butyl ester
N-[N-(3,5-dimethoxyphenyl)alanyl]-2-aminohexanoic acid methyl ester
and pharmaceutically acceptable salts thereof.
Still further, this invention provides for novel compounds of the formula III:
wherein:
R1 is selected from the group consisting of
(a) phenyl,
(b) a substituted phenyl group of formula II:
xe2x80x83wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring,
Rb and Rbxe2x80x2 are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rbxe2x80x2 are either both hydrogen or both substituents other than hydrogen,
(c) 2-naphthyl,
(d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positions with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, and heteroaryl,
(e) heteroaryl, and
(f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy provided that said substituents are not ortho to the heteroaryl attachment to the xe2x80x94NH group;
R2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl provided that the substituents are not ortho to the attachment of the aryl or heteroaryl atom to the carbon atom;
R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and heterocyclic;
X is xe2x80x94C(O)Y where Y is selected from the group consisting of
(a) alkyl,
(b) substituted alkyl with the proviso that the substitution on said substituted alkyl does not include xcex1-haloalkyl, xcex1-diazoalkyl or xcex1-OC(O)alkyl groups,
(c) alkoxy or thioalkoxy,
(d) substituted alkoxy or substituted thioalkoxy,
(e) hydroxy,
(f) aryl,
(g) heteroaryl,
(h) heterocyclic,
(i) xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where Rxe2x80x2 and Rxe2x80x3 are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and
when R3 contains at least 3 carbon atoms, X can also be xe2x80x94CR4R4Yxe2x80x2 where each R4 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Yxe2x80x2 is selected from the group consisting of hydroxyl, amino, thiol, xe2x80x94OC(O)R5, xe2x80x94SSR5, xe2x80x94SSC(O)R5 where R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
and with the proviso that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derived from D-phenylglycine, then X is not xe2x80x94C(O)OCH3,
and still with the further proviso excluding the following known compounds:
when R1 is phenyl, R2 is methyl, X is xe2x80x94C(O)NHxcfx86, then R3 is not methyl, iso-propyl, iso-butyl; and
when R1 is phenyl, R2 is methyl, X is xe2x80x94C(O)NH2, then R3 is not benzyl.
Preferred compounds of formula III above include those set forth below in Table I below:
As above, this invention relates to compounds which inhibit xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease. However, prior to describing this invention in further detail, the following terms will first be defined.
Definitions
The term xe2x80x9cxcex2-amyloid peptidexe2x80x9d refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD which peptide is substantially homologous to the form of the protein described by Glenner, et al.1 including mutations and post-translational modifications of the normal xcex2-amyloid peptide. In whatever form, the xcex2-amyloid peptide is approximately a 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the xcex2-amyloid precursor protein (APP). Its 43-amino acid sequence is:
or a sequence which is substantially homologous thereto.
xe2x80x9cAlkylxe2x80x9d refers to monovalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-cycloalkylamino, mono- and di-arylamino, mono- and di-heteroaryl-amino, mono- and di-heterocyclic amino, and unsymmetric di-substituted aminries having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAlkylenexe2x80x9d refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94) and the like.
xe2x80x9cAlkarylxe2x80x9d refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkyl-O-xe2x80x9d. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkyl-O-xe2x80x9d where substituted alkyl is as defined above.
xe2x80x9cAlkylalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-O-alkylxe2x80x9d where alkylene and alkyl are as defined above. Such groups include, by way of example, methylenemethoxy (xe2x80x94CH2OCH3), ethylenemethoxy (xe2x80x94CH2CH2OCH3), n-propylene-iso-propoxy (xe2x80x94CH2CH2(,H2OCH(CH3)2), methylene-tert-butoxy (xe2x80x94CH2xe2x80x94Oxe2x80x94C(CH3)3) and the like.
xe2x80x9cAlkylthioalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-S-alkylxe2x80x9d where alkylene and alkyl are as defined above. Such groups include, by way of example, methylenethiomethoxy (xe2x80x94CH2SCH3), ethylenethiomethoxy (xe2x80x94CH2CH2SCH3), n-propylene-iso-thiopropoxy (xe2x80x94CH2CH2CH2SCH(CH3)2), methylenethio-tert-butoxy (xe2x80x94CH2SC(CH3)3) and the like.
xe2x80x9cAlkenylxe2x80x9d refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), iso-propenyl (xe2x80x94C(CH3)xe2x95x90CH2), and the like.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, cycloalkyl, oxyacylamino, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkzxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-cycloalkyl, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAlkynylxe2x80x9d refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH) and the like.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, cycloalkyl, oxyacylamino, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-cycloalkylamino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAcylxe2x80x9d refers to the groups alkylxe2x80x94C(O)xe2x80x94, substituted alkylxe2x80x94C(O)xe2x80x94, cycloalkylxe2x80x94C(O)xe2x80x94, arylxe2x80x94C(O)xe2x80x94, heteroarylxe2x80x94C(O)xe2x80x94 and heterocyclicxe2x80x94C(O)xe2x80x94 where alkyl, substituted alkyl, cycloalkyl, arvl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl. and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAcyloxyxe2x80x9d refers to the groups xe2x80x94OC(O)-alkyl, xe2x80x94OC(O)-substituted alkyl, xe2x80x94OC(O)-cycloalkyl, xe2x80x94OC(O)-aryl, xe2x80x94C(O)O-heteroaryl-, and xe2x80x94C(O)O-heterocyclic where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAminoacyloxyxe2x80x9d refers to the groups xe2x80x94NRC(O)O-alkyl, xe2x80x94NRC(O)O-substituted alkyl, xe2x80x94NRC(O)O-cycloalkyl, xe2x80x94NRC(O)O-aryl, xe2x80x94NRC(O)O-heteroaryl-, and xe2x80x94NRC(O)O-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, he,eroaryl and heterocyclic are as defined herein.
xe2x80x9cOxyacylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NR-alkyl, xe2x80x94OC(O)NR-substituted alkyl, xe2x80x94OC(O)NR-aryl, xe2x80x94OC(O)NR-heteroaryl-, and xe2x80x94OC(O)NR-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, acylamino, aminoacyloxy, oxyacylamino, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, trihalomethyl, thioalkoxy, substituted thioalkoxy, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-cycloalkylamino, mono- and di-arylainino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. When so substituted, such aryl groups are sometimes referred to herein as xe2x80x9csubstituted arylxe2x80x9d.
xe2x80x9cAryloxyxe2x80x9d refers to the group aryl-O- wherein the aryl group is as defined above including optionally SLubstituted aryl groups as also defined above.
xe2x80x9cCarboxyalkylxe2x80x9d refers to the groups xe2x80x94C(O)O-alkyl and xe2x80x94C(O)O-substituted alkyl where alkyl and substituted alkyl are as defined herein.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings (including aromatic rings fused to the cycloalkyl ring) which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as dibenzosuberane, adamantanyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring or multiple condensed rings and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
xe2x80x9cHeteroarylxe2x80x9d refers to a monovalent aromatic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, acylamino, aminoacyloxy, oxyacylamino, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, trihalomethyl, thioalkoxy., substituted thioalkoxy, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-cycloalkylamino, mono- and di-arylamino, mono-and di-heteroarilamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and the like. Such heteroaryl groups can have a single ring (e.g., pyridyl, furyl, etc.) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, and furyl. When so substituted, such heteroaryl groups are sometimes referred to herein as xe2x80x9csubstituted heteroarylxe2x80x9d.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a monovalent saturated or unsaturated group having a single ring, or multiple condensed rings, from 1 to 12 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, acylamino, aminoacyloxy, oxyacylamino, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, trihalomethyl, thioalkoxy, substituted thioalkoxy, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono-and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, and the like.
Examples of heterocycles and heteroaryls include, but are not limited to, furan, thiophene, thiazole, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkoxyxe2x80x9d refers to the group xe2x80x94S-alkyl.
xe2x80x9cSubstituted thioalkoxyxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
xe2x80x9cThioaryloxyxe2x80x9d refers to the group aryl-Sxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
xe2x80x9cThioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
In the compounds of formula I, Rb and Rc can be fused to form a heteroaryl or heterocyclic ring with the phenyl ring. Fusion in this manner results in a fused bicyclic ring structure of the formula:
where Rxe2x80x2 is as defined above and A is the fused heteroaryl or heterocyclic group as these terms are as defined above wherein the two atoms of the phenyl ring are included in the total atoms present in the heteroaryl or heterocyclic group. Examples of such fused ring systems include, for instance, indol-5-yl, indol-6-yl, thionaphthen-5-yl, thionaphthen-6-yl, isothionaphthen-5-yl, isothionaphthen-6-yl, indoxazin-5-yl, indoxazin-6-yl, benzoxazol-5-yl, benzoxazol-6-yl, anthranil-5-yl, anthiranil-6-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-6-yl, isoquinolin-7-yl, cinnolin-6yl, cinnolin-7-yl, quinazolin-6yl, quinazolin-7-yl, benzofuran-5-yl, benzofuran-6-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, and the like.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
Compound Preparation
The compounds of formula I above are readily prepared via several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, the commercial availability of starting materials, and the like.
In one synthetic method, the R1 group of the amino acid NH2CH(R2)COOH or an ester thereof is first introduced onto the molecule. Afterwards, conventional coupling of the first R1NHCH(R2)COOH or ester thereof with the amine of NH2CH(R3)C(O)Y provides for compounds of formula I wherein X is xe2x80x94C(O)Y.
Similarly, conventional reduction of the xe2x80x94C(O)Y group leads to xe2x80x94CH2OH groups and the like.
The introduction of the R1 group onto the amino acid NH2CH(R2)COOH or ester thereof can be accomplished using several methods. For example, conventional coupling of a halo acetic acid with a primary amine forms an amino acid as shown in reaction (1) below:
wherein R1 and R2 are as defined above and Xxe2x80x2 is preferably a halo group such as chloro or bromo. Alternatively, leaving groups other than halo may be employed such as triflate, mesylate, tosylate and the like. Additionally, suitable esters of 1 may be employed in this reaction.
Reaction (1) involves coupling of a suitable haloacetic acid derivative 1 with a primary aryl/heteroarylamine 2 under conditions which provide for amino acid 3. This reaction is described by, for example, Yates, et al.10 and proceeds by combining approximately stoichiometric equivalents of haloacetic acid 1 with primary aryl/heteroarylamine 2 in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like. The reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction. The reaction is preferably conducted at from about 25xc2x0 C. to about 100xc2x0 C. until reaction completion which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Pat. No. 3,598,859, which is incorporated herein by reference in its entirety. Upon reaction completion, N-aryl/N-heteroaryl amino acid 3 is recovered by conventional methods including precipitation, chromatography, filtration and the like.
In reaction (1), each of the reagents (haloacetic acid 1, primary aryl/heteroarylamine 2 and alcohol 3 are well known in the art with a plurality of each being commercially available.
In an alternative embodiment, the R1 group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation. For example, a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a haloaryl compound, X-R1 where X is a halo group such as fluoro, chloro or bromo and R1 is as defined above. The reaction is conducted in the presence of an excess of base such as sodium hydroxide to scavenge the acid generated by the reaction. The reaction typically proceeds at from 15xc2x0 C. to about 250xc2x0 C. and is complete in about 1 to 24 hours. Upon reaction completion, N-aryl amino acid ester is recovered by conventional methods including chromatography, filtration and the like.
In still another alternative embodiment, the esterified amino acids of formula I above can be prepared by reductive amination of a suitable 2-oxocarboxylic acid ester (such as a pyruvate ester) in the manner illustrated in Reaction (2) below:
wherein R1 and R2 are as defined above.
In reaction (2), approximately stoichiometric equivalents of a 2-oxocarboxylic acid ester 6 and arylainine 2 are combined in an inert diluent such as methanol, ethanol and the lilce and the reaction solution treated under conditions which provide for imine formation (not shown). The imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H2/palladium on carbon and the like to form the N-aryl amino acid ester 5. In a particularly preferred embodiment, the reducing agent is H2/palladium on carbon which is incorporated into the initial reaction medium which permits irvirte reduction in situ in a one pot procedure to provide for the N-aryl amino acid ester 5.
The reaction is preferably conducted at from about 20xc2x0 C. to about 80xc2x0 C. at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours. Upon reaction completion, N-aryl amino acid ester 5 is recovered by conventional methods including chromatography, filtration and the like.
Subsequent hydrolysis of the ester 5 leads to the corresponding carboxylic acid derivative.
A further embodiment for preparing N-aryl amino acids includes aromatic nucleophilic substitution of fluorobenzenes by the amine group of an amino acid.
The carboxylic acid derivative 5 is then coupled under conventional conditions well known in the art with a compound of the formula NH2CH(R3)C(O)Y where R3 and Y are as defined above. Such coupling leads to compounds of formula I. Subsequent modifications (e.g., reduction) lead to further compounds of formula I.
When Y is an ester group, conventional transesterification techniques can be used to prepare a variety of different ester groups on the compounds of formula I. Numerous techniques are known in the art to effect transesterification and each technique merely replaces the ester group with a different ester group derived from the corresponding alcohol or thioalcohol and, in some cases, a catalyst such as titanium (IV) iso-propoxide is used to facilitate reaction completion. In one technique, the alcohol or thioalcohol is first treated with sodium hydride in a suitable diluent such as toluene to form the corresponding sodium alkoxide or thioalkoxide which is then employed to effect transesterification. The efficierncy of this technique makes it particularly useful with high boiling and/or expensive alcohols.
In another transesterification technique, the ester to be transesterified is placed in a large excess of the alcohol or thioalcohol which effects transesterification. A catalytic amount of sodium hydride is then added and the reaction proceeds quickly under conventional conditions to provide the desired transesterified product. Because this protocol requires the use of a large excess of alcohol or thioalcohol, this procedure is particularly useful when the alcohol is inexpensive.
Transesterification provides a lacile means to provide for a multiplicity of different ester substituents on the compounds of formula I above. In all cases, the alcohols and thioalcohols employed to effect transesterification are well known in the art with a significant number being commercially available.
Other methods for preparing the esters of this invention include, by way of example, first hydrolyzing the ester to the free acid followed by O-alkylation with, e.g., a haloalkyl group in the presence of a base such as potassium carbonate.
Still other methods for the preparation of compounds of formula I are provided in the examples below.
Compounds where X is xe2x80x94CR4R4Yxe2x80x2 are readily prepared by coupling, e.g., an amino alcohol H2NCHR3CR4R4OH, to the carboxyl group of R1NHCHR2C(O)OH under standard coupling conditions well known in peptide coupling chemistry which can use well known coupling reagents such as S carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. If necessary, well known blocking groups on Yxe2x80x2 can be employred to protect the group during coupling. Such blocking groups are particularly desirable when Yxe2x80x2 is an amino group.
The reaction is conventionally conducted in an inert aprotic diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Upon reaction completion, any blocking groups on Yxe2x80x2 are selectively removed to provide for the desired compound.
When Yxe2x80x2 is xe2x80x94OH or xe2x80x94SH, post-synthetic conversion of these groups to the corresponding esters (i.e., xe2x80x94OC(O)R5), disulfides (i.e., xe2x80x94SSR5) and xe2x80x94SSC(O)R5 groups is accomplished using well known chemistry. For example, ester synthesis requires only reaction with a suitable acid such as acetic acid (R7=methyl), acid halide (e.g., acid chloride) or acid anhydride under suitable esterification conditions.
When one of R4 groups is hydrogen, post-synthetic oxidation of the xe2x80x94CHR4OH group leads to the ketone derivatives. Alternatively, such ketones can be prepared by coupling the suitable aminoketone HCl salt with the terminal carboxyl group of the amino acid.
In these synthetic methods, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of diastereomers or R,S enantiomers. Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols can involve inversion of the chiral center during synthesis.
Accordingly, unless otherwise indicated, the products of this invention are a mixture of diastereomers (if two or more chiral centers are present) or R,S enantiomers (if only one chiral center is present). Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. Alternatively, chiral products can be obtained via purification techniques which separates diastereomers or enantiomers from a R,S mixture to provide for one or the other stereoisomer. Such techniques are well known in the art.
Pharmaceutical Formulations
When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These 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.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such 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, semi-solid, 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, sterile 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 formsxe2x80x9d 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. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, 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, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

N-(aryl/heteroaryl) amino acid derivatives, pharmaceutical compositions comprising same, and methods for inhibiting xcex2-amyloid peptide release and/or its synthesis by use of such compounds


A combination of frequency and time division multiplexed signals communicates using bursts of higher frequency sinusoidal waves superimposed upon the alternating current in a two-wire power distribution network. A synchronization pattern precedes data, all bursts having the same frequency to overcome problems caused by varying reactances, and all bursts being confined within negative half-cycles of the AC power. Such networks minimize the amount of wire needed to connect large numbers of devices to a common controller while covering large distances, and requiring no particular connection pattern or terminations, whether near the surface, above ground, or in deep earth wells. In an irrigation system they accommodate at once solenoid valves and distributed environmental sensors. Landscape changes that would otherwise require new wiring to accommodate new irrigation zones are facilitated by merely tapping into the two-wire communications lines at the nearest accessible point. Outdoor lighting controls and security sensors are easily accommodated.

Early remote control of electrical devices was accomplished through the use of radio frequency transmitters. Though these systems could address devices over a very large area, they were rather expensive, especially where several controllable devices were to be addressed. With advances in technology these transmitters have been reduced in size to pocket pagers and are still a common means of control, though their relatively high cost still limits their application. For less expensive control within smaller, more local regions, ultrasonic transmitters were used, as for home television sets, until these were largely replaced by infrared systems upon the advent of Light-Emitting Diodes.
Many systems exist where remote control is not required to be wireless. Utility companies within the power industry recognized that, with their vast array of long-line wired connections, wireless for them might not be necessary. In 1972 Paull (U.S. Pat. No. 3,656,112) taught one means of remotely reading utility meters. The power that supplied the circuitry to generate and transmit data when requested was drawn from the same power line that was being metered. However, Paull's application was limited to relatively local rather than long distance use since the transfer of data was still accomplished wirelessly by radio or acoustic signals,
Remote control systems that were fully wired, as opposed to being wireless, continued to use separate cables to carry power and data. For systems that covered a large area, this presented considerable expense, both in the cost of material for extra data cables and the labor involved in their installation. The application of control signals, data signals and power all being transmitted along a single pair of conductors was yet to come.
About the same time as Paull was using wireless means to read information from power lines, Durkee in U.S. Pat. No. 3,689,886 used sets of receivers attached to a power line to remotely control individual devices with both power and control carried by the same two conductors. Each receiver was tuned for sensitivity to one particular frequency from among a set of frequencies. A receiver would enable its controlled device if its assigned frequency was detected within a pre-assigned time slot following zero-crossings of the alternating current (AC) power. The delay and duration of the time slots were established by one-shots which were set manually. If the required frequency was not present within the prescribed window, the device controlled by the receiver would be disabled. This approach allowed for activation of only one device code at a time since the coded frequency had to be repeated on each cycle of the AC power in order to keep a device enabled.
To allow more than one device to be independently enabled at any given time, Sherwin described his "Frequency Selective Remote Control System" in U.S. Pat. No. 3,729,710 (1973). It used the two-wire power line to carry enabling signals to each of a set of remote devices. A set of discrete frequencies within the band of 10 kHz to 35 kHz were superimposed on the power line, each device's receiver being tuned to a specific frequency. By sequentially scanning multiple frequencies onto the power line, for say 10 msec each, more than one device could be activated within any particular period of time. Once enabled, a receiver would hold its controlled device in the enabled state long enough to allow the transmitter to scan all of the devices in the system before allowing the device to drop out for lack of freshly updated enabling input.
So far these were essentially analog systems where control capabilities were limited to two states, the controlled devices being either On or Off. Fowler (U.S. Pat. No. 4,093,946) in 1976 was among the first to describe a method that was more generally capable of communicating data over a two-wire power system. He taught how a current source could be used to superimpose pulses representing a binary signal onto a low impedance power line. However, the data carried by Fowler's system was limited to small numeric values. There was no encoding involved. Addresses of controlled devices and the data that they returned in response to their being selected was simply a count of pulses that occurred within a transmission window. The power supplied was DC (direct current) that was stored in a capacitor at each controller in order to carry it through what might be considered blackout periods during which the power line was shorted out in order to transmit data.
U.S. Pat. No. 4,200,862 assigned to Pico Electronics Limited of Fife, Scotland in 1980 by Campbell, et al. may have been the first to transmit control and data over a two-wire power line. The protocol described by Campbell, et al. has now become pervasive. Commonly known as the X-10 interface, a de facto standard, the home automation industry has grown up around this particular technology that was enhanced by Thompson's U.S. Pat. No. 4,628,440 and again by Campbell in U.S. Pat. No. 4,638,299 over the next few years.
Though the X-10 system allows selection of devices by binary codes up to 255, it is still somewhat limited in control and data capabilities. Initially X-10 controllers were limited to the On or Off states of previous designs with the additional capability of sending a "Dim" signal to lamps.
In the 1996 U.S. Pat. No. 5,491,463 issued to Sargeant, et al., mention is made of the allowance in the X-10 protocol for a reserved byte code to indicate an extension for transmission of a data stream. A special code was to be followed immediately by a series of 8-bit bytes with the first 8-bit byte identifying the number of data bytes to follow. However, at that time Sargeant, et al. were not aware of any commercially available product in which that feature had been implemented, and so they proceeded to describe how to do so.
Advances in the above-described technologies have continued, but with the emphasis being on automation within the home or other interior'spaces such as offices and hotels. The X-10 protocol with its use of 120 kHz signaling does not seem to have migrated well to the outdoors where the reactances and line lengths encountered are not suitable for binary data transmissions. Even the X-10's attempt to overcome noise by transmitting code patterns twice, first in their true form followed by a second copy in complementary form, has been insufficient to adapt the system for use in the less predictable outdoor and underground environments. Meanwhile, other techniques have developed for outdoor use, but there do not seem to be any standards, and no technique is nearly as pervasive as the X-10 is indoors.
Control of turf irrigation systems presents a frequent, if not the most common, requirement for outdoor automation. Several two-wire power and communications networks have been developed for underground turf irrigation systems. Their purpose is to reduce the amount of copper wire needed to install the system and to facilitate landscape upgrades and wiring repairs. Typically these have been developed with an emphasis on the communications means, many of them being wireless, and have overlooked the utility of using 24 Volts AC as the power option for the solenoid valves and other devices on the network. The departure from the commonly available, and therefore relatively inexpensive, 24 Volt AC components has necessitated the use of special valves operating at higher voltages or the need to generate a valve power signal that simulates 24 Volts AC, the latter alternative in some cases being at the expense of reliable valve response.
Some of the two-wire systems described above and their more recent enhancements have employed binary communications signals superimposed on the power network. Binary signals require that the two-wire bus be well-managed. That is, it may be required that the two-wire pair be twisted or that the conductors remain in close proximity to one another or that they must run from device to device with terminations and repeaters at each node. Without such control of line quality, reflections from the ends of the lines add signal artifacts, such as 'porches', to the ends of the binary signals. Poorly managed reactances cause distortion of digital signals in general, and the two-wire networks treated here are particularly susceptible.
A further limitation of two-wire systems based on the communication of binary signals is the result of noise spikes from the environment masquerading as data signals. Such broadband spikes easily disrupt the communication of binary signals leading to errors and the necessity for repeated transmissions at the expense of data rates. The disclosed invention deals with these issues from the basis of a scheme that combines Time Division Multiplex and Frequency Division Multiplex methods. The combination maintains the advantages of each method, achieving extremely low error rates while using simple hardware supported by sophisticated though relatively inexpensive microcontroller code.

Subterranean two-wire power and communications network


An OLED display according to an exemplary embodiment includes: a substrate; an organic light emitting diode formed on the substrate; an overcoat covering the organic light emitting diode; and a patterned metal sheet attached on the overcoat and having a plurality of protrusion and depression portions. A plurality of protrusions may be formed in a bottom surface of the patterned metal sheet where the protrusion and depression portions of the patterned metal sheet and the overcoat face each other.

1. Technical Field
The described technology relates generally to an organic light emitting diode (OLED) display and a manufacturing method thereof.
2. Description of Related Art
Unlike the liquid crystal display (LCD), an organic light emitting diode (OLED) display does not require a separate light source, thereby making it possible to be implemented as a slim and lightweight display. Furthermore, as the organic light emitting diode display has high quality characteristics such as lower power consumption, high luminance, and short response time, it has been spotlighted as a next generation display device.
The OLED includes a plurality of light emitting diodes, each having a hole injection electrode, an organic emission layer, and an electron injection electrode. Electrons and holes are combined with each other in the organic emissive layer, thereby generating excitons. When the excitons shift from the excited state to the ground state, energy is generated, thereby emitting light, and images are displayed from the emitted light.
However, because the organic emission layer is sensitive to external factors such as moisture or oxygen, when the organic emission layer is exposed to moisture and oxygen, the quality of the OLED display deteriorates. Therefore, in order to protect the OLED and to prevent moisture or oxygen from penetrating the organic emission layer, an encapsulation substrate is sealed and adhered through an additional sealing process, a thick protective layer is formed on the OLED, or an inorganic layer and an organic layer are alternately layered (more than one layer) to cover the display area with a thin film encapsulation layer.
The above information disclosed in this Background section is presented solely to enhance the understanding of the background of the described technology, and therefore may contain information that is not prior art or that is already known in this country to a person of ordinary skill in the art.

Organic light emitting diode display and manufacturing method thereof


An organic hydroxyl compound is reacted with polyphosphoric acid under such conditions that the ratio, as defined by formula (1), has a value exceeding 3.2; and phosphorus pentaoxide is added to the reaction product thus obtained in such an amount that the ratio, as defined by formula (1), has a value in the range of from 2.8 to 3.2: ##EQU1## If necessary, the obtained reaction product is deodorized by the removal of the organic hydroxyl compound unreacted therefrom. The process does not give any product of high-viscous gel and therefore enables the industrially easy manufacture of a phosphoric monoester having an extremely high purity, a lowered orthophosphoric acid content, and a good odor.

1. Field of the Invention
The present invention relates to a process for the preparation of a phosphoric monoester through the phosphorylation of an organic hydroxyl compound. More particularly, the present invention relates to a process for the preparation of a phosphoric monoester which can easily provide a phosphoric ester mixture having a high phosphoric monoester purity, a reduced orthophosphoric acid content and good odor.
2. Description of the Related Art
Phosphoric esters of organic hydroxyl compounds are used in a wide field as a detergent, a textile treating agent, an emulsifying agent, a rust inhibiter, a liquid ion exchanger and a medicament.
Although the reaction of an organic hydroxyl compound with phosphorus pentaoxide has been known as an industrial process for the preparation of phosphoric esters in the prior art, the product of the reaction comprises mainly a nearly equimolar mixture of a phosphoric monoester represented by the following formula (A) and a phosphoric diester represented by the following general formula (B) (hereinafter, this mixture is referred to as "sesquiphosphate"): ##STR1## wherein R represents a linear or branched alkyl or alkenyl group having 6 to 30 carbon atoms.
There are great differences in properties between a phosphoric monoester and a phosphoric diester. To give an explanation about, e.g., alkali metal salts and alkanolamine salts of long-chain alkyl phosphates, phosphoric monoester salts are soluble in water, excellent in foaming power and detergency, less toxic and lowly irritant to the skin to be useful as an excellent detergent, while phosphoric diester salts are little soluble in water and exhibit little foaming power or rather have defoaming properties, and accordingly they can not be used as high foaming detergents. Therefore, when sesquiphosphate salts are employed, the above performances inherent in phosphoric monoester salts can not be exhibited, and, therefore, sesquiphosphate salts are unusable as substitutes for phosphoric monoester salts.
Under these circumstances, the development of a process by which a phosphoric ester mixture having a high phosphoric monoester content can be prepared on an industrial scale safely and easily has been eagerly expected and the following processes have been reported to answer this expectation:
(1) a process which comprises reacting an organic hydroxyl compound with phosphorus oxychloride and hydrolyzing the obtained monoalkyl phosphorodichloridate; PA1 (2) a process which comprises adding water to an organic hydroxyl compound and thereafter adding phosphorus pentaoxide to the obtained mixture to conduct phosphorylation with the amount of water preliminarily added being 0.5 to 3 mol per mol of phosphorus pentaoxide; PA1 (3) a process which comprises reacting an organic hydroxyl compound with orthophosphoric acid and phosphorus pentaoxide; PA1 (4) a process which comprises reacting an organic hydroxyl compound with a condensed phosphoric acid (polyphosphoric acid); PA1 (5) a process which comprises reacting an organic hydroxyl compound with phosphorus pentaoxide in the presence of water while blowing steam into the reaction system; and PA1 (6) a process which comprises reacting an organic hydroxyl compound with a phosphorylating agent mixture comprising phosphorus pentaoxide, phosphoric acid and a polyphosphoric acid under such a condition that phosphoric acid components are excess, adding an organic hydroxyl compound to the obtained reaction mixture to make up to a stoichiometric amount and conducting further phosphorylation see U.S. Pat. No. 4,350,645 (published on Sep. 21, 1982, assignee: Kao Corporation)!. PA1 (1) a first step of reacting an organic hydroxyl compound with polyphosphoric acid under such conditions that the ratio, as defined by formula (1), has a value exceeding 3.2, and PA1 (2) a second step of adding phosphorus pentaoxide in such an amount that the ratio, as defined by formula (1), has a value in the range of from 2.8 to 3.2: ##EQU2##
However, these processes have respective disadvantages as will now be described, being unsatisfactory as industrial processes for the preparation of phosphoric ester mixtures.
The process (1) gives hydrogen chloride as a by-product to be significantly problematic in the corrosion of equipment and the disposal of hydrochloric acid. Further, this process involves the formation of an alkyl chloride as a by-product, so that it is difficult to enhance the phosphoric monoester content of the reaction product.
According to the processes (2) and (3), the ratio of the phosphoric monoester to the phosphoric diester in the reaction product can be enhanced by increasing the amount of water or orthophosphoric acid used. However, the use of a large amount of water or orthophosphoric acid remarkably lowers the degree of conversion of phosphorus to give a remarkably increased amount of orthophosphoric acid. The contamination of the product with a large amount of orthophosphoric acid has undesirable influence on some fields, so that the use field of the product is limited.
According to the process (4), a phosphoric monoester can be prepared selectively. However, the process (4) as well as the processes (2) and (3) gives a large amount of orthophosphoric acid as a by-product. To decrease the amount of orthophosphoric acid formed as a by-product according to the process (4), it is necessary to use a polyphosphoric acid having an extremely high degree of condensation. However, such a polyphosphoric acid is in the form of a high-viscosity gel, which necessitates the use of an industrially special reactor and makes the manufacture difficult.
According to the process (5), the ratio of the phosphoric monoester to the phosphoric diester is enhanced by blowing steam into the reaction system. However, the blowing of steam into the reaction system increases the amount of orthophosphoric acid formed. As described above, the contamination of the product with a large amount of orthophosphoric acid has undesirable influence on some fields, so that the use field of the product is limited.
According to the process (6), only a small amount of an organic hydroxyl compound is present in the reaction system in the early stages of the reaction, so that the phosphoric monoester/phosphoric diester ratio of the reaction product is enhanced. However, when the amount of an organic hydroxyl compound used in the early stages lies within a certain range, the reaction product takes the form of a high-viscosity gel to necessitate the use of an industrially special reactor. In some cases according to the process (6), additionally, the decomposition of the phosphoric monoester formed proceeds, so that the yield of the phosphoric monoester is lowered with an increase in the orthophosphoric acid content of the reaction product. The increase in the orthophosphoric acid content has undesirable influence on some fields, so that the use field of the resulting product is limited.

Process for the preparation of phosphoric monoester


The instant invention relates to a method for establishing a satellite navigation system, using the satellite networks provided for mobile communications, below the geostationary orbit, in particular in LEO (low earth orbiting) or MEO (medium earth orbiting) constellations, as well as its connection to communications satellites in the geostationary orbit. The establishment of satellite navigation networks in accordance with the invention is made possible by means of the employment of special optical ISL (inter-satellite link) terminals with ranging functions in various LEO or MEO satellite networks, and possibly by including GEO satellite constellations.

Existing satellite navigation systems, such as GPS (Global Positioning System), GLONASS or planned European systems (GNSS) have been realized or are planned by means of special constellations of several satellites orbiting the earth on polar paths or on geostationary paths. The planned European system GNSS, for example, could be implemented by including the satellites of the INMARSAT network moving in geostationary orbits. The satellites of the GPS move in polar orbits at an attitude of approximately 20,000 km above ground and emit radio signals, depending on the user group, on one or two frequencies in the range between 1 and 2 GHz, which transmit exact time markers to the user on the ground by means of a permanently repeated modulation with a very broadband data sequence of great length. Because of the very broadband modulation signal and the relatively low rate of its repetition, the spectrum of these radio signals gives the impression of white noise in the close vicinity of its respective center frequency. Since the phase of the radio signal is modulated, it is possible to return it to its unmodulated state in the receiver by means of negative modulation with the same modulation signal, which can be very easily reproduced because of its particular structure, and can be detected with little noise by means of a very narrow band filter.
The synchronization of the second modulating process in the receiver required for this makes possible the determination of distance differences from several satellites which are to be received simultaneously, whose respective instantaneous positions are known, and from this, analogously with the hyperbolic navigation process, the exact determination of the position of the user.
By means of the operation on two different frequencies, a compensation of the properties of the ionosphere surrounding the earth, whose structure changes in the course of a sunspot cycle during a period of approximately eleven years, as well as seasonally and daily, is offered to an appropriately equipped group of users (Lambert Wanninger "Der Einfluss der Ionosphare auf die Positionierung mit GPS" [The Effects of the Ionosphere on Positioning by Means of GPS], Hannover University, 1994, ISSN 0174-1454).
Furthermore, errors are deliberately generated by the operator (US Air Force) in order to prevent the use of commercially available receivers, for example for the rapid and easy placement of gun positions. As a result all remaining, parallel existing and planned systems with satellites in higher orbits have the main purpose of breaking the monopoly of a single system and to make available world-wide, highly exact position determinations independently of marginal political and military conditions.
The mentioned systems do not operate cooperatively, there is no bidirectional linkage between the satellites and the individual user of the systems, and therefore the number of users is infinite and, with the full operability of the system, also uncontrollable. The good viewing ability of the satellites, assured by the high orbits of the respective satellites, makes it possible to keep their number low for covering the entire surface of the earth. Twenty-one operating satellites are sufficient for GPS. However, it is hardly possible to selectively cancel the availability of the system in narrowly defined regions of the world in order to prevent their integration into the optimized operation of military systems. Furthermore, a hypothetical system operated by means of satellites in relatively high orbits with a cooperative position determination for the purpose of controlling unwanted usage, only allows a limited number of users, given the existing scarcity of frequencies.


Embodiments of the present invention provide a label-based measurement method, apparatus, and system. The method includes: allocating at least two labels to the same FEC; obtaining a label insertion mode for the at least two labels; receiving data packet, where one of the at least two labels is inserted in the data packet; and performing, according to the label insertion mode and the data packet, performance measurement on a network that the FEC passes through. By using the technical solutions provided in the embodiments of the present invention, a problem of network bandwidth occupation caused by inserting a test packet and an OAM packet during performance measurement and a problem of measurement result inaccuracy caused by OAM packet loss may be solved.

A lot of MPLS (Multi-Protocol Label Switching)-based applications, for example, an L3VPN (Layer 3 Virtual Private Network) and the like have already been deployed on a large scale on actual networks, but an MPLS OAM (Operation, Administration and Maintenance) function is relatively weak. Currently, measurement technologies with respect to metrics reflecting network performance such as packet loss and delay on an MPLS network need further research.
An FEC (Forwarding Equivalence Class) represents a group of data packets with similar or identical forwarding characteristics on the MPLS network. Data packets belonging to the same FEC are assigned a determined MPLS label on different network nodes. A label (Label) is a fixed-length identifier, and is generally located between a data link layer encapsulation header and a layer 3 data packet. The FEC is bound to the label, and data packets are forwarded according to the label. Data packets belonging to the same FEC pass through the same LSP (Label Switched Path). On the MPLS network, an LSR (Label Switching Router) forms an MPLS network node, and provides functions of label switching and label distribution.

Label-based measurement method, apparatus, and system


An inkjet printer includes: a print head; a maintaining unit; a timing unit; a notifying unit; a maintenance command determining unit; and a maintenance operation executing unit. The print head is formed with one or more ink ejection opening for printing a printing medium by ejecting ink through the ink ejection opening. The maintaining unit restores the ink ejection state of the print head by flowing ink through the ink ejection opening. The timing unit keeps track of an elapsed time after the maintaining unit has executed a maintenance operation. The notifying unit notifies a user when it is time to execute a maintenance operation if the elapsed time measured by the timing unit exceeds a prescribed time. The maintenance command determining unit determines whether or not the user has issued a command to execute a maintenance operation with the maintaining unit after the notifying unit has issued a notification. The maintenance operation executing unit executes a maintenance operation with the maintaining unit when the maintenance command determining unit determines that the user has issued a command to execute the maintenance operation.

Conventional inkjet printers print on recording paper by ejecting ink from a print head having a plurality of ink ejection openings or nozzles formed therein. In this inkjet printer, ink ejection problems can occur when air bubbles are generated in the ink while the print head is in use, when ink or microparticles of foreign matter are deposited on the surface of the ink ejection openings, and the like. Further, if the printer is left unused for a long period of time, the ink ejection openings may become clogged with ink, leading to ink ejection problems. Since printing quality suffers if a printing operation is performed while ink ejection is problematic, a purge process is generally performed to restore the ink ejection openings to a good ejection state. The purge process is performed, for example, by generating a negative pressure with a pump to draw ink out of the print head after hermetically sealing the print head with a suction cap, or performing a preliminary ejection process to eject ink from the nozzles.
Since the user executes this purge process manually after detecting printing problems, printing complications occur once at the very least. In order to overcome this problem, an inkjet printer such as that disclosed in U.S. Pat. No. 6,386,677B1 has been proposed to execute a purge process automatically when conditions indicating the potential for printing problems have been met. In this inkjet printer, if conditions indicating the potential for printing complications are met, for example, if a prescribed time or more has elapsed since the previous purge process, the inkjet printer executes a purge process before such printing problems can occur, thereby preventing the occurrence of printing complications.


A method and apparatus for descrambling data that is characterized by shift registers that realize an operation of generating polynomial and that have a ring-shaped structure that realizes plural and continuous operation. The method and apparatus further includes an initial value setting means for setting initial values in m shift registers; after setting the initial values, shifting the initial values while synchronizing the initial values with input clocks, and outputting the exclusive OR of data which is input while being synchronized with clocks and the lowermost latch outputs. Scrambled data with a byte is treated as a unit by using an exclusive OR circuit block.

A data scrambling method has conventionally been employed to facilitate detection of timing at a signal change point on a receiver side by averaging changes in amplitude, polarity, and phase of a transmitted signal, even when input data have a periodicity or a constant pattern. In order to realize such a data scrambling method, a data scrambling apparatus has been employed.
Hereinafter, a conventional data scrambling apparatus will be described with reference to figures.
FIGS. 16(a) and 16(b) show a conventional data scrambling apparatus and a conventional data descrambling apparatus, respectively. For simplification, a data scrambling apparatus and a data descrambling apparatus, both employing a generating polynomial, G(X)=1+X.sup.-6 +X.sup.-7, are taken as examples. In FIG. 16, reference numeral 161 designates a data input terminal, numeral 162 designates a scrambled data output terminal, numeral 163 designates registers, numeral 164 designates a mod 2 adder, numeral 165 designates an initialization table, numeral 166 designates a scrambled data input terminal, and numeral 167 designates a data output terminal.
A description is given of the operation of the data scrambling apparatus shown in FIG. 16(a). First of all, initialization values are sent to the respective registers 163 from the initialization table 165 to set initial values. Next, serial data Di are input to the data input terminal 161. The input data are shifted, by one bit for each step, to the subsequent register 163. This shifting of data is successively carried out, and scrambled output data Ds are serially output from the data output terminal 162.
A description is now given of the operation of the data descrambling apparatus shown in FIG. 16(b). First of all, initialization values are set in the respective register 163, and serial data Ds are input to the data input terminal 166. The input data are shifted by one bit for each step, and descrambled output data Do are serially output from the output terminal 167.
Next, a data scrambling apparatus and a data descrambling apparatus which are used in a recording and reproducing apparatus using an optical disk as a medium will be described. In such a recording and reproducing apparatus, generally, scrambling is performed to avoid coincidence of patterns of data recorded in adjacent tracks.
FIGS. 17(a) and 17 (b) show a conventional data scrambling apparatus and a conventional data descrambling apparatus, respectively, employed in an optical disk recording and reproducing device. For simplification, a scrambling apparatus and a descrambling apparatus employing a generating polynomial, G(X)=X.sup.7 +X.sup.6 +1, are taken as examples.
In these figures, reference numeral 171 designates a data input terminal, numeral 172 designates a scrambled data output terminal, numeral 173 designate registers, numeral 174 designates a mod 2 adder, numeral 175 designates an initialization table, numeral 176 designates a scrambled data input terminal, and numeral 177 designates a data output terminal.
A description is given of the operation of the data scrambling apparatus shown in FIG. 17(a). First of all, initialization values are sent to the respective registers 173 from the initialization table 175 to set initial values. Next, serial data Di are input to the data input terminal 171. The initialized data in the respective registers 173 are synchronized with the input data Di and shifted, by one bit for each step, to the subsequent register 173. The shifting of the initialized data and the data input are successively carried out, and data obtained by an exclusive- or operation between the input data and the data output from the register in the rightmost stage are output from the data output terminal 172 as scrambled data Ds.
The operation of the data descrambling apparatus shown in FIG. 17(b) is similar to the operation of the scrambling apparatus shown in FIG. 17(a). That is, scrambled data Ds are input to the scrambled data input terminal 176, and descrambled data Do are output from the data output terminal 177.
As described above, in the conventional scrambling or descrambling apparatus, data are scrambled or descrambled in binary format. In recent years, however, since data are processed with a byte as a unit, it is necessary to convert binary data to byte data, or vice versa.

Data scrambling method, data scrambling apparatus, data descrambling method, and data descrambling apparatus

Matsushita Electric Industrial Co., Ltd.


A method is disclosed that enables an improvement in the scalability of a centralized server by reallocating to the client endpoints some, but not all, of the feature functionality of the server. Each logical user in the system is represented by his own private domain of endpoint entities, from which an endpoint is selected to serve as a super peer to represent the user to the centralized server. Furthermore, a designated endpoint is selected, also from the private domain of devices, to handle some of the telecommunications features that the server otherwise would have handled. Each endpoint in the private domain is permitted to have limited direct access to the server, typically for the purposes of registering and subscribing to features, in addition to and in contrast with the indirect access through the super peer. During the subscribing process, the server redirects a subscribing endpoint to the designated endpoint that is handling the feature.

FIG. 1 depicts telecommunications system 100 in the prior art. System 100 comprises telecommunications network 101; client endpoints 102-1 through 102-H, wherein H is a positive integer; and servers 103-1 through 103-L, wherein L is a positive integer. The elements of system 100 are interconnected as shown. System 100 enables calls, via network 101, between endpoints 102-1 through 102-H and servers 103-1 through 103-L. Network 101 comprises one or more of the Internet, the Public Switched Telephone Network (PSTN), a local area network (LAN), and so forth.
Client endpoints 102-1 through 102-H are telecommunications devices such as an Internet-protocol telephone, a notebook computer, a personal digital assistant (PDA), a tablet computer, and so forth. Each endpoint is capable of originating outgoing calls and receiving incoming calls, in well-known fashion. In addition, each endpoint is capable of one or more communication modes that comprise but are not limited to voice, video, data, email, and instant messaging.
Servers 103-1 through 103-L are data-processing systems that handle telecommunications features that can be subscribed to by the endpoints. The servers are capable of handling features such as voice calling, video streaming, data retrieval, email, instant messaging, availability and presence monitoring, and so forth.
Telecommunications system 100 operates in accordance with the Session Initiation Protocol (SIP), a set of standardized communication rules for initiating and maintaining communication for telephony, presence-based systems, instant messaging, and other telecommunications applications. The increasing use of SIP-based systems represents a fundamental shift in telecommunications, in which a user can be addressed as a logical entity that might possess one or more devices, with each device going in and out of service based on the usage patterns of the user.
As new telecommunications features are built onto the SIP infrastructure, issues are emerging that affect performance throughout telecommunications system 100 and, in particular, servers 103-1 through 103-L. One such issue is an increase in network traffic. For example, as features that are related to monitoring the client endpoints are introduced at a centralized server that also handles call processing, the number of SIP-related events that the server must handle also increases, and consequently the server's capacity to process calls becomes severely degraded.
In some techniques in the prior art, the scalability issue that arises in a centralized server architecture is partially mitigated by partitioning the client endpoint users across multiple servers. Doing so, however, often has the effect of spreading out the call processing-related resource utilization, but not necessarily the SIP events-related utilization. Consequently, there are at least three issues with the centralized server architecture in the long run. First, as the user acquires more and more SIP-enabled endpoints that can communicate media or report presence, there will be less of an opportunity for scalability through mere partitioning; this is because the call processing-related resource utilization will amount to a smaller and smaller fraction of the total utilization. Second, as the variety of endpoint types increases and the demand for ease-of-use by the end user increases, the complexity of the centralized server will increase exponentially. And third, as the server complexity increases, so will the effort that will be required for the development of new features.
What is needed is a way to mitigate the server scalability issue, without some of the disadvantages in the prior art.

Centralized controller for distributed handling of telecommunications features


Head stack fixtures for securing head stack assemblies to spin stand testing systems, and spin stand testing systems incorporating such fixtures, are disclosed. Exemplary head stack fixtures comprise a base supporting a piezoelectric actuator. The base includes an attachment mechanism for securing the HSA in such a way that the HSA will pivot relative to the base. When the HSA is secured to the base, the piezoelectric actuator engages the HSA. The piezoelectric actuator is therefore able to pivot the HSA relative to the base for fine positioning of a head of the HSA.

1. Field of the Invention
The disclosure relates generally to the field of magnetic disk drives, and more particularly to apparatus and methods related to testing disk drive components.
2. Description of the Prior Art
Magnetic disk drives are used to store and retrieve data for digital electronic apparatuses such as computers. A typical magnetic disk drive comprises a head, including a slider and a transducer, in very close proximity to a surface of a rotatable magnetic disk. The transducer, in turn, includes a write element and/or a read element. As the magnetic disk rotates beneath the head, a very thin air bearing is formed between the surface of the magnetic disk and an air bearing surface of the slider. The air bearing causes the head to "fly" above the surface of the magnetic disk with a separation ("fly height") that is typically less than 40 nanometers in contemporary disk drives. As the head flies over the magnetic disk, the write element and the read element can be alternately employed to write and read data bits along a magnetic "track" on the magnetic disk.
It will be appreciated that the head is a highly complex component and, accordingly, heads are preferably qualified before being assembled into disk drives. Commonly, heads are tested after being assembled into either a Head Gimbal Assembly (HGA) or after one or more HGAs are assembled into a Head Stack Assembly (HSA). The HGA typically comprises the head, a load beam, a gimbal that attaches the head to the load beam, a swage mount, and electrical traces to facilitate electrical connection of the transducer of the head to a pre-amplifier circuit. The HSA comprises one or more HGAs in a stacked arrangement for use with one or both sides of a magnetic disk and/or multiple magnetic disks. The HSA also typically comprises an actuator arm structure that can pivot in response to torques applied by a voice coil motor.
A spin stand is a common testing apparatus for testing writing and reading characteristics of heads. Generally, the spin-stand includes a rotatable disk and a positioning device that secures a HGA or HSA. The positioning device allows the head to be moved to a desired position over the disk. Accordingly, the positioning device typically includes two coarse motors for moving the head in two orthogonal directions relative to the disk.
One issue with spin stand testing relates to the problem of keeping the head aligned with a track on the disk. In a disk drive, a feedback loop known as a closed-loop servo is employed to keep the head properly aligned. The closed-loop servo relies on regularly spaced patterns on the disk, known as servo bursts, to determine any misalignment, and then corrects for the misalignment by adjusting the position of the head. However, spin stands historically have been "open-loop" systems, meaning that there is no feedback mechanism for keeping the head aligned with a track. Open-loop systems designed to have very high mechanical precision worked adequately when tracks were relatively wide. However, the demand for increased information storage density and associated improvements in write and read elements have lead to narrower track widths and narrower read elements, and therefore, what were once considered to be very small sources of mechanical imprecision now can cause the head to move significantly off-track during testing.
Accordingly, what is needed is a spin stand that is able to dynamically adjust the position of the head to keep the head aligned with a track during testing.

Spin stand testing system with fine positioner for head stack assembly