The present invention relates to novel tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidine compounds that are antagonists of alpha V (xcex1v) integrins, for example xcex1vxcex23 and xcex1vxcex25 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds may be used in the treatment and/or prevention of pathological conditions mediated by xcex1vxcex23 and xcex1vxcex25 integrins such as tumor growth, metastasis, restenosis, osteoporosis, inflammation, macular degeneration, diabetic retinopathy, rheumatoid arthritis, sickle cell anemia, and in treatment and/or prevention of central nervous system (CNS) related disorders such as neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, surgery, neurodegenerative diseases, such as Alzheimer""s disease and Parkinson""s disease, adverse consequences of overstimulation of one or more excitatory amino acids, anxiety, convulsions, chronic pain, psychosis, schizophrenia, anesthesia, and opiate tolerance. The compounds have the general formula:

1. Field of the Invention The present invention relates to novel tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidine compounds that are antagonists of alpha V (xcex1v) integrins, for example xcex1vxcex23 and xcex1vxcex25 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
2. Background Art
Integrins are cell surface glycoprotein receptors which bind extracellular matrix proteins and mediate cellxe2x80x94cell and cell-extracellular matrix interactions (generally referred to as cell adhesion events) (Hynes, R. O., Cell 69:11-25 (1992)). These receptors are composed of noncovalently associated alpha (xcex1) and beta (xcex2) chains which combine to give a variety of heterodimeric proteins with distinct cellular and adhesive specificities (Albeda, S. M., Lab. Invest. 68:4-14 (1993)). Recent studies have implicated integrins in the regulation of cellular adhesion, migration, invasion, proliferation, apoptosis and gene expression (Albeda, S. M., Lab. Invest. 68:4-14 (1993); Juliano, R., Cancer Met. Rev. 13:25-30 (1994); Ruoslahti, E. and Reed, J. C., Cell 77:477-478 (1994); and Ruoslahti, E. and Giancotti, F. G., Cancer Cells 1:119-126 (1989)).
One member of the integrin family which has been shown to play a significant role in a number of pathological conditions is the integrin xcex1vxcex23, or vitronectin receptor (Brooks, P. C., DNandP 10(8):456-461 (1997)). This integrin binds a variety of extracellular matrix components and other ligands, including fibrin, fibrinogen, fibronectin, vitronectin, laminin, thrombospondin, and proteolyzed or denatured collagen (Cheresh, D. A., Cancer Met. Rev. 10:3-10 (1991) and Shattil, S. J., Thromb. Haemost. 74:149-155 (1995)). The two related xcex1v integrins, xcex1vxcex25 and xcex1vxcex21 (also vitronectin receptors), are more specific and bind vitronectin (xcex1vxcex25) or fibronectin and vitronectin (xcex1vxcex21) exclusively (Horton, M., Int. J. Exp. Pathol. 71:741-759 (1990)). xcex1vxcex23 and the other integrins recognize and bind to their ligands through the tripeptide sequence Arg-Gly-Asp (xe2x80x9cRGDxe2x80x9d) (Cheresh, D. A., Cancer Met. Rev. 10:3-10 (1991) and Shattil, S. J., Thromb. Haemost. 74:149-155 (1995)) found within all the ligands mentioned above.
The xcex1vxcex23 integrin has been implicated in a number of pathological processes and conditions, including metastasis and tumor growth, pathological angiogenesis, and restenosis. For example, several studies have clearly implicated xcex1vxcex23 in the metastatic cascade (Cheresh, D. A., Cancer Met. Rev. 10:3-10 (1991); Nip, J. et al., J. Clin. Invest. 95:2096-2103 (1995); and Yun, Z., et al., Cancer Res. 56:3101-3111 (1996)). Vertically invasive lesions in melanomas are also commonly associated with high levels of xcex1vxcex23, whereas horizontally growing noninvasive lesions have little if any xcex1vxcex23 (Albeda, S. M., et al., Cancer Res. 50:6757-6764 (1990)). Moreover, Brooks et al. (in Cell 79:1157-1164 (1994)) have demonstrated that systemic administration of xcex1vxcex23 antagonists disrupts ongoing angiogenesis on chick chorioallantoic membrane (xe2x80x9cCAMxe2x80x9d), leading to the rapid regression of histologically distinct human tumors transplanted onto the CAM. These results indicate that antagonists of xcex1vxcex23 may provide a therapeutic approach for the treatment of neoplasia (solid tumor growth).
xcex1vxcex23 has also been implicated in angiogenesis, which is the development of new vessels from preexisting vessels, a process that plays a significant role in a variety of normal and pathological biological events. It has been demonstrated that xcex1vxcex23 is up-regulated in actively proliferating blood vessels undergoing angiogenesis during wound healing as well as in solid tumor growth. Also, antagonists of xcex1vxcex23 have been shown to significantly inhibit angiogenesis induced by cytokines and solid tumor fragments (Brooks, P. C., et al., Science 264:569-571 (1994); Enenstein, J. and Kramer, R. H., J. Invest. Dermatol. 103:381-386 (1994); Gladson, C. L., J. Neuropathol. Exp. Neurol 55:1143-1149 (1996); Okada, Y., et al., Amer. J. Pathol. 149:37-44 (1996); and Brooks, P. C., et al., J. Clin. Invest. 96:1815-1822 (1995)). Such xcex1vxcex23 antagonists would be useful for treating conditions that are associated with pathological angiogenesis, such as rheumatoid arthritis, diabetic retinopathy, macular degeneration, and psoriasis (Nicosia, R. F. and Madri, J. A., Amer. J. Pathol. 128:78-90 (1987); Boudreau, N. and Rabinovitch, M., Lab. Invest. 64:187-199 (1991); and Brooks, P. C., Cancer Met. Rev. 15:187-194 (1996)).
There is also evidence that xcex1vxcex23 plays a role in neointimal hyperplasia after angioplasty and restenosis. For example, peptide antagonists and monoclonal antibodies directed to both xcex1vxcex23 and the platelet receptor xcex1IIbxcex23 have been shown to inhibit neointimal hyperplasia in vivo (Choi, E. T., et al., J. Vasc. Surg. 19:125-134 (1994); and Topol, E. J., et al., Lancet 343:881-886 (1994)), and recent clinical trials with a monoclonal antibody directed to both xcex1IIbxcex23 and xcex1vxcex23 have resulted in significant reduction in restenosis, providing clinical evidence of the therapeutic utility of xcex23 antagonists (Topol, E. J., et al., Lancet 343:881-886 (1994)).
It has also been reported that xcex1vxcex23 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption. When bone resorbing activity exceeds bone forming activity, the result is osteoporosis, a condition which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of xcex1vxcex23 have been shown to be potent inhibitors of osteoclastic activity both in vitro (Sato, M., el al., J. Cell Biol. 111:1713-1723 (1990)) and in vivo (Fisher, J. E., et al., Endocrinology 132:1411-1413 (1993)).
Lastly, White (in Current Biology 3(9):596-599 (1993)) has reported that adenovirus uses xcex1vxcex23 for entering host cells. The xcex1vxcex23 integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit xcex1vxcex23 could be useful as antiviral agents.
The xcex1vxcex25 integrin has been implicated in pathological processes as well. Friedlander et al. have demonstrated that a monoclonal antibody for xcex1vxcex25 can inhibit VEGF-induced angiogenesis in rabbit cornea and chick chorioalloantoic membrane, indicating that the xcex1vxcex25 integrin plays a role in mediating growth factor-induced angiogenesis (Friedlander, M. C., et al., Science 270:1500-1502 (1995)). Compounds that act as xcex1vxcex25 antagonists could be used to inhibit pathological angiogenesis in tissues of the body, including ocular tissue undergoing neovascularization, inflamed tissue, solid tumors, metastases, or tissues undergoing restenosis.
Discovery of the involvement of xcex1vxcex23 and xcex1vxcex25 in such processes and pathological conditions has led to an interest in these integrins as potential therapeutic targets, as suggested in the preceding paragraphs. A number of specific antagonists of xcex1vxcex23 and xcex1vxcex25 that can block the activity of these integrins have been developed. One major group of such antagonists includes non-peptide mimetics and organic-type compounds. For example, a number of organic non-peptidic mimetics have been developed that appear to inhibit tumor cell adhesion to a number of xcex1vxcex23 ligands, including vitronectin, fibronectin, and fibrinogen (Greenspoon, N., et al., Biochemistry 32:1001-1008 (1993); Ku, T. W., et al., J. Amer. Chem. Soc. 115:8861-8862 (1993); Hershkoviz, R., et al., Clin. Exp. Immunol. 95:270-276 (1994); and Hardan, L., et al., Int. J. Cancer 55:1023-1028 (1993)).
Additional organic compounds developed specifically as xcex1vxcex23 or xcex1vxcex25 integrin antagonists or as compounds useful in the treatment of xcex1v-mediated conditions have been described in several recent publications.
For example, U.S. Pat. No. 5,731,324, issued Mar. 24, 1998, discloses bicyclic compounds of formula:
wherein the bicyclic nucleus is preferably selected from the group consisting of benzopyran, isoquinoline, isoquinolone, tetrahydronaphthalene, dihydronaphthalene and tetralone. The compounds are disclosed to be useful as glycoprotein IIb/IIIa antagonists for the prevention of thrombosis.
PCT Published Application WO 97/06791, published February 1997, discloses methods for inhibition of angiogenesis in tissue using vitronectin xcex1vxcex25 antagonists.
More recently, PCT Published Application WO 97/23451, published Jul. 3, 1997, discloses tyrosine derivatives of the general formula:
wherein
X is C1-6alkylene or 1,4-piperidyl;
Y is absent, O, CONH or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R1 is H, CN, N3, NH2, H2Nxe2x80x94C(xe2x95x90NH), or H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NH, where the primary amino groups can also be provided with conventional amino protective groups;
R2 and R3 are independently H, A, Axe2x80x94SO2xe2x80x94, Arxe2x80x94SO2xe2x80x94, camphor-10-SO2, COOA or a conventional amino protective group;
A and R4 are independently H, C1-10alkyl, or benzyl; and
Ar is phenyl or benzyl, each of which is unsubstituted or monosubstituted by CH3;
and their physiologically acceptable salts.
The disclosed compounds are described as xcex1v-integrin inhibitors (especially xcex1vxcex23 inhibitors) useful in the treatment of tumors, osteoporoses, and osteolytic disorders and for suppressing angiogenesis.
PCT Published Application WO 98/00395, published Jan. 8, 1998, discloses novel tyrosine and phenylalanine derivatives as xcex1v integrin and GPIIb/IIIa antagonists having the general formula:
wherein
X can be, among other groups, alkyl, aryl or cycloalkyl;
Y and Z can be alkyl, O, S, NH, C(xe2x95x90O), CONH, NHCO, C(xe2x95x90S), SO2NH, NHSO2, CAxe2x95x90CAxe2x80x2 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R1 can be H2Nxe2x80x94C(xe2x95x90NH) or H2Nxe2x80x94(Cxe2x95x90NH)xe2x80x94NH;
R2is A, aryl or aralkyl;
R3 is hydrogen or A;
R4 is hydrogen, halogen, OA, NHA, NAAxe2x80x2, xe2x80x94NH-Acyl, xe2x80x94O-Acyl, CN, NO2, SA, SOA, SO2A, SO2Ar or SO3H; and
A and Axe2x80x2 can be hydrogen, alkyl or cycloalkyl.
The publication discloses the use of the compounds in pharmaceutical preparations for the treatment of thrombosis, infarction, coronary heart disease, tumors, arteriosclerosis, infection and inflammation.
A need continues to exist for non-peptide compounds that are potent and selective integrin antagonists, and which possess greater bioavailability or fewer side-effects than currently available integrin antagonists.
The present invention is directed to novel tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidine compounds having Formula I (below). Also provided is a process for preparing compounds of Formula I. The novel compounds of the present invention exhibit inhibition of xcex1vxcex23 and xcex1vxcex25 integrin receptor binding. Also provided is a method of treating and/or preventing xcex1vxcex23 integrin- and xcex1vxcex25 integrin-mediated pathological conditions such as tumor growth, metastasis, osteoporosis, restenosis, inflammation, macular degeneration, diabetic retinopathy, rheumatoid arthritis and sickle cell anemia in a mammal in need of such treatment and/or prevention comprising administering to said mammal an effective amount of a compound of Formula I. Further provided is a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable carriers or diluents. The invention is also directed to a method of treating and/or preventing a central nervous system (CNS) related disorder such as neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, and surgery, neurodegenerative diseases including Alzheimer""s disease and Parkinson""s disease, adverse consequences of the overstimulation of one or more excitatory amino acids, anxiety, convulsions, chronic pain, psychosis, schizophrenia, anesthesia, and opiate tolerance, in a mammal in need of such treatment and/or prevention, comprising administering to said mammal an effective amount of a compound of Formula I.
The present invention is directed to compounds of Formula I:
and pharmaceutically acceptable salts thereof, wherein
R1 is hydrogen, alkyl, aralkyl, R11SO2, R11OOC, R11CO or R11CH2, where R11 is (i) hydrogen, or (ii) alkyl, cycloalkyl, camphor-10-yl, alkenyl, alkynyl, heterocycle, aryl, aralkyl, or aralkenyl, any of which can be optionally substituted by one or more alkyl, alkenyl, aryl, aryloxy (further optionally substituted by nitro, halo, or cyano), aralkyl, aryldiazenyl (further optionally substituted by amino, alkylamino, or dialkylamino), alkoxy, haloalkyl, haloalkoxy, alkylcarbonylamino, alkylsulfonyl, mono- or di-alkylamino, hydroxy, carboxy, cyano, nitro, halo, or a heteroaryl which is optionally substituted with one or more alkyl, haloalkyl, or halo;
and when R1 is R11CO, then R11 can also be N-attached pyrrolidinyl, piperidinyl or morpholinyl;
R2 is hydrogen or a functionality which acts as a prodrug ( i.e., converts to the active species by an endogenous biological process such as an esterase, lipase, or other hydrolases), such as alkyl, aryl, aralkyl, dialkylaminoalkyl, 1-morpholinoalkyl, 1-piperidinylalkyl, pyridinylalkyl, alkoxy(alkoxy)alkoxyalkyl, or (alkoxycarbonyl)oxyethyl;
R3 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino;
R4, R5, and R6 are independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylamninoalkyl or carboxyalkyl;
or R3 and R4 are taken together to form xe2x80x94(CH2)yxe2x80x94, where y is zero (a bond), 1 or 2, while R5 and R6 are defined as above; or R3 and R6 are taken together to form xcex1(CH2)qxe2x80x94, where q is zero (a bond), or 1 to 8, while R4 and R5 are defined as above; or R4 and R5 are taken together to form xe2x80x94(CH2)rxe2x80x94, where r is 2-8, while R3 and R6 are defined as above;
R7 is hydrogen, alkyl, aralkyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
R8, R9, and R10 are independently hydrogen, alkyl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or xe2x80x94COORw;
Rw is alkyl, cycloalkyl, phenyl, benzyl,
xe2x80x83where Ra and Rb are independently hydrogen, alkyl, alkenyl or phenyl; Rc is hydrogen, alkyl, alkenyl or phenyl; Rd is hydrogen, alkyl, alkenyl or phenyl; and Re is aralkyl or alkyl;
n is from zero to 8; and m is from zero to 4, provided that n is other than zero when R3 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or dialkylamino.
Preferred compounds of the present invention are those of Formula I wherein:
R1 represents hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, R11SO2, R11OOC, R11CO or R11CH2, where R11 is hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C4-7 cycloalkyl(C1-4)alkyl, camphor-10-yl, or C6-10 aryl substituted by one or more C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C6-10 ar(C1-6)alkyl, C6-10 aryloxy (further optionally substituted by nitro, halo, or cyano), C6-10 aryldiazenyl (further optionally substituted by amino, C1-4 alkylamino or di-(C1-4)alkylamino), C1-6 alkoxy, halo(C1-6)alkyl, halo(C1-6)alkoxy, C1-6 alkylcarbonylamino, C1-6 alkylsulfonyl, mono- or di-(C1-6)alkylamino, hydroxy, carboxy, cyano, nitro, halo, or a heteroaryl which is optionally substituted with one or more C1-6 alkyl, halo(C1-6)alkyl, or halo;
and when R1 is R11CO, then R11 can also be N-attached pyrrolidinyl, piperidinyl or morpholinyl.
Preferred values of R1 include hydrogen, t-butylcarbonyl, butylsulfonyl, propylsulfonyl, optionally substituted benzylsulfonyl, optionally substituted phenylsulfonyl, pentylsulfonyl, 4-tolylsulfonyl, naphthylsulfonyl and camphor-10-sulfonyl.
Especially preferred compounds are those of Formula I wherein:
R1 is R11SO2 wherein R11 is hydrogen, C1-6 alkyl, C4-7 cycloalkyl, camphor-10-yl, C2-6 alkenyl, C2-6 alkynyl, thienyl, thiazolyl, benzo[b]thiophenyl, pyrazolyl, chromanyl, imidazolyl, benzo[2,3-c]1,2,5-oxadiazole, C6-10 aryl, C6-10 ar(C1-6)alkyl, or C6-10 ar(C2-6)alkenyl, any of which can be optionally substituted by one or more C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C6-10 aryloxy (further optionally substituted by nitro, halo, or cyano), C6-10 ar(C1-6)alkyl, 4-dimethylaminophenyldiazenyl, C1-6 alkoxy, halo(C1-6)alkyl, halo(C1-6)alkoxy, C1-6 alkylcarbonylamino, C1-6 alkylsulfonyl, mono- or di-(C1-6)alkylamino, hydroxy, carboxy, cyano, nitro, halo, or pyrazolyl which is optionally substituted with one or more C1-6 alkyl, halo(C1-6)alkyl, or halo.
Suitable values of R11 include methyl, butyl, chloropropyl, phenyl, benzyl, methylphenyl, ethylphenyl, propylphenyl, butylphenyl, tert-butylphenyl, pentylphenyl, phenylphenyl, camphoryl, nitrophenyl, nitrophenylmethyl, cyanophenyl, chlorophenyl, fluorophenyl, bromophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, acetylaminophenyl, butoxyphenyl, biphenyl, vinylphenyl, methoxyphenyl, methylsulfonylphenyl, 4-(3-chloro-2-cyanophenoxy)phenyl, 4-(1,1-dimethylpropyl)phenyl, 6-chloro-2-methylphenyl, 2-methyl-5-nitrophenyl, 2,3,4-trichlorophenyl, 4-bromo-2,5-difluorophenyl, 5-bromo-2-methoxyphenyl, 2-chloro-5-(trifluoromethyl)phenyl, 4-(2-chloro-6-nitrophenoxy, 4-bromo-2-(trifluoromethoxy)phenyl, 3-chloro-2-cyanophenyl, 3-chloro-2-methylphenyl, 2-methyl-5-nitrophenyl, 4-methyl-3-nitrophenyl, 2,5-bis(2,2,2-trifluoroethoxy)phenyl, 2-chloro-4-(trifluoromethyl)phenyl, 4-chloro-2,5-dimethylphenyl, 5-chloro-2-methoxyphenyl, 4,6-dichloro-2-methylphenyl, 4-bromo-2-methylphenyl, 4-bromo-2-ethylphenyl, 2,4,6-trimethylphenyl, 2,3,4,5,6-pentamethylphenyl, 3,5-dichloro-2-hydroxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethylphenyl, 2-chloro-4-(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dibromophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-tris(methylethyl)phenyl, 4-bromo-2-ethylphenyl, 4-chloro-3-nitrophenyl, 2-methoxy-5-methylphenyl, 5-fluoro-2-methylphenyl, 4-methoxy-2,3,6-trimethylphenyl, 3-chloro-4-methylphenyl, 1-methylimidazol-4-yl,carboxyphenyl, naphthyl, 2,2,5,7,8-pentamethyl-chroma-6-yl, thienyl, 5-chloro-2-thienyl, 3-bromo-5-chloro-2-thienyl, 4-bromo-2,5-dichloro-3-thienyl, 4,5-dibromo-2-thienyl, 4-bromo-5-chloro-2-thienyl, 5-bromo-2-thienyl, 2,5-dichloro-3-thienyl, 2-(acetylamino)-4-methyl-1,3-thiazol-5-yl, 5-chloro- 1,3-dimethylpyrazol-4-yl, 5-[1-methyl-5-(trifluoromethyl)-pyrazol-3-yl]-2-thienyl, 5-chloro-3-methylbenzo[b]thiophen-2-yl, 5-chloro- 1,3-dimethylpyrazol-4-yl, 4-[4-(dimethylaminophenyl)diazenyl]phenyl, 4-[3-(amidinoarninooxy)-propoxy]-phenyl, benzo[2,3-c]1,2,5-oxadiazol-4-yl, and 2-phenylvinyl.
Preferred R2 groups include hydrogen, C1-6alkyl and benzyl.
Preferred values of R3 include hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, C2-7 carboxyalkyl, mono(C1-4 alkyl)amino(C1-8)alkyl, and di(C1-4 alkyl)amino(C1-8)alkyl. Suitable values of R3 include methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl and 2-(dimethylamino)ethyl.
Preferred compounds are those of Formula I in which R4, R5 and R6 are independently hydrogen, C1-6 alkyl, C6-10 ar(C1-6)alkyl, C6-10 aryl, C2-10 hydroxyalkyl or C2-7 carboxyalkyl. Useful values of R4, R5, and R6 include hydrogen, methyl, ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl and 4-carboxybutyl. In the most preferred embodiments, R4, R5 and R6 are each hydrogen.
Preferred values of R7 include hydrogen or C1-6 alkyl.
Preferred values of R8, R9 and R10 in Formula I include hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, cyano or xe2x80x94CO2Rw, where Rw, in each instance, is preferably one of C1-4 alkyl, C4-7 cycloalkyl, phenyl, or benzyl. Suitable values of R8, R9 and R10 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3 and xe2x80x94CO2CH2CH2CH3. In the most preferred embodiments, R8, R9 and R10 are each hydrogen.
Preferred values of n in Formula I include zero to 6, more preferably zero to 4, and most preferably zero, 1, or 2.
Preferred values of m include zero to 4, and most preferably zero, 1, or 2.
Useful compounds of the present invention include, without limitation:
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-[(2,5-dimethoxyphenyl)-sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-(2-naphthylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
(3S)-7-[3-(Amidinoaminooxy)propoxy)]-2-{[2-(methylsulfonyl)-phenyl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-(butylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-[(2,6-dichlorophenyl)-sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-[(2-methyl-5-nitrophenyl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
(3S)-7-[3-(Amidinoaminooxy)propoxy]-2-{[(7,7-dimethyl-2-oxobicyclo[2.2.1]heptyl)methyl]sulfonyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid;
or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. Preferred salts include the HCI and TFA (trifluoroacetic acid) salts.
It is also to be understood that the present invention is considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in selected compounds of the present series.
When any variable occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term xe2x80x9calkylxe2x80x9d as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, 1-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. Preferred alkyl groups have from 1 to 6 carbon atoms.
The term xe2x80x9calkenylxe2x80x9d is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length.
The termr xe2x80x9calkoxyxe2x80x9d is used herein to mean a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length.
The term xe2x80x9carylxe2x80x9d as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
The term xe2x80x9caryloxyxe2x80x9d as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, bonded to an oxygen atom. Examples include, but are not limited to, phenoxy, naphthoxy, and the like.
The term xe2x80x9cheteroarylxe2x80x9d as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14xcfx80 electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups).
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d as employed herein by itself or as part of another group refers to C1-6 alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The term xe2x80x9ccycloalkylxe2x80x9d as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
The term xe2x80x9cheterocyclexe2x80x9d as used herein, except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, chromanyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzo[b]thiophenyl, benzo[2,3-c]1,2,5-oxadiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
The term xe2x80x9cmonoalkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms.
The term xe2x80x9cdialkylaminexe2x80x9d as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms.
The term xe2x80x9chydroxyalkylxe2x80x9d as employed herein refers to any of the above alkyl groups substituted by one or more hydroxyl moieties.
The term xe2x80x9ccarboxyalkylxe2x80x9d as employed herein refers to any of the above alkyl groups substituted by one or more carboxylic acid moieties.
The term xe2x80x9chaloalkylxe2x80x9d as employed herein refers to any of the above alkyl groups substituted by one or more chlorine, bromine, fluorine or iodine with fluorine and chlorine being preferred, such as chloromethyl, lodomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 2-chloroethyl.
The term xe2x80x9chaloalkoxyxe2x80x9d as used herein refers to any of the above haloalkyl groups bonded to an oxygen atom, such as trifluromethoxy, trichloromethoxy, and the like.
Another aspect of the present invention is a process for preparing a tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidine compound of Formula I, comprising reacting a compound of Formula II:
or a salt, hydrate, solvate or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, m and n are as defined above, with a deprotection reagent and a guanidinylating reagent, to form a compound of Formula III:
or a salt, hydrate, solvate or prodrug thereof, where R1, R2, R3, R4, R5, R6, R8, R9, m and n are as defined as above. Preferred deprotection reagents include hydrazine or methylamine. Preferred guanidinylating reagents include aminoiminosulfonic acid, 1H-pyrazole-1-carboxamidine hydrochloride, N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea, or Nxe2x80x94R8, Nxe2x80x94R9-1H-pyrazole-1-carboxamidine, where R8 and R9 are defined as above.
The compounds of the present invention may be prepared by the general procedures outlined in Schemes I, II, and III (below), where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, Rw, n, and m are as defined above.
Scheme I outlines the synthetic steps to produce compounds of the present invention where R1 is R11COxe2x80x94 or R11OOCxe2x80x94 or R11CH2xe2x80x94. The carboxyl group of the (3S)-1,2,3,4-tetrahydro-7-hydroxy-isoquinoline-3-carboxylic acid 1 is protected as an ester by methods well known in the art (Bodanszky, M. and Bodanszky, A., The Practice of Peptide Synthesis, Springer-Verlag, Berlin (1984)). The resulting amine is reacted with acyl chlorides (R11COCl) in the presence of a suitable base such as a tertiary amine to produce carboxamides 2 (R1xe2x95x90R11CO). Alternatively, the carboxamides 2 may be produced by the reaction of (3S)-1,2,3,4-tetrahydro-7-hydroxy-isoquinoline-3-carboxylate with carboxylic acids (R11COOH) by any of the known peptide coupling reagents, such as 1,3-dicyclohexylcarbodiimide or Castro""s reagent (BOP) (Castro, B., et al., Tetrahedron Letter 1219 (1975)). Still alternatively, the (3S)-1,2,3,4-tetrahydro-7-hydroxy-isoquinoline-3-carboxylate can be converted to carboxamides 2 (R1xe2x95x90R11OOC) by reaction with chloroformates (R11OCOCl) in the presence of a base, such as a tertiary amine. Still alternatively, reductive amination of the secondary amine can be achieved by reaction with an aldehyde (R11CHO) under reducing conditions to give 2 (R1xe2x95x90R11CH2). The preferred reducing agent is tetramnethylammonium triacetoxyborohydride. Alternatively, sodium triacetoxyborohydride or sodium cyanoborohydride may be used. As an alternative to reduction methods, the (3S)-1,2,3,4-tetrahydro-7-hydroxy-isoquinoline-3-carboxylate may be reacted with R11CH2L, where L is a reactive leaving group, such as a halide or sulfonate, to produce the carboxamide 2 (R1xe2x95x90R11CH2).
The phenolic functionality of 2 is coupled to alcohol 3, where L is a reactive leaving group, such as a halide or sulfonate, under basic conditions, such as cesium carbonate in a solvent such as acetonitrile. Alternatively, the phenolic functionality of 2 may be coupled to 3 (Lxe2x95x90OH) using a Mitsunobu coupling procedure (Mitsunobu, O., Synthesis 1 (1981)). Preferred coupling conditions include using a trialkylphosphine or triarylphosphine, such as tri-n-butylphosphine or triphenylphosphine, in a suitable solvent, such as tetrahydrofuran, and an azodicarbonyl reagent, such as diethyl azodicarboxylate or 1,1xe2x80x2-(azodicarbonyl)dipiperidine.
Alcohol 4 is converted to 5 employing a Mitsunobu reaction with a N-hydroxycyclic imide derivative such as N-hydroxyphthalimide. Unveiling of the phthalimide protecting group of 5 is accomplished using standard conditions well known in the art (Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, Inc. New York (1999)), for example using hydrazine or methylamine. An alternative method is using sodium borohydride in a mixture of an appropriate alcohol (e.g., ethanol/water) followed by acidification.
Guanidinylation of the resulting alkoxyamine to 6 is achieved using standard reagents such as aminoiminosulfonic acid (Miller, A. E. and Bischoff, J. J., Synthesis 777 (1986)), or 1H-pyrazole-1-carboxamidine hydrochloride (Bernatowicz, M. S. et al., J. Org. Chem. 57 (8), 2497 (1992)), or with substituted guanidinylating reagents such as N,Nxe2x80x2-bis(tert-butoxycarbonyl)-S-methylisothiourea (Bergeron, R. J. and McManis, J. S., J. Org. Chem. 52:1700 (1987)) or Nxe2x80x94R8, Nxe2x80x94R9-1H-pyrazole-I-carboxamidine, where R8 and R9 are defined as above for Formula I. When R8 and R9 are protecting groups, for example f-butyloxycarbonyl (Boc), the compound can be optionally reacted with R10OH using standard Mitsunobu reaction condition as reviewed above to produce alkylated compounds 7. These protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water, or by HCl gas dissolved in a suitable solvent, such as 1,4-dioxane to produce targeted compounds 8.
Scheme II outlines the synthetic steps to produce compounds of the present invention where R1 of Formula I is R11SO2xe2x80x94. Thus, compound 9, where R1 is Nv-benzyloxycarbonyl (Cbz) is removed by catalytic hydrogenation using a catalyst such as palladiumon carbon and hydrogen to reveal the amino functionality, which is subsequently sulfonylated with sulfonyl chlorides (R11SO2Cl) or sulfoanhydrides (R11SO2)2O to produce sulfonamides 10. When R8 and R9 are protecting groups, for example t-butyloxycarbonyl (Boc), the compound can be optionally reacted with R10OH using standard Mitsunobu reaction condition as reviewed above to produce alkylated compounds 11. These protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromethane or water, or by HCI gas dissolved in a suitable solvent, such as 1,4-dioxane to produce targeted compounds 12.
Further functionalization of the amidinoaminooxy group in 8 and 12 (where R1 is R11SO2) is described in Scheme III. The aminooxy nitrogen of 8 and 12 may be optionally alkylated using basic conditions such as solid sodium bicarbonate in a suitable solvent such as N,N-dimethylformamide with R7X, where X is a reactive leaving group such as a halide or sulfonate to give 13. Additionally, 13 may be reacted with pyrocarbonates such as diethyl pyrocarbonate in a suitable solvent such as acetonitrile or N,N-dimethylformamide in the presence of a tertiary amine base such as N,N-diisopropylethylamine to give carbamates of either mono- or di-substitution on the amidino nitrogens as in 14 and 15 as well as tri-carbamates with additional substitution on the aminooxy nitrogen as in 16.
Compounds of the present invention can be tested for the ability to inhibit or antagonize xcex1vxcex23 or xcex1vxcex25 cell surface receptors by assays known to those of ordinary skill in the art. Such assays are described in Example 9 herein.
The present invention relates to a method of treating and/or preventing xcex1vxcex23 integrin- or xcex1vxcex25 integrin-mediated conditions by selectively inhibiting or antagonizing xcex1vxcex23 and xcex1vxcex25 cell surface receptors, which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted by Formula I, wherein one or more compounds of Formula I is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
More specifically, the present invention provides a method for inhibition of the xcex1vxcex23 cell surface receptor. Most preferably, the present invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget""s disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity and other neo-vascular eye diseases, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including neointimal hyperplasia and restenosis.
The present invention also provides a method for inhibition of the xcex1vxcex25 cell surface receptor. Most preferably, the present invention provides a method for inhibiting angiogenesis associated with pathological conditions such as inflammatory disorders such as immune and non-immune inflammation, chronic articular rheumatism and psoriasis, disorders associated with inappropriate or inopportune invasion of vessels such as restenosis, capillary proliferation in atherosclerotic plaques and osteoporosis, and cancer associated disorders, such as solid tumors, solid tumor metastases, angiofibromas, retrolental fibroplasia, hemangiomas, Kaposi sarcoma and similar cancers which require neovascularization to support tumor growth. The present invention also provides a method for treating eye diseases characterized by angiogenesis, such as diabetic retinopathy, age-related macular degeneration, presumed ocular histoplasmosis, retinopathy of prematurity, and neovascular glaucoma.
The compounds of the present invention are useful in treating cancer, including tumor growth, metastasis and angiogenesis. For example, compounds of the present invention can be employed to treat breast cancer and prostate cancer.
The compounds of the present invention are also useful in the treatment of sickle cell anemia. xcex1vxcex23 integrin has recently been implicated in the mechanism of adhesion of sickled red blood cells (RBCs) to vascular structures within the circulatory system of those suffering from sickle cell anemia. Adhesion of RBC""s is responsible for the reoccurring episodes of painful vasocclusive crisis and multiple organ damage. (Kaul el al., Blood 95(2):368-373 (2000)). Monoclonal antibodies which bind to xcex1vxcex23 have been shown to inhibit the adhesion of sickled RBCs in the ex vivo mesocecum vasculature of the rat. By blocking xcex1vxcex23 integrin which assists in adhesion of sickled cells to vascular components, a reduction in the harmful affects of sickle cell anemia is realized.
The compounds of the present invention are also useful in the treatment and/or prevention of central nervous system (CNS) related disorders. Treatment and/or prevention of such CNS related disorders includes, but is not limited to: neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, surgery, neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease, adverse consequences of the overstimulation of one or more of the excitatory amino acids, anxiety, convulsions, chronic pain, psychosis. schizophrenia, anesthesia, and opiate tolerance.
Studies have shown that there is a correlation between the activity of 4 integrin and the establishment of inflammatory lesions in the CNS. Brocke, S. et al., Proc. Natl. Acad Sci. USA 96:6896-6901 (1999). Specifically, antibodies directed against CD44 and 4 integrin could interfere in several ways with the establishment of inflammatory lesions in the CNS and thus prevent experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the CNS similar to multiple sclerosis.
Relton and co-workers have also shown that inhibition of 4 integrin activity protects the brain against ischemic brain injury, thereby implicating 4 integrin as a factor in acute brain injury. Relton et al., Stroke 32(1):199-205 (2001).
The compounds of the present invention may be administered in an effective amount within the dosage range of about 0.01 mg/kg to about 300 mg/kg, preferably between 1.0 mg/kg to 100 mg/kg body weight. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
The pharmaceutical compositions of the present invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or concurrently, administration can be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
In addition to the pharmacologically active compounds, the pharmaceutical preparations of the compounds can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The pharmaceutical preparations of the present invention are manufactured in a maimer that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings, that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids such as fatty oils or liquid paraffin. In addition, stabilizers may be added.
Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example water-soluble salts and alkaline solutions. Especially preferred alkaline salts are ammonium salts prepared, for example, with Tris, choline hydroxide, bis-Tris propane, N-methylglucamine, or arginine. In addition, suspensions of the active compounds as appropriate oily injection suspensions can be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
The compounds of the present invention may be administered to the eye in animals and humans as a drop, or within ointments, gels, liposomes, or biocompatible polymer discs, pellets or carried within contact lenses. The intraocular composition may also contain a physiologically compatible ophthalmic vehicle as those skilled in the art can select using conventional criteria. The vehicles may be selected from the known ophthalmic vehicles which include but are not limited to water, polyethers such as polyethylene glycol 400, polyvinyls such as polyvinyl alcohol, povidone, cellulose derivatives such as carboxymcthylcellulose, methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, vegetable fats such as peanut oil, polymers of acrylic acid such as carboxylpolymethylene gel, polysaccharides such as dextrans and glycosaminoglycans, salts such as sodium chloride, potassium chloride, and zinc chloride, and buffers such as sodium bicarbonate or sodium lactate. High molecular weight molecules can also be used. Physiologically compatible preservatives which do not inactivate the compounds of the present invention in the composition include alcohols such as chlorobutanol, benzalknonium chloride and EDTA, or any other appropriate preservative known to those skilled in the art.

Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists

Abstract: where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, m and n are defined herein.


An integrated circuit comprises a heat sink devoid of electronic components and interposed between a back side of a bottom electronic chip and an upper exterior side of an encapsulation, the sink comprising a front side placed on the back side of the bottom electronic chip. The back side of the bottom electronic chip comprises pads and the front side of the sink comprises pads mechanically fastened to facing pads of the back side of the bottom electronic chip.

The trend over the last few decades has been to increase the functionality of integrated circuits by reducing lithographic dimensions following Moore's law. For less than a decade, it has also been feasible to add functionalities to integrated circuits using the possibilities offered by integration in the vertical dimension, this being referred to as 3-D integration. This increase in integration density in the three available dimensions of integrated circuits has had the direct effect of increasing power density, leading to an increase in transistor junction temperatures and, in general, electronic chip operating temperatures.
Thus, known integrated circuits comprise:
a substrate that extends mainly in a plane referred to as the "plane of the substrate", this substrate being equipped with electrical connections for electrically connecting the integrated circuit to an exterior electronic circuit and having an interior side;
a top electronic chip and a bottom electronic chip, each of these electronic chips being electrically connected to the electrical connections by way of the substrate and each electronic chip comprising a front side turned toward the interior side of the substrate and a back side opposite the front side, the back side of the top electronic chip being located at a height H above the interior side of the substrate and being further from the interior side of the substrate than the back side of the bottom electronic chip; and
an encapsulation formed by a thick layer made of an electrically insulating material that coats the electronic chips, this thick layer forming an upper exterior side of the encapsulation parallel to the plane of the substrate.
Such integrated circuits are cooled via their upper exterior side. For example, for this purpose, a cooling system is fastened to this upper exterior side.
However, the bottom electronic chip is less well cooled than the top electronic chip because it is further from the upper exterior side. Under these conditions, to prevent the bottom electronic chip from becoming too hot, one solution consists in over-specifying the cooling system of the upper exterior side in order to take account of this distance to the bottom electronic chip. Another solution consists in doing nothing and in making allowance for the fact that the bottom electronic chip is less well cooled than the top electronic chip. Lastly, other solutions consist in inserting a heat sink, devoid of electronic components, between the back side of the bottom electronic chip and the upper exterior side of the encapsulation. This sink comprises a front side that is placed on the back side of the bottom electronic chip, and a back side opposite the front side, this back side being located on the same level as the back side of the top electronic chip. Examples of this last solution are described in patent applications US 2009/127700 A1 and JP 2013/008748 A. However, integration of a heat sink above the bottom electronic chip complexifies the fabrication of the integrated circuit.
Prior art is also known from: US 2013/043581 A1, EP 1 271 649 A2, US 2006/039118 A1 and US 2008/237840 A1.

Stacked chips attached to heat sink having bonding pads

Commissariat à l'energie atomique et aux énergies alternatives


A method and system for programming a remote control unit to control the operation of a controllable device. A group of code sets associated with a particular type and brand of controllable device are selected from a database of code sets stored in the memory of the remote control unit. The commands of each code set in the group of code sets are compared to identify similarities and dissimilarities between command formats within each respective code set. The user tests a command and provides feedback to the remote control unit regarding the results of such testing. When the testing of a command is successful, the remote control unit eliminates code sets containing a command format that is dissimilar to the format of the command that was successfully tested. By eliminating code sets from the group of code sets and testing other commands, the remote control unit eliminates all but one code set. The one remaining code set is identified as the best code set and is added to the remote control unit to allow the remote control unit to transmit signals to control operation of the controllable device.

Many electronic devices frequently found in the home, such as televisions, video cassette recorders, and stereos, support remote control operational capabilities. Remote control units are typically hand-held units that allow the user to more easily and conveniently control the operation of a controllable device from a remote location by manipulating controls on the remote control unit rather than requiring the user to manipulate buttons or other controls on the controllable device itself. Remote control units typically include buttons, switches, or other control mechanisms that allow the user to perform most, or all, of the operations associated with the controllable device.
Remote control capability typically involves a remote control unit and a receiver associated with the device to be controlled. The remote control unit includes a transmitter for sending command signals to the receiver. Command signals are usually transmitted via an infrared signal, responsive to the user activating a button on the remote control unit. The infrared signal is detected by an infrared receiver located on or near the front surface of the device to be controlled.
Many different types of devices support remote control capabilities. Each different device typically has a separate, dedicated remote control unit associated with it. When a user wishes to control multiple devices, the user must use the correct one of the multiple remote control units to operate the device. For a typical entertainment center in the home, three, four, or even more remote control units may be required to operate all devices. This use of multiple remote control units can be cumbersome and confusing.
Universal remote control units have been devised to control multiple devices with a single remote control unit. A universal remote control unit can be programmed to communicate with a number of different devices and thus replace a multiplicity of dedicated remote control units. Universal remote control units can typically control multiple models or brands of a single type of device and also can control multiple types of devices. For example, not only can a universal remote control unit control different models and brands of televisions, but such units can also control different types of devices, such as video cassette recorders, stereos, and the like.
Universal remote control units include programming that allows the user to perform a set-up process to program the universal remote control unit to operate a specific device. Typically, a universal remote control unit includes a code set for each device that it controls. A code set is a group of commands that operate a controllable device and are typically different for each type and brand of device. For example, the code set that controls a SONY brand television is most likely different than the code set that controls a MAGNAVOX brand stereo. The universal remote control unit, therefore, must be programmed by the user to operate each type, brand, and model of a device.
Programming a universal remote control unit during a set-up process can be a tedious task. Typically, the user is required to look in an instruction manual to identify the proper code set for each device to be controlled from a large number of possible code sets. Perusing a user's manual to identify the correct code set for many different types and brands of devices is time-consuming and interjects a high probability of error into the set-up process.
Also, each universal remote control unit is typically programmed by the user via a special sequence of programming steps. Most universal remote control units, however, do not provide the user with feedback during the programming process. A single mistake by the user during the programming process may cause the process to fail and thus may require that the entire process be repeated. Programming the universal remote control unit can therefore be a frustrating and time-consuming endeavor.
Therefore, a need exists for an automated set-up process for a remote control unit, thereby minimizing or eliminating the need for the user to use an instruction manual to manually identify the correct code set for a controllable device.

Method and system for programming a remote control unit


A component support assembly releasably retains, electrically insulates and improves thermal transfer of a plurality of vertically stacked electrical components associated with the operation of a printed circuit card. Each of a plurality of integrally-molded component support structures made of a electrically insulating material has a base member, a receiving member for releasably retaining electrical components thereto and pins for anchoring the base member to a printed circuit card. The base member has apertures so that the electrical leads of the electrical components can pass through the base member and connect to the conductors of the printed circuit card. The base member is shaped so that major planar surfaces of the electrical components are retained at an acute angle relative to vertical, thereby improving thermal transfer from the electrical components to the ambient air when a plurality of like component support structures are mounted on the printed circuit card.

The present invention relates to the field of computerized control systems hardware and in particular to a component support structure and a method for retaining, for electrically insulating and for dissipating heat from electrical components of a printed circuit card operating in computerized control systems.
Various methods of preventing components from becoming dislodged from a printed circuit card are known in the art. A known method of retaining the components to the printed circuit card utilizes a bracket and suitable screw. This method also incorporates a metal bar with standoff portions machined into the printed circuit card to effect electrical insulation of the component. Circuit cards often carry exposed live conductors suitable for connecting to the components. A known method of insulating the live conductors of the printed circuit card from manual contact is to cover the printed circuit card with a film of nonconducting material such as resin, polymer or rubber. The potential of electrical shock during careless repair and replacement as well as the threat of electrical arcing decreases. Some of these prior art devices thus provide electrical insulation and retainment for an electrical element. However, these prior art devices and methods do not adequately address thermal transfer from the components. Though it is known in the art that effective thermal transfer improves reliability and permits greater component density associated with the circuit card.
Electrical components that carry, relay or convert large amounts of electrical current generate heat and are an obstacle to the design of densely-packed printed circuit cards. Thus, the elimination of heat islands that adversely impact reliability has long been a goal in the design of efficient control systems. Cooling fans or other dedicated mechanisms have been traditionally used in the art to dissipate heat generated from the various elements used in computing architecture. These mechanisms add weight, cost and complexity to cool the components.
These prior art approaches to attachment and electrical insulation of components do not adequately address thermal transfer necessary to dissipate heat from the components associated with the printed circuit card. Thus, a need exists for a component support structure that improves thermal transfer from densely-packed electrical components associated with printed circuit cards of modern computer architecture.


A present invention is related to a method for transmitting a data packet in a wireless network. An exemplary method comprises requesting to allocate a bi-directional channel time block including a first channel time block for transmitting a specific data packet and a second channel time block for receiving a response to the specific data packet; transmitting the specific data packet through the first channel time block; and receiving the response to the specific data packet through the second channel time block, wherein the bi-directional channel time block is predetermined to be allocated in an unreserved region in a superframe.

Recently, with communication, computer and networking technology having been developed, a various kinds of network are developed and thereby, they are materialized in real life.
For example, there are a large-scaled network which connects all over the world like a wire/wireless Internet, and a small-scaled network which allows audio or video data to be exchanged between devices by configuring a wire/wireless network between a relatively small number of digital devices in limited places such as homes or small-scaled companies. By developing network, interfacing technology which allows network-to-network communication or device-to-device communication becomes also various.
A device transmits a Bandwidth Request command to a coordinator to be allocated channel resource to transmit data in a network. Then, the coordinator checks whether allocable channel resource for the device remains or not and allocates requested channel resource to the device if could. At this time, allocation information for the allocated channel resource form example, timing allocation information is transmitted to devices in the network through a beacon.
Generally a reserved region by the channel allocation method in a channel is used for transmitting a command, a data stream, or an asynchronous data. And an un-reserved region in the channel is user for transmitting control information for between a coordinator and a device or between devices, MAC command, or asynchronous data.
For general data stream or command transmitting, aforesaid channel allocation method can be useful. But, if there is a specific limit condition, which could be a specific time limit to transmit a message from a device to another device and to receive a response for message, other channel allocation method may be needed.

Method for transmitting a data packet and a method of allocating a channel in a wireless network


A novel shaped charge device that produces a hollow cylindrical jet capable of creating a hole in a target larger than the overall diameter of the device. In the conical family of axisymmetric circular linear shaped charge liners (Conical, Tulip, and Trumpet), this novel swept conical-like profile shaped explosive device produces a large diameter stretching hollow cylindrical jet and corresponding slug. The hollow jet is formed by peripherally initiating a high explosive (HE) that collapses the circular linear liner into the hollow cylindrical jet. The precision of the circular simultaneous peripheral initiation of the HE billet is accomplished by the use of a novel Circular Precision Initiation Coupler (CPIC). This CPIC uses a single point initiation to create a simultaneous peripheral detonation of the HE billet that collapses and drives the swept liner into a high speed stretching hollow cylindrical projectile, or more commonly called a jet in the industry.

Shaped charges come in many sizes and shapes and are used mainly for military weaponry and oil well perforating; to a lesser extent demolition and rescue are also users of this complex technology.
The concept of shaping an explosive charge, in order to focus its energy was known in 1792. ("The History of Shaped Charges" Donald R Kennedy)
In 1884 Max von Foerster conducted experiments in Germany showing that a hollow cavity explosive charge will focus the explosive energy and produce a collimated jet of high speed gasses along the longitudinal axis of the cavity, this jet also could penetrate steel.
In 1888, while conducting research for the U.S Navy, at Newport R.I., Charles Munroe discovered that not only could explosive energy be focused, but lining the hollow cavity in the explosive with metal increased the penetration dramatically, the effect is commonly called the Munroe effect.
These discoveries were further studied in 1910 by Egon Neumann of Germany who conducted similar experiment's, which showed that a cylinder of explosive with a metal lined conical hollow cavity could penetrate through steel plates. The military implications of this phenomenon were not realized until the lead up to world war two.
In the 1930's flash x-ray technology was developed which allowed the in depth study of the Shaped Charge jetting process. With this new and other diagnostics, it was possible to take XRay pictures of the collapse of the liner and the resulting jet. This led to a more scientific and complete understanding of the Munroe principle and emphasized the power of shaped charges.
Modern shaped charges as used in anti-tank weapons produce a long stretching rod like metal jet that penetrates about 5 to 8 charge diameters in steel, deeper in masonry or rock. The average diameter of a 5 CD through hole in steel from these charges is less than 15% of the explosive charge diameter (CD) of the device. The holes made by these jets do not provide sufficient diameter to allow follow on or follow through devices to pass into the perforation and add to the hole depth.
There have been some specialized efforts by Haliburton to produce other than conical type shaped charges for special purposes such as pipe cutting and anchor chain cutting. These types of charges are called linear shaped charges and use the two dimensional collapse to produce a thin sheet like jet with somewhat similar cutting power to the usual conical shaped charge. These linear shaped charges are flexible and can be formed by hand into desired shapes. The British Wall AXE circa 1960 is an example of a formable linear shape charge with a wide angle liner; the device is used against light structures such as wooden doors and thin walls and does not give very deep penetration.
Patent Application US2011/0232519 A1 by Erick J. Sagebiel discloses a diverging jet. The Sagebiel design is limited to a diverging jet trajectory of 1 to 45 degrees relative to the device axis of symmetry and produces a circular cookie cutter cut in a finite target leaving a center plug of material in the target.
The Sagebiel device contains a core plug that Sagebiel teaches could be used as a projectile to impact the annular ring cut pattern of a finite target.
The Sagebiel device is basically a symmetrical linear shaped charge device that has been formed into a circle around a symmetrical axis with planar, frusto-conical liner walls, which explains why it produces a round cookie cutter cut leaving behind a center core of the target material. Since Sagebiel's device is designed symmetrically like linear shaped charge it does not offer a solution for matching the momentums of the radially converging and diverging liner walls by balancing the liner wall masses and the amount of HE driving each wall. It does not teach the directional varying of the inner and outer wall thicknesses to compensate for the volume and mass differences, of the outside and inside liner walls, due to the vastly differing diameters in relation to the axis of symmetry.
Throughout the history of shaped charges the primary effort of research in this field was directed toward depth of penetration by the jet. Although hole size is worth considering, little research has been done on significantly increasing jet diameter and cross-sectional shape of the jet to produce a larger hole diameter. In oil field applications a larger hole is most desirable as the flow area of the hole increases rapidly with an increase in hole diameter. With the ability to produce a full caliber hole, a follow on or follow through device can be deployed into the hole to the correct standoff from the bottom of the hole. When detonated at the correct standoff this will increase the hole depth by that of the primary hole producing device, this can be repeated numerous times in the same hole.

Swept conical-like profile axisymmetric circular linear shaped charge


The preferred embodiment comprising a truncated cone valve plug, or a truncated cone with curved sides as in the tractrix valve is described. A step is fabricated into the large end of the valve plug. A secondary seal, called a Veri-Seal, is placed on the large end of the valve plug on the step at an intermediate location between the outer diameter of the plug and the stem. Pressure forces acting downward on the step on the top of the valve plug balance the pressure forces acting upward in the channel through the valve plug. By placing the Veri-Seal at this intermediate location on the top of the plug, the spring force can be minimized and the resulting torque to open and close the valve is consequently reduced.

1. Field of the Invention
This invention relates to valves, specifically those valves known as plug valves. Plug valves have a rotating element called the plug, in the shape of a truncated cone with a hole through it. By rotating the plug a quarter turn, the valve can be opened or closed by aligning or mis-aligning the hole through the plug with the pipeline.
2. Background Information
The purpose of the plug valve is to contain fluid within the pipeline, exercise control over the starting and stopping of the fluid in the pipeline, hold the internal pressure within the plug valve, and prevent leaks to the surrounding environment. Prior art uses heavy spring forces to hold the plug against the body of the valve to ensure that the plug valve is leak tight. Plug valves are very hard to open and close because of the large spring forces employed to overcome unbalanced internal forces within the plug valve. Because the plug is tapered, there is slightly more area on top of the channel through the plug than on the bottom of the channel. See FIG. 1. As a result, the internal pressure produces an unbalanced force caused by the pressure acting on the larger area and this unbalanced force acts toward the larger end of the plug. It tends to try to push the plug away from the body of the valve, which, if allowed to happen, would allow leaking of the valve through the seat. To overcome this force unbalance, a somewhat higher spring force is needed. Since opening torque depends on the spring force, a larger spring force results in a higher torque required to open and close the valve. This level of torque makes it difficult to open and close the valve, especially by women or disabled workers. When an actuator is used to open and close the valve, usually a large, expensive actuator is needed. Clearly, a means is needed to lower the required torque on a plug valve while maintaining the valve leak tight.
A step is fabricated on the large end of the plug. See FIG. 2. A special secondary seal is located at approximately half the radius of the large end of the plug on the step. This is called a Veri-Seal. Internal pressures act on the area of the step create a force that is nearly equal in magnitude to the unbalanced pressure force acting within the channel and acting in the opposite direction. By careful placement and sizing of a step and location of the Veri-Seal on the large end of the plug, all internal pressures are balanced. This eliminates the need to have extremely high spring forces to overcome the unbalanced internal pressures and subsequent high opening and closing torque.


A storage capacitor structural configuration for memory cell units of DRAM devices and a process for constructing the capacitor. The capacitor includes a first electrode and a second electrode that are each electrically conducting layers, and a storage dielectric that is a dielectric layer sandwiched between the two electrodes. The silicon substrate of the device has formed thereon a field oxide layer and a transistor including a gate and a pair of source/drain regions. A first dielectric layer covers the transistor and includes a contact opening over one of the source/drain regions. The first electrode includes a first electrically conducting layer formed inside the contact opening and covering the revealed surface of the source/drain region and the first dielectric layer. A second electrically conducting layer having a rugged surface is formed on the surface of the first electrically conducting layer. A number of deep grooves are formed in the second and first electrically conducting layers, forming a grid-like configuration. The storage dielectric includes a second dielectric layer covering the surface of the grid-like configuration of the second and first electrically conducting layers. The second electrode includes a third electrically conducting layer that covers the surface of the storage dielectric.

1. Field of the Invention
The invention relates in general to a storage capacitor structure for a memory cell in a semiconductor dynamic random access memory (DRAM) integrated circuit (IC) device and a process for fabricating the capacitor. In particular, the invention relates to a storage capacitor structure providing increased capacitance for a memory cell of DRAM IC devices, and its fabrication process.
2. Technical Background
As microprocessors become more and more powerful, the software programs they execute also become more and more complicated and require ever larger processing memory space. Since DRAMs currently provide the primary operating memory space for microprocessors, their operating characteristics are critical to the overall performance of the entire computer system. FIG. 1 is a schematic circuit diagram of a conventional memory cell unit that is organized in arrays to form the storage memory space for DRAM devices. FIG. 1 shows that the typical DRAM memory cell unit includes an n-type metal-oxide semiconductor field-effect transistor (NMOS transistor) 100 and a capacitor 102.
As shown in the drawing, the gate of the NMOS transistor 100 is connected to the word line WL of the device memory cell array, the source is connected to the bit line BL of the cell array, and the drain is connected to one electrode of the data storage capacitor 102, with the other electrode of the capacitor 102 being connected to the system ground plane. As persons skilled in the art are aware, a capacitor 102 utilized by the memory cell unit of FIG. 1 holds electric charges signifying the status of a stored data bit, while an NMOS transistor 100 is utilized as a bidirectional switch. Because the MOS transistor 100 has its source/drain pair functioning as either the current source or the drain, depending on whether the transistor is reading or writing digital data from or to the storage capacitor, respectively, the source and drain are generally designated as the source/drain pair herein.
A semiconductor structural configuration for a storage capacitor used in the memory cell units of a conventional DRAM device is schematically shown in the cross-sectional view of FIG. 2. The typical physical capacitor structure, which has a stacked configuration, is briefly examined with reference to this drawing. To fabricate such a capacitor element for the memory cell units of DRAM devices, a field oxide layer 202, a gate oxide layer 204, a first polysilicon layer 206, a sidewall spacer 208, and source/drain regions 210 of the NMOS transistor are sequentially formed over the surface of a silicon substrate 200. After the formation of the transistor, an oxide layer 212, such as silicon dioxide (SiO.sub.2), is then deposited over the substrate surface. Then, a contact opening 214 is formed at a designated location above the source/drain region 210 by etching the oxide layer 212. The contact opening 214 is then filled with a second polysilicon layer 216 to provide an external contact for the source/drain region 210 of the transistor element. Next, a dielectric layer 218 is deposited on top of the second polysilicon layer 216. The dielectric layer 218 can be, for example, a nitride/oxide (NO) layer or an oxide/nitride/oxide (ONO) layer. Finally, a third polysilicon layer 220 is formed atop the dielectric layer 218. Thus, at this stage, the second polysilicon layer 216, the dielectric layer 218, and the third polysilicon layer 220 form the storage capacitor 102 shown in the schematic circuit diagram of FIG. 1.
As is well known, capacitance and leakage characteristics of this storage capacitor are important to the performance of a DRAM device composed of memory cell arrays utilizing these capacitors. Specifically, a larger capacitor electrode surface area sustains data content longer, therefore requiring a lower memory cell content refresh rate. This results directly in improved memory subsystem performance in a host digital system. However, physically larger capacitors go against the trend of device miniaturization in manufacturing high-density DRAM devices.
Conventional storage capacitors for DRAM memory cell units such as the one depicted in FIG. 2 suffer from unsatisfactory capacitance characteristics. Specifically, conventional DRAM devices are equipped with storage capacitors for their memory cell units that have insufficient capacitance values. These capacitors require improvement to meet the standards set for modern microprocessor-based computer systems, in order to provide improved overall system performance.


Among various methods, systems, and apparatuses, a number of methods are provided for forming a 3D conformance model of a particular portion of a subject's anatomy using 3D digitized imaging data and a rapid prototyping technique. One such a method includes distinguishing at least one particular structural feature associated with the exterior of the particular portion from at least one particular structural feature associated with the interior of the particular portion. Such a method can include using the conformance model to test suitability of an appliance to participate in performing an intended function that includes penetrating the interior of the particular portion through the exterior of the particular portion.

Rapid prototyping is the automated construction of physical objects using solid freeform fabrication. Techniques for rapid prototyping became available in the late 1980s and have been used, for instance, to produce models and prototype parts. Rapid prototyping later became useful for a broader range of applications including, in some instances, making production quality parts in relatively small numbers. As an illustration, some sculptors have used rapid prototyping technologies for producing objects having complex shapes for fine art exhibitions.
In some instances, rapid prototyping may take three-dimensional (3D) modeling from computer-aided design (CAD) software and transform such modeling into thin, horizontal, virtual cross-sections. Such virtual cross-sections may then be formed sequentially in physical space until a complete physical representation of an intended object has been created using one or more of a number of rapid prototyping techniques.
Implementation of various rapid prototyping techniques may enable additive fabrication where an appropriate apparatus reads CAD data input and lays down successive layers of liquid, powder, and/or sheet material to build up the intended object in a series of physical cross-sections. These physical cross-sections, which correspond to the virtual cross-sections of the CAD modeling, may be joined together, fused, and/or cured to create the intended physical object.
Stereolithography is an example of rapid prototyping technology that may be used to produce physical objects having accuracy and a good surface finish. An apparatus capable of performing stereolithography may be referred to as a Stereolithography Apparatus (SLA).


A batch rice production system suitable for retort sterilization operations is provided. The system includes blanching a dry rice product to a desired hydration pick-up to yield a partially hydrated rice product; and topically coating the partially hydrated rice product by mixing with an oil-in-water lubricating slurry including oil, an amount of water, desired seasonings, and optional additives, wherein the amount of water includes an amount necessary to substantially achieve a desired target hydration pick-up prior to charging a retort pouch with the hydrated rice product. The system permits manipulation of two points of hydration pick-up to achieve a target hydration pick-up enabling use of gentler fill feed mechanisms and increasing versatility in the selection of rice types and flavoring additives. A superior microwaveable, shelf-stable, commercially sterile, highly palatable rice product that resembles consumer-preferred stove-top prepared rice products is also provided.

Today's fast-paced cultural climate, combined with the specific needs of certain populations such as, for example, field-deployed military combatants and outdoor recreational enthusiasts, has led to a surge in consumer demand for high-quality non-refrigerated shelf-stable food products that require a minimum of consumer time and effort to prepare. The essential characteristic of shelf-stable food product is that it is not susceptible to the spoilage effects of microorganisms. In order for shelf-stable food products to meet the minimum preparation needs, they should ideally be available to the consumer as pre-cooked and either instantly consumable, or consumable upon heating as through microwaving.
Due to having a moisture content too low to support microbial growth, raw and par-boiled rice are naturally very shelf-stable. Cooking of raw rice is subject to narrow acceptability parameters, and parboiled rice was developed to overcome this disadvantage. Parboiled rice is typically produced by soaking paddy rice and then heating it until gelatinization of the starch in the kernel. This causes many of the nutrients in the husk and bran of the paddy rice to diffuse into the kernel. Dry heat methods of preparation are also known. Convenient preparation of both raw and parboiled rice, however, suffer from the drawback of long cooking times, and parboiled rice, especially brown parboiled rice, takes even longer to cook making it unsuitable for short preparation demands.
The development of pre-cooked dry rice product provide consumers with a more convenient preparation time, but resulted in a reconstituted rice product having an often unacceptable texture and mouth feel.
Canned rice suffered from the disadvantages of discoloration, expensive production, and corrosion of the can by the rice product necessitating relatively high quality cans. Further, canned goods are often negatively perceived by consumers as inferior products. In addition, the canned rice product typically has to be removed from the can and placed into another container before it can be microwaved, diminishing convenience to the consumer.
The development of microwavable retort-pouches comprised of polymeric materials enabled the food industry to economically provide consumers with a commercially sterile rice product that is fully microwavable in its own packaging. Though very convenient with respect to consumer preparation, the rice product itself suffered from texture, mouthfeel and reduced shelf-stability deficiencies. It was discovered that shelf-stability could be enhanced by the addition of acid during processing, but this resulted in the need for additives to mask the acidic taste, and typically the expense of batch processing increased due to the packaging complications and additional steps related to the use of acidic and alkaline compounds.
The current industry-standard batch retort-pouch rice product processing methods result in a pouch-packaged rice product that is not fully hydrated and which only achieves full moisturization upon exposure to steam during consumer preparation, as, for example, during microwaving. Typically, the industry-standard batch processing begins by blanching the rice to partial hydration, for example, to an approximately 1 to 1.1 pick-up of moisture. An oil and flavoring mixture is prepared in a volume of water that is sufficient to fully hydrate the rice and the partially hydrated rice is added to this. However, the watery consistency and very low viscosity of this mixture necessitates the addition of starch and starch emulsifiers, such as lecithin, in order to keep the viscosity at a production-acceptable level and create a rice product that is suitably pumpable according to the standard "liquid fill" method of charging the retort pouches. The starch emulsifiers cause pitting on the surface of the rice grain, resulting in the undesirable batch processing phenomena of "fuzzy rice."
Under the currently known methods, theoretically, during the thermally sterilizing retort cycle the added heat would allow the rice to cook to complete hydration. However, in reality, as the charged pouches sit through the retort cycle the added starch complexes with some of the flavoring and settles to the bottom of the pouch resulting in an unappealing stratified product.
Across the shelf life of the product, the moisture in the pouch continues to equilibrate with the solid contents of the pouch which results in a hard, brick-like rice product after, typically, only several months. Upon heating by the consumer, a small amount of water steams and puffs the rice product, producing a barely acceptable consistency wherein the rice grains do not have individual identity and are substantially agglomerated. This conventional retort pouch rice product is clearly inferior in consistency, mouth feel and other sensory attributes when compared to consumer expectations of stove-top prepared rice.
Moreover, since the conventional batch processing methods involve the mechanical manipulation and transport of partially hydrated rice, production itself has diminished tolerances. For example, when even minor disruptions occur which stall the processing for longer than several minutes, the partially hydrated rice product is left sitting in manufacturing receptacles, piping and so on, quickly forming a hard, immovable mass that requires expensive and time-consuming production shut-downs to remove.
In addition, acceptable production tolerances permit some percentage, typically about 10% of rice product, to be "left behind" in an "emptied" vessel during certain production steps. Since the rice is only partially hydrated in conventional methods, this additional processing time for approximately 10% of the rice results in rice being charged into the retort pouches and entering the retort cycle in varying states of hydration, which results in a noticeable moisture content inconsistency in the rice when prepared by the consumer.
A further drawback to conventional retort processes which utilize the "liquid fill" method of charging the retort pouch, is the limitation this method places on the inclusion of potentially desirable "chunky" ingredients, for example, meat and other proteinaceous food stuffs.
The present invention seeks to provide a rice product that may be conveniently prepared by consumers, as, for instance, by microwaving, and that comes closer to the mouth feel, appearance and moisture content of what consumers expect from stove-top prepared rice than what is currently available. Specifically, the present invention seeks to provide a retort pouch rice product having substantially individual grain identity with improved consistency and appearance over an extended shelf life when compared to currently available retort pouch rice products. Further, the present invention seeks to provide retort pouch rice products which may optionally include a variety of other desirable chunky ingredients. In addition, the present invention seeks to provide improved batch rice production methods which overcome the aforementioned and other deficiencies in the currently employed state-of-the-art batch rice processing methods.

Batch rice production system and improved microwavable, commercially sterile, shelf-stable rice product


A signal processing device is provided that includes a modulation unit that produces an amplitude element as well as a phase element from components that are applied thereto. A correction device is also provided, in which at least one of the components is supplied and is compared with an ideal nominal value. This is used to produce a correction factor, which is multiplied by the component which has been compared with the nominal value. The correction factor determined is used to correct any offset or distortion of the components produced by analog circuits.

Modern communication appliances frequently contain a baseband unit and a radio-frequency unit, connected to it, in their transmitters. The baseband unit is used to preprocess the data to be transmitted. This includes, inter alia, modulation of the phase and amplitude of the data on a so-called baseband signal. The type of modulation used for modulation is in this case dependent on the chosen mobile communication standard. Examples of communication standards such as these are WCDMA/UMTS, GSM, EDGE, Bluetooth, 802.11 and HyperLan.
The baseband signal produced in this way in this case contains a real component I as well as a quadrature component Q, and is accordingly also referred to as an I/Q signal. The sum of the two components contains the modulated signal. In a final step, the digital baseband signal from the baseband unit is converted by means of a digital/analog converter to an analog baseband signal, and is emitted at the output of the baseband unit. In the following text, the expressions analog signal or analog component are intended to mean a signal or component which has a continuous value or is continuous over time. A digital signal or a digital component corresponds to a signal or component which has a discrete value or is present for a discrete time.
A radio-frequency unit which is connected to the output of the baseband unit adds the two components I and Q of the baseband signal and modulates them onto a carrier signal at the desired output frequency. The signal is suitably amplified in the radio-frequency unit, and is then emitted via an antenna.
In practice, the baseband unit and the radio-frequency unit are in the form of integrated circuits in two different semiconductor bodies, and are coupled to one another in a further step. This has the advantage that the baseband unit and radio-frequency unit can be developed separately from one another in order to take account of different conditions during manufacture, different requirements and different operating parameters. In addition, it is possible to use different manufacturing techniques and circuit techniques optimized to radio-frequency and baseband signal processing.
Analog circuits, in particular at the interfaces between the baseband unit and the radio-frequency unit, can lead to distortion and interference in the baseband signal that is produced. Interference and distortion such as this is referred to as an IQ signal error ("ISE" for "IQ signal error"). These have a direct influence on the output accuracy of the overall system. It is thus necessary to take account of any possible signal error even during the development of the circuits. This is done, for example, by derating individual components in order to compensate for the signal fluctuations caused by the interference. However, any enlargement increases the power consumption of a circuit, and the space that it occupies. If, furthermore, the baseband unit and the radio-frequency unit have different design requirements, the IQ signal inaccuracies caused in the interface could be sufficiently great that it is no longer possible to satisfy the desired performance parameters of the overall system.

Signal processing device, use of the signal processing device and method for signal processing


The present invention relates to an oral liquid suspension that includes lamotrigine and methods of medical treatment that include administering the oral liquid suspension. The oral liquid suspension has desirable physicochemical properties and technical attributes. The oral liquid suspension is useful in patients having difficulties in swallowing tablets and provide medical practitioners with additional options for dose titration.

Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. For epilepsy it is used to treat partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Lamotrigine also acts as a mood stabilizer. It is the first medication since lithium to be granted approval by the U.S. Food and Drug Administration (FDA) for the maintenance treatment of bipolar type I. Chemically unrelated to other anti convulsants (due to lamotrigine being a phenyltriazine), lamotrigine has relatively few side-effects and does not require blood monitoring in monotherapy. The exact way lamotrigine works is currently unknown. Some think that it is a Na+ (sodium) channel blocker, though it is interesting to note that lamotrigine shares very few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, (e.g. oxcarbazepine), which may suggest that lamotrigine has a different mechanism of action.
Lamictal® (lamotrigine) is available as scored tablets (25 mg, 100 mg, 150 mg and 200 mg) and chewable dispersible tablets (2 mg, 5 mg and 25 mg). Five-week sample kits are also available; these include titration instructions and scored tablets (25 mg for patients taking valproate, 25 mg and 100 mg for patients not taking valproate). Lamotrigine is also available in un-scored tablet form. In 2005, Teva Pharmaceutical Industries Ltd. began selling generic lamotrigine in the United States, but only in 5 mg and 25 mg chewable dispersible tablets. On 23 Jul. 2008 Teva began offering the full line of generic lamotrigine in the US. Lamotrigine is also available in generic form in the United States, the United Kingdom and Canada.
Lamotrigine is BCS class II molecule with low solubility and high permeability. Oral administration is associated with a delayed onset of the desired pharmacological action as lamotrigine is a poorly soluble in water which causes low rate of dissolution of the drug in aqueous media including biological fluids like gastrointestinal fluid. It is also difficult to formulate lamotrigine into a suspension dosage form due to various challenges like bitter taste of the drug and maintaining the chemical stability of the drug in the suspension dosage form. Further, the formulated suspension should exhibit desirable technical attributes like pourability, viscosity, dissolution, stability, re-suspendability and re-dispersibility complying with demanding requirements and regulations of health and medicine regulatory agencies across the world, especially USFDA, EMEA, Health Canada, MHRA and TGA.
Currently, there are no liquid formulations of lamotrigine commercially available and, as a result, hospital pharmacists are often required to compound liquid formulations using crushed lamotrigine tablets for pediatric patients and patients who cannot swallow tablets. A need therefore exists for an improved formulation of lamotrigine.
Several oral dosage forms containing lamotrigine are believed to exist and offered for sale outside the U.S. It is believed that no oral liquid suspension containing lamotrigine has yet received approval from the U.S. Food and Drug Administration (FDA). As such, it is currently unknown whether an oral liquid suspension containing lamotrigine has been successfully developed, while achieving the desired strength of lamotrigine and performance characteristics, as required for FDA approval. These performance characteristics include, e.g., pharmacokinetic (PK) profile (e.g., AUC, Cmax, tmax, and t1/2), stability, redispersibility, and dissolution. It is therefore also unknown whether any such oral liquid suspension would further possess the desired physical dimensions, physical properties, and/or performance characteristics (e.g., pH, viscosity, specific gravity, and/or suitable taste) to be manufactured on a commercial scale, while demonstrating to the FDA that the oral liquid suspension is safe and effective to consumers for its intended use. This also includes formulating and configuring the oral liquid suspension to deliver the lamotrigine enterally, given the administration is oral.

This patent is subject to a terminal disclaimer.

Lamotrigine oral liquid suspension and use thereof