The present invention provides for 8-hydroxy-7-substituted quinoline compounds such as formula IA

The present invention provides for 8-hydroxy-7-substituted quinoline compounds and pharmaceutically acceptable salts thereof which are useful as antiviral agents. The invention also relates to a pharmaceutical composition containing such compound in combination with a suitable excipient, the composition being useful in combating viral infections. The invention also relates to a method for selectively combating viral infections in animals, including man. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus, and the human herpes virus type 8 (HHV-8).
The herpesviruses comprise a large family of double stranded DNA viruses. The herpesvirus family can be divided into three subfamilies (xcex1, xcex2, xcex3) based upon a number of biological properties such as host range and tropism, viral life cycle, and viral persistence and latency. Eight of the herpesviruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 are the prototypic ot-herpesviruses. These two serotypes share approximately 50% nucleotide homology. Both are neurotropic viruses, but their primary sites of replication are different. HSV-1 typically infects the oral mucosa resulting in ulcerations commonly refered to as cold sores. HSV-2 infects and cuases ulcerations of the genital mucosa. HSV infection can also result in disseminated disease and encephalitis, especially in immunocompromised patients. D. O. White and F. J. Fenner, In Medical Virology, D. O. White and F. J. Fenner, eds., Academic Press, p. 318-347 (1994).
VZV is also an xcex1-herpesvirus and is the causitive agent of chicken pox. VZV establishes a latent infection in the dorsal root ganglia of the peripheral nervous system. From its latent site, VZV can cause recurrent disease commonly refered to as shingles or zoster. The probability of shingles increases with age and frequently occurs in immunocompromised patients. A. M. Arvin, In Virology, B. N. Field, D. M. Knipe, and P. M. Howley, ed., Lippincott-Raven Press, New York, p. 2547-2586 (1996).
Human cytomegalovirus (HCMV), a xcex2-herpesvirus, is an ubiquitous agent producing infection in individuals of all age groups. Infection rates of 60-100%, depending on geographic area and socioeconomic status have been reported. R. J. Whitley, S. Goldsmith and J. Gnann, In Society for General Microbiology. 45th Symposium: Control of Virus Diseases, Mimmock, N. J.; P. D. Griffiths and C. R. Madely, eds., Cambridge University Press, Cambridge, p. 315 (1990). The majority of infections are asymptomatic. However infections occuring in the immuno-compromised patient, including organ transplant recipients and individuals with AIDS may be severe and include HCMV induced pneumonia, colitis, and retinitis. L. W. Drew, Clin. Infect. Dis. 14:608-615 (1992). HCMV is the leading cause of blindness in AIDS patients. T. C. Merigan and S. Resta, Rev. Infect. Dis.12:S693 (1990). HCMV also establishes lifelong latency in the host.
HCMV DNA polymerase (HCMV pol) is an enzyme essential for viral replication. D. H. Spector, K. M. Klucher, D. K. Rabert and D. A. Wright, In Herpesvirus Transcription and Its Regulation, E. K. Wagner, ed., CRC Press, Boca Raton, Fla., p. 261: (1991). The current therapies for HCMV; Ganciclovir, Foscarnet and Vistide act by inhibition of HCMV pol. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13 (1994). See also U.S. Pat. Nos. 4,199,574; 4,215,113; 4,355,032; and E. DeClercq et al., Antiviral Research, Vol 8, pages 261-272 (1987). Ganciclovir and Foscarnet display significant toxicity and induction therapy is restricted to an intravenous route of administration. D. Faulds and R. C. Heel, Drugs, 39:597 (1990). Maintenance therapy with Ganciclovir and Foscarnet will likely contribute to drug resistant virus. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13 (1994). Clearly less toxic, orally bioavailable alternatives are needed.
EBV is a xcex3-herpesvirus which replicates in the epithelial cells of the nasopharynx and salivary glands and resides latently in xcex2-cells. Childhood infections of EBV are normally asymptomatic. However, EBV infection is associated with several diseases in adults such as infectious mononucleosis, Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. A. B. Rickinson and E. Kieff, In Virology, B. N. Fields, D. M. Knipe, and P. M. Howley, eds., Lippincott-Raven Press, New York, p. 2397-2446 (1996).
HHV-6 is a xcex2-herpesvirus which causes roseola (exanthem subitum) in children. P. Lusso, Antivir. Res. 31:1-21 (1996). HHV-7 shares 50-60% nucleotide sequence homology with HHV-6. It""s disease association is unclear, but it may be involved in some cases of roseola. N. Frenkel and E. Roffman, In Virology, B. N. Fields, D. M. Knipe, P. M. Howley, eds., Lippincott-Raven Press, New York, p. 2609-2622 (1996). HHV-8, also known as Kaposi""s sarcoma associated herpesvirus (KSHV), is a xcex3-herpesvirus which has recently been associated with Kaposi""s sarcoma in AIDS patients and multiple myeloma. M. B. Rettig et al., Science, 276:1851-1854 (1997).
Published Japanese patent application H1-136152 published May 29, 1989 discloses a silver halide photographic light-sensitive material comprising a support, and thereon, at least 1 silver halide emulsion layer containing a cyan dye-forming coupler represented by a broad generic formula. This broad generic formula includes 8-hydroxy-quinoline derivatives substituted by a wide variety of substituents, e.g., substituted carboxamide groups at the 7-position. None of the specific compounds disclosed in this reference are structurally similar to the compounds of the present invention. Also, the compounds of the present invention are useful as pharmaceutical agents, specifically HCMV inhibitors, whereas the reference compounds are useful in color photography.
Published Japanese patent application HEI 3-73949 published Mar. 29, 1991 discloses a thermally developable color light-sensitive material comprising at least a light-sensitive silver halide, a reducing agent, a binder, and a coupler represented by a first generic formula and/or a second generic formula on a support. These broad generic formulas include 8-hydroxy-quinoline derivatives substituted by a wide variety of substituents, e.g., substituted carboxamide groups at the 7-position. As noted for the previous Japanese reference, none of the specific compounds disclosed in this reference are structurally similar to the compounds of the present invention. Also, the compounds of the present invention are useful as pharmaceutical agents, specifically HCMV inhibitors, whereas the reference compounds are useful in color photography.
Published Japanese patent application 02152966 A2 discloses 4-hydroxy-carbostyryl derivatives as anti-allergy and antuinflammatory agents. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
U.S. Pat. No. 4,959,363 discloses 1-(N-substituted)-1,4-dihydro-4-oxo-6-and/or-7-substituted-3-quinolinecarboxamides as antiviral agents. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
U.S. Pat. Nos. 5,459,146 and 5,506,236 disclose 4-substituted-3-alkyl-pyrazolo[3,4-b]quinoline compounds as antiviral agents. Basically, these compounds are the tricyclic version of compounds such as those disclosed in the ""363 patent above, and are structurally very different from the compounds of the present invention.
U.S. Pat. No. 5,378,694 discloses compounds such as 1-(N-substituted)-3-substituted-4-hydroxy-2-quinolinones, and generically, 3-substituted-4-hydroxycoumarin compounds as antiviral agents. U.S. Pat. No. 5,412,104 discloses compounds similar to those disclosed in the ""694 patent for anti-viral or anti-hypertensive use; however, these 1-(N-substituted) reference compounds are disclosed as having substituents other than hydroxy at the 4-position of the quinolinone ring. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
German patent DE 1 908 548 discloses a variety of compounds including 4-hydroxy-quinoline compounds which may be substituted at the 3-position by carboxamide groups, and which are useful against cold viruses.
Published German patent application DE 44 25 647 A1 discloses heterocyclic-1-phenyl substituted quinolone and naphthyridone carboxylic acids for treating retroviral infections; Published German patent application DE 44 25 648 A1 discloses 6 and 6,8-substituted 1-[4-(1H-1,2,4-triazol-1-yl-methyl)phenyl]quinolone carboxylic acids for treating retroviral infections; Published German patent application DE 44 25 650 A1 discloses substituted triazolylmethylphenyl- naphthyridone carboxylic acids for treating retroviral infections; Published German patent application DE 44 25 659 A1 discloses N1-diverse 6-fluoro-8-difluoromethoxy substituted quinolone carboxylic acids for treating retroviral infections. The compounds of these references are structurally very different from the compounds of the present invention.
Derwent Abstract 96-246942/25 of JP 8099957-A discloses optionally heterocyclyl substituted 4-oxo-quinoline and naphthyridine derivatives which are useful for treating herpes, particularly herpes simplex virus, herpex zoster virus and cytomegalovirus.
Derwent Abstract 95-271358/36 of JP 7165748-A discloses compounds having heterocyclic ketones which are used in antiviral agents for treating cytomegalovirus infectious disease.
Nowhere do these references teach or suggest the specific 8-hydroxyquinoline-7-carboxamide compounds of the present invention which are useful as anti-HCMV agents.
U.S. Pat. No. 5,463,072 discloses a process for the preparation of naphtholic 2-equivalent cyan couplers which are useful in color photography. It discloses an 8-hydroxy-quinoline compound having a substituted triazole moiety at the 6-position and a carbamoyl moiety at the 7-position.
International Publication WO 95/11592, published May 4, 1995, discloses a marine structure carrying a coating comprising a layer which contains a quinoline compound, or an N-oxide or a salt thereof, having antifouling activity. It generically discloses such compounds with a variety of substituents, such as hydroxy, (optionally substituted C1-12-alkyl)sulphonyl, (optionally substituted aryl)sulphonyl, mono or di (optionally substituted C1-12alkyl)aminosulphonyl.
Derwent Abstract 91-232424/32 (Sandoz AG) discloses the use of 5HT-3 antagonists for the prevention or reduction of dependence on alcohol, psycho-stimulants, nicotine or opiates. A variety of compounds is disclosed including quinoline compounds having unsubstituted phenyl rings.
Derwent Abstract 90-343755/46 (Sandoz Ltd.) discloses serotonin 5-HT3 antagonists used for treating stress-related psychiatric disorders, rhinitis, nasal disorders and lung embolism. It discloses a variety of compounds, including quinoline compounds substituted by bridged piperidine groups.
Derwent Abstract 90-290145/38 (DuPont DeNemours Co.) discloses n-substituted naphthalene or quinoline sulphonamides which are radio and chemo-sensitising agents in tumour treatment. Other than the sulfonamide bonds, the quinoline compounds are not further substituted on their phenyl rings.
Derwent Abstract 90-264471/35 (Yoshitomi Pharm. Ind. KK.) discloses (iso)quinoline-sulphonamide compounds and their acid addition salts as vasodilators and cerebral circulation improving agents.
Derwent Abstract 85-063337/11 (Sandoz-Patent-Gmbh) discloses a variety of new fused heterocyclic sulphonic amide and ester derivatives with analgesic, antiarrythmic and antipsychotic activities.
Derwent Abstract 22,706 (Pfizer and Co.) discloses quinoline derivatives and their acid addition salts as bronchodilators, but no sulfonamide substituents are disclosed for these compounds.
U.S. Pat. No. 5,240,940 discloses fungicidal compositions comprising a combination of two fungicides, one of which is a quinoline or cinnoline compound. U.S. Pat. No. 4,881,969 discloses sulfonamides as herbicidal agents.
European Published applications 0326330 and 0326328 discloses quinoline, quinazoline and cinnoline fungicides.
JP 63307451 discloses a silver halide color photographic photosensitive material with improved granularity containing a water-soluble coupler capable of a coupling reaction with an oxidant main ingredient in color developing, which coupler may include specific 8-hydroxy-quinoline compounds.
JPO7033729-A discloses the production of N-cyano-N-substituted-arylcarboxyimidamide compounds in which aryl may be 8-quinolyl groups.
International Publication Number WO 96/25399, published Aug. 22, 1996, discloses aroylaniline derivatives which exhibit anti-retroviral activity.
International Publication Number WO 97/03069, published Jan. 30, 1997, discloses substituted heteroaromatic compounds which are protein tyrosine kinase inhibitors, in particular to substituted quinolines and quinazolines.
International Publication Number WO 96/06084, published Feb. 29, 1996, discloses quinolylamine derivatives which are useful for the treatment of arrhythmia.
European Patent Application No. 0206751, published Dec. 30, 1996, discloses 2-substituted-phenylalkenyl-quinoline derivatives which are useful as selective antagonists of leukotrienes of D4.
International Application No. WO 9632015 discloses synergistic fungicidal compositions made of quinoline derivatives and cytochrome complex III inhibitors.
European Patent Application No. 0399818 discloses diarylstyrylquinoline diacids which are leukotriene antagonists and inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.
The present invention particularly provides:
A compound of formula IA
wherein R0 is
a) xe2x80x94(CH2)nxe2x80x94X1,
b) xe2x80x94(CH2)nxe2x80x94C3-C8 cycloalkyl substituted by zero (0) or one (1) R8,
c) xe2x80x94(CH2)pW1X2,
d) xe2x80x94(CH2)pW1CH2X1, or
e) xe2x80x94(CH2)nxe2x80x94CHR9xe2x80x94(CH2)nxe2x80x94X1;
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94CF3, or
f) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94C1-C3alkyl,
c) xe2x80x94OH,
d) xe2x80x94CF3,
e) xe2x80x94CHxe2x95x90CH-furanyl,
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4,
g) xe2x80x94CHxe2x95x90CH-pyridinyl,
h) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4,
i) xe2x80x94NHV1,
j) xe2x80x94CH2NHV1, or
k) xe2x80x94CH2Z1;
wherein R3 is
a) xe2x80x94H,
b) xe2x80x94OH,
c) xe2x80x94CF3, or
d) xe2x80x94C1-C3alkyl;
wherein R4 is
a) xe2x80x94H
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94NO2,
f) xe2x80x94CF3,
g) xe2x80x94W1xe2x80x94R10,
h) xe2x80x94C1-C6 alkyl,
i) xe2x80x94C3-C8 cycloalkyl,
j) xe2x80x94[CH2]n-aryl,
k) xe2x80x94[CH2]n-het,
l) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl,
m) xe2x80x94SO2NH-het
n) xe2x80x94CN,
o) xe2x80x94I, or
p) xe2x80x94CH2xe2x80x94OH;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94W1xe2x80x94R10,
f) xe2x80x94CF3,
g) xe2x80x94C1-C6 alkyl,
h) xe2x80x94C3-C8 cycloalkyl,
i) xe2x80x94(CH2)n-aryl substituted by R6,
j) xe2x80x94(CH2)n-het substituted by R7, or
k) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R8 is
a) xe2x80x94C1-C4 alkyl,
b) xe2x80x94W1xe2x80x94H, or
c) xe2x80x94CH2W1H;
wherein R9 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11,
e) xe2x80x94CH(OH)R11,
f) xe2x80x94CH2OH,
g) xe2x80x94CO2R11, or
h) -aryl;
wherein R10 is
a) xe2x80x94H,
b) xe2x80x94C1-C6 alkyl,
c) xe2x80x94C3-C8 cycloalkyl,
d) xe2x80x94(CH2)n-aryl optionally substituted with F, Cl, CH2OH or xe2x80x94NO2,
e) xe2x80x94(CH2)n-het, or
f) xe2x80x94CH2xe2x80x94C3-C3 cycloalkyl;
wherein R1 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94(CH2)nX1, or
d) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl;
wherein X1 is
a) -aryl substituted by zero (0), one (1), two (2), or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl,
e) xe2x80x94S-phenyl,
f) xe2x80x94NHSO2-phenyl substituted by one (1), two (2) or three (3) R4,
g) xe2x80x94CN,
h) xe2x80x94OH,
i) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R8, or
j) -4-cyano-2,3,5,6-tetrafluoro-phenyl;
wherein X2 is
a) -aryl substituted by zero (0), one (1), two (2) or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl, or
e) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R8;
wherein W1 is
a) xe2x80x94NH,
b) -oxygen, or
c) -sulfur;
wherein V1 is
a) xe2x80x94R11,
b) xe2x80x94C(O)R11,
c) xe2x80x94SO2R11, or
d) xe2x80x94C(O)NHR11;
wherein Z1 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11, or p1 e) xe2x80x94CO2R11;
wherein -aryl is
a) -phenyl,
b) -naphthyl,
c) -biphenyl,
d) -tetrahydro-naphthyl, or
e) fluorenyl;
wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic;
wherein -cycloalkyl is a saturated or unsaturated hydrocarbon ring including any bicyclic group in which the above ring is connected to a benzene, heterocyclic or other hydrocarbon ring;
wherein n is zero (0) to six (6), inclusive;
wherein p is one (1), two (2) or three (3);
or a pharmaceutically acceptable salt or N-oxide thereof.
The present invention further provides:
The compound of formula IA provided that:
a) when R0 is xe2x80x94(CH2)nxe2x80x94X1 and X1 is xe2x80x94OH, then n is one or greater; and
b) when R0 is xe2x80x94(CH2)pW1X2, W1 is -oxygen or -sulfur and X2 is phenyl then R4 is other than t-pentyl.
The present invention also provides:
A compound of formula I
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94CF3, or
f) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94C1-C3alkyl,
c) xe2x80x94OH,
d) xe2x80x94CF3,
e) xe2x80x94CHxe2x95x90CH-furanyl,
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4,
g) xe2x80x94CHxe2x95x90CH-pyridinyl, or
h) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4;
wherein R3 is
a) xe2x80x94H,
b) xe2x80x94OH,
c) xe2x80x94CF3, or
d) xe2x80x94C1-C3alkyl;
wherein X1 is
a) -phenyl substituted by zero (0) or one (1) R4,
b) -het substituted by zero (0) or one (1) R5,
c) xe2x80x94C1-C12 alkyl,
d) xe2x80x94CH(OH)-phenyl,
e) xe2x80x94S-phenyl,
f) -naphthyl,
g) xe2x80x94NHSO2-phenyl substituted by one (1) R4, or
h) xe2x80x94CN;
wherein het is
a) -1,3,4-thiadiazol-2-yl,
b) -4,5-dihydro-4-oxo-2-thiazolyl,
c) -thiazolyl,
d) -benzothiazolyl,
e) -pyridinyl,
f) -morpholinyl, or
g) -imidazolyl;
wherein R4 is
a) xe2x80x94H
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94NO2,
f) xe2x80x94OCH3,
g) xe2x80x94CF3, or
h) xe2x80x94C1-C4 alkyl;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94(CH2)nxe2x80x94(phenyl substituted by R6),
f) -thienyl substituted by R7, or
g) xe2x80x94OH;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein n is zero (0) to six (6) inclusive;
or a pharmaceutically acceptable salt or a N-oxide thereof.
The present invention further provides compounds of formula II
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94Cl,
c) xe2x80x94Br, or
d) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94CH3,
c) xe2x80x94CF3,
d) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4,
e) xe2x80x94CHxe2x95x90CH-furanyl, or
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4;
wherein X1 is
a) -phenyl substituted by one (1) R4,
b) -het substituted by one (1) R5,
c) xe2x80x94CH(OH)-phenyl,
d) xe2x80x94S-phenyl,
e) -naphthyl,
f) xe2x80x94NHSO2-phenyl substituted by one (1), two (2) or three (3) R4, or
g) xe2x80x94CN;
wherein het is
a) -1,3,4-thiadiazol-2-yl,
b) -4,5-dihydro-4-oxo-2-thiazolyl,
c) -2-thiazolyl, or
d) -2-benzothiazolyl;
wherein R4 is
a) xe2x80x94H,
b) xe2x80x94Cl,
c) xe2x80x94Br,
d) xe2x80x94NO2, or
e) xe2x80x94OCH3;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94Cl,
c) xe2x80x94(CH2)n-(phenyl substituted by R6),
d) -2-thienyl substituted by R7, or
e) OH;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94Cl, or
c) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94Cl, or
c) xe2x80x94Br,
In another aspect, the present invention provides
A use of a compound of formula IA to prepare a medicament for treating a susceptible cytomegaloviral infection in a mammal
wherein R0 is
a) xe2x80x94(CH2)nxe2x80x94X1,
b) xe2x80x94(CH2)nxe2x80x94C3-C8 cycloalkyl substituted by zero (0) or one (1) R8,
c) xe2x80x94(CH2)pW1X2,
d) xe2x80x94(CH2)pW1CH2X1, or
e) xe2x80x94(CH2)nxe2x80x94CHR9xe2x80x94(CH2)nxe2x80x94X1;
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94CF3, or
f) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94C1-C3alkyl,
c) xe2x80x94OH,
d) xe2x80x94CF3,
e) xe2x80x94CHxe2x95x90CH-furanyl,
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4,
g) xe2x80x94CHxe2x95x90CH-pyridinyl,
h) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4,
i) xe2x80x94NHV1,
j) xe2x80x94CH2NHV1, or
k) xe2x80x94CH2Z1;
wherein R3 is
a) xe2x80x94H,
b) xe2x80x94OH,
c) xe2x80x94CF3, or
d) xe2x80x94C1-C3alkyl;
wherein R4 is
a) xe2x80x94H
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94NO2,
f) xe2x80x94CF3,
g) xe2x80x94W1-R10,
h) xe2x80x94C1-C6 alkyl,
i) xe2x80x94C3-C8 cycloalkyl,
j) xe2x80x94[CH2]n-aryl,
k) xe2x80x94[CH2]n-het,
l) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl,
m) xe2x80x94SO2NH-het
n) xe2x80x94CN,
o) xe2x80x94I, or
p) xe2x80x94CH2xe2x80x94OH;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94W1xe2x80x94R10,
f) xe2x80x94CF3,
g) xe2x80x94C1-C6 alkyl,
h) xe2x80x94C3-C8 cycloalkyl,
i) xe2x80x94(CH2)n-aryl substituted by R6,
j) xe2x80x94(CH2)n-het substituted by R7, or
k) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R8 is
a) xe2x80x94C1-C4 alkyl,
b) xe2x80x94W1xe2x80x94H, or
c) xe2x80x94CH2W1H;
wherein R9 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11,
e) xe2x80x94CH(OH)R11,
f) xe2x80x94CH2OH,
g) xe2x80x94CO2R11, or
h) -aryl;
wherein R10 is
a) xe2x80x94H,
b) xe2x80x94C1-C6 alkyl,
c) xe2x80x94C3-C8 cycloalkyl,
d) xe2x80x94(CH2)n-aryl optionally substituted with F, Cl, CH2OH or xe2x80x94NO2,
e) xe2x80x94(CH2)n-het, or
f) xe2x80x94CH2xe2x80x94C3-C3 cycloalkyl;
wherein R11 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94(CH2)nX1, or
d) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl,
wherein X1 is
a) -aryl substituted by zero (0), one (1), two (2), or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl,
e) xe2x80x94S-phenyl,
f) xe2x80x94NHSO2-phenyl substituted by one (1), two (2) or three (3) R4,
g) xe2x80x94CN,
h) xe2x80x94OH,
i) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R1, or
j) -4-cyano-2,3,5,6-tetrafluoro-phenyl;
wherein X2 is
a) -aryl substituted by zero (0), one (1), two (2) or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl, or
e) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R8;
wherein W1 is
a) xe2x80x94NH,
b) -oxygen, or
c) -sulfur;
wherein V1 is
a) xe2x80x94R11,
b) xe2x80x94C(O)R11,
c) xe2x80x94SO2R11, or
d) xe2x80x94C(O)NHR11;
wherein Z1 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11, or
e) xe2x80x94CO2R11;
wherein -aryl is
a) -phenyl,
b) -naphthyl,
c) -biphenyl,
d) -tetrahydro-naphthyl, or
e) fluorenyl;
wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic;
wherein -cycloalkyl is a saturated or unsaturated hydrocarbon ring including any bicyclic group in which the above ring is connected to a benzene, heterocyclic or other hydrocarbon ring;
wherein n is zero (0) to six (6), inclusive;
wherein p is one (1), two (2) or three (3);
or a pharmaceutically acceptable salt or N-oxide thereof; as well as a method of treating a cytomegalovirus comprising the administration of an effective amount of a compound of the formula IA.
The present invention also provides:
An antiviral pharmaceutical composition which comprises a pharmaceutically acceptable excipient and an effective amount of a compound of formula I.
Further, the present invention provides:
A compound of the formula III
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94C1-C5 alkyl, or
c) xe2x80x94CHxe2x95x90CH-aryl;
wherein R2 is
a) xe2x80x94C1-C10 alkyl,
b) xe2x80x94(CH2)nR3,
c) xe2x80x94CH(R4)R3, or
d) xe2x80x94(CH2)nxe2x80x94X2xe2x80x94R3;
wherein R3 is
a) -aryl,
b) -het substituted by zero (0) to two (2) R5, or
c) xe2x80x94C3-C6 cycloalkyl;
wherein R4 is
a) xe2x80x94C1-C5 alkyl, or
b) -aryl;
wherein X1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br, or
e) xe2x80x94I;
wherein X2 is
a) xe2x80x94Oxe2x80x94,
b) xe2x80x94Sxe2x80x94, or
c) xe2x80x94NHxe2x80x94;
wherein n is zero (0) to four (4) inclusive;
wherein aryl is
a) phenyl substituted by zero (0) to two (2) R5, or
b) naphthyl substituted by zero (0) to two (2) R1;
wherein het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and if chemically feasible, the nitrogen atom may be in the protected form;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94C1-C5 alkyl,
c) xe2x80x94F,
d) xe2x80x94Cl,
e) xe2x80x94OCH3,
f) xe2x80x94CF3,
g) xe2x80x94NHSO2-het substituted by zero (0) to two (2) xe2x80x94C1-C5 alkyl, or
h) xe2x80x94NHSO2-phenyl;
or a pharmaceutically acceptable salt thereof;
A compound of formula III
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94CH3, or
c) xe2x80x94CHxe2x95x90CH-phenyl;
wherein R2 is
a) xe2x80x94(CH2)nR3,
b) xe2x80x94(CH2)nxe2x80x94X2xe2x80x94R3, or
c) xe2x80x94CH(R4)R3;
wherein R3 is
a) -phenyl substituted by zero (0) to two (2) R5,
b) -het,
c) -naphthyl, or
d) xe2x80x94C3-6 cycloalkyl;
wherein R4 is
a) xe2x80x94CH3, or
b) -phenyl;
wherein R5 is
a) xe2x80x94F,
b) xe2x80x94Cl,
c) xe2x80x94NHSO2-phenyl;
wherre in X1 is
a) xe2x80x94Cl, or
b) xe2x80x94Br;
wherein X2 is
a) xe2x80x94Oxe2x80x94, or
b) xe2x80x94Sxe2x80x94;
wherein het is
a) -imidazolyl, or
b) -indolyl.
The present invention also provides:
A compound of the formula IV
where X1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br, or
e) xe2x80x94I;
wherein R2, R3 and R4 may be the same or different and are
a) xe2x80x94C1-C5 alkyl, or
b) -phenyl.
Also provided is:
A compound of formula V
wherein X1 is
a) phenyl substituted by zero (0) to three (3) R4,
b) naphthyl substituted by zero (0) to three (3) R4,
c) fluorenyl substituted by zero (0) to three (3) R4,
d) het substituted by zero (0) to one (1) R5, or
e) 4-cyano-2,3,5,6-tetrafluorophenyl;
wherein R4 is
a) xe2x80x94F,
b) xe2x80x94Cl,
c) xe2x80x94Br,
d) xe2x80x94I,
e) xe2x80x94NO2,
f) xe2x80x94CN,
g) xe2x80x94CF3,
h) xe2x80x94C1-C6 alkyl,
i) phenyl,
j) cyclohexyl,
k) hydroxymethyl,
l) xe2x80x94OR10,
m) xe2x80x94SR10, or
n) xe2x80x94SO2NH-het;
wherein het is
a) 1,3-benzodioxol-4-yl,
b) 1,3-benzodioxo-5-yl,
c) coumarinyl,
d) indazoyl,
e) indolyl,
f) benzothiazolyl,
g) benzothiadiazolyl,
h) quinolinyl,
i) pyridinyl,
j) 1,3,4-thiadiazol-2-yl, or
k) isoxazolyl substituted with one or two C1-C4 alkyl;
wherein R5 is
a) xe2x80x94F,
b) xe2x80x94Cl,
c) xe2x80x94Br,
d) xe2x80x94I,
e) xe2x80x94CF3,
f) xe2x80x94C1-C4-alkyl, or
g) xe2x80x94C1-C2-alkylsubstituted with an
wherein R10 is
a) hydrogen,
b) xe2x80x94C1-C4 alkyl,
c) phenyl,
d) benzyl, or
e) 4-nitrophenyl; as well as
A compound of formula V
wherein het is
a) indazoyl,
b) indoyl, or
c) isoxazolyl substituted with one (1) or two (2) C1-C4 alkyl.
Finally, the present invention provides:
A compound of formula VI or VII
wherein X is
a) xe2x80x94C, or
b) xe2x80x94SO;
wherein Y is
a) xe2x80x94NH,
b) xe2x80x94O, or
c) xe2x80x94S;
wherein EWG is an electron withdrawing group;
wherein R1, R2 and R3 are as defined in claim 1;
wherein R4 is
a) xe2x80x94H,
b) xe2x80x94(CH2)nxe2x80x94CO2xe2x80x94C1-C6 alkyl,
c) xe2x80x94(CH2)m-phenyl optionally substituted with one (1) or two (2) R7,
d) xe2x80x94(CH2)m-het,
e) xe2x80x94C1-C6 alkyl optionally substituted by one R6,
f) xe2x80x94C1-C4 alkyl-NHxe2x80x94COOCH2-benzyl, or
g) xe2x80x94C1-C4 alkyl-Sxe2x80x94CH3;
wherein R5 is pyrrolidin-1-yl optionally substituted with EWG or R6;
wherein n is zero (0) to three (3);
wherein m is zero (0) to one (1);
wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic;
wherein R6 is
a) hydroxy,
b) xe2x80x94C1-C6 alkyloxy,
c) mercapto, or
d) xe2x80x94C1-C6 alkylmercapto;
wherein R7 is
a) hydroxy, or
b) xe2x80x94C1-C6 alkyloxy; as well as
A compound of formula VI or VII
wherein R7 is t-butyl;
wherein EWG is
a) xe2x80x94NHxe2x80x94CO2C(CH3)3,
b) xe2x80x94CN,
c) xe2x80x94COX2xe2x80x94C1-C6 alkyl, or
d) xe2x80x94COOH;
wherein X2 is
a) xe2x80x94Oxe2x80x94, or
b) xe2x80x94NH; and
wherein het is
a) 1,3-benzodioxol-4-yl,
b) 1,3-benzodioxol-5-yl, or
c) indolyl.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable.
xe2x80x9cN-oxidexe2x80x9d refers to the oxidized form of the nitrogen in the ring of the 8-hydroxy-quinoline compounds of the present invention. The preparation of such compounds is well known to one of ordinary skill in organic chemistry, including methods such as oxidation with metachloro-peroxy-benzoic acid.
xe2x80x9cElectron-withdrawing groupxe2x80x9d means any substituent on the ring which tends to draw electron density from the ring. Examples of such groups include halogen, nitro, cyano, carboxylic acids, carboxylic esters, sulfoxides, sulfones, sulfonamides, ketones and aldehydes.
xe2x80x9cHalogenxe2x80x9d means fluroine, chlorine, or bromine.
xe2x80x9cHetxe2x80x9d is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and if chemically feasible, the nitrogen atom may be in the protected form; and substituted or unsubstituted. Examples of xe2x80x9chetxe2x80x9d include the following: thiadiazolyl, thiazolyl, benzothiazolyl, pyridinyl (or pyridyl), morpholinyl, imidazolyl, indolyl, and piperazinyl.
The compounds of the present invention are named according to the IUPAC or CAS nomenclature system.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-Cj indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, (C1-C3)alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight and branched forms thereof.
Throughout this application, abbreviations which are well known to one of ordinary skill in the art may be used, such as xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, and xe2x80x9cEtxe2x80x9d for ethyl.
The following Charts A-I describe the preparation of the compounds of the present invention. All of the starting materials are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the claims.
The preparation of the starting materials, 8-hydroxyquinoline-7-carboxylic acids, is accomplished in low to moderate yields by the carboxylation of 8-hydroxy-quinolines, which are either commercially available or which are prepared by literature methods: G. S. Bajwa, K. E. Hartman, and M. N. Jouillie, Journal of Medicinal Chemistry, Vol.16, No. 2, pages 134-138 (1973); L. C. March, W. A. Romanchick, G. S. Bajwa, and M. M. Jouillie, Journal of Medicinal Chemistry, Vol. 16, No. 4, pages 337-342 (1973). The compound of formula A-1 is reacted with K2CO3 (3 eq.), CO2(800 p.s.i) at 170xc2x0 for 7 days, to yield the compound of formula A-2. J. Hannah et al., Journal of Medicinal Chemistry, Vol. 21, No. 11, pages 1093-1100 (1978). (R1 and R2 in formula A-1 are the same as R1 and R2 in formula A-2.) The compound of formula A-2 wherein R1 is xe2x80x94H and R2 is xe2x80x94H is the intermediate compound of Preparation 1 below. The compound of formula A-2 wherein R1 is xe2x80x94F and R2 is xe2x80x94H is the intermediate compound of Preparation 4 below. The compound of formula A-2 wherein R1 is xe2x80x94Cl and R2 is xe2x80x94H is the intermediate compound of Preparation 3 below. The compound of formula A-2 wherein R1 is xe2x80x94H and R2 is xe2x80x94CH3 is the intermediate compound of Preparation 5 below.
Bromination of 8-hydroxyquinoline-7-carboxylic acid of formula B-1 with one equivalent of bromine (HOAc, reflux, 1 hr) yields 5-bromo-8-hydroxy-7-quinoline-carboxylic acid of formula B-2 in quantitative yield, which is prepared in Preparation 2 below. R. Schmitt and F. Engelmann, Chem. Ber., 20; 1887; 2694.
The acid of formula C-1, prepared as described in Charts A and B above, is condensed with the amine of formula C-2, which is commercially available (e.g, p-chloro or p-nitrobenzylamine), under appropriate conditions (EDC is used as the coupling agent, HOBt, DMF, rt, 18 hr) to yield the compound of formula C-3. (R1 and R2 in formula C-1 are the same as R1 and R2 in formula C-3. X in formula C-2 is the same as X in formula C-3.) The compound of formula C-3 wherein R1 is xe2x80x94Br, R2 is xe2x80x94H and X is xe2x80x94Cl is the final compound of Example 9 below. The compound of formula C-3 wherein R1 is xe2x80x94H, R2 is xe2x80x94CH3 and X is xe2x80x94Cl is the final compound of Example 10 below. The compound of formula C-3 wherein R1 is xe2x80x94Cl, R2 is xe2x80x94H and X is xe2x80x94Cl is the final compound of Example 11 below. The compound of formula C-3 wherein R1 is xe2x80x94H, R2 is xe2x80x94H and X is xe2x80x94NO2 is the final compound of Example 12 below. The compound of formula C-3 wherein R1 is xe2x80x94F, R2 is xe2x80x94H and X is xe2x80x94Cl is the final compound of Example 16 below. Chart C is the preferred coupling method for benzylamines.
Under the same conditions as in Chart C above (i.e., EDC, HOBT, DMF, rt, 7 days), the acid of formula D-1 is condensed with the heterocyclic amine of formula D-2 to give the final compound of formula D-3, which is prepared in Example 8 below.
Chart E discloses a more efficient method of coupling the 8-hydroxyquinoline-7-carboxylic acids with anilines and heterocyclic amines utilizing PCl3 as the condensing agent. H. Singh, A. K. Singh, S. Sharma, R. N. Iyer, J. Med. Chem., 20:826 (1977); H. Singh, S. Sharma, R. N. Iyer, Ind. J. Chem., 15B:73 (1977); S. K. Dubey, A. K. Singh, H. Singh, S. Sharma, R. N. Iyer, J. Med. Chem., 37:999 (1994). The compound of formula E-1 is coupled with the compound of formula E-2 (using PC3, xylenes, at reflux, for 18 hr) to yield the compound of formula E-3 wherein X is xe2x80x94H (which is the final compound of Example 5 below) or X is xe2x80x94Br (which is the final compound of Example 6 below). (X in formula E-1 is the same as X in formula E-3.) Chart E is the preferred coupling method for heterocyclic amines.
The required thiazolones of formula F-3 are prepared in three steps from commercially available acids of formula F-1 as follows: the compound of formula F-1 is first treated with P(red) in Br and is then treated with AcCl in methanol to yield the compound of formula F-2. This compound is then reacted with thiourea at ethanol at reflux to yield the compound of formula F-3. T. Sohda et al., Chem. Pharm. Bull., Vol. 30, No. 10, pages 3601-3616 (1982).
Anilines are also coupled in low to moderate yields under the conditions of Chart E. Thus, the compound of formula G-1 is coupled with the compound of formula G-2 (using PCl3, xylenes, at reflux, for 18 hours) to yield the compound of formula G-3. (R1 in formula G-1 is the same as R1 in formula G-3.) The compound of formula G-3 wherein R1 is xe2x80x94H is the final compound of Example 3 below; the compound of formula G-3 wherein R1 is xe2x80x94Br is the final compound of Example 4 below; and the compound of formula G-3 wherein R1 is xe2x80x94Cl is the final compound of Example 15 below. The coupling conditions of this reaction are preferred when anilines are used.
Chart H discloses another method of coupling which is used in the condensation of benzylamines, although the yields are lower than found for the EDC couplings. The compound of formula H-1 is coupled with the compound of formula H-2 (using PCl3, xylenes, at reflux for 18 hr) to yield the compound of formula H-3, which is the final compound of Example 1 below.
Other heterocyclic amines are also condensed with quinoline carboxylic acids under these conditions. The quinoline carboxylic acid of formula I-1 (which was prepared in Chart A above) is coupled with the appropriate heterocyclic amine of formula I-2, I-4, I-6 or I-8 (using PCl3, xylenes, at reflux, for 18 hours) to yield the compound of formula I-3, I-5, I-7 or I-9, respectively. The compound of formula I-3 is the final compound of Example 2 below; the compound of formula I-5 is the final compound of Example 7 below; the compound of formula I-7 is the compound of Example 13 below which is useful as an intermediate; and the compound of formula I-9 is the final compound of Example 14 below.
The preparation of the starting materials is accomplished by O-methylation of commercially-avaiable 5,7-dihalo-8-hydroxyquinolines according to the procedure of R. A. W. Johnstone and M. E. Rose in Tetrahedron, vol. 35, page 21169 (1979). The compound of formula J-1 is treated with t-butyllithium or n-butyllithium at low temperature in ether/toluene, then exposed to sulfur dioxide gas to prepare the compound of formula J-2. Conversion of the compound of formula J-2 to the sulfonyl chloride of formula J-3 is accomplished by treatment with N-chlorosuccinimide (CH2Cl2, 3 hr). The sulfonamide of formula J-4 is then prepared by reaction of the sulfonyl chloride of formula J-3 with 1 equivalent of a primary amine of the formula R2NH2 and 2 equivalents of pyridine in CH2Cl2 (15 hr). Finally, the compound of formula J-5 is prepared using either excess pyridinium hydrochloride (220xc2x0 C., 10 min) or excess boron tribromide (CH2Cl2, 1.5 hr).
Compounds of the structure K-3 are prepared from commercially-available 5,7-dihalo-8-hydroxyquinolines (K-1) in two steps. Formation of the silylether intermediates K-2 is accomplished by reaction of the 8-hydroxyquinolines K-1 with chlorotrialkylsilanes in the presence of imidazole and DMF at room temperature for 18-20 hours. The intermediates are then treated with t-butyllithium or n-butyllithium at low temperature in THF to give the compound of formula K-3.
To a mixture of o-anidisine of L-1 and ethyl-4,4,4-trifluoroacetoacetate of L-2 is added 6N HCl. The resulting enamine is heated in diphenylether at 250xc2x0 C. to produce 4-hydroxy-8-methoxy-2-trifluoromethylquioline of L-3.
The compound of M-1 is chlorinated with phosphorus oxychloride in CH2Cl2/DMF at room temperature. The resulting chloride of M-2 is reductively cleaved by hydrogenation in EtOH, Et3N to give M-3. Methyl ether deprotection with pyridine hydrochloride at 220xc2x0 C. gives 2-trifluoromethyl-8-hydroxyquinoline of M-4. This material is carboxylated to M-5 under Kolbe-Schmidt conditions. Standard amide couplings gives the desired products of M-6.
Alternatively, pyridine hydrochloride deprotection of N-1 gives the 4,8-dihydroxy-quinoline of N-2, which again is carboxylated under Kolbe-Schmidt conditions to give N-3. Standard amide couplings give the desired products of N-4.
Aryl aldehydes of O-2 are condensed with 8-hydroxyquinaldine of O-1 at 180xc2x0 C. to form the 2-styryt-8-hydroxyquinolines of O-3. These are carboxylated under Kolbe-Schmidt conditions to give O-4. Standard couplings of the resulting acid with amines gives the desired amides O-5.
The preparation of the starting material of formula P-1 is accomplished by chlorination of commercially-available 8-hydroxyquinaldine according to the procedure described in DE 1770065. The compound of formula P-1 is then treated with neat flourosulfonic acid at 120xc2x0 C. to form the compound of formula P-2. Finally, the sulfonamides of formula P-3 are prepared by heating to 140xc2x0 C. a mixture of 1 eq of the sulfonyl flouride of formula P-2, 2 eq of the primary amine of formula RNH2 and 3 eq of N,N-diisopropylethylamine in chlorobenzene.
The preparation of the starting material of formula Q-1 is accomplished by O-methylation of commercially-available 5,7-dibromo-2-methyl-8-quinolinol according to the procedure of R. A. W. Johnstone and M. E. Rose in Tetrahedron, vol. 35, page 21169 (1979). The styrene derivative of formula Q-2 is obtained by heating the 2-methylquinoline of formula Q-1 with benzaldehyde for 18 h. The intermediate of formula Q-2 (which corresponds to J-1, R1=CHxe2x95x90CHPh, X1=X2=Br) is then advanced in four steps to the sulfonamides of formula Q-3 (which corresponds to J-5, R1=CHxe2x95x90CHPh, X1=Cl; R2=R) following the route previously described in Chart J.
The preparation of the starting material of formula R-1 is accomplished by chlorination of commercially-available 8-hydroxyquinaldine according to the procedure described in DE 1770065. The 7-iodo derivative of formula R-2 is then prepared by reaction of the quinoline of formula R-1 with iodine monochloride in methanol. The compound of formula R-2 is treated successively with methyl magnesium bromide and n-butyllithium at xe2x88x9278xc2x0 C. in THF, then exposed to sulfur dioxide gas to prepare the compound of formula R-3. Conversion of the compound of formula R-3 to the sulfonyl chloride of formula R-4 is accomplished by treatment with N-chlorosuccinimide in methylene chloride at room temperature for 2 h. The sulfonamide of formula R-5 is then prepared by reaction of the sulfonyl chloride of formula R-4 with 2-(4-aminophenyl)ethylamine and pyridine in methylene chloride. Finally, the compound of formula R-6 is prepared by reaction of the compound of formula R-5 with excess sulfonyl chloride of the formula RSO2Cl in pyridine.
The commercially-available 5-flouro-8-hydroxyquinoline of formula S-1 is treated with neat chlorosulfonic acid at 90-105xc2x0 C. to form the sulfonyl chloride of formula S-2. The sulfonamide of formula S-3 is then prepared by reaction of 1 eq of the sulfonyl chloride of formula S-2 with 3 eq of benzylamine in THF.
Commercially available 8-hydroxyquinoline (T-1) is converted to the 7-carboxylic acid (T-2) by heating at 175xc2x0 C. in the presence of potassium carbonate under 800 psi carbon dioxide gas for 7 days. The acid is then condensed with various aliphatic amines after activation with either 1,1xe2x80x2-carbonyldiimidazole, or alternatively 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole to afford the desired amides of the formula T-3. The above amides are prepared either as discrete analogues or as part of a parallel synthesis block.
Anhydride U-1 is prepared from 8-hydroxy-7-quinoline carboxylic acid using 2,2,2-trichloroethyl chloroformate and diisopropylethylamine. The purity of the starting materials is crucial for this reaction to succeed; particularly, any trace of any metalic cations but alkali cations, or Lewis acids, has to be avoided, as they lead to an inhibition of the reaction as well as to decarboxylation of anhydride U-1, probably through a chelation of both starting material and product; during the whole course of the reaction, strictly basic conditions have to be maintained, acidic conditions favoring a decarboxylation of the product as well. Ester U-3 is prepared from 8-hydroxy-7-quinoline carboxylic acid as well, the 8-hydroxy substituent being first protected to ester U-2 according to a literature procedure (German Patent No. 540842, Dec. 10, 1931) and subsequent activation of the 7-carboxylic acid as its fluoride, using cyanuric fluoride and diisopropylethylamine.
N-Aryl-8-hydroxy-7-quinolinecarboxamides V-4-14 are prepared as single compounds from anhydride U-1 (Chart U) following GP II described below. Both amide coupling and deprotection of the 8-hydroxy substituent can be realized in a single step with primary amines, provided some traces of water are present in the reaction mixture. (No water needs to be added; water coming from glassware and used solvents is enough to ensure a complete deprotectino, at least on small scale.) Probably, the amide function of the still protected intermediate is nucleophilic enough to attack the carbonate at the 7-position via a six-membered ring; subsequent hydrolysis, catalyzed by pyridinium chloride, leads to the desired amides. Similarly, N-Aryl-8-hydroxy-7-quinolinecarboxamides V-21-36 are prepared by parallel synthesis from anhydride U-1, following GP III described below. N-Aryl-8-hydroxy-7-quinolinecarboxamides V-15-20 are prepared as single compounds following GP IV described below from ester U-3 (Chart U). After the coupling step is achieved (6 h to 5 days depending on the amine), methanol is added, which leads to the deprotection of the 8-hydroxy substituent within 6 to 24 h. N-aryl-8-hydroxyquinoline-7-carboxamides V-17-20 as well as V-37-94 are also prepared by parallel synthesis from ester U-3, following GP V described below.
When parallel synthesis is used, some impurities appear occasionally besides the desired product, mainly the carbamate resulting from an attack of the amine at the carbonate positions when anhydride U-1 is involved, or methyl 8-hydroxy-7-quinoline carboxylate after methanolic treatment of the reaction mixture from ester U-3.
The synthesis of 2-amino-5-alkyl-1,3,4-thiadiazoles W-95-98, W-100-102, W-105, W-108 and X-109-117, which are to be coupled with the activated 8-hydroxy-7-quinoline carboxylic acid derivatives U-1 or U-3 (refer to Chart U) to afford the corresponding 8-hydroxy-N-(1,3,4-thiadiazol-2-yl)-7-quinolinecarboxamides X-118-136, required one to four steps. 2-Amino-5-bromo-1,3,4-thiadiazole W-95 is prepared through bromination of commercially available 2-amino-1,3,4-thiadiazole. Thiadiazole derivatives W-96-98 are prepared through direct bromide displacement of thiadiazole W-95 with the corresponding amines. Using the same strategy, nitrile W-100 is prepared from aminonitrile W-99, itself prepared from piperonal through a Strecker synthesis. Displacement of the bromide of thiadiazole W-95 with L- and D-phenylalanine methyl esters leads to esters W-101 and W-102, though in low yields. Known literature procedures are used to prepare amino acids W-103 and W-106, of which acid groups are converted into the corresponding tert-butyl esters (compounds W-104 and W-107) by standard procedures; subsequent bromide displacement as last step affords esters W-105 and W-108.
Bromide displacement with commercially available piperonyl amine leads to thiadiazole W-109; similarly, using some amino acid tert-butyl esters leads to esters X-110 to X-117.
These thiadiazoles, as well as commercially available 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole, are then coupled using the same methodology as described for the amides V-4-20 from anhydride U-1 or ester U-3 to give amides Y-118-125 or xcex3-126-136, respectively. Depending on the applied work-up procedure, these compounds are isolated as the free compounds, as the hydrochloride salt or as a hydrate.
The tert-butyl esters are hydrolyzed in selected examples to yield acids Z-137-139. These acids are isolated as their corresponding hydrotrifluoroacetates.
N-(5-alkylamino-1,3,4-thiadiazol-2-yl)-8-hydroxy-7-quinolinesul fonamides are prepared from the corresponding thiadiazoles and 8-hydroxy-7-quinolinesulfonyl chloride AA-C, prepared in two steps from a 8-hydroxy-7-halogenoquinoline AA-A.
It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry.
The compounds of the present invention and pharmaceutically acceptable salts thereof are useful as antiviral agents. Thus, these compounds are useful to combat viral infections in animals, including man. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus, and the human herpes virus type 8 (HHV-8).
Also, while many of the compounds of the present invention have shown activity against the CMV polymerase, these compounds may be active against the cytomegalovirus by this or other mechanisms of action. Thus, the description below of these compounds"" activity against the CMV polymerase is not meant to limit the present invention to a:specific mechanism of action.
The compounds of the present invention have shown activity in one or more of the assays described below. All of these assays are indicative of a compound""s activity and thus of its use as an anti-viral agent.
The HCMV polymerase assay is performed using a scintillation proximity assay (SPA) as described in several references, such as N. D. Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K. Takeuchi, Laboratory Practice, September issue (1992); U.S. Pat. No. 4,568,649 (1986); which are incorporated by reference herein. Reactions are performed in 96-well plates. The assay is conducted in 100 xcexcl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl2, 0.36 mg/ml BSA, and 90 nM 3H-dTTP. Assays are run with and without CHAPS, (3-[(3-Cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a final concentration of 2 mM. HCMV is diluted in enzyme dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 pg/ml BSA, and 0.01% sodium azide. The HCMV polymerase, which is expressed in recombinant baculovirus-infected SF-9 cells and purified according to literature procedures, is added at 10% (or 10 xcexcl) of the final reaction volume, i.e., 100 xcexcl. Compounds are diluted in 50% DMSO and 10 xcexcl are added to each well. Control wells contain an equivalent concentration of DMSO. Unless noted otherwise, reactions are initiated via the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primer to reaction mixtures containing the enzyme, substrate, and compounds of interest. Plates are incubated in a 25xc2x0 C. of 37xc2x0 C. H2O bath and terminated via the addition of 40 xcexcl/reaction of 0.5 M EDTA (pH 8) per well. Reactions are terminated within the time-frame during which substrate incorporation is linear and varied depending upon the enzyme and conditions used, i.e., 30 min. for HCMV polymerase. Ten xcexcl of streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added following termination of the reaction. Plates are incubated 10 min. at 37xc2x0 C., then equilibrated to room temperature, and counted on a Packard Topcount. Linear regressions are performed and IC50""s are calculated using computer software. Results of the testing of compounds of the present invention in this assay are shown in Tables 1, 2, 5, 9, 10, 11, 13 (except for the last compound which was tested under modified conditions) and 14 below.
A modified version of the above HCMV polymerase assay is performed as described above, but with the following changes: Compounds are diluted in 100% DMSO until final dilution into assay buffer. In the previous assay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol (DTT) is added to the polymerase buffer. Also, a different lot of CMV polymerase is used, which appears to be more active resulting in a more rapid polymerase reaction. Results of the testing of compounds of the present invention in this assay are shown in Tables 3, 6 and 7 below.
Compounds are tested for direct antiviral activity against HCMV using a cell culture based assay. An ELISA (enzyme linked immunosorbant assay) format is used as described in W. A. Tatarowicz, N. S. Lurain and K. D. Thompson, J. Virol. Meth., 35:207-215 (1991). Human foreskin fibroblast cells are infected with HCMV at a multiplicity of 0.025 plaque forming units per microtiter plate well for a period of 90 minutes. The virus inocula is removed and a suspension of test compound prepared in tissue culture media is added for a period of 4 days. The growth media is aspirated and replaced with 95% ethanol to allow fixation of virus infected cultures. The ethanol is removed and the wells are washed twice with saline. A solution of 2% dry fat milk, 1% bovine sera albumin prepared in saline is added to wells to allow for non-specific binding of protein material to plastic surfaces for 1 hr. Murine monoclonal antibody prepared in saline directed against the late (65 KD) matrix protein of HCMV is added to test wells for 1 hr. The wells are washed twice and antibody, conjugated with the enzyme horse radish peroxidase, with specificity against murine IgG is added to test wells for 1 hr. Test wells are washed three times with saline. A solution of o-phenylene diamine, a substrate for horse radish peroxidase is added for 15 minutes at which time enzymatic conversion occurs indicating reactivity of the enzyme with its substrate. This conversion is evident as a color reaction which was spectrophoretically monitored at 490 nm. The intensity of the color indirectly reflects the presence of antibody directed against the viral 65 KD matrix antigen. The presence of the viral matrix antigen refects the amount of HCMV replication. Thus, test wells, in which little viral replication has occurred, would have little or no antibody binding and are present with low levels of color. Non-infected wells serve as the assay background control. Results of the testing of compounds of the present invention in this assay are shown in Tables 4, 7 and 12 below.
These compounds of the present invention are administered in a pharmaceutical composition containing the compound in combination with a suitable excipient, the composition being useful in combating viral infections. Pharmaceutical compositions containing a compound appropriate for antiviral use are prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington""s Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., 1975), which is hereby incorporated by reference herein.
The compounds of the present invention are administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, or rectally, depending on whether the preparation is used to treat internal or external viral infections.
For internal infections, the compositions are administered orally or parenterally at dose levels, calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and are used in man in a unit dosage form, administered one to four times daily in the amount of 1 to 1000 mg per unit dose.
For parenteral administration or for administration as drops, as for eye infections, the compounds are presented in aqueous solution in a concentration of from about 0.1 to 10%, more preferably about 0.1 to 7%. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers.
The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending practitioner.
The following compounds of the present invention are preferred:
N-[5-[(4-Chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;
5-Bromo-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide;
5-Chloro-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;
8-Hydroxy-N-(2-hydroxy-2-phenylethyl)-2-(2-phenylethenyl)-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide;
8-Hydroxy-2-(2-phenylethenyl)-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide;
8-Hydroxy-N-(2-hydroxy-2-phenylethyl )-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-2-[2-(2-furyl)ethenyl]-8-hydroxy-7-quinolinecarboxamide;
5-chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinecarboxamide;
5-chloro-8-hydroxy-2-methyl-N-[(2-phenylthio)ethyl]-7-quinolinecarboxamide;
8-hydroxy-N-[5-[4-[(1-methylethyl)phenylsulfonyl]amino]pentyl]-7-quinolinecarboxamide;
8-hydroxy-N-(cyanomethyl)-7-quinolinecarboxamide;
8-hydroxy-N-(2-hydroxy-2-phenylethyl)-2-[2-(4-methoxyphenyl)ethyl]-7-quinolinecarboxamide;
N-(2,2-Diphenylethyl)-8-hydroxy-7-quinolinecarboxamide;
N-(3,3-Diphenylpropyl)-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-(cis-myrtanyl)-7-quinolinecarboxamide;
8-Hydroxy-N-(diphenylmethyl)-7-quinolinecarboxamide;
8-Hydroxy-N-(2-octyl)-7-quinolinecarboxamide;
N-[2-((1R,2S)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-nonyl-7-quinolinecarboxamide;
N-(4-tert-Butylcyclohexyl)-8-hydroxy-7-quinolinecarboxamide;
R-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxamide;
S-N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;
N-[2-((1S,2R)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;
S-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxarnide;
N-[(2-Chloro-6-phenoxy-phenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;
S-8-Hydroxy-N-[2-(1-hydroxy-3-[4-hydroxyphenyl])propyl]-7-quinolinecarboxamide;
8-Hydroxy-N-undecyl-7-quinolinecarboxamide;
8-Hydroxy-N-(2-methylcyclohexyl)-7-quinolinecarboxamide;
N-[1-(2-Ethyl)hexyl]-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-(1-naphthalenylmethyl)-7-quinolinecarboxamide;
8-Hydroxy-N-[2-(2-[4-phenoxy]phenyl)ethyl]-7-quinolinecarboxamide;
R-N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;
S-O-Benzyl-N-[7-(7-Carboxy-8-hydroxy)quinolyl]-tyrosine, methyl ester;
N-[2-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;
N-(4-Cyanophenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-(3-Chlorophenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-Fluoren-2-yl-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
8-Hydroxy-N-{4-[(indazo-6-ylamino)sulfonyl]phenyl}-7-quinolinecarboxamide monohydrochloride;
N-(3-Benzoxyphenyl )-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-(4-Benzoxyphenyl)-8-hydroxy-7-quinol inecarboxamide monohydrochloride;
8-Hydroxy-N-[4-(4-nitrophenoxy)phenyl]-7-quinolinecarboxamide monohydrochloride;
8-Hydroxy-N-naphth-1-yl-7-quinolinecarboxamide;
N-(2-Chloro-4-nitrophenyl)-8-hydroxy-7-quinolinecarboxamide;
N-Biphen-2-yl-8-hydroxy-7-quinolinecarboxamide;
N-(4-Chloro-2-methylphenyl)-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-(4-propylphenyl)-7-quinolinecarboxamide;
8-Hydroxy-N-[4-(hydroxymethyl)phenyl]-7-quinolinecarboxamide;
8-Hydroxy-N-indazol-5-yl-7-quinolinecarboxamide;
8-Hydroxy-N-(5-iodo-2-methylphenyl)-7-quinolinecarboxamide;
8-Hydroxy-N-[5-(2-phenylethyl)amino-1,3,4-thiadiazol-2-yl]-7-quinolinecarboxamide monohydrochloride;
N-[5-(Butylamino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
5-Bromo-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;
5-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;
N-Heptyl-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;
N-Heptyl-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide;
8-Hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide;
5-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-8-hydroxy-5-nitro-7-quinolinecarboxamide;
N-[5-[3-(4-Chlorophenyl)methyl]-4,5-dihydro-4-oxo-2-thiazolyl]-8-hydroxy-7-quinolinecarboxamide;
(E)-8-Hydroxy-2-(2-phenylethenyl)-N-(3-phenylpropyl)-7-quinolinecarboxamide;
N-{5-[(1,3-Benzodioxol-5-ylcyanomethyl)amino]-1,3,4-thiadiazol-2-yl}-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-[5-({1,3-Benzodioxol-5-yl-[(tert-butoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide semihydrate;
N-[5-({1,3-Benzodioxol-4-yl-[(tert-butoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide semihydrate;
(S)-N-[5-({[(tert-Butoxy)carbonyl]-[4-hydroxybenzyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;
(S)-N-[5-({5-[Benzoxy]amido-1-[(tert-butoxy)carbonyl]pentyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;
(S)-N-[5-({1-[(tert-Butoxy)carbonyl]-2-indol-3-ylethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide monohydrate; and
(S)-N-[5-({1-[(tert-Butoxy)carbonyl]-2-[4-(tert-butoxy)phenyl]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide monohydrate.
The following sulfonamide compounds of the present invention are preferred:
5-Chloro-8-hydroxy-2-methyl-N-[2-(phenylthio)ethyl]-7-quinolinesulfonamide;
5-Chloro-N-(4-chlorophenyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;
5-Chloro-N-[4-fluorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide;
5-Chloro-8-hydroxy-2-methyl-N-(1-naphthalenylmethyl)-7-quinolinesulfonamide;
5-Chloro-N-(cyclohexylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;
5-Chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinesulfonamide;
5-Chloro-8-hydroxy-2-methyl-N-(2-phenoxyethyl )-7-quinolinesulfonamide;
5-Chloro-N-(diphenylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;
(R)-5-Chloro-8-hydroxy-2-methyl-N-(1-phenylethyl)-7-quinolinesulfonamide;
(S)-5-Chloro-8-hydroxy-2-methyl-N-(1-phenylethyl)-7-quinolinesulfonamide;
5-Chloro-N-[2-(4-chlorophenyl)ethyl]-8-hydroxy-7-quinolinesulfonamide;
5-Bromo-8-hydroxy-N-(phenylmethyl)-7-quinolinesulfonamide;
5-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide;
(E)-5-Chloro-8-hydroxy-2-(2-phenylethenyl)-N-[2-(phenylthio)ethyl]-7-quinolinesulfonamide; and
5-Chloro-8-hydroxy-2-methyl-N-[2-[4-[(phenylsulfonyl)amino]phenyl]ethyl]-7-quinolinesulfonamide.

8-Hydroxyquinoline (50.0 g) and potassium carbonate (142.8 g) are mixed together in a stainless steel bomb and heated at 170xc2x0 C. under 1200 p.s.i. CO2 for 7 days. The reaction is then cooled and the resulting solid is partitioned between water (6 L) and EtOAc (1 L). The organic layer is extracted with water (2xc3x97300 mL). The combined aqueous layers are extracted with EtOAc (3xc3x97500 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, dried and triturated with i-PrOH to yield 51.97 g of the title compound as a tan solid.
Physical characteristics are as follows:
1H NMR (300 MHz, DMSO) xcex4 8.89, 8.58, 7.89, 7.78, 7.28.

8-hydroxy-7-substituted quinolines as anti-viral agents

Abstract: These compounds are useful as anti-viral agents. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus and the human herpes virus type 8 (HHV-8).


A set-top-box (STB) provides capability for monitoring and control of power usage and the ability to establish communications. A smart residential service system (SRSS) is provided that uses power line communication (PLC) technology to provide secure in-home LAN communication and also to monitor and provide remote control of connected appliances in the home. An embodiment combines the STB with a master unit (MST) that is used with PLC to meet the requirements of the central device in the SRSS.

Technical Field
The invention relates to devices that are used for power monitoring, data collection, and control and communication over power lines to reduce the carbon footprint of in-home equipment. More particularly, the invention relates to centralized control of intelligent homes, in which multiple entertainment, communication, media streaming, and other appliances are connected to remote power monitoring and control capable devices for power usage monitoring and control over power line networking.
Description of the Background Art
Communication using power lines has been known from early in the 20th century. Due to the higher cost and other limitations for extending the connectivity, the use of this type of power line communication (PLC) system has been limited to local area networks (LANs) within homes or offices or, at best, within apartment complexes. PLC has also found a limited number of applications where other types of communication methods do not provide the security and remote connectivity, such as for power line control applications. Basic devices for connecting to the power line for communication and power supply have been designed and used to provide service within LANs.
Due to more efficient competing technologies, the infrastructure for power line communication never developed to make it a mainstream technology. Thus, despite this early start, PLC technology has not become a mainstream communication technology and the adaptation of this technology has been slow. This can be attributed to various reasons, including the higher cost of available devices, the lack of suitable devices for communication using PLC technology, etc. The result has been that PLC has not found a path for growth in the standard voice and data communication field, which is presently catered to by technologies such as xDSL, cell phones, and satellite communications.
The development of 'green' technologies and the need for monitoring and control of the carbon footprint of homes and offices has created a need to assess power usage patterns remotely, determine the magnitude of such usage, and provide the ability to supervise and control such power usage remotely. In such case, it is necessary for the consumer to monitor and control the power use on a micro level. If the proper tools were provided, the consumer could be able to exercise the necessary constraints on such power usage.
It is also necessary to monitor the usage pattern and collect data on a macro level to develop policies that are beneficial to the overall reduction in the carbon footprint at the home and office level, as well as on a national level. Empowering the individual and the society to exercise the necessary controls by monitoring the power usage is an area where the power line communication and control can be effectively and optimally used.

This patent is subject to a terminal disclaimer.

Set-top-box having a built-in master node that provides an external interface for communication and control in a power-line-based residential communication system


A decision support tool is provided for predicting a patient's length of stay within a healthcare unit, such as the emergency department. The predicted length of stay may be determined using patient information and facility information, which includes information about the department and the facility in which the department is located. The patient information and the facility information may be used to determine feature values input into a plurality of machine learning models. The models may be used sequentially such that initial models are used to predict variables relating to the patient's length of stay and output of such models is used with a length-of-stay model to determine the predicted length of stay. One or more response actions may be automatically initiated based on the predicted length of stay. Such response actions may include resource management actions to allocate resources within the healthcare unit.

For certain departments within a healthcare facility, such as the emergency department, the volume of patients changes frequently, and the volume at any current time will depend on the length of time each person stays in the department. Longer lengths of stays can result in congestion, poor patient outcomes, inefficient resource utilization, and staff stress and burnout. Predicting the length of time of each person's stay can help estimate the volume of the department at a future time and, consequently, can be used for more efficient and effective allocation of resources, such as staffing, beds, equipment, medications, and the like. In turn, more efficient allocation of resources can help to reduce lengths of stays, which can ultimately lead to better patient outcomes. For a department like the emergency department where there is a wide variety of patients and healthcare concerns, the length of a stay is very context specific and is based on several factors relating to the patient and the state of the department and healthcare facility. Conventional technologies for determining a length of stay consider only one factor at a time, which results in less accurate and less useful predictions.

Decision support tool for determining patient length of stay within an emergency department


A valve gear for an internal combustion engine capable of promptly switching the position of a piston in a rocker arm to thereby change the engine operating condition with a satisfactory response, even in a low rotation region in which an adequate amount of oil discharged from an oil pump cannot be expected. Depending on positions of pistons slidably fitted in low-speed and high-speed cylinder portions provided in an intake driven rocker arm, a low-speed or high-speed drive rocker arm is selectively operated to press a corresponding one of the pistons. The piston in the low-speed cylinder portion switched in a low rotation region is made smaller in diameter than the piston in the high-speed cylinder portion, to be enabled to be promptly switched.

1. Field of the Invention
The present invention relates to a valve gear of an internal combustion engine (hereinafter referred to as engine).
2. Description of the Related Art
To realize engine-output characteristics optimum for operating regions, there have been proposed a variety of engines adapted to switch valve-opening periods and lift amounts of intake and exhaust valves, etc. (refer to Japanese provisional patent publication no. 2001-41017, for example).
The engine disclosed in this publication is provided with a driven rocker arm supported by a rocker shaft so as to be rocked by a first cam for low speed to thereby drive the intake valve to open and close, and a drive rocker arm supported by the rocker shaft at a location adjacent to the driven rocker arm so as to be rocked by a second cam for high speed. The driven rocker arm is formed with a cylinder in which a piston is accommodated for sliding motion when supplied with oil pressure, and the drive rocker arm is formed with an engaging projection adapted to be engaged with the piston when the drive rocker arm is rocked.
In a low rotation region of the engine for example, the piston of the driven rocker arm is switched to a lower position where the engaging projection of the drive rocker arm runs at idle, so that the intake valve is driven to open and close by the driven rocker arm along the shape of the first cam. In a high rotation region of the engine, on the other hand, the piston of the driven rocker arm is switched to an upper position where the engaging projection of the drive rocker arm acts to press the piston, so that the driven rocker arm is rocked in conjunction with the drive rocker arm, whereby the intake valve is driven to open and close along the shape of the second cam.
As described above, the engine disclosed in Japanese provisional patent publication No. 2001-41017 is designed to make the switching between the two operating conditions in each of which the intake valve is driven to open and close by a corresponding one of the first and second cams. There is the demand such as for example that the engine of this type be provided with not only the just-mentioned function but also a cylinder suspending function of suspending the operation of a particular cylinder.
To meet such demand, it is considered that a further drive rocker arm may be provided so as to be rocked by the first cam as in the case of the drive rocker arm associated with the second cam, and a pair of pistons may be provided in the driven rocker arm to be slidable for engagement with engaging projections of these drive rocker arms. In such valve gear, depending on the sliding positions of the pistons, the driven rocker arm is rocked in conjunction with either one of the drive rocker arms to thereby drive the intake valve to open and close according to the shape of a corresponding one of the cams. When the pistons assume their sliding positions where the engaging projections of the drive rocker arms run at idle, the driven rocker arm maintains the intake valve closed, whereby a cylinder suspending operation is performed.
To be noted, the switching of the piston position in the driven rocker arm is made utilizing oil that is discharged from a lubricant oil pump of the engine. In a low rotation region of the engine, the rotation speed of the oil pump is low and hence an adequate amount of discharge cannot be expected. For this reason, in a low rotation region where the piston position is switched in the driven rocker arm on the side of the first low-speed cam, the piston's sliding motion is slow in speed. This poses a problem that the engine operating condition cannot be switched promptly.
Meanwhile, an upper portion of the piston of the driven rocker arm, which, when pressed by the engaging projection of the drive rocker arm, causes the entire driven rocker arm to be rocked against the inertial mass, is required to have a higher rigidity as compared to the lower portion of the piston that mainly receives an oil pressure alone. In this regard, the engine disclosed in Japanese provisional patent publication No. 2001-41017 has a piston that is made in its entirety of a material that satisfies the characteristic required for the upper portion of the piston. As a result, each individual piston becomes inevitably high in fabrication cost, which affects the fabrication cost of the entire valve gear requiring the provision of the piston for every drive rocker arm of each cylinder.

Valve gear of an internal combustion engine

Mitsubishi Jidosha Kogyo Kabushiki Kaisha

Mitsubishi Jidosha Engineering Kabushiki Kaisha


A system, comprising various methods and apparatus, for Reverse Link Admission Control (RLAC) with QoS differentiation in wireless communication systems is disclosed. With the present invention, wireless systems may admit new calls or transmission flows based upon sector loading conditions QoS requirements or characteristics of an incoming transmission—providing optimal system performance and stability while addressing QoS needs.

In general, performance and capacity of wireless mobile communication systems are limited by air-interface propagation-channel characteristics; such as co-channel interference, path loss, multipath fading, etc. In a cellular wireless mobile communication system, a plurality of mobile stations (MSs) located in one cell perform wireless communication with a base station (BS) that manages that cell. The BS receives uplink signals from each MS.
A signal transmitted by a first MS may act as an interference component in relation to a signal transmitted by a second MS. When there are many MSs, or some MSs transmitting at high power, in a given area (i.e., sector) of a cell, the sector is considered as having high load; and the reverse link interference for that sector is generally high. As such—in a wireless mobile communication system—reverse link admission or load control should be performed in order for a BS to receive signals from MSs in a stable manner.
In a Code Division Multiple Access (CDMA)-based cellular wireless mobile communication system, reverse link interference is measured using a Rise-Over-Thermal (ROT) index. The term "ROT" as used herein refers to a ratio of a sum of total received power to thermal noise; or a difference of the sum of total received power (RSSI), in dBm, and thermal noise, also in dBm. ROT can be represented by Equation (1):ROT(dB)=RSSI(dBm)−Thermal_Noise_Floor(dBm)  (1).Load (L) is another measure for Reverse Link loading level. In principle, ROT and L should be related to each other—that relationship being expressed as:
                    ROT        =                              1                          (                              1                -                L                            )                                .                                    (        2        )            If Y is defined as intra-cell computed load, then the actual sector load is (1+f)(Y); where f is an inter-cell interference factor. Correspondingly, ROT can be obtained from Y:
                    ROT        =                              1                          1              -                                                (                                      1                    +                    f                                    )                                                                  (                  Y                  )                                                              .                                    (        3        )            There are conventional methods to control admission by setting a fixed threshold of ROT or Load [1]. This may not apply, or may not utilize the full capacity of a deployed wireless network with multimedia services because the ROT and Load are fluctuating over a large range.
Conventional methods of Reverse Link Admission Control generally control ROT or Load level in one dimension, or as a total value—without considering that different loads can not or do not account for quality of service (QoS) metrics for new or already-initiated transmissions (i.e., calls). As wireless networks and communications system evolve to become more QoS-aware, it becomes critical that Reverse Link Admission Control differentiates new or already-initiated transmissions according to their corresponding QoS levels.
Differentiation by QoS facilitates transmissions of different types of multimedia services. Most such services can be categorized into a number of types, according to delay constraints and bandwidth requirements. As a convention in 1xEV-DO system, for example, service flows are categorized as: Expedited Forwarding (EF); Assured Forwarding (AF); and Best Effort (BE). The EF flow is delay sensitive and characterized by a low data rate; the AF flow is delay sensitive and elastic; and the BE flow is delay tolerant and elastic.
As an example, IS-856 (1xEV-DO) systems have a mechanism to control reverse link load—called Closed-loop Load Control, via direct ROT measurement. With this mechanism, ROT is measured at a sector and compared with a set ROT Threshold. If the measured value is higher than the threshold, the value of a Reverse Activity Bit (RAB) is set to 1. If the measured value is lower than the threshold, the RAB value is set to 0 or −1. The RAB value is broadcast to terminals within the sector, so as to increase or decrease data rate of each terminal. A filtered RAB (FRAB) value—measured or estimated over a period of time—indicates long-term sector loading. At a BS, a ratio of time when RAB is set to 1 may be determined—which is called BusyTimeRatio and is denoted by b.
In 1xEV-DO RevA (DOrA) system that supports QoS and multi-flow packet applications, Reverse Link Load Control is further enhanced by a TraffictoPilot (T2P) allocation mechanism—where T2P is a ratio of Traffic Channel power to Pilot Channel power. T2P allocation is sector loading dependent, and is determined by flow QoS and packet transmission rate of a mobile user. Conversely, load is function of T2P values of each terminal within a sector.
Channels in DOrA system reverse link comprise: a Pilot channel; a Data Rate Control (DRC) channel; a Data Source Control (DSC) channel; an ACK channel; a Reverse Rate Indicator (RRI) channel; and a Traffic channel. The DRC, DSC, ACK and RRI are overhead channels and always on, as long as a DO connection is established between an MS and a BS.
As a result, there is a need for an admission control system that differentiates QoS requirements and, to the greatest extent possible, utilizes and cooperates with already-existing system metrics and mechanisms—such as ROT and the load estimated via T2P and b.

System for QOS aware reverse link admission control in wireless communication systems


Provided is an electronic control device that can reduce a usage amount of an adhesive constituting a seal member, by relieving a stress caused in the seal member disposed in a gap between a first housing part and a second housing part in a high-temperature environment. In an electronic control device including: a component mounting board mounted with an electronic component; and a first housing part and a second housing part that are fixed to each other via a seal member and define a first space that accommodates the component mounting board, at least one predetermined housing part of the first or second housing part has a recess formed on a surface facing the seal member, and a second space is formed between the recess and the seal member.

In recent years, with an increase in output of engines in automobiles and improvement in performance of vehicles, mounting environment in an engine room and a driving condition of an electronic control device are becoming increasingly severe. Meanwhile, cost reduction of vehicles is also progressing. Therefore, even for electronic control devices mounted in engine rooms, a demand for high reliability and low cost is increasing.
An electronic control device mounted in an engine room is required to have a waterproof structure since there is a possibility of being wet with water. As the waterproof structure, a structure that seals a gap of a housing with a silicone waterproof adhesive or rubber packing is generally used. As a structure for sealing a gap of a housing with a waterproof adhesive, for example, there is a structure described in PTL 1.
PTL 1 describes "an onboard electronic apparatus including: a circuit board mounted with an integrated circuit and provided with a connector for input and output; a first housing fixed with the circuit board; a second housing fixed to the first housing and covering the circuit board such that a connecting part of the connector is exposed to outside the housing; and a waterproof seal that fixes and seals the first housing and the second housing, and seals a gap between these housings and the connector, in which the waterproof seal is obtained by mixing a water absorbing or hygroscopic organic filler and an inorganic filler in a resin that reacts with moisture in the atmosphere and is cured by cross-linking of polymers with each other" (refer to claim 1).

Electronic control device and assembly method thereof


According to some embodiments, a structure of vertical transistor includes gate electrodes distanced by a predetermined interval in an active region, formed in a vertical shape to have a predetermined depth from a top surface of a semiconductor substrate. A gate insulation layer is formed between one side wall of the gate electrode and the substrate. A gate spacer is formed in another sidewall of the gate electrode, covering the gate electrode. A contact plug is formed between the gate spacer. A plug impurity layer is formed in a lower part of the contact plug, and source and drain are formed opposite to the gate electrode within the active region. Thereby, an area occupied by a gate electrode is substantially reduced, so a unit memory cell has a 4F2 structure, reducing a memory cell size, by forming a vertical-type gate electrode within an active region.

1. Field of the Invention
This disclosure relates to semiconductor devices, and more particularly, to a vertical transistor structure having a vertical-type gate and to a method of forming the same.
2. Description of the Related Art
Requirements for semiconductor devices with lower electricity consumption and higher capacitance have prompted researchers to develop higher integrated and higher speed semiconductor devices. In particular, a semiconductor memory cell, a DRAM (Dynamic Random Access Memory), has been used widely, and research is focused on ways to enhance the speed and integration of this device.
In general, a DRAM is constructed of one MOS (Metal Oxide Semiconductor) transistor and one storage capacitor. The MOS transistor is incorporated to move charges from a storage capacitor while writing and reading data, the data being represented by the charges. The DRAM also performs a refresh operation by periodically providing charge to the storage capacitor to prevent data loss caused by leakage current, etc.
To obtain a high integration of DRAM, a capacitor capable of sufficiently guaranteeing a storage capacitance even if a storage capacitance size is reduced, is required, and it needs to substantially reduce an occupied area of a unit memory cell. A manufacturing of a general DRAM device is limited by a minimum lithography feature size (F) by a photolithography process. According to the conventional art, the size of a DRAM cell is equal to the square of the given lithography feature size (F) multiplied by a coefficient of eight (8F2). A DRAM device, in which a unit memory cell as a planar type transistor has an (8F2) structure, is disclosed in U.S. Pat. No. 5,900,659 with the title of "Buried bit line DRAM cells". A DRAM device, in which a unit memory cell as a recess type transistor has an (8F2) structure, is disclosed in U.S. Pat. No. 6,555,872 with the title of "TRENCH GATE FERMI-THRESHOLD FIELD EFFECT TRANSISTORS". A DRAM device, in which a unit memory cell as a fin type transistor has an (8F2) structure, is disclosed in U.S. Pat. No. 6,525,403 with the title of "SEMICONDUCTOR DEVICE HAVING MIS FIELD EFFECT TRANSISTORS OR THREE-DIMENSIONAL STRUCTURE".
FIG. 1 is a plan view of a layout structure of a MOS transistor according to a prior art.
With reference to FIG. 1, two gate electrodes 130 having a predetermined thickness are formed in a vertical direction on an active region 120 surrounded by a non-active region 110. A contact 150 connected to a bit line is formed on the active region between the gate electrodes 130. A contact 160 connected to a storage node is formed in both side faces of the gate electrodes, and a bit line 140 is disposed in a horizontal direction between the active regions.
According to a related art, since two gate electrodes are formed with a predetemined thickness on one active region and contacts arc formed between the gate electrodes, a gate electrode and a contact occupy a specific horizontal area. Thus, a unit memory cell 170 has an (8F2) structure and this is applied equally to a planar type transistor, a recess type transistor and a fin type transistor. Hence, obtaining a highly-integrated semiconductor device has difficulties and limitations, in particular to integrate beyond a given level.

Vertical transistor structure for use in semiconductor device and method of forming the same


An x-ray converter element has an x-ray-permeable and moisture-impermeable substrate, an x-ray-permeable carrier that is connected to the substrate, and a scintillator that is applied on the substrate, and an optically-transparent and moisture-impermeable protective layer that covers the scintillator.

1. Field of the Invention
The present invention concerns an x-ray converter element.
2. Description of the Prior Art
An x-ray converter element is a component of a digital detector for radiography that is, for example, described in the article by R. F. Schulz, "Digitale Detektorsysteme für die Projektionsradiographie" in Fortschr. Röntgenstr. (2001) 173, pages 1137 to 1146, in particular illustration 5.
The x-ray converter element (that includes a scintillator) is conventionally used in combination with a CCD camera (CCD—charge-coupled device). Most of the incident x-ray radiation is absorbed in the scintillator (luminescent screen) and converted into visible light. The light image is projected onto the CCD camera with the aid of imaging optics (for example optical lenses, mirrors, prisms etc.). The CCD camera transduces the light image into electrical signals. The electrical signals are further processed and are output as a digital image.
This detector system has the advantage that it is composed only of relatively easily obtainable and inexpensive components and therefore can be produced in a relatively cost-effective manner. Such a detector system thus represents a relatively cost-effective solution with the known advantages of a digital detector system (film-less, image processing etc.).
The dose requirement in such a detector system is comparable to the dose requirement of classical film-foil systems. The dose savings that is possible to achieve with a planar image detector (flat panel detector) cannot be achieved with this detector system. Flat panel detectors are described in the article by M. Spahn et al. "Flachbilddetektoren in der Röntgendiagnostik" in "Der Radiologe 43 (2003)", pages 340 through 350.
The reason for the relatively high dose requirement in radiography is the occurrence of phenomena known as "secondary quantum sinks".
The signal-to-noise ratio of an ideal x-ray detector (negligible electronic noise, no structural noise) is defined by the number of the absorbed x-ray quanta and is designated as a "primary quantum sink".
In a flat panel detector an absorbed x-ray quantum is transduced into, for example, 1000 electrons. The additional statistical electron noise thus is negligible due to the relatively large number of electrons.
However, when fewer than 10 electrons are generated per x-ray quantum, this additional noise is no longer negligible and impairs the image quality or increases the dose requirement. This is designated as a "secondary quantum sink". This is explained in the publication by R. M. Gagne et al., "Optically coupled digital radiography: sources of inefficiency" in "Processing. SPIE Vol. 4320 (2001)", pages 156 to 162.
It is a basic requirement of the scintillator that every x-ray quantum striking the scintillator should generate an optimally large number of light quanta in the scintillator that must in turn be optimally transduced into electrons without loss.
A further requirement of the scintillator is mechanical stability. For installation the scintillator is fixed only at its outer edge. The relatively large x-ray converter element (for example 44 cm×44 cm) can oscillate similar to a drum head. During operation, and even more during transport, the x-ray detector is exposed to significant shocks and vibrations, for example given freight vehicle or rail transport.
In order to ensure that the scintillator is not damaged by such oscillations, URL http://sales.hamamatsu.com/assets/pdf/parts_J/ALS_ACS_FOS.pdf) discloses using use converter layers in which case the scintillator made from Cdl:Tl is applied either on a 1 mm-thick carrier made from aluminum, or on a 2 mm-thick carrier made from amorphous carbon. In order to achieve a sufficient mechanical stability, care must be taken that these layer thickness are observed as a minimum.
Since the carrier is arranged in the beam path in front of the scintillator, however, it acts as a ray filter. The energy that is absorbed in the carrier is therefore no longer available for light generation in the scintillator.
The transmission for x-ray radiation given 2 mm amorphous carbon is good, only slightly reducing the transmission for x-ray energies smaller than 30 keV. A disadvantage of the use of amorphous carbon is its high price.
In contrast to this, aluminum is a low-priced material. A disadvantage in the use of aluminum is its relatively low transmission for x-ray energies less than 40 keV.


The present invention relates to a system for three-dimensional (3-D) acoustic imaging of a scattering structure using information from a two-dimensional (2-D) image. The system uses a characterized sensor array to emit a signal from the sensor array into an object of interest to generate at least one 2-D representation of the object of interest. The 2-D representation comprises a plurality of x and y coordinate pairs and at least one candidate scattering structure. The candidate scattering structure comprises a shape defined by at least one pair of x and y coordinates. The candidate scattering structure shape is restricted to at least one pair of x and y coordinates. The pair of x and y coordinates of the candidate scattering structure shape are then compared with a first coordinate-dependent response function to assign an x, y, and z position of a scattering structure in 3-D space.

(1) Technical Field
The present invention relates to a system for determining three-dimension (3-D) positional information of a scattering structure embedded within a material that is outside the traditional focal region of a characterized acoustic impulse signal and, more particularly, to a process for producing the 3-D positional information, size, and material composition of a scattering structure by inspecting artifacts in the form of sidelobes and other sources of distortion via the use of a look-up table or comparison function.
(2) Background
Two-dimensional (2-D) imaging techniques may be used to determine the location of a material or scattering structure within another material with varying degrees of resolution and certainty. In standard 2-D imaging, only objects within the region of focus of a sensor array system become well-defined areas in an image slice. Objects outside the region of focus introduce blurred and warped artifacts. Thus, existing 2-D imaging systems do not provide sufficient imaging information with respect to objects in the extended region.
However, in many circumstances, it is desirable to obtain well-defined imaging information from the extended region. Therefore, a continuing need exists for a process that allows a user to gather acoustic imaging information of a scattering object contained within a known material quickly, using information from the extended region.

3-dimensional imaging by acoustic warping and defocusing